@article {pmid33639094,
year = {2021},
author = {Kockler, ZW and Comeron, JM and Malkova, A},
title = {A unified alternative telomere-lengthening pathway in yeast survivor cells.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2021.02.004},
pmid = {33639094},
issn = {1097-4164},
abstract = {Alternative lengthening of telomeres (ALT) is a recombination process that maintains telomeres in the absence of telomerase and helps cancer cells to survive. Yeast has been used as a robust model of ALT; however, the inability to determine the frequency and structure of ALT survivors hinders understanding of the ALT mechanism. Here, using population and molecular genetics approaches, we overcome these problems and demonstrate that contrary to the current view, both RAD51-dependent and RAD51-independent mechanisms are required for a unified ALT survivor pathway. This conclusion is based on the calculation of ALT frequencies, as well as on ultra-long sequencing of ALT products that revealed hybrid sequences containing features attributed to both recombination pathways. Sequencing of ALT intermediates demonstrates that recombination begins with Rad51-mediated strand invasion to form DNA substrates that are matured by a Rad51-independent ssDNA annealing pathway. A similar unified ALT pathway may operate in other organisms, including humans.},
}
@article {pmid33636955,
year = {2017},
author = {Blauwkamp, MN and Fasching, CL and Lin, J and Guegler, K and Hytopoulos, E and Watson, D and Harley, CB},
title = {Analytical Validation of Relative Average Telomere Length Measurement in a Clinical Laboratory Environment.},
journal = {The journal of applied laboratory medicine},
volume = {2},
number = {1},
pages = {4-16},
doi = {10.1373/jalm.2016.022137},
pmid = {33636955},
issn = {2576-9456},
abstract = {BACKGROUND: Average telomere length in whole blood has become a biomarker of aging, disease, and mortality risk across a broad range of clinical conditions. The most common method of telomere length measurement for large patient sample sets is based on quantitative PCR (qPCR). For laboratory-developed tests to be performed on clinical samples, they must undergo a rigorous analytical validation, currently regulated under CLIA.<br><br>METHODS: Whole blood samples from 40 donors were used in the analytical validation of methods for relative average telomere length (rATL) measurement. Three technical replicate DNA samples were extracted from each whole blood sample and placed in three independent wells on a sample plate. Each of these sample plates was assayed 12 times during the validation process. The study was conducted over a 20-day period, once in the morning and once in the evening, using 3 different operators.<br><br>RESULTS: Our process of rATL measurement beginning with DNA extraction followed by qPCR-based assay resulted in repeatability and reproducibility CV of <5% and amplification efficiencies near 100%. The validated assay was used to establish a reference interval derived from 2 cohorts of individuals: (a) San Francisco Bay area (n = 504) and (b) a US cross-sectional, demographic population (n = 357).<br><br>CONCLUSIONS: We present advances in the establishment of a highly reproducible analytically validated process for determining rATLs in a CLIA laboratory environment.},
}
@article {pmid33634147,
year = {2021},
author = {Sullivan, DI and Jiang, M and Hinchie, AM and Roth, MG and Bahudhanapati, H and Nouraie, M and Liu, J and McDyer, JF and Mallampalli, RK and Zhang, Y and Kass, DJ and Finkel, T and Alder, JK},
title = {Transcriptional and Proteomic Characterization of Telomere-Induced Senescence in a Human Alveolar Epithelial Cell Line.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {600626},
doi = {10.3389/fmed.2021.600626},
pmid = {33634147},
issn = {2296-858X},
abstract = {Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modeled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways in vitro and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted differences in response to telomere dysfunction. We conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the possibility of species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.},
}
@article {pmid33628118,
year = {2021},
author = {Lin, Z and Gao, H and Wang, B and Wang, Y},
title = {Cytomegalovirus Infection and Its Relationship with Leukocyte Telomere Length: A Cross-Sectional Study.},
journal = {Mediators of inflammation},
volume = {2021},
number = {},
pages = {6675353},
doi = {10.1155/2021/6675353},
pmid = {33628118},
issn = {1466-1861},
abstract = {Background: Telomeres undergo shortening with each cell division, which could be accelerated by infection. The association between virus infection and telomere length is poorly understood. In the present study, we investigated the putative associations between leukocyte telomere length (TL), cytomegalovirus (CMV) infection, and C-reactive protein (CRP) in a national representative sample of noninstitutionalized population.<br><br>Methods: We analyzed data that was collected in a cross-sectional setting, where 3,987 participants were enrolled with available data on telomere length. The association between telomere length with previous CMV infection and CRP was analyzed using multivariable linear regression models. We further tested if obesity, measured by body mass index (BMI), and smoking could modify this relationship.<br><br>Results: In total, around 46% percent of the study population were men and 54% were women. Average ages were 35.1 years for men and 35.0 years for women. One unit increase of CMV antibody IgG titer was associated with -0.07 (95% confidence interval: -0.12, -0.01) unit decrease of leukocyte TL when sex was adjusted for. After additionally adjusting for BMI and smoking status, the magnitude of the association was only slightly decreased to -0.06 (95% confidence interval: -0.11, -0.01). The effect sizes were comparable after additionally adjusting for CRP. These analyses imply that previous CMV infection affects leukocyte TL through pathways other than CRP.<br><br>Conclusions: Previous CMV infection was associated with shorter leukocyte TL. This association was independent of CRP.},
}
@article {pmid33627664,
year = {2021},
author = {Hartlieb, SA and Sieverling, L and Nadler-Holly, M and Ziehm, M and Toprak, UH and Herrmann, C and Ishaque, N and Okonechnikov, K and Gartlgruber, M and Park, YG and Wecht, EM and Savelyeva, L and Henrich, KO and Rosswog, C and Fischer, M and Hero, B and Jones, DTW and Pfaff, E and Witt, O and Pfister, SM and Volckmann, R and Koster, J and Kiesel, K and Rippe, K and Taschner-Mandl, S and Ambros, P and Brors, B and Selbach, M and Feuerbach, L and Westermann, F},
title = {Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1269},
pmid = {33627664},
issn = {2041-1723},
abstract = {Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.},
}
@article {pmid33624913,
year = {2021},
author = {Li, X and Zhang, J and Yang, Y and Wu, Q and Ning, H},
title = {microRNA-340-5p increases telomere length by targeting telomere protein POT1 to improve Alzheimer disease in mice.},
journal = {Cell biology international},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbin.11576},
pmid = {33624913},
issn = {1095-8355},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder which is the primary cause of dementia in the elderly. Telomere attrition has been proposed as a hallmark of aging. Our study aimed to explore the mechanism of POT1 regulating telomere length and affecting cellular senescence in AD. AD mouse model was established by D-galactose and aluminum chloride, and water maze test and dark avoidance test were used to detect the behavior of mice and confirm the success of mouse AD model. AD cell model was established with HT22 cells induced by Aβ42 oligomers. POT1 expression in AD model was detected by qRT-PCR. Cellular telomere length in hippocampal tissue was analyzed by telomere restriction fragment. Localization of intracellular POT1, telomerase and telomeres was analyzed by immunofluorescence and FISH. Dual-luciferase was used to validate the targeted binding relationship between miR-340-5p and POT1. After inhibiting POT1 expression, symptoms of AD in mice were improved. Aβ1-42 deposition was reduced while telomere length and telomerase activity was increased. Dual-luciferase verified the binding relationship between miR-340-5p and POT1. Increase of miR-340-5p expression could alleviate cellular senescence and AD symptoms. miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms. This study made a conclusion that miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms in mice. This article is protected by copyright. All rights reserved.},
}
@article {pmid33624078,
year = {2020},
author = {Banach, M and Penson, PE},
title = {Cellular senescence, telomeres, and cardiovascular risk in familial hypercholesterolaemia.},
journal = {European journal of preventive cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurjpc/zwaa145},
pmid = {33624078},
issn = {2047-4881},
}
@article {pmid33624064,
year = {2020},
author = {Baragetti, A and Bonacina, F and Da Dalt, L and Moregola, A and Zampoleri, V and Pellegatta, F and Grigore, L and Pirillo, A and Spina, R and Cefalù, AB and Averna, M and Norata, GD and Catapano, AL},
title = {Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors.},
journal = {European journal of preventive cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurjpc/zwaa115},
pmid = {33624064},
issn = {2047-4881},
abstract = {AIMS: Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects.<br><br>METHODS AND RESULTS: LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27 ± 0.07 vs. 1.59 ± 0.04, P = 0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35 y) (1.34 ± 0.08 vs. 1.64 ± 0.08, P = 0.019); moreover, LTL was shorter in statin-naïve HeFH subjects as compared to controls (1.23 ± 0.08 vs. 1.58 ± 0.04, P = 0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33 ± 0.05 vs. 1.55 ± 0.08, P = 0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls.<br><br>CONCLUSIONS: We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.},
}
@article {pmid33624047,
year = {2020},
author = {Michels, N and van Aart, CJC and Martens, DS and De Henauw, S and Nawrot, TS},
title = {Telomere length and cardiovascular disease precursors: a 7-year follow-up from childhood to early adolescence.},
journal = {European journal of preventive cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurjpc/zwaa123},
pmid = {33624047},
issn = {2047-4881},
}
@article {pmid33621803,
year = {2021},
author = {Mehta, SR and Iudicello, JE and Lin, J and Ellis, RJ and Morgan, E and Okwuegbuna, O and Cookson, D and Karris, M and Saloner, R and Heaton, R and Grant, I and Letendre, S and , },
title = {Telomere length is associated with HIV infection, methamphetamine use, inflammation, and comorbid disease risk.},
journal = {Drug and alcohol dependence},
volume = {221},
number = {},
pages = {108639},
doi = {10.1016/j.drugalcdep.2021.108639},
pmid = {33621803},
issn = {1879-0046},
abstract = {BACKGROUND: HIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers.<br><br>METHODS: The study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF).<br><br>RESULTS: HIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R2 = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003).<br><br>CONCLUSIONS: HIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.},
}
@article {pmid33612129,
year = {2021},
author = {Poláková, E and Záhonová, K and Albanaz, ATS and Butenko, A and Lukeš, J and Yurchenko, V},
title = {Diverse telomeres in trypanosomatids.},
journal = {Parasitology},
volume = {},
number = {},
pages = {1-35},
doi = {10.1017/S0031182021000378},
pmid = {33612129},
issn = {1469-8161},
}
@article {pmid33609998,
year = {2021},
author = {Bi, J and Wu, M and Liu, Y and Song, L and Wang, L and Liu, Q and Chen, K and Xiong, C and Li, Y and Xia, W and Xu, S and Zhou, A and Wang, Y},
title = {Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study.},
journal = {Ecotoxicology and environmental safety},
volume = {213},
number = {},
pages = {112037},
doi = {10.1016/j.ecoenv.2021.112037},
pmid = {33609998},
issn = {1090-2414},
abstract = {OBJECTIVE: Telomere length (TL) is a biomarker for biological aging, and the initial setting of TL at birth is a determinant factor of TL in later life. Newborn TL is sensitive to maternal metals concentrations, while study about the association between maternal manganese (Mn) concentrations and newborn TL was not found. Our study aimed to investigate whether newborn TL is related to maternal Mn concentrations.<br><br>METHODS: Data were collected from a birth cohort study of 762 mother-newborn pairs conducted from November 2013 to March 2015 in Wuhan, China. We measured the Mn concentrations in spot urine samples collected during three trimesters by inductively coupled plasma mass spectrometry (ICP-MS) and relative cord blood TL by quantitative real-time polymerase chain reaction (qPCR). We applied multiple informant models to investigate the associations between maternal Mn concentrations and cord blood TL.<br><br>RESULTS: The geometric mean of creatinine-corrected urinary Mn concentrations were 1.58 μg/g creatinine, 2.53 μg/g creatinine, and 2.62 μg/g creatinine in the first, second, and third trimester, respectively. After adjusting for potential confounders, a doubling of maternal urinary Mn concentration during the second trimester was related to a 2.10% (95% CI: 0.25%, 3.99%) increase in cord blood TL. Mothers with the highest tertile of urinary Mn concentrations during the second trimester had a 9.67% (95% CI: 2.13%, 17.78%) longer cord blood TL than those with the lowest tertile. This association was more evident in male infants. No relationship was found between maternal urinary Mn concentrations and cord blood TL during the first and third trimesters in our study.<br><br>CONCLUSIONS: Our findings suggested that maternal Mn concentration during the second trimester was positively associated with newborn TL. These results might provide an epidemiology evidence on the protective role of maternal Mn for newborn TL and offer clues for the early prevention of telomere shortening related diseases.},
}
@article {pmid33608692,
year = {2021},
author = {Lim, CJ and Cech, TR},
title = {Publisher Correction: Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.},
journal = {Nature reviews. Molecular cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41580-021-00353-x},
pmid = {33608692},
issn = {1471-0080},
}
@article {pmid33608273,
year = {2021},
author = {Augereau, A and Mariotti, M and Pousse, M and Filipponi, D and Libert, F and Beck, B and Gorbunova, V and Gilson, E and Gladyshev, VN},
title = {Naked mole rat TRF1 safeguards glycolytic capacity and telomere replication under low oxygen.},
journal = {Science advances},
volume = {7},
number = {8},
pages = {},
doi = {10.1126/sciadv.abe0174},
pmid = {33608273},
issn = {2375-2548},
abstract = {The naked mole rat (NMR), a long-lived and cancer-resistant rodent, is highly resistant to hypoxia. Here, using robust cellular models wherein the mouse telomeric protein TRF1 is substituted by NMR TRF1 or its mutant forms, we show that TRF1 supports maximal glycolytic capacity under low oxygen, shows increased nuclear localization and association with telomeres, and protects telomeres from replicative stress. We pinpoint this evolutionary gain of metabolic function to specific amino acid changes in the homodimerization domain of this protein. We further find that NMR TRF1 accelerates telomere shortening. These findings reveal an evolutionary strategy to adapt telomere biology for metabolic control under an extreme environment.},
}
@article {pmid33608013,
year = {2021},
author = {Córdoba-Lanús, E and Cazorla-Rivero, S and García-Bello, MA and Mayato, D and Gonzalvo, F and Ayra-Plasencia, J and Celli, B and Casanova, C},
title = {Telomere length dynamics over 10-years and related outcomes in patients with COPD.},
journal = {Respiratory research},
volume = {22},
number = {1},
pages = {56},
pmid = {33608013},
issn = {1465-993X},
support = {12/00355//Instituto de Salud Carlos III/ ; 13/007//Sociedad Española de Neumología y Cirugía Torácica/ ; },
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been proposed as a disease of accelerated aging. Several cross-sectional studies have related a shorter telomere length (TL), a marker of biological aging, with COPD outcomes. Whether accelerated telomere shortening over time relates to worse outcomes in COPD patients, is not known.<br><br>METHODS: Relative telomere length (T/S) was determined by qPCR in DNA samples from peripheral blood in 263 patients at baseline and up to 10 years post enrolment. Yearly clinical and lung function data of 134 patients with at least two-time measures of T/S over this time were included in the analysis.<br><br>RESULTS: At baseline, T/S inversely correlated with age (r = - 0.236; p < 0.001), but there was no relationship between T/S and clinical and lung function variables (p > 0.05). Over 10 years of observation, there was a median shortening of TL of 183 bp/year for COPD patients. After adjusting for age, gender, active smoking and mean T/S, patients that shortened their telomeres the most over time, had worse gas exchange, more lung hyperinflation and extrapulmonary affection during the follow-up, (PaO2 p < 0.0001; KCO p = 0.042; IC/TLC p < 0.0001; 6MWD p = 0.004 and BODE index p = 0.009). Patients in the lowest tertile of T/S through the follow-up period had an increased risk of death [HR = 5.48, (1.23-24.42) p = 0.026].<br><br>CONCLUSIONS: This prospective study shows an association between accelerated telomere shortening and progressive worsening of pulmonary gas exchange, lung hyperinflation and extrapulmonary affection in COPD patients. Moreover, persistently shorter telomeres over this observation time increase the risk for all-cause mortality.},
}
@article {pmid33607270,
year = {2021},
author = {Puttabyatappa, M and Ciarelli, JN and Chatoff, AG and Padmanabhan, V},
title = {Developmental Programming: Metabolic Tissue-Specific Changes in Endoplasmic Reticulum Stress, Mitochondrial Oxidative and Telomere Length Status induced by Prenatal Testosterone Excess in the Female Sheep.},
journal = {Molecular and cellular endocrinology},
volume = {},
number = {},
pages = {111207},
doi = {10.1016/j.mce.2021.111207},
pmid = {33607270},
issn = {1872-8057},
abstract = {Prenatal testosterone (T) excess-induced metabolic dysfunctions involve tissue specific changes in insulin sensitivity with insulin resistant, oxidative and lipotoxic state in liver / muscle and insulin sensitive but inflammatory and oxidative state in visceral adipose tissues (VAT). We hypothesized that mitochondrial dysfunction, endoplasmic reticulum (ER) stress and premature cellular senescence are contributors to the tissue-specific changes in insulin sensitivity. Markers of mitochondrial oxidative phosphorylation (OxPhos), number, and function, ER stress and cellular senescence (telomere length) were assessed in liver, muscle and 4 adipose (VAT, subcutaneous [SAT], epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep at 21 months of age. Prenatal T treatment led to: (a) reduction in mitochondrial number and OxPhos complexes and increase in ER stress markers in muscle; (b) increase in fibrosis with trend towards increase in short telomere fragments in liver (c) depot-specific mitochondrial changes with OxPhos complexes namely increase in SAT and reduction in PRAT and increase in mitochondrial number in ECAT; (d) depot-specific ER stress marker changes with increase in VAT, reduction in SAT, contrasting changes in ECAT and no changes in PRAT; and (d) reduced shorter telomere fragments in SAT, ECAT and PRAT. These changes indicate insulin resistance may be driven by mitochondrial and ER dysfunction in muscle, fibrosis and premature senescence in liver, and depot-specific changes in mitochondrial function and ER stress without involving cellular senescence in adipose tissue. These findings provide mechanistic insights into pathophysiology of metabolic dysfunction among female offspring from hyperandrogenic pregnancies.},
}
@article {pmid33599797,
year = {2021},
author = {Akincilar, SC and Chan, CHT and Ng, QF and Fidan, K and Tergaonkar, V},
title = {Non-canonical roles of canonical telomere binding proteins in cancers.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {},
number = {},
pages = {},
pmid = {33599797},
issn = {1420-9071},
support = {OFYIRG/18MAY-0008//National Medical Research Council (SG)/ ; },
abstract = {Reactivation of telomerase is a major hallmark observed in 90% of all cancers. Yet paradoxically, enhanced telomerase activity does not correlate with telomere length and cancers often possess short telomeres; suggestive of supplementary non-canonical roles that telomerase might play in the development of cancer. Moreover, studies have shown that aberrant expression of shelterin proteins coupled with their release from shortening telomeres can further promote cancer by mechanisms independent of their telomeric role. While targeting telomerase activity appears to be an attractive therapeutic option, this approach has failed in clinical trials due to undesirable cytotoxic effects on stem cells. To circumvent this concern, an alternative strategy could be to target the molecules involved in the non-canonical functions of telomeric proteins. In this review, we will focus on emerging evidence that has demonstrated the non-canonical roles of telomeric proteins and their impact on tumorigenesis. Furthermore, we aim to address current knowledge gaps in telomeric protein functions and propose future research approaches that can be undertaken to achieve this.},
}
@article {pmid33597559,
year = {2021},
author = {Katoto, PDMC and Kayembe-Kitenge, T and Pollitt, KJG and Martens, DS and Ghosh, M and Nachega, JB and Nemery, B and Nawrot, TS},
title = {Telomere length and outcome of treatment for pulmonary tuberculosis in a gold mining community.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {4031},
pmid = {33597559},
issn = {2045-2322},
support = {1D43TW010937-01A1/NH/NIH HHS/United States ; 12X9620N//Fonds Wetenschappelijk Onderzoek/ ; },
abstract = {Telomere length (TL) is a marker of ageing and mitochondrial DNA (mtDNA) is an early marker of inflammation caused by oxidative stress. We determined TL and mtDNA content among active pulmonary tuberculosis (PTB) patients to assess if these cellular biomarkers differed between artisanal miners and non-miners, and to assess if they were predictive of treatment outcome. We conducted a prospective cohort study from August 2018 to May 2019 involving newly diagnosed PTB patients at three outpatient TB clinics in a rural Democratic Republic of Congo. We measured relative TL and mtDNA content in peripheral blood leukocytes (at inclusion) via qPCR and assessed their association with PTB treatment outcome. We included 129 patients (85 miners and 44 non-miners) with PTB (median age 40 years; range 5-71 years, 22% HIV-coinfected). For each increase in year and HIV-coinfection, TL shortened by - 0.85% (- 0.19 to - 0.52) (p ≤ 0.0001) and - 14% (- 28.22 to - 1.79) (p = 0.02) respectively. Independent of these covariates, patients with longer TL were more likely to have successful TB treatment [adjusted hazard ratio; 95% CI 1.27 for a doubling of leucocyte telomere length at baseline; 1.05-1.44] than patients with a shorter TL. Blood mtDNA content was not predictive for PTB outcome. For a given chronological age, PTB patients with longer telomeres at time of diagnosis were more likely to have successful PTB treatment outcome.},
}
@article {pmid33597549,
year = {2021},
author = {Kim, C and Sung, S and Kim, JS and Lee, H and Jung, Y and Shin, S and Kim, E and Seo, JJ and Kim, J and Kim, D and Niida, H and Kim, VN and Park, D and Lee, J},
title = {Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {1097},
pmid = {33597549},
issn = {2041-1723},
abstract = {Telomeres are part of a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes to protect chromosomal ends; however, in some species or telomerase-defective situations, an alternative lengthening of telomeres (ALT) mechanism is used. ALT mainly utilises recombination-based replication mechanisms and the constituents of ALT-based telomeres vary depending on models. Here we show that mouse telomeres can exploit non-telomeric, unique sequences in addition to telomeric repeats. We establish that a specific subtelomeric element, the mouse template for ALT (mTALT), is used for repairing telomeric DNA damage as well as for composing portions of telomeres in ALT-dependent mouse embryonic stem cells. Epigenomic and proteomic analyses before and after ALT activation reveal a high level of non-coding mTALT transcripts despite the heterochromatic nature of mTALT-based telomeres. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributes to the maintenance of telomere stability by regulating telomeric transcription. These findings provide a molecular basis to study the evolution of new structures in telomeres.},
}
@article {pmid33595114,
year = {2021},
author = {Raghunandan, M and Geelen, D and Majerova, E and Decottignies, A},
title = {NHP2 downregulation counteracts hTR-mediated activation of the DNA damage response at ALT telomeres.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {e106336},
doi = {10.15252/embj.2020106336},
pmid = {33595114},
issn = {1460-2075},
support = {2018-072//Fondation contre le Cancer/ ; FNRS 7.4506.17//Fonds National de la Recherche Scientifique, Télévie/ ; FNRS 7.4513.19//Fonds National de la Recherche Scientifique, Télévie/ ; ARC 14/19-059//Actions de Recherche Concertées/ ; },
abstract = {About 10% of cancer cells employ the &quot;alternative lengthening of telomeres&quot; (ALT) pathway instead of re-activating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT+ cells not expressing hTERT, suggesting a possible negative non-canonical impact of hTR on ALT. Indeed, we show that ectopically expressed hTR reduces phosphorylation of ssDNA-binding protein RPA (p-RPAS33) at ALT telomeres by promoting the hnRNPA1- and DNA-PK-dependent depletion of RPA. The resulting defective ATR checkpoint signaling at telomeres impairs recruitment of the homologous recombination protein, RAD51. This induces ALT telomere fragility, increases POLD3-dependent C-circle production, and promotes the recruitment of the DNA damage marker 53BP1. In ALT+ cells that naturally retain hTR expression, NHP2 H/ACA ribonucleoprotein levels are downregulated, likely in order to restrain DNA damage response (DDR) activation at telomeres through reduced 53BP1 recruitment. This unexpected role of NHP2 is independent from hTR's non-canonical function in modulating telomeric p-RPAS33 . Collectively, our study shines new light on the interference between telomerase- and ALT-dependent pathways and unravels a crucial role for hTR and NHP2 in DDR regulation at ALT telomeres.},
}
@article {pmid33593713,
year = {2021},
author = {Gutierrez-Rodrigues, F and Alves-Paiva, RM and Scatena, NF and Martinez, EZ and Scheucher, PS and Calado, RT},
title = {Association between leukocyte telomere length and sex by quantile regression analysis.},
journal = {Hematology, transfusion and cell therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.htct.2020.12.005},
pmid = {33593713},
issn = {2531-1387},
abstract = {INTRODUCTION: Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex.<br><br>METHODS: We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis.<br><br>RESULTS: By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, p < 0.0001 vs. 45 pb kb per year, p < 0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model.<br><br>CONCLUSION: The quantile regression analysis accurately reproduced a third-order polynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.},
}
@article {pmid33586226,
year = {2021},
author = {Sparks, AM and Spurgin, LG and van der Velde, M and Fairfield, EA and Komdeur, J and Burke, T and Richardson, DS and Dugdale, HL},
title = {Telomere heritability and parental age at conception effects in a wild avian population.},
journal = {Molecular ecology},
volume = {},
number = {},
pages = {},
doi = {10.1111/mec.15804},
pmid = {33586226},
issn = {1365-294X},
support = {NE/B504106/1//NERC/ ; NE/I021748/1//NERC/ ; NE/P011284/1//NERC/ ; NE/F02083X/1//NERC/ ; NE/K005502/1//NERC/ ; 825.09.013//NWO/ ; 040.11.232//NWO/ ; 854.11.003//NWO/ ; 823.01.014//NWO/ ; //Lucie Burgers Foundation/ ; SBP2013/04//KNAW Schure Beijerinck Poppings/ ; },
abstract = {Individual variation in telomere length is predictive of health and mortality risk across a range of species. However, the relative influence of environmental and genetic variation on individual telomere length in wild populations remains poorly understood. Heritability of telomere length has primarily been calculated using parent-offspring regression which can be confounded by shared environments. To control for confounding variables, quantitative genetic &quot;animal models&quot; can be used, but few studies have applied animal models in wild populations. Furthermore, parental age at conception may also influence offspring telomere length, but most studies have been cross-sectional. We investigated within- and between-parental age at conception effects and heritability of telomere length in the Seychelles warbler using measures from birds caught over 20 years and a multigenerational pedigree. We found a weak negative within-paternal age at conception effect (as fathers aged, their offspring had shorter telomeres) and a weak positive between-maternal age at conception effect (females that survived to older ages had offspring with longer telomeres). Animal models provided evidence that heritability and evolvability of telomere length were low in this population, and that variation in telomere length was not driven by early-life effects of hatch period or parental identities. Quantitative polymerase chain reaction plate had a large influence on telomere length variation and not accounting for it in the models would have underestimated heritability. Our study illustrates the need to include and account for technical variation in order to accurately estimate heritability, as well as other environmental effects, on telomere length in natural populations.},
}
@article {pmid33581499,
year = {2021},
author = {Shen, M and Young, A and Autexier, C},
title = {PCNA, a focus on replication stress and the alternative lengthening of telomeres pathway.},
journal = {DNA repair},
volume = {100},
number = {},
pages = {103055},
doi = {10.1016/j.dnarep.2021.103055},
pmid = {33581499},
issn = {1568-7856},
abstract = {The maintenance of telomeres, which are specialized stretches of DNA found at the ends of linear chromosomes, is a crucial step for the immortalization of cancer cells. Approximately 10-15 % of cancer cells use a homologous recombination-based mechanism known as the Alternative Lengthening of Telomeres (ALT) pathway to maintain their telomeres. Telomeres in general pose a challenge to DNA replication owing to their repetitive nature and potential for forming secondary structures. Telomeres in ALT+ cells especially are subject to elevated levels of replication stress compared to telomeres that are maintained by the enzyme telomerase, in part due to the incorporation of telomeric variant repeats at ALT+ telomeres, their on average longer lengths, and their modified chromatin states. Many DNA metabolic strategies exist to counter replication stress and to protect stalled replication forks. The role of proliferating cell nuclear antigen (PCNA) as a platform for recruiting protein partners that participate in several of these DNA replication and repair pathways has been well-documented. We propose that many of these pathways may be active at ALT+ telomeres, either to facilitate DNA replication, to manage replication stress, or during telomere extension. Here, we summarize recent evidence detailing the role of PCNA in pathways including DNA secondary structure resolution, DNA damage bypass, replication fork restart, and DNA damage synthesis. We propose that an examination of PCNA and its post-translational modifications (PTMs) may offer a unique lens by which we might gain insight into the DNA metabolic landscape that is distinctively present at ALT+ telomeres.},
}
@article {pmid33580702,
year = {2021},
author = {Choi, JY and Abdulkina, LR and Yin, J and Chastukhina, IB and Lovell, JT and Agabekian, IA and Young, PG and Razzaque, S and Shippen, DE and Juenger, TE and Shakirov, EV and Purugganan, MD},
title = {Natural variation in plant telomere length is associated with flowering time.},
journal = {The Plant cell},
volume = {},
number = {},
pages = {},
doi = {10.1093/plcell/koab022},
pmid = {33580702},
issn = {1532-298X},
abstract = {Telomeres are highly repetitive DNA sequences found at the ends of chromosomes that protect the chromosomes from deterioration duringcell division. Here, using whole-genome re-sequencing and terminal restriction fragment assays, we found substantial natural intraspecific variation in telomere length in Arabidopsis thaliana, rice (Oryza sativa), and maize (Zea mays). Genome-wide association study (GWAS) mapping in A. thaliana identified 13 regions with GWAS-significant associations underlying telomere length variation, including a region that harbors the telomerase reverse transcriptase (TERT) gene. Population genomic analysis provided evidence for a selective sweep at the TERT region associated with longer telomeres. We found that telomere length is negatively correlated with flowering time variation not only in A. thaliana, but also in maize and rice, indicating a link between life-history traits and chromosome integrity. Our results point to several possible reasons for this correlation, including the possibility that longer telomeres may be more adaptive in plants that have faster developmental rates (and therefore flower earlier). Our work suggests that chromosomal structure itself might be an adaptive trait associated with plant life-history strategies.},
}
@article {pmid33579245,
year = {2021},
author = {Lee, SW and Lim, KH and Lee, KJ and Heo, YR and Lee, JH},
title = {No association between telomere length and osteonecrosis of the femoral head.},
journal = {BMC musculoskeletal disorders},
volume = {22},
number = {1},
pages = {176},
pmid = {33579245},
issn = {1471-2474},
abstract = {BACKGROUND: Telemore length (TL) shortening has been found in many diseases. However, clinical characteristics of TL shortening in osteonecrosis of the femoral head (ONFH) has not been investigated. Therefore, we studied whether TL changes have clinicopathological values in ONFH.<br><br>METHODS: The TL in the synovial tissues of 36 ONFH and 127 control patients (femoral neck fracture) was examined by quantitative real-time PCR as relative length, Δ Ct value. In addition, the correlation between TL and clinical features of ONFH and controls was analyzed.<br><br>RESULTS: The average TL in the femoral tissues was 1.46 ± 3.12 (standard deviation). The average TL in the ONFH and control tissues was 1.92 ± 4.11 and 1.34 ± 2.78, respectively, however, the difference was absent (p = 0.324). Furthermore, a shorter TL was tended to be associated with erythrocyte sedimentation rate (100% vs. 61.5%, p = 0.073); however, the association was not statistically significant.<br><br>CONCLUSIONS: In this study, we demonstrated that there is no association between the TL and clinicopathologic characteristics of ONFH patients. However, further studies considering the genetic factors are needed to be performed.},
}
@article {pmid33578394,
year = {2021},
author = {Blagosklonny, MV},
title = {DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.},
journal = {Aging},
volume = {13},
number = {},
pages = {},
doi = {10.18632/aging.202674},
pmid = {33578394},
issn = {1945-4589},
abstract = {Failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor telomere shortening limits normal lifespan or causes normal aging.},
}
@article {pmid33578128,
year = {2021},
author = {Quintana-Sosa, M and León-Mejía, G and Luna-Carrascal, J and De Moya, YS and Rodríguez, IL and Acosta-Hoyos, A and Anaya-Romero, M and Trindade, C and Narváez, DM and Restrepo, HG and Dias, J and Niekraszewicz, L and Garcia, ALH and Rohr, P and da Silva, J and Henriques, JAP},
title = {Cytokinesis-block micronucleus cytome (CBMN-CYT) assay biomarkers and telomere length analysis in relation to inorganic elements in individuals exposed to welding fumes.},
journal = {Ecotoxicology and environmental safety},
volume = {212},
number = {},
pages = {111935},
doi = {10.1016/j.ecoenv.2021.111935},
pmid = {33578128},
issn = {1090-2414},
abstract = {During the welding activities many compounds are released, several of these cause oxidative stress and inflammation and some are considered carcinogenic, in fact the International Agency for Research on Cancer established that welding fumes are carcinogenic to humans. The aim of the present study was to analyze the cytotoxic and genotoxic potential of exposure to welding fumes and to determine concentrations of metals in blood and urine of occupationally exposed workers. We included 98 welders and 100 non-exposed individuals. Our results show significant increase in the frequency of micronuclei (MN), nucleoplasmic bridges (NPB), nuclear buds (NBUD) and necrotic cells (NECR) in cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, as well as in the telomere length (TL) of the exposed individuals with respect to the non-exposed group. In the analysis of the concentrations of inorganic elements using PIXE method, were found higher concentrations of Cr, Fe and Cu in the urine, and Cr, Fe, Mg, Al, S, and Mn in the blood in the exposed group compared to the non-exposed group. A significant correlation was observed between MN and age and between NPB and years of exposure. Additionally, we found a significant correlation for TL in relation to MN, NPB, age and years of exposure in the exposed group. Interestingly, a significant correlation between MN and the increase in the concentration of Mg, S, Fe and Cu in blood samples of the exposed group, and between MN and Cr, Fe, Ni and Cu in urine. Thus, our findings may be associated with oxidative and inflammatory damage processes generated by the components contained in welding fumes, suggesting a high occupational risk in welding workers.},
}
@article {pmid33568707,
year = {2021},
author = {Baquero, JM and Benítez-Buelga, C and Rajagopal, V and Zhenjun, Z and Torres-Ruiz, R and Müller, S and Hanna, BMF and Loseva, O and Wallner, O and Michel, M and Rodríguez-Perales, S and Gad, H and Visnes, T and Helleday, T and Benítez, J and Osorio, A},
title = {Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {3490},
pmid = {33568707},
issn = {2045-2322},
support = {FPU15/01978//Spanish Ministry of Education, Culture and Sport./ ; Fellowship//AECC scientific Foundation/ ; PI17/02303//Spanish National Research and Development Plan, Institute of Health Carlos III and FEDER/ ; no. 722729//European Union's Horizon 2020 research and 20 innovation program under the Marie Sklodowska-Curie grant/ ; PI16/00440//FIS/ ; FIS PI19/00640//FEDER/ ; },
abstract = {The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.},
}
@article {pmid33568696,
year = {2021},
author = {Mei, Y and Deng, Z and Vladimirova, O and Gulve, N and Johnson, FB and Drosopoulos, WC and Schildkraut, CL and Lieberman, PM},
title = {TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {3509},
pmid = {33568696},
issn = {2045-2322},
support = {GM045751/NH/NIH HHS/United States ; CA010815/CA/NCI NIH HHS/United States ; },
abstract = {Telomere dysfunction causes chromosomal instability which is associated with many cancers and age-related diseases. The non-coding telomeric repeat-containing RNA (TERRA) forms a structural and regulatory component of the telomere that is implicated in telomere maintenance and chromosomal end protection. The basic N-terminal Gly/Arg-rich (GAR) domain of telomeric repeat-binding factor 2 (TRF2) can bind TERRA but the structural basis and significance of this interaction remains poorly understood. Here, we show that TRF2 GAR recognizes G-quadruplex features of TERRA. We show that small molecules that disrupt the TERRA-TRF2 GAR complex, such as N-methyl mesoporphyrin IX (NMM) or genetic deletion of TRF2 GAR domain, result in the loss of TERRA, and the induction of γH2AX-associated telomeric DNA damage associated with decreased telomere length, and increased telomere aberrations, including telomere fragility. Taken together, our data indicates that the G-quadruplex structure of TERRA is an important recognition element for TRF2 GAR domain and this interaction between TRF2 GAR and TERRA is essential to maintain telomere stability.},
}
@article {pmid33565341,
year = {2021},
author = {Banevicius, M and Gedvilaite, G and Vilkeviciute, A and Kriauciuniene, L and Zemaitiene, R and Liutkeviciene, R},
title = {Association of relative leukocyte telomere length and genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TNKS2, TRF2) with atrophic age-related macular degeneration.},
journal = {Ophthalmic genetics},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/13816810.2021.1881976},
pmid = {33565341},
issn = {1744-5094},
abstract = {Background: In an experimental model, telomere shortening inhibits neovascularization. It is thus possible that telomere shortening might have a role in the pathogenesis of geographic atrophy in case of age-related macular degeneration (AMD). This is why we aimed to find any associated differences of telomere length and genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TNKS2, and TRF2) in patients with atrophic AMD compared to healthy controls. Methods: The study enrolled patients with atrophic AMD (n = 56) and healthy (n = 73) controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using a real-time polymerase chain reaction method. The results were assessed using the statistical analysis method of &quot;IBM SPSS Statistics 20.0&quot;. Results: We found statistically significantly higher T/S in atrophic AMD patients than in healthy controls (T/S, median (IQR): 1.638 (1.110) vs. 0.764 (0.801), p < .001). Also, statistically significant differences were found in TRF1 rs10107605 allele (A and C) distributions between the atrophic AMD and control groups (88.36% and 11.64% vs. 95.54% and 4.46%, respectively, p = .041), as well as between the short telomere and long telomere groups (86.92% and 13.08% vs. 96.09% and 3.91%, respectively, p = .008). Conclusions: Our research revealed the leukocyte telomere length having a role in atrophic AMD development, also the association between TRF1 rs10107605 and the telomere length.},
}
@article {pmid33564874,
year = {2021},
author = {Nettle, D and Gadalla, SM and Lai, TP and Susser, E and Bateson, M and Aviv, A},
title = {Telomere length measurement for longitudinal analysis: implications of assay precision.},
journal = {American journal of epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/aje/kwab025},
pmid = {33564874},
issn = {1476-6256},
abstract = {Researchers increasingly wish to test hypotheses concerning the impact of environmental or disease exposures on telomere length (TL), and use longitudinal study designs to do so. In population studies, TL is usually measured using a quantitative polymerase chain reaction (qPCR)-based method. This method has been validated by presenting a correlation with a gold standard method such as Southern blotting (SB) in cross-sectional datasets. However, in a cross-section, the range of true variation in TL is large, and measurement error is introduced only once. In a longitudinal study, the target variation of interest is small, and measurement error is introduced both at baseline and follow-up. We present a small dataset (n = 20) where leukocyte TL was measured 6.6 years apart by both qPCR and SB. The cross-sectional correlations between qPCR and SB were high both at baseline (r = 0.90) and follow-up (r = 0.85), yet their correlation for TL change was poor (r = 0.48). Moreover, the qPCR but not SB data showed strong signatures of measurement error. Through simulation, we show that the statistical power gain from performing a longitudinal analysis is much greater for SB than qPCR. We discuss implications for optimal study design and analysis.},
}
@article {pmid33564645,
year = {2021},
author = {Bevelacqua, JJ and Welsh, J and Mortazavi, SAR and Keshavarz, M and Mortazavi, SMJ},
title = {Space Medicine: Why Do Recently Published Papers about Telomere Length Alterations Increase our Uncertainty Rather than Reduce it?.},
journal = {Journal of biomedical physics &amp; engineering},
volume = {11},
number = {1},
pages = {103-108},
pmid = {33564645},
issn = {2251-7200},
abstract = {There is a growing interest in examining alterations in telomere length as a reliable biomarker of general health, as well as a marker for predicting later morbidity and mortality. Substantial evidence shows that telomere length is associated with aging; telomere shortening acts as a &quot;counting mechanism&quot; that drives replicative senescence by limiting the mitotic potential of normal (but not malignant) cells. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. This discussion includes three major research areas regarding telomere length: environmental stressors, aging, and life span. Our review suggests that activation of telomerase activity due to stressors in space might be a double-edged sword with both favorable and unfavorable consequences. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. Both positive and negative consequences must be clearly addressed in order to bolster the conclusions, as well as identify future research directions.},
}
@article {pmid33564154,
year = {2021},
author = {Lim, CJ and Cech, TR},
title = {Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.},
journal = {Nature reviews. Molecular cell biology},
volume = {},
number = {},
pages = {},
pmid = {33564154},
issn = {1471-0080},
support = {R00 GM131023/GM/NIGMS NIH HHS/United States ; },
abstract = {The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires coordination between telomeric protein complexes and the ribonucleoprotein telomerase, which extends the telomeric DNA. Telomeric proteins modulate telomere architecture, recruit telomerase to accessible telomeres and orchestrate the conversion of the newly synthesized telomeric single-stranded DNA tail into double-stranded DNA. Dysfunctional telomere maintenance leads to telomere shortening, which causes human diseases including bone marrow failure, premature ageing and cancer. Recent studies provide new insights into telomerase-related interactions (the 'telomere replisome') and reveal new challenges for future telomere structural biology endeavours owing to the dynamic nature of telomere architecture and the great number of structures that telomeres form. In this Review, we discuss recently determined structures of the shelterin and CTC1-STN1-TEN1 (CST) complexes, how they may participate in the regulation of telomere replication and chromosome end-capping, and how disease-causing mutations in their encoding genes may affect specific functions. Major outstanding questions in the field include how all of the telomere components assemble relative to each other and how the switching between different telomere structures is achieved.},
}
@article {pmid33561231,
year = {2021},
author = {Gonzalez de la Rosa, PM and Thomson, M and Trivedi, U and Tracey, A and Tandonnet, S and Blaxter, M},
title = {A telomere-to-telomere assembly of Oscheius tipulae and the evolution of rhabditid nematode chromosomes.},
journal = {G3 (Bethesda, Md.)},
volume = {11},
number = {1},
pages = {},
doi = {10.1093/g3journal/jkaa020},
pmid = {33561231},
issn = {2160-1836},
abstract = {Eukaryotic chromosomes have phylogenetic persistence. In many taxa, each chromosome has a single functional centromere with essential roles in spindle attachment and segregation. Fusion and fission can generate chromosomes with no or multiple centromeres, leading to genome instability. Groups with holocentric chromosomes (where centromeric function is distributed along each chromosome) might be expected to show karyotypic instability. This is generally not the case, and in Caenorhabditis elegans, it has been proposed that the role of maintenance of a stable karyotype has been transferred to the meiotic pairing centers, which are found at one end of each chromosome. Here, we explore the phylogenetic stability of nematode chromosomes using a new telomere-to-telomere assembly of the rhabditine nematode Oscheius tipulae generated from nanopore long reads. The 60-Mb O. tipulae genome is resolved into six chromosomal molecules. We find the evidence of specific chromatin diminution at all telomeres. Comparing this chromosomal O. tipulae assembly with chromosomal assemblies of diverse rhabditid nematodes, we identify seven ancestral chromosomal elements (Nigon elements) and present a model for the evolution of nematode chromosomes through rearrangement and fusion of these elements. We identify frequent fusion events involving NigonX, the element associated with the rhabditid X chromosome, and thus sex chromosome-associated gene sets differ markedly between species. Despite the karyotypic stability, gene order within chromosomes defined by Nigon elements is not conserved. Our model for nematode chromosome evolution provides a platform for investigation of the tensions between local genome rearrangement and karyotypic evolution in generating extant genome architectures.},
}
@article {pmid33557298,
year = {2021},
author = {Glapa-Nowak, A and Mutt, SJ and Lisowska, A and Sapiejka, E and Goździk-Spychalska, J and Wieczorek-Filipiak, M and Drzymała-Czyż, S and Nowak, JK and Thalmann, O and Herzig, KH and Walkowiak, J},
title = {Leukocyte Telomere Length Is Not Reduced in Children and Adults with Cystic Fibrosis but Associates with Clinical Characteristics-A Cross-Sectional Study.},
journal = {Journal of clinical medicine},
volume = {10},
number = {4},
pages = {},
doi = {10.3390/jcm10040590},
pmid = {33557298},
issn = {2077-0383},
support = {2017/25/N/NZ5/02126//Narodowe Centrum Nauki/ ; },
abstract = {We hypothezied that telomere length is considerably altered in cystic fibrosis (CF) patients compared to healthy subjects (HS), and that leukocyte telomere length variation reflects the severity of CF. Relative telomere length (RTL) was assessed by qPCR in 70 children aged 5-10 (34 CF; 36 HS) and 114 adults aged 18-45 (53 CF; 61 HS). Telomere length was similar in CF and HS (median (interquartile range): 0.799 (0.686-0.950) vs. 0.831 (0.707-0.986); p = 0.5283) both in children and adults. In adults, women had longer telomeres than men (0.805 (0.715-0.931) vs. 0.703 (0.574-0.790); p = 0.0002). Patients treated with inhaled corticosteroids had a shorter RTL compared to those without steroid therapy (0.765 (0.664-0.910) vs. 0.943 (0.813-1.191); p = 0.0007) and this finding remained significant after adjusting for gender, age, BMI, and child/adult status (p = 0.0003). Shorter telomeres were independently associated with the presence of comorbidities (0.763 (0.643-0.905) vs. 0.950 (0.783-1.130); p = 0.0006) and antibiotic treatment at the moment of blood sampling (0.762 (0.648-0.908) vs. 0.832 (0.748-1.129); p = 0.0172). RTL correlated with number of multiple-day hospitalizations (rho = -0.251; p = 0.0239), as well as number of hospitalization days (rho = -0.279; p = 0.0113). Leukocyte RTL in children and adults with CF was not shorter than in healthy controls, and did not seem to have any potential as a predictor of CF survival. However, it inversely associated with the investigated clinical characteristics.},
}
@article {pmid33556205,
year = {2021},
author = {On, K and Crevel, G and Cotterill, S and Itoh, M and Kato, Y},
title = {Drosophila telomere capping protein HOAP interacts with DSB sensor proteins Mre11 and Nbs.},
journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms},
volume = {},
number = {},
pages = {},
doi = {10.1111/gtc.12836},
pmid = {33556205},
issn = {1365-2443},
abstract = {In eukaryotes, specific DNA-protein structures called telomeres exist at linear chromosome ends. Telomere stability is maintained by a specific capping protein complex. This capping complex is essential for the inhibition of the DNA damage response (DDR) at telomeres and contributes to genome integrity. In Drosophila the central factors of telomere capping complex are HOAP and HipHop. Furthermore, a DDR protein complex Mre11-Rad50-Nbs (MRN) is known to be important for the telomere association of HOAP and HipHop. However, whether MRN interacts with HOAP and HipHop, and the telomere recognition mechanisms of HOAP and HipHop are poorly understood. Here, we show that Nbs interacts with Mre11 and transports the Mre11-Rad50 complex from the cytoplasm to the nucleus. In addition, we report that HOAP interacts with both Mre11 and Nbs. The N-terminal region of HOAP is essential for its co-localization with HipHop. Finally, we reveal that Nbs interacts with the N-terminal region of HOAP.},
}
@article {pmid33555479,
year = {2021},
author = {Zhang, N and Li, Y and Lai, TP and Shay, JW and Danuser, G},
title = {Imaging assay to probe the role of telomere length shortening on telomere-gene interactions in single cells.},
journal = {Chromosoma},
volume = {},
number = {},
pages = {},
pmid = {33555479},
issn = {1432-0886},
support = {RP160157//Cancer Prevention and Research Institute of Texas/ ; RP1225//Cancer Prevention and Research Institute of Texas/ ; GM067230/NH/NIH HHS/United States ; GM136428//National Institutes of Health (US)/ ; CA142543/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres are repetitive non-coding nucleotide sequences (TTAGGGn) capping the ends of chromosomes. Progressive telomere shortening with increasing age has been associated with shifts in gene expression through models such as the telomere position effect (TPE), which suggests reduced interference of the telomere with transcriptional activity of increasingly more distant genes. A modification of the TPE model, referred to as Telomere Position Effects over Long Distance (TPE-OLD), explains why some genes 1-10 MB from a telomere are still affected by TPE, but genes closer to the telomere are not. Here, we describe an imaging approach to systematically examine the occurrence of TPE-OLD at the single cell level. Compared to existing methods, the pipeline allows rapid analysis of hundreds to thousands of cells, which is necessary to establish TPE-OLD as an acceptable mechanism of gene expression regulation. We examined two human genes, ISG15 and TERT, for which TPE-OLD has been described before. For both genes, we found less interaction with the telomere on the same chromosome in old cells compared to young cells; and experimentally elongated telomeres in old cells rescued the level of telomere interaction for both genes. However, the dependency of the interactions on the age progression from young to old cells varied. One model for the differences between ISG15 and TERT may relate to the markedly distinct interstitial telomeric sequence arrangement in the two genes. Overall, this provides a strong rationale for the role of telomere length shortening in the regulation of gene expression.},
}
@article {pmid33553179,
year = {2021},
author = {Ge, J and Li, C and Sun, H and Xin, Y and Zhu, S and Liu, Y and Tang, S and Han, L and Huang, Z and Wang, Q},
title = {Telomere Dysfunction in Oocytes and Embryos From Obese Mice.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {617225},
pmid = {33553179},
issn = {2296-634X},
abstract = {Maternal obesity impairs oocyte quality and embryo development. However, the potential molecular pathways remain to be explored. In the present study, we examined the effects of obesity on telomere status in oocytes and embryos obtained from mice fed with high-fat diet (HFD). Of note, telomere shortening was observed in both oocytes and early embryos from obese mice, as evidenced by the reduced expression of telomerase reverse transcriptase and activity of telomerase. Moreover, quantitative analysis of telomere dysfunction-induced foci (TIFs) revealed that maternal obesity induces the defective telomeres in oocytes and embryos. Meanwhile, the high frequency of aneuploidy was detected in HFD oocytes and embryos as compared to controls, accompanying with the increased incidence of apoptotic blastocysts. In conclusion, these results indicate that telomere dysfunction might be a molecular pathway mediating the effects of maternal obesity on oocyte quality and embryo development.},
}
@article {pmid33552142,
year = {2020},
author = {Vaiserman, A and Krasnienkov, D},
title = {Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.},
journal = {Frontiers in genetics},
volume = {11},
number = {},
pages = {630186},
pmid = {33552142},
issn = {1664-8021},
abstract = {Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.},
}
@article {pmid33549587,
year = {2021},
author = {Xu, M and Axhemi, A and Malgowska, M and Chen, Y and Leonard, D and Srinivasan, S and Jankowsky, E and Taylor, DJ},
title = {Active and passive destabilization of G-quadruplex DNA by the telomere POT1-TPP1 complex.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {166846},
doi = {10.1016/j.jmb.2021.166846},
pmid = {33549587},
issn = {1089-8638},
abstract = {Chromosome ends are protected by guanosine-rich telomere DNA that forms stable G-quadruplex (G4) structures. The heterodimeric POT1-TPP1 complex interacts specifically with telomere DNA to shield it from illicit DNA damage repair and to resolve secondary structure that impedes telomere extension. The mechanism by which POT1-TPP1 accomplishes these tasks is poorly understood. Here, we establish the kinetic framework for POT1-TPP1 binding and unfolding of telomere G4 DNA. Our data identify two modes of POT1-TPP1 destabilization of G4 DNA that are governed by protein concentration. At low concentrations, POT1-TPP1 passively captures transiently unfolded G4s. At higher concentrations, POT1-TPP1 proteins bind to G4s to actively destabilize the DNA structures. Cancer-associated POT1-TPP1 mutations impair multiple reaction steps in this process, resulting in less efficient destabilization of G4 structures. The mechanistic insight highlights the importance of cell cycle dependent expression and localization of the POT1-TPP1 complex and distinguishes diverse functions of this complex in telomere maintenance.},
}
@article {pmid33547621,
year = {2021},
author = {Hecker, M and Fitzner, B and Jäger, K and Bühring, J and Schwartz, M and Hartmann, A and Walter, M and Zettl, UK},
title = {Leukocyte Telomere Length in Patients with Multiple Sclerosis and Its Association with Clinical Phenotypes.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {33547621},
issn = {1559-1182},
abstract = {Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS. We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS), and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex. The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis. Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence, and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.},
}
@article {pmid33544428,
year = {2021},
author = {Kosebent, EG and Ozturk, S},
title = {The spatiotemporal expression of TERT and telomere repeat binding proteins in the postnatal mouse testes.},
journal = {Andrologia},
volume = {},
number = {},
pages = {e13976},
doi = {10.1111/and.13976},
pmid = {33544428},
issn = {1439-0272},
abstract = {Telomeres consist of repetitive DNA sequences and telomere-associated proteins. Telomeres located at the ends of eukaryotic chromosomes undergo shortening due to DNA replication, genotoxic factors and reactive oxygen species. The short telomeres are elongated by the enzyme telomerase expressed in the germ line, embryonic and stem cells. Telomerase is in the structure of ribonucleoprotein composed of telomerase reverse transcriptase (TERT), telomerase RNA component (Terc) and other components. Among telomere-associated proteins, telomeric repeat binding factor 1 (TRF1) and 2 (TRF2) exclusively bind to the double-stranded telomeric DNA to regulate its length. However, protection of telomeres 1 (POT1) interacts with the single-stranded telomeric DNA to protect from DNA damage response. Herein, we characterised the spatial and temporal expression of the TERT, TRF1, TRF2 and POT1 proteins in the postnatal mouse testes at the ages of 6, 8, 16, 20, 29, 32 and 88 days by using immunohistochemistry. Significant differences in the spatiotemporal expression patterns and levels of these proteins were determined in the postnatal testes (p < .05). These findings indicate that TERT and telomere repeat binding proteins seem to be required for maintaining the length and structural integrity of telomeres in the spermatogenic cells from newborn to adult terms.},
}
@article {pmid33543592,
year = {2021},
author = {Meshkani, SE and Kooshki, A and Alahabadi, A and Lari Najafi, M and Rad, A and Riahimanesh, F and Miri, M},
title = {Dietary pattern and telomere length in preschool children in a middle-income country.},
journal = {Maternal &amp; child nutrition},
volume = {},
number = {},
pages = {e13146},
doi = {10.1111/mcn.13146},
pmid = {33543592},
issn = {1740-8709},
support = {//Sabzevar University of Medical Sciences/ ; },
abstract = {Telomere length (TL) has been associated with lifestyle and dietary pattern. However, the available evidence on this association in children is scarce, especially in low- and middle-income countries (LMICs). Therefore, this study aimed to evaluate the association of dietary pattern and leukocyte TL (LTL) in preschool children, Sabzevar, Iran (2017). This cross-sectional study was based on 187 preschool children (aged 5 to 7) recruited from 27 kindergartens. Nutrition information including amounts of consumed dairy products, meat and processed meat products, nuts and seeds, white bread and refined grains, fruits, vegetables, simple sugars, fats and drinks was obtained through a questionnaire. Linear mixed-effects models were fitted with polymerase chain reaction (PCR) plate ID and kindergartens as random effects to estimate the association of each food group consumption with LTL, controlled for relevant covariates. Higher consumption of dairy products and sugar was associated with shorter LTL (β = -0.180, 95% confidence interval [CI]: -0.276, -0.085, P value <0.001 and β = -0.139, 95% CI: -0.193, -0.086, P value <0.001, respectively). An increase in consumption of fish, nuts and seeds, coloured fruits, green leafy vegetables, cruciferous vegetables and olive was significantly associated with the increase in relative LTL. The associations for the consumption of legumes, other fruits, yellow and orange vegetables, red meat, egg, white bread and refined grains, solid and liquid fats, processed meats, potato chips, carbonated drinks, tea (black) and soft drinks groups were not statistically significant. Our findings showed that there was an association between the consumption of certain food groups with LTL.},
}
@article {pmid33542458,
year = {2021},
author = {Lister-Shimauchi, EH and Dinh, M and Maddox, P and Ahmed, S},
title = {Gametes deficient for Pot1 telomere binding proteins alter levels of telomeric foci for multiple generations.},
journal = {Communications biology},
volume = {4},
number = {1},
pages = {158},
pmid = {33542458},
issn = {2399-3642},
support = {Career Award 1652512//National Science Foundation (NSF)/ ; R01GM135470//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; },
abstract = {Deficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance. C. elegans Protection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes from pot-2 mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes from pot-1 mutants or pot-1; pot-2 double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose that C. elegans POT-1 may interact with H3K9 methyltransferases during pot-2 mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci.},
}
@article {pmid33539370,
year = {2021},
author = {McGrath, SL and Huang, SH and Kobryn, K},
title = {Single stranded DNA annealing is a conserved activity of telomere resolvases.},
journal = {PloS one},
volume = {16},
number = {2},
pages = {e0246212},
pmid = {33539370},
issn = {1932-6203},
abstract = {Bacterial species of the genera Agrobacterium and Borrelia possess chromosomes terminated by hairpin telomeres. Replication produces dimeric replication intermediates fused via replicated telomere junctions. A specialized class of enzymes, referred to as telomere resolvases, promotes the resolution of the replicated intermediate into linear monomers terminated by hairpin telomeres. Telomere resolution is catalyzed via DNA cleavage and rejoining events mechanistically similar to those promoted by topoisomerase-IB and tyrosine recombinase enzymes. Examination of the borrelial telomere resolvase, ResT, revealed unanticipated multifunctionality; aside from its expected telomere resolution activity ResT possessed a singled-stranded DNA (ssDNA) annealing activity that extended to both naked ssDNA and ssDNA complexed with its cognate single-stranded DNA binding protein (SSB). At present, the role this DNA annealing activity plays in vivo remains unknown. We have demonstrated here that single-stranded DNA annealing is also a conserved property of the agrobacterial telomere resolvase, TelA. This activity in TelA similarly extends to both naked ssDNA and ssDNA bound by its cognate SSB. TelA's annealing activity was shown to stem from the N-terminal domain; removal of this domain abolished annealing without affecting telomere resolution. Further, independent expression of the N-terminal domain of TelA produced a functional annealing protein. We suggest that the apparent conservation of annealing activity in two telomere resolvases, from distantly related bacterial species, implies a role for this activity in hairpin telomere metabolism. Our demonstration of the separation of the telomere resolution and annealing activities of TelA provides a platform for future experiments aimed at identifying the role DNA annealing performs in vivo.},
}
@article {pmid33539012,
year = {2021},
author = {Engin, AB and Engin, A},
title = {The Connection Between Cell Fate and Telomere.},
journal = {Advances in experimental medicine and biology},
volume = {1275},
number = {},
pages = {71-100},
pmid = {33539012},
issn = {0065-2598},
mesh = {Animals ; Ataxia Telangiectasia Mutated Proteins ; DNA Damage ; DNA End-Joining Repair ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; *Telomeric Repeat Binding Protein 2/genetics/metabolism ; },
abstract = {Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the &quot;Hayflick limit&quot;, and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double-stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length-associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell-cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.},
}
@article {pmid33537752,
year = {2021},
author = {Červenák, F and Sepšiová, R and Nosek, J and Tomáška, Ľ},
title = {Step-by-Step Evolution of Telomeres: Lessons from Yeasts.},
journal = {Genome biology and evolution},
volume = {13},
number = {2},
pages = {},
pmid = {33537752},
issn = {1759-6653},
abstract = {In virtually every eukaryotic species, the ends of nuclear chromosomes are protected by telomeres, nucleoprotein structures counteracting the end-replication problem and suppressing recombination and undue DNA repair. Although in most cases, the primary structure of telomeric DNA is conserved, there are several exceptions to this rule. One is represented by the telomeric repeats of ascomycetous yeasts, which encompass a great variety of sequences, whose evolutionary origin has been puzzling for several decades. At present, the key questions concerning the driving force behind their rapid evolution and the means of co-evolution of telomeric repeats and telomere-binding proteins remain largely unanswered. Previously published studies addressed mostly the general concepts of the evolutionary origin of telomeres, key properties of telomeric proteins as well as the molecular mechanisms of telomere maintenance; however, the evolutionary process itself has not been analyzed thoroughly. Here, we aimed to inspect the evolution of telomeres in ascomycetous yeasts from the subphyla Saccharomycotina and Taphrinomycotina, with special focus on the evolutionary origin of species-specific telomeric repeats. We analyzed the sequences of telomeric repeats from 204 yeast species classified into 20 families and as a result, we propose a step-by-step model, which integrates the diversity of telomeric repeats, telomerase RNAs, telomere-binding protein complexes and explains a propensity of certain species to generate the repeat heterogeneity within a single telomeric array.},
}
@article {pmid33530115,
year = {2021},
author = {Onat, T and Çaltekin, MD and Inandiklioglu, N and Baser, E and Kirmizi, DA and Kara, M and Ercan, F and Yalvac, ES},
title = {Telomere Length in Idiopathic Recurrent Pregnancy Loss.},
journal = {Zeitschrift fur Geburtshilfe und Neonatologie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-1345-9821},
pmid = {33530115},
issn = {1439-1651},
support = {Yozgat Bozok University Project Coordination Application and Research Center//6602a-TF/18-202/ ; },
abstract = {OBJECTIVE: Telomere length is used as an indicator of biological aging. It is well known that one of the most remarkable risk factors of recurrent pregnancy losses is advanced maternal age. The objective of this study was to investigate the correlation between idiopathic recurrent pregnancy loss and telomere length.<br><br>METHOD: The study group included 40 women, while the control group consisted of 41 healthy women whose age and body mass index were matched. A venous blood sample was taken from all participants into EDTA tubes in the early follicular phase, and telomere length was measured through the qPCR technique.<br><br>RESULTS: When the mean TL of the groups was compared, it was determined that TL was significantly shorter among the iRPL group (7763.89±924.58 base pair) compared to the control group (8398.84±1102.95 base pair) (p<0.006). Whereas FSH and E2 were higher in the iRPL group, TAFC was lower (p<0.001). When the correlation between telomere length and endocrine parameters was statistically tested in the iRPL group, a negative correlation was found between FSH and telomere length (r=-0.437; p<0.001).<br><br>CONCLUSION: Shortened telomere length might play a role in the etiology of iRPL. We are of the opinion that patients with RPL should be screened for the presence of cardiovascular diseases and other chronic diseases, as is the case for POF.},
}
@article {pmid33529748,
year = {2021},
author = {Dragović, G and Andjić, M and Toljić, B and Jevtović, D and Lukić, R and de Luka, S and Trbovich, A and Milašin, J},
title = {Correlation between metabolic syndrome and relative telomere length shortening in HIV/AIDS patients on combined antiretroviral therapy.},
journal = {Experimental gerontology},
volume = {147},
number = {},
pages = {111269},
doi = {10.1016/j.exger.2021.111269},
pmid = {33529748},
issn = {1873-6815},
abstract = {BACKGROUND: Components of the metabolic syndrome (MetS) play an important role in the accelerated aging process. Relative telomere length (RTL) is a marker of biological aging. The aim of our study was to determine RTL and its possible association with MetS and the components of MetS in HIV-infected patients treated with cART.<br><br>METHODS: We included 24 HIV-infected men, all Caucasians, with successful cART (<50 HIV-RNA copies/mL) and on stable cART for at least 24 months. The presence of MetS and its components was determined by the criteria prescribed by the International Diabetes Federation. RTL was determined by Real-Time PCR and ΔΔCt method. We performed a multiple linear regression modeling on log-transformed RTL (dependant variable) to evaluate which components of the metabolic syndrome as well as cART duration and cART type, had an impact on RTL.<br><br>RESULTS: Eleven (45.8%) patients had and 13 (54.2%) had not MetS. All patients, had an undetectable viral RNA and a relatively good immune status. The mean RTL was 0.62 ± 0.15 and 0.95 ± 0.36 in patients with and without MetS, respectively (p = 0.01). Multiple linear regression model showed no significant association between duration of cART, cART type and RTL (p = 0.2165, p = 0.8628, respectively). The same analysis showed that an increase in number of MetS components was associated with shorter telomere length (β = -0.4982, p = 0.042).<br><br>CONCLUSIONS: We showed for the first time association between RTL shortening in HIV-infected men with metabolic syndrome. Furthermore, our study also indicated that an increment of metabolic syndrome components is strongly associated with shorter telomere length.},
}
@article {pmid33529269,
year = {2021},
author = {de Fluiter, KS and Codd, V and Denniff, M and Kerkhof, GF and van Beijsterveldt, IALP and Breij, LM and Samani, NJ and Abrahamse-Berkeveld, M and Hokken-Koelega, ACS},
title = {Longitudinal telomere length and body composition in healthy term-born infants during the first two years of life.},
journal = {PloS one},
volume = {16},
number = {2},
pages = {e0246400},
pmid = {33529269},
issn = {1932-6203},
abstract = {OBJECTIVE: Leukocyte telomere length (LTL) is one of the markers of biological aging as shortening occurs over time. Shorter LTL has been associated with adiposity and a higher risk of cardiovascular diseases. The objective was to assess LTL and LTL shortening during the first 2 years of life in healthy, term-born infants and to associate LTL shortening with potential stressors and body composition.<br><br>STUDY DESIGN: In 145 healthy, term-born infants (85 boys), we measured LTL in blood, expressed as telomere to single-gene copy ratio (T/S ratio), at 3 months and 2 years by quantitative PCR technique. Fat mass (FM) was assessed longitudinally by PEAPOD, DXA, and abdominal FM by ultrasound.<br><br>RESULTS: LTL decreased by 8.5% from 3 months to 2 years (T/S ratio 4.10 vs 3.75, p<0.001). LTL shortening from 3 months to 2 years associated with FM%(R = 0.254), FM index(R = 0.243) and visceral FM(R = 0.287) at 2 years. LTL shortening tended to associate with gain in FM% from 3 to 6 months (R = 0.155, p = 0.11), in the critical window for adiposity programming. There was a trend to a shorter LTL in boys at 2 years(p = 0.056). LTL shortening from 3 months to 2 years was not different between sexes.<br><br>CONCLUSION: We present longitudinal LTL values and show that LTL shortens considerably (8.5%) during the first 2 years of life. LTL shortening during first 2 years of life was associated with FM%, FMI and visceral FM at age 2 years, suggesting that adverse adiposity programming in early life could contribute to more LTL shortening.},
}
@article {pmid33528568,
year = {2021},
author = {Benetos, A and Lai, TP and Toupance, S and Labat, C and Verhulst, S and Gautier, S and Ungeheuer, MN and Perret-Guillaume, C and Levy, D and Susser, E and Aviv, A},
title = {The Nexus between Telomere Length and Lymphocyte Count in Seniors hospitalized with Covid-19.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glab026},
pmid = {33528568},
issn = {1758-535X},
abstract = {Profound T-cell lymphopenia is the hallmark of severe Covid-19. T-cell proliferation is telomere length (TL)-dependent and telomeres shorten with age. Older Covid-19 patients, we hypothesize, are therefore at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting of the terminal restriction fragments (SB) in peripheral blood mononuclear cells of 17 Covid-19 and 21 non-Covid-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields two key metrics: the proportion of telomeres with different lengths (expressed in %), and their mean, TeSLA mTL (expressed in kb). Lymphocyte count (10 9/L) was 0.91 ± 0.42 in Covid-19 patients and 1.50 ± 0.50 in non-Covid-19 patients (P < 0.001). In Covid-19 patients, but not in non-Covid-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (P = 0.005) and positively correlated with TeSLA mTL (P = 0.03). Lymphocyte count was not significantly correlated with SB mTL in either Covid-19 or non-Covid-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to Covid-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.},
}
@article {pmid33520723,
year = {2020},
author = {Jebaraj, BMC and Stilgenbauer, S},
title = {Telomere Dysfunction in Chronic Lymphocytic Leukemia.},
journal = {Frontiers in oncology},
volume = {10},
number = {},
pages = {612665},
pmid = {33520723},
issn = {2234-943X},
abstract = {Telomeres are nucleprotein structures that cap the chromosomal ends, conferring genomic stability. Alterations in telomere maintenance and function are associated with tumorigenesis. In chronic lymphocytic leukemia (CLL), telomere length is an independent prognostic factor and short telomeres are associated with adverse outcome. Though telomere length associations have been suggested to be only a passive reflection of the cell's replication history, here, based on published findings, we suggest a more dynamic role of telomere dysfunction in shaping the disease course. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. In addition, cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation thus may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. On the other hand, activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. In summary, multiple components of the telomere system are affected and they play an important role in CLL pathogenesis, progression, and clonal evolution. However, processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered.},
}
@article {pmid33517527,
year = {2021},
author = {Wirth, A and Wolf, B and Huang, CK and Glage, S and Hofer, SJ and Bankstahl, M and Bär, C and Thum, T and Kahl, KG and Sigrist, SJ and Madeo, F and Bankstahl, JP and Ponimaskin, E},
title = {Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {33517527},
issn = {2509-2723},
support = {Smartage//BMBF/ ; PO732//DFG/ ; KFO311//DFG/ ; SFB LIPOTOX F3007 &amp; F3012, W1226, P29203, P29262, P27893, P 31727//Austrian Science Fund/ ; BA5631/2//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.},
}
@article {pmid33513745,
year = {2021},
author = {Vodicka, P and Andera, L and Opattova, A and Vodickova, L},
title = {The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction.},
journal = {Cancers},
volume = {13},
number = {3},
pages = {},
pmid = {33513745},
issn = {2072-6694},
support = {18-09709S//Grantová Agentura České Republiky/ ; 19-10543S//Grantová Agentura České Republiky/ ; NV18-00199//Agentura Pro Zdravotnický Výzkum České Republiky/ ; PROGRES Q 28//Grantová Agentura, Univerzita Karlova/ ; UNCE/MED/006//Grantová Agentura, Univerzita Karlova/ ; CZ.02.1.01/0.0./0.0/16_019/0000787//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; },
abstract = {The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.},
}
@article {pmid33510409,
year = {2021},
author = {Sperka, T and Song, Z and Morita, Y and Nalapareddy, K and Guachalla, LM and Lechel, A and Begus-Nahrmann, Y and Burkhalter, MD and Mach, M and Schlaudraff, F and Liss, B and Ju, Z and Speicher, MR and Rudolph, KL},
title = {Author Correction: Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction.},
journal = {Nature cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41556-021-00633-w},
pmid = {33510409},
issn = {1476-4679},
}
@article {pmid33509633,
year = {2021},
author = {Stone, RC and Aviv, A and Paus, R},
title = {Telomere Dynamics and Telomerase in the Biology of Hair Follicles and their Stem Cells as a Model for Aging Research.},
journal = {The Journal of investigative dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jid.2020.12.006},
pmid = {33509633},
issn = {1523-1747},
abstract = {In this review, we propose that telomere length dynamics play an important but underinvestigated role in the biology of the hair follicle (HF), a prototypic, cyclically remodeled miniorgan that shows an intriguing aging pattern in humans. Whereas the HF pigmentary unit ages quickly, its epithelial stem cell (ESC) component and regenerative capacity are surprisingly aging resistant. Telomerase-deficient mice with short telomeres display an aging phenotype of hair graying and hair loss that is attributed to impaired HF ESC mobilization. Yet, it remains unclear whether the function of telomerase and telomeres in murine HF biology translate to the human system. Therefore, we propose new directions for future telomere research of the human HF. Such research may guide the development of novel treatments for selected disorders of human hair growth or pigmentation (e.g., chemotherapy-induced alopecia, telogen effluvium, androgenetic alopecia, cicatricial alopecia, graying). It might also increase the understanding of the global role of telomeres in aging-related human disease.},
}
@article {pmid33509090,
year = {2021},
author = {Saud, Z and Kortsinoglou, AM and Kouvelis, VN and Butt, TM},
title = {Telomere length de novo assembly of all 7 chromosomes and mitogenome sequencing of the model entomopathogenic fungus, Metarhizium brunneum, by means of a novel assembly pipeline.},
journal = {BMC genomics},
volume = {22},
number = {1},
pages = {87},
pmid = {33509090},
issn = {1471-2164},
abstract = {BACKGROUND: More accurate and complete reference genomes have improved understanding of gene function, biology, and evolutionary mechanisms. Hybrid genome assembly approaches leverage benefits of both long, relatively error-prone reads from third-generation sequencing technologies and short, accurate reads from second-generation sequencing technologies, to produce more accurate and contiguous de novo genome assemblies in comparison to using either technology independently. In this study, we present a novel hybrid assembly pipeline that allowed for both mitogenome de novo assembly and telomere length de novo assembly of all 7 chromosomes of the model entomopathogenic fungus, Metarhizium brunneum.<br><br>RESULTS: The improved assembly allowed for better ab initio gene prediction and a more BUSCO complete proteome set has been generated in comparison to the eight current NCBI reference Metarhizium spp. genomes. Remarkably, we note that including the mitogenome in ab initio gene prediction training improved overall gene prediction. The assembly was further validated by comparing contig assembly agreement across various assemblers, assessing the assembly performance of each tool. Genomic synteny and orthologous protein clusters were compared between Metarhizium brunneum and three other Hypocreales species with complete genomes, identifying core proteins, and listing orthologous protein clusters shared uniquely between the two entomopathogenic fungal species, so as to further facilitate the understanding of molecular mechanisms underpinning fungal-insect pathogenesis.<br><br>CONCLUSIONS: The novel assembly pipeline may be used for other haploid fungal species, facilitating the need to produce high-quality reference fungal genomes, leading to better understanding of fungal genomic evolution, chromosome structuring and gene regulation.},
}
@article {pmid33507936,
year = {2021},
author = {Han, X and Kubota, R and Tanaka, KI and Hayashi, H and Seki, M and Sakai, N and Kawaguchi-Ihara, N and Arakawa, K and Murohashi, I},
title = {The correlation of salivary telomere length and single nucleotide polymorphisms of the ADIPOQ, SIRT1 and FOXO3A genes with lifestyle-related diseases in a Japanese population.},
journal = {PloS one},
volume = {16},
number = {1},
pages = {e0243745},
pmid = {33507936},
issn = {1932-6203},
abstract = {BACKGROUND: It has been reported that genetic factors are associated with risk factors and onset of lifestyle-related diseases, but this finding is still the subject of much debate.<br><br>OBJECTIVE: The aim of the present study was to investigate the correlation of genetic factors, including salivary telomere length and three single nucleotide polymorphisms (SNPs) that may influence lifestyle-related diseases, with lifestyle-related diseases themselves.<br><br>METHODS: In one year at a single facility, relative telomere length and SNPs were determined by using monochrome multiplex quantitative polymerase chain reaction and TaqMan SNP Genotyping Assays, respectively, and were compared with lifestyle-related diseases in 120 Japanese individuals near our university.<br><br>RESULTS: In men and all participants, age was inversely correlated with relative telomere length with respective p values of 0.049 and 0.034. In men, the frequency of hypertension was significantly higher in the short relative telomere length group than in the long group with unadjusted p value of 0.039, and the difference in the frequency of hypertension between the two groups was of borderline statistical significance after adjustment for age (p = 0.057). Furthermore, in men and all participants, the sum of the number of affected lifestyle-related diseases, including hypertension, was significantly higher in the short relative telomere length group than in the long group, with p values of 0.004 and 0.029, respectively. For ADIPOQ rs1501299, men's ankle brachial index was higher in the T/T genotype than in the G/G and G/T genotypes, with p values of 0.001 and 0.000, respectively. For SIRT1 rs7895833, men's body mass index and waist circumference and all participants' brachial-ankle pulse wave velocity were higher in the A/G genotype than in the G/G genotype, with respective p values of 0.048, 0.032 and 0.035. For FOXO3A rs2802292, women's body temperature and all participants' saturation of peripheral oxygen were lower in the G/T genotype than in the T/T genotype, with respective p values of 0.039 and 0.032. However, relative telomere length was not associated with physiological or anthropometric measurements except for height in men (p = 0.016). ADIPOQ rs1501299 in men, but not the other two SNPs, was significantly associated with the sum of the number of affected lifestyle-related diseases (p = 0.013), by genotype. For each SNPs, there was no significant difference in the frequency of hypertension or relative telomere length by genotype.<br><br>CONCLUSION: Relative telomere length and the three types of SNPs determined using saliva have been shown to be differentially associated with onset of and measured risk factors for lifestyle-related diseases consisting mainly of cardiovascular diseases and cancer.},
}
@article {pmid33503312,
year = {2021},
author = {Heidinger, BJ and Slowinski, SP and Sirman, AE and Kittilson, J and Gerlach, NM and Ketterson, ED},
title = {Experimentally elevated testosterone shortens telomeres across years in a free-living songbird.},
journal = {Molecular ecology},
volume = {},
number = {},
pages = {},
doi = {10.1111/mec.15819},
pmid = {33503312},
issn = {1365-294X},
support = {BSR 91-11498//National Science Foundation/ ; BSR 87-18358//National Science Foundation/ ; IBN 94-08061//National Science Foundation/ ; IBN 97-28384//National Science Foundation/ ; IOS 1656194//National Science Foundation/ ; 2 T32 HD049336-11A1//National Institute of Health Common Themes in Reproductive Diversity Pre-doctoral Fellowship/ ; },
abstract = {Reproductive investment often comes at a cost to longevity, but the mechanisms that underlie these long-term effects are not well understood. In male vertebrates, elevated testosterone has been shown to increase reproductive success, but simultaneously to decrease survival. One factor that may contribute to or serve as a biomarker of these long-term effects of testosterone on longevity is telomeres, which are often positively related to lifespan and have been shown to shorten in response to reproduction. In this longitudinal study, we measured the effects of experimentally elevated testosterone on telomere shortening in free-living, male dark-eyed juncos (Junco hyemalis carolinensis), a system in which the experimental elevation of testosterone has previously been shown to increase reproductive success and reduce survival. We found a small, significant effect of testosterone treatment on telomeres, with testosterone-treated males exhibiting significantly greater telomere shortening with age than controls. These results are consistent with the hypothesis that increased telomere shortening may be a long-term cost of elevated testosterone exposure. As both testosterone and telomeres are conserved physiological mechanisms, our results suggest that their interaction may apply broadly to the long-term costs of reproduction in male vertebrates.},
}
@article {pmid33501739,
year = {2021},
author = {Ooi, DSQ and Dorajoo, R and Gurung, RL and Dehghan, R and Lim, YY and Ho, CWL and Tay, V and Karuppiah, V and Loke, KY and Lim, SC and Liu, JJ and Sng, AA and Lee, YS},
title = {Association of leukocyte telomere length with obesity-related traits in Asian children with early-onset obesity.},
journal = {Pediatric obesity},
volume = {},
number = {},
pages = {e12771},
doi = {10.1111/ijpo.12771},
pmid = {33501739},
issn = {2047-6310},
support = {CRIG14may015//National Medical Research Council/ ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) is associated with obesity and obesity-related traits, and there are ethnic-specific determinants of LTL.<br><br>OBJECTIVE: To evaluate LTL associations with obesity and metabolic parameters in Asian children with early-onset obesity.<br><br>METHODS: Genomic DNA was extracted from peripheral blood leukocytes of a cohort of children with (N = 371) and without obesity (N = 23), and LTL was measured using quantitative PCR (qPCR). Blood plasma was used for metabolic phenotyping. Statistical analysis was performed using SPSS and STATA.<br><br>RESULTS: Children with obesity had shorter LTL (coefficient = -0.683, PAdj = 1.24 × 10-3) as compared to children who were lean. LTL was found to be associated with waist circumference (coefficient = -0.326, PAdj = 0.044) and skin-fold measures (coefficient between 0.267 and 0.301, PAdj between 4.27 × 10-4 and 7.06 × 10-7) in children with obesity. However, no significant associations were observed between LTL and metabolic parameters, and between LTL and inflammatory cytokines. LTL also did not significantly mediate the risk of non-alcoholic fatty liver disease (NAFLD) in children with obesity.<br><br>CONCLUSIONS: We showed for the first time that Asian children with severe obesity had shorter LTL, and the shortening of LTL was associated with other adiposity measures including waist circumference and skin-fold measurements.},
}
@article {pmid33500500,
year = {2021},
author = {Kim, B and Ryu, KJ and Lee, S and Kim, T},
title = {Changes in telomere length and senescence markers during human ovarian tissue cryopreservation.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {2238},
pmid = {33500500},
issn = {2045-2322},
support = {NRF-2016R1C1B3015250//National Research Foundation of Korea Grant funded by the Korean government/ ; K1823991//Grant of Korea University Medical Center and Anam Hospital, Seoul, Republic of Korea/ ; },
abstract = {Ovarian tissue cryopreservation is considered as a useful option to preserve fertility for cancer patients. This study purposed to evaluate the change of telomere length and senescence markers during human ovarian tissue cryopreservation. Ovarian tissues were obtained from women who underwent benign ovarian surgery in the gynecology research unit of a university hospital with prior consent and IRB approval. DNA was extracted from the ovarian tissues using a DNeasy tissue kit and telomere lengths in the DNA samples were determined by real time PCR before and after cryopreservation. All tissues were stained with hematoxylin-eosin and subjected to immunohistochemistry and TUNEL assays. Other senescence markers, including p53, p16, p21, and phospho-pRb proteins, were evaluated using western blot analysis. Ovarian tissues were collected from ten patients and prepared for slow freezing with the same size of diameter 4 mm and 1 mm thickness. Mean age of patients was 26.7 ± 6.2 years (range, 16-34 years), and ovarian tissues were cryopreserved and thawed 4 weeks after cryopreservation. The mean telomere length was significantly decreased after cryopreservation (9.57 ± 1.47 bp vs. 8.34 ± 1.83 bp, p = 0.001). Western blot analysis revealed that p53, p16, and p21 proteins increased and phospho-pRb protein expression decreased after ovarian tissue cryopreservation. Ovarian tissue cryopreservation and transplantation is regarded as one of promising options for fertility preservation. However, clinicians and researchers should be aware of possible irreversible DNA changes such as shortening of telomere length and alterations of other senescence markers in human ovarian tissues.},
}
@article {pmid33500413,
year = {2021},
author = {Zhang, S and Yu, X and Zhang, Y and Xue, X and Yu, Q and Zha, Z and Gogol, M and Workman, JL and Li, S},
title = {Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {594},
pmid = {33500413},
issn = {2041-1723},
support = {R35 GM118068/GM/NIGMS NIH HHS/United States ; },
mesh = {Autophagy ; *Chromosomal Instability ; Gene Expression Regulation, Fungal ; Heterochromatin/metabolism ; Histones/*metabolism ; Multienzyme Complexes/*metabolism ; Phosphorylation ; Proteolysis ; Pyruvate Kinase/metabolism ; Saccharomyces cerevisiae/enzymology/*genetics ; Serine/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Sirtuin 2/metabolism ; Telomere/*metabolism ; },
abstract = {Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identify a function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which maintains SIR (silent information regulator) complex occupancy at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAME-catalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.},
}
@article {pmid33499376,
year = {2021},
author = {Pitkänen, N and Pahkala, K and Rovio, SP and Saijonmaa, OJ and Nyman, AE and Jula, A and Lagström, H and Viikari, JSA and Rönnemaa, T and Niinikoski, H and Simell, O and Fyhrquist, F and Raitakari, OT},
title = {Effects of Randomized Controlled Infancy-Onset Dietary Intervention on Leukocyte Telomere Length-The Special Turku Coronary Risk Factor Intervention Project (STRIP).},
journal = {Nutrients},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/nu13020318},
pmid = {33499376},
issn = {2072-6643},
support = {206374, 294834, 251360, 275595, 307996, 322112//Academy of Finland/ ; NA//Juho Vainion Säätiö/ ; NA//Sydäntutkimussäätiö/ ; NA//Opetus- ja Kulttuuriministeriö/ ; NA//Suomen Kulttuurirahasto/ ; NA//Sigrid Juséliuksen Säätiö/ ; NA//Yrjö Jahnssonin Säätiö/ ; NA//Suomen Lääketieteen Säätiö/ ; NA//Special Governmental grants for Health Sciences Research (Turku University Hospital)/ ; NA//Turku University Foundation/ ; },
abstract = {Reduced telomere length (TL) is a biological marker of aging. A high inter-individual variation in TL exists already in childhood, which is partly explained by genetics, but also by lifestyle factors. We examined the influence of a 20-year dietary/lifestyle intervention on TL attrition from childhood to early adulthood. The study comprised participants of the longitudinal randomized Special Turku Coronary Risk Factor Intervention Project (STRIP) conducted between 1990 and 2011. Healthy 7-month-old children were randomized to the intervention group (n = 540) receiving dietary counseling mainly focused on dietary fat quality and to the control group (n = 522). Leukocyte TL was measured using the Southern blot method from whole blood samples collected twice: at a mean age of 7.5 and 19.8 years (n = 232; intervention n = 108, control n = 124). Yearly TL attrition rate was calculated. The participants of the intervention group had slower yearly TL attrition rate compared to the controls (intervention: mean = -7.5 bp/year, SD = 24.4 vs. control: mean = -15.0 bp/year, SD = 30.3; age, sex and baseline TL adjusted β = 0.007, SE = 0.004, p = 0.040). The result became stronger after additional adjustments for dietary fat quality and fiber intake, serum lipid and insulin concentrations, systolic blood pressure, physical activity and smoking (β = 0.013, SE = 0.005, p = 0.009). A long-term intervention focused mainly on dietary fat quality may affect the yearly TL attrition rate in healthy children/adolescents.},
}
@article {pmid33498968,
year = {2021},
author = {Henckel, E and James, A and Konradsen, JR and Nordlund, B and Kjellberg, M and Berggren-Broström, E and Hedlin, G and Degerman, S and Bohlin, K},
title = {A Novel Association between YKL-40, a Marker of Structural Lung Disease, and Short Telomere Length in 10-Year-Old Children with Bronchopulmonary Dysplasia.},
journal = {Children (Basel, Switzerland)},
volume = {8},
number = {2},
pages = {},
doi = {10.3390/children8020080},
pmid = {33498968},
issn = {2227-9067},
abstract = {Extremely preterm infants are born with immature lungs and are exposed to an inflammatory environment as a result of oxidative stress. This may lead to airway remodeling, cellular aging and the development of bronchopulmonary dysplasia (BPD). Reliable markers that predict the long-term consequences of BPD in infancy are still lacking. We analyzed two biomarkers of cellular aging and lung function, telomere length and YKL-40, respectively, at 10 years of age in children born preterm with a history of BPD (n = 29). For comparison, these markers were also evaluated in sex-and-age-matched children born at term with childhood asthma (n = 28). Relative telomere length (RTL) was measured in whole blood with qPCR and serum YKL-40 with ELISA, and both were studied in relation to gas exchange and the regional ventilation/perfusion ratio using three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) in children with BPD. Higher levels of YKL-40 were associated with shorter leukocyte RTL (Pearson's correlation: -0.55, p = 0.002), but were not associated with a lower degree of matching between ventilation and perfusion within the lung. Serum YKL-40 levels were significantly higher in children with BPD compared to children with asthma (17.7 vs. 13.2 ng/mL, p < 0.01). High levels of YKL-40 and short RTLs were associated to the need for ventilatory support more than 1 month in the neonatal period (p < 0.01). The link between enhanced telomere shortening in childhood and structural remodeling of the lung, as observed in children with former BPD but not in children with asthma at the age of 10 years, suggests altered lung development related to prematurity and early life inflammatory exposure. In conclusion, relative telomere length and YKL-40 may serve as biomarkers of altered lung development as a result of early-life inflammation in children with a history of prematurity.},
}
@article {pmid33498228,
year = {2021},
author = {D'Amico-Willman, KM and Anderson, ES and Gradziel, TM and Fresnedo-Ramírez, J},
title = {Relative Telomere Length and Telomerase Reverse Transcriptase (TERT) Expression Are Associated with Age in Almond (Prunus dulcis [Mill.] D.A.Webb).},
journal = {Plants (Basel, Switzerland)},
volume = {10},
number = {2},
pages = {},
doi = {10.3390/plants10020189},
pmid = {33498228},
issn = {2223-7747},
support = {2018113//College of Food, Agricultural, and Environmental Sciences, Ohio State University/ ; Fellowship//Center for Applied Plant Sciences, Ohio State University/ ; 2019-67011-29558//National Institute of Food and Agriculture/ ; },
abstract = {While all organisms age, our understanding of how aging occurs varies among species. The aging process in perennial plants is not well-defined, yet can have implications on production and yield of valuable fruit and nut crops. Almond exhibits an age-related disorder known as non-infectious bud failure (BF) that affects vegetative bud development, indirectly affecting kernel yield. This species and disorder present an opportunity to address aging in a commercially relevant and vegetatively propagated perennial crop. The hypothesis tested in this study was that relative telomere length and/or telomerase reverse transcriptase (TERT) expression can serve as biomarkers of aging in almond. Relative telomere lengths and expression of TERT, a subunit of the enzyme telomerase, were measured via qPCR methods using bud and leaf samples collected from distinct age cohorts over a two-year period. Results from this work show a marginal but significant association between both relative telomere length and TERT expression, and age, suggesting that as almonds age, telomeres shorten and TERT expression decreases. This work provides information on potential biomarkers of perennial plant aging, contributing to our knowledge of this process. In addition, these results provide opportunities to address BF in almond breeding and nursery propagation.},
}
@article {pmid33495397,
year = {2021},
author = {Caslini, C and Connelly, JA and Serna, A and Broccoli, D and Hess, JL},
title = {Erratum for Caslini et al., &quot;MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription&quot;.},
journal = {Molecular and cellular biology},
volume = {41},
number = {2},
pages = {},
doi = {10.1128/MCB.00566-20},
pmid = {33495397},
issn = {1098-5549},
support = {R01 CA092251/CA/NCI NIH HHS/United States ; },
}
@article {pmid33495152,
year = {2021},
author = {Adler, BL and Boin, F and Wolters, PJ and Bingham, CO and Shah, AA and Greider, C and Casciola-Rosen, L and Rosen, A},
title = {Autoantibodies targeting telomere-associated proteins in systemic sclerosis.},
journal = {Annals of the rheumatic diseases},
volume = {},
number = {},
pages = {},
doi = {10.1136/annrheumdis-2020-218918},
pmid = {33495152},
issn = {1468-2060},
abstract = {OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.<br><br>METHODS: Sera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.<br><br>RESULTS: In a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher's exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.<br><br>CONCLUSIONS: Autoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis.},
}
@article {pmid33493798,
year = {2021},
author = {Needham, BL},
title = {Newborn telomere length and the early life origins of age-related disease.},
journal = {EBioMedicine},
volume = {64},
number = {},
pages = {103214},
doi = {10.1016/j.ebiom.2021.103214},
pmid = {33493798},
issn = {2352-3964},
support = {R01 MD011721/MD/NIMHD NIH HHS/United States ; R21 MD012683/MD/NIMHD NIH HHS/United States ; },
}
@article {pmid33493537,
year = {2021},
author = {Adli, A and Hosseini, SM and Lari Najafi, M and Behmanesh, M and Ghezi, E and Rasti, M and Kazemi, AA and Rad, A and Falanji, F and Mohammadzadeh, M and Miri, M and Dadvand, P},
title = {Polycyclic aromatic hydrocarbons exposures and telomere length: A cross-sectional study on preschool children.},
journal = {Environmental research},
volume = {195},
number = {},
pages = {110757},
doi = {10.1016/j.envres.2021.110757},
pmid = {33493537},
issn = {1096-0953},
abstract = {Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with shorter telomere length (TL), a marker of ageing at cellular level. However, the available evidence on this association among children is still scarce. We therefore aimed to assess, the relationship between urinary 1-hydroxipayrene (1-OHP), a marker of exposure to PAHs, and relative leukocyte TL (LTL) in children at preschool age. Our study was based on 200 children enrolled from 27 randomly-selected kindergartens in the city of Sabzevar, Iran (2017). 1-OHP levels in the participants' urine samples were measured using solid phase extraction (SPE) method and high-performance liquid chromatography (HPLC). Moreover, real-time PCR was used to measure the LTL in the participants' blood samples. Linear mixed effects models, controlled for relevant covariates, were applied to investigate the association of 1-OHP concentration and LTL. The median (interquartile range (IQR)) of relative LTL and urinary 1-OHP were 0.83 (0.7) and 257 (375.5) ng/L, respectively. In the fully adjusted model, an IQR increase in urinary 1-OHP was related to -0.05 (95% confidence interval (CI): 0.09, -0.01, P-value = 0.02) decrease in relative LTL. This association was similar among boys and girls; however, we observed indications for a stronger association for those children whose parents had university education. Our study suggested an inverse relationship between urinary 1-OHP and LTL in children at preschool age. However, further longitudinal research with repeated measures of PAHs and LTL are needed to confirm these findings.},
}
@article {pmid33482595,
year = {2020},
author = {Grill, S and Nandakumar, J},
title = {Molecular mechanisms of telomere biology disorders.},
journal = {The Journal of biological chemistry},
volume = {296},
number = {},
pages = {100064},
doi = {10.1074/jbc.REV120.014017},
pmid = {33482595},
issn = {1083-351X},
abstract = {Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.},
}
@article {pmid33480989,
year = {2021},
author = {Subecz, C and Sun, JS and Roger, L},
title = {Effect of DNA repair inhibitor AsiDNA on the incidence of telomere fusion in crisis.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddab008},
pmid = {33480989},
issn = {1460-2083},
abstract = {Telomere fusions lead to a state of genomic instability, and are thought to drive clonal evolution and tumorigenesis. Telomere fusions occur via both Classical and Alternative Non-Homologous End Joining repair pathways. AsiDNA is a DNA repair inhibitor that acts by mimicking a DNA double strand break (DSB) and hijacking the recruitment of proteins involved in various DNA repair pathways. In this study, we investigated whether the inhibition of DSB-repair pathways by AsiDNA could prevent telomere fusions during crisis. The present study showed that AsiDNA decreased the frequency of telomere fusions without affecting the rate of telomere erosion. Further, it indicated that AsiDNA does not impact the choice of the repair pathway used for the fusion of short dysfunctional telomeres. AsiDNA is thought to prevent short telomeres from fusing by inhibiting DNA repair. An alternative, non-mutually exclusive possibility is that cells harbouring fusions preferentially die in the presence of AsiDNA, thus resulting in a reduction in fusion frequency. This important work could open the way for investigating the use of AsiDNA in the treatment of tumours that have short dysfunctional telomeres and/or are experiencing genomic instability.},
}
@article {pmid33479235,
year = {2021},
author = {Lippert, TP and Marzec, P and Idilli, AI and Sarek, G and Vancevska, A and Bower, M and Farrell, PJ and Ojala, PM and Feldhahn, N and Boulton, SJ},
title = {Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {512},
pmid = {33479235},
issn = {2041-1723},
support = {FC0010048/CRUK_/Cancer Research UK/United Kingdom ; FC0010048/WT_/Wellcome Trust/United Kingdom ; FC0010048/MRC_/Medical Research Council/United Kingdom ; MR/S022597/1/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; },
mesh = {Carcinogenesis ; Cell Line ; Cell Line, Tumor ; DNA Damage ; DNA Replication/genetics ; HeLa Cells ; Herpesvirus 8, Human/physiology ; Host-Pathogen Interactions ; Humans ; In Situ Hybridization, Fluorescence ; Neoplasms/*genetics/pathology/virology ; Proteome/genetics/metabolism ; Telomerase/genetics/metabolism ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi's sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.},
}
@article {pmid33478187,
year = {2021},
author = {Han, S and Ma, X and Fang, J},
title = {[Clinical Application and Challenges of Telomere and Telomerase Research 
in Lung Cancer].},
journal = {Zhongguo fei ai za zhi = Chinese journal of lung cancer},
volume = {24},
number = {1},
pages = {25-30},
pmid = {33478187},
issn = {1999-6187},
abstract = {Lung cancer is one of the malignant tumors with high incidence rate and high mortality worldwide. Telomere and telomerase are closely related to the occurrence and development of lung cancer. Although telomerase may not be the direct cause of carcinogenesis, it plays a key role in maintaining telomere length and tumor growth. The length of most tumors, including lung cancer, is shortened. The change of telomere length is related to the risk of lung cancer, and may become the therapeutic target and predictive index. Target drugs for telomere and telomerase signaling pathway are constantly being explored, and drugs represented by telomerase inhibitors are expected to be used in clinical treatment of lung cancer in the future. However, the research on telomere and telomerase is far from enough. The bypass mechanism of telomere length maintenance may be the direction of further research.
.},
}
@article {pmid33478114,
year = {2021},
author = {Levstek, T and Redenšek, S and Trošt, M and Dolžan, V and Podkrajšek, KT},
title = {Assessment of the Telomere Length and Its Effect on the Symptomatology of Parkinson's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {1},
pages = {},
pmid = {33478114},
issn = {2076-3921},
support = {P1-0170//Javna Agencija za Raziskovalno Dejavnost RS/ ; },
abstract = {Telomeres, which are repetitive sequences that cap the end of the chromosomes, shorten with each cell division. Besides cellular aging, there are several other factors that influence telomere length (TL), in particular, oxidative stress and inflammation, which play an important role in the pathogenesis of neurodegenerative brain diseases including Parkinson's disease (PD). So far, the majority of studies have not demonstrated a significant difference in TL between PD patients and healthy individuals. However, studies investigating the effect of TL on the symptomatology and disease progression of PD are scarce, and thus, warranted. We analyzed TL of peripheral blood cells in a sample of 204 PD patients without concomitant autoimmune diseases and analyzed its association with several PD related phenotypes. Monochrome multiplex quantitative PCR (mmqPCR) was used to determine relative TL given as a ratio of the amount of DNA between the telomere and albumin as the housekeeping gene. We found a significant difference in the relative TL between PD patients with and without dementia, where shorter TL presented higher risk for dementia (p = 0.024). However, the correlation was not significant after adjustment for clinical factors (p = 0.509). We found no correlations between TLs and the dose of dopaminergic therapy when the analysis was adjusted for genetic variability in inflammatory or oxidative factors. In addition, TL influenced time to onset of motor complications after levodopa treatment initiation (p = 0.0134), but the association did not remain significant after adjustment for age at inclusion and disease duration (p = 0.0781). Based on the results of our study we conclude that TL contributes to certain PD-related phenotypes, although it may not have a major role in directing the course of the disease. Nevertheless, this expends currently limited knowledge regarding the association of the telomere attrition and the disease severity or motor complications in Parkinson's disease.},
}
@article {pmid33471860,
year = {2021},
author = {Lindrose, AR and McLester-Davis, LWY and Tristano, RI and Kataria, L and Gadalla, SM and Eisenberg, DTA and Verhulst, S and Drury, S},
title = {Method comparison studies of telomere length measurement using qPCR approaches: A critical appraisal of the literature.},
journal = {PloS one},
volume = {16},
number = {1},
pages = {e0245582},
pmid = {33471860},
issn = {1932-6203},
support = {U24 AG066528/AG/NIA NIH HHS/United States ; },
abstract = {Use of telomere length (TL) as a biomarker for various environmental exposures and diseases has increased in recent years. Various methods have been developed to measure telomere length. Polymerase chain reaction (PCR)-based methods remain wide-spread for population-based studies due to the high-throughput capability. While several studies have evaluated the repeatability and reproducibility of different TL measurement methods, the results have been variable. We conducted a literature review of TL measurement cross-method comparison studies that included a PCR-based method published between January 1, 2002 and May 25, 2020. A total of 25 articles were found that matched the inclusion criteria. Papers were reviewed for quality of methodologic reporting of sample and DNA quality, PCR assay characteristics, sample blinding, and analytic approaches to determine final TL. Overall, methodologic reporting was low as assessed by two different reporting guidelines for qPCR-based TL measurement. There was a wide range in the reported correlation between methods (as assessed by Pearson's r) and few studies utilized the recommended intra-class correlation coefficient (ICC) for assessment of assay repeatability and methodologic comparisons. The sample size for nearly all studies was less than 100, raising concerns about statistical power. Overall, this review found that the current literature on the relation between TL measurement methods is lacking in validity and scientific rigor. In light of these findings, we present reporting guidelines for PCR-based TL measurement methods and results of analyses of the effect of assay repeatability (ICC) on statistical power of cross-sectional and longitudinal studies. Additional cross-laboratory studies with rigorous methodologic and statistical reporting, adequate sample size, and blinding are essential to accurately determine assay repeatability and replicability as well as the relation between TL measurement methods.},
}
@article {pmid33471805,
year = {2021},
author = {Belfort, MB and Qureshi, F and Litt, J and Enlow, MB and De Vivo, I and Gregory, K and Tiemeier, H},
title = {Telomere length shortening in hospitalized preterm infants: A pilot study.},
journal = {PloS one},
volume = {16},
number = {1},
pages = {e0243468},
pmid = {33471805},
issn = {1932-6203},
abstract = {Leukocyte telomere length is a biomarker of aging-related health risks. Hospitalized preterm infants frequently experience elevated oxidative stress and inflammation, both of which contribute to telomere shortening. Our aim was to examine changes in telomere length during neonatal intensive care unit (NICU) hospitalization in a cohort of preterm infants <32 weeks' gestation. We conducted a longitudinal study of 10 infants (mean gestational age 27 weeks, range 23.5 to 29, at birth). We isolated DNA from dried blood spots and used Real Time Quantitative PCR to measure relative leukocyte telomere length in triplicate at three time points for each participant. From birth to discharge, infants experienced an average decline in relative telomere length of 0.021 units per week (95% CI -0.040, -0.0020; p = 0.03), after adjustment for gestational age at birth. Our results suggest a measurable decline in telomere length during NICU hospitalization. We speculate that telomere length change may convey information about NICU exposures that carry short- and long-term health risks.},
}
@article {pmid33471779,
year = {2021},
author = {Barbé-Tuana, FM and Grun, LK and Pierdoná, V and Parisi, MM and Friedrich, F and Guma, FTCR and Pinto, LA and Stein, RT and Pitrez, PMC and Jones, MH},
title = {Shorter telomeres in children with severe asthma, an indicative of accelerated aging.},
journal = {Aging},
volume = {13},
number = {2},
pages = {1686-1691},
doi = {10.18632/aging.202527},
pmid = {33471779},
issn = {1945-4589},
abstract = {Severe therapy-resistant asthma (STRA) is closely associated with distinct clinical and inflammatory pheno-endotypes, which may contribute to the development of age-related comorbidities. Evidence has demonstrated a contribution of accelerated telomere shortening on the poor prognosis of respiratory diseases in adults. Eotaxin-1 (CCL11) is an important chemokine for eosinophilic recruitment and the progression of asthma. In the last years has also been proposed as an age-promoting factor. This study aimed to investigate the association of relative telomere length (rTL) and eotaxin-1 in asthmatic children. Children aged 8-14 years (n=267) were classified as healthy control (HC, n=126), mild asthma (MA, n=124) or severe therapy-resistant asthma (STRA, n=17). rTL was performed by qPCR from peripheral blood. Eotaxin-1 was quantified by ELISA from fresh-frozen plasma. STRA had shorter telomeres compared to HC (p=0.02) and MA (p=0.006). Eotaxin-1 levels were up-regulated in STRA [median; IQR25-75)] [(1,190 pg/mL; 108-2,510)] compared to MA [(638 pg/mL; 134-1,460)] (p=0.03) or HC [(627 pg/mL; 108-1,750)] (p<0.01). Additionally, shorter telomeres were inversely correlated with eotaxin-1 levels in STRA (r=-0.6, p=0.013). Our results suggest that short telomeres and up-regulated eotaxin-1, features of accelerated aging, could prematurely contribute to a senescent phenotype increasing the risk for early development of age-related diseases in asthma.},
}
@article {pmid33469834,
year = {2021},
author = {Huang, Z and Liu, C and Ruan, Y and Guo, Y and Sun, S and Shi, Y and Wu, F},
title = {Dynamics of leukocyte telomere length in adults aged 50 and older: a longitudinal population-based cohort study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {33469834},
issn = {2509-2723},
support = {OGHA 04034785, YA1323-08-CN-0020, Y1-AG-1005-01/WHO_/World Health Organization/International ; R01-AG034479/AG/NIA NIH HHS/United States ; 2019LJ24//Program for Outstanding Medical Academic Leader/ ; 201840118//Shanghai Municipal Health Commission/ ; 20204Y0196//Shanghai Municipal Health Commission/ ; 2020YJZX0113//Shanghai Municipal Health Commission/ ; },
abstract = {It is well established from previous cross-sectional studies that telomeres shorten with age. However, due to a considerable inter-individual variation in telomere length (TL), its relationship with biological aging is difficult to unpick. Longitudinal repeated assessments of TL changes within individuals should augment our understanding of TL dynamics in aging. This study disentangles within- and inter-individual effects of age on leukocyte telomere length (LTL) dynamics in a large population-based cohort of older adults. A total of 4053 subjects aged 50 and older from the WHO Study on global AGEing and adult health (SAGE) in Shanghai were studied. Relative LTL (T/S ratio) was measured at baseline (2009-2010) and follow-up (2017-2018) by quantitative real-time polymerase chain reaction. We used linear random slope models to analyze LTL dynamics in relation to age and sex and within-subject centering method to distinguish within- versus between-subject effects. We observed LTL shortening in 66.32%, maintenance in 11.23%, and elongation in 22.45% of the study participants. LTL declined significantly with age both cross-sectionally and longitudinally. More importantly, the longitudinal decline in LTL was much greater than the cross-sectional decline (- 0.017 (p < 0.001) versus - 0.002 (p < 0.001) per year). Furthermore, women had a lower within-subject LTL shortening rate than men (- 0.014 versus - 0.020 per year, p < 0.001). The within-individual longitudinal decline in LTL was much greater than the inter-individual cross-sectional decline, indicating that chronological age might impose a greater impact on LTL shortening than other influencing factors combined. Moreover, women showed a lower within-individual LTL shortening rate than men.},
}
@article {pmid33469644,
year = {2021},
author = {Monsen, RC and Chakravarthy, S and Dean, WL and Chaires, JB and Trent, JO},
title = {The solution structures of higher-order human telomere G-quadruplex multimers.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkaa1285},
pmid = {33469644},
issn = {1362-4962},
abstract = {Human telomeres contain the repeat DNA sequence 5'-d(TTAGGG), with duplex regions that are several kilobases long terminating in a 3' single-stranded overhang. The structure of the single-stranded overhang is not known with certainty, with disparate models proposed in the literature. We report here the results of an integrated structural biology approach that combines small-angle X-ray scattering, circular dichroism (CD), analytical ultracentrifugation, size-exclusion column chromatography and molecular dynamics simulations that provide the most detailed characterization to date of the structure of the telomeric overhang. We find that the single-stranded sequences 5'-d(TTAGGG)n, with n = 8, 12 and 16, fold into multimeric structures containing the maximal number (2, 3 and 4, respectively) of contiguous G4 units with no long gaps between units. The G4 units are a mixture of hybrid-1 and hybrid-2 conformers. In the multimeric structures, G4 units interact, at least transiently, at the interfaces between units to produce distinctive CD signatures. Global fitting of our hydrodynamic and scattering data to a worm-like chain (WLC) model indicates that these multimeric G4 structures are semi-flexible, with a persistence length of ∼34 Å. Investigations of its flexibility using MD simulations reveal stacking, unstacking, and coiling movements, which yield unique sites for drug targeting.},
}
@article {pmid33466545,
year = {2021},
author = {Konečná, K and Sováková, PP and Anteková, K and Fajkus, J and Fojtová, M},
title = {Distinct Responses of Arabidopsis Telomeres and Transposable Elements to Zebularine Exposure.},
journal = {International journal of molecular sciences},
volume = {22},
number = {1},
pages = {},
pmid = {33466545},
issn = {1422-0067},
support = {CZ.02.1.01/0.0/0.0/16_026/0008446//European Regional Development Fund/ ; INTER-COST LTC20003//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; },
abstract = {Involvement of epigenetic mechanisms in the regulation of telomeres and transposable elements (TEs), genomic regions with the protective and potentially detrimental function, respectively, has been frequently studied. Here, we analyzed telomere lengths in Arabidopsis thaliana plants of Columbia, Landsberg erecta and Wassilevskija ecotypes exposed repeatedly to the hypomethylation drug zebularine during germination. Shorter telomeres were detected in plants growing from seedlings germinated in the presence of zebularine with a progression in telomeric phenotype across generations, relatively high inter-individual variability, and diverse responses among ecotypes. Interestingly, the extent of telomere shortening in zebularine Columbia and Wassilevskija plants corresponded to the transcriptional activation of TEs, suggesting a correlated response of these genomic elements to the zebularine treatment. Changes in lengths of telomeres and levels of TE transcripts in leaves were not always correlated with a hypomethylation of cytosines located in these regions, indicating a cytosine methylation-independent level of their regulation. These observations, including differences among ecotypes together with distinct dynamics of the reversal of the disruption of telomere homeostasis and TEs transcriptional activation, reflect a complex involvement of epigenetic processes in the regulation of crucial genomic regions. Our results further demonstrate the ability of plant cells to cope with these changes without a critical loss of the genome stability.},
}
@article {pmid33465329,
year = {2021},
author = {Molbert, N and Angelier, F and Alliot, F and Ribout, C and Goutte, A},
title = {Fish from urban rivers and with high pollutant levels have shorter telomeres.},
journal = {Biology letters},
volume = {17},
number = {1},
pages = {20200819},
pmid = {33465329},
issn = {1744-957X},
abstract = {Environmental pressures, such as urbanization and exposure to pollutants may jeopardize survival of free-living animals. Yet, much remains to be known about physiological and ecological responses to currently-released pollutants, especially in wild vertebrate ectotherms. We tested the effect of urbanization and pollution (phthalates, organochlorine and pyrethroid pesticides, polychlorobiphenyls, polybromodiphenylethers, polycyclic aromatic hydrocarbons, and some of their metabolites) on telomere length, a suggested biomarker of life expectancy, in the European chub, Squalius cephalus, from urban and agricultural rivers of the Marne hydrographic network, France. We showed that telomere length was reduced in chub from urban rivers. Moreover, among the wide range of anthropogenic contaminants investigated, high levels of phthalate metabolites in liver were associated with shorter telomeres. This study suggests that urbanization and chemical pollution may compromise survival of wild fish, by accelerating telomere attrition.},
}
@article {pmid33460462,
year = {2021},
author = {Vedder, O and Moiron, M and Bichet, C and Bauch, C and Verhulst, S and Becker, PH and Bouwhuis, S},
title = {Telomere length is heritable and genetically correlated with lifespan in a wild bird.},
journal = {Molecular ecology},
volume = {},
number = {},
pages = {},
doi = {10.1111/mec.15807},
pmid = {33460462},
issn = {1365-294X},
support = {BE 916/8 &amp; 9//Deutsche Forschungsgemeinschaft/ ; 863.14.010//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; //Alexander von Humboldt-Stiftung/ ; },
abstract = {Telomeres are protective caps at the end of eukaryotic chromosomes that shorten with age and in response to stressful or resource-demanding conditions. Their length predicts individual health and lifespan across a wide range of animals, but whether the observed positive association between telomere length and lifespan is environmentally induced, or set at conception due to a shared genetic basis, has not been tested in wild animals. We applied quantitative genetic &quot;animal models&quot; to longitudinal telomere measurements collected over a 10-year period from individuals of a wild seabird (common tern; Sterna hirundo) with known pedigree. We found no variation in telomere shortening with age among individuals at the phenotypic and genetic level, and only a small permanent environmental effect on adult telomere length. Instead, we found telomere length to be highly heritable and strongly positively genetically correlated with lifespan. Such heritable differences between individuals that are set at conception may present a hitherto underappreciated component of variation in somatic state.},
}
@article {pmid33459354,
year = {2021},
author = {Samavat, H and Luu, HN and Beckman, KB and Jin, A and Wang, R and Koh, WP and Yuan, JM},
title = {Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese Health Study.},
journal = {International journal of cancer},
volume = {148},
number = {2},
pages = {352-362},
doi = {10.1002/ijc.33211},
pmid = {33459354},
issn = {1097-0215},
support = {R01 CA144034/CA/NCI NIH HHS/United States ; T32CA186873//National Institutes of Health/National Cancer Institute/ ; UM1 CA182876/CA/NCI NIH HHS/United States ; NMRC/CSA/0055/2013//Singapore National Medical Research Council/ ; },
abstract = {Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all-cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26 540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%-44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (Ptrend < .0001). In contrast, longer telomeres were associated with lower risk of all-cause mortality (HR = 0.93; 95% CI: 0.84-1.03), noncancer death (HR = 0.81; 95% CI: 0.71-0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70-0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42-0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death.},
}
@article {pmid33453166,
year = {2021},
author = {Zhang, JM and Genois, MM and Ouyang, J and Lan, L and Zou, L},
title = {Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2020.12.030},
pmid = {33453166},
issn = {1097-4164},
abstract = {Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we induced telomere clustering in ALT-associated PML bodies (APBs) and a POLD3-dependent ATR response at telomeres, showing that BIR generates replication stress. Ablation of BLM helicase activity in APBs abolishes telomere synthesis but causes multiple chromosome bridges between telomeres, revealing a function of BLM in processing inter-telomere BIR intermediates. Interestingly, the accumulation of BLM in APBs requires its own helicase activity and POLD3, suggesting that BIR triggers a feedforward loop to further recruit BLM. Enhancing BIR induces PIAS4-mediated TRF2 SUMOylation, and PIAS4 loss deprives APBs of repair proteins and compromises ALT telomere synthesis. Thus, a BLM-driven and PIAS4-mediated feedforward loop operates in APBs to perpetuate BIR, providing a critical mechanism to extend ALT telomeres.},
}
@article {pmid33450878,
year = {2021},
author = {Samad, MA and Saiman, MZ and Abdul Majid, N and Karsani, SA and Yaacob, JS},
title = {Berberine Inhibits Telomerase Activity and Induces Cell Cycle Arrest and Telomere Erosion in Colorectal Cancer Cell Line, HCT 116.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {2},
pages = {},
pmid = {33450878},
issn = {1420-3049},
support = {RP030C-15AFR//Universiti Malaya/ ; RU004C-2020//Universiti Malaya/ ; CEBAR RU006-2018//Universiti Malaya/ ; },
abstract = {Colorectal cancer (CRC) is the most common cancer among males and females, which is associated with the increment of telomerase level and activity. Some plant-derived compounds are telomerase inhibitors that have the potential to decrease telomerase activity and/or level in various cancer cell lines. Unfortunately, a deeper understanding of the effects of telomerase inhibitor compound(s) on CRC cells is still lacking. Therefore, in this study, the aspects of telomerase inhibitors on a CRC cell line (HCT 116) were investigated. Screening on HCT 116 at 48 h showed that berberine (10.30 ± 0.89 µg/mL) is the most effective (lowest IC50 value) telomerase inhibitor compared to boldine (37.87 ± 3.12 µg/mL) and silymarin (>200 µg/mL). Further analyses exhibited that berberine treatment caused G0/G1 phase arrest at 48 h due to high cyclin D1 (CCND1) and low cyclin-dependent kinase 4 (CDK4) protein and mRNA levels, simultaneous downregulation of human telomerase reverse transcriptase (TERT) mRNA and human telomerase RNA component (TERC) levels, as well as a decrease in the TERT protein level and telomerase activity. The effect of berberine treatment on the cell cycle was time dependent as it resulted in a delayed cell cycle and doubling time by 2.18-fold. Telomerase activity and level was significantly decreased, and telomere erosion followed suit. In summary, our findings suggested that berberine could decrease telomerase activity and level of HCT 116, which in turn inhibits the proliferative ability of the cells.},
}
@article {pmid33450357,
year = {2021},
author = {Gala, K and Khattar, E},
title = {Long non-coding RNAs at work on telomeres: Functions and implications in cancer therapy.},
journal = {Cancer letters},
volume = {502},
number = {},
pages = {120-132},
doi = {10.1016/j.canlet.2020.12.036},
pmid = {33450357},
issn = {1872-7980},
abstract = {Long non-coding RNAs (lncRNAs) are known to regulate various biological processes including cancer. Cancer cells possess limitless replicative potential which is attained by telomere length maintenance while normal somatic cells have a limited lifespan because their telomeres shorten with every cell division ultimately triggering replicative senescence. Two lncRNAs have been observed to play a key role in telomere length maintenance. First is the lncRNA TERC (telomerase RNA component) which functions as a template for telomeric DNA synthesis in association with telomerase reverse transcriptase (TERT) which serves as the catalytic component. Together they constitute the telomerase complex which functions as a reverse transcriptase to elongate telomeres. Second lncRNA that helps in regulating telomere length is the telomeric repeat-containing RNA (TERRA) which is transcribed from the subtelomeric region and extends to the telomeric region. TERC and TERRA exhibit important functions in cancer with implications in precision oncology. In this review, we discuss various aspects of these important lncRNAs in humans and their role in cancer along with recent advancements in their anticancer therapeutic application.},
}
@article {pmid33450206,
year = {2021},
author = {Chakravarti, D and LaBella, KA and DePinho, RA},
title = {Telomeres: history, health, and hallmarks of aging.},
journal = {Cell},
volume = {184},
number = {2},
pages = {306-322},
doi = {10.1016/j.cell.2020.12.028},
pmid = {33450206},
issn = {1097-4172},
abstract = {The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.},
}
@article {pmid33447828,
year = {2021},
author = {Liddiard, K and Grimstead, JW and Cleal, K and Evans, A and Baird, DM},
title = {Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response.},
journal = {NAR cancer},
volume = {3},
number = {1},
pages = {zcaa044},
pmid = {33447828},
issn = {2632-8674},
abstract = {Identifying attributes that distinguish pre-malignant from senescent cells provides opportunities for targeted disease eradication and revival of anti-tumour immunity. We modelled a telomere-driven crisis in four human fibroblast lines, sampling at multiple time points to delineate genomic rearrangements and transcriptome developments that characterize the transition from dynamic proliferation into replicative crisis. Progression through crisis was associated with abundant intra-chromosomal telomere fusions with increasing asymmetry and reduced microhomology usage, suggesting shifts in DNA repair capacity. Eroded telomeres also fused with genomic loci actively engaged in transcription, with particular enrichment in long genes. Both gross copy number alterations and transcriptional responses to crisis likely underpin the elevated frequencies of telomere fusion with chromosomes 9, 16, 17, 19 and most exceptionally, chromosome 12. Juxtaposition of crisis-regulated genes with loci undergoing de novo recombination exposes the collusive contributions of cellular stress responses to the evolving cancer genome.},
}
@article {pmid33446513,
year = {2021},
author = {Henslee, G and Williams, C and Liu, P and Bertuch, A},
title = {Identification and characterization of novel ACD variants: Modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.},
journal = {Cold Spring Harbor molecular case studies},
volume = {},
number = {},
pages = {},
doi = {10.1101/mcs.a005454},
pmid = {33446513},
issn = {2373-2873},
abstract = {Telomere biology disorders (TBDs), largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominant and autosomal recessive TBDs. TPP1 is responsible for recruitment of telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1): c.505_507delGAG, p.E169del; and c.619delG, p.D207Tfs*22; as well as a second proband with a heterozygous chromosomal deletion encompassing ACD: arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening. Further analysis of lymphoblastoid cell lines revealed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.D207Tfs*22, or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.},
}
@article {pmid33440881,
year = {2021},
author = {Lejawa, M and Osadnik, K and Osadnik, T and Pawlas, N},
title = {Association of Metabolically Healthy and Unhealthy Obesity Phenotypes with Oxidative Stress Parameters and Telomere Length in Healthy Young Adult Men. Analysis of the MAGNETIC Study.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {1},
pages = {},
pmid = {33440881},
issn = {2076-3921},
support = {UMO-2014113IBINZ5/03166//Narodowe Centrum Nauki/ ; KNW-1-039/N/8/K//Śląski Uniwersytet Medyczny/ ; },
abstract = {Obesity is a significant factor related to metabolic disturbances that can lead to metabolic syndrome (MetS). Metabolic dysregulation causes oxidative stress, which affects telomere structure. The current study aimed to evaluate the relationships between telomere length, oxidative stress and the metabolically healthy and unhealthy phenotypes in healthy young men. Ninety-eight participants were included in the study (49 healthy slim and 49 obese patients). Study participants were divided into three subgroups according to body mass index and metabolic health. Selected oxidative stress markers were measured in serum. Relative telomere length (rTL) was measured using quantitative polymerase chain reaction. The analysis showed associations between laboratory markers, oxidative stress markers and rTL in metabolically healthy and unhealthy participants. Total oxidation status (TOS), total antioxidant capacity (TAC) and rTL were significantly connected with metabolically unhealthy obesity. TAC was associated with metabolically healthy obesity. Telomeres shorten in patients with metabolic dysregulation related to oxidative stress and obesity linked to MetS. Further studies among young metabolically healthy and unhealthy individuals are needed to determine the pathways related to metabolic disturbances that cause oxidative stress that leads to MetS.},
}
@article {pmid33435578,
year = {2021},
author = {Sławińska, N and Krupa, R},
title = {Molecular Aspects of Senescence and Organismal Ageing-DNA Damage Response, Telomeres, Inflammation and Chromatin.},
journal = {International journal of molecular sciences},
volume = {22},
number = {2},
pages = {},
pmid = {33435578},
issn = {1422-0067},
abstract = {Cells can become senescent in response to stress. Senescence is a process characterised by a stable proliferative arrest. Sometimes it can be beneficial-for example, it can suppress tumour development or take part in tissue repair. On the other hand, studies show that it is also involved in the ageing process. DNA damage response (DDR) is triggered by DNA damage or telomere shortening during cell division. When left unresolved, it may lead to the activation of senescence. Senescent cells secrete certain proteins in larger quantities. This phenomenon is referred to as senescence-associated secretory phenotype (SASP). SASP can induce senescence in other cells; evidence suggests that overabundance of senescent cells contributes to ageing. SASP proteins include proinflammatory cytokines and metalloproteinases, which degrade the extracellular matrix. Shortening of telomeres is another feature associated with organismal ageing. Older organisms have shorter telomeres. Restoring telomerase activity in mice not only slowed but also partially reversed the symptoms of ageing. Changes in chromatin structure during senescence include heterochromatin formation or decondensation and loss of H1 histones. During organismal ageing, cells can experience heterochromatin loss, DNA demethylation and global histone loss. Cellular and organismal ageing are both complex processes with many aspects that are often related. The purpose of this review is to bring some of these aspects forward and provide details regarding them.},
}
@article {pmid33435482,
year = {2021},
author = {Selvaraju, V and Phillips, M and Fouty, A and Babu, JR and Geetha, T},
title = {Telomere Length as a Biomarker for Race-Related Health Disparities.},
journal = {Genes},
volume = {12},
number = {1},
pages = {},
pmid = {33435482},
issn = {2073-4425},
abstract = {Disparities between the races have been well documented in health and disease in the USA. Recent studies show that telomere length, a marker of aging, is associated with obesity and obesity-related diseases, such as heart disease and diabetes. The current study aimed to evaluate the connection between telomere length ratio, blood pressure, and childhood obesity. The telomere length ratio was measured in 127 children from both European American (EA) and African American (AA) children, aged 6-10 years old. AA children had a significantly high relative telomere to the single copy gene (T/S) ratio compared to EA children. There was no significant difference in the T/S ratio between normal weight (NW) and overweight/obese (OW/OB) groups of either race. Blood pressure was significantly elevated in AA children with respect to EA children. Hierarchical regression analysis adjusted for race, gender, and age expressed a significant relationship between the T/S ratio and diastolic pressure. Low T/S ratio participants showed a significant increase in systolic pressure, while a high T/S ratio group showed an increase in diastolic pressure and heart rate of AA children. In conclusion, our findings show that AA children have high T/S ratio compared to EA children. The high T/S ratio is negatively associated with diastolic pressure.},
}
@article {pmid33434830,
year = {2020},
author = {Lee, HH and Okuzono, SS and Kim, ES and De Vivo, I and Raffield, LM and Glover, L and Sims, M and Grodstein, F and Kubzansky, LD},
title = {Optimism and telomere length among African American adults in the Jackson Heart Study.},
journal = {Psychoneuroendocrinology},
volume = {125},
number = {},
pages = {105124},
doi = {10.1016/j.psyneuen.2020.105124},
pmid = {33434830},
issn = {1873-3360},
support = {R01 AG053273/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Optimism is linked with greater longevity in both White and African American populations. Optimism may enhance longevity by slowing cellular aging, for which leukocyte telomere shortening is a biomarker. However, limited studies have examined the association of optimism with leukocyte telomere length among African Americans.<br><br>METHODS: Data are from 723 men and 1244 women participating in the Jackson Heart Study (age = 21-93 years). We used multivariable linear regression models to conduct cross-sectional analyses examining whether higher optimism was associated with longer mean absolute leukocyte telomere length (assayed with Southern blot analysis). Models adjusted for sociodemographic characteristics, depressive symptomatology, health conditions, and health behavior-related factors. We also considered potential effect modification by key factors.<br><br>RESULTS: In the age-adjusted model, optimism, measured as a continuous variable, was not associated with leukocyte telomere length (β = 0.01, 95%CI: -0.02, 0.04). This association remained null in the fully-adjusted model (β = 0.02, 95%CI: -0.02, 0.05) and was also null when considering optimism as a binary measure (higher vs. lower optimism). We found no evidence of effect modification by sex, age, body mass index, income, or chronic conditions.<br><br>CONCLUSIONS: Optimism was not associated with leukocyte telomere length among African American adults. Future studies should investigate alternate biological and behavioral mechanisms that may explain the optimism-health association.},
}
@article {pmid33434042,
year = {2021},
author = {McCulloch, MJ and Ward Gauthier, NA and Vaillancourt, L},
title = {Use of telomere fingerprinting to identify clonal lineages of Colletotrichum fioriniae in Kentucky mixed-fruit orchards.},
journal = {Plant disease},
volume = {},
number = {},
pages = {},
doi = {10.1094/PDIS-08-20-1713-SC},
pmid = {33434042},
issn = {0191-2917},
abstract = {Multiple species in the fungal genus Colletotrichum cause anthracnose fruit rot diseases that are responsible for major yield losses of as much as 100%. Individual species of Colletotrichum typically have broad host ranges and can infect multiple fruit species. Colletotrichum fioriniae causes anthracnose fruit rots of apples, blueberries and strawberries in Kentucky orchards where these fruits grow in close proximity. This raises the possibility of cross-infection, which may have significant management implications. The potential occurrence of cross-infection was investigated by using telomere fingerprinting to identify C. fioriniae clones in several mixed-fruit orchards. Telomere fingerprints were highly polymorphic among a test group of C. fioriniae strains and effectively defined clonal lineages. Fingerprints were compared among apple, blueberry and strawberry isolates of C. fioriniae from three different orchards and similarity matrices were calculated to build phylograms for each orchard group. Multiple clonal lineages of C. fioriniae were identified within each orchard on the same fruit host. Related lineages were found among isolates from different hosts, but the results did not provide direct evidence for cross-infection of different fruit species by the same clones. Recovery of the same clonal lineages within orchards across multiple years suggested that local dispersal was important in pathogen population structure and that C. fioriniae strains persisted within orchards over time. Isolates from blueberry were less diverse than isolates from apple, perhaps related to more intensive anthracnose management protocols on apple versus blueberry. Telomere fingerprinting is a valuable tool for understanding population dynamics of Colletotrichum fruit rot fungi.},
}
@article {pmid33432658,
year = {2021},
author = {Lee, JS and La, J and Aziz, S and Dobrinskikh, E and Brownell, R and Jones, KD and Achtar-Zadeh, N and Green, G and Elicker, BM and Golden, JA and Matthay, MA and Kukreja, J and Schwartz, DA and Wolters, PJ},
title = {Molecular Markers of Telomere Dysfunction and Senescence are Common Findings in the Usual Interstitial Pneumonia Pattern of Lung Fibrosis.},
journal = {Histopathology},
volume = {},
number = {},
pages = {},
doi = {10.1111/his.14334},
pmid = {33432658},
issn = {1365-2559},
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a genetically-mediated, age-associated, progressive form of pulmonary fibrosis characterized pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (Non-IPF UIP) whose clinical course is similarly poor, suggesting common molecular drivers.<br><br>METHODS: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissue from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared.<br><br>RESULTS: Histopathologic changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, noncaseating granulomas, airway centered inflammation or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs compared to age-similar, unused donor, controls. Molecular markers of senescence (p16, p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localized expression of these proteins to AECII cells. The MUC5B promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients and MUC5B protein expression was similar in IPF and non-IPF UIP lungs.<br><br>CONCLUSIONS: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.},
}
@article {pmid33431974,
year = {2021},
author = {Evans, JR and Torres-Pérez, JV and Miletto Petrazzini, ME and Riley, R and Brennan, CH},
title = {Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio).},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {339},
pmid = {33431974},
issn = {2045-2322},
support = {RGP 0008/2017//Human Frontier Science Program/ ; RPG-2016-143//Leverhulme Trust/ ; Marie Sklodowska-Curie Action 750200//Horizon 2020 Framework Programme/ ; STARS@UNIPD-2019//MetaZeb/ ; },
abstract = {Individual differences in personality are associated with variation in healthy aging. Health behaviours are often cited as the likely explanation for this association; however, an underlying biological mechanism may also exist. Accelerated leukocyte telomere shortening is implicated in multiple age-related diseases and is associated with chronic activation of the hypothalamus-pituitary-adrenal (HPA) axis, providing a link between stress-related personality differences and adverse health outcomes. However, the effects of the HPA axis are tissue specific. Thus, leukocyte telomere length may not accurately reflect telomere length in disease-relevant tissues. Here, we examined the correlation between stress reactivity and telomere length in heart and brain tissue in young (6-9 month) and aging (18 month) zebrafish. Stress reactivity was assessed by tank diving and through gene expression. Telomere length was assessed using quantitative PCR. We show that aging zebrafish have shorter telomeres in both heart and brain. Telomere length was inversely related to stress reactivity in heart but not brain of aging individuals. These data support the hypotheses that an anxious predisposition contributes to accelerated telomere shortening in heart tissue, which may have important implications for our understanding of age-related heart disease, and that stress reactivity contributes to age-related telomere shortening in a tissue-specific manner.},
}
@article {pmid33431711,
year = {2021},
author = {Crocco, P and De Rango, F and Dato, S and Rose, G and Passarino, G},
title = {Telomere length as a function of age at population level parallels human survival curves.},
journal = {Aging},
volume = {13},
number = {1},
pages = {204-218},
pmid = {33431711},
issn = {1945-4589},
abstract = {Telomeres are subject to age related shortening which can be accelerated by oxidative stress and inflammation. Many studies have reported an inverse correlation between telomere length and survival, but such inverse correlation has not been always confirmed in different populations. We analyzed the trend of Leukocyte Telomere Length (LTL) as a function of age in a cohort of 516 subjects aged 65-106 years from Southern Italy. The trend of LTL obtained was quite similar to demographic survival curves reported with data of western societies. We observed a decrease of LTL after 70 years of age and then an increase after 92 years, in agreement with the sharp decrease of survival after 70 years of age and its increase after 90 years, due to the deceleration of mortality at old ages. Our data suggest that a generalized LTL attrition after 70 years of age, associated to organismal decline, affects most of the population. Such generalized attrition may exacerbate senescence in these subjects, predisposing them to high mortality risk. Conversely, the subjects with better physical conditions, experience a lower attrition and, consequently, a delayed senescence, contributing to the deceleration of mortality which has been observed among very old subjects in modern societies.},
}
@article {pmid33428591,
year = {2021},
author = {Sanchez-Vazquez, R and Guío-Carrión, A and Zapatero-Gaviria, A and Martínez, P and Blasco, MA},
title = {Shorter telomere lengths in patients with severe COVID-19 disease.},
journal = {Aging},
volume = {13},
number = {1},
pages = {1-15},
pmid = {33428591},
issn = {1945-4589},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*genetics ; COVID-19/diagnosis/drug therapy/*genetics ; Female ; Humans ; Male ; Middle Aged ; Risk Assessment ; Risk Factors ; Severity of Illness Index ; Telomere/*genetics ; *Telomere Shortening ; },
abstract = {The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.},
}
@article {pmid33422989,
year = {2021},
author = {Martens, DS and Van Der Stukken, C and Derom, C and Thiery, E and Bijnens, EM and Nawrot, TS},
title = {Newborn telomere length predicts later life telomere length: Tracking telomere length from birth to child- and adulthood.},
journal = {EBioMedicine},
volume = {63},
number = {},
pages = {103164},
doi = {10.1016/j.ebiom.2020.103164},
pmid = {33422989},
issn = {2352-3964},
abstract = {BACKGROUND: Telomere length (TL) is considered a biological marker of aging and may indicate age-related disease susceptibility. Adults and children show a fixed ranking and tracking of TL over time. However, the contribution of an individual's initial birth TL to their later life TL is unknown. We evaluated change and tracking of TL from birth to child- and adulthood.<br><br>METHODS: Telomere length at birth was measured using qPCR in two independent prospective birth cohorts. After a median follow-up period of 4 years in ENVIRONAGE (n = 273) we assessed leukocyte telomere length (LTL) and after 23 years in EFPTS (n = 164) buccal TL was assessed. Correlations and multivariable regression models were applied to study telomere tracking and determinants of TL change from birth onwards.<br><br>FINDINGS: In children, LTL at the age of 4 correlates with TL at the start of life both in cord blood (r = 0.71, P < 0.0001;) and placenta (r = 0.60, P < 0.0001) and was -11.2% and -33.1% shorter, respectively. In adulthood, buccal TL at the age of 23 correlates with placental TL (r = 0.46, P < 0.0001) and was -35.9% shorter. TL attrition was higher in individuals with longer birth TL. However, based on TL ranking, individuals do not tend to change dramatically from TL rank after 4 or 23 years of follow-up. Finally, longer maternal TL associates with lower telomere attrition in the next generation.<br><br>INTERPRETATION: The high prediction of newborn TL for later life TL, and stable TL ranking from birth onwards underscores the importance of understanding the initial setting of newborn TL and its significance for later life.<br><br>FUNDING: European Research Council (ERC-StG310898) and Flemish Scientific Fund (12X9620N).},
}
@article {pmid33422583,
year = {2021},
author = {Cheng, F and Luk, AO and Wu, H and Kp Lim, C and Carroll, L and Ht Tam, C and Fan, B and Yang, A and Sh Lau, E and Cw Ng, A and Man Lee, H and Chow, E and Kong, AP and Keech, AC and V Joglekar, M and Yee So, W and Jenkins, AJ and Cn Chan, J and Hardikar, AA and Cw Ma, R},
title = {Shortened Relative Leukocyte Telomere Length is Associated with All-cause Mortality in Type 2 Diabetes- Analysis from the Hong Kong Diabetes Register.},
journal = {Diabetes research and clinical practice},
volume = {},
number = {},
pages = {108649},
doi = {10.1016/j.diabres.2021.108649},
pmid = {33422583},
issn = {1872-8227},
abstract = {AIMS: Few studies have investigated the relationship between rLTL and mortality in patients with type 2 diabetes in a large prospective study, particularly in the Asian population. This study investigates the relationship between rLTL and the risk of death in Chinese patients with type 2 diabetes.<br><br>METHODS: Consecutive Chinese patients with type 2 diabetes (N=5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using a quantitative polymerase chain reaction. Mortality and clinical outcomes were obtained based on ICD-9 codes.<br><br>RESULTS: The mean (SD) age of the subjects was 57.5 (13.3) years and mean (SD) follow-up duration was 13.4 (5.5) years. Baseline rLTL was significantly shorter in the 1,925 subjects who subsequently died compared with the remaining subjects (4.3±1.2 vs. 4.7±1.2, P<0.001). Shorter rLTL was associated with a higher risk of mortality (HR: 1.19 (1.14-1.23), P<0.001), which remained significant after adjusting for traditional risk factors.<br><br>CONCLUSIONS: Shorter rLTL was significantly associated with an increased risk of all-cause and CVD mortality in patients with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for mortality risk in patients with type 2 diabetes.},
}
@article {pmid33413962,
year = {2021},
author = {Sethuram, R and Bazzi, AA and Salih, SM and Puscheck, EE},
title = {Peripheral lymphocyte telomere dysfunction: a valid surrogate marker for female fertility?.},
journal = {Fertility and sterility},
volume = {115},
number = {1},
pages = {85-86},
doi = {10.1016/j.fertnstert.2020.10.063},
pmid = {33413962},
issn = {1556-5653},
}
@article {pmid33413203,
year = {2021},
author = {Liu, X and Liu, X and Shi, Q and Fan, X and Qi, K},
title = {Association of telomere length and telomerase methylation with n-3 fatty acids in preschool children with obesity.},
journal = {BMC pediatrics},
volume = {21},
number = {1},
pages = {24},
pmid = {33413203},
issn = {1471-2431},
support = {2020-bjsekyjs//the Research Funds of Profession Quota Budget from Beijing Municipal Science and Technology Commission/ ; },
abstract = {BACKGROUND: Telomeres play a crucial role in cellular survival and its length is a predictor for onset of chronic non-communicable diseases. Studies on association between telomeres and obesity in children have brought discrepant results and the underlying mechanisms and influential factors are to be elucidated. This study aimed to investigate changes in telomere length and telomerase reverse transcriptase (TERT) DNA methylation, and further to determine their correlation with n-3 polyunsaturated fatty acids (PUFAs) in preschool children with obesity.<br><br>METHODS: Forty-six preschool children with obesity aged 3 to 4 years were included in the study, with equal numbers of age- and gender-matched children with normal weight as control. Leukocyte telomere length was determined by the ratio of telomeric product and single copy gene obtained using real-time qPCR. DNA methylation of TERT promoter was analyzed by bisulfite sequencing. Fatty acids in erythrocytes were measured by gas chromatography with a total of 15 fatty acids analyzed. The total saturated fatty acids (SFAs), total n-6 PUFAs, total n-3 PUFAs, and the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA) were calculated. Then the correlation between leukocyte telomere length, TERT promoter methylation and fatty acids was determined.<br><br>RESULTS: In preschool children with obesity, leukocyte telomeres were shortened and had a negative association with the body mass index. The methylated fractions in 13 of 25 CpG sites in the TERT promoter were increased by approximately 3 to 35% in the children with obesity compared to the normal weight children. Erythrocyte lauric acid and total SFAs, lenoleic acid and total n-6 PUFAs were higher, and DHA was lower in the children with obesity than those in the children with normal weight. Correlative analysis showed that leukocyte telomere length had a positive association with total SFAs and DHA, and a negative association with the AA/DHA ratio. However, no association between erythrocyte DHA and the TERT promoter methylation was found.<br><br>CONCLUSION: These data indicate that the reduced body DHA content and increased AA/DHA ratio may be associated with shortened leukocyte telomeres in child obesity, which is probably not involved in the TERT promoter methylation.},
}
@article {pmid33407441,
year = {2021},
author = {Kalungi, A and Kinyanda, E and Womersley, JS and Joloba, ML and Ssembajjwe, W and Nsubuga, RN and Kaleebu, P and Levin, J and Kidd, M and Seedat, S and Hemmings, SMJ},
title = {TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda.},
journal = {BMC medical genomics},
volume = {14},
number = {1},
pages = {15},
pmid = {33407441},
issn = {1755-8794},
support = {MR/L004623/1//MRC/DfID African Research Leader Award/ ; 50288/N7145//Alliance for Global Health and Science of the Center for Emerging and Neglected Diseases/ ; Project ID: P151847, IDA Number:5797-UG//Africa Center of Excellence in Materials, Product Development and Nanotechnology/ ; },
abstract = {BACKGROUND: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years).<br><br>RESULTS: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months.<br><br>CONCLUSIONS: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.},
}
@article {pmid33406938,
year = {2021},
author = {Godhamgaonkar, AA and Sundrani, DP and Joshi, SR},
title = {Role of maternal nutrition and oxidative stress in placental telomere attrition in women with preeclampsia.},
journal = {Hypertension in pregnancy},
volume = {40},
number = {1},
pages = {63-74},
doi = {10.1080/10641955.2020.1869248},
pmid = {33406938},
issn = {1525-6065},
abstract = {Background:Maternal nutrition influences the growth and development of the fetus and influences pregnancy outcome. We have earlier demonstrated altered maternal nutrition and increased oxidative stress in women with preeclampsia. Oxidative stress is known to be associated with reduced telomere length and short telomere aggregates. Increased telomere attrition leads to increased cellular senescence and tissue ageing. Methods:The present review focuses on the role of maternal nutrition and oxidative stress in telomere attrition in preeclampsia. Results and Conclusion:Future studies need to examine the association between maternal nutritional status in early pregnancy, oxidative stress and telomere attrition in preeclampsia.},
}
@article {pmid33406566,
year = {2020},
author = {Fan, YL and Ye, Q},
title = {[A concise review of telomere and telomerase-related genetic markers in fibrotic lung diseases].},
journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases},
volume = {38},
number = {12},
pages = {952-956},
doi = {10.3760/cma.j.cn121094-20200305-00104},
pmid = {33406566},
issn = {1001-9391},
support = {81970061//National Natural Science Foundation of China/ ; 2015ZX09J15104//National Major Scientific and Technological Special Project for Significant New Drugs Development/ ; },
mesh = {Aged ; Genetic Markers ; Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; *Telomerase/genetics ; Telomere/genetics ; Telomere Shortening ; },
abstract = {Fibrotic lung diseases are a heterogeneous group of diffuse parenchymal lung diseases caused by various factors. Pulmonary fibrosis is one of the common pathological changes of advanced fibrotic lung diseases. Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disorder with unknown etiology. IPF mainly affects the elderly that is considered as an aging related disease. Telomeres are specialized structures at the ends of chromosomes. Telomere shortening results in cellular senescence or apoptosis. Telomerase is a ribonucleoprotein complex that maintains telomere length and genome stability. The telomere shortening and mutations in telomere-related genes are associated with incidence and prognosis of pulmonary fibrosis. Here, a concise review of telomere and telomerase-related genomic markers in IPF and other fibrotic lung diseases is written.},
}
@article {pmid33401959,
year = {2021},
author = {Elmadawy, MA and Abdullah, OA and El Gazzar, WB and Ahmad, ES and Ameen, SG and Abdelkader, A},
title = {Telomere length and signal joint T-cell receptor rearrangement excision circles as biomarkers for chronological age estimation.},
journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/1354750X.2020.1871412},
pmid = {33401959},
issn = {1366-5804},
abstract = {BACKGROUND: Chronological age estimation is a challenging marker in the field of forensic medicine. The current study aimed to investigate the accuracy of signal joint T-cell receptor rearrangement excision circles (sjTRECs) quantification and telomere length measurement as methods for estimating chronological age.<br><br>METHODS: Telomere length was estimated in the DNA derived from the buccal cells through estimating the telomeric restriction fragment (TRF) length using TeloTTAGGG Telomere Length Assay while the sjTRECs quantification was carried out on DNA isolated from the blood samples using qPCR.<br><br>RESULTS: The TRF length was shortened with increased age (r = -0.722, p < 0.001). The sjTRECs were also decreased with increased age (r = -0.831, p < 0.001). Stronger coefficient and lower standard error of the estimate was obtained when multiple regression analysis for age prediction based on the values of both methods was applied (r = -0.876, p < 0.001).},
}
@article {pmid33397920,
year = {2021},
author = {Viswanath, P and Batsios, G and Mukherjee, J and Gillespie, AM and Larson, PEZ and Luchman, HA and Phillips, JJ and Costello, JF and Pieper, RO and Ronen, SM},
title = {Non-invasive assessment of telomere maintenance mechanisms in brain tumors.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {92},
pmid = {33397920},
issn = {2041-1723},
support = {R01 CA239288/CA/NCI NIH HHS/United States ; R01 NS105087/NS/NINDS NIH HHS/United States ; P01 CA118816/CA/NCI NIH HHS/United States ; R01 CA197254/CA/NCI NIH HHS/United States ; R01 CA172845/CA/NCI NIH HHS/United States ; P41 EB013598/EB/NIBIB NIH HHS/United States ; },
mesh = {Alanine/metabolism ; Animals ; Biomarkers, Tumor/metabolism ; Brain Neoplasms/*genetics/metabolism/pathology ; Carbon Isotopes/metabolism ; Cell Line, Tumor ; Genetic Engineering ; Glioma/genetics/metabolism/pathology ; Lactic Acid/metabolism ; Male ; Metabolome ; Models, Biological ; Neoplasm Grading ; Neoplasm Proteins/metabolism ; Proton Magnetic Resonance Spectroscopy ; Pyruvic Acid/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Nude ; Telomerase/genetics/metabolism ; Telomere/*metabolism ; *Telomere Homeostasis ; Xenograft Model Antitumor Assays ; },
abstract = {Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique 1H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-13C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-13C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.},
}
@article {pmid33397445,
year = {2021},
author = {Starnino, L and Dupuis, G and Busque, L and Bourgoin, V and Dubé, MP and Busseuil, D and D'Antono, B},
title = {The associations of hostility and defensiveness with telomere length are influenced by sex and health status.},
journal = {Biology of sex differences},
volume = {12},
number = {1},
pages = {2},
pmid = {33397445},
issn = {2042-6410},
support = {#111015/CAPMC/CIHR/Canada ; },
abstract = {BACKGROUND: Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex.<br><br>METHODS: One thousand thirty-six individuals (Mage = 65.40 ± 6.73 years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook-Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants.<br><br>RESULTS: A hostility by sex interaction emerged (β = - .08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (β = - .06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (β = .52, p = .006) but lower hostility (β = - .43, p = .049).<br><br>CONCLUSION: Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.},
}
@article {pmid33395949,
year = {2021},
author = {Li, X and Liu, J and Zhou, G and Sang, Y and Zhang, Y and Jing, L and Shi, Z and Zhou, X and Sun, Z},
title = {BDE-209 and DBDPE induce male reproductive toxicity through telomere-related cell senescence and apoptosis in SD rat.},
journal = {Environment international},
volume = {146},
number = {},
pages = {106307},
doi = {10.1016/j.envint.2020.106307},
pmid = {33395949},
issn = {1873-6750},
abstract = {Decabrominated diphenyl ether (BDE-209) and decabromodiphenyl ethane (DBDPE) are common flame retardants utilized in many kinds of electronic and textile products. Due to their persistence and bioaccumulation, BDE-209 and DBDPE extensively exist in the surrounding environment and wild animals. Previous studies have indicated that BDE-209 could induce male reproductive toxicity, whereas those of DBDPE remains relatively rare. In this study, we investigated the effects of both BDE-209 and DBDPE on reproductive system in male SD rats, and explored the potential mechanisms under the reproductive toxicity of BDE-209 and DBDPE. Male rats were orally administered with BDE-209 and DBDPE (0, 5, 50 and 500 mg/kg/day) for a 28-day exposure experiment. The current results showed that BDE-209 and DBDPE led to testicular damage in physiological structure, decreased the sperm number and motility, and increased the sperm malformation rates in rat. Moreover, BDE-209 and DBDPE could damage the telomeric function by shortening telomere length and reducing telomerase activity, which consequently caused cell senescence and apoptosis in testis of rat. This could contribute to the decline of sperm quality and quantity. In conclusion, BDE-209 and DBDPE led to reproductive toxicity by inducing telomere dysfunction and the related cell senescence and apoptosis in testis of SD rat. Comparatively, BDE-209 had more severe effects on male reproduction. Our findings may provide new insight into the potential deleterious effects of BFRs on male reproductive health.},
}
@article {pmid33394227,
year = {2021},
author = {Shah, A and George, M and Dhangar, S and Rajendran, A and Mohan, S and Vundinti, BR},
title = {Severe telomere shortening in Fanconi anemia complementation group L.},
journal = {Molecular biology reports},
volume = {48},
number = {1},
pages = {585-593},
pmid = {33394227},
issn = {1573-4978},
support = {EEQ/2016/000510;B.R.V.//Department of Science and Technology, Government of India(IN)/ ; },
abstract = {Fanconi Anemia (FA) is a rare genetic disease with the incidence of 1 in 360,000 and is characterised by bone marrow failure, physical abnormalities, pancytopenia, and high frequency of chromosomal breakage and increased risk of evolving into malignancy. Telomere plays an important role in genomic stability, ageing process and cancers. Telomere shortening has been reported in FA. We studied telomere length in FA subjects and compared with complementation groups. Chromosomal breakage analysis from PHA stimulated, MMC induced peripheral blood culture was carried out in 37 clinically diagnosed FA. Molecular study of FANCA, G, and L was done through Sanger sequencing and next generation sequencing. Telomere length was estimated using real time quantitative polymerase chain reaction (qPCR) method. Student t-test was applied to test the significance. A high frequency of chromosomal breakage was observed in all the patients compared to healthy controls. We found significantly shorter telomere length in all the three complementation groups compare to age matched healthy controls. Among all complementation groups, FANCL showed severe telomere shortening (P value 0.0001). A negative correlation was observed between telomere length and chromosomal breakage frequency (R = -0.3116). Telomere shortening is not uncommon in FA subjects. However the telomere length shortening is different in complementation groups as FANCL showed severe telomere shortening in FA subjects. Though BM transplantation is essential for the management of the FA subjects, the telomere length can be considered as biological marker to understand the prognosis of the disease as FA subjects primarily treated with androgens.},
}
@article {pmid33393836,
year = {2021},
author = {Mizuno, Y and Konishi, S and Goto, C and Yoshinaga, J and Hidaka, M and Imai, H},
title = {Association between nutrient intake and telomere length in Japanese female university students.},
journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/1354750X.2020.1871409},
pmid = {33393836},
issn = {1366-5804},
abstract = {OBJECTIVE: Telomere length can be a biomarker of cumulative oxidative stress and inflammation indicating biological aging. Previous studies examined association of nutrient intake with telomere length targeting middle-aged and elderly individuals. This study examined whether dietary macro- and micronutrient intake was associated with telomere length in young females.<br><br>METHODS: Seventy-four Japanese young females (median (interquartile range) age was 19 (19 - 20) years) participated. We estimated their intake of nutrients (energy, protein, fat, carbohydrate, essential elements, vitamins, fatty acids, and dietary fibre) using a semi-quantitative food frequency questionnaire and measured telomere length (T/S ratio, the ratio of telomere repeat copy number (T) to single-copy gene number (S)) of DNA extracted from blood by qPCR. The association between telomere length and tertiles of nutrient intake were analysed.<br><br>RESULTS: The median (interquartile range) of telomere length was 0.70 (0.52 - 0.98). Vitamin A intake was positively associated with telomere length (tertile 1 vs. 2, coefficient [95% confidence interval] = 0.42 [0.12, 0.71]; tertile 1 vs. 3, coefficient [95% confidence interval] = 0.33 [0.04, 0.62]) after adjusting for covariates (age, BMI, passive smoking, and drinking).<br><br>CONCLUSIONS: Our findings suggest that variation in vitamin A intake might influence telomere attrition in healthy individuals.},
}
@article {pmid33393513,
year = {2021},
author = {Begus-Nahrmann, Y and Hartmann, D and Kraus, J and Eshraghi, P and Scheffold, A and Grieb, M and Rasche, V and Schirmacher, P and Lee, HW and Kestler, HA and Lechel, A and Rudolph, KL},
title = {Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis.},
journal = {The Journal of clinical investigation},
volume = {131},
number = {1},
pages = {},
doi = {10.1172/JCI145852},
pmid = {33393513},
issn = {1558-8238},
}
@article {pmid33391781,
year = {2020},
author = {Remot, F and Ronget, V and Froy, H and Rey, B and Gaillard, JM and Nussey, DH and Lemaître, JF},
title = {No sex differences in adult telomere length across vertebrates: a meta-analysis.},
journal = {Royal Society open science},
volume = {7},
number = {11},
pages = {200548},
pmid = {33391781},
issn = {2054-5703},
abstract = {In many mammalian species, females live on average longer than males. In humans, women have consistently longer telomeres than men, and this has led to speculation that sex differences in telomere length (TL) could play a role in sex differences in longevity. To address the generality and drivers of patterns of sex differences in TL across vertebrates, we performed meta-analyses across 51 species. We tested two main evolutionary hypotheses proposed to explain sex differences in TL, namely the heterogametic sex disadvantage and the sexual selection hypotheses. We found no support for consistent sex differences in TL between males and females among mammal, bird, fish and reptile species. This absence of sex differences in TL across different classes of vertebrates does not support the heterogametic sex disadvantage hypothesis. Likewise, the absence of any negative effect of sexual size dimorphism on male TL suggests that sexual selection is not likely to mediate the magnitude of sex differences in TL across vertebrates. Finally, the comparative analyses we conducted did not detect any association between sex differences in TL and sex differences in longevity, which does not support the idea that sex differences in TL could explain the observed sex differences in longevity.},
}
@article {pmid33389530,
year = {2021},
author = {Goswami, A and Huda, N and Yasmin, T and Hosen, MI and Hasan, AKMM and Nabi, AHMN},
title = {Association study of leukocyte telomere length and genetic polymorphism within hTERT promoter with type 2 diabetes in Bangladeshi population.},
journal = {Molecular biology reports},
volume = {48},
number = {1},
pages = {285-295},
pmid = {33389530},
issn = {1573-4978},
support = {15-167 RG/BIO/AS_G - FR3240287016//The World Academy of Sciences/ ; },
abstract = {Telomeres are protective cap on the ends of DNA of non-coding tandem repeats of TTAGGG. Human telomerase reverse transcriptase (hTERT) is a catalytic subunit of telomerase that maintains the structure of telomeres. Type 2 diabetes (T2D) affects multi-organ and telomere length by altering telomerase activity. We aimed to evaluate the relative telomere length (RTL) and risk association of rs2853669 with T2D in Bangladeshi population. RTL was measured in 408 unrelated Bangladeshi (224 T2D and 184 healthy) using primers for target gene and reference gene albumin. Genotypic frequencies for rs2853669 were determined using TaqMan® probes. The mean level of age adjusted RTL (AARTL) varied significantly between the healthy and individuals with T2D for all the genotypes with respect to rs2853669. Moreover, healthy individuals had significantly higher AARTL than T2D. Similar findings were observed when study participants were stratified based on their gender. Association studies revealed that under codominant model of inheritance, TC genotype showed protective role against development of type 2 diabetes. This study suggests a possible role of telomere biology in T2DM, but their association needs to be evaluated further with a larger series and matched healthy controls.},
}
@article {pmid33388564,
year = {2021},
author = {Hautekiet, P and Nawrot, TS and Janssen, BG and Martens, DS and De Clercq, EM and Dadvand, P and Plusquin, M and Bijnens, EM and Saenen, ND},
title = {Child buccal telomere length and mitochondrial DNA content as biomolecular markers of ageing in association with air pollution.},
journal = {Environment international},
volume = {147},
number = {},
pages = {106332},
doi = {10.1016/j.envint.2020.106332},
pmid = {33388564},
issn = {1873-6750},
abstract = {BACKGROUND: Pro-inflammatory conditions such as air pollution might induce biological ageing. However, the available evidence on such an impact in children is still very scarce. We studied in primary schoolchildren the association of ambient residential air pollution exposure with telomere length (TL) and mitochondrial DNA content (mtDNAc), two important targets of the core axis of ageing.<br><br>METHODS: Between 2012 and 2014, buccal TL and mtDNAc were repeatedly assessed using qPCR in 197 Belgian primary schoolchildren (mean age 10.3 years) as part of the COGNAC study. At the child's residence, recent (week), sub-chronic (month) and chronic (year) exposure to nitrogen dioxide (NO2), particulate matter ≤ 2.5 µm (PM2.5) and black carbon (BC) were estimated using a high resolution spatiotemporal model. A mixed-effects model with school and subject as random effect was used while adjusting for a priori chosen covariates.<br><br>RESULTS: An interquartile range (IQR) increment (1.9 µg/m3) in chronic PM2.5 exposure was associated with a 8.9% (95% CI: -15.4 to -1.9%) shorter TL. In contrast to PM2.5, chronic exposure to BC and NO2 was not associated with TL but recent exposure to BC and NO2 showed significant inverse associations with TL: an IQR increment in recent exposure to BC (0.9 µg/m3) and NO2 (10.2 µg/m3) was associated with a 6.2% (95% CI: -10.6 to -1.6%) and 6.4% (95% CI: -11.8 to -0.7%) shorter TL, respectively. Finally, an IQR increment in chronic PM2.5 exposure was associated with a 12.7% (95% CI: -21.7 to -2.6%) lower mtDNAc. However, no significant associations were seen for NO2 and BC or for other exposure windows.<br><br>CONCLUSION: Chronic exposure to PM2.5 below the EU threshold was associated with child's shorter buccal TL and lower mtDNAc, while traffic-related pollutants (BC and NO2) showed recent effects on telomere biology. Our data add to the literature on air pollution-induced effects of TL and mtDNAc, two measures part of the core axis of cellular ageing, from early life onwards.},
}
@article {pmid33387607,
year = {2020},
author = {Aguiar, SS and Sousa, CV and Santos, PA and Barbosa, LP and Maciel, LA and Coelho-Júnior, HJ and Motta-Santos, D and Rosa, TS and Degens, H and Simões, HG},
title = {Master athletes have longer telomeres than age-matched non-athletes. A systematic review, meta-analysis and discussion of possible mechanisms.},
journal = {Experimental gerontology},
volume = {146},
number = {},
pages = {111212},
doi = {10.1016/j.exger.2020.111212},
pmid = {33387607},
issn = {1873-6815},
abstract = {The aim of this systematic review and meta-analysis was 1) to assess whether master athletes have longer telomeres than age-matched non-athletes and 2) discuss possible underlying mechanisms underlying telomere length preservation in master athletes. A literature search was performed in PubMed, Web of Science, Scopus and SPORTDiscus up to August 2020. Only original articles published in peer-reviewed journals that compared telomere length between master athletes and aged-matched non-athletes were included. Eleven studies fulfilled eligibility criteria and were included in the final analysis. Overall, 240 master athletes (51.9±7.5 years) and 209 age-matched non-athletes (50.1±9.1 years) were analyzed. Master athletes had been participating in high-level competitions for approximately 16.6 years. Pooled analyses revealed that master athletes had longer telomeres than aged-matched non-athletes (SMD=0.89; 95% CI=0.45 to 1.33; p<0.001). Master athletes showed lower pro-oxidant damage (SMD=0.59; 95% CI=0.26 to 0.91; p<0.001) and higher antioxidant capacity (SMD=-0.46; 95% CI=-0.89 to -0.03; p=0.04) than age-matched non-athletes. Further, greater telomere length in master athletes is associated with lower oxidative stress and chronic inflammation, and enhanced shelterin protein expression and telomerase activity. In conclusion, 1) master athletes have longer telomeres than age-matched non-athletes, which may be the result of 2) lower levels of oxidative stress and chronic inflammation, and elevated shelterin expression and telomerase activity.},
}
@article {pmid33384420,
year = {2020},
author = {Fransson, S and Martinez-Monleon, A and Johansson, M and Sjöberg, RM and Björklund, C and Ljungman, G and Ek, T and Kogner, P and Martinsson, T},
title = {Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {22432},
pmid = {33384420},
issn = {2045-2322},
abstract = {Neuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.},
}
@article {pmid33377991,
year = {2021},
author = {Salas-Huetos, A and Tüttelmann, F and Wyrwoll, MJ and Kliesch, S and Lopes, AM and Gonçalves, J and Boyden, SE and Wöste, M and Hotaling, JM and , and Nagirnaja, L and Conrad, DF and Carrell, DT and Aston, KI},
title = {Correction to: Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.},
journal = {Human genetics},
volume = {140},
number = {1},
pages = {229},
doi = {10.1007/s00439-020-02244-1},
pmid = {33377991},
issn = {1432-1203},
}
@article {pmid33371776,
year = {2020},
author = {Yu, YL and Liu, H},
title = {Marital Quality and Salivary Telomere Length Among Older Men and Women in the United States.},
journal = {Journal of aging and health},
volume = {},
number = {},
pages = {898264320980250},
doi = {10.1177/0898264320980250},
pmid = {33371776},
issn = {1552-6887},
abstract = {Objective: The link between marital quality and cellular aging remains underexplored. This study examined how both positive and negative marital quality were associated with salivary telomere length among partnered adults in the United States over the age of 50°years. Methods: Data were from the 2008 Health and Retirement Study (N = 3203). Ordinary least squares regression was used to estimate the link between marital quality and telomere length. Results: While neither positive nor negative marital quality was significantly associated with telomere length among older women, positive and negative marital quality had an interacting effect on telomere length among men. Specifically, when negative marital quality was low, higher positive marital quality was associated with shorter telomere length, whereas when negative marital quality was high, higher positive marital quality was associated with longer telomere length. Discussion: The findings speak to the complex nature of intimate partnerships and the implications of these partnerships for cellular aging processes.},
}
@article {pmid33371195,
year = {2020},
author = {Perona, R},
title = {The Different Roads to Maintain Telomeres in Cancer Cells.},
journal = {Genes},
volume = {11},
number = {12},
pages = {},
pmid = {33371195},
issn = {2073-4425},
abstract = {Telomeres are the protective structures at the ends of linear chromosomes that progressively shorten each time that a cell divides, which is in part caused by the end-replication problem [...].},
}
@article {pmid33370275,
year = {2020},
author = {Wagner, T and Pérez-Martínez, L and Schellhaas, R and Barrientos-Moreno, M and Öztürk, M and Prado, F and Butter, F and Luke, B},
title = {Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence.},
journal = {PLoS genetics},
volume = {16},
number = {12},
pages = {e1008603},
pmid = {33370275},
issn = {1553-7404},
mesh = {*DNA Replication ; Histone Deacetylases/genetics/*metabolism ; Methyltransferases/genetics/*metabolism ; Rad51 Recombinase/genetics/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics/metabolism ; Repressor Proteins/genetics/*metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/*metabolism ; Sirtuin 2/genetics/*metabolism ; Telomere/chemistry/*genetics ; Telomere Homeostasis ; },
abstract = {Telomeres have the ability to adopt a lariat conformation and hence, engage in long and short distance intra-chromosome interactions. Budding yeast telomeres were proposed to fold back into subtelomeric regions, but a robust assay to quantitatively characterize this structure has been lacking. Therefore, it is not well understood how the interactions between telomeres and non-telomeric regions are established and regulated. We employ a telomere chromosome conformation capture (Telo-3C) approach to directly analyze telomere folding and its maintenance in S. cerevisiae. We identify the histone modifiers Sir2, Sin3 and Set2 as critical regulators for telomere folding, which suggests that a distinct telomeric chromatin environment is a major requirement for the folding of yeast telomeres. We demonstrate that telomeres are not folded when cells enter replicative senescence, which occurs independently of short telomere length. Indeed, Sir2, Sin3 and Set2 protein levels are decreased during senescence and their absence may thereby prevent telomere folding. Additionally, we show that the homologous recombination machinery, including the Rad51 and Rad52 proteins, as well as the checkpoint component Rad53 are essential for establishing the telomere fold-back structure. This study outlines a method to interrogate telomere-subtelomere interactions at a single unmodified yeast telomere. Using this method, we provide insights into how the spatial arrangement of the chromosome end structure is established and demonstrate that telomere folding is compromised throughout replicative senescence.},
}
@article {pmid33367858,
year = {2020},
author = {Kroupa, M and Rachakonda, S and Vymetalkova, V and Tomasova, K and Liska, V and Vodenkova, S and Cumova, A and Rossnerova, A and Vodickova, L and Hemminki, K and Soucek, P and Kumar, R and Vodicka, P},
title = {Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients.},
journal = {Mutagenesis},
volume = {35},
number = {6},
pages = {491-497},
doi = {10.1093/mutage/geaa030},
pmid = {33367858},
issn = {1464-3804},
abstract = {Disruption of telomere length (TL) homeostasis in peripheral blood lymphocytes has been previously assessed as a potential biomarker of breast cancer (BC) risk. The present study addressed the relationship between lymphocyte TL (LTL), prognosis and clinicopathological features in the BC patients since these associations are insufficiently explored at present. LTL was measured in 611 BC patients and 154 healthy controls using the monochrome multiplex quantitative Polymerase Chain Reaction assay. In addition, we genotyped nine TL-associated single-nucleotide polymorphisms that had been identified through genome-wide association studies. Our results showed that the patients had significantly (P = 0.001, Mann-Whitney U-test) longer LTL [median (interquartile range); 1.48 (1.22-1.78)] than the healthy controls [1.27 (0.97-1.82)]. Patients homozygous (CC) for the common allele of hTERT rs2736108 or the variant allele (CC) of hTERC rs16847897 had longer LTL. The latter association remained statistically significant in the recessive genetic model after the Bonferroni correction (P = 0.004, Wilcoxon two-sample test). We observed no association between LTL and overall survival or relapse-free survival of the patients. LTL did not correlate with cancer staging based on Union for International Cancer Control (UICC), The tumor node metastasis (TNM) staging system classification, tumour grade or molecular BC subtypes. Overall, we observed an association between long LTL and BC disease and an association of the hTERC rs16847897 CC genotype with increased LTL. However, no association between LTL, clinicopathological features and survival of the patients was found.},
}
@article {pmid33367599,
year = {2020},
author = {Pudas, S and Josefsson, M and Nordin Adolfsson, A and Landfors, M and Kauppi, K and Veng-Taasti, LM and Hultdin, M and Adolfsson, R and Degerman, S},
title = {Short leukocyte telomeres, but not telomere attrition rates, predict memory decline in the 20-year longitudinal Betula study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaa322},
pmid = {33367599},
issn = {1758-535X},
abstract = {Leukocyte telomere length (LTL) is a proposed biomarker for aging-related disorders, including cognitive decline and dementia. Long-term longitudinal studies measuring intra-individual changes in both LTL and cognitive outcomes are scarce, precluding strong conclusions about a potential aging-related relationship between LTL shortening and cognitive decline. This study investigated associations between baseline levels and longitudinal changes in LTL and memory performance across an up to 20-year follow-up in 880 dementia-free participants from a population-based study (mean baseline age: 56.8 years, range: 40-80; 52% female). Shorter baseline LTL significantly predicted subsequent memory decline (r=0.34, 95% CI: 0.06, 0.82), controlling for age, sex, and other relevant covariates. No significant associations were however observed between intra-individual changes in LTL and memory, neither concurrently nor with a 5-year time-lag between LTL shortening and memory decline. These results support the notion of short LTL as a predictive factor for aging-related memory decline, but suggest that LTL dynamics in adulthood and older age may be less informative of cognitive outcomes in aging. Furthermore, the results highlight the importance of long-term longitudinal evaluation of outcomes in biomarker research.},
}
@article {pmid33367550,
year = {2020},
author = {Gadalla, SM},
title = {Telomere length in hematopoietic cell transplant.},
journal = {Blood},
volume = {136},
number = {26},
pages = {2972-2973},
pmid = {33367550},
issn = {1528-0020},
}
@article {pmid33367544,
year = {2020},
author = {Myllymäki, M and Redd, R and Reilly, CR and Saber, W and Spellman, SR and Gibson, CJ and Hu, ZH and Wang, T and Orr, EH and Grenier, JG and Chen, MM and Steensma, DP and Cutler, C and De Vivo, I and Antin, JH and Neuberg, D and Agarwal, S and Lindsley, RC},
title = {Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome.},
journal = {Blood},
volume = {136},
number = {26},
pages = {3070-3081},
pmid = {33367544},
issn = {1528-0020},
abstract = {Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.},
}
@article {pmid33358512,
year = {2020},
author = {Tomos, I and Karakatsani, A and Manali, ED and Kottaridi, C and Spathis, A and Argentos, S and Papiris, SA},
title = {Telomere length across different UIP fibrotic-Interstitial Lung Diseases: a prospective Greek case-control study.},
journal = {Pulmonology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pulmoe.2020.11.005},
pmid = {33358512},
issn = {2531-0437},
abstract = {INTRODUCTION: Short telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE).<br><br>AIM AND METHODS: TL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls.<br><br>RESULTS: Seventy-nine individuals were included (mean age 69.77 ± 0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (±0.05) vs 2.26 (±0.36), p < 0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p = 0.029). Patients with IPF and shorter than the median TL (0-0.72) showed reduced overall survival (p = 0.004). T/S < 0.72 was associated with increased risk for IPF-AE (OR = 30.787, 95% CI: 2.153, 440.183, p = 0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR = 0.174, 95%CI: 0.036, 0.846, p = 0.030) and IPF patients (HR = 0.096, 95%CI: 0.011, 0.849, p = 0.035).<br><br>CONCLUSIONS: Shorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.},
}
@article {pmid33357657,
year = {2020},
author = {Gupta, MD and Miglani, M and Bansal, A and Jain, V and Arora, S and Kumar, S and Virani, SS and Kalra, A and Yadav, R and Pasha, Q and Yusuf, J and Mukhopadhyay, S and Tyagi, S and Girish, MP},
title = {Telomere length in young patients with acute myocardial infarction without conventional risk factors: A pilot study from a South Asian population.},
journal = {Indian heart journal},
volume = {72},
number = {6},
pages = {619-622},
pmid = {33357657},
issn = {2213-3763},
abstract = {BACKGROUND: There is need to identify novel markers that lead to an early occurrence of myocardial infarction (MI) in young South Asian population. This population has different risk profile as compared with others. Telomere length is known to be a marker of aging, and shorter telomeres have been reported in cardiovascular diseases (CVDs). We aimed to identify the association of telomere length in young nonsmokers and non-diabetic MI patients.<br><br>METHODS: In a case-control study of 154 subjects (n = 77 cases (ages 18-45 years, non-diabetic, non-smoker patients with MI) and n = 77, age and sex matched healthy controls), DNA extraction from peripheral blood leukocytes was carried out and the relative telomere length was estimated by quantitative PCR. The results were adjusted with various demographic parameters like age, gender and body mass index (BMI). The correlation studies were carried out between telomere length, sex and type of MI.<br><br>RESULTS: The relative telomere length was significantly shorter in young MI patients (31-45 years) compared with matched healthy controls (p < 0.0001). Interestingly, in a gender-based comparison, the female patients had shorter telomere length (p < 0.01).<br><br>CONCLUSION: In this pilot study, we found that the telomere length was shorter among young, non-diabetic, non-smoker MI patients as compared with similar young controls without MI in a South Asian cohort. Thus, telomere length may be a potential screening tool for young patients who don't have conventional risk factors. Larger studies are needed to confirm these findings.},
}
@article {pmid33357405,
year = {2020},
author = {Le, R and Huang, Y and Zhang, Y and Wang, H and Lin, J and Dong, Y and Li, Z and Guo, M and Kou, X and Zhao, Y and Chen, M and Zhu, Q and Zhao, A and Yin, J and Sun, J and Su, Z and Shi, K and Gao, Y and Chen, J and Liu, W and Kang, L and Wang, Y and Li, C and Liu, X and Gao, R and Wang, H and Ju, Z and Gao, S},
title = {Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells.},
journal = {Cell stem cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.stem.2020.11.018},
pmid = {33357405},
issn = {1875-9777},
abstract = {Telomeres play vital roles in ensuring chromosome stability and are thus closely linked with the onset of aging and human disease. Telomeres undergo extensive lengthening during early embryogenesis. However, the detailed molecular mechanism of telomere resetting in early embryos remains unknown. Here, we show that Dcaf11 (Ddb1- and Cul4-associated factor 11) participates in telomere elongation in early embryos and 2-cell-like embryonic stem cells (ESCs). The deletion of Dcaf11 in embryos and ESCs leads to reduced telomere sister-chromatid exchange (T-SCE) and impairs telomere lengthening. Importantly, Dcaf11-deficient mice exhibit gradual telomere erosion with successive generations, and hematopoietic stem cell (HSC) activity is also greatly compromised. Mechanistically, Dcaf11 targets Kap1 (KRAB-associated protein 1) for ubiquitination-mediated degradation, leading to the activation of Zscan4 downstream enhancer and the removal of heterochromatic H3K9me3 at telomere/subtelomere regions. Our study therefore demonstrates that Dcaf11 plays important roles in telomere elongation in early embryos and ESCs through activating Zscan4.},
}
@article {pmid33355657,
year = {2021},
author = {Allsopp, R},
title = {Take a Ride on the Telomere-Aging Train.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {1-2},
doi = {10.1093/gerona/glaa245},
pmid = {33355657},
issn = {1758-535X},
}
@article {pmid33355654,
year = {2020},
author = {Červenák, F and Sepšiová, R and Nosek, J and Tomáška, Ľ},
title = {Step-by-step evolution of telomeres: lessons from yeasts.},
journal = {Genome biology and evolution},
volume = {},
number = {},
pages = {},
pmid = {33355654},
issn = {1759-6653},
abstract = {In virtually every eukaryotic species, the ends of nuclear chromosomes are protected by telomeres, nucleoprotein structures counteracting the end-replication problem and suppressing recombination and undue DNA repair. Although in most cases, the primary structure of telomeric DNA is conserved, there are several exceptions to this rule. One is represented by the telomeric repeats of ascomycetous yeasts, which encompass a great variety of sequences, whose evolutionary origin has been puzzling for several decades. At present, the key questions concerning the driving force behind their rapid evolution and the means of co-evolution of telomeric repeats and telomere-binding proteins remain largely unanswered. Previously published studies addressed mostly the general concepts of the evolutionary origin of telomeres, key properties of telomeric proteins as well as the molecular mechanisms of telomere maintenance, however, the evolutionary process itself has not been analyzed thoroughly. Here, we aimed to inspect the evolution of telomeres in ascomycetous yeasts from the subphyla Saccharomycotina and Taphrinomycotina, with special focus on the evolutionary origin of species-specific telomeric repeats. We analyzed the sequences of telomeric repeats from 204 yeast species classified into 20 families and as a result, we propose a step-by-step model, which integrates the diversity of telomeric repeats, telomerase RNAs, telomere-binding protein complexes and explains a propensity of certain species to generate the repeat heterogeneity within a single telomeric array.},
}
@article {pmid33355185,
year = {2020},
author = {Joshu, CE and Heaphy, CM and Barber, JR and Lu, J and Zarinshenas, R and Davis, C and Han, M and Lotan, TL and Sfanos, KS and De Marzo, AM and Meeker, AK and Platz, EA},
title = {Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer.},
journal = {Cancer prevention research (Philadelphia, Pa.)},
volume = {},
number = {},
pages = {},
doi = {10.1158/1940-6207.CAPR-20-0250},
pmid = {33355185},
issn = {1940-6215},
abstract = {In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4',6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (<25), overweight (25 ≤ BMI < 30), or obese (≥30). Analyses were stratified by grade and stage. Men were divided into tertiles of TMA- (overall) or TMA- and disease aggressiveness- (stratified) specific distributions; short CAS telomere status was defined by the bottom two tertiles. We used generalized linear mixed models to estimate the association between obesity and short CAS telomeres, adjusting for age, race, TMA set, pathologic stage, and grade. Obesity was not associated with short CAS telomeres overall, or among men with nonaggressive disease. Among men with aggressive disease (Gleason≥4+3 and stage>T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07-8.75; Ptrend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis. PREVENTION RELEVANCE: This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.},
}
@article {pmid33354567,
year = {2020},
author = {Yu, SN and Chen, SQ and Fan, GQ and Pan, WZ and Jia, J and Wang, Q and Ma, L and Li, B and Qiang, M and Qiu, YL and Wang, T},
title = {Relative Telomere Length in Peripheral Blood Cells and Hypertension Risk among Mine Workers: A Case-Control Study in Chinese Coal Miners.},
journal = {BioMed research international},
volume = {2020},
number = {},
pages = {5681096},
pmid = {33354567},
issn = {2314-6141},
abstract = {Hypertension is a common chronic disease in middle-aged and elderly people and is an important risk factor for many cardiovascular diseases. Its pathogenesis remains unclear. Epidemiological studies have found that the loss of telomere length in peripheral blood cells can increase the risk of coronary heart disease, myocardial infarction, and other diseases. However, a correlation between loss of telomere length and hypertension has not been established. In this study, we aimed to explore the association between telomere length and the risk of essential hypertension (EH) in Chinese coal miners. A case-control study was performed with 215 EH patients and 222 healthy controls in a large coal mining group located in North China. Face-to-face interviews were conducted by trained staff with the necessary medical knowledge. Relative telomere length (RTL) was measured by a quantitative real-time PCR assay using DNA extracted from peripheral blood. In the control group, the age-adjusted RTL was statistically significantly lower in miners performing hard physical labour compared with nonphysical labour (P = 0.043). A significantly shorter age-adjusted RTL was found in the control group of participants who consumed alcohol regularly compared with those who do not consume alcohol (P = 0.024). Age-adjusted RTL was negatively correlated with body mass index (BMI) and alcohol consumption. Hypertension was also found to be significantly correlated with factors such as age, BMI, alcohol consumption, smoking, and tea consumption. Our results suggest that RTL is associated with hypertension in coal miners.},
}
@article {pmid33353140,
year = {2020},
author = {Minamoto, T and Nakayama, K and Ishibashi, T and Ishikawa, M and Nakamura, K and Yamashita, H and Shanta, K and Mahmud, HM and Razia, S and Iida, K and Sakashita, G and Nakamura, T and Kanda, H and Kyo, S},
title = {Pregnancy by Assisted Reproductive Technology Is Associated with Shorter Telomere Length in Neonates.},
journal = {International journal of molecular sciences},
volume = {21},
number = {24},
pages = {},
pmid = {33353140},
issn = {1422-0067},
abstract = {Telomere length (TL) influences the development of lifestyle-related diseases, and neonatal TL may influence their prevalence. Various factors have been reported to affect neonatal TL. Although the fetus is exposed to multiple conditions in utero, the main factors affecting the shortening of neonatal TL are still not known. In this study, we sought to identify factors that influence fetal TL. A total of 578 mother-newborn pairs were included for TL analysis. TL was measured in genomic DNA extracted from cord blood samples using quantitative PCR. The clinical factors examined at enrollment included the following intrauterine environmental factors: maternal age, assisted reproductive technology (ART) used, body mass index (BMI), gestational diabetes mellitus (GDM), maternal stress, smoking, alcohol consumption, preterm delivery, small-for-gestational-age, neonatal sex, and placental weight. Univariate and multivariate regression analyses were used to verify the relationship between neonatal TL and these clinical factors. The median neonatal TL to single-copy gene ratio was 1.0. Pregnancy with ART was among the 11 factors associated with shorter neonatal TL. From multiple regression analysis, we determined that neonatal TL was significantly shorter for pregnancies in the ART group than in the other groups. We conclude that pregnancy with ART is associated with shorter neonatal TL.},
}
@article {pmid33351357,
year = {2020},
author = {Dudinskaya, EN and Tkacheva, ON and Brailova, NV and Strazhesko, ID and Shestakova, MV},
title = {[Telomere biology and metabolic disorders: the role of insulin resistance and type 2 diabetes].},
journal = {Problemy endokrinologii},
volume = {66},
number = {4},
pages = {35-44},
doi = {10.14341/probl12510},
pmid = {33351357},
issn = {2308-1430},
abstract = {BACKGROUND: Insulin resistance accelerates the aging process, but its speed depends on the individual characteristics of the metabolism. One of the reasons for the different aging rates in individuals with insulin resistance is the initially different &quot;genetic protection&quot; of cells, which many scientists associate with replicative cellular aging.<br><br>AIMS: to study the relationship between the state of carbohydrate metabolism and markers of replicative cell aging in individuals with different sensitivity to insulin.<br><br>MATERIALS AND METHODS: The observation study included 305 patients. The parameters of glucose metabolism and telomere biology were studied.<br><br>RESULTS: The mean age of the patients was 51.5±13.3 years. Patients were divided into three groups depending on presence of insulin resistance: healthy, with insulin resistance and with type 2 diabetes. The mean age of healthy patients was 48.82±13.87 years, in insulin resistance group - 53.04±12.8, in 2 diabetes mellitus - 58.4±7.90. The median telomere length was 9.76. The median telomerase activity was 0.48. Both telomere length and telomerase activity progressively decrease as insulin resistance increases. In patients with diabetes, short telomere lengths and low telomerase activity predominated. The insulin resistance index has the greatest impact on the risk of detecting &quot;short&quot; telomeres. In patients with insulin resistance, an increase in glycated hemoglobin increases the likelihood of detecting short telomeres by 2.4 times, and in diabetes mellitus by 4.26 times, an increase in fasting plasma glucose by 90%, and an increase in HOMA-IR by 35%. An increase in insulin resistance increases the risk of detecting «low» telomerase activity by 53% and the risk of detecting «very low» telomerase activity by 92%. A decrease in synsulin resistance increases the chance of increasing telomerase activity to «very high» by 51%.<br><br>CONCLUSION: Shorter telomeres are associated with more pronounced disorders of carbohydrate metabolism and a higher degree of insulin resistance. Further studies of metabolic status are necessary to personalize their lifestyle and treatment goals.},
}
@article {pmid33350936,
year = {2020},
author = {Saint-Leandre, B and Christopher, C and Levine, MT},
title = {Adaptive evolution of an essential telomere protein restricts telomeric retrotransposons.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {33350936},
issn = {2050-084X},
support = {R00 GM107351/GM/NIGMS NIH HHS/United States ; R35 GM124684/GM/NIGMS NIH HHS/United States ; },
abstract = {Essential, conserved cellular processes depend not only on essential, strictly conserved proteins but also on essential proteins that evolve rapidly. To probe this poorly understood paradox, we exploited the rapidly evolving Drosophila telomere-binding protein, cav/HOAP, which protects chromosomes from lethal end-to-end fusions. We replaced the D. melanogaster HOAP with a highly diverged version from its close relative, D. yakuba. The D. yakuba HOAP ('HOAP[yak]') localizes to D. melanogaster telomeres and protects D. melanogaster chromosomes from fusions. However, HOAP[yak] fails to rescue a previously uncharacterized HOAP function: silencing of the specialized telomeric retrotransposons that, instead of telomerase, maintain chromosome length in Drosophila. Whole genome sequencing and cytogenetics of experimentally evolved populations revealed that HOAP[yak] triggers telomeric retrotransposon proliferation, resulting in aberrantly long telomeres. This evolution-generated, separation-of-function allele resolves the paradoxical observation that a fast-evolving essential gene directs an essential, strictly conserved function: telomeric retrotransposon containment, not end-protection, requires evolutionary innovation at HOAP.},
}
@article {pmid33347580,
year = {2021},
author = {Li, X and Wang, M and Zheng, W and Huang, W and Wang, Z and Jin, K and Liu, L and Yu, Z},
title = {Dynamics of TRF1 organizing a single human telomere.},
journal = {Nucleic acids research},
volume = {49},
number = {2},
pages = {760-775},
pmid = {33347580},
issn = {1362-4962},
mesh = {Biotinylation ; Digoxigenin ; Humans ; Inverted Repeat Sequences ; K562 Cells ; Magnets ; Micromanipulation/*methods ; Single Molecule Imaging ; Telomere/chemistry/*ultrastructure ; Telomere-Binding Proteins/chemistry/physiology ; Telomeric Repeat Binding Protein 1/*metabolism ; },
abstract = {Chromosome stability is primarily determined by telomere length. TRF1 is the core subunit of shelterin that plays a critical role in telomere organization and replication. However, the dynamics of TRF1 in scenarios of telomere-processing activities remain elusive. Using single-molecule magnetic tweezers, we here investigated the dynamics of TRF1 upon organizing a human telomere and the protein-DNA interactions at a moving telomeric fork. We first developed a method to obtain telomeres from human cells for directly measuring the telomere length by single-molecule force spectroscopy. Next, we examined the compaction and decompaction of a telomere by TRF1 dimers. TRF1 dissociates from a compacted telomere with heterogenous loops in ∼20 s. We also found a negative correlation between the number of telomeric loops and loop sizes. We further characterized the dynamics of TRF1 at a telomeric DNA fork. With binding energies of 11 kBT, TRF1 can modulate the forward and backward steps of DNA fork movements by 2-9 s at a critical force of F1/2, temporarily maintaining the telomeric fork open. Our results shed light on the mechanisms of how TRF1 organizes human telomeres and facilitates the efficient replication of telomeric DNA. Our work will help future research on the chemical biology of telomeres and shelterin-targeted drug discovery.},
}
@article {pmid33347069,
year = {2021},
author = {Luxton, JJ and Bailey, SM},
title = {Twins, Telomeres, and Aging-in Space!.},
journal = {Plastic and reconstructive surgery},
volume = {147},
number = {1S-2},
pages = {7S-14S},
doi = {10.1097/PRS.0000000000007616},
pmid = {33347069},
issn = {1529-4242},
abstract = {BACKGROUND: The landmark National Aeronautics and Space Administration Twins Study represented an integrated effort to launch human space life science research into the modern age of molecular- and &quot;omics&quot;-based studies. As part of the first One-Year Mission aboard the International Space Station, identical twin astronauts Scott and Mark Kelly were the subjects of this &quot;out of this world&quot; research opportunity. Telomeres, the natural ends of chromosomes that shorten with cell division and a host of lifestyle factors and stresses, are key molecular determinants of aging and aging trajectories.<br><br>METHODS: We proposed that telomere length dynamics (changes over time) represent a particularly relevant and integrative biomarker for astronauts, as they reflect the combined experiences and environmental exposures encountered during spaceflight. Telomere length (quantitative polymerase chain reaction and telomere fluorescence in situ hybridization) and telomerase activity (quantitative polymerase chain reaction -telomere repeat amplification protocol) were longitudinally assessed in the space- and earth-bound twins. Chromosome aberrations (directional genomic hybridization), signatures of radiation exposure, were also evaluated.<br><br>RESULTS: The twins had relatively similar telomere lengths before spaceflight, and the earth-bound twins' telomeres remained relatively stable over the course of the study. Surprisingly, the space twins' telomeres were longer during spaceflight, and upon return to Earth shortened rapidly, resulting in many more short telomeres after spaceflight than before. Chromosomal signatures of space radiation exposure were also elevated during spaceflight, and increased inversion frequencies persisted after spaceflight, suggestive of ongoing genome instability.<br><br>CONCLUSION: Although the definitive mechanisms underlying such dramatic spaceflight-associated shifts in telomere length remain unclear, improved maintenance of telomere length has important implications for aging science and improving healthspan for those on Earth, as well.},
}
@article {pmid33345078,
year = {2020},
author = {Simões, HG and Rosa, TS and Sousa, CV and Aguiar, SDS and Motta-Santos, D and Degens, H and Korhonen, MT and Campbell, CSG},
title = {Does Longer Leukocyte Telomere Length and Higher Physical Fitness Protect Master Athletes From Consequences of Coronavirus (SARS-CoV-2) Infection?.},
journal = {Frontiers in sports and active living},
volume = {2},
number = {},
pages = {87},
pmid = {33345078},
issn = {2624-9367},
}
@article {pmid33344901,
year = {2020},
author = {Goncalves, T and Zoumpoulidou, G and Alvarez-Mendoza, C and Mancusi, C and Collopy, LC and Strauss, SJ and Mittnacht, S and Tomita, K},
title = {Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors.},
journal = {ACS pharmacology &amp; translational science},
volume = {3},
number = {6},
pages = {1253-1264},
pmid = {33344901},
issn = {2575-9108},
abstract = {To avoid replicative senescence or telomere-induced apoptosis, cancers employ telomere maintenance mechanisms (TMMs) involving either the upregulation of telomerase or the acquisition of recombination-based alternative telomere lengthening (ALT). The choice of TMM may differentially influence cancer evolution and be exploitable in targeted therapies. Here, we examine TMMs in a panel of 17 osteosarcoma-derived cell lines, defining three separate groups according to TMM and the length of telomeres maintained. Eight were ALT-positive, including the previously uncharacterized lines, KPD and LM7. While ALT-positive lines all showed excessive telomere length, ALT-negative cell lines fell into two groups according to their telomere length: HOS-MNNG, OHSN, SJSA-1, HAL, 143b, and HOS displayed subnormally short telomere length, while MG-63, MHM, and HuO-3N1 displayed long telomeres. Hence, we further subcategorized ALT-negative TMM into long-telomere (LT) and short-telomere (ST) maintenance groups. Importantly, subnormally short telomeres were significantly associated with hypersensitivity to three different therapeutics targeting the protein kinase ataxia telangiectasia and Rad3-related (ATR) (AZD-6738/Ceralasertib, VE-822/Berzoserib, and BAY-1895344) compared to long telomeres maintained via ALT or telomerase. Within 24 h of ATR inhibition, cells with short but not long telomeres displayed chromosome bridges and underwent cell death, indicating a selective dependency on ATR for chromosome stability. Collectively, our work provides a resource to identify links between the mode of telomere maintenance and drug sensitivity in osteosarcoma and indicates that telomere length predicts ATR inhibitor sensitivity in cancer.},
}
@article {pmid33338512,
year = {2020},
author = {Ningarhari, M and Caruso, S and Hirsch, TZ and Bayard, Q and Franconi, A and Védie, AL and Noblet, B and Blanc, JF and Amaddeo, G and Ganne, N and Ziol, M and Paradis, V and Guettier, C and Calderaro, J and Morcrette, G and Kim, Y and MacLeod, AR and Nault, JC and Rebouissou, S and Zucman-Rossi, J},
title = {Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target.},
journal = {Journal of hepatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jhep.2020.11.052},
pmid = {33338512},
issn = {1600-0641},
abstract = {BACKGROUND &amp; AIMS: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. We aimed to elucidate telomere length (TL) control during liver carcinogenesis.<br><br>METHODS: TL was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, clinical and molecular features of HCC analyzed by genome, exome, targeted or RNA sequencing. Preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model.<br><br>RESULTS: Aging, liver fibrosis, male gender and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC developed in liver with long telomeres were frequently TERT wildtype with progenitor features and BAP1 mutation. In contrast, HCC developed on liver with short TL were enriched in non-proliferative HCC class and somatic TERT promoter mutations. In HCCs, TL is stabilized around 5.7 Kb by various mechanism activating TERT expression, in a narrow biological range similar to non-tumor livers. Long telomeres in tumors are features of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with antisense oligonucleotide was efficient in highly proliferative and poorly differentiated cells. Treatment during 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and apoptosis activation. Therapeutic effect was also obtained in a xenograft mouse model.<br><br>CONCLUSIONS: Telomere maintenance in HCC carcinogenesis is diverse, associated with tumor progression and aggressiveness. Anti-TERT ASO efficacy in HCC cell lines revealed TERT oncogenic addiction and a preclinical rationale for TERT ASO in HCC clinical trial.},
}
@article {pmid33335933,
year = {2020},
author = {Iyengar, S and Cȏté, HCF and Fitch, KV and Torriani, M and Feldpausch, M and Srinivasa, S},
title = {Relationship of Telomere Length to Fat Redistribution in HIV.},
journal = {Open forum infectious diseases},
volume = {7},
number = {12},
pages = {ofaa523},
pmid = {33335933},
issn = {2328-8957},
support = {P30 DK040561/DK/NIDDK NIH HHS/United States ; },
abstract = {Persons with HIV demonstrate increased risk for aging-associated complications and have reduced telomere length (TL) compared with age-matched persons without HIV. Our data show that greater visceral fat is related to reduced TL in HIV, independent of age and smoking. Fat redistribution may be a relevant mediator of TL attrition in HIV.},
}
@article {pmid33335813,
year = {2020},
author = {Leonida, SRL and Bennett, NC and Leitch, AR and Faulkes, CG},
title = {Patterns of telomere length with age in African mole-rats: New insights from quantitative fluorescence in situ hybridisation (qFISH).},
journal = {PeerJ},
volume = {8},
number = {},
pages = {e10498},
pmid = {33335813},
issn = {2167-8359},
abstract = {Naked mole-rats Heterocephalus glaber (NMRs) are the longest-lived rodent and also resist the normal signs of senescence. In a number of species, cellular ageing has been correlated with a reduction in telomere length, yet relatively little is known about telomeres and their age-related dynamics in NMRs and other African mole-rats. Here, we apply fluorescence in situ hybridisation (FISH) to quantify telomeric repeat sequences in the NMR, the Damaraland mole-rat, Fukomys damarensis (DMR) and the Mahali mole-rat, Cryptomys hottentotus mahali (MMR). Both terminal and non-terminal telomeric sequences were identified in chromosomes of the NMR and DMR, whilst the MMR displayed only terminal telomeric repeats. Measurements of tooth wear and eruption patterns in wild caught DMRs and MMRs, and known ages in captive bred NMRs, were used to place individuals into relative age classes and compared with a quantitative measure of telomeric fluorescence (as a proxy for telomere size). While NMRs and MMRs failed to show an age-related decline in telomeric fluorescence, the DMR had a significant decrease in fluorescence with age, suggesting a decrease in telomere size in older animals. Our results suggest that among African mole-rats there is variation between species with respect to the role of telomere shortening in ageing, and the replicative theory of cellular senescence.},
}
@article {pmid33331615,
year = {2021},
author = {Zarei, M and Zarezadeh, M and Hamedi Kalajahi, F and Javanbakht, MH},
title = {The Relationship Between Vitamin D and Telomere/Telomerase: A Comprehensive Review.},
journal = {The Journal of frailty &amp; aging},
volume = {10},
number = {1},
pages = {2-9},
doi = {10.14283/jfa.2020.33},
pmid = {33331615},
issn = {2260-1341},
mesh = {Aging/blood/genetics/metabolism/pathology ; Cellular Senescence/*physiology ; Humans ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Vitamin D/*blood/*metabolism ; },
abstract = {Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Evidences from various organisms suggests that several factors influence telomere length regulation, such as telomere binding proteins, telomere capping proteins, telomerase, and DNA replication enzymes. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. In this study, our main goal is investigating the relationship between telomerase enzyme and vitamin D. Findings of this study suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases. Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. Significant Low levels of telomerase activity create short telomeres, which in turn signal exit from the cell cycle resulting in cell senescence and apoptosis. In follow-up examination, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were depleted. Increasing 25-hydroxyvitamin D levels in patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.},
}
@article {pmid33329978,
year = {2020},
author = {Gutlapalli, SD and Kondapaneni, V and Toulassi, IA and Poudel, S and Zeb, M and Choudhari, J and Cancarevic, I},
title = {The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling.},
journal = {Cureus},
volume = {12},
number = {11},
pages = {e11482},
pmid = {33329978},
issn = {2168-8184},
abstract = {Post myocardial infarction (MI) remodeling is the term used to define the changes in cardiac musculature after sustaining an ischemic injury. These changes decrease myocardial function and ultimately lead to heart failure. We review the contributing factors to post-MI remodeling, its association with telomere biology, as well as a myriad of other factors affecting aging and telomere length in relation to cardiovascular health. The main focus is on the effects of resveratrol in the cardiovascular system and its potential for therapeutic use in preventing long-term cardiovascular morbidity and mortality. We tried to answer important questions regarding the potential for resveratrol as a therapeutic drug to prevent adverse post-MI remodeling. In our search, we gathered 62 studies and narrowed our data down to 44 studies. The database used was PubMed, and the keywords used are &quot;Resveratrol&quot;, &quot;Telomere&quot;, &quot;Post Myocardial Infarction&quot;. All the studies were carefully screened for relevant articles regarding our topic manually, Articles related to a positive association between resveratrol and its anti-aging, cardioprotective effects have been included in our study, as we could not find any articles in our search which showed a negative correlation. Our review concluded that resveratrol had pro-telomerase effects which could counter the development of adverse post-MI remodeling. Therefore resveratrol could be a useful therapeutic add-on drug to prevent cardiovascular disease. It is essential that further research including observational and large-scale clinical trials should be conducted to increase our understanding of the efficacy and viability of these novel therapeutic interventions.},
}
@article {pmid33328546,
year = {2020},
author = {Yu, EY and Zahid, SS and Ganduri, S and Sutherland, JH and Hsu, M and Holloman, WK and Lue, NF},
title = {Structurally distinct telomere-binding proteins in Ustilago maydis execute non-overlapping functions in telomere replication, recombination, and protection.},
journal = {Communications biology},
volume = {3},
number = {1},
pages = {777},
pmid = {33328546},
issn = {2399-3642},
support = {R01 GM107287/GM/NIGMS NIH HHS/United States ; MCB-1817331//National Science Foundation (NSF)/ ; GM107287//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; },
abstract = {Duplex telomere binding proteins exhibit considerable structural and functional diversity in fungi. Herein we interrogate the activities and functions of two Myb-containing, duplex telomere repeat-binding factors in Ustilago maydis, a basidiomycete that is evolutionarily distant from the standard fungi. These two telomere-binding proteins, UmTay1 and UmTrf2, despite having distinct domain structures, exhibit comparable affinities and sequence specificity for the canonical telomere repeats. UmTay1 specializes in promoting telomere replication and an ALT-like pathway, most likely by modulating the helicase activity of Blm. UmTrf2, in contrast, is critical for telomere protection; transcriptional repression of Umtrf2 leads to severe growth defects and profound telomere aberrations. Comparative analysis of UmTay1 homologs in different phyla reveals broad functional diversity for this protein family and provides a case study for how DNA-binding proteins can acquire and lose functions at various chromosomal locations. Our findings also point to stimulatory effect of telomere protein on ALT in Ustilago maydis that may be conserved in other systems.},
}
@article {pmid33325602,
year = {2020},
author = {Oskouei, Z and Mehri, S and Kalalinia, F and Hosseinzadeh, H},
title = {Evaluation of the effect of thymoquinone in d-galactose-induced memory impairments in rats: Role of MAPK, oxidative stress, and neuroinflammation pathways and telomere length.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.6982},
pmid = {33325602},
issn = {1099-1573},
support = {940993//the Vice-Chancellor of Research, Mashhad University of Medical Sciences, Mashhad/ ; },
abstract = {D-galactose (d-gal) induces aging and memory impairment via oxidative stress and neuroinflammation pathways. This study evaluated the neuroprotective activity of thymoquinone (TQ) against d-gal. d-gal (400 mg/kg, SC), d-gal plus TQ (2.5, 5, 10 mg/kg, i.p.), and TQ alone (2.5 and 10 mg/kg) for 8 weeks were administered to rats. The effect of TQ on learning and memory were studied using the Morris water maze test. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the hippocampus. The levels of MAPKs (p-ERK/ERK, p-P38/P38), cAMP response elements binding (p-CREB/CREB), advanced glycation end products (AGEs), inflammatory markers (TNFα, IL-1β), glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF) were analyzed by western blotting. Telomere length was evaluated using real-time PCR. Memory and learning impairment, MDA enhancement, GSH reduction, and neuroinflammation via increasing the TNFα, IL-1β, and GFAP contents were observed in d-gal group. TQ with d-gal, improved memory impairment, reduced oxidative stress, and alleviated neuroinflammation. The elevated level of AGEs decreased by TQ compared to d-gal. No changes were observed in the levels of p-ERK/ERK, p-CREB/CREB, p-P38/P38, BDNF, and telomere length following administration of d-gal or TQ plus d-gal. TQ improved memory deficits of d-gal through anti-oxidative and anti-inflammatory mechanisms.},
}
@article {pmid33324010,
year = {2020},
author = {Gao, Z and Daquinag, AC and Fussell, C and Zhao, Z and Dai, Y and Rivera, A and Snyder, BE and Eckel-Mahan, KL and Kolonin, MG},
title = {Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease.},
journal = {Nature metabolism},
volume = {2},
number = {12},
pages = {1482-1497},
pmid = {33324010},
issn = {2522-5812},
support = {R01 LM012806/LM/NLM NIH HHS/United States ; },
mesh = {Adipocytes/*pathology ; Adipocytes, Beige/metabolism ; Adipocytes, White/metabolism ; Aging/*pathology ; Animals ; Cell Differentiation ; Cell Lineage/genetics ; Cell Proliferation ; Diet, High-Fat ; Female ; Humans ; Insulin Resistance/genetics ; Intra-Abdominal Fat ; Male ; Metabolic Diseases/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor, Platelet-Derived Growth Factor alpha/genetics/metabolism ; Stem Cells/*pathology ; Subcutaneous Fat/metabolism/pathology ; Telomerase/genetics/metabolism ; *Telomere Homeostasis ; },
abstract = {White and beige adipocytes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are maintained by proliferation and differentiation of adipose progenitor cells (APCs). Here we use mice with tissue-specific telomerase reverse transcriptase (TERT) gene knockout (KO), which undergo premature telomere shortening and proliferative senescence in APCs, to investigate the effect of over-nutrition on APC exhaustion and metabolic dysfunction. We find that TERT KO in the Pdgfra+ cell lineage results in adipocyte hypertrophy, inflammation and fibrosis in SAT, while TERT KO in the Pdgfrb+ lineage leads to adipocyte hypertrophy in both SAT and VAT. Systemic insulin resistance is observed in both KO models and is aggravated by a high-fat diet. Analysis of human biopsies demonstrates that telomere shortening in SAT is associated with metabolic disease progression after bariatric surgery. Our data indicate that over-nutrition can promote APC senescence and provide a mechanistic link between ageing, obesity and diabetes.},
}
@article {pmid33323554,
year = {2020},
author = {Lee, EH and Han, MH and Ha, J and Park, HH and Koh, SH and Choi, SH and Lee, JH},
title = {Relationship between telomere shortening and age in Korean individuals with mild cognitive impairment and Alzheimer's disease compared to that in healthy controls.},
journal = {Aging},
volume = {13},
number = {2},
pages = {2089-2100},
doi = {10.18632/aging.202206},
pmid = {33323554},
issn = {1945-4589},
abstract = {Although telomere length (TL) is highly variable, a shorter TL indicate increased biological age. This multicenter study was conducted to identify the overall correlation between age and TL in Koreans and investigate the associations between age and TL in healthy individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). TL was measured in peripheral leukocyte DNA. MCI and AD were diagnosed based on clinical examinations and amyloid deposition on positron emission tomography. This study enrolled 437 individuals. Multivariable linear analysis showed an overall approximate TL decrease of 37 bp per 1-year increase in age in all individuals (B=-0.037; P=0.002). There was no significant difference in the mean TL between healthy individuals and individuals with AD. Multivariable linear regression analysis showed that the mean rate of telomere shortening was 60 bp per year in individuals with AD (B=-0.060; P=0.006). There was a negative association between age and TL in our study. Our study results showed more significant telomere shortening per year in women than that in men. In addition, individuals with AD had greater telomere shortening every year than healthy individuals and individuals with MCI.},
}
@article {pmid33323545,
year = {2020},
author = {Wu, F and Huang, Y and Hu, J and Shao, Z},
title = {Mendelian randomization study of telomere length and bone mineral density.},
journal = {Aging},
volume = {13},
number = {2},
pages = {2015-2030},
doi = {10.18632/aging.202197},
pmid = {33323545},
issn = {1945-4589},
abstract = {PURPOSE: Some epidemiological studies and animal studies have reported a relationship between leukocyte telomere length (LTL) and bone mineral density (BMD). However, the causality underlying the purported relationship has not been determined. Here we performed a two-sample MR analysis to test the causal link between telomere length and BMD.<br><br>RESULTS: Our research suggested no causal link of LTL and BMD using IVW method. The weighted median, MR-Egger regression and MR.RAPS method yielded a similar pattern of effects. MR-Egger intercept test demonstrated our results were not influenced by pleiotropy. Heterogeneities among the genetic variants on heel estimated BMD and TB-BMD vanished after excluding rs6028466. &quot;Leave-one-out&quot; sensitivity analysis confirmed the stability of our results.<br><br>CONCLUSION: Our MR analysis did not support causal effect of telomere length on BMD.<br><br>METHODS: We utilized 5 independent SNPs robustly associated with LTL as instrument variables. The outcome results were obtained from GWAS summary data of BMD. The two-sample MR analysis was conducted using IVW, weighted median, MR-Egger regression and MR.RAPS method. MR-Egger intercept test, Cochran's Q test and I2 statistics and &quot;leave-one-out&quot; sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities and stability of these genetic variants on BMD.},
}
@article {pmid33323453,
year = {2020},
author = {Fan, Y and Zheng, C and Wu, N and Li, Y and Huang, X and Ye, Q},
title = {Telomerase gene variants and telomere shortening in patients with silicosis or asbestosis.},
journal = {Occupational and environmental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1136/oemed-2020-107046},
pmid = {33323453},
issn = {1470-7926},
abstract = {OBJECTIVES: Telomerase gene variants that lead to accelerated telomere shortening are linked to progressive-fibrosing interstitial lung diseases. However, little is known about their relationships with pneumoconiosis. This study aimed to identify TERT/TERC variants and leucocyte telomere lengths (LTL) in patients with silicosis or asbestosis.<br><br>METHODS: In the present study, Sanger sequencing of TERT/TERC variants was performed in 193 Chinese Han patients with pneumoconiosis, including 109 with silicosis and 84 with asbestosis. Quantitative PCR was used to measure LTL in peripheral blood of the patients and 200 age and sex-matched healthy controls.<br><br>RESULTS: In total, 7.3% patients with pneumoconiosis had 17 TERT/TERC variants. Among which 8.3% of patients with silicosis and 3.6% of patients with asbestosis had TERT variants, respectively. No TERC variants were detected in silicosis, whereas 3.6% of patients with asbestosis had TERC variants. Telomeres were significantly shorter in the patients with pneumoconiosis compared with healthy controls (p<0.001). No significant differences in LTL were found between TERT/TERC variant carriers and non-carriers. Exposure to silica dust was associated with the severity of pneumoconiosis after adjusting for covariates (OR 4.92, p=0.002). However, TERT/TERC variants and short telomeres were not associated with the severity of pneumoconiosis.<br><br>CONCLUSION: Telomerase gene variants and short telomeres may be identified in the patients with silicosis and asbestosis in response to the exposure to silica or asbestos dust but are not related to disease severity.},
}
@article {pmid33321495,
year = {2021},
author = {Huang, J and Peng, X and Dong, K and Tao, J and Yang, Y},
title = {The Association between Antidiabetic Agents and Leukocyte Telomere Length in the Novel Classification of Type 2 Diabetes Mellitus.},
journal = {Gerontology},
volume = {67},
number = {1},
pages = {60-68},
doi = {10.1159/000511362},
pmid = {33321495},
issn = {1423-0003},
abstract = {AIMS: This study aimed to explore the new role of telomere length (TL) in the novel classification of type 2 diabetes mellitus (T2DM) patients driven by cluster analysis.<br><br>MATERIALS AND METHODS: A total of 541 T2DM patients were divided into 4 subgroups by k-means analysis: mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), and mild age-related diabetes (MARD). After patients with insufficient data were excluded, further analysis was conducted on 246 T2DM patients. The TL was detected using telomere restriction fragment, and the related diabetic indexes were also measured by clinical standard procedures.<br><br>RESULTS: The MARD group had significantly shorter TLs than the MOD and SIDD groups. Then, we subdivided all T2DM patients into the MARD and NONMARD groups, which included the MOD, SIDD, and SIRD groups. The TLs of the MARD group, associated with age, were discovered to be significantly shorter than those of the NONMARD group (p = 0.0012), and this difference in TL disappeared after metformin (p = 0.880) and acarbose treatment (p = 0.058). The linear analysis showed that metformin can more obviously reduce telomere shortening in the MARD group (r = 0.030, 95% CI 0.010-0.051, p = 0.004), and acarbose can more apparently promote telomere attrition in the SIRD group (r = -0.069, 95% CI -0.100 to -0.039, p< 0.001) compared with other T2DM patients after adjusting for age and gender.<br><br>CONCLUSIONS: The MARD group was found to have shorter TLs and benefit more from the antiaging effect of metformin than other T2DM. Shorter TLs were observed in the SIRD group after acarbose use.},
}
@article {pmid33321417,
year = {2021},
author = {Solek, P and Shemedyuk, N and Shemedyuk, A and Dudzinska, E and Koziorowski, M},
title = {Risk of wild fungi treatment failure: Phallus impudicus-induced telomere damage triggers p21/p53 and p16-dependent cell cycle arrest and may contribute to male fertility reduction in vitro.},
journal = {Ecotoxicology and environmental safety},
volume = {209},
number = {},
pages = {111782},
doi = {10.1016/j.ecoenv.2020.111782},
pmid = {33321417},
issn = {1090-2414},
mesh = {Agaricales/metabolism ; Apoptosis ; *Basidiomycota ; Cell Cycle ; Cell Cycle Checkpoints/drug effects ; DNA Damage ; Fertility/*drug effects ; Humans ; Male ; Mycotoxins/*toxicity ; Telomere ; Treatment Failure ; Tumor Suppressor Protein p53/metabolism ; },
abstract = {The multifunctional characteristics of Phallus impudicus extract encourage to conduct research for its potential use in medical applications. Well, science is constantly seeking new evidence for the biological activity of extracts of natural origin. Drugs of natural origin should not cause any side effects on the physiological functions of the human body; however, this is not always successful. In this study, we used in vitro approach to evaluate the toxicity of alcohol Phallus impudicus extract on spermatogenic cells. We show, for the first time, cytotoxic properties of Phallus impudicus treatment associated with a decrease in cellular metabolic activity, dysregulation of redox homeostasis and impairment of selected antioxidant cell protection systems. As a consequence, p53/p21- and p16-mediated cell cycle arrest followed by p27 activation is initiated. The observed changes were associated with telomere shortening and numerous DNA damage at the chromosome ends (altered expression pattern of TRF1 and TRF2 proteins), as well as upregulation of cleaved caspase-3 with a decrease in Bcl-2 expression, suggesting induction of apoptotic death. Therefore, these results provide molecular evidence for mechanistic pathways and novel adverse outcomes linked to the Phallus impudicus treatment towards men's health and fertility reduction.},
}
@article {pmid33318425,
year = {2021},
author = {Corbo, RM and Businaro, R and Scarabino, D},
title = {Leukocyte telomere length and plasma interleukin-1β and interleukin-18 levels in mild cognitive impairment and Alzheimer's disease: new biomarkers for diagnosis and disease progression?.},
journal = {Neural regeneration research},
volume = {16},
number = {7},
pages = {1397-1398},
doi = {10.4103/1673-5374.300986},
pmid = {33318425},
issn = {1673-5374},
}
@article {pmid33317189,
year = {2020},
author = {Alnafakh, R and Choi, F and Bradfield, A and Adishesh, M and Saretzki, G and Hapangama, DK},
title = {Endometriosis Is Associated with a Significant Increase in hTERC and Altered Telomere/Telomerase Associated Genes in the Eutopic Endometrium, an Ex-Vivo and In Silico Study.},
journal = {Biomedicines},
volume = {8},
number = {12},
pages = {},
pmid = {33317189},
issn = {2227-9059},
support = {RG2137//Wellbeing of Women/ ; RA thesis//Higher Committee for Education Development in Iraq/ ; Mres projects//North West Cancer Research Fund/ ; },
abstract = {Telomeres protect chromosomal ends and they are maintained by the specialised enzyme, telomerase. Endometriosis is a common gynaecological disease and high telomerase activity and higher hTERT levels associated with longer endometrial telomere lengths are characteristics of eutopic secretory endometrial aberrations of women with endometriosis. Our ex-vivo study examined the levels of hTERC and DKC1 RNA and dyskerin protein levels in the endometrium from healthy women and those with endometriosis (n = 117). The in silico study examined endometriosis-specific telomere- and telomerase-associated gene (TTAG) transcriptional aberrations of secretory phase eutopic endometrium utilising publicly available microarray datasets. Eutopic secretory endometrial hTERC levels were significantly increased in women with endometriosis compared to healthy endometrium, yet dyskerin mRNA and protein levels were unperturbed. Our in silico study identified 10 TTAGs (CDKN2A, PML, ZNHIT2, UBE3A, MCCC2, HSPC159, FGFR2, PIK3C2A, RALGAPA1, and HNRNPA2B1) to be altered in mid-secretory endometrium of women with endometriosis. High levels of hTERC and the identified other TTAGs might be part of the established alteration in the eutopic endometrial telomerase biology in women with endometriosis in the secretory phase of the endometrium and our data informs future research to unravel the fundamental involvement of telomerase in the pathogenesis of endometriosis.},
}
@article {pmid33310362,
year = {2021},
author = {Zhang, B and Liu, L and Guo, L and Guo, S and Zhao, X and Liu, G and Li, Q and Jiang, L and Pan, B and Nie, J and Yang, J},
title = {Telomere length mediates the association between polycyclic aromatic hydrocarbons exposure and abnormal glucose level among Chinese coke oven plant workers.},
journal = {Chemosphere},
volume = {266},
number = {},
pages = {129111},
doi = {10.1016/j.chemosphere.2020.129111},
pmid = {33310362},
issn = {1879-1298},
mesh = {Asian Continental Ancestry Group ; *Coke/analysis ; Cross-Sectional Studies ; Glucose ; Humans ; *Occupational Exposure/analysis ; *Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; Pyrenes ; Telomere ; },
abstract = {INTRODUCTION: Diabetes is a chronic and complex disease determined by environmental and genetic factors. This study aimed to investigate the association between polycyclic aromatic hydrocarbons (PAHs) exposure and fasting blood glucose levels and telomere length among coke-oven plant workers, to explore potential role of telomere length (TL) in the association between PAHs exposure and abnormal glucose level.<br><br>METHODS: The cross-sectional survey was conducted in 2017. The high-performance liquid chromatography mass spectrometry (HPLC-MS) was used to detect 11 urine biomarkers of PAHs exposure. TL was measured using the Real-time quantitative polymerase chain reaction (RT-qPCR) method. Logistic regression model, the modified Poisson regression models, and mediation analysis were used to evaluate the associations between PAHs exposure, TL, and abnormal glucose.<br><br>RESULTS: The results showed that the urinary 1-hydroxypyrene (1-PYR) was positively related to abnormal glucose in a dose-dependent manner (Ptrend = 0.007), the prevalence ratio of abnormal glucose was 8% (95% CI: 1.01-1.16) higher in 3rd tertile of urinary 1-PYR levels. Urinary 1-PYR in the 2nd tertile and 3rd tertile were associated with a 53% (OR = 0.47, 95% CI: 0.28-0.79) and 59% (OR = 0.41, 95% CI: 0.23-0.76) higher risk of shortening TL. And there was a negatively association between 1-PYR and TL in a dose-dependent manner (Ptrend = 0.045). We observed that the association between 1-PYR and abnormal glucose was more significantly positive among participants with median TL level (Ptrend = 0.006). In addition, mediation analysis showed the TL could explain 11.7% of the effect of abnormal glucose related to PAHs exposure.<br><br>CONCLUSIONS: Our findings suggested the effect of abnormal glucose related to PAHs exposure was mediated by telomere length in coke oven plant workers.},
}
@article {pmid33310082,
year = {2021},
author = {Uppuluri, L and Varapula, D and Young, E and Riethman, H and Xiao, M},
title = {Single-molecule telomere length characterization by optical mapping in nano-channel array: Perspective and review on telomere length measurement.},
journal = {Environmental toxicology and pharmacology},
volume = {82},
number = {},
pages = {103562},
doi = {10.1016/j.etap.2020.103562},
pmid = {33310082},
issn = {1872-7077},
abstract = {In humans, the telomere consists of tandem 5'TTAGGG3' DNA repeats on both ends of all 46 chromosomes. Telomere shortening has been linked to aging and age-related diseases. Similarly, telomere length changes have been associated with chemical exposure, molecular-level DNA damage, and tumor development. Telomere elongation has been associated to tumor development, caused due to chemical exposure and molecular-level DNA damage. The methods used to study these effects mostly rely on average telomere length as a biomarker. The mechanisms regulating subtelomere-specific and haplotype-specific telomere lengths in humans remain understudied and poorly understood, primarily because of technical limitations in obtaining these data for all chromosomes. Recent studies have shown that it is the short telomeres that are crucial in preserving chromosome stability. The identity and frequency of specific critically short telomeres potentially is a useful biomarker for studying aging, age-related diseases, and cancer. Here, we will briefly review the role of telomere length, its measurement, and our recent single-molecule telomere length measurement assay. With this assay, one can measure individual telomere lengths as well as identify their physically linked subtelomeric DNA. This assay can also positively detect telomere loss, characterize novel subtelomeric variants, haplotypes, and previously uncharacterized recombined subtelomeres. We will also discuss its applications in aging cells and cancer cells, highlighting the utility of the single molecule telomere length assay.},
}
@article {pmid33309414,
year = {2020},
author = {Chen, L and Shivappa, N and Dong, X and Ming, J and Zhao, Q and Xu, H and Liang, P and Cheng, M and Liu, J and Sun, P and Ban, B},
title = {Association between appendicular skeletal muscle index and leukocyte telomere length in adults: A study from National Health and Nutrition Examination Survey (NHANES) 1999-2002.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clnu.2020.11.031},
pmid = {33309414},
issn = {1532-1983},
abstract = {BACKGROUND: A higher body mass index (BMI) is associated with shorter telomeres. The loss of muscle mass with aging is associated with adverse outcomes. The appendicular skeletal muscle index (ASMI) is currently used to quantify muscle mass.<br><br>OBJECTIVE: We investigated the association of the ASMI with leukocyte telomere length in adult Americans.<br><br>METHODS: This cross-sectional study used the National Health and Nutrition Examination Survey (NHANES) 1999-2002 dataset. Body composition was measured by dual-energy X-ray absorptiometry. Low muscle mass was defined using sex-specific thresholds of the appendicular skeletal muscle mass index (ASMI). The telomere-to-single-copy gene ratio (T/S ratio) was converted to base pairs. Generalized linear models were performed to evaluate the association of ASMI with telomere length.<br><br>RESULTS: In multivariable adjustment regression models, higher ASMI was associated with longer telomeres in US adults (β = 70.2, P < 0.001, P trend<0.001). In participants with preserved muscle mass, the ASMI was related to longer telomere length (β = 75.1, P < 0.001), but not significantly in low muscle mass participants (β = 68.7, P = 0.30). Further subgroup analysis by a combination of age groups and muscle mass status showed positive association with young-preserved muscle mass (β = 82.6, P < 0.001), old-preserved muscle mass (β = 44.4, P = 0.12), young-low muscle mass (β = 135.4, P = 0.20), and old-low muscle mass (β = 52.7, P = 0.55). Because each additional year of chronological age was associated with telomeres that were 15.3 base pairs shorter, on average, this would equate to 5.4 fewer years of biological aging (82.6 ÷ 15.3) in the young-preserved muscle mass participants.<br><br>CONCLUSIONS: A higher ASMI is associated with longer telomeres. The prevention of skeletal muscle loss has the potential to delay telomere shortening and account for less biological aging.},
}
@article {pmid33301453,
year = {2020},
author = {Izano, MA and Cushing, LJ and Lin, J and Eick, SM and Goin, DE and Epel, E and Woodruff, TJ and Morello-Frosch, R},
title = {The association of maternal psychosocial stress with newborn telomere length.},
journal = {PloS one},
volume = {15},
number = {12},
pages = {e0242064},
pmid = {33301453},
issn = {1932-6203},
support = {P01 ES022841/ES/NIEHS NIH HHS/United States ; UG3 OD023272/OD/NIH HHS/United States ; UH3 OD023272/OD/NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Female ; Fetal Blood/cytology ; Humans ; Infant, Newborn ; Leukocytes/metabolism ; Male ; Maternal Health/*statistics &amp; numerical data ; Pregnancy ; Pregnant Women/*psychology ; Prenatal Exposure Delayed Effects/*genetics ; Stress, Psychological/complications/*epidemiology/genetics/physiopathology ; Telomere/metabolism ; Telomere Homeostasis/physiology ; *Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Telomere length in early life predicts later length, and shortened telomere length among adults and children has been linked to increased risk of chronic disease and mortality. Maternal stress during pregnancy may impact telomere length of the newborn.<br><br>METHODS: In a diverse cohort of 355 pregnant women receiving prenatal and delivery care services at two hospitals in San Francisco, California, we investigated the relationship between self-reported maternal psychosocial stressors during the 2nd trimester of pregnancy and telomere length (T/S ratio) in newborn umbilical cord blood leukocytes. We examined financial strain, food insecurity, high job strain, poor neighborhood quality, low standing in one's community, experience of stressful/traumatic life events, caregiving for a dependent family member, perceived stress, and unplanned pregnancy. We used linear regression and Targeted Minimum Loss-Based Estimation (TMLE) to evaluate the change in the T/S ratio associated with exposure to each stressor controlling for maternal age, education, parity, race/ethnicity, and delivery hospital.<br><br>RESULTS: In TMLE analyses, low community standing (-0.09; 95% confidence interval [CI]-0.19 to 0.00) and perceived stress (-0.07; 95% CI -0.15 to 0.021 was marginally associated with shorter newborn telomere length, but the associations were not significant after adjusting for multiple comparisons. All linear regression estimates were not statistically significant. Our results also suggest that the association between some maternal stressors and newborn telomere length varies by race/ethnicity and infant sex.<br><br>CONCLUSIONS: This study is the first to examine the joint effect of multiple stressors during pregnancy on newborn TL using a flexible modeling approach.},
}
@article {pmid33300081,
year = {2021},
author = {Li, H and Wang, B and Li, D and Li, J and Luo, Y and Dan, J},
title = {Roles of telomeres and telomerase in age‑related renal diseases (Review).},
journal = {Molecular medicine reports},
volume = {23},
number = {2},
pages = {},
pmid = {33300081},
issn = {1791-3004},
abstract = {Age‑related renal diseases, which account for various progressive renal disorders associated with cellular and organismal senescence, are becoming a substantial public health burden. However, their aetiologies are complicated and their pathogeneses remain poorly understood. Telomeres and telomerase are known to be essential for maintaining the integrity and stability of eukaryotic genomes and serve crucial roles in numerous related signalling pathways that activate renal functions, such as repair and regeneration. Previous studies have reported that telomere dysfunction served a role in various types of age‑related kidney disease through various different molecular pathways. The present review aimed to summarise the current knowledge of the association between telomeres and ageing‑related kidney diseases and explored the contribution of dysfunctional telomeres to these diseases. The findings may help to provide novel strategies for treating patients with renal disease.},
}
@article {pmid33296627,
year = {2020},
author = {Cherfils-Vicini, J and Gilson, É},
title = {[Longevity clocks: The promoting role of telomeres?].},
journal = {Medecine sciences : M/S},
volume = {36},
number = {12},
pages = {1113-1117},
doi = {10.1051/medsci/2020242},
pmid = {33296627},
issn = {1958-5381},
mesh = {Aging/genetics/physiology ; Animals ; Cellular Senescence/genetics ; Circadian Clocks/genetics/*physiology ; Humans ; Longevity/*genetics ; Telomere/*physiology ; },
abstract = {Aging is an alteration of our physiological capacities that is accompanied by an increased susceptibility to develop a wide range of diseases and which determines in large part our longevity. Despite intensive research on the origin of aging, its etiology is still poorly understood. We discuss here the hypothesis that the telomere shortening, programmed to start at the end of embryogenesis in numerous tissues, couples development with aging by a time-dependent regulation of a set of interconnected processes essential for the somatic maintenance of genome, epigenome, metabolism, circadian clock and immunity.},
}
@article {pmid33293233,
year = {2020},
author = {Lee, JJ and Lee, J and Lee, H},
title = {Alternative paths to telomere elongation.},
journal = {Seminars in cell &amp; developmental biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.semcdb.2020.11.003},
pmid = {33293233},
issn = {1096-3634},
abstract = {Overcoming cellular senescence that is induced by telomere shortening is critical in tumorigenesis. A majority of cancers achieve telomere maintenance through telomerase expression. However, a subset of cancers takes an alternate route for elongating telomeres: recombination-based alternative lengthening of telomeres (ALT). Current evidence suggests that break-induced replication (BIR), independent of RAD51, underlies ALT telomere synthesis. However, RAD51-dependent homologous recombination is required for homology search and inter-chromosomal telomere recombination in human ALT cancer cell maintenance. Accumulating evidence suggests that the breakdown of stalled replication forks, the replication stress, induces BIR at telomeres. Nevertheless, ALT research is still in its early stage and a comprehensive view is still unclear. Here, we review the current findings regarding the genesis of ALT, how this recombinant pathway is chosen, the epigenetic regulation of telomeres in ALT, and perspectives for clinical applications with the hope that this overview will generate new questions.},
}
@article {pmid33292353,
year = {2020},
author = {Noppert, GA and Feinstein, L and Dowd, JB and Stebbins, RC and Zang, E and Needham, BL and Meier, HCS and Simanek, A and Aiello, AE},
title = {Pathogen burden and leukocyte telomere length in the United States.},
journal = {Immunity &amp; ageing : I &amp; A},
volume = {17},
number = {1},
pages = {36},
pmid = {33292353},
issn = {1742-4933},
support = {K99AG062749-01A1/AG/NIA NIH HHS/United States ; AG000029-41/AG/NIA NIH HHS/United States ; T32 HD007168/HD/NICHD NIH HHS/United States ; R01AG033592/AG/NIA NIH HHS/United States ; T32 HD091058/HD/NICHD NIH HHS/United States ; P2C HD050924/HD/NICHD NIH HHS/United States ; },
abstract = {BACKGROUND: Prior studies in humans have suggested that telomere shortening may be accelerated by infection, but research on multiple pathogens and use of large population-based study samples has been limited. We estimated cross-sectional associations between seropositivity to five persistent pathogens (Herpes Simplex Virus Type-1 (HSV-1), Herpes Simplex Virus Type-2 (HSV-2), cytomegalovirus (CMV), Helicobacter pylori (H.pylori), and Hepatitis B) as well as total pathogen burden and leukocyte telomere length. Data were derived from the National Health and Nutrition Examination Survey (1999-2000) for individuals 20-49 years of age, N = 1708. We analyzed the influence of each pathogen separately, a pathogen count score and a latent class model of pathogen burden on log telomere length using linear regression models, adjusted for covariates.<br><br>RESULTS: Individuals in a latent pathogen burden class characterized by high probabilities of infection with HSV-1, CMV, and H. pylori, had significantly decreased log telomere length (- 0.30 [95% CI: - 0.36, - 0.24]) compared to those in a latent class characterized by low probabilities of all five infections. There were limited significant associations using other pathogen measures.<br><br>CONCLUSIONS: These results suggest that infection with specific combinations of pathogens may be one mechanism contributing to accelerated cellular senescence with possible origins early in the life course.},
}
@article {pmid33289498,
year = {2020},
author = {Thomas, MD and Sohail, S and Mendez, RM and Márquez-Magaña, L and Allen, AM},
title = {Racial Discrimination and Telomere Length in Midlife African American Women: Interactions of Educational Attainment and Employment Status.},
journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine},
volume = {},
number = {},
pages = {},
doi = {10.1093/abm/kaaa104},
pmid = {33289498},
issn = {1532-4796},
support = {UL1 GM118985/GM/NIGMS NIH HHS/United States ; },
abstract = {BACKGROUND: Over the life course, African American (AA) women have faster telomere attrition, a biological indicator of accelerated aging, than White women. Race, sex, age, and composite socioeconomic status (SES) modify associations of institutional racial discrimination and telomere length. However, interactions with everyday racial discrimination have not been detected in AA women, nor have interactions with individual socioeconomic predictors.<br><br>PURPOSE: We estimated statistical interaction of institutional and everyday racial discrimination with age, education, employment, poverty, and composite SES on telomere length among midlife AA women.<br><br>METHODS: Data are from a cross-section of 140 AA women aged 30-50 years residing in the San Francisco Bay Area. Participants completed questionnaires, computer-assisted self-interviews, physical examinations, and blood draws. Adjusted linear regression estimated bootstrapped racial discrimination-relative telomere length associations with interaction terms.<br><br>RESULTS: Racial discrimination did not interact with age, poverty, or composite SES measures to modify associations with telomere length. Interactions between independent SES variables were nonsignificant for everyday discrimination whereas institutional discrimination interacted with educational attainment and employment status to modify telomere length. After adjusting for covariates, we found that higher institutional discrimination was associated with shorter telomeres among employed women with lower education (β = -0.020; 95% confidence interval = -0.036, -0.003). Among unemployed women with higher education, higher institutional discrimination was associated with longer telomeres (β = 0.017; 95% confidence interval = 0.003, 0.032). Factors related to having a post-high school education may be protective against the negative effects of institutional racism on cellular aging for AA women.},
}
@article {pmid33287595,
year = {2020},
author = {Samuel, P and Tsapekos, M and de Pedro, N and Liu, AG and Casey Lippmeier, J and Chen, S},
title = {Ergothioneine Mitigates Telomere Shortening under Oxidative Stress Conditions.},
journal = {Journal of dietary supplements},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/19390211.2020.1854919},
pmid = {33287595},
issn = {1939-022X},
abstract = {Shortened telomeres are associated with aging and age-related diseases. Oxidative stress is thought to be a major contributor to telomere shortening, and antioxidants may be able to mitigate these effects. Ergothioneine is a naturally occurring amino acid with potent antioxidant properties. In order to investigate ergothioneine's effects on telomere length, we cultured primary human fibroblasts under standard and oxidative (10 µM H2O2) conditions and treated cells with 0.04, 0.1, 0.3, or 1.0 mg/ml ergothioneine for 8 weeks. Telomere length measurements were performed using high-throughput quantitative fluorescent in situ hybridization (HT Q-FISH). Treatment with ergothioneine transiently increased relative telomerase activity after 24 h (p < 0.05 for all concentrations). Under oxidative conditions, ergothioneine treatment resulted in significantly longer median telomere length and 20th percentile telomere length, and significantly reduced the percentage of short telomeres (<3 kilobase pairs) for all treatment concentrations after 8 weeks. Telomere shortening rate was also reduced. Overall, ergothioneine demonstrated beneficial effects by decreasing the rate of telomere shortening and preserving telomere length under oxidative stress conditions. Our data support a potential role for ergothioneine in oxidative stress-related conditions and healthy aging.},
}
@article {pmid33285115,
year = {2021},
author = {Nayis, A and Liebl, K and Frost, CV and Zacharias, M},
title = {Targeting Telomeres: Molecular Dynamics and Free Energy Simulation of Gold-Carbene Binding to DNA.},
journal = {Biophysical journal},
volume = {120},
number = {1},
pages = {101-108},
pmid = {33285115},
issn = {1542-0086},
abstract = {DNA sequences in regulatory regions and in telomers at the ends of chromosomes frequently contain tandem repeats of guanine nucleotides that can form stacked structures stabilized by Hoogsten pairing and centrally bound monovalent cations. The replication and elongation of telomeres requires the disruption of these G-quadruplex structures. Hence, drug molecules such as gold (Au)-carbene that stabilize G-quadruplexes may also interfere with the elongation of telomeres and, in turn, could be used to control cell replication and growth. To better understand the molecular mechanism of Au-carbene binding to G-quadruplexes, we employed molecular dynamics simulations and free energy simulations. Whereas very restricted mobility of two Au-carbene ligands was found upon binding as a doublet to one side of the G-quadruplex, much larger translational and orientational mobility was observed for a single Au-carbene binding at the second G-quadruplex surface. Comparative simulations on duplex DNA in the presence of Au-carbene ligands indicates a preference for the minor groove and weaker unspecific and more salt-dependent binding than to the G-quadruplex surface. Analysis of energetic contributions reveals a dominance of nonpolar and van der Waals interactions to drive binding. The simulations can also be helpful for proposing possible modifications that could improve Au-carbene affinity and specificity for G-quadruplex binding.},
}
@article {pmid33280738,
year = {2020},
author = {van Moorsel, CHM},
title = {Putting Genetics Into Practice: Challenges Associated With the Genetics of Short Telomere Syndromes.},
journal = {Chest},
volume = {158},
number = {6},
pages = {2249-2250},
doi = {10.1016/j.chest.2020.09.071},
pmid = {33280738},
issn = {1931-3543},
}
@article {pmid33276807,
year = {2020},
author = {Alhareeri, AA and Archer, KJ and Fu, H and Lyon, DE and Elswick, RK and Kelly, DL and Starkweather, AR and Elmore, LW and Bokhari, YA and Jackson-Cook, CK},
title = {Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study.},
journal = {Breast cancer research : BCR},
volume = {22},
number = {1},
pages = {137},
pmid = {33276807},
issn = {1465-542X},
support = {R01 NR012667/NR/NINR NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Survival rates for breast cancer (BC) have improved, but quality of life post-diagnosis/treatment can be adversely affected, with survivors reporting a constellation of psychoneurological symptoms (PNS) including stress, anxiety, depression, pain, fatigue, sleep disturbance, and cognitive dysfunction.<br><br>METHODS: To assess a potential relationship between telomere length (TL) and the development/persistence of PNS, we longitudinally studied 70 women (ages 23-71) with early stage BC (I-IIIA) at 5 time-points: prior to treatment (baseline), the mid-point of their chemotherapy cycle, 6 months, 1 year, and 2 years following the initiation of chemotherapy. Measures quantified included assessments of each of the PNS noted above and TL [using both a multiplex qPCR assay and a chromosome-specific fluorescence in situ hybridization (FISH) assay].<br><br>RESULTS: Variables associated with qPCR mean TLs were age (p = 0.004) and race (T/S ratios higher in Blacks than Whites; p = 0.019). Significant differences (mostly decreases) in chromosome-specific TLs were identified for 32 of the 46 chromosomal arms at the mid-chemo time-point (p = 0.004 to 0.049). Unexpectedly, the sequential administration of doxorubicin [Adriamycin], cyclophosphamide [Cytoxan], and docetaxel [Taxotere] (TAC regimen) was consistently associated with higher TLs, when compared to TLs in women receiving a docetaxel [Taxotere], Carboplatin [Paraplatin], and trastuzumab [Herceptin] [TCH] chemotherapy regimen [association was shown with both the qPCR and FISH assays (p = 0.036)]. Of the PNS, pain was significantly negatively associated with TL (higher pain; shorter telomeres) for a subset of chromosomal arms (5q, 8p, 13p, 20p, 22p, Xp, Xq) (p = 0.014-0.047). Chromosomal TLs were also associated with 7 of the 8 cognitive domains evaluated, with the strongest relationship being noted for chromosome 17 and the visual memory domain (shorter telomeres; lower scores).<br><br>CONCLUSIONS: We showed that race and age were significantly associated with telomere length in women treated for early stage BC and that acquired telomere alterations differed based on the woman's treatment regimen. Our study also demonstrated that pain and cognitive domain measures were significantly related to telomere values in this study cohort. Expanding upon the knowledge gained from this longitudinal study could provide insight about the biological cascade of events that contribute to PNS related to BC and/or its treatment.},
}
@article {pmid33276262,
year = {2021},
author = {Brown, R and Hailu, EM and Needham, BL and Roux, AD and Seeman, TE and Lin, J and Mujahid, MS},
title = {Neighborhood social environment and changes in leukocyte telomere length: The Multi-Ethnic Study of Atherosclerosis (MESA).},
journal = {Health &amp; place},
volume = {67},
number = {},
pages = {102488},
doi = {10.1016/j.healthplace.2020.102488},
pmid = {33276262},
issn = {1873-2054},
abstract = {Given limited research on the impact of neighborhood environments on accelerated biological aging, we examined whether changes in neighborhood socioeconomic and social conditions were associated with change in leukocyte telomere length using 10 years of longitudinal data from the Multi-Ethnic Study of Atherosclerosis (years 2000-2011; N = 1031; mean age = 61, SD = 9.4). Leukocyte telomere length change was corrected for regression to the mean and neighborhood was defined as census tract. Neighborhood socioeconomic indicators (factor-based score of income, education, occupation, and wealth of neighborhood) and neighborhood social environment indicators (aesthetic quality, social cohesion, safety) were obtained from the U.S Census/American Community Survey and via study questionnaire, respectively. Results of linear mixed-effects models showed that independent of individual sociodemographic characteristics, each unit of improvement in neighborhood socioeconomic status was associated with slower telomere length attrition over 10-years (β = 0.002; 95% Confidence Interval (CI): 0.0001, 0.004); whereas each unit of increase in safety (β = -0.043; 95% CI: -0.069, -0.016) and overall neighborhood social environment score (β = -0.005; 95% CI: -0.009, -0.0004) were associated with more pronounced telomere attrition, after additionally adjusting for neighborhood socioeconomic status. This study provides support for considerations of the broader social and socioeconomic contexts in relation to biological aging. Future research should explore potential psychosocial mechanisms underlying these associations using longitudinal study designs with repeated observations.},
}
@article {pmid33275732,
year = {2020},
author = {Schratz, KE},
title = {Extrahematopoietic manifestations of the short telomere syndromes.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {2020},
number = {1},
pages = {115-122},
pmid = {33275732},
issn = {1520-4383},
abstract = {The short telomere syndromes encompass a spectrum of clinical manifestations that present from infancy to late adulthood. They are caused by mutations in telomerase and other telomere maintenance genes and have a predominantly degenerative phenotype characterized by organ failure across multiple systems. They are collectively one of the most common inherited bone marrow failure syndromes; however, their most prevalent presentations are extrahematopoietic. This review focuses on these common nonhematologic complications, including pulmonary fibrosis, liver pathology, and immunodeficiency. The short telomere syndrome diagnosis informs clinical care, especially in guiding diagnostic evaluations as well as in the solid organ transplant setting. Early recognition allows an individualized approach to screening and management. This review illustrates a myriad of extrahematopoietic presentations of short telomere syndromes and how they impact clinical decisions.},
}
@article {pmid33272640,
year = {2020},
author = {Hanson, BM and Tao, X and Zhan, Y and Kim, JG and Klimczak, AM and Herlihy, NS and Scott, RT and Seli, E},
title = {Shorter telomere length of white blood cells is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization.},
journal = {Fertility and sterility},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.fertnstert.2020.09.164},
pmid = {33272640},
issn = {1556-5653},
abstract = {OBJECTIVE: To evaluate whether the telomere length of white blood cells (WBC) and cumulus cells (CC) in an infertile population is associated with ovarian and embryonic performance.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING: Academic-affiliated private practice.<br><br>PATIENTS: A total of 175 infertile women undergoing in vitro fertilization (IVF) at a single center between July 2017 and December 2018.<br><br>INTERVENTIONS: On the day of oocyte retrieval, genomic DNA was isolated from WBC and CC samples. Telomere length assessment was performed for both tissue types using quantitative real-time polymerase chain reaction. Telomere lengths were normalized using an AluYa5 sequence as an endogenous control, and linear regressions were applied.<br><br>MAIN OUTCOME MEASURES: This study assessed the relationship between relative telomere length of WBC and CC samples and measures of ovarian and embryonic performance. Specifically, patient age, antimüllerian hormone (AMH) level, peak estradiol (E2) level, number of oocytes retrieved, number of mature (MII) oocytes retrieved, blastulation rate, and aneuploidy rate were assessed.<br><br>RESULTS: There was a statistically significant relationship between WBC relative telomere length and patient age as well as rates of embryonic aneuploidy, with shorter WBC relative telomere length associated with increasing patient age (P<.01) and higher rates of aneuploidy (P=.01). No statistically significant relationships were observed between WBC relative telomere length and the other outcome measures. No significant associations were noted between CC relative telomere length and any outcomes assessed in this study.<br><br>CONCLUSION: The relationship between WBC relative telomere length and aneuploidy warrants further investigation, particularly because significant overlap exists between increasing maternal age and rates of embryonic aneuploidy.},
}
@article {pmid33272625,
year = {2021},
author = {M'kacher, R and Colicchio, B and Marquet, V and Borie, C and Najar, W and Hempel, WM and Heidingsfelder, L and Oudrhiri, N and Al Jawhari, M and Wilhelm-Murer, N and Miguet, M and Dieterlen, A and Deschênes, G and Tabet, AC and Junker, S and Grynberg, M and Fenech, M and Bennaceur-Griscelli, A and Voisin, P and Carde, P and Jeandidier, E and Yardin, C},
title = {Telomere aberrations, including telomere loss, doublets, and extreme shortening, are increased in patients with infertility.},
journal = {Fertility and sterility},
volume = {115},
number = {1},
pages = {164-173},
doi = {10.1016/j.fertnstert.2020.07.005},
pmid = {33272625},
issn = {1556-5653},
abstract = {OBJECTIVE: To test the hypothesis that telomere shortening and/or loss are risk factors for infertility.<br><br>DESIGN: Retrospective analysis of the telomere status in patients with infertility using conventional cytogenetic data collected prospectively.<br><br>SETTING: Academic centers.<br><br>PATIENT(S): Cytogenetic slides with cultured peripheral lymphocytes from 50 patients undergoing fertility treatment and 150 healthy donors, including 100 donors matched for age.<br><br>INTERVENTION(S): Cytogenetic slides were used to detect chromosomal and telomere aberrations.<br><br>MAIN OUTCOME MEASURE(S): Telomere length and telomere aberrations were analyzed after telomere and centromere staining.<br><br>RESULT(S): The mean telomere length of patients consulting for infertility was significantly less than that of healthy donors of similar age. Moreover, patients with infertility showed significantly more extreme telomere loss and telomere doublet formation than healthy controls. Telomere shortening and/or telomere aberrations were more pronounced in patients with structural chromosomal aberrations. Dicentric chromosomes were identified in 6/13 patients, with constitutional chromosomal aberrations leading to chromosomal instability that correlated with chromosomal end-to-end fusions.<br><br>CONCLUSION(S): Our findings demonstrate the feasibility of analyzing telomere aberrations in addition to chromosomal aberrations, using cytogenetic slides. Telomere attrition and/or dysfunction represent the main common cytogenetic characteristic of patients with infertility, leading to potential implications for fertility assessment. Pending further studies, these techniques that correlate the outcome of assisted reproduction and telomere integrity status may represent a novel and useful diagnostic and/or prognostic tool for medical care in this field.},
}
@article {pmid33270890,
year = {2020},
author = {Liu, JC and Li, QJ and He, MH and Hu, C and Dai, P and Meng, FL and Zhou, BO and Zhou, JQ},
title = {Swc4 positively regulates telomere length independently of its roles in NuA4 and SWR1 complexes.},
journal = {Nucleic acids research},
volume = {48},
number = {22},
pages = {12792-12803},
pmid = {33270890},
issn = {1362-4962},
mesh = {Adenosine Triphosphatases/*genetics ; Chromatin/genetics ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Fungal/genetics ; Histone Acetyltransferases/*genetics ; Histones/genetics ; Humans ; Multiprotein Complexes/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/genetics ; },
abstract = {Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C.},
}
@article {pmid33269665,
year = {2020},
author = {Ackerson, SM and Gable, CI and Stewart, JA},
title = {Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {19},
number = {24},
pages = {3491-3507},
pmid = {33269665},
issn = {1551-4005},
abstract = {CST (CTC1-STN1-TEN1) is a heterotrimeric, RPA-like complex that binds to single-stranded DNA (ssDNA) and functions in the replication of telomeric and non-telomeric DNA. Previous studies demonstrated that deletion of CTC1 results in decreased cell proliferation and telomere DNA damage signaling. However, a detailed analysis of the consequences of conditional CTC1 knockout (KO) has not been fully elucidated. Here, we investigated the effects of CTC1 KO on cell cycle progression, genome-wide replication and activation of the DNA damage response. Consistent with previous findings, we demonstrate that CTC1 KO results in decreased cell proliferation, G2 arrest and RPA-bound telomeric ssDNA. However, despite the increased levels of telomeric RPA-ssDNA, global ATR-dependent CHK1 and p53 phosphorylation was not detected in CTC1 KO cells. Nevertheless, we show that RPA-ssDNA does activate ATR, leading to the phosphorylation of RPA and autophosphorylation of ATR. Further analysis determined that inactivation of ATR, but not CHK1 or ATM, suppressed the accumulation of G2 arrested cells and phosphorylated RPA following CTC1 removal. These results suggest that ATR is localized and active at telomeres but is unable to elicit a global checkpoint response through CHK1. Furthermore, CTC1 KO inhibited CHK1 phosphorylation following hydroxyurea-induced replication stress. Additional studies revealed that this suppression of CHK1 phosphorylation, following replication stress, is caused by decreased levels of the ATR activator TopBP1. Overall, our results identify CST as a novel regulator of the ATR-CHK1 pathway.},
}
@article {pmid33264397,
year = {2020},
author = {Stivison, EA and Young, KJ and Symington, LS},
title = {Interstitial telomere sequences disrupt break-induced replication and drive formation of ectopic telomeres.},
journal = {Nucleic acids research},
volume = {48},
number = {22},
pages = {12697-12710},
pmid = {33264397},
issn = {1362-4962},
support = {R35 GM126997/GM/NIGMS NIH HHS/United States ; },
mesh = {DEAD-box RNA Helicases/*genetics ; DNA Breaks, Double-Stranded ; DNA Damage/genetics ; DNA Helicases/genetics ; DNA Polymerase III/genetics ; DNA Repair/genetics ; DNA Replication/*genetics ; *Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Break-induced replication (BIR) is a mechanism used to heal one-ended DNA double-strand breaks, such as those formed at collapsed replication forks or eroded telomeres. Instead of utilizing a canonical replication fork, BIR is driven by a migrating D-loop and is associated with a high frequency of mutagenesis. Here we show that when BIR encounters an interstitial telomere sequence (ITS), the machinery frequently terminates, resulting in the formation of an ectopic telomere. The primary mechanism to convert the ITS to a functional telomere is by telomerase-catalyzed addition of telomeric repeats with homology-directed repair serving as a back-up mechanism. Termination of BIR and creation of an ectopic telomere is promoted by Mph1/FANCM helicase, which has the capacity to disassemble D-loops. Other sequences that have the potential to seed new telomeres but lack the unique features of a natural telomere sequence, do not terminate BIR at a significant frequency in wild-type cells. However, these sequences can form ectopic telomeres if BIR is made less processive. Our results support a model in which features of the ITS itself, such as the propensity to form secondary structures and telomeric protein binding, pose a challenge to BIR and increase the vulnerability of the D-loop to dissociation by helicases, thereby promoting ectopic telomere formation.},
}
@article {pmid33264196,
year = {2020},
author = {Wei, H and Zhang, C and Silveyra, P},
title = {The Relationships Between Prenatal Smoking Exposure and Telomere Lengths in Fetuses, Infants, and Children: A Systematic Literature Review.},
journal = {Journal of addictions nursing},
volume = {31},
number = {4},
pages = {243-252},
doi = {10.1097/JAN.0000000000000364},
pmid = {33264196},
issn = {1548-7148},
abstract = {OBJECTIVE: The aim of this study was to evaluate the relationships between prenatal smoking exposure and telomere lengths (TLs) in fetuses, infants, and children.<br><br>METHODS: This is a systematic review guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Databases searched were Biomedical Reference Collection, MEDLINE via PubMed, CINAHL, PsycINFO, and Google Scholar. The latest search was on October 18, 2019.<br><br>RESULTS: Seven studies met the inclusion criteria and thus were reviewed. Five of the studies showed significant inverse relationships between prenatal tobacco exposure and TLs in fetuses, infants, and children. One study showed a modification effect of the postconceptual age, indicating that older fetuses with prenatal smoking exposure had shorter TLs than their counterparts. This effect was more prominent after 93 days of postconception. Another study reported a finding that was contrary to the above results, showing that the telomeres of newborns with prenatal smoking exposure were longer than those of their counterparts.<br><br>CONCLUSION/RECOMMENDATIONS: This review shows that the impact of prenatal smoking on the health of unborn fetuses, infants, and children is an understudied area. Because of the inconsistent findings and cross-sectional study designs, more research is required, especially longitudinally studies. Nonetheless, the findings of the review provide partial evidence that prenatal smoking can potentially impact the genetic biomarker, TLs, and, thus, health of fetuses, infants, and children. The evidence confirms the current practice that pregnant women should be encouraged to stop smoking as soon as they become pregnant.},
}
@article {pmid33261558,
year = {2020},
author = {Eckhardt, F and Pauliny, A and Rollings, N and Mutschmann, F and Olsson, M and Kraus, C and Kappeler, PM},
title = {Stress-related changes in leukocyte profiles and telomere shortening in the shortest-lived tetrapod, Furcifer labordi.},
journal = {BMC evolutionary biology},
volume = {20},
number = {1},
pages = {160},
pmid = {33261558},
issn = {1471-2148},
mesh = {Animals ; Leukocytes/*metabolism ; Lizards/*genetics ; *Longevity/genetics ; Madagascar ; Stress, Physiological/*genetics ; *Telomere/genetics ; *Telomere Shortening/genetics ; },
abstract = {BACKGROUND: Life history theory predicts that during the lifespan of an organism, resources are allocated to either growth, somatic maintenance or reproduction. Resource allocation trade-offs determine the evolution and ecology of different life history strategies and define an organisms' position along a fast-slow continuum in interspecific comparisons. Labord's chameleon (Furcifer labordi) from the seasonal dry forests of Madagascar is the tetrapod species with the shortest reported lifespan (4-9 months). Previous investigations revealed that their lifespan is to some degree dependent on environmental factors, such as the amount of rainfall and the length of the vegetation period. However, the intrinsic mechanisms shaping such a fast life history remain unknown. Environmental stressors are known to increase the secretion of glucocorticoids in other vertebrates, which, in turn, can shorten telomeres via oxidative stress. To investigate to what extent age-related changes in these molecular and cellular mechanisms contribute to the relatively short lifetime of F. labordi, we assessed the effects of stressors indirectly via leukocyte profiles (H/L ratio) and quantified relative telomere length from blood samples in a wild population in Kirindy Forest. We compared our findings with the sympatric, but longer-lived sister species F. cf. nicosiai, which exhibit the same annual timing of reproductive events, and with wild-caught F. labordi that were singly housed under ambient conditions.<br><br>RESULTS: We found that H/L ratios were consistently higher in wild F. labordi compared to F. cf. nicosiai. Moreover, F. labordi already exhibited relatively short telomeres during the mating season when they were 3-4 months old, and telomeres further shortened during their post-reproductive lives. At the beginning of their active season, telomere length was relatively longer in F. cf. nicosiai, but undergoing rapid shortening towards the southern winter, when both species gradually die off. Captive F. labordi showed comparatively longer lifespans and lower H/L ratios than their wild counterparts.<br><br>CONCLUSION: We suggest that environmental stress and the corresponding accelerated telomere attrition have profound effects on the lifespan of F. labordi in the wild, and identify physiological mechanisms potentially driving their relatively early senescence and mortality.},
}
@article {pmid33261163,
year = {2020},
author = {Zannas, AS and Kosyk, O and Leung, CS},
title = {Prolonged Glucocorticoid Exposure Does Not Accelerate Telomere Shortening in Cultured Human Fibroblasts.},
journal = {Genes},
volume = {11},
number = {12},
pages = {},
pmid = {33261163},
issn = {2073-4425},
abstract = {Psychosocial stress, especially when chronic or excessive, can increase disease risk and accelerate biological aging. Although the underlying mechanisms are unclear, in vivo studies have associated exposure to stress and glucocorticoid stress hormones with shorter telomere length. However, the extent to which prolonged glucocorticoid exposure can shorten telomeres in controlled experimental settings remains unknown. Using a well-characterized cell line of human fibroblasts that undergo gradual telomere shortening during serial passaging in culture, we show that prolonged exposure (up to 51 days) to either naturalistic levels of the human endogenous glucocorticoid cortisol or the more potent synthetic glucocorticoid dexamethasone is not sufficient to accelerate telomere shortening. While our findings await extension in other cell types and biological contexts, they indicate that the in vivo association of psychosocial stress with telomere shortening is unlikely to be mediated by a direct and universal glucocorticoid effect on telomere length.},
}
@article {pmid33258446,
year = {2020},
author = {Schmutz, I and Mensenkamp, AR and Takai, KK and Haadsma, M and Spruijt, L and de Voer, RM and Choo, SS and Lorbeer, FK and van Grinsven, EJ and Hockemeyer, D and Jongmans, MC and de Lange, T},
title = {TINF2 is a haploinsufficient tumor suppressor that limits telomere length.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {33258446},
issn = {2050-084X},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; W81XWH-19-1-0586//U.S. Department of Defense/International ; 133396-RSG-19-029-01-DMC//American Cancer Society/International ; R35 CA210036/CA/NCI NIH HHS/United States ; 577521/MRA/Melanoma Research Alliance/United States ; },
abstract = {Telomere shortening is a presumed tumor suppressor pathway that imposes a proliferative barrier (the Hayflick limit) during tumorigenesis. This model predicts that excessively long somatic telomeres predispose to cancer. Here, we describe cancer-prone families with two unique TINF2 mutations that truncate TIN2, a shelterin subunit that controls telomere length. Patient lymphocyte telomeres were unusually long. We show that the truncated TIN2 proteins do not localize to telomeres, suggesting that the mutations create loss-of-function alleles. Heterozygous knock-in of the mutations or deletion of one copy of TINF2 resulted in excessive telomere elongation in clonal lines, indicating that TINF2 is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the TINF2 truncations predispose to a tumor syndrome. We conclude that TINF2 acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.},
}
@article {pmid33257117,
year = {2021},
author = {Zhou, L and Li, L and Hao, G and Li, B and Yang, S and Wang, N and Liang, J and Sun, H and Ma, S and Yan, L and Zhao, C and Wei, Y and Niu, Y and Zhang, R},
title = {Sperm mtDNA copy number, telomere length, and seminal spermatogenic cells in relation to ambient air pollution: Results of a cross-sectional study in Jing-Jin-Ji region of China.},
journal = {Journal of hazardous materials},
volume = {406},
number = {},
pages = {124308},
doi = {10.1016/j.jhazmat.2020.124308},
pmid = {33257117},
issn = {1873-3336},
abstract = {Evidences on the association of air pollutants and semen quality were limited and mechanism-based biomarkers were sparse. We enrolled 423 men at a fertility clinic in Shijiazhuang, China to evaluate associations between air pollutants and semen quality parameters including the conventional ones, sperm mitochondrial DNA copy number (mtDNAcn), sperm telomere length (STL) and seminal spermatogenic cells. PM2.5, PM10, CO, SO2, NO2 and O3 exposure during lag0-90, lag0-9, lag10-14 and lag70-90 days were evaluated with ordinary Kringing model. The exposure-response correlations were analyzed with multiple linear regression models. CO, PM2.5 and PM10 were adversely associated with conventional semen parameters including sperm count, motility and morphology. Besides, CO was positively associated with seminal primary spermatocyte (lag70-90, 0.49; 0.14, 0.85) and mtDNAcn (lag0-90, 0.37; 0.12, 0.62, lag10-14, 0.31; 0.12, 0.49), negatively associated with STL (lag0-9, -0.30; -0.57, -0.03). PM2.5 was positively associated with mtDNAcn (0.50; 0.24, 0.75 and 0.38; 0.02, 0.75 for lag0-90 and lag70-90) while negatively associated with STL (lag70-90, -0.49; -0.96, -0.01). PM10 and NO2 were positively associated with mtDNAcn. Our findings indicate CO and PM might impair semen quality testicularly and post-testicularly while seminal spermatogenic cell, STL and mtDNAcn change indicate necessity for more attention on these mechanisms.},
}
@article {pmid33257049,
year = {2021},
author = {Wu, M and Wang, L and Song, L and Liu, B and Liu, Y and Bi, J and Liu, Q and Chen, K and Li, Y and Xia, W and Xu, S and Cao, Z and Zhou, A and Tian, Y and Wang, Y},
title = {The association between prenatal exposure to thallium and shortened telomere length of newborns.},
journal = {Chemosphere},
volume = {265},
number = {},
pages = {129025},
doi = {10.1016/j.chemosphere.2020.129025},
pmid = {33257049},
issn = {1879-1298},
mesh = {Child ; China ; Cohort Studies ; Female ; Humans ; Infant, Newborn ; Maternal Exposure/adverse effects ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Telomere ; Telomere Shortening ; *Thallium/toxicity ; },
abstract = {BACKGROUND: Thallium is a widely known toxic heavy metal that has been reported have embryo toxicity.<br><br>OBJECTIVE: We aimed to investigate the relationship of prenatal thallium exposure with neonatal telomere length.<br><br>METHODS: A total of 746 mother-newborn pairs were recruited from Wuhan Children Hospital between November 2013 and March 2015 in Wuhan City, China. Maternal thallium exposure levels were measured in spot urine samples collected during the three trimesters and during hospital delivery using inductively coupled plasma mass spectrometry. Neonatal relative telomere length (rTL) was measured by a real-time quantitative polymerase chain reaction assay in cord blood. Multiple informant models were used to evaluate the association of maternal thallium exposure with neonatal rTL.<br><br>RESULTS: After adjustment for multiple potential confounders, each 25% incremental increase of maternal thallium exposure, measured in urine samples collected during hospital delivery, was associated with a 1.85% shortened neonatal rTL (95% CI: -3.62%, -0.05%; P = 0.044). Similarly, mothers in the highest quartile of urinary thallium exposure had a 11.74% (95% CI: -21.57%, -0.68%; P = 0.038) shorter cord blood leukocyte rTL than those in the lowest quartile. However, no significant association was found between neonatal rTL and maternal thallium exposure measured in urine samples collected during the three trimesters of pregnancy.<br><br>CONCLUSIONS: This study reveals that prenatal thallium exposure was related to shortened neonatal telomere length in Chinese population, pointing to the important role of thallium exposure in accelerating biological aging.},
}
@article {pmid33256968,
year = {2021},
author = {Mergny, JL and Guittat, L and Ségal-Bendirdjian, É},
title = {[Are telomeres and telomerase still relevant targets in oncology?].},
journal = {Bulletin du cancer},
volume = {108},
number = {1},
pages = {30-38},
doi = {10.1016/j.bulcan.2020.10.007},
pmid = {33256968},
issn = {1769-6917},
mesh = {Enzyme Inhibitors/*pharmacology ; Humans ; Immunotherapy/methods ; Neoplasms/*enzymology/immunology/therapy ; Nucleic Acids/chemistry ; Oncolytic Virotherapy ; Oncolytic Viruses/immunology ; RNA/*physiology ; Telomerase/antagonists &amp; inhibitors/*physiology ; Telomere/*physiology ; },
}
@article {pmid33250812,
year = {2020},
author = {Mehrsafar, AH and Serrano Rosa, MA and Moghadam Zadeh, A and Gazerani, P},
title = {Stress, Professional Lifestyle, and Telomere Biology in Elite Athletes: A Growing Trend in Psychophysiology of Sport.},
journal = {Frontiers in psychology},
volume = {11},
number = {},
pages = {567214},
pmid = {33250812},
issn = {1664-1078},
abstract = {Professional lifestyle and championship period often put a great deal of pressure on athletes, who usually experience highly stressful periods during training for competitions. Recently, biomarkers of cellular aging, telomere length (TL) and telomerase activity (TA), have been considered to investigate the effects of stress and lifestyle factors. Studies in non-athletic populations have shown that stress and poor lifestyle decrease TL and TA. On the other hand, it has been shown that in general, exercise increases TL and its activity, although the underlying mechanisms remained largely unexplored. TL and TA outcomes in elite athletes remain inconclusive and mainly affected by confounding factors, such as age. Elite athletes, therefore, might offer a unique target group for studying exercise-telomere hypothesis for further investigation of the roles of stressors on telomere-related biomarkers. In this perspective, we highlight the potentials for studying these psychophysiological markers in elite athletes in order to understand stress-aging relationship and potential underlying mechanisms. Moreover, we present important methodological aspects that could help in the development of future experimental designs.},
}
@article {pmid33249778,
year = {2020},
author = {Opstad, TB and Berg, TJ and Holte, KB and Arnesen, H and Solheim, S and Seljeflot, I},
title = {Reduced leukocyte telomere lengths and sirtuin 1 gene expression in long-term survivors of type 1 diabetes: A Dialong substudy.},
journal = {Journal of diabetes investigation},
volume = {},
number = {},
pages = {},
doi = {10.1111/jdi.13470},
pmid = {33249778},
issn = {2040-1124},
support = {//Oslo Diabetes Research Centre/ ; //Stein Erik Hagen Foundation for Clinical Heart Research, Oslo Norway/ ; //The Norwegian Council for Cardiovascular Diseases/ ; //Norwegian Diabetics' Centre/ ; },
abstract = {AIMS/INTRODUCTION: The shortening of leukocyte telomere length with age has been associated with coronary disease, whereas the association with type 1 diabetes is unclear. We aimed to explore telomere lengths in diabetes patients with regard to coronary artery disease, compared with healthy controls. The longevity factors sirtuin 1 and growth-differentiating factor 11 were investigated accordingly.<br><br>MATERIALS AND METHODS: We carried out a cross-sectional study of 102 participants with long-term type 1 diabetes and 75 controls (mean age 62 and 63 years, respectively), where 88 cases and 60 controls without diagnosed coronary artery disease completed computed tomography coronary angiography. Telomere lengths and gene expression of sirtuin 1 and growth-differentiating factor 11 were quantified in leukocytes.<br><br>RESULTS: Telomere lengths and sirtuin 1 were reduced in diabetes patients versus controls, medians (25th to 75th percentiles): 0.97 (0.82-1.15) versus 1.08 (0.85-1.29) and 0.88 (0.65-1.14) vs 1.01 (0.78-1.36), respectively, adjusted P < 0.05, both. Previous coronary artery disease in diabetes patients (n = 15) was associated with lower sirtuin 1 and growth-differentiating factor 11 messenger ribonucleic acid expression (adjusted P < 0.03, both). In the combined diabetes and control group, previous artery coronary disease (n = 18) presented with significantly shorter telomeres (adjusted P = 0.038). Newly diagnosed obstructive coronary artery disease, defined as >50% stenosis, was not associated with the investigated variables.<br><br>CONCLUSIONS: Long-term type 1 diabetes presented with reduced telomeres and sirtuin 1 expression, with additional reduction in diabetes patients with previous coronary artery disease, showing their importance for cardiovascular disease development with potential as novel biomarkers in diabetes and coronary artery disease.},
}
@article {pmid33248477,
year = {2021},
author = {Cheng, F and Carroll, L and Joglekar, MV and Januszewski, AS and Wong, KK and Hardikar, AA and Jenkins, AJ and Ma, RCW},
title = {Diabetes, metabolic disease, and telomere length.},
journal = {The lancet. Diabetes &amp; endocrinology},
volume = {9},
number = {2},
pages = {117-126},
doi = {10.1016/S2213-8587(20)30365-X},
pmid = {33248477},
issn = {2213-8595},
mesh = {Diabetes Complications/*genetics ; Diabetes Mellitus/*genetics ; Humans ; Metabolic Diseases/*genetics ; Risk Factors ; Telomere/*genetics ; },
abstract = {Telomeres are regions of repetitive nucleotide sequences at the ends of chromosomes. Telomere length is a marker of DNA damage, which is often considered a biomarker for biological ageing, and has also been linked with cardiovascular disease, diabetes, and cancer. Emerging studies have highlighted the role of genetic and environmental factors, and explored the effect of modulating telomere length. We provide an overview of studies to date on diabetes and telomere length, and compare different methods and assays for evaluating telomere length and telomerase activity. We highlight the limitations of current studies and areas that warrant further research to unravel the link between diabetes and telomere length. The value of adding telomere length to clinical risk factors to improve risk prediction of diabetes and related complications also merits further investigation.},
}
@article {pmid33244044,
year = {2020},
author = {Alhendi, ASN and Royle, NJ},
title = {The absence of (TCAGGG)n repeats in some telomeres, combined with variable responses to NR2F2 depletion, suggest that this nuclear receptor plays an indirect role in the alternative lengthening of telomeres.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {20597},
pmid = {33244044},
issn = {2045-2322},
abstract = {The alternative lengthening of telomeres (ALT) facilitates telomere lengthening by a DNA strand invasion and copying mechanism. The nuclear receptors (NRs), NR2F2 and NR2C2, can bind to (TCAGGG)n variant repeats within telomeres and it has been proposed that this facilitates telomere interactions in ALT+ cells. Here we show that the frequency of cells with detectable NR2F2 and NR2C2 nuclear foci varies considerably between ALT+ cell lines and does not correlate with the level of protein expression. In addition, four of five ALT+ cell lines lack (TCAGGG)n repeats in some telomeres, indicating that direct NR binding does not play a role in ALT at these telomeres. NR2F2-depletion altered the abundance of C-circles and APBs but the direction of the response was inconsistent between three ALT+ cell lines. Moreover, transcriptome analysis following NR2F2-depletion in the ALT+ cell lines revealed different very responses. For example, NR2F2-depletion down-regulated many genes in U2OS cells, consistent with the cell cycle arrest and changes to ALT markers, but these features were not shared by the other two ALT+ cell lines. Among 86 ALT-associated genes, only MND1 showed consistent down-regulation across three NR2F2-depleted ALT+ cell lines. Altogether our data suggest that NR2F2 does not play a direct role in ALT and we speculate about an alternative role for this NR in a DNA damage response at telomeres.},
}
@article {pmid33243459,
year = {2020},
author = {Moazzam, M and Yim, T and Kumaresan, V and Henderson, DC and Farrer, LA and Zhang, H},
title = {Analysis of telomere length variation and Shelterin complex subunit gene expression changes in ethanol-exposed human embryonic stem cells.},
journal = {Journal of psychiatric research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpsychires.2020.11.027},
pmid = {33243459},
issn = {1879-1379},
abstract = {Telomeres protect chromosome ends from degradation. Telomere length (TL) can be altered by aging and environmental stress. Shortened TL has been observed in peripheral blood leukocytes of alcohol dependent subjects and ethanol-exposed somatic cells. To understand the impact of ethanol on telomeres in pluripotent stem cells, we investigated the influence of ethanol on TL and the expression of six Shelterin complex subunit or telomere-regulating genes (POT1, RAP1, TIN2, TPP1, TRF1, and TRF2) in human embryonic stem cells (hESCs), which were exposed to 0, 25, 50, or 100 mM of ethanol for 3, 7, or 14 days. Ethanol-induced TL and Shelterin complex subunit gene expression changes were examined by quantitative polymerase chain reactions. Two-way ANOVA tests indicated that TL variation and expression changes of four associated Shelterin complex subunit genes (POT1, TPP1, TIN2, and TRF2) were mainly dependent on the length of ethanol exposure, while TRF1 and RAP1expression was influenced by ethanol concentration, exposure time, and the interaction of ethanol concentration and exposure time. Tukey's multiple comparison tests showed that TL and the expression of POT1, RAP1, TIN2, TPP1, and TRF1 were decreased after a 7-day (versus a 3-day) ethanol exposure. However, the decreased expression of all six Shelterin complex subunit genes was recovered and TL was not further shortened after a 14-day (versus a 7-day) ethanol exposure, likely due to the adaptation of hESCs to ethanol-induced stress. Our study provided further evidence that TL is regulated and maintained by telomere-regulating genes in stem cells under ethanol stress.},
}
@article {pmid33243026,
year = {2019},
author = {Needham, BL and Salerno, S and Roberts, E and Boss, J and Allgood, KL and Mukherjee, B},
title = {Do black/white differences in telomere length depend on socioeconomic status?.},
journal = {Biodemography and social biology},
volume = {65},
number = {4},
pages = {287-312},
pmid = {33243026},
issn = {1948-5573},
support = {R01 AG033592/AG/NIA NIH HHS/United States ; },
abstract = {Social and economic disadvantage are hypothesized to increase the risk of disease and death via accelerated biological aging. Given that US blacks are socially and economically disadvantaged relative to whites, health disparities scholars expected that blacks would have shorter telomere length-a biomarker of cell aging-than whites. Yet the majority of studies have found that blacks have longer telomere length than whites. Using data from the National Health and Nutrition Examination Survey (n = 3,761; 28.3% non-Hispanic black, 71.7% non-Hispanic white), we found that leukocyte telomere length was 4.00% (95% CI: 1.12%, 6.87%) longer among blacks compared to whites in the full sample, but differences were greatest among those with lower SES (5.66%; 95% CI: 0.10%, 10.32%), intermediate among those with middle SES (4.14%; 95% CI: 0.05%, 8.24%), and smallest among those with higher SES (2.33%; 95% CI: -3.02%, 7.67%). These results challenge purely genetic explanations for race differences in telomere length and point to a potential social-environmental cause of longer telomere length in US blacks.},
}
@article {pmid33242471,
year = {2020},
author = {Baskind, MJ and Hawkins, J and Heyman, MB and Wojcicki, JM},
title = {Obesity at Age 6 Months Is Associated with Shorter Preschool Leukocyte Telomere Length Independent of Parental Telomere Length.},
journal = {The Journal of pediatrics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpeds.2020.11.025},
pmid = {33242471},
issn = {1097-6833},
abstract = {OBJECTIVE: To assess whether early modifiable dietary factors and obesity measures are associated with leukocyte telomere length at 3-5 years of age after controlling for the heritability of leukocyte telomere length in a prospective cohort of low-income Latina mothers and their children in San Francisco.<br><br>STUDY DESIGN: We analyzed data from the Latinx, Eating and Diabetes cohort, a prospective study of 97 woman-infant dyads. We used linear regression models to evaluate associations between early dietary factors and obesity measures and child leukocyte telomere length at 3-5 years of age. Multivariable models included child age at the time of telomere collection, breastfeeding at 6 months (yes/no), obesity at 6 months, maternal education, child sex, and maternal and paternal leukocyte telomere length.<br><br>RESULTS: Data for 73 of the 97 children at 3-5 years of age were analyzed. Any breastfeeding at 6 months was positively associated (β = 0.14; P = .02) and obesity at 6 months was negatively associated (β = -0.21; P < .001) with leukocyte telomere length in bivariate analyses. In multivariable models including parental leukocyte telomere length, obesity at 6 months was associated with a shorter leukocyte telomere length at 3-5 years of age (β = -0.15; P = .02). Analyses of dietary factors showed high flavored milk consumption at 3 years of age was associated with shorter leukocyte telomere length after adjustment for possible confounders.<br><br>CONCLUSIONS: In a low-income Latinx population, obesity at 6 months of age is negatively associated with cellular health at 3-5 years of age after controlling for genetic factors (parental leukocyte telomere length) associated with leukocyte telomere length. Early life obesity may be more deleterious for cellular health than obesity later in childhood.},
}
@article {pmid33242411,
year = {2020},
author = {Luxton, JJ and McKenna, MJ and Taylor, LE and George, KA and Zwart, SR and Crucian, BE and Drel, VR and Garrett-Bakelman, FE and Mackay, MJ and Butler, D and Foox, J and Grigorev, K and Bezdan, D and Meydan, C and Smith, SM and Sharma, K and Mason, CE and Bailey, SM},
title = {Temporal Telomere and DNA Damage Responses in the Space Radiation Environment.},
journal = {Cell reports},
volume = {33},
number = {10},
pages = {108435},
doi = {10.1016/j.celrep.2020.108435},
pmid = {33242411},
issn = {2211-1247},
abstract = {Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration's (NASA's) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.},
}
@article {pmid33242406,
year = {2020},
author = {Luxton, JJ and McKenna, MJ and Lewis, A and Taylor, LE and George, KA and Dixit, SM and Moniz, M and Benegas, W and Mackay, MJ and Mozsary, C and Butler, D and Bezdan, D and Meydan, C and Crucian, BE and Zwart, SR and Smith, SM and Mason, CE and Bailey, SM},
title = {Telomere Length Dynamics and DNA Damage Responses Associated with Long-Duration Spaceflight.},
journal = {Cell reports},
volume = {33},
number = {10},
pages = {108457},
doi = {10.1016/j.celrep.2020.108457},
pmid = {33242406},
issn = {2211-1247},
abstract = {Telomere length dynamics and DNA damage responses were assessed before, during, and after one-year or shorter duration missions aboard the International Space Station (ISS) in a comparatively large cohort of astronauts (n = 11). Although generally healthy individuals, astronauts tended to have significantly shorter telomeres and lower telomerase activity than age- and sex-matched ground controls before and after spaceflight. Although telomeres were longer during spaceflight irrespective of mission duration, telomere length shortened rapidly upon return to Earth, and overall astronauts had shorter telomeres after spaceflight than they did before; inter-individual differences were identified. During spaceflight, all crewmembers experienced oxidative stress, which positively correlated with telomere length dynamics. Significantly increased frequencies of chromosomal inversions were observed during and after spaceflight; changes in cell populations were also detected. We propose a telomeric adaptive response to chronic oxidative damage in extreme environments, whereby the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway is transiently activated in normal somatic cells.},
}
@article {pmid33241110,
year = {2020},
author = {Chartrand, P and Sfeir, A},
title = {A single-molecule view of telomerase regulation at telomeres.},
journal = {Molecular &amp; cellular oncology},
volume = {7},
number = {6},
pages = {1818537},
pmid = {33241110},
issn = {2372-3556},
abstract = {Telomerase plays a key role in the immortalization of cancer cells by maintaining telomeres length. Using single-molecule imaging of telomerase RNA molecules in cancer cells, we recently reported novel insights into the role of Cajal bodies in telomerase biogenesis and the regulation of telomerase recruitment to telomeres.},
}
@article {pmid33240643,
year = {2020},
author = {Cherdsukjai, P and Buddhachat, K and Brown, J and Kaewkool, M and Poommouang, A and Kaewmong, P and Kittiwattanawong, K and Nganvongpanit, K},
title = {Age relationships with telomere length, body weight and body length in wild dugong (Dugong dugon).},
journal = {PeerJ},
volume = {8},
number = {},
pages = {e10319},
pmid = {33240643},
issn = {2167-8359},
abstract = {The ability to estimate age and determine the growth status of free-ranging dugongs (Dugong dugon) is vital to providing insight into the basic biology of this endangered species. Currently, age estimation in dugong carcasses relies on counting dentin growth layer groups (GLGs) in tusks, but a disadvantage is they need to be intact. We explored whether measures of telomere length could be used as an alternative approach to age estimation in dugongs given that in other species, telomere length and age are inversely related. In this study, relative telomere length (rTL) was measured by qPCR in skin samples from 24 dugongs of varying ages determined by counts of GLGs. In addition, relationships between age by GLG counts and body weight and length and were examined. Our findings indicate that age estimated by GLGs was negatively correlated with telomere length using the logistic formula with a rate of telomere attrition of approximately 0.036 rTL/year between the ages of 5-20 years. By comparison, both body weight and length were positively correlated with GLG-based age, with growth rates of ~8.8 kg/year for weight and ~3.58 cm/year for length, respectively. After that, growth rates slowed substantially and then plateaued. The results suggest that physical maturity in dugongs occurs at 20 years of age and that measures of rTL might serve as a tool for age estimation in dugongs, living and deceased.},
}
@article {pmid33239785,
year = {2021},
author = {Markiewicz-Potoczny, M and Lobanova, A and Loeb, AM and Kirak, O and Olbrich, T and Ruiz, S and Lazzerini Denchi, E},
title = {TRF2-mediated telomere protection is dispensable in pluripotent stem cells.},
journal = {Nature},
volume = {589},
number = {7840},
pages = {110-115},
pmid = {33239785},
issn = {1476-4687},
abstract = {In mammals, telomere protection is mediated by the essential protein TRF2, which binds chromosome ends and ensures genome integrity1,2. TRF2 depletion results in end-to-end chromosome fusions in all cell types that have been tested so far. Here we find that TRF2 is dispensable for the proliferation and survival of mouse embryonic stem (ES) cells. Trf2-/- (also known as Terf2) ES cells do not exhibit telomere fusions and can be expanded indefinitely. In response to the deletion of TRF2, ES cells exhibit a muted DNA damage response that is characterized by the recruitment of γH2AX-but not 53BP1-to telomeres. To define the mechanisms that control this unique DNA damage response in ES cells, we performed a CRISPR-Cas9-knockout screen. We found a strong dependency of TRF2-null ES cells on the telomere-associated protein POT1B and on the chromatin remodelling factor BRD2. Co-depletion of POT1B or BRD2 with TRF2 restores a canonical DNA damage response at telomeres, resulting in frequent telomere fusions. We found that TRF2 depletion in ES cells activates a totipotent-like two-cell-stage transcriptional program that includes high levels of ZSCAN4. We show that the upregulation of ZSCAN4 contributes to telomere protection in the absence of TRF2. Together, our results uncover a unique response to telomere deprotection during early development.},
}
@article {pmid33234683,
year = {2021},
author = {Kärkkäinen, T and Teerikorpi, P and Schuett, W and Stier, A and Laaksonen, T},
title = {Interplays between pre- and post-natal environments affect early-life mortality, body mass and telomere dynamics in the wild.},
journal = {The Journal of experimental biology},
volume = {224},
number = {Pt 1},
pages = {},
doi = {10.1242/jeb.231290},
pmid = {33234683},
issn = {1477-9145},
abstract = {Early-life conditions are crucial determinants of phenotype and fitness. The effects of pre- and post-natal conditions on fitness prospects have been widely studied but their interactive effects have received less attention. In birds, asynchronous hatching creates challenging developmental conditions for the last-hatched chicks, but differential allocation in last-laid eggs might help to compensate this initial handicap. The relative importance and potential interaction between pre- and post-hatching developmental conditions for different fitness components remains mostly unknown. We manipulated hatching order in wild pied flycatchers (Ficedula hypoleuca), creating three groups: natural asynchrony (last-laid eggs hatching last), reversed asynchrony (last-laid eggs hatching first) and hatching synchrony (all eggs hatching at once). We examined the effects of these manipulations on early-life survival, growth and telomere length, a potential cellular biomarker of fitness prospects. Mortality was mostly affected by hatching order, with last-hatched chicks being more likely to die. Early-life telomere dynamics and growth were influenced by the interplays between laying and hatching order. Last-laid but first-hatched chicks were heavier but had shorter telomeres 5 days after hatching than their siblings, indicating rapid early growth with potential adverse consequences on telomere length. Synchronous chicks did not suffer any apparent cost of hatching synchronously. Impaired phenotypes only occurred when reversing the natural hatching order (i.e. developmental mismatch), suggesting that maternal investment in last-laid eggs might indeed counterbalance the initial handicap of last-hatched chicks. Our experimental study thus highlights that potential interplays between pre- and post-natal environments are likely to shape fitness prospects in the wild.},
}
@article {pmid33230966,
year = {2020},
author = {Gurung, RL and M, Y and Moh, AMC and Dorajoo, R and Liu, S and Liu, JJ and Shabbir, A and So, JBY and Tan, CH and Cheng, AKS and Lim, SC},
title = {Correlation of Telomere Length in Adipose Tissue and Leukocytes and its Association with Postsurgical Weight Loss.},
journal = {Obesity (Silver Spring, Md.)},
volume = {28},
number = {12},
pages = {2424-2430},
doi = {10.1002/oby.23017},
pmid = {33230966},
issn = {1930-739X},
support = {Enabling Grant AHEG1706//Alexandra Health Fund Ltd/ ; Enabling grant AHEG 1915//Alexandra Health Fund Ltd/ ; Science-Translational &amp; Applied Research Grant STA//Alexandra Health Fund Ltd/ ; Small Innovative Grant SIG14034//Alexandra Health Fund Ltd/ ; },
abstract = {OBJECTIVE: The aim of this study was to determine the relationship between telomere length (TL) in subcutaneous adipose tissue (SAT), visceral adipose tissues (VAT), and leukocytes, as well as to examine the associations of TL in these tissues with postsurgical weight loss in Asians with severe obesity.<br><br>METHODS: Presurgery TL was measured in leukocytes, SAT, and VAT of 91 patients who underwent weight loss surgery. Correlation between TL in multiple tissues was assessed using Pearson correlation. The association of presurgery TL and postsurgical weight loss at 6 or 12 months, expressed as a percentage of weight loss, was determined using linear regression in 70 patients.<br><br>RESULTS: Telomeres were longer in VAT compared with those in leukocytes and SAT (P < 0.001) but were highly correlated between tissues. The strongest correlation was observed between TL in VAT and leukocytes (r = 0.739, P = 6.22 × 10-17). Compared with individuals in the highest tertile, those in the lowest tertile of VAT TL showed greater weight loss (β = 6.23, SE = 3.10, P = 0.044) independent of age, sex, ethnicity, types of surgery, diabetes condition, preoperative BMI, and follow-up period.<br><br>CONCLUSIONS: Among patients with severe obesity, TL in leukocytes and adipose tissue was highly correlated. However, there was variability in the association of TL in these tissues with weight loss after surgery.},
}
@article {pmid33229517,
year = {2020},
author = {Wight, DJ and Aimola, G and Aswad, A and Jill Lai, CY and Bahamon, C and Hong, K and Hill, JA and Kaufer, BB},
title = {Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {49},
pages = {31410-31416},
pmid = {33229517},
issn = {1091-6490},
mesh = {Chromosomes, Human/genetics ; Genome, Viral ; Herpesvirus 6, Human/genetics/*physiology ; Host-Pathogen Interactions ; Humans ; *Optical Imaging ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus-subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.},
}
@article {pmid33226680,
year = {2020},
author = {Tschirren, B and Romero-Haro, AÁ and Zahn, S and Criscuolo, F},
title = {Sex-specific effects of experimental ectoparasite infestation on telomere length in great tit nestlings.},
journal = {Journal of evolutionary biology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jeb.13744},
pmid = {33226680},
issn = {1420-9101},
support = {//CNRS/ ; //Université de Strasbourg/ ; grant agreement: 842085//H2020 Marie Skłodowska-Curie Actions/ ; },
abstract = {Telomere length is a biomarker of biological ageing and lifespan in various vertebrate taxa. Evidence is accumulating that telomeres shorten more rapidly when an individual is exposed to environmental stressors. Parasites are potent selective agents that can cause physiological stress directly or indirectly through the activation of the host's immune system. Yet to date, empirical evidence for a role of parasites in telomere dynamics in natural populations is limited. Here, we show experimentally that exposure to ectoparasitic hen fleas (Ceratophyllus gallinae) during growth results in shorter telomeres in female, but not male, great tit (Parus major) nestlings. Females had longer telomeres than males when growing up in experimentally deparasitized nests but, likely because of the sex-specific effects of ectoparasitism on telomere length, this sexual dimorphism was absent in birds growing up in experimentally infested nests. Our results provide the first experimental evidence for a role of ectoparasitism in telomere dynamics in a natural vertebrate population, and suggest that the costs of infection manifest in sex-specific ways.},
}
@article {pmid33221306,
year = {2021},
author = {Isaevska, E and Moccia, C and Asta, F and Cibella, F and Gagliardi, L and Ronfani, L and Rusconi, F and Stazi, MA and Richiardi, L},
title = {Exposure to ambient air pollution in the first 1000 days of life and alterations in the DNA methylome and telomere length in children: A systematic review.},
journal = {Environmental research},
volume = {193},
number = {},
pages = {110504},
doi = {10.1016/j.envres.2020.110504},
pmid = {33221306},
issn = {1096-0953},
abstract = {BACKGROUND: Exposure to air pollution during the first 1000 days of life (from conception to the 2nd year of life) might be of particular relevance for long-term child health. Changes in molecular markers such as DNA methylation and telomere length could underlie the association between air pollution exposure and pollution-related diseases as well as serve as biomarkers for past exposure. The objective of this systematic review was to assess the association between air pollution exposure during pregnancy and the first two years of life and changes in DNA methylation or telomere length in children.<br><br>METHODS: PubMed was searched in October 2020 by using terms relative to ambient air pollution exposure, DNA methylation, telomere length and the population of interest: mother/child dyads and children. Screening and selection of the articles was completed independently by two reviewers. Thirty-two articles matched our criteria. The majority of the articles focused on gestational air pollution exposure and measured DNA methylation/telomere length in newborn cord blood or placental tissue, to study global, candidate-gene or epigenome-wide methylation patterns and/or telomere length. The number of studies in children was limited.<br><br>RESULTS: Ambient air pollution exposure during pregnancy was associated with global loss of methylation in newborn cord blood and placenta, indicating the beginning of the pregnancy as a potential period of susceptibility. Candidate gene and epigenome-wide association studies provided evidence that gestational exposure to air pollutants can lead to locus-specific changes in methylation, in newborn cord blood and placenta, particularly in genes involved in cellular responses to oxidative stress, mitochondrial function, inflammation, growth and early life development. Telomere length shortening in newborns and children was seen in relation to gestational pollutant exposure.<br><br>CONCLUSIONS: Ambient air pollution during pregnancy is associated with changes in both global and locus-specific DNA methylation and with telomere length shortening. Future studies need to test the robustness of the association across different populations, to explore potential windows of vulnerability and assess the role of the methylation and telomere length as mediators in the association between early exposure to ambient air pollutants and specific childhood health outcomes.},
}
@article {pmid33221021,
year = {2021},
author = {Takahashi, S and Arima, H and Nakano, M and Ohki, T and Morita, J and Tabata, K and Takayama, Y and Tanno, K and Yamamoto, T},
title = {Telomere shortening as a stress-related biomarker in children exposed to maternal chronic stress in utero measured 7 years after the Great East Japan Earthquake.},
journal = {Psychiatry research},
volume = {295},
number = {},
pages = {113565},
doi = {10.1016/j.psychres.2020.113565},
pmid = {33221021},
issn = {1872-7123},
abstract = {Seven years after the Great East Japan Earthquake, we investigated telomeres as a potential biomarker of maternal chronic stress in children according to the timing of exposure to the disaster. The subjects were children aged 5-9 years living in Rikuzentakata, Japan. Relative telomere length (rTL) was measured with PCR in saliva samples. The partial regression coefficient of the rTL was significantly shorter in the group of children conceived after the disaster than in the children who were in utero on the day of the disaster. Telomere length should be investigated as a biomarker for assessing disaster-related trauma in future studies.},
}
@article {pmid33219062,
year = {2020},
author = {Baltrus, PT and Li, C and H Gaglioti, A},
title = {Having a Usual Source of Care Is Associated with Longer Telomere Length in a National Sample of Older Adults.},
journal = {Journal of the American Board of Family Medicine : JABFM},
volume = {33},
number = {6},
pages = {832-841},
pmid = {33219062},
issn = {1558-7118},
support = {P30 AG031054/AG/NIA NIH HHS/United States ; U54 MD007588/MD/NIMHD NIH HHS/United States ; },
abstract = {OBJECTIVE: To provide a potential biological, mechanistic link for the well-established association between primary care access and reduced mortality, this study sought to measure the impact of having a usual source of health care on leukocyte telomere length (LTL).<br><br>DATA SOURCES: Our study population included 3202 participants aged 50 to 84 years from National Health and Nutrition Examination Survey 1999 to 2001.<br><br>STUDY DESIGN: Cross-sectional Study. LTLs between people with and without a usual source of care were compared using unadjusted and adjusted linear regression models. Fully adjusted models accounted for demographic characteristics, health conditions, and health behaviors.<br><br>PRINCIPAL FINDINGS: After controlling for individual factors, health conditions, and health behaviors, people who had a usual source of health care had significantly longer LTL (β = 89.8 base pairs, P-value = .005) compared with those without a usual source of care; corresponding to approximately 7 years of life.<br><br>CONCLUSIONS: Having a usual source of health care is associated with longer LTL among older adults. This study provides a potential biologic link for the noted association between primary care access and reduced mortality that has been observed at the individual and population level.},
}
@article {pmid33219058,
year = {2020},
author = {Seehusen, DA and Bowman, MA},
title = {Must-Read Family Medicine Research-Glucosamine/Chondroitin Supplements and Mortality, Telomere Length and the Doctor-Patient Relationship, Reducing Opioid Use, and More.},
journal = {Journal of the American Board of Family Medicine : JABFM},
volume = {33},
number = {6},
pages = {823-826},
doi = {10.3122/jabfm.2020.06.200513},
pmid = {33219058},
issn = {1558-7118},
abstract = {This issue of the Journal contains some exceptional research articles. A few are truly &quot;must-reads,&quot; including a fascinating look at the relationship between having a usual source of care and telomere length. Glucosamine/chrondroitin supplementation seems to be helpful for more than just arthritis pain. There is a very practical advice on keeping patients discharged from the emergency department out of the hospital and on reducing patient requests for inappropriate antibiotics. This issue also features 5 articles addressing how family physicians can combat the opioid epidemic. Three articles highlight research on diabetes and another 3 on breast cancer. Payment reform, dermoscopy, and telemedicine are among many other topics covered.},
}
@article {pmid33218817,
year = {2021},
author = {Li, R and Li, S and Pan, M and Chen, H and Liu, X and Chen, G and Chen, R and Mao, Z and Huo, W and Wang, X and Yu, S and Duan, Y and Guo, Y and Hou, J and Wang, C},
title = {Physical activity attenuated the association of air pollutants with telomere length in rural Chinese adults.},
journal = {The Science of the total environment},
volume = {759},
number = {},
pages = {143491},
doi = {10.1016/j.scitotenv.2020.143491},
pmid = {33218817},
issn = {1879-1026},
mesh = {Adolescent ; Adult ; Aged ; *Air Pollutants/analysis ; *Air Pollution/analysis ; Asian Continental Ancestry Group ; China ; Cohort Studies ; *Diabetes Mellitus, Type 2 ; Environmental Exposure/analysis ; Exercise ; Humans ; Middle Aged ; Nitrogen Dioxide/analysis ; Particulate Matter/analysis ; Telomere ; Young Adult ; },
abstract = {BACKGROUND: Exposure to air pollutants (nitrogen dioxide (NO2) and particulate matters (PMs)) or physical inactivity is linked to telomere length (TL) shortening. However, there is a lack of research on combined effects of either NO2 or PMs and physical activity (PA) on TL. This study aimed to explore the joint associations of air pollutants (NO2 or PMs) and PA with relative TL in rural Chinese adults.<br><br>METHODS: This study was conducted among 2704 participants aged 18-79 years in rural China. Concentrations of NO2 and PMs (PM with an aerodynamics diameter ≤ 1.0 μm (PM1), ≤2.5 μm (PM2.5) or ≤10 μm (PM10)) were estimated using random forest models incorporated with satellites data, meteorological data, and land use information. Relative TL of each participant was measured by a quantitative real-time polymerase chain reaction. Linear regression models were applied to examine the independent associations between PA, NO2 or PMs and relative TL. Interaction plots were used to depict the altered associations between NO2, PM1, PM2.5, or PM10 and relative TL along with increasing PA levels.<br><br>RESULTS: Each 1 μg/m3 increment in NO2, PM1, PM2.5, or PM10 was associated with a 0.038 (95% confidence intervals (CI): -0.044, -0.033), 0.036 (95% CI: -0.041, -0.031), 0.052 (95% CI: -0.059, -0.045), or 0.022 (95% CI: -0.025, -0.019) decrease in relative TL among all participants; similar findings were observed among normal glucose tolerance or impaired fasting glucose (IFG) participants as well as type 2 diabetes mellitus (T2DM) patients. PA at certain levels counteracted the association of air pollutants (NO2, PM1, PM2.5, and PM10) with relative TL among IFG participants or T2DM patients.<br><br>CONCLUSIONS: Long-term exposure to NO2 and PMs was associated with relative TL shortening and these effects may be counteracted by PA at certain levels in IFG participants or T2DM patients.},
}
@article {pmid33216348,
year = {2021},
author = {Nathan, V and Johansson, PA and Palmer, JM and Hamilton, HR and Howlie, M and Brooks, KM and Hayward, NK and Pritchard, AL},
title = {A rare missense variant in protection of telomeres 1 (POT1) predisposes to a range of haematological malignancies.},
journal = {British journal of haematology},
volume = {192},
number = {2},
pages = {e57-e60},
doi = {10.1111/bjh.17218},
pmid = {33216348},
issn = {1365-2141},
support = {9353763//Highlands and Islands Enterprise/ ; 1093017//National Health and Medical Research Council/ ; 1117663//National Health and Medical Research Council/ ; //Cure Cancer Australia Foundation/ ; },
}
@article {pmid33216232,
year = {2020},
author = {Lee, KH and Kimmel, M},
title = {Stationary Distribution of Telomere Lengths in Cells with Telomere Length Maintenance and its Parametric Inference.},
journal = {Bulletin of mathematical biology},
volume = {82},
number = {12},
pages = {150},
doi = {10.1007/s11538-020-00811-1},
pmid = {33216232},
issn = {1522-9602},
support = {5R01HL128173-04/NH/NIH HHS/United States ; },
abstract = {Telomeres are nucleotide caps located at the ends of each eukaryotic chromosome. Under normal physiological conditions as well as in culture, they shorten during each DNA replication round. Short telomeres initiate a proliferative arrest of cells termed 'replicative senescence'. However, cancer cells possessing limitless replication potential can avoid senescence by the telomere maintenance mechanism, which offsets telomeric loss. Therefore, cancer cells have sufficiently long telomeres even though their lengths are significantly shorter than their normal counterparts. This implies that the attrition and elongation rates play crucial roles in deciding whether and when cells ultimately become carcinogenic. In this research, we propose a concise mathematical model that shows the shortest telomere length at each cell division and prove mathematical conditions related to the attrition and elongation rates, which are necessary and sufficient for the existence of stationary distribution of telomere lengths. Moreover, we estimate the parameters of the telomere length maintenance process based on frequentist and Bayesian approaches. This study expands our knowledge of the mathematical relationship between the telomere attrition and elongation rates in cancer cells, which is important because the telomere length dynamics is a useful biomarker of cancer diagnosis and prognosis.},
}
@article {pmid33214205,
year = {2021},
author = {Justet, A and Klay, D and Porcher, R and Cottin, V and Ahmad, K and Molina Molina, M and Nunes, H and Reynaud-Gaubert, M and Naccache, JM and Manali, E and Froidure, A and Jouneau, S and Wemeau, L and Andrejak, C and Gondouin, A and Hirschi, S and Blanchard, E and Bondue, B and Bonniaud, P and Tromeur, C and Prévot, G and Marchand-Adam, S and Funke-Chambour, M and Gamez, AS and Ba, I and Papiris, S and Grutters, J and Crestani, B and van Moorsel, C and Kannengiesser, C and Borie, R and , },
title = {Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation.},
journal = {The European respiratory journal},
volume = {57},
number = {2},
pages = {},
doi = {10.1183/13993003.03198-2020},
pmid = {33214205},
issn = {1399-3003},
}
@article {pmid33211388,
year = {2020},
author = {Bicanova, L and Kreilmeier-Berger, T and Reifinger, M and Holzmann, K and Kleiter, M},
title = {Prevalence and potentially prognostic value of C-circles associated with alternative lengthening of telomeres in canine appendicular osteosarcoma.},
journal = {Veterinary and comparative oncology},
volume = {},
number = {},
pages = {},
doi = {10.1111/vco.12665},
pmid = {33211388},
issn = {1476-5829},
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism (TMM) with high prevalence in human osteosarcomas but remains unknown in canine osteosarcomas. The aim of this study was to evaluate the prevalence of ALT by detection of extra-chromosomal circles of telomeric DNA and to assess clinical outcome in canine patients with spontaneous occurring appendicular osteosarcoma. Fifty dogs with histopathological confirmed osteosarcomas were included into this study. Medical records were retrospectively analysed for patient characteristics, oncologic therapy and survival. DNA was isolated from archived FFPE tumour tissue specimens and applied for C- and G-circle assay (CCA and GCA) and for telomeric content (TC) measurement with radiolabeled probes. ALT activity was detected for 10 of 50 (20%) cases by CCA. Four CCA positive cases were detected even with input DNA below 1 ng and demonstrated the high sensitivity of CCA for canine tumours. G-circles and TC were not suitable to distinguish CCA positive and negative cases. CCA-status showed an association with male gender and Rottweiler breed. Dogs with CCA positive osteosarcomas had shorter overall survival times than patients with CCA-tumours and CCA-status was a significant prognostic factor besides treatment in the Cox proportional hazard model. These findings make canine osteosarcomas an interesting model for comparative TMM research, but future studies are warranted to investigate if CCA-status can serve as novel prognostic marker.},
}
@article {pmid33211200,
year = {2021},
author = {Salas-Huetos, A and Tüttelmann, F and Wyrwoll, MJ and Kliesch, S and Lopes, AM and Goncalves, J and Boyden, SE and Wöste, M and Hotaling, JM and , and Nagirnaja, L and Conrad, DF and Carrell, DT and Aston, KI},
title = {Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.},
journal = {Human genetics},
volume = {140},
number = {1},
pages = {217-227},
pmid = {33211200},
issn = {1432-1203},
support = {P50 HD096723/HD/NICHD NIH HHS/United States ; R01 HD078641/HD/NICHD NIH HHS/United States ; DFG CRU326//German Research Foundation/ ; R01HD078641//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
abstract = {Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.},
}
@article {pmid33206065,
year = {2021},
author = {Tang, J and Wu, J and Zhu, R and Wang, Z and Zhao, C and Tang, P and Xie, W and Wang, D and Liang, L},
title = {Reversible photo-regulation on the folding/unfolding of telomere G-quadruplexes with solid-state nanopores.},
journal = {The Analyst},
volume = {146},
number = {2},
pages = {655-663},
doi = {10.1039/d0an01930e},
pmid = {33206065},
issn = {1364-5528},
mesh = {Azo Compounds/chemistry ; *G-Quadruplexes ; *Nanopores ; Nanotechnology/*methods ; Telomere/*chemistry ; },
abstract = {The formation of G-quadruplexes (G4) in human telomere and other important biological regions inhibits the replication and transcription of DNA, thereby influencing further cell proliferation. The investigation of G4 formation and unfolding is vital for understanding their modulation in biological processes and life science. Photo regulation is a facile and sensitive approach for monitoring the structures of biomacromolecules and material surface properties. The nanopore-based technique is also prevalent for label-free single-molecule characterization with high accuracy. This study provides a combination of solid-state nanopore technology with light-switch as a platform for the modulation of human telomere G4 formation and splitting under switchable light exposure. The introduction of molecular switch, namely azobenzene moiety at different positions of the DNA sequence influences the formation and stability of G4. Three azobenzenes immobilized on each of the G-quartet plane (hTelo-3azo-p) or four azobenzenes on the same plane (hTelo-4azo-4p) of the human telomere G4 sequence realized the reversible control of G4 folding/unfolding at the temporal scale upon photo regulation, and the formation and splitting of G4 with hTelo-4azo-4p is slower and not thorough compared to that with hTelo-3azo-p due to the coplanar steric hindrance. Moreover, the G4 formation recorded with the combined nanopore and photo-responsive approach was also characterized with fluorescence, and the variation in the fluorescence intensity of the NMM and G4 complex exhibited a different tendency under reverse light irradiation due to the distinct interactions of NMM with the azobenzene-modified G4. Our study demonstrated a controllable and sensitive way for the manipulation of G4 structures, which will be inspiring for the intervention of G4-related cell senescence, cancer diagnosis and drug exploration.},
}
@article {pmid33206062,
year = {2020},
author = {Hachmo, Y and Hadanny, A and Abu Hamed, R and Daniel-Kotovsky, M and Catalogna, M and Fishlev, G and Lang, E and Polak, N and Doenyas, K and Friedman, M and Zemel, Y and Bechor, Y and Efrati, S},
title = {Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial.},
journal = {Aging},
volume = {12},
number = {22},
pages = {22445-22456},
pmid = {33206062},
issn = {1945-4589},
abstract = {INTRODUCTION: Aging is characterized by the progressive loss of physiological capacity. At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence. Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. The aim of the current study was to evaluate whether HBOT affects TL and senescent cell concentrations in a normal, non-pathological, aging adult population.<br><br>METHODS: Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed.<br><br>RESULTS: Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells which increased at the 30th session, 60th session and post HBOT by 25.68%±40.42 (p=0.007), 29.39%±23.39 (p=0.0001) and 37.63%±52.73 (p=0.007), respectively. There was a significant decrease in the number of senescent T helpers by -37.30%±33.04 post-HBOT (P<0.0001). T-cytotoxic senescent cell percentages decreased significantly by -10.96%±12.59 (p=0.0004) post-HBOT. In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.},
}
@article {pmid33203878,
year = {2020},
author = {Cicconi, A and Rai, R and Xiong, X and Broton, C and Al-Hiyasat, A and Hu, C and Dong, S and Sun, W and Garbarino, J and Bindra, RS and Schildkraut, C and Chen, Y and Chang, S},
title = {Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {5861},
pmid = {33203878},
issn = {2041-1723},
mesh = {Aminopeptidases/genetics/metabolism ; Animals ; Binding Sites ; Calorimetry ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Cytoskeletal Proteins/chemistry/genetics/*metabolism ; DNA Damage ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/metabolism ; Fibroblasts ; HeLa Cells ; Histones/genetics/metabolism ; Humans ; Mice ; Microcephaly/*genetics ; Mutation ; Protein Interaction Domains and Motifs ; Serine Proteases/genetics/metabolism ; Telomere/*genetics/metabolism ; Telomere-Binding Proteins/genetics/metabolism ; Telomeric Repeat Binding Protein 2/chemistry/genetics/*metabolism ; },
abstract = {Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1-TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.},
}
@article {pmid33203829,
year = {2020},
author = {Ferrer, A and Mangaonkar, AA and Stroik, S and Zimmermann, MT and Sigafoos, AN and Kamath, PS and Simonetto, DA and Wylam, ME and Carmona, EM and Lazaridis, KN and Peters, S and Stewart, K and Klee, EW and Hendrickson, EA and Patnaik, MM},
title = {Functional validation of TERT and TERC variants of uncertain significance in patients with short telomere syndromes.},
journal = {Blood cancer journal},
volume = {10},
number = {11},
pages = {120},
pmid = {33203829},
issn = {2044-5385},
}
@article {pmid33201323,
year = {2020},
author = {Criscuolo, F and Pillay, N and Zahn, S and Schradin, C},
title = {Seasonal variation in telomere dynamics in African striped mice.},
journal = {Oecologia},
volume = {194},
number = {4},
pages = {609-620},
pmid = {33201323},
issn = {1432-1939},
mesh = {Aging ; Animals ; Food ; Humans ; Male ; Mice ; *Murinae/genetics ; Seasons ; *Telomere ; Telomere Shortening ; },
abstract = {Telomere shortening has been used as an indicator of aging and is believed to accelerate under harsh environmental conditions. This can be attributed to the fact that telomere shortening has often been regarded as non-reversible and negatively impacting fitness. However, studies of laboratory mice indicate that they may be able to repair telomere loss to recover from environmental harshness, as indicated by recent studies in hibernating rodents. We studied seasonal variation in telomere dynamics in African striped mice (Rhabdomys pumilio) living in a highly seasonal environment. In our annual species, individuals born in the moist spring (high food availability) need to survive the harsh dry summer (low food availability) to be able to reproduce in the following spring. We studied the effect of the harsh dry vs. the benign moist season on telomere dynamics. We also tested if telomere length or the rate of change in telomere length over the dry season predicted the probablity of dissapearance from the population at the same time. Male, but not female, stripped mice showed age-related telomere erosion. Telomeres were longer at the beginning of the dry season compared to the rest of the year. Telomeres increased significantly in length during the moist season. Neither telomere length at the onset of the dry season nor telomere loss over the dry season predicted whether or not individuals disappeared. In conclusion, our data suggest that seasonal attrition and restoring of telomeres also occurs in non-hibernating wild rodents living in hot food restricted environments.},
}
@article {pmid33198936,
year = {2020},
author = {Gaikwad, AS and Mahmood, R and B, R and Kondhalkar, S},
title = {Evaluation of telomere length and genotoxicity among asphalt associated workers.},
journal = {Mutation research},
volume = {858-860},
number = {},
pages = {503255},
doi = {10.1016/j.mrgentox.2020.503255},
pmid = {33198936},
issn = {1873-135X},
abstract = {There are contradictory reports about bitumen exposure and malignancy risk worldwide. Also, the evidence for genotoxicity risk among workers occupationally exposed to asphalt is insufficient. The study intended to evaluate particulate matter 10 (PM10) at the workplace and biomarkers of genotoxicity effects among a group of asphalt workers in and around Bangalore, India. This study involved a total of 107 participants (54 exposed group and 53 unexposed control group). To evaluate the genotoxicity, the urinary 8-OHdG and relative telomere length as oxidative damage while micronucleus (MN) assay for cytogenetic damage was carried out during the study. The majority of workers have reported health complaints and 57.4% of them were not using any personal protective equipments (PPE's). The level of PM10 detected was 104 ± 9.5 μg/m3 and 619 ± 22.7 μg/m3 in the road paving and asphalt mixing sites respectively. The biomonitoring study observed a highly significant (p = <0.001) increase in the level of 8-hydroxy-2-deoxyguanosine (8-OHdG) in the exposed group (23.17 ± 8.65 ng/mg creatinine) compared to the control (13.6 ± 7.12 ng/mg creatinine), revealed age significant associated and non-smoking borderline significant associated for oxidative stress. The relative telomere length (TL) analysis revealed its highly significant (p = 0.004) reduction in the exposed group, adjusted mean 0.95 (95% CI 0.83-1.07) compared to the control 1.06 (95% CI 0.91-1.26). The job category (p = 0.028), non-smoking (p = 0.026), and tobacco chewing (p = 0.013) were associated with reduced relative TL in the asphalt exposed group. In cytogenotoxicity analysis, the mean micronucleus (MN) frequency per 100 cells in the exposed group (26.46 ± 19.8) was significantly (p = <0.001) increased over the control group (8.56 ± 7.18). Neither smoking habit nor age appeared to influence the MN frequencies in either group. In the present study, we have demonstrated genetic damage in workers occupationally exposed to asphalt and particulate matter, raising concern for an increased risk of malignancy in these workers.},
}
@article {pmid33198931,
year = {2020},
author = {Xue, Y and Guo, X and Huang, X and Zhu, Z and Chen, M and Chu, J and Yang, G and Wang, Q and Kong, X},
title = {Shortened telomere length in peripheral blood leukocytes of patients with lung cancer, chronic obstructive pulmonary disease in a high indoor air pollution region in China.},
journal = {Mutation research},
volume = {858-860},
number = {},
pages = {503250},
doi = {10.1016/j.mrgentox.2020.503250},
pmid = {33198931},
issn = {1873-135X},
abstract = {Lung cancer and chronic obstructive pulmonary disease (COPD) are closely linked diseases. In Xuanwei, China, the extremely high incidence and mortality rates of lung cancer and COPD are associated with exposure to household smoky coal burning. Previous studies found that telomere length was related to lung disease. The objective of this study is to investigate the relationship of peripheral blood leukocyte telomere length to both lung cancer and COPD, as well as indoor coal smoke exposure in Xuanwei. We measured telomere length using quantitative polymerase chain reaction (qPCR) in peripheral blood leukocytes of 216 lung cancer patients, 296 COPD patients, and 426 healthy controls from Xuanwei. The telomere length ratios (mean ± SD) in patients with lung cancer (0.76 ± 0.35) and COPD (0.81 ± 0.35) were significantly shorter than in that of controls (0.95 ± 0.39). Individuals with the shortest tertile telomere length had 3.90- and 4.54-fold increased risks of lung cancer and COPD, respectively, compared with individuals with the longest tertile telomere length. No correlation was found between telomere length and pack-years of smoking. In healthy subjects, coal smoke exposure level affected telomere length. Lung function was positively and negatively associated with telomere length and environmental exposure, respectively, when combination the control and COPD groups. The result suggests that shortened telomere length in peripheral blood leukocytes was associated with lung cancer and COPD and might be affected by coal smoke exposure level in Xuanwei. Whether variation in telomere length caused by environmental exposure has a role in lung cancer and COPD development and exacerbation needs further research.},
}
@article {pmid33198352,
year = {2020},
author = {Gadji, M and Mathur, S and Bélanger, B and Jangamreddy, JR and Lamoureux, J and Tsanaclis, AMC and Fortin, D and Drouin, R and Mai, S},
title = {Three-Dimensional Nuclear Telomere Profiling as a Biomarker for Recurrence in Oligodendrogliomas: A Pilot Study.},
journal = {International journal of molecular sciences},
volume = {21},
number = {22},
pages = {},
pmid = {33198352},
issn = {1422-0067},
support = {763110142//Leukemia and Lymphoma Society of Canada/ ; },
abstract = {Mechanisms of recurrence in oligodendrogliomas are poorly understood. Recurrence might be driven by telomere dysfunction-mediated genomic instability. In a pilot study, we investigated ten patients with oligodendrogliomas at the time of diagnosis (first surgery) and after recurrence (second surgery) using three-dimensional nuclear telomere analysis performed with quantitative software TeloView® (Telo Genomics Corp, Toronto, Ontario, Canada). 1p/19q deletion status of each patient was determined by fluorescent in situ hybridization on touch preparation slides. We found that a very specific 3D telomeric profile was associated with two pathways of recurrence in oligodendrogliomas independent of their 1p/19q status: a first group of 8 patients displayed significantly different 3D telomere profiles between both surgeries (p < 0.0001). Their recurrence happened at a mean of 231.375 ± 117.42 days and a median time to progression (TTP) of 239 days, a period defined as short-term recurrence; and a second group of three patients displayed identical 3D telomere profiles between both surgery samples (p > 0.05). Their recurrence happened at a mean of 960.666 ± 86.19 days and a median TTP of 930 days, a period defined as long-term recurrence. Our results suggest a potential link between nuclear telomere architecture and telomere dysfunction with time to recurrence in oligodendrogliomas, independently of the 1p/19q status.},
}
@article {pmid33197388,
year = {2020},
author = {Duckworth, A and Gibbons, MA and Allen, RJ and Almond, H and Beaumont, RN and Wood, AR and Lunnon, K and Lindsay, MA and Wain, LV and Tyrrell, J and Scotton, CJ},
title = {Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study.},
journal = {The Lancet. Respiratory medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/S2213-2600(20)30364-7},
pmid = {33197388},
issn = {2213-2619},
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD.<br><br>METHODS: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls).<br><br>FINDINGS: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33-7·55; p=0·0031) but not COPD (1·07, 0·88-1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05-30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71-1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56-9·50; p=2·19 × 10-12). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90-1·27; p=0·46).<br><br>INTERPRETATION: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted.<br><br>FUNDING: Medical Research Council.},
}
@article {pmid33193711,
year = {2020},
author = {Gao, Y and Wei, Y and Zhou, X and Huang, S and Zhao, H and Zeng, P},
title = {Assessing the Relationship Between Leukocyte Telomere Length and Cancer Risk/Mortality in UK Biobank and TCGA Datasets With the Genetic Risk Score and Mendelian Randomization Approaches.},
journal = {Frontiers in genetics},
volume = {11},
number = {},
pages = {583106},
pmid = {33193711},
issn = {1664-8021},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Background: Telomere length is an important indicator of tumor progression and survival for cancer patients. Previous work investigated the associations between genetically predicted telomere length and cancers; however, the types of cancers investigated in those studies were relatively limited or the telomere length-associated genetic variants employed often came from genome-wide association studies (GWASs) with small sample sizes.<br><br>Methods: We constructed the genetic risk score (GRS) for leukocyte telomere length based on 17 associated genetic variants available from the largest telomere length GWAS up to 78,592 individuals. Then, a comprehensive analysis was undertaken to evaluate the association between the constructed GRS and the risk or mortality of a wide range of cancers [i.e., 37 cancers in the UK Biobank and 33 cancers in The Cancer Genome Atlas (TCGA)]. We further applied the two-sample Mendelian randomization (MR) to estimate the causal effect of leukocyte telomere length on UK Biobank cancers via summary statistics.<br><br>Results: In the UK Biobank dataset, we found that the GRS of leukocyte telomere length was associated with a decreased risk of nine types of cancer (i.e., significant association with multiple myeloma, chronic lymphocytic leukemia, kidney/renal cell cancer, bladder cancer, malignant melanoma, basal cell carcinoma, and prostate cancer and suggestive association with sarcoma/fibrosarcoma and Hodgkin's lymphoma/Hodgkin's disease). In addition, we found that the GRS was suggestively associated with an increased risk of leukemia. In the TCGA dataset, we observed suggestive evidence that the GRS was associated with a high death hazard of rectum adenocarcinoma (READ), sarcoma (SARC), and skin cutaneous melanoma (SKCM), while the GRS was associated with a low death hazard of kidney renal papillary cell carcinoma (KIRP). The results of MR further supported the association for leukocyte telomere length on the risk of malignant melanoma, Hodgkin's lymphoma/Hodgkin's disease, chronic lymphocytic leukemia and multiple myeloma.<br><br>Conclusion: Our study reveals that telomere played diverse roles in different types of cancers. However, further validations in large-scale prospective studies and deeper investigations of the biologic mechanisms are warranted.},
}
@article {pmid33192450,
year = {2020},
author = {Linghui, D and Shi, Q and Chi, C and Xiaolei, L and Lixing, Z and Zhiliang, Z and Birong, D},
title = {The Association Between Leukocyte Telomere Length and Cognitive Performance Among the American Elderly.},
journal = {Frontiers in aging neuroscience},
volume = {12},
number = {},
pages = {527658},
pmid = {33192450},
issn = {1663-4365},
abstract = {Background: Age-related cognitive decline begins in middle age and persists with age. Leukocyte telomere length (LTL) decreases with age and is enhanced by inflammation and oxidative stress. However, whether shorter LTL correlates with cognitive decline remains controversial.<br><br>Aims: We aimed to investigate the relationship between LTL and cognitive decline in the American elderly.<br><br>Methods: We used data from the 1999 to 2002 U.S. National Health and Nutrition Examination Survey (NHANES). We included participants aged 65-80 with available data on LTL and cognitive assessments. The cognitive function assessment used the digit symbol substitution test (DSST). We applied multivariate modeling to estimate the association between LTL and cognitive performance. Additionally, to ensure robust data analysis, we converted LTL into categorical variables through quartile and then calculated the P for trend.<br><br>Results: After adjusting for age, cardiovascular disease (CAD) score, gender, race, body mass index (BMI), and educational level, LTL showed a positive correlation with DSST score (odds ratio [OR] 3.47 [0.14, 6.79], P = 0.04). Additionally, to further quantify the LTL-DSST interaction, we found a similar trend when LTL was regarded as a categorical variable (quartile) (P for trend = 0.03).<br><br>Conclusion: LTL was associated with cognitive capabilities among the elderly, implying that LTL might be a biomarker of cognitive aging.},
}
@article {pmid33190211,
year = {2020},
author = {El Assar, M and Angulo, J and Carnicero, JA and Walter, S and García-García, FJ and Rodríguez-Artalejo, F and Rodríguez-Mañas, L},
title = {Association between telomere length, frailty and death in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11357-020-00291-0},
pmid = {33190211},
issn = {2509-2723},
support = {305483//Seventh Framework Programme/ ; PI15/00674, PI15/01160, CB16/10/00464//Instituto de Salud Carlos III/ ; },
abstract = {Frailty is considered a clinical marker of functional ageing. Telomere length (TL) has been proposed as a biomarker of biological age but its role in human ageing is controversial. The main aim of the study was to evaluate the longitudinal association of TL with incident frailty and mortality in two cohorts of Spanish community-dwelling older adults. TL was determined at baseline in blood samples from older adults included in Toledo Study for Healthy Aging and ENRICA cohorts while frailty was determined by frailty phenotype (FP) at baseline and at follow-up (3.5 years). Deaths occurring during follow-up were also recorded. Associations of TL with frailty and mortality were analysed by logistic regression with progressive adjustment. Data were separately analysed in the two cohorts and in all subjects by performing a meta-analysis. TL was not different between frail and non-frail subjects. Longer telomeres were not associated with lower risk of prevalent frailty. Similarly, TL at baseline failed to predict incident frailty (OR: 1.04 [0.88-1.23]) or even the development of a new FP criterion (OR: 0.97 [0.90-1.05]) at follow-up. Lack of association was also observed when analysing the development of specific FP criteria. Finally, while frailty at baseline was significantly associated with higher risk of death at follow-up (OR: 4.08 [1.97-8.43], p < 0.001), TL did not significantly change the mortality risk (OR: 1.05 [0.94-1.16]). Results show that TL does not predict incident frailty or mortality in older adults. This suggests that TL is not a reliable biomarker of functional age.},
}
@article {pmid33188147,
year = {2021},
author = {Mangosh, TL and Awadallah, WN and Grabowska, MM and Taylor, DJ},
title = {SLX4IP Promotes Telomere Maintenance in Androgen Receptor-Independent Castration-Resistant Prostate Cancer through ALT-like Telomeric PML Localization.},
journal = {Molecular cancer research : MCR},
volume = {19},
number = {2},
pages = {301-316},
doi = {10.1158/1541-7786.MCR-20-0314},
pmid = {33188147},
issn = {1557-3125},
abstract = {In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer (CRPC), and defining mechanisms critical for survival is of utmost importance for targeting this lethal disease. Our studies focus on identifying telomere maintenance mechanism (TMM) hallmarks adopted by CRPC to promote survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC demonstrates an atypical ALT-like phenotype with variable telomerase expression and activity, whereas AR-dependent models lack discernible ALT hallmarks. In addition, AR-independent CRPC cells exhibited elevated levels of SLX4IP, a protein implicated in promoting ALT. SLX4IP overexpression in AR-dependent C4-2B cells promoted an ALT-like phenotype and telomere maintenance. SLX4IP knockdown in AR-independent DU145 and PC-3 cells led to ALT-like hallmark reduction, telomere shortening, and induction of senescence. In PC-3 xenografts, this effect translated to reduced tumor volume. Using an in vitro model of AR-independent progression, loss of AR in AR-dependent C4-2B cells promoted an atypical ALT-like phenotype in an SLX4IP-dependent manner. Insufficient SLX4IP expression diminished ALT-like hallmarks and resulted in accelerated telomere loss and senescence. IMPLICATIONS: This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT-like hallmarks and loss of these hallmarks induces telomere shortening and senescence, thereby impairing replicative immortality.},
}
@article {pmid33187969,
year = {2021},
author = {Antwi, SO and Bamlet, WR and Cawthon, RM and Rabe, KG and Druliner, BR and Sicotte, H and Jatoi, A and Mahipal, A and Boardman, LA and Oberg, AL and Petersen, GM},
title = {Shorter Treatment-Naïve Leukocyte Telomere Length is Associated with Poorer Overall Survival of Patients with Pancreatic Ductal Adenocarcinoma.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {30},
number = {1},
pages = {210-216},
pmid = {33187969},
issn = {1538-7755},
support = {K01 CA237875/CA/NCI NIH HHS/United States ; P50 CA102701/CA/NCI NIH HHS/United States ; R01 CA204013/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Critically shortened telomeres contribute to chromosomal instability and neoplastic transformation and are associated with early death of patients with certain cancer types. Shorter leukocyte telomere length (LTL) has been associated with higher risk for pancreatic ductal adenocarcinoma (PDAC) and might be associated also with survival of patients with PDAC. We investigated the association between treatment-naïve LTL and overall survival of patients with incident PDAC.<br><br>METHODS: The study included 642 consecutively enrolled PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreas Research. Blood samples were obtained at the time of diagnosis, before the start of cancer treatment, from which LTL was assayed by qRT-PCR. LTL was first modeled as a continuous variable (per-interquartile range decrease in LTL) and then as a categorized variable (short, medium, long). Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated for overall mortality using Cox proportional hazard models.<br><br>RESULTS: Shorter treatment-naïve LTL was associated with higher mortality among patients with PDAC (HRcontinuous = 1.13, 95% CI: 1.01-1.28, P = 0.03; HRshortestvs. longest LTL = 1.29, 95% CI: 1.05-1.59, Ptrend = 0.01). There was a difference in the association between LTL and overall mortality by tumor stage at diagnosis; resectable tumors (HRcontinuous = 0.91; 95% CI: 0.73-1.12), locally advanced tumors (HRcontinuous = 1.29; 95% CI: 1.07-1.56), and metastatic tumors (HRcontinuous = 1.17; 95% CI: 0.96-1.42), Pinteraction = 0.04.<br><br>CONCLUSION: Shorter treatment-naïve LTL is associated with poorer overall survival of patients with incident PDAC.<br><br>IMPACT: Peripheral blood LTL might be a prognostic marker for PDAC.},
}
@article {pmid33187486,
year = {2020},
author = {Nsereko, E and Uwase, A and Muvunyi, CM and Rulisa, S and Ntirushwa, D and Moreland, P and Corwin, EJ and Santos, N and Lin, J and Chen, JL and Nzayirambaho, M and Wojcicki, JM},
title = {Association between micronutrients and maternal leukocyte telomere length in early pregnancy in Rwanda.},
journal = {BMC pregnancy and childbirth},
volume = {20},
number = {1},
pages = {692},
pmid = {33187486},
issn = {1471-2393},
support = {Investment ID: OPP1107312//Bill and Melinda Gates Foundation/ ; },
abstract = {BACKGROUND: Exposure to environmental stressors can lead to shorter leukocyte telomere length and increase the risk of chronic diseases. Preservation of leukocyte telomere length by reducing oxidative stress exposure and reinforcing immunity may be a mechanism by which nutritional factors delay or prevent chronic disease development.<br><br>METHODS: Healthy pregnant women (aged 18-45 years) at 9-15 weeks of gestation living in Gasabo District, Kigali, Rwanda, were recruited from 10 health centers for a prospective, longitudinal study from September to October 2017 to determine possible associations between nutrition health, infectious disease and leukocyte telomere length. Anthropometric and laboratory measurements were performed using standard procedures; sociodemographic parameters and health histories were assessed via surveys, and leukocyte telomere length was assessed using quantitative PCR expressed as the ratio of a telomeric product to a single-copy gene product (T/S).<br><br>RESULTS: Mean gestational age of participants (n = 297) at enrollment was 13.04 ± 3.50 weeks, age was 28.16 ± 6.10 years and leukocyte telomere length was 1.16 ± 0.22 (T/S). Younger age; no schooling vs. primary schooling; and lower levels of ferritin, soluble transferrin receptors and retinol-binding protein were independent predictors of longer telomere length in multivariable models.<br><br>CONCLUSIONS: Leukocyte telomere length is an indicator of biological aging in pregnant Rwandan women. Maternal micronutrient status, specifically lower ferritin, soluble transferrin receptor levels, and retinol-binding protein levels were associated with longer maternal telomere length in contrast with some studies from North America and Europe. There were no associations between inflammation and infectious disease status and maternal leukocyte telomere length. Further studies are needed to enhance our understanding of the interplay between maternal nutritional status and infectious disease in relation to leukocyte telomere length in developing countries.},
}
@article {pmid33176222,
year = {2021},
author = {Bosquet Enlow, M and Petty, CR and Hacker, MR and Burris, HH},
title = {Maternal psychosocial functioning, obstetric health history, and newborn telomere length.},
journal = {Psychoneuroendocrinology},
volume = {123},
number = {},
pages = {105043},
pmid = {33176222},
issn = {1873-3360},
support = {K23 ES022242/ES/NIEHS NIH HHS/United States ; UL1 TR001102/TR/NCATS NIH HHS/United States ; },
abstract = {There is growing interest in elucidating the determinants of newborn telomere length, given its potential as a biomarker of lifetime disease risk affected by prenatal exposures. There is limited evidence that increased maternal stress during pregnancy predicts shorter newborn telomere length. However, the few studies published to date have been conducted primarily with small samples utilizing inconsistent definitions of maternal stress. Moreover, the potential influence of fetal sex as a moderator of maternal stress effects on newborn telomere length has been largely ignored despite compelling evidence of likely impact. In a prospective cohort study of pregnant women seeking routine prenatal care, we tested whether a range of maternal measures of stressor exposures, subjective feelings of stress, and mental health (depression, anxiety) were associated with newborn telomere length assessed from cord blood among 146 pregnant women and their newborn infants. We further examined whether the pattern of associations differed by infant sex. Sociodemographic and maternal and newborn health indicators were considered as potential covariates. When examined within the whole sample, none of the maternal psychosocial measures were associated with newborn telomere length. Among potential covariates, maternal history of smoking and preeclampsia in a previous pregnancy were negatively associated with newborn telomere length. In adjusted linear regression analyses that considered potential sex-specific effects, maternal depression, general anxiety, and pregnancy-specific anxiety symptoms were positively associated with newborn telomere length among males. Overall, the findings provide some evidence for an association between maternal psychosocial wellbeing in pregnancy and newborn telomere length in males, although in the opposite direction than previously reported. Maternal smoking and obstetric history prior to conception may be associated with shorter offspring telomere length.},
}
@article {pmid33176178,
year = {2020},
author = {Shoeb, M and Meier, HCS and Antonini, JM},
title = {Telomeres in toxicology: Occupational health.},
journal = {Pharmacology &amp; therapeutics},
volume = {},
number = {},
pages = {107742},
doi = {10.1016/j.pharmthera.2020.107742},
pmid = {33176178},
issn = {1879-016X},
abstract = {The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.},
}
@article {pmid33176153,
year = {2020},
author = {Drosopoulos, WC and Deng, Z and Twayana, S and Kosiyatrakul, ST and Vladimirova, O and Lieberman, PM and Schildkraut, CL},
title = {TRF2 Mediates Replication Initiation within Human Telomeres to Prevent Telomere Dysfunction.},
journal = {Cell reports},
volume = {33},
number = {6},
pages = {108379},
pmid = {33176153},
issn = {2211-1247},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01 CA140652/CA/NCI NIH HHS/United States ; R01 GM045751/GM/NIGMS NIH HHS/United States ; T32 AG023475/AG/NIA NIH HHS/United States ; },
abstract = {The telomeric shelterin protein telomeric repeat-binding factor 2 (TRF2) recruits origin recognition complex (ORC) proteins, the foundational building blocks of DNA replication origins, to telomeres. We seek to determine whether TRF2-recruited ORC proteins give rise to functional origins in telomere repeat tracts. We find that reduction of telomeric recruitment of ORC2 by expression of an ORC interaction-defective TRF2 mutant significantly reduces telomeric initiation events in human cells. This reduction in initiation events is accompanied by telomere repeat loss, telomere aberrations and dysfunction. We demonstrate that telomeric origins are activated by induced replication stress to provide a key rescue mechanism for completing compromised telomere replication. Importantly, our studies also indicate that the chromatin remodeler SNF2H promotes telomeric initiation events by providing access for ORC2. Collectively, our findings reveal that active recruitment of ORC by TRF2 leads to formation of functional origins, providing an important mechanism for avoiding telomere dysfunction and rescuing challenged telomere replication.},
}
@article {pmid33175128,
year = {2020},
author = {Sindi, S and Solomon, A and Kåreholt, I and Hovatta, I and Antikainen, R and Hänninen, T and Levälahti, E and Laatikainen, T and Lehtisalo, J and Lindström, J and Paajanen, T and Peltonen, M and Singh Khalsa, D and Wolozin, B and Strandberg, T and Tuomilehto, J and Soininen, H and Ngandu, T and Kivipelto, M and , },
title = {Telomere length change in a multidomain lifestyle intervention to prevent cognitive decline: a randomized clinical trial.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaa279},
pmid = {33175128},
issn = {1758-535X},
abstract = {BACKGROUND: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia has not been investigated in randomised controlled trials (RCT).<br><br>METHODS: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year RCT enrolling 1260 participants at-risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. Primary outcome was cognitive change (Neuropsychological Test Battery NTB z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction. Trial registration: NCT01041989.<br><br>RESULTS: This exploratory LTL sub-study included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. Mean annual LTL change (SD) was -0.016 (0.19) in intervention, and -0.023 (0.17) in control group. Between-group difference was non-significant (unstandardised β-coefficient 0.007, 95%CI -0.015-0.030). Interaction analyses indicated better LTL maintenance among APOEε4 carriers vs non-carriers: 0.054 (95%CI 0.007-0.102); younger vs older participants: -0.005 (95%CI -0.010 ‒ -0.001); and those with more vs less healthy lifestyle changes: 0.047 (95%CI 0.005-0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95%CI 0.057-0.396) and long-term memory (0.257, 95%CI 0.024 - 0.489), with a similar trend for NTB total score (0.127, 95%CI -0.011-0.264).<br><br>CONCLUSION: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among sub-groups of elderly at-risk for dementia, including APOEε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits.},
}
@article {pmid33174947,
year = {2020},
author = {Bastos, MF and Matias, MST and Alonso, AC and Silva, LCR and de Araújo, AL and Silva, PR and Benard, G and Bocalini, DS and Steven Baker, J and Leme, LEG},
title = {Moderate levels of physical fitness maintain telomere length in non-senescent T CD8+ cells of aged men.},
journal = {Clinics (Sao Paulo, Brazil)},
volume = {75},
number = {},
pages = {e1628},
pmid = {33174947},
issn = {1980-5322},
abstract = {OBJECTIVES: Immunosenescence is an age-associated change characterized by a decreased immune response. Although physical activity has been described as fundamental for maintaining the quality of life, few studies have evaluated the effects of different levels of exercise on telomere length in aged populations. The present study aimed to analyze the effects of different levels of physical activity, classified by the Maximal oxygen consumption (VO2 max) values, on the telomere length of memory Cluster of differentiation (CD) CD4+(CD45ROneg and CD45RO+), effector CD8+CD28neg, and CD8+CD28+ T cells in aged individuals.<br><br>METHODS: Fifty-three healthy elderly men (aged 65-85 years) were included in this study. Their fitness level was classified according to the American College of Sports Medicine (ACSM) for VO2 max (mL/kg/min). Blood samples were obtained from all participants to analyze the percentage of CD3, CD4, CD8, CD28+, naïve, and subpopulations of memory T cells by using flow cytometry. Furthermore, using the Flow-FISH methodology, the CD4+CD45RO+, CD4+CD45ROneg, CD8+CD28+, and CD8+CD28negT cell telomere lengths were measured.<br><br>RESULTS: There was a greater proportion of effector memory T CD4+ cells and longer telomeres in CD8+CD28+ T cells in the moderate physical fitness group than in the other groups. There was a higher proportion of terminally differentiated memory effector T cells in the low physical fitness group.<br><br>CONCLUSION: A moderate physical activity may positively influence the telomere shortening of CD28+CD8+T cells. However, additional studies are necessary to evaluate the importance of this finding with regard to immune function responses in older men.},
}
@article {pmid33173912,
year = {2020},
author = {Clarity, C and Trowbridge, J and Gerona, R and Ona, K and McMaster, M and Bessonneau, V and Rudel, RA and Buren, H and Morello-Frosch, R},
title = {Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2020.11.05.20226183},
pmid = {33173912},
abstract = {Background Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential marker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA. Methods We measured serum levels of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters and office workers who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length. Results Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (β(95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis(2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (-0.14(-0.28, -0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and levels of exposure between the two groups and/or potential unmeasured confounding. Conclusion Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.},
}
@article {pmid33171154,
year = {2020},
author = {Boniewska-Bernacka, E and Pańczyszyn, A and Klinger, M},
title = {Telomeres and telomerase in risk assessment of cardiovascular diseases.},
journal = {Experimental cell research},
volume = {397},
number = {2},
pages = {112361},
doi = {10.1016/j.yexcr.2020.112361},
pmid = {33171154},
issn = {1090-2422},
abstract = {Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes. Reduction in the number of repetitions causes cell senescence. Cells with high proliferative potential age with each replication cycle. Post-mitotic cells (e.g. cardiovascular cells) have a different aging mechanism. During the aging of cardiovascular system cells, permanent DNA damage occurs in the telomeric regions caused by mitochondrial dysfunction, which is a phenomenon independent of cell proliferation and telomere length. Mitochondrial dysfunction is accompanied by increased production of reactive oxygen species and development of inflammation. This phenomenon in the cells of blood vessels can lead to atherosclerosis development. Telomere damage in cardiomyocytes leads to the activation of the DNA damage response system, histone H2A.X phosphorylation, p53 activation and p21 and p16 protein synthesis, resulting in the SASP phenotype (senescence-associated secretory phenotype), increased inflammation and cardiac dysfunction. Cardiovascular cells show the activity of the TERT subunit of telomerase, an enzyme that prevents telomere shortening. It turns out that disrupting the activity of this enzyme can also contribute to the formation of cardiovascular diseases. Measurements of telomere length according to the &quot;blood-muscle&quot; model may help in the future to assess the risk of cardiovascular complications in people undergoing cardiological procedures, as well as to assess the effectiveness of some drugs.},
}
@article {pmid33171077,
year = {2020},
author = {Stier, A and Hsu, BY and Marciau, C and Doligez, B and Gustafsson, L and Bize, P and Ruuskanen, S},
title = {Born to be young? Prenatal thyroid hormones increase early-life telomere length in wild collared flycatchers.},
journal = {Biology letters},
volume = {16},
number = {11},
pages = {20200364},
pmid = {33171077},
issn = {1744-957X},
mesh = {Animals ; Cross-Sectional Studies ; Female ; Humans ; Longevity ; Male ; Pregnancy ; *Songbirds ; *Telomere/genetics ; Telomere Shortening ; Thyroid Hormones ; },
abstract = {The underlying mechanisms of the lifelong consequences of prenatal environmental condition on health and ageing remain little understood. Thyroid hormones (THs) are important regulators of embryogenesis, transferred from the mother to the embryo. Since prenatal THs can accelerate early-life development, we hypothesized that this might occur at the expense of resource allocation in somatic maintenance processes, leading to premature ageing. Therefore, we investigated the consequences of prenatal TH supplementation on potential hallmarks of ageing in a free-living avian model in which we previously demonstrated that experimentally elevated prenatal TH exposure accelerates early-life growth. Using cross-sectional sampling, we first report that mitochondrial DNA (mtDNA) copy number and telomere length significantly decrease from early-life to late adulthood, thus suggesting that these two molecular markers could be hallmarks of ageing in our wild bird model. Elevated prenatal THs had no effect on mtDNA copy number but counterintuitively increased telomere length both soon after birth and at the end of the growth period (equivalent to offsetting ca 4 years of post-growth telomere shortening). These findings suggest that prenatal THs might have a role in setting the 'biological' age at birth, but raise questions about the nature of the evolutionary costs of prenatal exposure to high TH levels.},
}
@article {pmid33164936,
year = {2020},
author = {Yang, T and Wang, H and Xiong, Y and Chen, C and Duan, K and Jia, J and Ma, F},
title = {Vitamin D Supplementation Improves Cognitive Function Through Reducing Oxidative Stress Regulated by Telomere Length in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized Controlled Trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {78},
number = {4},
pages = {1509-1518},
doi = {10.3233/JAD-200926},
pmid = {33164936},
issn = {1875-8908},
abstract = {BACKGROUND: Cognitive decline in older adults is a serious public health problem today. Association between vitamin D supplementation and cognition remains controversial.<br><br>OBJECTIVE: To determine whether a 12-month vitamin D supplementation improves cognitive function in elderly subjects with mild cognitive impairment (MCI), and whether it is mediated through the mechanism in which telomere length (TL) regulate oxidative stress.<br><br>METHODS: This was a double-blind, randomized, placebo-controlled trial in Tianjin, China. Participants were all native Chinese speakers aged 65 years and older with MCI. 183 subjects were randomized to an intervention group (vitamin D 800 IU/day, n = 93) or a placebo group (the matching starch granules, n = 90), and followed up for 12 months. Tests of cognitive function and mechanism-related biomarkers were evaluated at baseline, 6 months, and 12 months.<br><br>RESULTS: Repeated-measures ANOVA showed substantial improvements in the full scale intelligence quotient (FSIQ), information, digit span, vocabulary, block design, and picture arrangement scores in the vitamin D group over the placebo group (p < 0.001). Leukocyte TL was significantly higher, while serum 8-OXO-dG, OGG1mRNA, and P16INK4amRNA revealed greater decreases in the vitamin D group over the placebo group (p < 0.001). According to mixed-model repeated-measures ANOVA analysis, vitamin D group showed a significant enhancement in the FSIQ score for 12 months compared with the control (estimate value = 5.132, p < 0.001).<br><br>CONCLUSION: Vitamin D supplementation for 12 months appears to improve cognitive function through reducing oxidative stress regulated by increased TL in order adults with MCI. Vitamin D may be a promising public health strategy to prevent cognitive decline.},
}
@article {pmid33163366,
year = {2020},
author = {Alam, MR and Kim, DK},
title = {Alterations in telomere length and mitochondrial DNA copy number in human lymphocytes on short-term exposure to moderate hypoxia.},
journal = {Toxicology reports},
volume = {7},
number = {},
pages = {1443-1447},
pmid = {33163366},
issn = {2214-7500},
abstract = {Hypoxia is related to a variety of diseases, such as cardiovascular and inflammatory diseases and various cancers. Telomere length (TL) may vary according to the hypoxia level and cell types. To the best of our knowledge, no study has investigated the effect of moderate hypoxia on TL and mitochondrial DNA copy number (mtDNAcn) in human lymphocytes. Therefore, in this study, we analyzed the effect of moderate hypoxia on TL in correlation with mtDNAcn. This study included 32 healthy male nonsmoker's subjects; in this cohort, we had previously studied sister chromatid exchange and microsatellite instability. Blood samples from each subject were divided into three groups: a control group and two experimental groups exposed to moderate hypoxia for 12 or 24 h. Relative TL and mtDNAcn were measured by a quantitative real-time polymerase chain reaction. The TL in the control group did not significantly differ from that in the experimental group subjected to hypoxia for 12 h; however, the TL in the 24 h hypoxia-treated experimental group was significantly higher than that in the control group. The correlation between TL and mtDNAcn was not statistically significant in the two hypoxic states. The increase in TL was observed on exposure to hypoxia for 24 h and not for 12 h; thus, the findings suggest that telomere elongation is related to hypoxia exposure duration. The mtDNAcn in the two experimental groups did not significantly differ from that in the control group. These observations suggest that mtDNAcn alterations show more genetic stability than TL alterations. To the best of our knowledge, this is the first in vitro study on human lymphocytes reporting an increase in TL and no alteration in mtDNAcn after short-time exposure to moderate hypoxia.},
}
@article {pmid33163281,
year = {2020},
author = {Chen, M and Tsai, CW and Chang, WS and Xu, J and Xu, Y and Bau, DT and Gu, J},
title = {Prognostic value of leukocyte telomere length in renal cell carcinoma patients.},
journal = {American journal of cancer research},
volume = {10},
number = {10},
pages = {3428-3439},
pmid = {33163281},
issn = {2156-6976},
abstract = {Telomeres play important roles in cancer initiation and progression. Leukocyte telomere length (LTL) can modulate cancer risk and outcome. We hypothesize that genetically predicted short LTL is associated with worse prognosis in renal cell carcinoma (RCC). A total of 1,086 histologically confirmed RCC patients were included in this study. A weighted genetic risk score (GRS) predictive of LTL was constructed using 10 confirmed LTL-associated single nucleotide polymorphisms (SNPs). The associations of individual SNPs and GRS with recurrence and survival were determined by multivariate Cox proportional hazards analysis. In individual SNP analysis, long LTL-associated allele of rs7675998 in NAF1 gene at chromosome 4 was significantly associated with a reduced risk of recurrence (HR=0.85, 95% CI, 0.73-0.99, P=0.043), while the long LTL-associated allele of rs10936599 in TERC at chromosome 3 conferred a reduced risk of death (HR=0.85, 95% CI, 0.73-1.00, P=0.047). More importantly, genetically predicted LTL was associated with both recurrence and survival. Dichotomized at the median value of GRS, patients with low GRS (indicating short LTL) exhibited significantly increased risks of recurrence (HR=1.26, 95% CI, 1.03-1.54, P=0.025) and death (HR=1.23, 95% CI, 1.00-1.50, P=0.045). Hence, we concluded that genetically predicted short LTL is associated with worse prognosis in RCC patients.},
}
@article {pmid33161111,
year = {2021},
author = {Zhou, X and Li, X and Wei, W and Duan, X and Zhang, H and Ding, M and Yao, W and Wang, Q and Wang, W and Yang, Y},
title = {Association between genetic polymorphisms of telomere pathway genes and hydrogen peroxide level in omethoate exposure workers.},
journal = {Environmental toxicology and pharmacology},
volume = {82},
number = {},
pages = {103541},
doi = {10.1016/j.etap.2020.103541},
pmid = {33161111},
issn = {1872-7077},
abstract = {OBJECTIVE: The aim of this study was to explore the association between genetic variations in telomere pathway genes and the level of hydrogen peroxide (H2O2) in omethoate exposure workers.<br><br>METHODS: A total of 180 omethoate exposure workers and 115 healthy controls were recruited. The level of H2O2 in plasma was determined with molybdenic acid colorimetry. Polymerase chain reaction and restriction fragment length was used to detect polymorphisms in POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242, and TERT rs2736098.<br><br>RESULTS: The level of H2O2 in exposure group (4.26 ± 0.71) was significantly higher than that in control group (3.29 ± 0.46). Generalized linear models indicated that risk factors for the increase H2O2 level were exposure [β(95 % CI) = 0.951 (0.806, 1.096), P < 0.001] and AA + AT genotype in POT1 rs034794 [β(95 % CI) = 0.397 (0.049, 0.745), P = 0.025].<br><br>CONCLUSION: The increase H2O2 level was associated with omethoate exposure and AA + AT genotypes in POT1 gene rs1034794. It provided a new idea that polymorphisms in telomere pathway genes may indirectly regulate telomere length by influencing oxidative stress.},
}
@article {pmid33157092,
year = {2021},
author = {McKnight, I and Hart, C and Park, IH and Shim, JW},
title = {Genes causing congenital hydrocephalus: Their chromosomal characteristics of telomere proximity and DNA compositions.},
journal = {Experimental neurology},
volume = {335},
number = {},
pages = {113523},
doi = {10.1016/j.expneurol.2020.113523},
pmid = {33157092},
issn = {1090-2430},
support = {P20 GM103434/GM/NIGMS NIH HHS/United States ; },
abstract = {Congenital hydrocephalus (CH) is caused by genetic mutations, but whether factors impacting human genetic mutations are disease-specific remains elusive. Given two factors associated with high mutation rates, we reviewed how many disease-susceptible genes match with (i) proximity to telomeres or (ii) high adenine and thymine (A + T) content in human CH as compared to other disorders of the central nervous system (CNS). We extracted genomic information using a genome data viewer. Importantly, 98 of 108 genes causing CH satisfied (i) or (ii), resulting in >90% matching rate. However, such a high accordance no longer sustained as we checked two factors in Alzheimer's disease (AD) and/or familial Parkinson's disease (fPD), resulting in 84% and 59% matching, respectively. A disease-specific matching of telomere proximity or high A + T content predicts causative genes of CH much better than neurodegenerative diseases and other CNS conditions, likely due to sufficient number of known causative genes (n = 108) and precise determination and classification of the genotype and phenotype. Our analysis suggests a need for identifying genetic basis of both factors before human clinical studies, to prioritize putative genes found in preclinical models into the likely (meeting at least one) and more likely candidate (meeting both), which predisposes human genes to mutations.},
}
@article {pmid33156376,
year = {2021},
author = {Kabaha, MM and Tzfati, Y},
title = {Telomerase, the recombination machinery and Rap1 play redundant roles in yeast telomere protection.},
journal = {Current genetics},
volume = {67},
number = {1},
pages = {153-163},
pmid = {33156376},
issn = {1432-0983},
support = {2005088//United States - Israel Binational Science Foundation/ ; 2009204//United States - Israel Binational Science Foundation/ ; I-849-253.13/2004//German-Israeli Foundation for Scientific Research and Development/ ; 3-5363/2008-2009//Ministry of Science and Technology, Israel/ ; },
abstract = {Telomeres are specialized nucleoprotein complexes that protect the ends of eukaryotic chromosomes and distinguish them from broken DNA ends. Disruption of telomere protection may cause aging-associated pathologies and cancer. Here, we examined what makes telomere protection durable and resistant to perturbations using a budding yeast model organism. The protein Rap1 binds the telomeric repeats, negatively regulates telomere length, and protects telomeres by repressing homologous recombination and non-homologous end joining (NHEJ). A single-nucleotide mutation in the Kluyveromyces lactis telomerase RNA (TER1) template, ter1-16T, is incorporated into the telomeric repeats, disrupting the binding of Rap1 and causing dramatic telomere elongation. However, cell viability is not significantly affected, suggesting the existence of additional mechanism(s) for telomere protection. To examine this hypothesis, we explored the contribution of the recombination factor Rad52 and telomerase to telomere protection in the background of ter1-16T. To disrupt the function of telomerase, we exploited small mutations in a stem-loop domain of TER1 (Reg2), which result in short but stable telomeres. We generated K. lactis strains with combinations of three different mutations: ter1-16T, RAD52 deletion, and a two-nucleotide substitution in Reg2. Our results show that upon Rap1 depletion from telomeres, telomerase and the recombination machinery compensate for the loss of Rap1 protection and play redundant but critical roles in preventing NHEJ and maintaining telomere integrity and cell viability. These results demonstrate how redundant pathways make the essential role of telomeres-protecting our genome integrity and preventing cancer-more robust and resistant to assaults and perturbations.},
}
@article {pmid33154635,
year = {2020},
author = {Cagsin, H and Uzan, A and Tosun, O and Rasmussen, F and Serakinci, N},
title = {Tissue-Specific Ultra-Short Telomeres in Chronic Obstructive Pulmonary Disease.},
journal = {International journal of chronic obstructive pulmonary disease},
volume = {15},
number = {},
pages = {2751-2757},
pmid = {33154635},
issn = {1178-2005},
abstract = {Purpose: Telomere biology, especially tissue-specific ultra-short telomeres, might provide a strong contribution to our current knowledge in COPD development as well as a predictive marker for prognosis. To test this hypothesis, we investigated telomere lengths in lung tissue and leukocytes in patients diagnosed with COPD.<br><br>Patients and Methods: Thirty-two patients were included in the current study. All patients showed a post-bronchodilator ratio of less than 70% post-bronchodilator predicted value of forced expiratory volume in second (FEV1%), mean 56%; range [19% to 86%]. To be able to investigate ultra-short telomeres, universal single telomere length analysis (U-STELA) was used.<br><br>Results: Our results showed a higher level of the ultra-short telomere presence in bronchoalveolar lavage (BAL) cells when compared to leukocytes with statistical significance t(62)=5.771, p<0.00001. The FEV1% was lower in subjects with ultra-short telomeres in BAL (50.6% vs 81.6%: p<0.001) and in ultra-short telomeres in blood leukocytes (37.3% vs 58.5%: p=0.051) when compared to subjects without ultra-short telomeres in leukocytes. Furthermore, the patients who had ultra-short telomeres in BAL samples were significantly older (p=0.014) than patients who did not have ultra-short telomeres. Ultra-short telomeres in BAL (p=0.05) but not in leukocytes (p=0.33) were associated with FEV1% in a regressions model adjusting for age (p<0.0001), ever smoking (p<0.0001) and sex (p=0.71). The patients with ultra-short telomeres were graded higher in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification (p=0.006).<br><br>Conclusion: This study emphasizes the need to investigate the correct tissue to get a representative evaluation of the stage or advancedness of COPD. To our knowledge, this is the first study to show that there is a correlation between the presence of ultra-short telomeres in lung tissue and COPD severity. Our results suggest that ultra-short telomeres are involved in the molecular pathogenesis of COPD and might be used as a tissue-specific predictive biomarker.},
}
@article {pmid33144412,
year = {2020},
author = {Nogueira, BMD and Machado, CB and Montenegro, RC and DE Moraes, MEA and Moreira-Nunes, CA},
title = {Telomere Length and Hematological Disorders: A Review.},
journal = {In vivo (Athens, Greece)},
volume = {34},
number = {6},
pages = {3093-3101},
pmid = {33144412},
issn = {1791-7549},
abstract = {Telomeres compose the end portions of human chromosomes, and their main function is to protect the genome. In hematological disorders, telomeres are shortened, predisposing to genetic instability that may cause DNA damage and chromosomal rearrangements, inducing a poor clinical outcome. Studies from 2010 to 2019 were compiled and experimental studies using samples of patients diagnosed with hematological malignancies that reported the size of the telomeres were described. Abnormal telomere shortening is described in cancer, but in hematological neoplasms, telomeres are still shortened even after telomerase reactivation. In this study, we compared the sizes of telomeres in leukemias, myelodysplastic syndrome and lymphomas, identifying that the smallest telomeres are present in patients at relapse. In conclusion, the experimental and clinical data analyzed in this review demonstrate that excessive telomere shortening is present in major hematological malignancies and its analysis and measurement is a crucial step in determining patient prognosis, predicting disease risk and assisting in the decision for targeted therapeutic strategies.},
}
@article {pmid33144154,
year = {2021},
author = {Lemaître, JF and Carbillet, J and Rey, B and Palme, R and Froy, H and Wilbourn, RV and Underwood, SL and Cheynel, L and Gaillard, JM and Hewison, AJM and Verheyden, H and Débias, F and Duhayer, J and Régis, C and Pardonnet, S and Pellerin, M and Nussey, DH and Gilot-Fromont, E},
title = {Short-term telomere dynamics is associated with glucocorticoid levels in wild populations of roe deer.},
journal = {Comparative biochemistry and physiology. Part A, Molecular &amp; integrative physiology},
volume = {252},
number = {},
pages = {110836},
doi = {10.1016/j.cbpa.2020.110836},
pmid = {33144154},
issn = {1531-4332},
abstract = {While evidence that telomere length is associated with health and mortality in humans and birds is accumulating, a large body of research is currently seeking to identify factors that modulate telomere dynamics. We tested the hypothesis that high levels of glucocorticoids in individuals under environmental stress should accelerate telomere shortening in two wild populations of roe deer (Capreolus capreolus) living in different ecological contexts. From two consecutive annual sampling sessions, we found that individuals with faster rates of telomere shortening had higher concentrations of fecal glucocorticoid metabolites, suggesting a functional link between glucocorticoid levels and telomere attrition rate. This relationship was consistent for both sexes and populations. This finding paves the way for further studies of the fitness consequences of exposure to environmental stressors in wild vertebrates.},
}
@article {pmid33143762,
year = {2020},
author = {Ojeda-Rodríguez, A and Zazpe, I and Alonso-Pedrero, L and Zalba, G and Martínez-González, MA and Marti, A},
title = {Higher adherence to an empirically derived Mediterranean dietary pattern is positively associated with telomere length: the Seguimiento Universidad de Navarra (SUN) project.},
journal = {The British journal of nutrition},
volume = {},
number = {},
pages = {1-10},
doi = {10.1017/S0007114520004274},
pmid = {33143762},
issn = {1475-2662},
abstract = {Telomere integrity is influenced by oxidative stress. Also, inflammation-related factors, including nutritional factors, could modulate telomere integrity. The relationship between a posteriori-derived dietary patterns and telomere length (TL) has been scarcely investigated. Thus, our objective was to examine the association between empirically derived dietary patterns ascertained through principal component analysis (PCA) and TL in an older adult Spanish population. A total of 886 older adults (>55 years old; 645 males and 241 females) from the Seguimiento Universidad de Navarra (SUN) cohort were included in the study. TL was measured by monochrome multiplex real-time quantitative PCR. Age-adjusted TL was used for all analyses. Dietary patterns were identified by PCA based on thirty predefined candidate food groups collected from a validated 136-food items frequency questionnaire. Generalised linear models were fitted to obtain β-coefficients and their 95 % CI evaluating differences in TL between each of the four upper quintiles of adherence to dietary patterns and the lowest quintile. Sensitivity analyses by rerunning all multiple linear models under different stratifications were performed to evaluate the robustness of our results. Two major dietary patterns were empirically identified, Western dietary pattern (WDP) and Mediterranean dietary pattern (MDP). After adjustment for potential confounders, longer TL was found among subjects in the highest quintile of MDP (β = 0·064; 95 % CI 0·004, 0·123). The WDP showed no significant association with TL. In conclusion, higher adherence to a posteriori-derived MDP was independently associated with longer telomeres in an older adult Spanish population of the SUN project.},
}
@article {pmid33142697,
year = {2020},
author = {Garrido-Navas, MC and Tippins, F and Barwell, J and Hoffman, J and Codd, V and Royle, NJ},
title = {Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers.},
journal = {Life (Basel, Switzerland)},
volume = {10},
number = {11},
pages = {},
pmid = {33142697},
issn = {2075-1729},
support = {PhD studentship//Univeristy of Leicester/ ; Development Funding//Cancer Research UK Leicester Centre/ ; },
abstract = {Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR+/- carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in MSH2+/- carriers compared to MLH1+/- carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither MSH2+/- or MLH1+/- children had consistently shorter or longer telomeres than their MMR+/- parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with MSH2 mutations, had significantly longer XpYp telomeres than their MMR+/- parent. Altogether our data suggest that MMR insufficiency, particularly in MSH2+/- carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.},
}
@article {pmid33140570,
year = {2020},
author = {Yu, QQ and Gao, JJ and Lang, XX and Li, HY and Wang, MQ},
title = {Microenvironment-Sensitive Fluorescent Ligand Binds Ascaris Telomere Antiparallel G-Quadruplex DNA with Blue-Shift and Enhanced Emission.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbic.202000671},
pmid = {33140570},
issn = {1439-7633},
support = {21907042//National Natural Science Foundation of China/ ; BK20180857//Natural Science Foundation of Jiangsu Province/ ; },
abstract = {The development of small molecules that can selectively target G-quadruplex (G4) DNAs has drawn considerable attention due to their unique physiological and pathological functions. However, only a few molecules have been found to selectively bind a particular G4 DNA structure. We have developed a fluorescence ligand Q1, a molecular scaffold with a carbazole-pyridine core bridged by a phenylboronic acid side chain, that acts as a selective ascaris telomere antiparallel G4 DNA ASC20 ligand with about 18 nm blue-shifted and enhanced fluorescence intensity. Photophysical properties revealed that Q1 was sensitive to the microenvironment and gave the best selectivity to ASC20 with an equilibrium binding constant Ka =6.04×105 M-1 . Time-resolved fluorescence studies also demonstrated that Q1 showed a longer fluorescence lifetime in the presence of ASC20. The binding characteristics of Q1 with ASC20 were shown in detail in a fluorescent intercalator displacement (FID) assay, a 2-Ap titration experiment and by molecular docking. Ligand Q1 could adopt an appropriate pose at terminal G-quartets of ASC20 through multiple interactions including π-π stacking between aromatic rings; this led to strong fluorescence enhancement. In addition, a co-staining image showed that Q1 is mainly distributed in the cytoplasm. Accordingly, this work provides insights for the development of ligands that selectively targeting a specific G4 DNA structure.},
}
@article {pmid33140537,
year = {2020},
author = {Navarro-Mateu, F and Husky, M and Cayuela-Fuentes, P and Álvarez, FJ and Roca-Vega, A and Rubio-Aparicio, M and Chirlaque, MD and Cayuela, ML and Martínez, S and Sánchez-Meca, J},
title = {The association of telomere length with substance use disorders: a systematic review and meta-analysis of observational studies.},
journal = {Addiction (Abingdon, England)},
volume = {},
number = {},
pages = {},
doi = {10.1111/add.15312},
pmid = {33140537},
issn = {1360-0443},
support = {//Observatorio sobre Drogas de la Región de Murcia/ ; },
abstract = {BACKGROUND AND AIMS: Several recent studies have investigated the relationship between telomere length and substance use disorders with inconsistent results. We aimed to assess this association and to identify moderators of the relationship.<br><br>METHODS: Systematic review and meta-analysis. Selection criteria were observational studies reporting telomere length in people with a substance use disorder compared with a control group. Studies focused solely on nicotine addiction, employing other study designs, and non-human studies were excluded. Study selection and data extraction were independently conducted by two researchers following a standardized protocol and included studies until December 2019. Standardized mean differences were used as the effect size index [d; 95% confidence interval (CI)] and random-effects models were used for the meta-analysis. Cochran's Q-statistic, I2 index, visual inspection of the forest plot and a 95% prediction interval were applied to verify study heterogeneity. Subgroup analyses and meta-regressions were conducted to explore heterogeneity. Small study effects were examined using the 'funnel plot', the Egger test, Duval &amp; Tweedie's trim-and-fill method and the precision-effect test-precision-effect estimate with standard error (PET-PEESE) method. The risk of bias and the quality of evidence were assessed.<br><br>RESULTS: Ten studies (12 analysis units with 2671 cases and 4532 controls) met the selection criteria. An overall effect size of moderate magnitude was found (d+ = -0.63; 95% CI = -1.00 and -0.26; P = 0.0008). A potential small study effect was detected, as well as large heterogeneity between studies (Q-statistic P < 0.001, I2 = 97.3%). Selection of controls, reporting laboratory quality control procedures and total sample size significantly affected the effect size. The quality of the evidence was very low, based on risk of bias analysis and the grading of recommendations assessment, development and evaluation (GRADE) system.<br><br>CONCLUSIONS: People with substance use disorders appear to have shorter telomere length than controls; however, this finding should be interpreted with caution due to the poor quality of the evidence.},
}
@article {pmid33139395,
year = {2020},
author = {Criscuolo, F and Torres, R and Zahn, S and Williams, TD},
title = {Telomere dynamics from hatching to sexual maturity and maternal effects in the 'multivariate egg'.},
journal = {The Journal of experimental biology},
volume = {223},
number = {Pt 23},
pages = {},
doi = {10.1242/jeb.232496},
pmid = {33139395},
issn = {1477-9145},
abstract = {Avian eggs contain a large number of molecules deposited by the mother that provide the embryo with energy but also potentially influence its development via the effects of maternally derived hormones and antibodies: the avian egg is thus 'multivariate'. Multivariate effects on offspring phenotype were evaluated in a study on captive zebra finches, by simultaneously manipulating maternally derived antibodies (MAb) by lipopolysaccharide (LPS) treatment of mothers and injection of testosterone into the egg yolk. LPS treatment had a positive effect on body mass growth at 30 days after hatching and immune response at sexual maturity, while egg testosterone treatment positively influenced immune response at fledging and courtship behaviour in sexually mature male offspring. Maternal effects are known to modulate offspring telomere length (TL). However, the multivariate effects of egg-derived maternal components on offspring telomere dynamics from hatching to sexual maturity are undefined. Here, we tested: (1) the effects of LPS and testosterone treatments on TL from hatching to sexual maturity (day 82); (2) how LPS treatment modulated TL over reproduction in adult females; and (3) the relationship between maternal and offspring TL. We predicted that TL would be shorter in LPS fledglings (as a cost of faster growth) and that TL would be longer in sexually mature adults after yolk testosterone treatment (as a proxy of individual quality). In adult females, there was an overall negative relationship between laying and rearing investments and TL, this relationship was weaker in LPS-treated females. In chicks, there was an overall negative effect of LPS treatment on TL measured at fledging and sexual maturity (day 25-82). In addition, at fledging, there was a Sex×LPS×Testosterone interaction, suggesting the existence of antagonistic effects of our treatments. Our data partially support the hypothesis that telomeres are proxies of individual quality and that individual differences in TL are established very early in life.},
}
@article {pmid33132941,
year = {2020},
author = {Lundberg, M and Millischer, V and Backlund, L and Martinsson, L and Stenvinkel, P and Sellgren, CM and Lavebratt, C and Schalling, M},
title = {Lithium and the Interplay Between Telomeres and Mitochondria in Bipolar Disorder.},
journal = {Frontiers in psychiatry},
volume = {11},
number = {},
pages = {586083},
pmid = {33132941},
issn = {1664-0640},
abstract = {Bipolar disorder is a severe psychiatric disorder which affects more than 1% of the world's population and is a leading cause of disability among young people. For the past 50 years, lithium has been the drug of choice for maintenance treatment of bipolar disorder due to its potent ability to prevent both manic and depressive episodes as well as suicide. However, though lithium has been associated with a multitude of effects within different cellular pathways and biological systems, its specific mechanism of action in stabilizing mood remains largely elusive. Mitochondrial dysfunction and telomere shortening have been implicated in both the pathophysiology of bipolar disorder and as targets of lithium treatment. Interestingly, it has in recent years become clear that these phenomena are intimately linked, partly through reactive oxygen species signaling and the subcellular translocation and non-canonical actions of telomerase reverse transcriptase. In this review, we integrate the current understanding of mitochondrial dysfunction, oxidative stress and telomere shortening in bipolar disorder with documented effects of lithium. Moreover, we propose that lithium's mechanism of action is intimately connected with the interdependent regulation of mitochondrial bioenergetics and telomere maintenance.},
}
@article {pmid33128602,
year = {2021},
author = {Minasi, S and Baldi, C and Gianno, F and Antonelli, M and Buccoliero, AM and Pietsch, T and Massimino, M and Buttarelli, FR},
title = {Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma.},
journal = {Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery},
volume = {37},
number = {3},
pages = {809-818},
pmid = {33128602},
issn = {1433-0350},
abstract = {PURPOSE: The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined.<br><br>METHODS: We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR.<br><br>RESULTS: Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length.<br><br>CONCLUSION: Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.},
}
@article {pmid33128102,
year = {2020},
author = {Smith, LE and Jones, ME and Hamede, R and Risques, R and Patton, AH and Carter, PA and Storfer, A},
title = {Telomere Length is a Susceptibility Marker for Tasmanian Devil Facial Tumor Disease.},
journal = {EcoHealth},
volume = {17},
number = {3},
pages = {280-291},
pmid = {33128102},
issn = {1612-9210},
support = {R01 GM126563/GM/NIGMS NIH HHS/United States ; 1316549//Division of Environmental Biology/International ; },
abstract = {Telomeres protect chromosomes from degradation during cellular replication. In humans, it is well-documented that excessive telomere degradation is one mechanism by which cells can become cancerous. Increasing evidence from wildlife studies suggests that telomere length is positively correlated with survival and health and negatively correlated with disease infection intensity. The recently emerged devil facial tumor disease (DFTD) has led to dramatic and rapid population declines of the Tasmanian devil throughout its geographic range. Here, we tested the hypothesis that susceptibility to DFTD is negatively correlated with telomere length in devils across three populations with different infection histories. Our findings suggest telomere length is correlated with DFTD resistance in three ways. First, devils from a population with the slowest recorded increase in DFTD prevalence (West Pencil Pine) have significantly longer telomeres than those from two populations with rapid and exponential increases in prevalence (Freycinet and Narawantapu). Second, using extensive mark-recapture data obtained from a long-term demographic study, we found that individuals with relatively long telomeres tend to be infected at a significantly later age than those with shorter telomeres. Third, a hazard model showed devils with longer telomeres tended to become infected at a lower rate than those with shorter telomeres. This research provides a rare study of telomere length variation and its association with disease in a wildlife population. Our results suggest that telomere length may be a reliable marker of susceptibility to DFTD and assist with future management of this endangered species.},
}
@article {pmid33126880,
year = {2020},
author = {Chang, X and Dorajoo, R and Sun, Y and Wang, L and Ong, CN and Liu, J and Khor, CC and Yuan, JM and Koh, WP and Friedlander, Y and Heng, CK},
title = {Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population.},
journal = {Nutrition journal},
volume = {19},
number = {1},
pages = {119},
pmid = {33126880},
issn = {1475-2891},
support = {R01 CA144034/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established.<br><br>METHODS: A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling.<br><br>RESULTS: Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p < 5 × 10- 8). Mediation analysis showed that PUFA and LTL affected CAD risk independently.<br><br>CONCLUSIONS: Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.},
}
@article {pmid33126043,
year = {2020},
author = {Grandin, N and Gallego, ME and White, CI and Charbonneau, M},
title = {Inhibition of the alternative lengthening of telomeres pathway by subtelomeric sequences in Saccharomyces cerevisiae.},
journal = {DNA repair},
volume = {96},
number = {},
pages = {102996},
doi = {10.1016/j.dnarep.2020.102996},
pmid = {33126043},
issn = {1568-7856},
abstract = {In the budding yeast Saccharomyces cerevisiae, telomerase is constitutively active and is essential for chromosome end protection and illimited proliferation of cell populations. However, upon inactivation of telomerase, alternative mechanims of telomere maintenance allow proliferation of only extremely rare survivors. S. cerevisiae type I and type II survivors differ by the nature of the donor sequences used for repair by homologous recombination of the uncapped terminal TG1-3 telomeric sequences. Type I amplifies the subtelomeric Y' sequences and is more efficient than type II, which amplifies the terminal TG1-3 repeats. However, type II survivors grow faster than type I survivors and can easily outgrow them in liquid cultures. The mechanistic interest of studying S. cerevisiae telomeric recombination is reinforced by the fact that type II recombination is the equivalent of the alternative lengthening of telomeres (ALT) pathway that is used by 5-15 % of cancer types as an alternative to telomerase reactivation. In budding yeast, only around half of the 32 telomeres harbor Y' subtelomeric elements. We report here that in strains harboring Y' elements on all telomeres, type II survivors are not observed, most likely due to an increase in the efficiency of type I recombination. However, in a temperature-sensitive cdc13-1 mutant grown at semi-permissive temperature, the increased amount of telomeric TG1-3 repeats could overcome type II inhibition by the subtelomeric Y' sequences. Strikingly, in the 100 % Y' strain the replicative senescence crisis normally provoked by inactivation of telomerase completely disappeared and the severity of the crisis was proportional to the percentage of chromosome-ends lacking Y' subtelomeric sequences. The present study highlights the fact that the nature of subtelomeric elements can influence the selection of the pathway of telomere maintenance by recombination, as well as the response of the cell to telomeric damage caused by telomerase inactivation.},
}
@article {pmid33125425,
year = {2020},
author = {Warner, ET and Zhang, Y and Gu, Y and Taporoski, TP and Pereira, A and DeVivo, I and Spence, ND and Cozier, Y and Palmer, JR and Kanaya, AM and Kandula, NR and Cole, SA and Tworoger, S and Shields, A},
title = {Physical and sexual abuse in childhood and adolescence and leukocyte telomere length: A pooled analysis of the study on psychosocial stress, spirituality, and health.},
journal = {PloS one},
volume = {15},
number = {10},
pages = {e0241363},
pmid = {33125425},
issn = {1932-6203},
support = {K24 HL112827/HL/NHLBI NIH HHS/United States ; R01 HL093009/HL/NHLBI NIH HHS/United States ; K01 CA188075/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; R01 CA098663/CA/NCI NIH HHS/United States ; R01 CA058420/CA/NCI NIH HHS/United States ; R01 HL120725/HL/NHLBI NIH HHS/United States ; UL1 RR024131/RR/NCRR NIH HHS/United States ; UL1 TR001872/TR/NCATS NIH HHS/United States ; P30 DK098722/DK/NIDDK NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; R01 CA163451/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; 75N92019D00027/HL/NHLBI NIH HHS/United States ; 75N92019D00028/HL/NHLBI NIH HHS/United States ; 75N92019D00029/HL/NHLBI NIH HHS/United States ; 75N92019D00030/HL/NHLBI NIH HHS/United States ; R01 HL109315/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; R01 HL109282/HL/NHLBI NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Humans ; Leukocytes/*metabolism ; Physical Abuse ; Telomere/*genetics ; },
abstract = {INTRODUCTION: We examined whether abuse in childhood and/or adolescence was associated with shorter telomere length in a pooled analysis of 3,232 participants from five diverse cohorts. We also assessed whether religion or spirituality (R/S) could buffer deleterious effects of abuse.<br><br>METHODS: Physical and sexual abuse in childhood (age <12) and adolescence (age 12-18) was assessed using the Revised Conflict Tactics Scale and questions from a 1995 Gallup survey. We measured relative leukocyte telomere lengths (RTL) using quantitative real time polymerase chain reaction. We used generalized estimating equations to assess associations of physical and sexual abuse with log-transformed RTL z-scores. Analyses were conducted in each cohort, overall, and stratified by extent of religiosity or spirituality and religious coping in adulthood. We pooled study-specific estimates using random-effects models and assessed between-study heterogeneity.<br><br>RESULTS: Compared to no abuse, severe sexual abuse was associated with lower RTL z-scores, in childhood: -15.6%, 95% CI: -25.9, -4.9; p-trend = 0.04; p-heterogeneity = 0.58 and in adolescence: -16.5%, 95% CI: -28.1, -3.0; p-trend = 0.08; p-heterogeneity = 0.68. Sexual abuse experienced in both childhood and adolescence was associated with 11.3% lower RTL z-scores after adjustment for childhood and demographic covariates (95% CI: -20.5%, -2.0%; p-trend = 0.03; p-heterogeneity = 0.62). There was no evidence of effect modification by R/S. Physical abuse was not associated with telomere length.<br><br>CONCLUSIONS: Sexual abuse in childhood or adolescence was associated with a marker of accelerated biological aging, decreased telomere length. The lack of moderation by R/S may be due to inability to capture the appropriate time period for those beliefs and practices.},
}
@article {pmid33123024,
year = {2020},
author = {Polettini, J and da Silva, MG},
title = {Telomere-Related Disorders in Fetal Membranes Associated With Birth and Adverse Pregnancy Outcomes.},
journal = {Frontiers in physiology},
volume = {11},
number = {},
pages = {561771},
pmid = {33123024},
issn = {1664-042X},
abstract = {Telomere disorders have been associated with aging-related diseases, including diabetes, vascular, and neurodegenerative diseases. The main consequence of altered telomere is the induction of the state of irreversible cell cycle arrest. Though several mechanisms responsible for the activation of senescence have been identified, it is still unclear how a cell is indeed induced to become irreversibly arrested. Most tissues in the body will experience senescence throughout its lifespan, but intrinsic and extrinsic stressors, such as chemicals, pollution, oxidative stress (OS), and inflammation accelerate the process. Pregnancy is a state of OS, as the higher metabolic demand of the growing fetus results in increased reactive oxygen species production. As a temporary organ in the mother, senescence in fetal membranes and placenta is expected and linked to term parturition (>37 weeks of gestation). However, a persistent, overwhelming, or premature OS affects placental antioxidant capacity, with consequent accumulation of OS causing damage to lipids, proteins, and DNA in the placental tissues. Therefore, senescence and its main inducer, telomere length (TL) reduction, have been associated with pregnancy complications, including stillbirth, preeclampsia, intrauterine growth restriction, and prematurity. Fetal membranes have a notable role in preterm births, which continue to be a major health issue associated with increased risk of neo and perinatal adverse outcomes and/or predisposition to disease in later life; however, the ability to mediate a delay in parturition during such cases is limited, because the pathophysiology of preterm births and physiological mechanisms of term births are not yet fully elucidated. Here, we review the current knowledge regarding the regulation of telomere-related senescence mechanisms in fetal membranes, highlighting the role of inflammation, methylation, and telomerase activity. Moreover, we present the evidences of TL reduction and senescence in gestational tissues by the time of term parturition. In conclusion, we verified that telomere regulation in fetal membranes requires a more complete understanding, in order to support the development of successful effective interventions of the molecular mechanisms that triggers parturition, including telomere signals, which may vary throughout placental tissues.},
}
@article {pmid33122450,
year = {2020},
author = {Wu, Y and Pei, Y and Yang, Z and Li, K and Lou, X and Cui, W},
title = {Accelerated telomere shortening independent of LRRK2 variants in Chinese patients with Parkinson's disease.},
journal = {Aging},
volume = {12},
number = {20},
pages = {20483-20492},
pmid = {33122450},
issn = {1945-4589},
abstract = {Oxidative stress and inflammation play vital roles in Parkinson's disease (PD) development. Thus, telomere length is expected to be shortened in this disease, but current data are inconclusive. We performed a case-control study of 261 patients with PD and 270 sex and age-matched healthy controls treated at the Peking Union Medical College Hospital. We found leucocyte telomere length (LTL) was significantly shortened in PD as compared with controls [1.02 (0.84-1.39) vs. 1.48 (1.08-1.94), P<0.001] and shorter LTL was associated with a dramatically increased risk of PD (lowest vs. highest quartile odds ratio (OR) =9.54, 95% CI: 5.33-17.06, P<0.001). We also investigated the roles of six LRRK2 variants in the susceptibility to PD. R1441C/G/H, G2019S, and I2020T variations were not detected in our study. No significant differences were found in the presence of variants R1398H (15.4% vs. 17.0%, P=0.619) and R1628P (2.3% vs. 0.7%, P=0.159) in PD and controls, while the G2385R variant was found to be a risk factor associated with increased PD susceptibility (OR=2.14, 95% CI: 1.12-4.10, P=0.021). No significant association was found between different LRRK2 variants and telomere length. These findings suggest that shorter LTL might be associated with PD in a manner independent of LRRK2 variants.},
}
@article {pmid33122338,
year = {2020},
author = {Adegunsoye, A and Morisset, J and Newton, CA and Oldham, JM and Vittinghoff, E and Linderholm, AL and Strek, ME and Noth, I and Garcia, CK and Wolters, PJ and Ley, B},
title = {Leukocyte Telomere Length and Mycophenolate Therapy in Chronic Hypersensitivity Pneumonitis.},
journal = {The European respiratory journal},
volume = {},
number = {},
pages = {},
doi = {10.1183/13993003.02872-2020},
pmid = {33122338},
issn = {1399-3003},
support = {K23 HL146942/HL/NHLBI NIH HHS/United States ; K23 HL148498/HL/NHLBI NIH HHS/United States ; },
}
@article {pmid33122293,
year = {2020},
author = {Pinzaru, AM and Kareh, M and Lamm, N and Lazzerini-Denchi, E and Cesare, AJ and Sfeir, A},
title = {Replication stress conferred by POT1 dysfunction promotes telomere relocalization to the nuclear pore.},
journal = {Genes &amp; development},
volume = {34},
number = {23-24},
pages = {1619-1636},
pmid = {33122293},
issn = {1549-5477},
support = {P30 CA016087/CA/NCI NIH HHS/United States ; U01 CA231019/CA/NCI NIH HHS/United States ; },
abstract = {Mutations in the telomere-binding protein POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we define the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR interference and biotin-based proximity labeling, respectively. These screens reveal that replication stress is a major vulnerability in cells expressing mutant POT1, which manifests as increased telomere mitotic DNA synthesis at telomeres. Our study also unveils a role for the nuclear pore complex in resolving replication defects at telomeres. Depletion of nuclear pore complex subunits in the context of POT1 dysfunction increases DNA damage signaling, telomere fragility and sister chromatid exchanges. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity.},
}
@article {pmid33121962,
year = {2020},
author = {Michniacki, TF and Weyand, AC},
title = {Gastrointestinal Bleeding: Expanding the Shortened Telomere Disorder Phenotype.},
journal = {The Journal of pediatrics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpeds.2020.10.057},
pmid = {33121962},
issn = {1097-6833},
}
@article {pmid33120877,
year = {2020},
author = {Torrance, JB and Goldband, S},
title = {Mathematical Connection between Short Telomere Induced Senescence Calculation and Mortality Rate Data.},
journal = {International journal of molecular sciences},
volume = {21},
number = {21},
pages = {},
pmid = {33120877},
issn = {1422-0067},
abstract = {The last 20 years have seen a surge in scientific activity and promising results in the study of aging and longevity. Many researchers have focused on telomeres, which are composed of a series of TTAGGG repeat nucleotide sequences at the ends of each chromosome. Measurements of the length of these telomere strands show that they decrease in length with increasing age, leading many authors to propose that when the length of these telomere strands decreases sufficiently, the cells enter into a state of replicative senescence, eventually leading to disease and death. These ideas are supported by evidence that short telomere length is correlated with increased mortality. In this paper, we extend this idea to make an actual calculation of the predicted mortality rate caused by short telomere length induced senescence (STLIS). We derive a simple equation for the mathematical relationship between telomere length and mortality rate. Using only three parameters based on telomere length measurement data of Canadians, we have calculated both the magnitude and the age dependence of the mortality rate for both men and women. We show that these calculated data are in good quantitative agreement with the actual number of Canadians that die. This agreement demonstrates the quantitative correlation between the mortality calculated by the STLIS model and the mortality of the major diseases of aging (e.g., cardiovascular disease, many cancers and diabetes mellitus), which dominate human mortality. This result represents significant progress in our understanding of the factors behind the cause of aging.},
}
@article {pmid33120230,
year = {2021},
author = {Harnung Scholten, R and Møller, P and Jovanovic Andersen, Z and Dehlendorff, C and Khan, J and Brandt, J and Ketzel, M and Knudsen, LE and Mathiesen, L},
title = {Telomere length in newborns is associated with exposure to low levels of air pollution during pregnancy.},
journal = {Environment international},
volume = {146},
number = {},
pages = {106202},
doi = {10.1016/j.envint.2020.106202},
pmid = {33120230},
issn = {1873-6750},
abstract = {Telomere length (TL) is a biomarker of biological aging that may be affected by prenatal exposure to air pollution. The aim of this study was to assess the association between prenatal exposure to air pollution and TL in maternal blood cells (leukocytes), placenta and umbilical cord blood cells, sampled immediately after birth in 296 Danish mother-child pairs from a birth cohort. Exposure data was obtained using the high-resolution and spatial-temporal air pollution modeling system DEHM-UBM-AirGIS for PM2.5, PM10, SO2, NH4+, black carbon (BC), organic carbon (OC), CO, O3, NO2, and NOx at residential and occupational addresses of the participating women for the full duration of the pregnancy. The association between prenatal exposure to air pollutants and TL was investigated using distributed lag models. There were significant and positive associations between TL in umbilical cord blood cells and prenatal exposure to BC, OC, NO2, NOx, CO, and O3 during the second trimester. TL in umbilical cord blood was significantly and inversely associated with prenatal exposure to PM2.5, BC, OC, SO2, NH4+, CO and NO2 during the third trimester. There were similar inverse associations between TL from umbilical cord blood cells and air pollution exposure at the residential and occupational addresses. There were weaker or no associations between air pollution exposure and TL in placenta tissue and maternal blood cells. In conclusion, both the second and third trimesters of pregnancy are shown to be sensitive windows of exposure to air pollution affecting fetal TL.},
}
@article {pmid33115534,
year = {2020},
author = {Zhang, C and Ostrom, QT and Semmes, EC and Ramaswamy, V and Hansen, HM and Morimoto, L and de Smith, AJ and Pekmezci, M and Vaksman, Z and Hakonarson, H and Diskin, SJ and Metayer, C and , and Taylor, MD and Wiemels, JL and Bondy, ML and Walsh, KM},
title = {Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.},
journal = {Acta neuropathologica communications},
volume = {8},
number = {1},
pages = {173},
pmid = {33115534},
issn = {2051-5960},
support = {CA139020/CA/NCI NIH HHS/United States ; T32 CA151022/CA/NCI NIH HHS/United States ; CA190991/CA/NCI NIH HHS/United States ; CA52689/CA/NCI NIH HHS/United States ; R01 CA194189/CA/NCI NIH HHS/United States ; },
abstract = {Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case-control data from three studies: a population-based pediatric and adolescent ependymoma case-control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case-control study from Toronto's Hospital for Sick Children and the Children's Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case-control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case-control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12-19 (P = 4.0 × 10-3), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (ORPRS = 1.67; 95% CI 1.18-2.37; P = 3.97 × 10-3) and adult-onset ependymoma (PMR-Egger = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94-1.34; P = 0.21), nor with EPN-PF-A (PMR-Egger = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.},
}
@article {pmid33113831,
year = {2020},
author = {Rampazzo, E and Cecchin, E and Del Bianco, P and Menin, C and Spolverato, G and Giunco, S and Lonardi, S and Malacrida, S and De Paoli, A and Toffoli, G and Pucciarelli, S and De Rossi, A},
title = {Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients.},
journal = {Cancers},
volume = {12},
number = {11},
pages = {},
pmid = {33113831},
issn = {2072-6694},
support = {Grant n. RF-2011-02349645//Ministero della Salute/ ; Grant 5 x1000//Istituto Oncologico Veneto/ ; },
abstract = {Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating TERT post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1-19.1) and 3.0(1.3-6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating TERT and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9-17.8) and 5.3(1.4-19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating TERT had a significantly lower risk of disease progression [HR 0.4(0.1-0.9) and 0.3(0.1-0.8), respectively]. These findings suggest that TERT SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.},
}
@article {pmid33113164,
year = {2020},
author = {van Lieshout, SHJ and Sparks, AM and Bretman, A and Newman, C and Buesching, CD and Burke, T and Macdonald, DW and Dugdale, HL},
title = {Estimation of environmental, genetic and parental age at conception effects on telomere length in a wild mammal.},
journal = {Journal of evolutionary biology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jeb.13728},
pmid = {33113164},
issn = {1420-9101},
support = {NBAF984//NERC Biomolecular Analysis Facility/ ; //Priestley Centre Climate Bursary/ ; //Heredity Fieldwork Grant - Genetics Society/ ; //Leeds Anniversary Research Scholarship/ ; RG170425//Royal Society Research Grant/ ; NE/P011284/1//NERC grant/ ; },
abstract = {Understanding individual variation in fitness-related traits requires separating the environmental and genetic determinants. Telomeres are protective caps at the ends of chromosomes that are thought to be a biomarker of senescence as their length predicts mortality risk and reflect the physiological consequences of environmental conditions. The relative contribution of genetic and environmental factors to individual variation in telomere length is, however, unclear, yet important for understanding its evolutionary dynamics. In particular, the evidence for transgenerational effects, in terms of parental age at conception, on telomere length is mixed. Here, we investigate the heritability of telomere length, using the 'animal model', and parental age at conception effects on offspring telomere length in a wild population of European badgers (Meles meles). Although we found no heritability of telomere length and low evolvability (<0.001), our power to detect heritability was low and a repeatability of 2% across individual lifetimes provides a low upper limit to ordinary narrow-sense heritability. However, year (32%) and cohort (3%) explained greater proportions of the phenotypic variance in telomere length, excluding qPCR plate and row variances. There was no support for cross-sectional or within-individual parental age at conception effects on offspring telomere length. Our results indicate a lack of transgenerational effects through parental age at conception and a low potential for evolutionary change in telomere length in this population. Instead, we provide evidence that individual variation in telomere length is largely driven by environmental variation in this wild mammal.},
}
@article {pmid33110040,
year = {2020},
author = {Latour, CD and O'Connell, K and Romano, ME and Kantor, ED and Du, M},
title = {Maternal age at last birth and leukocyte telomere length in a nationally representative population of perimenopausal and postmenopausal women.},
journal = {Menopause (New York, N.Y.)},
volume = {27},
number = {11},
pages = {1242-1250},
doi = {10.1097/GME.0000000000001669},
pmid = {33110040},
issn = {1530-0374},
support = {R25 CA214255/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; P20 GM104416/GM/NIGMS NIH HHS/United States ; },
abstract = {OBJECTIVE: The primary aim of this study was to evaluate if maternal age at birth of last child is associated with leukocyte telomere length in a nationally representative population of perimenopausal and postmenopausal women.<br><br>METHODS: We conducted a cross-sectional analysis of 1,232 women from the National Health and Nutrition Examination Survey to examine maternal age at last birth and telomere length, surveyed between 1999 and 2002. We included perimenopausal and postmenopausal women age 40 years and older. Maternal age at last live birth was self-reported, and leukocyte telomere length was measured using quantitative polymerase chain reaction. We calculated least-squares geometric mean telomere length across categories of maternal age adjusted for age, race/ethnicity, number of live births, survey cycle, and history of hysterectomy or oophorectomy. P trend < 0.05 was considered statistically significant. For hypothesis-generation, we explored modification by reproductive and sociodemographic factors.<br><br>RESULTS: Maternal age at last birth was positively associated with telomere length: the multivariable-adjusted least-squares geometric mean leukocyte telomere length across categories of age at last birth (<25, 25-29, 30-34, 35-39, ≥40 y) was 0.90, 0.93, 0.93, 0.95, and 0.96, respectively (P trend = 0.04). There was suggestive evidence this association may be restricted to those women with one or two live births or women who reported ever using oral contraceptives (P interaction <0.10 for both).<br><br>CONCLUSIONS: Later maternal age was associated with longer telomere length in a nationally representative population of women. These data provide new insight into the biological relationship between reproductive history and long-term health. : Video Summary:http://links.lww.com/MENO/A662.},
}
@article {pmid33104521,
year = {2020},
author = {Froidure, A and Mahieu, M and Hoton, D and Laterre, PF and Yombi, JC and Koenig, S and Ghaye, B and Defour, JP and Decottignies, A},
title = {Short telomeres increase the risk of severe COVID-19.},
journal = {Aging},
volume = {12},
number = {20},
pages = {19911-19922},
pmid = {33104521},
issn = {1945-4589},
mesh = {Adult ; Aged ; Aged, 80 and over ; COVID-19 ; Cellular Senescence ; *Coronavirus Infections ; Female ; Humans ; Lung/pathology ; Male ; Middle Aged ; *Pandemics ; *Pneumonia, Viral ; Prospective Studies ; *Telomere ; *Telomere Homeostasis ; },
abstract = {Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group. Therefore, we hypothesized that TL influences COVID-19-related outcomes. In a prospective study, we measured TL by Flow-FISH in 70 hospitalized COVID-19 patients and compared TL distribution with our reference cohort of 491 healthy volunteers. We also correlated TL with baseline clinical and biological parameters. We stained autopsy lung tissue from six non-survivor COVID-19 patients to detect senescence-associated β-galactosidase activity, a marker of cellular aging. We found a significantly higher proportion of patients with short telomeres (<10th percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.},
}
@article {pmid33093047,
year = {2020},
author = {Sun, S and Shinya, R and Dayi, M and Yoshida, A and Sternberg, PW and Kikuchi, T},
title = {Telomere-to-Telomere Genome Assembly of Bursaphelenchus okinawaensis Strain SH1.},
journal = {Microbiology resource announcements},
volume = {9},
number = {43},
pages = {},
pmid = {33093047},
issn = {2576-098X},
abstract = {Bursaphelenchus okinawaensis is a self-fertilizing, hermaphroditic, fungus-feeding nematode used as a laboratory model for the genus Bursaphelenchus, which includes the important pathogen Bursaphelenchus xylophilus Here, we report the nearly complete genome sequence of B. okinawaensis The 70-Mbp assembly contained six scaffolds (>11 Mbp each) with telomere repeats on their ends, indicating complete chromosomes.},
}
@article {pmid33091002,
year = {2020},
author = {Mukherjee, AK and Sharma, S and Sengupta, S and Saha, D and Kumar, P and Hussain, T and Srivastava, V and Roy, SD and Shay, JW and Chowdhury, S},
title = {Correction: Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends.},
journal = {PLoS genetics},
volume = {16},
number = {10},
pages = {e1009152},
pmid = {33091002},
issn = {1553-7404},
abstract = {[This corrects the article DOI: 10.1371/journal.pgen.1007782.].},
}
@article {pmid33090998,
year = {2020},
author = {Brown, DW and Lin, SH and Loh, PR and Chanock, SJ and Savage, SA and Machiela, MJ},
title = {Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes.},
journal = {PLoS genetics},
volume = {16},
number = {10},
pages = {e1009078},
pmid = {33090998},
issn = {1553-7404},
support = {DP2 ES030554/ES/NIEHS NIH HHS/United States ; /BHF_/British Heart Foundation/United Kingdom ; },
mesh = {Adult ; Aged ; Cell Division/genetics ; Clonal Evolution/*genetics ; DNA Copy Number Variations/genetics ; Female ; Genetics, Population ; Humans ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; Neoplasms/*blood/epidemiology/genetics ; Telomere/*genetics ; Telomere Homeostasis/*genetics ; United Kingdom/epidemiology ; },
abstract = {Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10-15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (β = 0.004, 95% CI = 0.002-0.007, P = 6.61×10-4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential.},
}
@article {pmid33090930,
year = {2020},
author = {Arabadjiev, B and Pankov, R and Vassileva, I and Petrov, LS and Buchvarov, I},
title = {Photobiomodulation with 590 nm Wavelength Delays the Telomere Shortening and Replicative Senescence of Human Dermal Fibroblasts In Vitro.},
journal = {Photobiomodulation, photomedicine, and laser surgery},
volume = {38},
number = {11},
pages = {656-660},
doi = {10.1089/photob.2020.4822},
pmid = {33090930},
issn = {2578-5478},
abstract = {Background: Cellular senescence is one of the major factors contributing to the aging process. Photobiomodulation (PBM) is known to trigger an array of cellular responses, but there are no data on how it affects the process of cellular senescence. In this study, we analyze the effect of PBM on the cellular senescence and telomere dynamics. Methods: Human dermal fibroblasts were irradiated by a panel of light-emitting diodes with 590 nm and dose 30 J/cm2 accumulated over 1200 sec repeated in 4-day cycle within 40 days. After the last cycle of PBM treatment, the difference in number of senescent cells between PBM treated groups end nontreated control groups was measured by senescent sensitive β-galactosidase assay, and the difference in average telomere length between the experimental end control groups was analyzed using relative human telomere length quantitative Polymerase Chain Reaction (qPCR) assay. Results: After 10 cycles of irradiation, the percentage of senescent cells in PBM-treated cultures was 19.7% ± 4.5%, p < 0.05 smaller than the percentage of senescent cells in the control group, and their relative telomere length was 1.19 ± 0.09-fold, p < 0.05 greater than nontreated controls. Conclusions: Our study demonstrates for the first time that PBM with appropriate parameters can delay the attrition of the telomeres and the entry of cells into senescence, suggesting a potential involvement of telomerase reactivation. A hypothetical mechanism for this light-induced antiaging effect is discussed.},
}
@article {pmid33086033,
year = {2020},
author = {Wang, L and Chen, R and Li, G and Wang, Z and Liu, J and Liang, Y and Liu, JP},
title = {FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping.},
journal = {Cell metabolism},
volume = {32},
number = {5},
pages = {860-877.e9},
doi = {10.1016/j.cmet.2020.10.004},
pmid = {33086033},
issn = {1932-7420},
abstract = {Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.},
}
@article {pmid33082515,
year = {2020},
author = {Nie, X and Xiao, D and Ge, Y and Xie, Y and Zhou, H and Zheng, T and Li, X and Liu, H and Huang, H and Zhao, Y},
title = {TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41418-020-00637-3},
pmid = {33082515},
issn = {1476-5403},
support = {81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81771506, 31571410, 31570827, 31701196//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Telomeres are transcribed into telomeric RNA termed as TERRA. However, the transcription itself and excessive TERRA may interfere with telomere replication during S phase. The mechanism that coordinates telomere transcription and replication is unknown. Here, we report that TCOF1 leaves the nucleolus and is recruited to telomeres specifically during S phase by interacting with TRF2. Therein, TCOF1 acts to suppress telomere transcription by binding and inhibiting Pol II. Thus, TERRA is limited to low levels in S phase. Depletion of TCOF1 leads to abnormally elevated TERRA and formation of DNA/RNA hybrids (R-loops) at telomeres, which induces replication fork stalling and fragile telomeres. Importantly, telomere replication defect induced by TCOF1 deficiency can be rescued by either masking TERRA or expressing an R-loop eraser RNase H1, demonstrating a critical role of TCOF1 in coordinating telomere transcription and replication. These findings link nucleolus to telomeres and uncover a novel function of TCOF1 on ensuring telomere integrity.},
}
@article {pmid33082350,
year = {2020},
author = {Mazzucco, G and Huda, A and Galli, M and Piccini, D and Giannattasio, M and Pessina, F and Doksani, Y},
title = {Telomere damage induces internal loops that generate telomeric circles.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {5297},
pmid = {33082350},
issn = {2041-1723},
mesh = {Animals ; DNA, Single-Stranded/chemistry/genetics/metabolism ; Humans ; Mice ; Telomere/*chemistry/genetics/*metabolism ; Telomere Homeostasis ; },
abstract = {Extrachromosomal telomeric circles are commonly invoked as important players in telomere maintenance, but their origin has remained elusive. Using electron microscopy analysis on purified telomeres we show that, apart from known structures, telomeric repeats accumulate internal loops (i-loops) that occur in the proximity of nicks and single-stranded DNA gaps. I-loops are induced by single-stranded damage at normal telomeres and represent the majority of telomeric structures detected in ALT (Alternative Lengthening of Telomeres) tumor cells. Our data indicate that i-loops form as a consequence of the exposure of single-stranded DNA at telomeric repeats. Finally, we show that these damage-induced i-loops can be excised to generate extrachromosomal telomeric circles resulting in loss of telomeric repeats. Our results identify damage-induced i-loops as a new intermediate in telomere metabolism and reveal a simple mechanism that links telomere damage to the accumulation of extrachromosomal telomeric circles and to telomere erosion.},
}
@article {pmid33078399,
year = {2020},
author = {Weyburne, E and Bosco, G},
title = {Cancer-associated mutations in the condensin II subunit CAPH2 cause genomic instability through telomere dysfunction and anaphase chromosome bridges.},
journal = {Journal of cellular physiology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jcp.30113},
pmid = {33078399},
issn = {1097-4652},
support = {//Audrey and Theodor Geisel School of Medicine at Dartmouth/ ; },
abstract = {Genome instability in cancer drives tumor heterogeneity, undermines the success of therapies, and leads to metastasis and recurrence. Condensins are conserved chromatin-binding proteins that promote genomic stability, mainly by ensuring proper condensation of chromatin and mitotic chromosome segregation. Condensin mutations are found in human tumors, but it is not known how or even if such mutations promote cancer progression. In this study, we focus on condensin II subunit CAPH2 and specific CAPH2 mutations reported to be enriched in human cancer patients, and we test how CAPH2 cancer-specific mutations may lead to condensin II complex dysfunction and contribute to genome instability. We find that R551P, R551S, and S556F mutations in CAPH2 cause genomic instability by causing DNA damage, anaphase defects, micronuclei, and chromosomal instability. DNA damage and anaphase defects are caused primarily by ataxia telangiectasia and Rad3-related-dependent telomere dysfunction, as anaphase bridges are enriched for telomeric repeat sequences. We also show that these mutations decrease the binding of CAPH2 to the ATPase subunit SMC4 as well as the rest of the condensin II complex, and decrease the amount of CAPH2 protein bound to chromatin. Thus, in vivo the R551P, R551S, and S556F cancer-specific CAPH2 mutant proteins are likely to impair condensin II complex formation, impede condensin II activity during mitosis and interphase, and promote genetic heterogeneity in cell populations that can lead to clonal outgrowth of cancer cells with highly diverse genotypes.},
}
@article {pmid33073402,
year = {2020},
author = {Glousker, G and Briod, AS and Quadroni, M and Lingner, J},
title = {Human shelterin protein POT1 prevents severe telomere instability induced by homology-directed DNA repair.},
journal = {The EMBO journal},
volume = {39},
number = {23},
pages = {e104500},
pmid = {33073402},
issn = {1460-2075},
support = {KLS-3824-02-2016//Swiss Cancer League/ ; 182880//NCCR RNA &amp; disease network of the SNSF/ ; 812829//Initial Training Network (ITN) grant (aDDRess) from the European Commission's Seventh Framework Programme/ ; 310030_184718/SNSF_/Swiss National Science Foundation/Switzerland ; },
abstract = {The evolutionarily conserved POT1 protein binds single-stranded G-rich telomeric DNA and has been implicated in contributing to telomeric DNA maintenance and the suppression of DNA damage checkpoint signaling. Here, we explore human POT1 function through genetics and proteomics, discovering that a complete absence of POT1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies in human cells. Conditional deletion of POT1 in HEK293E cells gives rise to rapid telomere elongation and length heterogeneity, branched telomeric DNA structures, telomeric R-loops, and telomere fragility. We determine the telomeric proteome upon POT1-loss, implementing an improved telomeric chromatin isolation protocol. We identify a large set of proteins involved in nucleic acid metabolism that engage with telomeres upon POT1-loss. Inactivation of the homology-directed repair machinery suppresses POT1-loss-mediated telomeric DNA defects. Our results unravel as major function of human POT1 the suppression of telomere instability induced by homology-directed repair.},
}
@article {pmid33068677,
year = {2021},
author = {Nickels, M and Mastana, S and Denniff, M and Codd, V and Akam, E},
title = {Elite swimmers possess shorter telomeres than recreationally active controls.},
journal = {Gene},
volume = {769},
number = {},
pages = {145242},
doi = {10.1016/j.gene.2020.145242},
pmid = {33068677},
issn = {1879-0038},
mesh = {Adolescent ; *Athletic Performance ; Case-Control Studies ; Female ; Genotype ; Humans ; INDEL Mutation ; Male ; Peptidyl-Dipeptidase A/*genetics ; *Swimming ; *Telomere ; Young Adult ; },
abstract = {PURPOSE: Elite athletes are reported to possess longer telomeres than their less active counterparts. ACE gene (Insertion/Deletion) polymorphism has been previously associated with elite athletic performance, with the deletion (D) variant appearing more frequently in short distance swimmers. Additionally, the D allele has been reported to have a negative effect on telomere length. The aim of this study was to investigate the telomere length of elite swimmers and its potential association with ACE genotype.<br><br>METHODS: Telomere length was measured by real-time quantitative PCR and ACE I/D genotypes analysed by standard PCR and electrophoresis in 51 young elite swimmers and 56 controls.<br><br>RESULTS: Elite swimmers displayed shorter telomeres than controls (1.043 ± 0.127 vs 1.128 ± 0.177, p = 0.006). When split by sex, only elite female swimmers showed significantly shorter telomeres than their recreationally active counterparts (p = 0.019). ACE genotype distribution and allelic frequency did not differ between elite swimmers and controls, or by event distance among elite swimmers only. No association was observed between telomere length and ACE genotype in the whole cohort.<br><br>CONCLUSIONS: Elite swimmers possessed shorter telomeres than recreationally active controls. Our findings suggesting a negative effect of high-level swimming competition and/or training on telomere length and subsequent biological aging, particularly in females. However, this significant difference in telomere length does not appear to be attributed to the D allele as we report a lack of association between telomere length and ACE genotype frequency in elite swimmers and controls.},
}
@article {pmid33065771,
year = {2020},
author = {Noguera, JC and da Silva, A and Velando, A},
title = {Egg corticosterone can stimulate telomerase activity and promote longer telomeres during embryo development.},
journal = {Molecular ecology},
volume = {},
number = {},
pages = {},
doi = {10.1111/mec.15694},
pmid = {33065771},
issn = {1365-294X},
support = {ED431F 2017/07//Xunta de Galicia/ ; PGC2018-095412-B-I00//Ministerio de Ciencia e Innovación/ ; },
abstract = {It is often assumed that the transfer of maternal glucocorticoids (GCs; e.g., corticosterone or cortisol) to offspring is an inevitable cost associated with adverse or stressful conditions experienced by mothers. However, recent evidence indicates that maternal GCs may adaptively programme particular physiological and molecular pathways during development to enhance offspring fitness. In this context, an important mechanism through which maternal GCs may lastingly affect offspring phenotypic quality and survival is via effects on embryo telomerase activity and so on offspring postnatal telomere length. Here, using a field experimental design for which we manipulated the corticosterone content in yellow-legged gull (Larus michahellis) eggs, we show that embryos from corticosterone-injected eggs not only had a higher telomerase activity but also longer telomeres just after hatching. A complementary analysis further revealed that gull hatchlings with longer telomeres had a higher survival probability during the period when most of the chick mortality occurs. Given the important role that telomere length and its restoring mechanisms have on ageing trajectories and disease risk, our findings provide a new mechanistic link by which mothers may presumably shape offspring life-history trajectories and phenotype.},
}
@article {pmid33057192,
year = {2020},
author = {Feretzaki, M and Pospisilova, M and Valador Fernandes, R and Lunardi, T and Krejci, L and Lingner, J},
title = {RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops.},
journal = {Nature},
volume = {587},
number = {7833},
pages = {303-308},
pmid = {33057192},
issn = {1476-4687},
support = {206292/E/17/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Base Sequence ; Biocatalysis ; Genes, Reporter ; HeLa Cells ; Humans ; *R-Loop Structures ; RNA, Long Noncoding/*chemistry/genetics ; Rad51 Recombinase/*metabolism ; Ribonuclease H/metabolism ; Telomere/*chemistry/genetics/*metabolism ; Telomeric Repeat Binding Protein 1/metabolism ; },
abstract = {Telomeres-repeated, noncoding nucleotide motifs and associated proteins that are found at the ends of eukaryotic chromosomes-mediate genome stability and determine cellular lifespan1. Telomeric-repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends2,3; these RNAs in turn regulate telomeric chromatin structure and telomere maintenance through the telomere-extending enzyme telomerase4-6 and homology-directed DNA repair7,8. The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system with which to dissect the underlying mechanisms, and show that the UUAGGG repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA-RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation trigger telomere fragility and are promoted by the recombinase RAD51 and its interacting partner BRCA2, but counteracted by the RNA-surveillance factors RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyses R-loop formation with TERRA in vitro, suggesting a direct involvement of this DNA recombinase in the recruitment of TERRA by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA-mediated R-loop formation after transcription, providing a mechanism for the recruitment of lncRNAs to new loci in trans.},
}
@article {pmid33053112,
year = {2020},
author = {Normando, P and Bezerra, FF and Santana, BA and Calado, RT and Santos-Rebouças, CB and Epel, ES and Faerstein, E},
title = {Association between socioeconomic markers and adult telomere length differs according to sex: Pro-Saúde study.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {53},
number = {11},
pages = {e10223},
pmid = {33053112},
issn = {1414-431X},
mesh = {Adult ; Aging ; Brazil ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; *Telomere ; },
abstract = {Understanding the social determinants of telomere length is critical to evaluate the risk of early biological aging. We investigated sex differences on the association between socioeconomic status (SES) and demographic markers and leukocyte telomere length (LTL) in Brazilian adults. This cross-sectional study was conducted in a subsample (women=228; men=200) nested within the Pro-Saúde study, a prospective cohort study of university civil servants in Rio de Janeiro, Brazil (2012-2013). Adjusted multivariate models were used to test the relationship between SES markers (marital status, educational attainment, father's educational attainment, race/skin color, household income, and childhood experience of food deprivation) and LTL. After adjusting for age and potential health-related confounders, lower educational attainment was associated with shorter LTL among men (β=-0.05, 95% confidence interval (CI)=95%CI: -0.10, 0.00, P=0.03). In women, LTL was inversely associated with unmarried status (β=-0.05, 95%CI: -0.09, 0.00, P=0.03), lower father's educational attainment (β=-0.05, 95%CI: -0.13, 0.00, P=0.04), and childhood experience of food deprivation (β=-0.07, 95%CI: -0.13, 0.00, P=0.04). Our findings suggested that the association between SES markers and LTL differs according to sex. SES markers able to induce lifelong stress, reflected in LTL, appeared to be more related to individual factors in men, whereas in women they were family-related.},
}
@article {pmid33051039,
year = {2020},
author = {Keng, SL and Looi, PS and Tan, ELY and Yim, OS and Lai, PS and Chew, SH and Ebstein, RP},
title = {Effects of Mindfulness-Based Stress Reduction on Psychological Symptoms and Telomere Length: A Randomized Active-Controlled Trial.},
journal = {Behavior therapy},
volume = {51},
number = {6},
pages = {984-996},
doi = {10.1016/j.beth.2020.01.005},
pmid = {33051039},
issn = {1878-1888},
mesh = {Adult ; Anxiety ; *Anxiety Disorders/genetics/therapy ; Humans ; *Mindfulness ; *Stress, Psychological/genetics/therapy ; *Telomere ; Treatment Outcome ; },
abstract = {Much research has demonstrated the beneficial effects of mindfulness-based stress reduction (MBSR) on psychological and physical health, but it is not known whether MBSR may impact cellular aging in healthy populations. Further, little research has evaluated MBSR against an active control condition, which precludes strong conclusions regarding the unique effects of mindfulness on psychological functioning. The present study examined the effects of MBSR versus music therapy-based stress reduction (MTSR) on trait mindfulness, self-compassion, and several psychological health outcomes, as well as leukocyte telomere length (LTL). One hundred and fifty eight Singaporean Chinese adults were recruited and randomly assigned to an eight-week MBSR or MTSR course. Participants provided blood samples and completed a battery of self-report measures pre- and post-intervention. Analyses showed that participants in the MBSR condition demonstrated significantly greater improvements in depressive symptoms, trait mindfulness, and self-compassion compared to the control condition. Treatment condition did not predict changes in LTL, anxiety, stress, or happiness, though there was a trend for duration of home mindfulness practice to predict increases in LTL. Overall, the study demonstrated MBSR's unique effects in reducing depressive symptoms. Improvements in trait mindfulness and self-compassion correspond with theorized mechanisms of change underlying mindfulness training. The lack of intervention effect with regards to LTL suggests that a more intensive intervention may be required for mindfulness to exert noticeable impact on aging at the cellular level, or that the effect may only emerge over a longer term.},
}
@article {pmid33049239,
year = {2021},
author = {Cleber Gama de Barcellos Filho, P and Campos Zanelatto, L and Amélia Aparecida Santana, B and Calado, RT and Rodrigues Franci, C},
title = {Effects chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats.},
journal = {Brain research},
volume = {1750},
number = {},
pages = {147152},
doi = {10.1016/j.brainres.2020.147152},
pmid = {33049239},
issn = {1872-6240},
abstract = {Chronic stress is related to the acceleration of telomere shortening. Recent work showed a correlation between chronic psychosocial stress and reduced telomere length in certain cells. The exposure of T lymphocytes to cortisol promoted a significant reduction in telomerase activity. Although stress can promote changes in telomere length, whether increased glucocorticoid concentrations alter telomere length in brain tissue cells is unclear. In addition to modulating the activity of the stress system, estrogen also influences telomere length. The objective of this study was to verify whether chronic exposure to glucocorticoids promotes changes in the telomere length of encephalic areas involved in the control of HPA axis activity and whether estrogen affects these changes. Wistar rats were ovariectomized and treated with estradiol cypionate [(50 or 100 μg/kg, subcutaneously)] or oil and 20 mg/kg corticosterone or vehicle (isotonic saline with 2% Tween 80, subcutaneously) for 28 days. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland samples. Estrogen modulated the activity of the HPA axis. CRH, AVP and POMC mRNA levels were reduced by estrogen. At least in doses and treatment time used, there was no correlation between effects of exposure to glucocorticoids and estrogen on telomere length in the brain areas of female rats. However, estrogen treatment reduced the telomere length in the central amygdala and dorsal hippocampus, but not in the PVN, indicating a variation of reaction of telomeres for estrogen in different brain areas.},
}
@article {pmid33049101,
year = {2021},
author = {Power, ML and Power, S and Bertelsen, MF and Jones, G and Teeling, EC},
title = {Wing: A suitable nonlethal tissue type for repeatable and rapid telomere length estimates in bats.},
journal = {Molecular ecology resources},
volume = {21},
number = {2},
pages = {421-432},
doi = {10.1111/1755-0998.13276},
pmid = {33049101},
issn = {1755-0998},
support = {//Royal Irish Academy/ ; //Irish Research Council/ ; },
abstract = {Telomeres are used increasingly in ecology and evolution as biomarkers for ageing and environmental stress, and are typically measured from DNA extracted from nonlethally sampled blood. However, obtaining blood is not always possible in field conditions and only limited amounts can be taken from small mammals, such as bats, which moreover lack nucleated red blood cells and hence yield relatively low amounts of DNA. As telomere length can vary within species according to age and tissue, it is important to determine which tissues serve best as a representation of the organism as a whole. Here, we investigated whether wing tissue biopsies, a rapid and relatively noninvasive tissue collection method, could serve as a proxy for other tissues when measuring relative telomere length (rTL) in the Egyptian fruit bat (Rousettus aegyptiacus). Telomeres were measured from blood, brain, heart, kidney, liver lung, muscle and wing, and multiple wing biopsies were taken from the same individuals to determine intra-individual repeatability of rTL measured by using qPCR. Wing rTL correlated with rTL estimates from most tissues apart from blood. Blood rTL was not significantly correlated with rTL from any other tissue. Blood and muscle rTLs were significantly longer compared with other tissues, while lung displayed the shortest rTLs. Individual repeatability of rTL measures from wing tissue was high (>70%). Here we show the relationships between tissue telomere dynamics for the first time in a bat, and our results provide support for the use of wing tissue for rTL measurements.},
}
@article {pmid33046137,
year = {2020},
author = {Cao, W and Zheng, D and Zhang, J and Wang, A and Liu, D and Zhang, J and Singh, M and Maranga, IE and Cao, M and Wu, L and Song, M and Wang, W and Wang, Y},
title = {Association between telomere length in peripheral blood leukocytes and risk of ischemic stroke in a Han Chinese population: a linear and non-linear Mendelian randomization analysis.},
journal = {Journal of translational medicine},
volume = {18},
number = {1},
pages = {385},
pmid = {33046137},
issn = {1479-5876},
abstract = {BACKGROUND: Many contradictory conclusions pertaining to the telomere length in peripheral leukocyte chromosomes as a potential biomarker for ischemic stroke (IS) risk have been reported by the various observational studies in previous years. This study aims to investigate whether the leukocyte telomere length is associated with an increased IS risk or not, based on the Mendelian randomization (MR) approach.<br><br>METHODS: Based on the NHGRI-EBI GWAS Catalog database, the Chinese online genetic database as well as the previous published studies, twelve single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 0.05 were selected and the leukocyte telomere length was measured in 431 first-ever IS patients and 304 healthy controls (quantitative polymerase chain reaction). To explore linear and non-linear effect of telomere length on the IS risk, we preformed the linear MR analysis (the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method), and the non-linear MR analysis (semiparametric method with three tests for non-linearity, including the quadratic test, Cochran's Q test, and the fractional polynomial test).<br><br>RESULTS: Two verified SNPs (rs11125529 and rs412658) were chosen as instrumental variables. In linear MR analysis, the adjusted odds ratios and 95% confidence intervals of IS for genetically predicted telomere lengths, based on the two SNPs, were 1.312 (0.979 to 1.759), 1.326 (0.932 to 1.888) and 1.226 (0.844 to 1.781) for the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method, respectively. Three tests for nonlinearity failed to reject the null exactly, indicating that the relationship between telomere length and IS risk is unlikely to be non-linear.<br><br>CONCLUSION: This MR study based on individual data does not provide strong evidence for a positive linear or non-linear effect of telomere length on the IS risk.},
}
@article {pmid33045076,
year = {2021},
author = {Chang, X and Chua, KY and Wang, L and Liu, J and Yuan, JM and Khor, CC and Heng, CK and Koh, WP and Dorajoo, R},
title = {Midlife Leukocyte Telomere Length as an Indicator for Handgrip Strength in Late Life.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {172-175},
pmid = {33045076},
issn = {1758-535X},
abstract = {BACKGROUND: Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality.<br><br>METHODS: In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581).<br><br>RESULTS: We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010).<br><br>CONCLUSIONS: Longer midlife LTL was associated with increased handgrip strength later in life.},
}
@article {pmid33038659,
year = {2020},
author = {Osum, M and Serakinci, N},
title = {Impact of circadian disruption on health; SIRT1 and Telomeres.},
journal = {DNA repair},
volume = {96},
number = {},
pages = {102993},
doi = {10.1016/j.dnarep.2020.102993},
pmid = {33038659},
issn = {1568-7856},
abstract = {Circadian clock is a biochemical oscillator in organisms that regulates the circadian rhythm of numerous genes over 24 h. The circadian clock is involved in telomere homeostasis by regulating the diurnal rhythms of telomerase activity, TERT mRNA level, TERRA expression, and telomeric heterochromatin formation. Particularly, CLOCK and BMAL1 deficiency contribute to telomere shortening by preventing rhythmic telomerase activity and TERRA expression, respectively. Telomere shortening increases the number of senescent cells with impaired circadian rhythms. In return, telomerase reconstitution improves impaired circadian rhythms of senescent cells. SIRT1 that is an NAD+-dependent deacetylase positively regulates circadian clock and telomere homeostasis. SIRT1 contributes to the circadian clock by mediating CLOCK/BMAL1 complex formation, BMAL1 transcription and PER2 disruption. On the other hand, SIRT1 ensures telomere homeostasis by inducing telomerase and shelterin protein expression and regulating telomere heterochromatin formation. SIRT1 inhibition leads to both circadian clock and telomeres dysfunction that inhibit its activity. In light of this current evidence, we could suggest that the BMAL1/CLOCK complex regulates the telomere homeostasis in SIRT1 dependent manner, and also telomere dysfunction inhibits circadian clock function by suppressing SIRT1 activity to induce age-related diseases. We consider that increasing SIRT1 activity can prevent age-related diseases and help healthy aging by protecting telomere integrity and circadian clock function for individuals subjected to circadian rhythm disruption such as shift works, individuals with sleep disorders, and in the elderly population.},
}
@article {pmid33035329,
year = {2020},
author = {Feurstein, S and Adegunsoye, A and Mojsilovic, D and Vij, R and West DePersia, AH and Rajagopal, PS and Osman, A and Collins, RH and Kim, RH and Gore, SD and Greenberg, P and Godley, LA and Li, Z and Del Gaudio, D and Subramanian, HP and Das, S and Walsh, T and Gulsuner, S and Segal, JP and Husain, AN and Gurbuxani, S and King, MC and Strek, ME and Churpek, JE},
title = {Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.},
journal = {Blood advances},
volume = {4},
number = {19},
pages = {4873-4886},
pmid = {33035329},
issn = {2473-9537},
support = {R01 MH083989/MH/NIMH NIH HHS/United States ; R03 HL145253/HL/NHLBI NIH HHS/United States ; R35 CA197458/CA/NCI NIH HHS/United States ; },
abstract = {Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.},
}
@article {pmid33033864,
year = {2020},
author = {Zhan, Y and Hägg, S},
title = {Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11357-020-00283-0},
pmid = {33033864},
issn = {2509-2723},
abstract = {Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging (β = - 0.02, 95% confidence interval: - 0.04, - 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.},
}
@article {pmid33031470,
year = {2020},
author = {Protsenko, E and Rehkopf, D and Prather, AA and Epel, E and Lin, J},
title = {Are long telomeres better than short? Relative contributions of genetically predicted telomere length to neoplastic and non-neoplastic disease risk and population health burden.},
journal = {PloS one},
volume = {15},
number = {10},
pages = {e0240185},
pmid = {33031470},
issn = {1932-6203},
mesh = {Cardiovascular Diseases/epidemiology/*genetics ; Genetic Predisposition to Disease ; Humans ; Mendelian Randomization Analysis/methods ; Neoplasms/epidemiology/*genetics ; Neurodegenerative Diseases/epidemiology/*genetics ; *Telomere Homeostasis ; },
abstract = {BACKGROUND: Mendelian Randomization (MR) studies exploiting single nucleotide polymorphisms (SNPs) predictive of leukocyte telomere length (LTL) have suggested that shorter genetically determined telomere length (gTL) is associated with increased risks of degenerative diseases, including cardiovascular and Alzheimer's diseases, while longer gTL is associated with increased cancer risks. These varying directions of disease risk have long begged the question: when it comes to telomeres, is it better to be long or short? We propose to operationalize and answer this question by considering the relative impact of long gTL vs. short gTL on disease incidence and burden in a population.<br><br>METHODS AND FINDINGS: We used odds ratios (OR) of disease associated with gTL from a recently published MR meta-analysis to approximate the relative contributions of gTL to the incidence and burden of neoplastic and non-neoplastic disease in a European population. We obtained incidence data of the 9 cancers associated with long gTL and 4 non-neoplastic diseases associated with short gTL from the Institute of Health Metrics (IHME). Incidence rates of individual cancers from SEER, a database of United States cancer records, were used to weight the ORs in order to align with the available IHME data. These data were used to estimate the excess incidences due to long vs. short gTL, expressed as per 100,000 persons per standard deviation (SD) change in gTL. To estimate the population disease burden, we used the Disability Adjusted Life Years (DALY) metric from the IHME, a measure of overall disease burden that accounts for both mortality and morbidity, and similarly calculated the excess DALY associated with long vs. short gTL.<br><br>RESULTS: Our analysis shows that, despite the markedly larger ORs of neoplastic disease, the large incidence of degenerative diseases causes the excess incidence attributable to gTL to balance that of neoplastic diseases. Long gTL is associated with an excess incidence of 94.04 cases/100,000 persons/SD (45.49-168.84, 95%CI) from the 9 cancer, while short gTL is associated with an excess incidence of 121.49 cases/100,000 persons/SD (48.40-228.58, 95%CI) from the 4 non-neoplastic diseases. When considering disease burden using the DALY metric, long gTL is associated with an excess 1255.25 DALYs/100,000 persons/SD (662.71-2163.83, 95%CI) due to the 9 cancers, while short gTL is associated with an excess 1007.75 DALYs/100,000 persons/SD (411.63-1847.34, 95%CI) due to 4 non-neoplastic diseases.<br><br>CONCLUSIONS: Our results show that genetically determined long and short telomere length are associated with disease risk and burden of approximately equal magnitude. These results provide quantitative estimates of the relative impact of genetically-predicted short vs. long TL in a human population, and provide evidence in support of the cancer-aging paradox, wherein human telomere length is balanced by opposing evolutionary forces acting to minimize both neoplastic and non-neoplastic diseases. Importantly, our results indicate that odds ratios alone can be misleading in different clinical scenarios, and disease risk should be assessed from both an individual and population level in order to draw appropriate conclusions about the risk factor's role in human health.},
}
@article {pmid33026063,
year = {2020},
author = {Martín, M and Millan, A and Ferraro, F and Tetzlaff, WF and Lozano, CE and Botta, E and Castro, M and Boero, L and Rey, J and Daruich, J and Frechtel, G and Meroño, T and Cerrone, G and Brites, F},
title = {Leukocyte telomere length is associated with iron overload in male adults with hereditary hemochromatosis.},
journal = {Bioscience reports},
volume = {40},
number = {10},
pages = {},
pmid = {33026063},
issn = {1573-4935},
abstract = {BACKGROUND: Hereditary hemochromatosis (HH) is a primary iron overload (IO) condition. Absolute telomere length (ATL) is a marker of cellular aging and DNA damage associated with chronic diseases and mortality.<br><br>AIM: To evaluate the relationship between ATL and IO in patients with HH.<br><br>METHODS: Cross-sectional study including 25 patients with HH: 8 with IO and 17 without IO (ferritin < 300 ng/ml) and 25 healthy controls. Inclusion criteria were: age > 18 years, male sex and HH diagnosis. Patients with diabetes or other endocrine and autoimmune diseases were excluded. ATL was measured by real-time PCR.<br><br>RESULTS: HH patients with IO were older (P<0.001) and showed higher ferritin concentration (P<0.001). Patients with HH, disregarding the iron status, showed higher glucose and body mass index (BMI) than controls (both P<0.01). ATL was shorter in patients with IO than controls [with IO: 8 (6-14), without IO: 13 (9-20), and controls: 19 (15-25) kilobase pairs, P<0.01]; with a linear trend within groups (P for trend <0.01). Differences in ATL remained statistically significant after adjusting by age, BMI and glucose (P<0.05).<br><br>DISCUSSION: Patients with IO featured shorter ATL while patients without IO showed only mild alterations vs. controls. Screening for IO is encouraged to prevent iron-associated cellular damage and early telomere attrition.},
}
@article {pmid33024983,
year = {2020},
author = {Benetos, A and Lai, TP and Toupance, S and Labat, C and Verhulst, S and Perret-Guillaume, C and Gautier, S and Ungeheuer, MN and Levy, D and Susser, E and Aviv, A},
title = {A Mechanism for Severity of Disease in Older Patients with COVID-19: The Nexus between Telomere Length and Lymphopenia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2020.10.01.20205393},
pmid = {33024983},
abstract = {BACKGROUND: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count.<br><br>METHODS: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres.<br><br>RESULTS: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients.<br><br>CONCLUSIONS: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.},
}
@article {pmid33024526,
year = {2020},
author = {Menshawy, NE and Ashwah, SE and Ebrahim, MA},
title = {Short Dysfunctional Telomere Is Highly Predictive of Dismal Outcome in MDS but Not in AML Patients.},
journal = {International journal of hematology-oncology and stem cell research},
volume = {14},
number = {3},
pages = {188-199},
pmid = {33024526},
issn = {2008-3009},
abstract = {Background: A trigger for initiation the clonal hematopoietic stem cells disorders could be short telomere length probably due to chromosomal instability. The relationship between relative telomere length (RTL) and the two linked hematological stem cell disorders, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) is still unclear. Materials and Methods: We evaluated the role of RTL in MDS (n=96) and AML (n=130) at the time of diagnosis using a real time quantitative polymerase chain reaction (RT-PCR) technique. The median value of RTL (1) was set as the cutoff for statistical comparison. Overall survival (OS) is defined as the time from diagnosis to death or last follow-up. Results: RTL was significantly longer in both MDS and AML cases versus control (p<0.0001) and was significantly longer in MDS versus AML cases (p =0.03). RTL correlated negatively with age in MDS (p <0.0001) but not in AML cases. RTL was also significantly shorter in MDS cases with pancytopenia and poor risk cytogenetics (p < 0.0001 for each) and short RTL was significantly associated with inferior survival (p = 0.007), while RTL showed no significant impact on OS in AML cases. Moreover, short RTL retained independent prognostic value in multivariate analysis (HR= 3.42 [95% CI, 8.97-19.35], p = 0.004). Conclusion: RTL showed an association with both AML and MDS; however, short RTL was an independent poor prognostic factor in MDS patients only.},
}
@article {pmid33022284,
year = {2020},
author = {VanEtten, SL and Bonner, MR and Ren, X and Birnbaum, LS and Kostyniak, PJ and Wang, J and Olson, JR},
title = {Telomeres as targets for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) in rats.},
journal = {Toxicology and applied pharmacology},
volume = {408},
number = {},
pages = {115264},
doi = {10.1016/j.taap.2020.115264},
pmid = {33022284},
issn = {1096-0333},
mesh = {Animals ; Carcinogens/*toxicity ; Female ; Gene Expression Regulation/drug effects ; Liver/drug effects/metabolism ; Lung/drug effects/metabolism ; Polychlorinated Biphenyls/*toxicity ; Polychlorinated Dibenzodioxins/*toxicity ; Rats, Sprague-Dawley ; Telomere/*drug effects ; },
abstract = {Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.},
}
@article {pmid33015044,
year = {2020},
author = {Wang, G and Wu, X and Zhou, L and Gao, S and Yun, D and Liang, A and Sun, F},
title = {Tethering of Telomeres to the Nuclear Envelope Is Mediated by SUN1-MAJIN and Possibly Promoted by SPDYA-CDK2 During Meiosis.},
journal = {Frontiers in cell and developmental biology},
volume = {8},
number = {},
pages = {845},
pmid = {33015044},
issn = {2296-634X},
abstract = {During meiosis, telomeres attach to the nuclear envelope (NE) to promote homologous chromosome moving, pairing, synapsis, and recombination. The telomere-NE attachment is mediated by SUN1, TERB1-TERB2-MAJIN (TTM complex), and TRF1. The interaction of the TTM complex with shelterin is mediated by TERB1 and TRF1, but how SUN1 interacts with the TTM complex is not yet fully understood. In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. The binding sites of MAJIN and SPDYA at SUN1 were mapped, and both MAJIN and SPDYA bound to the N-terminal domain of SUN1 and the two binding sites were close to each other. Furthermore, SPDYA bound to SUN1 via the Ringo domain and recruited CDK2 to SUN1. Then, we found that the interaction of SUN1 with MAJIN was decreased by the CDK2 inhibitors. Taken together, our results provide the possible mechanism of SUN1, MAJIN, and SPDYA-CDK2 in promoting the telomere-NE attachment during meiosis.},
}
@article {pmid33015032,
year = {2020},
author = {Burgess, A and Caldon, CE},
title = {Editorial: Proceedings From ACCM19: Cell Cycle, DNA Damage Response and Telomeres.},
journal = {Frontiers in cell and developmental biology},
volume = {8},
number = {},
pages = {805},
pmid = {33015032},
issn = {2296-634X},
}
@article {pmid33013423,
year = {2020},
author = {Maremanda, KP and Sundar, IK and Li, D and Rahman, I},
title = {Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis.},
journal = {Frontiers in pharmacology},
volume = {11},
number = {},
pages = {584637},
pmid = {33013423},
issn = {1663-9812},
abstract = {Background: Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF).<br><br>Methods: Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: <55 years and older: >55 years).<br><br>Results: Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 &amp; 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 &amp; 2, GADD45A), and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases including the SARS-CoV-2 infection. Lung immunoblot analysis of smokers, COPD and IPF subjects revealed increased abundance of proteases and receptor/spike protein like TMPRSS2, furin, and DPP4 in association with a slight increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2 levels.<br><br>Conclusions: Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in COPD and IPF is associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis as pharmacological targets for COVID-19.},
}
@article {pmid33012014,
year = {2020},
author = {Thomas, N and Hudaib, AR and Romano-Silva, M and Bozaoglu, K and H X Thomas, E and Rossell, S and Kulkarni, J and Gurvich, C},
title = {Influence of cortisol awakening response on telomere length: Trends for males and females.},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.14996},
pmid = {33012014},
issn = {1460-9568},
support = {//Monash University Seed/ ; //Barbara Dicker Brain Science Foundation/ ; },
abstract = {Although telomere attrition is associated with the process of normal ageing, shorter telomere length (TL) has been associated with acute and chronic stressors. A neurobiological factor hypothesised to be responsible for this accelerated attrition is the dysregulation of the cortisol stress response, which can induce DNA damage affecting DNA telomeric caps. Marked sex differences are reported in both the cortisol stress response and telomere dynamics, yet no explicit investigation of sex specificity on the relationship between cortisol and TL exists. This study used mathematical equation modelling to describe the relationship between diurnal cortisol levels and telomere length within the context of sex, in a healthy population. Cortisol awakening responses (CAR) were measured via ELISA methodology in fifty-one healthy participants (28 males, 23 females). qPCRs determined TL from genomic DNA extracted from saliva. To assess the effect of free cortisol on relative TL ratio, a semi-log regression plot of the two variables trended for sex were fitted using spline curves. Results demonstrated significant differences between males and females in the relationship defining CAR and TL association (p = 0.03). These results suggest the relationship is not linear and can be represented as a complex arcsin function, and that the patterns are opposite in males and females. Males demonstrate a positive correlation, with higher levels of CAR being associated with longer telomere sequences. Females demonstrated a negative correlation. Future studies must carefully take into consideration moderating factors such as sex, and sex hormones across the lifespan when investigating telomere length.},
}
@article {pmid33007378,
year = {2021},
author = {Sethi, I and Bhat, GR and Kumar, R and Rai, E and Sharma, S},
title = {Dual labeled fluorescence probe based qPCR assay to measure the telomere length.},
journal = {Gene},
volume = {767},
number = {},
pages = {145178},
doi = {10.1016/j.gene.2020.145178},
pmid = {33007378},
issn = {1879-0038},
mesh = {DNA/genetics ; Fluorescence ; Fluorescent Dyes/chemistry/metabolism ; Humans ; In Situ Hybridization, Fluorescence/methods ; Organic Chemicals/chemistry ; Polymerase Chain Reaction/*methods ; Repetitive Sequences, Nucleic Acid/genetics ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/genetics ; },
abstract = {Telomeres are highly repetitive regions capping the chromosomes and composed of multiple units of hexa-nucleotides, TTAGGG, making their quantification difficult. Most of the methods developed to estimate telomeres are extensively cumbersome or expensive. The quantitative polymerase chain reaction (qPCR) based assay is relatively easy and cheaper method that applies SyBr Green dye chemistry to measure telomere length. SyBr Green dye fluoresces after intercalation into the double stranded DNA (dsDNA), thus detection of unspecific products has been a limitation as it may affect quantitation of telomeres. To overcome this limitation of SyBr Green dye, we developed a dual labeled fluorescence probe based quantitative polymerase chain reaction (qPCR) to measure the telomere length. This highly efficient, yet cost effective and easy method, utilizes a probe that targets primarily the telomeric DNA and this increases accuracy of an existing qPCR method.},
}
@article {pmid33006015,
year = {2020},
author = {Yildirim, H and Yildiz, P and Coskunpinar, E},
title = {Investigation of telomere related gene mutations in idiopathic pulmonary fibrosis.},
journal = {Molecular biology reports},
volume = {47},
number = {10},
pages = {7851-7860},
doi = {10.1007/s11033-020-05861-1},
pmid = {33006015},
issn = {1573-4978},
support = {2018/039//University of Health Sciences, Scientific Research Project Unit/ ; },
abstract = {Idiopathic Pulmonary Fibrosis (IPF) is the most common type of Idiopathic Interstitial Pneumonias (IIP). The aim of this study is to determine the mutation of variants in four telomere-related genes and to determine the possible relationship between these mutations and telomere shortening in order to contribute to the understanding of the pathophysiology of IPF. For this study, 34 individuals with IPF, 32 individuals with non-IPF ILD (Interstitial Lung Disease), and 31 healthy controls between the ages of 40 and 85 were included. The mutation analysis and telomere measurements were examined for the volunteers. According to the mutation screening results, no significant difference was found between the patients with IPF, non-IPF ILD groups and healthy individuals in terms of genotyping analysis. However, in terms of the allele distribution for two genes, statistically significant difference was found in IPF and non-IPF ILD patients (TERT; p = 0.002 and TERC; p = 0.001). According to the telomere length measurement, the telomeres of the patients were shorter than of the control group (p = 0.0001). In compliance with the results of our analysis, it is thought that genes that have allelic significance from the point of gene mutations as well as telomere shortening may be risk factors for the disease.},
}
@article {pmid33005120,
year = {2020},
author = {Polonio, AM and Chico-Sordo, L and Córdova-Oriz, I and Medrano, M and García-Velasco, JA and Varela, E},
title = {Impact of Ovarian Aging in Reproduction: From Telomeres and Mice Models to Ovarian Rejuvenation.},
journal = {The Yale journal of biology and medicine},
volume = {93},
number = {4},
pages = {561-569},
pmid = {33005120},
issn = {1551-4056},
abstract = {The trend in our society to delay procreation increases the difficulty to conceive spontaneously. Thus, there is a growing need to use assisted reproduction technologies (ART) to form a family. With advanced maternal age, ovaries not only produce a lower number of oocytes after ovarian stimulation but also a lower quality-mainly aneuploidies-requiring further complex analysis to avoid complications during implantation and pregnancy. Although there are different options to have a child at advanced maternal age (like donor eggs), this is not the preferred choice for most patients. Unless women had cryopreserved their eggs at a younger age, reproductive medicine should try to optimize their opportunities to become pregnant with their own oocytes, when chances of success are reasonable. Aging has many causes, but telomere attrition is ultimately one of the main pathways involved in this process. Several reports link telomere biology and reproduction, but the molecular reasons for the rapid loss of ovarian function at middle age are still elusive. This review will focus on the knowledge acquired during the last years about ovarian aging and disease, both in mouse models of reproductive senescence and in humans with ovarian failure, and the implication of telomeres in this process. In addition, the review will discuss recent results on ovarian rejuvenation, achieved with stem cell therapies that are currently under study, or ovarian reactivation by tissue fragmentation and the attempts to generate oocytes in vitro.},
}
@article {pmid33002310,
year = {2020},
author = {Huang, JW and Xie, C and Niu, Z and He, LJ and Li, JJ},
title = {The relation between Helicobacter pylori immunoglobulin G seropositivity and leukocyte telomere length in US adults from NHANES 1999-2000.},
journal = {Helicobacter},
volume = {25},
number = {6},
pages = {e12760},
doi = {10.1111/hel.12760},
pmid = {33002310},
issn = {1523-5378},
abstract = {BACKGROUND: Helicobacter pylori (H pylori) immunoglobulin G (IgG) seropositivity is prevalent but its relation with leukocyte telomere length (LTL), a cellular aging biomarker, is unclear.<br><br>METHODS: Among 3,472 participants from the National Health and Nutrition Examination Survey (NHANES) cycle 1999-2000, LTL was measured with the quantitative polymerase chain reaction. H pylori IgG was measured by enzyme-linked immunosorbent assays and defined as seropositivity with an immune status ratio score > 0.9. We used linear regression models to examine the relation of H pylori IgG seropositivity with continuous LTL and logistic regression for the relation with short LTL (<10th percentile of the population distribution) adjusting for potential confounders. We stratified the analyses by a priori selected variables.<br><br>RESULTS: Population prevalence of H pylori IgG seropositivity was 31.5% in the overall population with higher prevalence found in those with older age, other races than non-Hispanic whites, lower education, and being born out of the United States. Continuous LTL was non-significantly shorter in those with H Pylori IgG seropositivity versus seronegativity (mean difference = -40.3 bp, 95% CI: -112.4, 31.9). This difference was not significant after adjusting for potential confounders nor stratifying by potential effect modifiers. H Pylori IgG seropositivity was significantly associated with short LTL among the elderly (55-75 years, adjusted OR: 3.06, 95% CI: 1.17, 7.99), but not in the overall population (OR: 1.28, 95% CI: 0.81-2.02).<br><br>CONCLUSION: H Pylori IgG seropositivity was not associated with continuous LTL in the general population but may be associated with an excessively short LTL in the elderly.},
}
@article {pmid33001148,
year = {2020},
author = {Vyas, CM and Ogata, S and Reynolds, CF and Mischoulon, D and Chang, G and Cook, NR and Manson, JE and Crous-Bou, M and De Vivo, I and Okereke, OI},
title = {Telomere length and its relationships with lifestyle and behavioural factors: variations by sex and race/ethnicity.},
journal = {Age and ageing},
volume = {},
number = {},
pages = {},
doi = {10.1093/ageing/afaa186},
pmid = {33001148},
issn = {1468-2834},
abstract = {BACKGROUND: Adherence to healthy lifestyles/behaviours promotes healthy ageing. However, little is known about whether age, sex and/or race/ethnicity moderate associations of lifestyle/behavioural factors with relative telomere length (RTL), a potential biomarker of ageing.<br><br>METHODS: We included 749 midlife to older non-Hispanic White (n = 254), Black (n = 248) and Hispanic (n = 247) US participants [mean (standard deviation) age = 69.3 (7.2) years; women: 50.5%]. We extracted genomic DNA from peripheral leucocytes. RTL was assayed using real-time quantitative polymerase chain reaction. Multivariable regression was used to examine associations between lifestyle/behavioural exposures (i.e. physical activity, alcohol consumption, smoking and depression) with RTL.<br><br>RESULTS: Increasing chronological age was associated with shorter RTL (P < 0.01). Higher physical activity was associated with longer RTL (P-trend = 0.03); daily versus never/rare alcohol consumption and 30+ versus <5 smoking pack-year were associated with shorter RTLs (P-trend = 0.02). Associations varied significantly by sex and race/ethnicity. The association between physical activity and longer RTL appeared strongest among non-Hispanic Whites (P-interaction = 0.01). Compared to men, women had stronger associations between heavy smoking and shorter RTLs (P-interaction = 0.03). Light/moderate alcohol consumption (monthly/weekly) was associated with longer RTL among non-Hispanic Whites, while daily consumption was related to shorter RTLs among Blacks and Hispanics (P-interactions < 0.01). Associations of daily alcohol and heavy smoking with shorter RTLs were particularly apparent among Black women.<br><br>CONCLUSION: We observed novel variations by sex and race/ethnicity in associations between lifestyle/behavioural factors and RTL. Further work is needed to replicate these findings and to address potential public health implications for modifying strategies by sex or across racial/ethnic groups to optimise lifestyles/behaviours for healthy ageing.},
}
@article {pmid33000239,
year = {2020},
author = {Vodenkova, S and Kroupa, M and Polivkova, Z and Musak, L and Ambrus, M and Schneiderova, M and Kozevnikovova, R and Vodickova, L and Rachakonda, S and Hemminki, K and Kumar, R and Vodicka, P},
title = {Chromosomal damage and telomere length in peripheral blood lymphocytes of cancer patients.},
journal = {Oncology reports},
volume = {44},
number = {5},
pages = {2219-2230},
doi = {10.3892/or.2020.7774},
pmid = {33000239},
issn = {1791-2431},
abstract = {Accumulation of non‑specific structural chromosomal aberrations (CAs) and telomere shortening contribute to genome instability, which constitutes as one of the hallmarks of cancer. CAs arise due to direct DNA damage or telomere shortening. CAs in peripheral blood lymphocytes (PBL), which are considered to be markers of exposure, have been previously reported to serve a role in the pathophysiology and progression of cancer through mechanisms that are poorly understood. In addition, the prognostic relevance of telomere length (TL) in patients with cancer remains to be elucidated. In the present study, CAs and TL in PBL isolated from patients with newly diagnosed cancer (151 breast, 96 colorectal, 90 lung) and 335 cancer‑free control individuals were investigated. These results were then correlated with clinicopathological factors and follow‑up data. The accumulation of CAs in PBL was observed with increased susceptibility to breast and lung cancer (P<0.0001), while individuals with longer TL were found to be at a higher risk of breast cancer (P<0.0001). Increased chromatid‑type aberrations were also revealed to be associated with lower overall survival of patients with breast and colorectal cancers using a multivariate model. Compared with control individuals, no association was observed between TL and CAs or age in patients with cancer. In conclusion, the present study demonstrates the association between CAs/TL in PBL and the susceptibility, prognosis and survival of patients with breast, colorectal and lung cancer.},
}
@article {pmid32998948,
year = {2021},
author = {Chen, M and Xu, Y and Xu, J and Chancoco, H and Gu, J},
title = {Leukocyte Telomere Length and Bladder Cancer Risk: A Large Case-Control Study and Mendelian Randomization Analysis.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {30},
number = {1},
pages = {203-209},
doi = {10.1158/1055-9965.EPI-20-0351},
pmid = {32998948},
issn = {1538-7755},
abstract = {BACKGROUND: Leukocyte telomere length (LTL) has been associated with risk of several cancers. The association between LTL and bladder cancer is still inconsistent.<br><br>METHODS: In this large case-control study consisting of 2,011 patients with bladder cancer and 2,259 healthy controls of European ancestry, we investigated the associations of real-time qPCR-measured LTL (a retrospective case-control study) and genetically predicted LTL [a Mendelian randomization (MR) study] with bladder cancer risk. Genotypes from 10 LTL-associated SNPs were used as instrumental variables to predict LTL. We used an individual level data-based weighted genetic risk score (GRS) and a summary statistics-based inverse-variance weighting (IVW) method in MR analyses.<br><br>RESULTS: The qPCR-measured LTL was shorter in cases with muscle-invasive bladder cancer (MIBC) than those with non-muscle-invasive bladder cancer [NMIBC; ratio of telomere repeats copy number to single gene copy number (T/S): 1.19 ± 0.34 vs. 1.23 ± 0.36, P = 0.081]. Multivariable logistic regression analyses showed long qPCR-measured LTL was associated with a reduced risk of MIBC. In MR analyses, genetically predicted LTL was weakly associated with bladder cancer risk in both the GRS analysis [OR = 1.13, per SD increase; 95% confidence interval (CI), 0.73-1.75; P = 0.595] and the IVW analysis (OR = 1.14 per SD increase; 95% CI, 0.75-1.74; P = 0.543).<br><br>CONCLUSIONS: There was no strong evidence supporting an association between LTL and bladder cancer risk in European Americans.<br><br>IMPACT: This is the largest study of LTL and bladder cancer risk. The study showed that LTL does not play an important role in bladder cancer etiology.},
}
@article {pmid32998016,
year = {2020},
author = {Luo, M and Luo, H and Li, H and Liu, D and Lu, H},
title = {Single-stranded DNA-binding proteins in plant telomeres.},
journal = {International journal of biological macromolecules},
volume = {165},
number = {Pt A},
pages = {1463-1467},
doi = {10.1016/j.ijbiomac.2020.09.211},
pmid = {32998016},
issn = {1879-0003},
abstract = {Telomere single-stranded DNA-binding proteins bind to the terminal single-stranded DNA of telomeres, maintaining and protecting the chromosomal end in eukaryotes. This paper focuses on the protective mechanism of single-stranded DNA-binding proteins in plant telomeres. This review summarizes the roles of plant single-stranded DNA-binding proteins and their influence on telomere length and telomerase. This review provides insights into the mechanism and development of single-stranded DNA-binding proteins in plants.},
}
@article {pmid32996594,
year = {2020},
author = {Song, W and Yang, J and Niu, Z},
title = {Association of periodontitis with leukocyte telomere length in US adults: A cross-sectional analysis of NHANES 1999 to 2002.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/JPER.20-0269},
pmid = {32996594},
issn = {1943-3670},
abstract = {BACKGROUND: This study examines the association of periodontitis with telomere length (TL) and effect modification by population characteristics.<br><br>METHODS: We analyzed data from 3,478 participants from the 1999 to 2002 National Health and Nutrition Examination Survey. Probing depth, attachment loss, and bleed on probing (BOP, available for 1,973 participants only) were examined on the distal, mesial, or mid-facial site of each tooth in two randomly selected quadrants. We defined periodontitis severity according to the Centers for Disease Control/American Academy of Periodontology guideline. TL from leukocytes was measured with qPCR. We used linear and logistic regression to examine the adjusted association of different severity of periodontitis and BOP with continuous TL (bp) and dichotomized short TL (<median), respectively. To assess effect modification, we stratified the analyses by a priori selected population characteristics including sex, age, body weight status, smoking, and cardiometabolic comorbidity.<br><br>RESULTS: Moderate BOP (<10% bleeding sites) was significantly associated with a shorter continuous TL (β = -89.0, SE = 37.8). Moderate to severe periodontitis was significantly associated with 47% (95% confidence interval [IL], 1.04 to 2.09) higher odds of shorter TL, compared with those with mild or no periodontitis. The association was stronger in those who were female (adjusted OR, 1.76; 95% CI, 1.10 to 2.83), overweight or obese (adjusted OR, 1.64; 95% CI, 1.12 to 2.41), or had cardiometabolic comorbidities (adjusted OR, 2.13; 95% CI, 1.38 to 3.29).<br><br>CONCLUSIONS: Periodontitis was associated with TL, a biomarker of cellular aging. The association was stronger in females, overweight or obese, or those with cardiometabolic diseases. Treatment on periodontitis could potentially protect individuals from aging-related diseases.},
}
@article {pmid32995737,
year = {2020},
author = {Ahiawodzi, P and Fitzpatrick, AL and Djousse, L and Ix, JH and Kizer, JR and Mukamal, KJ},
title = {Non-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study.},
journal = {Metabolism open},
volume = {8},
number = {},
pages = {100058},
pmid = {32995737},
issn = {2589-9368},
abstract = {Background: Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults.<br><br>Material and methods: We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status.<br><br>Results: Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (β = -0.034; SE = 0.015; P = 0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error = 0.016; P = 0.007); for comparison the coefficient for a single year of age in the same model was -0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (β = -0.079; SE = 0.029; P = 0.01).<br><br>Conclusions: In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.},
}
@article {pmid32991882,
year = {2020},
author = {Wang, Y and Liu, Z and Huang, C and Zhao, L and Jiang, X and Liu, Y and Liu, Y and Wan, Y and Chou, Y and Li, X},
title = {Analysis of lens epithelium telomere length in age-related cataract.},
journal = {Experimental eye research},
volume = {201},
number = {},
pages = {108279},
doi = {10.1016/j.exer.2020.108279},
pmid = {32991882},
issn = {1096-0007},
abstract = {We aimed to investigate the associations among lens epithelium telomere length (LETL), cataract types, and systemic pro-senescence factors in patients with age-related cataract. In this prospective study, the general demographic factors, body mass index, smoking history, depression, hypertension, diabetes, various psychological measures, and uncorrected distant visual acuity of patients with age-related cataract were recorded. Lens Opacities Classification System III (LOCS III) scores and lens density measured by Scheimpflug imaging were used to evaluate the cataracts. LETL was measured by real-time polymerase chain reaction. Correlations among these parameters were analyzed. The LOCS III nuclear opalescence (NO) score was associated with age (β = 0.053, P < 0.001) and Patient Health Questionnaire-9 score (β = -0.042, P = 0.004). Smoking was identified as a risk factor affecting LOCS III NO score (odds ratio = 1.546, 95% confidence interval, 1.128-2.119), but not the LOCS III cortical or posterior subcapsular scores. LETLs showed a weak association with systemic factors and LOCS III scores, and a significantly moderate correlation with the average objective lens densities of different regions measured by Scheimpflug imaging (r values ranged from -0.278 to -0.523, P < 0.05). However, there was no correlation between the LETLs and the maximum lens densities. The groups with a relatively low lens density had longer LETLs. In Conclusion, being an age-related disease, cortical cataract was also associated with &quot;aging of the lens epithelium.&quot; Notably, lens epithelium activity rarely showed systemic effects. Thus, future studies should emphasize the importance of the telomeric system in cataractous process and aging.},
}
@article {pmid32991318,
year = {2020},
author = {Tan, J and Wang, X and Hwang, BJ and Gonzales, R and Konen, O and Lan, L and Lu, AL},
title = {An ordered assembly of MYH glycosylase, SIRT6 protein deacetylase, and Rad9-Rad1-Hus1 checkpoint clamp at oxidatively damaged telomeres.},
journal = {Aging},
volume = {12},
number = {18},
pages = {17761-17785},
pmid = {32991318},
issn = {1945-4589},
support = {R01 GM118837/GM/NIGMS NIH HHS/United States ; },
abstract = {In the base excision repair pathway, MYH/MUTYH DNA glycosylase prevents mutations by removing adenine mispaired with 8-oxoG, a frequent oxidative lesion. MYH glycosylase activity is enhanced by Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp and SIRT6 histone/protein deacetylase. Here, we show that MYH, SIRT6, and 9-1-1 are recruited to confined oxidatively damaged regions on telomeres in mammalian cells. Using different knockout cells, we show that SIRT6 responds to damaged telomeres very early, and then recruits MYH and Hus1 following oxidative stress. However, the recruitment of Hus1 to damaged telomeres is partially dependent on SIRT6. The catalytic activities of SIRT6 are not important for SIRT6 response but are essential for MYH recruitment to damaged telomeres. Compared to wild-type MYH, the recruitment of hMYHV315A mutant (defective in both SIRT6 and Hus1 interactions), but not hMYHQ324H mutant (defective in Hus1 interaction only), to damaged telomeres is severely reduced. The formation of MYH/SIRT6/9-1-1 complex is of biological significance as interrupting their interactions can increase cell's sensitivity to H2O2 and/or elevate cellular 8-oxoG levels after H2O2 treatment. Our results establish that SIRT6 acts as an early sensor of BER enzymes and both SIRT6 and 9-1-1 serve critical roles in DNA repair to maintain telomere integrity.},
}
@article {pmid32984752,
year = {2019},
author = {Niehoff, NM and Gammon, MD and Keil, AP and Nichols, HB and Engel, LS and Taylor, JA and White, AJ and Sandler, DP},
title = {Hazardous air pollutants and telomere length in the Sister Study.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {3},
number = {4},
pages = {},
pmid = {32984752},
issn = {2474-7882},
support = {T32 CA057726/CA/NCI NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; },
abstract = {Background: Telomeres are vital for genomic integrity and telomere length has been linked to many adverse health outcomes. Some hazardous air pollutants, or air toxics, increase oxidative stress and inflammation, two possible determinants of shortened telomere length. No studies have examined air toxic-telomere length associations in a non-occupational setting.<br><br>Methods: This study included 731 Sister Study participants (enrolled 2003-2007) who were randomly selected to assess telomere length in baseline blood samples. Multiplex qPCR was used to determine telomere to single copy gene (T/S) ratios. Census tract concentration estimates of 29 air toxics from the 2005 National Air Toxics Assessment were linked to baseline residential addresses. Air toxics were classified into tertile-based categories of the exposure. Multivariable linear regression was used to estimate β coefficients and 95% confidence intervals (CI) in single pollutant models. Multipollutant groups were identified with regression trees.<br><br>Results: The average T/S ratio was 1.24. Benzidine (T3vsT1 β= -0.08; 95% CI: -0.14, -0.01) and 1,4-dioxane (T3vsT1 β= -0.06; 95% CI: -0.13, 0.00) in particular, as well as carbon tetrachloride, chloroprene, ethylene dibromide, and propylene dichloride, were associated with shorter relative telomere length. Benzidine (p=0.02) and 1,4-dioxane (p=0.06) demonstrated some evidence of a monotonic trend. The regression tree identified age, BMI, physical activity, ethylene oxide, acrylonitrile, ethylidene dichloride, propylene dichloride, and styrene in multipollutant groups related to telomere length.<br><br>Conclusions: In this first study of air toxics and telomere length in a non-occupational setting, several air toxics, particularly 1,4-dioxane and benzidine, were associated with shorter relative telomere length.},
}
@article {pmid32984050,
year = {2020},
author = {Yuan, G and Song, J and Li, N and Song, Q and Li, Y and Du, Y and Wang, X and Jiao, Y and Wu, L},
title = {Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.},
journal = {Frontiers in oncology},
volume = {10},
number = {},
pages = {1707},
pmid = {32984050},
issn = {2234-943X},
abstract = {Purpose: Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs.<br><br>Methods: Next-generation sequencing was carried out on mucosal melanoma samples (n = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence in situ hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in TERT were detected by droplet digital polymerase chain reaction.<br><br>Results: In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. TERT promoter mutation was not detected in GMs (n = 40), but copy number variations in the TERT region were observed in 20% (7/35) of the samples. TERT amplification was mutually exclusive with ALT (P < 0.05). Kaplan-Meier revealed that ALT relative to TERT amplification was associated with longer overall survival in GM patients without metastasis.<br><br>Conclusion: These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.},
}
@article {pmid32980685,
year = {2020},
author = {Iannuzzi, A and Della Valle, G and Russo, M and Longobardi, V and Albero, G and De Canditiis, C and Kosior, MA and Pistucci, R and Gasparrini, B},
title = {Evaluation of bovine sperm telomere length and association with semen quality.},
journal = {Theriogenology},
volume = {158},
number = {},
pages = {227-232},
doi = {10.1016/j.theriogenology.2020.09.019},
pmid = {32980685},
issn = {1879-3231},
abstract = {The study aimed to evaluate if the sperm telomere length can be considered as a new biomarker for sperm quality in bulls. Sperm Telomere Length was evaluated by Monochrome Multiplex Quantitative PCR in group A (n = 8) and group B (n = 8) bulls, classified according to standard semen analysis. Also, this parameter was measured before and after Percoll gradient separation within bulls that produced semen of satisfactory quality. Sperm telomere length, measured as T/S ratio (average ratio of telomere repeats copy number to a single copy gene), was higher in group A than in group B bulls (0.77 ± 0.03 vs 0.43 ± 0.06; P < 0.01). Sperm telomere length was positively correlated with motility, viability and membrane integrity, and it was negatively correlated with sperm anomalies. Furthermore, Percoll gradient selected sperms with higher T/S ratio than unselected sperms (1.19 ± 0.02 vs 0.67 ± 0.03). These results suggest that sperm telomere length can be used as a new marker of bovine semen quality.},
}
@article {pmid32978426,
year = {2020},
author = {Tran, HTT and Herz, C and Lamy, E},
title = {Long-term exposure to &quot;low-dose&quot; bisphenol A decreases mitochondrial DNA copy number, and accelerates telomere shortening in human CD8 + T cells.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {15786},
pmid = {32978426},
issn = {2045-2322},
mesh = {Adult ; Benzhydryl Compounds/*pharmacology ; CD8-Positive T-Lymphocytes/drug effects/*metabolism ; Cell Proliferation ; Cells, Cultured ; *DNA Copy Number Variations ; DNA, Mitochondrial/*genetics ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Humans ; Leukocytes, Mononuclear/drug effects/*metabolism ; Male ; Phenols/*pharmacology ; Signal Transduction ; Telomere/*genetics ; Telomere Shortening/*drug effects ; Time Factors ; Young Adult ; },
abstract = {Exposure to the endocrine disruptor bisphenol A (BPA) has been linked with immune disorders and increased tumour risk. Our previous work in activated human peripheral blood mononuclear cells demonstrated that exposure to &quot;low-dose&quot; BPA diminished telomerase activity via an ER/GPR30-ERK signalling pathway. Leukocyte telomerase activity and telomere maintenance are crucial for normal immune function and homeostasis. We thus here further studied the effects of BPA on human T cell subpopulations. Exposure to 0.3-3 nM BPA, i. e. at doses in the realm of human exposure, notably reduced telomerase activity in activated CD8 + T but not CD4 + T cells in a non-monotonic response pattern as determined by the TRAP-ELISA assay. Under long-term BPA exposure, significant telomere length shortening, reduction in mitochondrial DNA copy number, cell proliferation and IFN-γ as well as hTERT protein suppression could be observed in CD8 + lymphocytes, as analysed by qRT-PCR, flow cytometry and western blot analysis. This study extends our previous in vitro findings that &quot;low-dose&quot; BPA has potential negative effects on healthy human cytotoxic T cell response. These results might merit some special attention to further investigate chronic BPA exposure in the context of adaptive immune response dysfunction and early onset of cancer in man.},
}
@article {pmid32973827,
year = {2020},
author = {Khosravi, S and Schindele, P and Gladilin, E and Dunemann, F and Rutten, T and Puchta, H and Houben, A},
title = {Application of Aptamers Improves CRISPR-Based Live Imaging of Plant Telomeres.},
journal = {Frontiers in plant science},
volume = {11},
number = {},
pages = {1254},
pmid = {32973827},
issn = {1664-462X},
abstract = {Development of live imaging techniques for providing information how chromatin is organized in living cells is pivotal to decipher the regulation of biological processes. Here, we demonstrate the improvement of a live imaging technique based on CRISPR/Cas9. In this approach, the sgRNA scaffold is fused to RNA aptamers including MS2 and PP7. When the dead Cas9 (dCas9) is co-expressed with chimeric sgRNA, the fluorescent coat protein-tagged for MS2 and PP7 aptamers (tdMCP-FP and tdPCP-FP) are recruited to the targeted sequence. Compared to previous work with dCas9:GFP, we show that the quality of telomere labeling was improved in transiently transformed Nicotiana benthamiana using aptamer-based CRISPR-imaging constructs. Labeling is influenced by the copy number of aptamers and less by the promoter types. The same constructs were not applicable for labeling of repeats in stably transformed plants and roots. The constant interaction of the RNP complex with its target DNA might interfere with cellular processes.},
}
@article {pmid32971146,
year = {2020},
author = {Himes, RW and Chiou, EH and Queliza, K and Shouval, DS and Somech, R and Agarwal, S and Jajoo, K and Ziegler, DS and Kratz, CP and Huang, J and Lucas, TL and Myers, KC and Nelson, AS and DiNardo, CD and Alter, BP and Giri, N and Khincha, PP and McReynolds, LJ and Dufour, C and Pierri, F and Goldman, FD and Sherif, Y and Savage, SA and Miloh, T and Bertuch, AA},
title = {Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders.},
journal = {The Journal of pediatrics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpeds.2020.09.038},
pmid = {32971146},
issn = {1097-6833},
abstract = {OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus.<br><br>STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record.<br><br>RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor.<br><br>CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.},
}
@article {pmid32971118,
year = {2020},
author = {Dratwa, M and Wysoczanska, B and Turlej, E and Anisiewicz, A and Maciejewska, M and Wietrzyk, J and Bogunia-Kubik, K},
title = {Heterogeneity of telomerase reverse transcriptase mutation and expression, telomerase activity and telomere length across human cancer cell lines cultured in vitro.},
journal = {Experimental cell research},
volume = {396},
number = {1},
pages = {112298},
doi = {10.1016/j.yexcr.2020.112298},
pmid = {32971118},
issn = {1090-2422},
abstract = {Promoter region of the telomerase reverse transcriptase gene (TERTp) constitutes a regulatory element capable to affect TERT expression (TE), telomerase activity (TA) and telomere length (TL). TERTp mutation status, TL, TA and TE were assessed in 27 in vitro cultured human cell lines, including 11 solid tumour, 13 haematological and 3 normal cell lines. C228T and C250T TERTp mutations were detected in 5 solid tumour and none of haematological cell lines (p = 0.0100). As compared to other solid tumour cell lines, those with the presence of somatic mutations were characterized by: shorter TL, lower TA and TE. Furthermore, cell lines carrying TERTp mutations showed a linear correlation between TE and TA (R = 0.9708, p = 0.0021). Moreover, haematological cell lines exhibited higher TE compared to solid tumour cell lines (p = 0.0007). TL and TA were correlated in both solid tumour (R = 0.4875, p = 0.0169) and haematological (R = 0.4719, p = 0.0095) cell lines. Our results based on the in vitro model suggest that oncogenic processes may differ between solid tumours and haematological malignancies with regard to their TERT gene regulation mechanisms.},
}
@article {pmid32970185,
year = {2020},
author = {Vinchure, OS and Whittemore, K and Kushwah, D and Blasco, MA and Kulshreshtha, R},
title = {miR-490 suppresses telomere maintenance program and associated hallmarks in glioblastoma.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00018-020-03644-2},
pmid = {32970185},
issn = {1420-9071},
abstract = {Glioblastoma (GBM) is the most aggressive cancer of central nervous system with worst patient outcome. Telomere maintenance is a crucial mechanism governing GBM initiation and progression making it an attractive target. microRNAs (miRNAs) have shown therapeutic potential in GBM. Earlier, we showed miR-490 is downregulated in GBM patients and plays a tumor suppressive role. Here, we show that miR-490 regulates telomere maintenance program in GBM by directly targeting Telomeric Repeat-binding Factor 2 (TERF2) of the shelterin complex, Tankyrase 2 (TNKS2) and Serine/Threonine-protein kinase, SMG1. Overexpression of miR-490 resulted in effects characteristic to hampered telomere maintenance via TERF2 inhibition. These include induction of telomere dysfunction-induced foci and global DNA damage (53BP1 foci), along with an increase in p-γH2AX levels. Further, it led to inhibition of telomere maintenance hallmarks via reduced stemness (SOX2 and SOX4 downregulation) and induction of senescence (H3K9me3 marks gain and SIRT1 downregulation). It also initiated downstream DNA damage response (DDR) leading to p53 pathway activation. Moreover, microarray data analysis highlighted an overlap between miR-490 expression and REST-inhibition responses in GBM. Thus, miR-490-mediated targeting of telomere maintenance could be therapeutically important in GBM.},
}
@article {pmid32969697,
year = {2020},
author = {Zerach, G and Shevlin, M and Solomon, Z},
title = {Associations between hardiness, C-reactive protein, and telomere length among former prisoners of war.},
journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association},
volume = {39},
number = {11},
pages = {1007-1012},
doi = {10.1037/hea0001030},
pmid = {32969697},
issn = {1930-7810},
mesh = {C-Reactive Protein/*metabolism ; Humans ; Longitudinal Studies ; Male ; Prisoners of War/*psychology ; Prospective Studies ; Stress Disorders, Post-Traumatic/*psychology ; Telomere/*physiology ; },
abstract = {BACKGROUND: War captivity and posttraumatic stress disorder (PTSD) are known to be associated with several poor health outcomes of an accelerated aging process. However, the contribution of personality protective factors to this phenomenon are rarely studied. The present 24-year prospective study examined associations between psychological hardiness and three health outcomes: C-reactive protein (CRP) levels, metabolic syndrome (MetS), and telomere length (TL).<br><br>METHOD: Eighty-eight Israeli former prisoners of war (ex-POWs) were assessed 18 (T1) and 42 (T2) years after repatriation. Data on hardiness was collected at T1 while leukocyte TL, CRP, and MetS data was collected 42 years after the war.<br><br>RESULTS: While adjusting for age, body mass index (BMI), self-rated health, depressive and PTSD symptoms at T2, higher levels of hardiness at T1 predicted decreased CRP and longer TL at T2.<br><br>CONCLUSIONS: Long-term health vulnerabilities of traumatized ex-POWs are manifested in an accelerated aging process and cellular senescence. Raising awareness of the importance of protective factors such as veterans' hardiness might be associated with improving their longevity and well-being. (PsycInfo Database Record (c) 2020 APA, all rights reserved).},
}
@article {pmid32968801,
year = {2021},
author = {Habibi, N and Bianco-Miotto, T and Phoi, YY and Jankovic-Karasoulos, T and Roberts, CT and Grieger, JA},
title = {Maternal diet and offspring telomere length: a systematic review.},
journal = {Nutrition reviews},
volume = {79},
number = {2},
pages = {148-159},
doi = {10.1093/nutrit/nuaa097},
pmid = {32968801},
issn = {1753-4887},
abstract = {CONTEXT: Many studies assert a negative influence of inappropriate maternal diet and nutritional status during pregnancy on offspring, not only in utero but throughout life, because of the role in the programing of noncommunicable diseases. Telomere length is a biomarker of aging, and shorter telomeres are associated with chronic disease later in life. Maternal nutrition and nutritional status may be an important determinant of offspring telomere length.<br><br>OBJECTIVE: A systematic review was conducted to determine the effect of maternal nutrition and nutritional status in pregnancy on offspring telomere length.<br><br>DATA SOURCES: This systematic review was conducted according to PRISMA guidelines. Database searches of PubMed, CINAHL, Scopus, Medline, and Web of Science were performed.<br><br>STUDY SELECTION: Included studies assessed the association between maternal nutrition (dietary intake and nutritional status) during pregnancy and offspring telomere length measured in cord blood, serum, plasma, and peripheral blood mononuclear cells.<br><br>DATA EXTRACTION: Three authors screened and determined the quality of the articles; disagreements were resolved by a fourth author. All authors compared the compiled data.<br><br>RESULTS: Seven studies were extracted and evaluated. Studies comprised a double-blind placebo-controlled trial (n = 1), prospective cohort studies (n = 5), and a cross-sectional study (n = 1). Higher circulating maternal folate and 25-hydroxyvitamin D3 concentrations, along with higher maternal dietary caffeine intakes, were associated with longer offspring telomere length, whereas higher dietary intake of carbohydrate, folate, n-3 polyunsaturated fatty acids, vitamin C, or sodium was not.<br><br>CONCLUSION: The limited but suggestive evidence highlights the need for further research to be conducted in this area, particularly longitudinal studies involving larger cohorts of pregnant women.<br><br>PROSPERO registration no. CRD42019136506.},
}
@article {pmid32967926,
year = {2020},
author = {Fan, J and Jin, H and Koch, BA and Yu, HG},
title = {Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast.},
journal = {Life science alliance},
volume = {3},
number = {12},
pages = {},
pmid = {32967926},
issn = {2575-1077},
support = {R01 GM117102/GM/NIGMS NIH HHS/United States ; R01 GM138838/GM/NIGMS NIH HHS/United States ; T32 HL007843/HL/NHLBI NIH HHS/United States ; MCB1951313//National Science Foundation/International ; },
abstract = {The linker of the nucleoskeleton and cytoskeleton (LINC) complex is composed of two transmembrane proteins: the KASH domain protein localized to the outer nuclear membrane and the SUN domain protein to the inner nuclear membrane. In budding yeast, the sole SUN domain protein, Mps3, is thought to pair with either Csm4 or Mps2, two KASH-like proteins, to form two separate LINC complexes. Here, we show that Mps2 mediates the interaction between Csm4 and Mps3 to form a heterotrimeric telomere-associated LINC (t-LINC) complex in budding yeast meiosis. Mps2 binds to Csm4 and Mps3, and all three are localized to the telomere. Telomeric localization of Csm4 depends on both Mps2 and Mps3; in contrast, Mps2's localization depends on Mps3 but not Csm4. Mps2-mediated t-LINC complex regulates telomere movement and meiotic recombination. By ectopically expressing CSM4 in vegetative yeast cells, we reconstitute the heterotrimeric t-LINC complex and demonstrate its ability to tether telomeres. Our findings therefore reveal the heterotrimeric composition of the t-LINC complex in budding yeast and have implications for understanding variant LINC complex formation.},
}
@article {pmid32959123,
year = {2020},
author = {Bose, S and Suescún, AV and Song, J and Castillo-González, C and Aklilu, BB and Branham, E and Lynch, R and Shippen, DE},
title = {tRNA ADENOSINE DEAMINASE 3 is required for telomere maintenance in Arabidopsis thaliana.},
journal = {Plant cell reports},
volume = {39},
number = {12},
pages = {1669-1685},
pmid = {32959123},
issn = {1432-203X},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; MCB151787//National Science Foundation/ ; R01 GM065383/NH/NIH HHS/United States ; },
abstract = {KEY MESSAGE: tRNA Adenosine Deaminase 3 helps to sustain telomere tracts in a telomerase-independent fashion, likely through regulating cellular metabolism. Telomere length maintenance is influenced by a complex web of chromatin and metabolism-related factors. We previously reported that a lncRNA termed AtTER2 regulates telomerase activity in Arabidopsis thaliana in response to DNA damage. AtTER2 was initially shown to partially overlap with the 5' UTR of the tRNA ADENOSINE DEAMINASE 3 (TAD3) gene. However, updated genome annotation showed that AtTER2 was completely embedded in TAD3, raising the possibility that phenotypes ascribed to AtTER2 could be derived from TAD3. Here we show through strand-specific RNA-Seq, strand-specific qRT-PCR and bioinformatic analyses that AtTER2 does not encode a stable lncRNA. Further examination of the original tad3 (ter2-1/tad3-1) mutant revealed expression of an antisense transcript driven by a cryptic promoter in the T-DNA. Hence, a new hypomorphic allele of TAD3 (tad3-2) was examined. tad3-2 mutants showed hypersensitivity to DNA damage, but no deregulation of telomerase, suggesting that the telomerase phenotype of tad3-1 mutants reflects an off-target effect. Unexpectedly, however, tad3-2 plants displayed progressive loss of telomeric DNA over successive generations that was not accompanied by alteration of terminal architecture or end protection. The phenotype was exacerbated in plants lacking the telomerase processivity factor POT1a, indicating that TAD3 promotes telomere maintenance through a non-canonical, telomerase-independent pathway. The transcriptome of tad3-2 mutants revealed significant dysregulation of genes involved in auxin signaling and glucosinolate biosynthesis, pathways that intersect the stress response, cell cycle regulation and DNA metabolism. These findings indicate that the TAD3 locus indirectly contributes to telomere length homeostasis by altering the metabolic profile in Arabidopsis.},
}
@article {pmid32958778,
year = {2020},
author = {Chakravarti, D and Hu, B and Mao, X and Rashid, A and Li, J and Li, J and Liao, WT and Whitley, EM and Dey, P and Hou, P and LaBella, KA and Chang, A and Wang, G and Spring, DJ and Deng, P and Zhao, D and Liang, X and Lan, Z and Lin, Y and Sarkar, S and Terranova, C and Deribe, YL and Blutt, SE and Okhuysen, P and Zhang, J and Vilar, E and Nielsen, OH and Dupont, A and Younes, M and Patel, KR and Shroyer, NF and Rai, K and Estes, MK and Wang, YA and Bertuch, AA and DePinho, RA},
title = {Telomere dysfunction activates YAP1 to drive tissue inflammation.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {4766},
pmid = {32958778},
issn = {2041-1723},
support = {K99 CA218891/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; P30 DK056338/DK/NIDDK NIH HHS/United States ; R01 CA084628/CA/NCI NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/antagonists &amp; inhibitors/genetics/*metabolism ; Animals ; Anti-Bacterial Agents/therapeutic use ; Ataxia Telangiectasia Mutated Proteins/antagonists &amp; inhibitors/metabolism ; Caspase 1/metabolism ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Child ; Colon/metabolism/microbiology/pathology ; Gastrointestinal Diseases/pathology ; Gastrointestinal Microbiome/drug effects/physiology ; Humans ; Inflammation/drug therapy/metabolism/microbiology/*pathology ; Interleukin-18/genetics/metabolism ; Intestinal Mucosa/metabolism/pathology ; Mice ; Mice, Mutant Strains ; Phosphorylation ; Protein Precursors/genetics/metabolism ; Signal Transduction ; Telomerase/genetics/metabolism ; Telomere/*pathology ; },
abstract = {Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.},
}
@article {pmid32955878,
year = {2020},
author = {Tsubono, Y and Kawamoto, Y and Hidaka, T and Pandian, GN and Hashiya, K and Bando, T and Sugiyama, H},
title = {A Near-Infrared Fluorogenic Pyrrole-Imidazole Polyamide Probe for Live-Cell Imaging of Telomeres.},
journal = {Journal of the American Chemical Society},
volume = {142},
number = {41},
pages = {17356-17363},
pmid = {32955878},
issn = {1520-5126},
support = {R01 CA236350/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres are closely associated with cellular senescence and cancer. Although some techniques have been developed to label telomeres in living cells for study of telomere dynamics, few biocompatible near-infrared probes based on synthetic molecules have been reported. In this study, we developed a near-infrared fluorogenic pyrrole-imidazole polyamide probe (SiR-TTet59B) to visualize telomeres by conjugating a silicon-rhodamine (SiR) fluorophore with a tandem tetramer pyrrole-imidazole polyamide targeting 24 bp in the telomeric double-stranded (ds) DNA. SiR-TTet59B was almost nonfluorescent in water but increased its fluorescence dramatically on binding to telomeric dsDNA. Using a peptide-based delivery reagent, we demonstrated the specific and effective visualization of telomeres in living U2OS cells. Moreover, SiR-TTet59B could be used to observe the dynamic movements of telomeres during interphase and mitosis. This simple imaging method using a synthetic near-infrared probe could be a powerful tool for studies of telomeres and for diagnosis.},
}
@article {pmid32953227,
year = {2020},
author = {Truta, B and Wohler, E and Sobreira, N and Datta, LW and Brant, SR},
title = {Role of telomere shortening in anticipation of inflammatory bowel disease.},
journal = {World journal of gastrointestinal pharmacology and therapeutics},
volume = {11},
number = {4},
pages = {69-78},
pmid = {32953227},
issn = {2150-5349},
abstract = {BACKGROUND: The existence of genetic anticipation has been long disputed in inflammatory bowel disease (IBD) in the absence of the explanatory mechanism.<br><br>AIM: To determine whether it was predictive of genetic anticipation, we evaluated telomere length in IBD. We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms.<br><br>METHODS: We studied three IBD families with multiple affected members in three successive generations. We determined telomere length (TL) in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization (flow FISH). We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance.<br><br>RESULTS: Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn's disease patients of one family. However, no gene variants were identified as potential candidates for inheritance.<br><br>CONCLUSION: Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD. Further studies using a larger sample size are required to confirm or refute our findings.},
}
@article {pmid32952122,
year = {2020},
author = {Cao, L and Li, ZQ and Shi, YY and Liu, Y},
title = {Telomere length and type 2 diabetes: Mendelian randomization study and polygenic risk score analysis.},
journal = {Yi chuan = Hereditas},
volume = {42},
number = {9},
pages = {882-888},
doi = {10.16288/j.yczz.20-077},
pmid = {32952122},
issn = {0253-9772},
mesh = {*Diabetes Mellitus, Type 2 ; *Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Telomere ; },
abstract = {Recent epidemiological studies suggest an association between shorter telomere length and higher risk for type 2 diabetes (T2D). However, results from observational studies are susceptible to confounding and reverse causation, and it is not clear whether there is a causal association between telomere length and T2D. Using Mendelian randomization (MR) and polygenic risk score (PRS) approaches, we had evaluated the causal effect of telomere length on T2D in the Chinese Han population. Using 8 telomere-length associated genetic variants as instrumental variables, an analysis of genetically predicted telomere length and T2D risk was performed in the MR study based on data from a T2D genome-wide association study (GWAS) in 2632 individuals (1318 cases and 1314 controls). We also applied a PRS approach to investigate the causal relationship using Chinese GWAS data. The inverse-variance weighted, MR-Egger regression, simple median, and weighted median methods yielded no evidence of association between genetically predicted longer telomere length and risk of T2D (OR = 0.78, 95% CI: 0.36 ~ 1.68, P = 0.522; OR = 0.23, 95% CI: 0.01 ~ 7.64, P = 0.412; OR = 0.60, 95% CI: 0.28 ~ 1.28, P = 0.185; OR = 0.64, 95% CI: 0.31 ~ 1.33,P = 0.233; respectively). Further, PRS analysis did not produce consistent genetic overlap between telomere length and T2D. Accordingly, this study found no evidence supporting a causal association between telomere length and T2D. Further studies with larger cohorts could yield more reliable results and conclusions.},
}
@article {pmid32950787,
year = {2020},
author = {Wang, T and Tu, Y and Zhang, G and Gong, S and Wang, K and Zhang, Y and Meng, Y and Wang, T and Li, A and Christiani, DC and Au, W and Zhu, Y and Xia, ZL},
title = {Development of a benchmark dose for lead-exposure based on its induction of micronuclei, telomere length changes and hematological toxicity.},
journal = {Environment international},
volume = {145},
number = {},
pages = {106129},
doi = {10.1016/j.envint.2020.106129},
pmid = {32950787},
issn = {1873-6750},
mesh = {*Benchmarking ; China ; Female ; Humans ; *Lead/toxicity ; Male ; Risk Assessment ; Telomere ; },
abstract = {BACKGROUND: Excessive lead exposure is associated with adverse health effects. However, there is a lack of systematic investigation using large populations to ascertain acceptable exposure limits.<br><br>OBJECTIVES: Our study was aimed to identify human exposure-response relationships between lead exposure and health-related outcomes, and to determine a benchmark dose (BMD).<br><br>METHODS: A total of 1896 participants from a lead-acid battery plant were recruited. Blood lead levels (BLLs) were detected for all participants. Hematological parameters (n = 1896), micronuclei (MN) frequencies (n = 934), and relative telomere length (rTL) (n = 757) were also determined. Multivariate linear/Poisson regression analyses were performed to examine associations between BLLs and these health outcomes. Restricted cubic splines were used to identify dose-response relationships. Three BMD approaches were used to calculate BMD and its 95% lower confidence limit (BMDL).<br><br>RESULTS: Among all participants, BLLs show a right-skewed distribution (median, 185.40 μg/L; 25th - 75th percentile, 104.63-271.70 μg/L). There existed significant differences for red blood cell (RBC), hemoglobin (Hb), MN and rTL among different BLL dose groups. After adjusting for possible confounders, all indicators were significantly associated with BLLs. Restricted cubic splines show that there were linear dose-response relationships for RBC and Hb with BLLs, while non-linear for MN and rTL. Results from the three BMD approaches indicate that the dichotomous models were better than continuous models to calculate BMD and BMDL of BLLs. The conservative BMDL obtained from RBC data was 135 for total, 104 for male and 175 μg/L for female. The corresponding BMDL obtained from Hb data was 105 for total, 116 for male and 70 μg/L for female. As for MN data, the BMDL estimate was 66 for total, 69 for male and 64 μg/L for female. Finally, the BMDL from rTL data was 35 for total, 32 for male and 43 μg/L for female.<br><br>CONCLUSIONS: Our data show significant dose-response relationships between lead exposure and expressions of hematological toxicity and genotoxicity. The new BMDLs of 135 and 105 μg/L based on RBC and Hb, and even more strict level of 66 and 35 μg/L based on MN and rTL are lower than current exposure limits in China. Therefore, the four values can be considered as novel exposure limits. In addition, sex effect should be taken into account when setting occupational health standard. Considering that different biomarkers have different sensitivities, better understanding their relationships will certainly improve the current emphasis on precision health risk assessment.},
}
@article {pmid32948591,
year = {2020},
author = {Afrin, M and Gaurav, AK and Yang, X and Pan, X and Zhao, Y and Li, B},
title = {TbRAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing.},
journal = {Science advances},
volume = {6},
number = {38},
pages = {},
pmid = {32948591},
issn = {2375-2548},
support = {R01 AI066095/AI/NIAID NIH HHS/United States ; S10 OD025252/OD/NIH HHS/United States ; },
abstract = {Localization of Repressor Activator Protein 1 (RAP1) to the telomere is essential for its telomeric functions. RAP1 homologs either directly bind the duplex telomere DNA or interact with telomere-binding proteins. We find that Trypanosoma brucei RAP1 relies on a unique double-stranded DNA (dsDNA) binding activity to achieve this goal. T. brucei causes human sleeping sickness and regularly switches its major surface antigen, variant surface glycoprotein (VSG), to evade the host immune response. VSGs are monoallelically expressed from subtelomeres, and TbRAP1 is essential for VSG regulation. We identify dsDNA and single-stranded DNA binding activities in TbRAP1, which require positively charged 737RKRRR741 residues that overlap with TbRAP1's nuclear localization signal in the MybLike domain. Both DNA binding activities are electrostatics-based and sequence nonspecific. The dsDNA binding activity can be substantially diminished by phosphorylation of two 737RKRRR741-adjacent S residues and is essential for TbRAP1's telomere localization, VSG silencing, telomere integrity, and cell proliferation.},
}
@article {pmid32939537,
year = {2020},
author = {Cheng, WH},
title = {Placental Telomere Length: Linking Maternal Nutrition to Transgenerational Healthy Aging?.},
journal = {The Journal of nutrition},
volume = {150},
number = {10},
pages = {2619-2620},
doi = {10.1093/jn/nxaa277},
pmid = {32939537},
issn = {1541-6100},
mesh = {Female ; *Healthy Aging ; Humans ; Placenta/*physiology ; Pregnancy ; Telomere/*physiology ; Telomere Homeostasis/*physiology ; },
}
@article {pmid32937369,
year = {2020},
author = {Luo, Y and Viswanathan, R and Hande, MP and Loh, AHP and Cheow, LF},
title = {Massively parallel single-molecule telomere length measurement with digital real-time PCR.},
journal = {Science advances},
volume = {6},
number = {34},
pages = {},
pmid = {32937369},
issn = {2375-2548},
abstract = {Telomere length is a promising biomarker for age-associated diseases and cancer, but there are still substantial challenges to routine telomere analysis in clinics because of the lack of a simple and rapid yet scalable method for measurement. We developed the single telomere absolute-length rapid (STAR) assay, a novel high-throughput digital real-time PCR approach for rapidly measuring the absolute lengths and quantities of individual telomere molecules. We show that this technique provides the accuracy and sensitivity to uncover associations between telomere length distribution and telomere maintenance mechanisms in cancer cell lines and primary tumors. The results indicate that the STAR assay is a powerful tool to enable the use of telomere length distribution as a biomarker in disease and population-wide studies.},
}
@article {pmid32937289,
year = {2020},
author = {Pańczyszyn, A and Boniewska-Bernacka, E and Goc, A},
title = {The role of telomeres and telomerase in the senescence of postmitotic cells.},
journal = {DNA repair},
volume = {95},
number = {},
pages = {102956},
doi = {10.1016/j.dnarep.2020.102956},
pmid = {32937289},
issn = {1568-7856},
abstract = {Senescence is a process related to the stopping of divisions and changes leading the cell to the SASP phenotype. Permanent senescence of many SASP cells contributes to faster aging of the body and development of age-related diseases due to the release of pro-inflammatory factors. Both mitotically active and non-dividing cells can undergo senescence as a result of activation of different molecular pathways. Telomeres, referred to as the molecular clock, direct the dividing cell into the aging pathway when reaching a critical length. In turn, the senescence of postmitotic cells depends not on the length of telomeres, but their functionality. Dysfunctional telomeres are responsible for triggering the signaling of DNA damage response (DDR). Telomerase subunits in post-mitotic cells translocate between the nucleus, cytoplasm and mitochondria, participating in the regulation of their activity. Among other things, they contribute to the reduction of reactive oxygen species generation, which leads to telomere dysfunction and, consequently, senescence. Some proteins of the shelterin complex also play a protective role by inhibiting senescence-initiating kinases and limiting ROS production by mitochondria.},
}
@article {pmid32937184,
year = {2021},
author = {AlDehaini, DMB and Al-Bustan, SA and Malalla, ZHA and Ali, ME and Sater, M and Giha, HA},
title = {The influence of TERC, TERT and ACYP2 genes polymorphisms on plasma telomerase concentration, telomeres length and T2DM.},
journal = {Gene},
volume = {766},
number = {},
pages = {145127},
doi = {10.1016/j.gene.2020.145127},
pmid = {32937184},
issn = {1879-0038},
mesh = {Acid Anhydride Hydrolases/*genetics ; Adult ; Aged ; Aged, 80 and over ; Alleles ; Diabetes Mellitus, Type 2/*genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; RNA/*genetics ; Telomerase/blood/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomeres are duplex tandem repeats of DNA sequence 5'-TTAGGG-3' at chromosomal ends synthesized by telomerase enzyme (TE). Telomeres length (TL) shortening is associated with age and age-related disorders. Recently, we demonstrated marked leukocytes TL (LTL) shortening in T2DM. To set the relationship between the TE, LTL and T2DM, we analyzed samples from 212 Kuwaiti subjects, 112 patients withT2DM and 100 non-diabetic subjects. The plasma TE and fasting insulin were measured by ELISA, the LTL was estimated by qPCR and three SNPs of genes related to TL; TERC rs12696304 (C/G), TERT rs2736100 (C/A) and ACYP2 rs6713088 (C/G) were genotyped by rtPCR. Results revealed comparable TE levels and alleles/genotypes between the cases and controls with no influence of either on the LTL. Interestingly, although the plasma concentration of the TE was generally low, it was significantly influenced by the TERT and ACYP2 but not TERC polymorphisms. The CC genotype carriers of rs2736100 (C/A) had significantly higher plasma TE levels compared to CA and AA carriers, p 0.009 and p 0.047, respectively, and the A-allele was associated with low TE, p 0.018. Similarly, significantly higher TE levels were detected in CC carriers of ACYP2 rs6713088 (C/G) compared with GC carriers, p 0.002, and the G-allele was associated with low TE, p 0.009. Finally, the TERT and ACYP2 polymorphisms had an influence on blood glucose levels. In conclusion, the telomeres shortening in T2DM was not due to TE deficiency or gene polymorphisms, while the TE levels were significantly associated with the TERT and ACYP2 but not TERC polymorphisms.},
}
@article {pmid32935380,
year = {2020},
author = {Sun, C and Wang, K and Stock, AJ and Gong, Y and Demarest, TG and Yang, B and Giri, N and Harrington, L and Alter, BP and Savage, SA and Bohr, VA and Liu, Y},
title = {Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.},
journal = {The EMBO journal},
volume = {39},
number = {21},
pages = {e103420},
pmid = {32935380},
issn = {1460-2075},
support = {//HHS | NIH | National Institute on Aging (NIA)/ ; //HHS | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (DCEG)/ ; },
abstract = {Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.},
}
@article {pmid32927181,
year = {2020},
author = {Carroll, JE and Mahrer, NE and Shalowitz, M and Ramey, S and Dunkel Schetter, C},
title = {Prenatal maternal stress prospectively relates to shorter child buccal cell telomere length.},
journal = {Psychoneuroendocrinology},
volume = {121},
number = {},
pages = {104841},
doi = {10.1016/j.psyneuen.2020.104841},
pmid = {32927181},
issn = {1873-3360},
support = {R01 HD072021/HD/NICHD NIH HHS/United States ; R03 HD059584/HD/NICHD NIH HHS/United States ; },
abstract = {Prenatal exposure to stress increases risk for suboptimal child and adult mental and physical health outcomes, hypothesized to occur via fetal exposure to maternal stress hormones that alter growth and development. One proposed pathway through which stress exposure in utero could affect the offspring is by accelerating cellular aging in the form of telomere attrition. We tested this hypothesis in a cohort of 111 mother-child dyads, where mothers were assessed over 6 or more years, beginning prior to conception, and later during pregnancy, postpartum, and when the children were 3-5 years old. Adjusting for child age and concurrent maternal stress, we found that higher maternal perceived stress in the 3rd trimesters of pregnancy was predictive of shorter child buccal telomere length (bTL) (β = -0.24, p < .05), while maternal preconception and postpartum maternal stress were not associated with bTL (all p's > 0.42). These findings suggest a vulnerable time period in pregnancy when maternal stress influences offspring telomere length, suggesting the early embedding of adult disease might occur through biological aging pathways.},
}
@article {pmid32922609,
year = {2020},
author = {Cheng, G and Dai, M and Xin, Q and Wang, L and Kong, F and Xu, D},
title = {Patients with benign prostatic hyperplasia show shorter leukocyte telomere length but no association with telomerase gene polymorphisms in Han Chinese males.},
journal = {International journal of clinical and experimental pathology},
volume = {13},
number = {8},
pages = {2123-2129},
pmid = {32922609},
issn = {1936-2625},
abstract = {OBJECTIVE: Benign prostatic hyperplasia (BPH) is an age-related disease, occurring in >70% of men of age >60. Because telomeres and telomerase play a key role in aging and age-related diseases, and certain telomerase gene single nucleotide polymorphisms (SNPs) are shown to be associated with the susceptibility to age-related diseases, we wanted to determine the relationship between BPH and leukocyte telomere length (LTL) and telomere length-related single nucleotide polymorphisms (SNPs) of the telomerase holoenzyme genes.<br><br>METHODS: Peripheral blood was collected from both BPH patients and age-matched healthy male controls and genomic DNA was extracted. rs2736100 and rs2736098 at the TERT and rs12696304 at the TERC locus were analysed using pre-designed TaqMan SNP genotyping assay kits. LTL was determined using qPCR.<br><br>RESULTS: Patients with BPH had significantly shorter LTL (1.231 ± 0.532 vs 0.899 ± 0.322, P < 0.001). The genotyping results show similar frequencies in rs2736100, rs2736098 and rs12696304 between healthy and BPH individuals.<br><br>CONCLUSIONS: Shorter telomeres but not telomerase SNPs at the TERT and TERC loci, are associated with BPH. Short telomeres may promote senescence of a fraction of prostatic epithelial cells, while senescent cells in turn facilitate epithelial and stromal cell proliferation by the senescence-associated secretory phenotype mechanism, thereby eventually leading to BPH development.},
}
@article {pmid32922179,
year = {2020},
author = {Cheng, G and Wang, L and Dai, M and Wei, F and Xu, D},
title = {Shorter Leukocyte Telomere Length coupled with lower expression of Telomerase Genes in patients with Essential Hypertension.},
journal = {International journal of medical sciences},
volume = {17},
number = {14},
pages = {2180-2186},
pmid = {32922179},
issn = {1449-1907},
abstract = {Background: The essential hypertension (EH) pathophysiology remains poorly understood. Many studies indicate that reduced leukocyte telomere length (LTL) is involved in the EH pathogenesis, however, the direct analysis of arterial telomere length (ATL) from EH patients and normotensive individuals did not show a difference. To address these discrepant observations between LTL and ATL, we performed comprehensive analyses of LTL, telomerase gene expression and their genetic variants in healthy normotensive controls and EH patients. Methods: Sex-matched 206 EH patients and equal numbers of healthy controls were recruited. LTL, and the expression of two key telomerase components, telomerase reverse transcriptase (TERT) and internal RNA template (TERC) were determined using qPCR. Genetic variants of rs2736100 at the TERT and rs12696304 at the TERC loci were determined using TaqMan genotyping kits. Results: LTL was significantly shorter in EH patients than in their normotensive controls (0.96 ± 0.52 vs 1.19 ± 0.58, P = 0.001). Moreover, TERT and TERC expression in patients' leukocytes were substantially lower compare to that in healthy controls (TERT, 0.98 ± 0.98 vs 1.76 ± 1.75, P = 0.003; TERC, 1.26 ± 1.62 vs 4.69 ± 3.61, P < 0.001). However, there were no differences in the genetic variants of rs2736100 and rs12696304 between patient and control groups. Conclusions: EH patients have significantly shorter LTL, which may result from defective TERT and TERC expression in leukocytes. Collectively, lower telomerase expression contributes to shorter LTL observed in EH patients, and telomerase activators may be considered for EH therapy.},
}
@article {pmid32920596,
year = {2020},
author = {Palmos, AB and Duarte, RRR and Smeeth, DM and Hedges, EC and Nixon, DF and Thuret, S and Powell, TR},
title = {Telomere length and human hippocampal neurogenesis.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {45},
number = {13},
pages = {2239-2247},
pmid = {32920596},
issn = {1740-634X},
support = {MR/N030087/1/MRC_/Medical Research Council/United Kingdom ; MR/N014863/1/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; MR/R006237/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10-5), and risk for schizophrenia (P ≤ 1 × 10-10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.},
}
@article {pmid32919410,
year = {2020},
author = {Squassina, A and Manchia, M and Pisanu, C and Ardau, R and Arzedi, C and Bocchetta, A and Caria, P and Cocco, C and Congiu, D and Cossu, E and Dettori, T and Frau, DV and Garzilli, M and Manca, E and Meloni, A and Montis, MA and Mura, A and Nieddu, M and Noli, B and Paribello, P and Pinna, F and Robledo, R and Severino, G and Sogos, V and Del Zompo, M and Ferri, GL and Chillotti, C and Vanni, R and Carpiniello, B},
title = {Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {45},
number = {13},
pages = {2229-2238},
pmid = {32919410},
issn = {1740-634X},
abstract = {Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F6, 137 = 20.128, p = 8.73 × 10-17, effect of diagnosis, F3 = 31.870; p = 1.08 × 10-15). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = -0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.},
}
@article {pmid32919107,
year = {2020},
author = {Yu, J and Kanchi, MM and Rawtaer, I and Feng, L and Kumar, AP and Kua, EH and Mahendran, R},
title = {The functional and structural connectomes of telomere length and their association with cognition in mild cognitive impairment.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {132},
number = {},
pages = {29-40},
doi = {10.1016/j.cortex.2020.08.006},
pmid = {32919107},
issn = {1973-8102},
abstract = {Previous findings on the relationship between telomere length and cognition have inconclusive, despite the relatively consistent telomere-shortening associated atrophy in the subcortical regions. Perhaps, there could be other more important telomere-associated factors in the brain, such as functional connectivity (FC) and structural connectivity (SC) that modulate cognition. The current study examined the relationship between telomere length, connectivity, and cognition. Telomere length measurements, neurocognitive scores, diffusion tensor and resting-state functional magnetic resonance imaging scans were collected from 82 older adults with mild cognitive impairment. SC and FC matrices were derived from these scans and, in various combinations, entered into connectome-based predictive models to predict telomere length. The telomere-associated features were then used to predict memory and executive functions. Leave-one-out cross-validation was performed. Predictive accuracy was assessed via the correlation between predicted and observed scores (rpredicted-observed). Correlation analyses were carried out between cognition and telomere length. Telomere length was significantly and negatively correlated with executive functions (EF), after controlling for demographical confounds. Telomere length was best predicted by negative SC and positive FC features (rpredicted-observed = .57; p < .001). The telomere-associated negative SC features significantly predicted EF scores (rpredicted-observed = -.26; p = .015). Telomere-shortening was associated with better EF and alterations in both FC and SC. This enhanced EF can be partly attributed to the telomere-associated changes in SC. Given that telomere is known to be a nonspecific marker of health, our findings illustrated a potential clinical use of telomere length to predict individualized health-related information from FC and SC features.},
}
@article {pmid32916703,
year = {2020},
author = {Miglani, M and Rain, M and Pasha, Q and Raj, VS and Thinlas, T and Mohammad, G and Gupta, A and Pandey, RP and Vibhuti, A},
title = {Shorter telomere length, higher telomerase activity in association with tankyrase gene polymorphism contribute to high-altitude pulmonary edema.},
journal = {Human molecular genetics},
volume = {29},
number = {18},
pages = {3094-3106},
doi = {10.1093/hmg/ddaa205},
pmid = {32916703},
issn = {1460-2083},
abstract = {High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High-altitude pulmonary edema patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200) and highland permanent healthy residents (HLs, n = 200). Variants of TNKS were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Plasma TNKS level was estimated using enzyme-linked immunosorbent assay, expression of TNKS and relative telomere length were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and telomerase activity was assessed by the telomere repeat amplification protocol assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (P = 0.006). TNKS was upregulated 9.27 folds in HAPE-p (P = 1.01E-06) and downregulated in HLs by 3.3 folds (P = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (P = 0.03) and HLs (P = 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (P = 0.01) and HLs (P = 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031 ng/μl) and the highest telomerase activity (0.0268 amoles/μl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.},
}
@article {pmid32913074,
year = {2020},
author = {Demanelis, K and Jasmine, F and Chen, LS and Chernoff, M and Tong, L and Delgado, D and Zhang, C and Shinkle, J and Sabarinathan, M and Lin, H and Ramirez, E and Oliva, M and Kim-Hellmuth, S and Stranger, BE and Lai, TP and Aviv, A and Ardlie, KG and Aguet, F and Ahsan, H and , and Doherty, JA and Kibriya, MG and Pierce, BL},
title = {Determinants of telomere length across human tissues.},
journal = {Science (New York, N.Y.)},
volume = {369},
number = {6509},
pages = {},
doi = {10.1126/science.aaz6876},
pmid = {32913074},
issn = {1095-9203},
support = {U01 HG007601/HG/NHGRI NIH HHS/United States ; F32 HG009987/HG/NHGRI NIH HHS/United States ; U01 HG007593/HG/NHGRI NIH HHS/United States ; R01 MH101814/MH/NIMH NIH HHS/United States ; R01 HL134840/HL/NHLBI NIH HHS/United States ; R01 MH106842/MH/NIMH NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; R01 MH109905/MH/NIMH NIH HHS/United States ; R01 GM124486/GM/NIGMS NIH HHS/United States ; U41 HG002371/HG/NHGRI NIH HHS/United States ; R01 CA107431/CA/NCI NIH HHS/United States ; R01 HG002585/HG/NHGRI NIH HHS/United States ; K99 HG009916/HG/NHGRI NIH HHS/United States ; P30 DK020595/DK/NIDDK NIH HHS/United States ; R01 HG010480/HG/NHGRI NIH HHS/United States ; UM1 HG008901/HG/NHGRI NIH HHS/United States ; R01 HG006855/HG/NHGRI NIH HHS/United States ; T32 DK110919/DK/NIDDK NIH HHS/United States ; T32 AG000243/AG/NIA NIH HHS/United States ; T32 HG000044/HG/NHGRI NIH HHS/United States ; U01 MH104393/MH/NIMH NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; R01 MH090937/MH/NIMH NIH HHS/United States ; U01 HG007598/HG/NHGRI NIH HHS/United States ; R01 GM122924/GM/NIGMS NIH HHS/United States ; R35 HG010718/HG/NHGRI NIH HHS/United States ; R01 MH107666/MH/NIMH NIH HHS/United States ; R01 MH090951/MH/NIMH NIH HHS/United States ; R01 HG008150/HG/NHGRI NIH HHS/United States ; R01 DA006227/DA/NIDA NIH HHS/United States ; T32 GM007281/GM/NIGMS NIH HHS/United States ; R01 GM108711/GM/NIGMS NIH HHS/United States ; R01 MH090941/MH/NIMH NIH HHS/United States ; R01 MH090936/MH/NIMH NIH HHS/United States ; UL1 TR002550/TR/NCATS NIH HHS/United States ; R01 HG010067/HG/NHGRI NIH HHS/United States ; R01 MH101822/MH/NIMH NIH HHS/United States ; R01 HL142028/HL/NHLBI NIH HHS/United States ; R01 ES020506/ES/NIEHS NIH HHS/United States ; R35 ES028379/ES/NIEHS NIH HHS/United States ; },
mesh = {Aging/*genetics ; Genetic Markers ; Genetic Variation ; Humans ; Organ Specificity ; Telomere/*physiology ; Telomere Homeostasis/*genetics ; Telomere Shortening/*genetics ; },
abstract = {Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.},
}
@article {pmid32911996,
year = {2021},
author = {Verner, G and Epel, E and Lahti-Pulkkinen, M and Kajantie, E and Buss, C and Lin, J and Blackburn, E and Räikkönen, K and Wadhwa, PD and Entringer, S},
title = {Maternal Psychological Resilience During Pregnancy and Newborn Telomere Length: A Prospective Study.},
journal = {The American journal of psychiatry},
volume = {178},
number = {2},
pages = {183-192},
pmid = {32911996},
issn = {1535-7228},
support = {R01 AG050455/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: In the context of the importance of elucidating the determinants of the initial, newborn setting of telomere length (TL), it is increasingly evident that maternal stress and stress-related processes during pregnancy play a major role. Although psychological resilience may function as a buffer, research in this area has not yet examined its potential role vis-à-vis that of stress. The authors examined the relationship between maternal psychological resilience during pregnancy and newborn TL.<br><br>METHODS: In a sample of 656 mother-child dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort, multiple serial assessments were conducted over the course of pregnancy to quantify maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. TL was measured using quantitative polymerase chain reaction in leukocytes extracted from cord blood shortly after birth. Linear regression was used to predict newborn TL from maternal resilience during pregnancy, adjusting for other potential determinants.<br><br>RESULTS: Maternal stress significantly predicted shorter newborn TL (β=-0.079), and positivity significantly predicted longer TL (β=0.135). Maternal resilience (positivity accounting for stress) was significantly and positively associated with newborn TL (β=0.114, 95% CI=0.035, 0.189), with each standard deviation increase in resilience predicting 12% longer newborn TL.<br><br>CONCLUSIONS: The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.},
}
@article {pmid32907975,
year = {2020},
author = {Khanal, S and Tang, Q and Cao, D and Zhao, J and Nguyen, LN and Oyedeji, OS and Dang, X and Nguyen, LNT and Schank, M and Thakuri, BKC and Ogbu, C and Morrison, ZD and Wu, XY and Zhang, Z and He, Q and El Gazzar, M and Li, Z and Ning, S and Wang, L and Moorman, JP and Yao, ZQ},
title = {Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections.},
journal = {Journal of virology},
volume = {94},
number = {22},
pages = {},
pmid = {32907975},
issn = {1098-5514},
support = {I01 BX002670/BX/BLRD VA/United States ; I01 BX004281/BX/BLRD VA/United States ; R01 AI114748/AI/NIAID NIH HHS/United States ; R21 AI138598/AI/NIAID NIH HHS/United States ; },
mesh = {Apoptosis ; Ataxia Telangiectasia/*genetics ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; CD4-Positive T-Lymphocytes/*metabolism ; Cell Line ; Cellular Senescence ; DNA Damage ; HEK293 Cells ; HIV Infections/*immunology ; HIV-1/genetics ; Humans ; Telomere/*metabolism ; Virus Replication ; },
abstract = {CD4 T-cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia-mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in vitro in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation of our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an in vitro HIV T-cell culture system with viral replication and raltegravir (RAL; an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection in vivo We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T-cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This in vitro model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T-cell homeostasis during HIV infection.IMPORTANCE The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.},
}
@article {pmid32906638,
year = {2020},
author = {Muresanu, C and Somasundaram, SG and Vissarionov, SV and Torres Solis, LF and Solís Herrera, A and Kirkland, CE and Aliev, G},
title = {Updated Understanding of Cancer as a Metabolic and Telomere-Driven Disease, and Proposal for Complex Personalized Treatment, a Hypothesis.},
journal = {International journal of molecular sciences},
volume = {21},
number = {18},
pages = {},
pmid = {32906638},
issn = {1422-0067},
support = {5-100//I.M. Sechenov First Moscow State Medical University/ ; Research Center//GALLY International Research Institute/ ; },
abstract = {In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over time-avoiding the natural DNA controls that otherwise repair or replace the rapidly replicating cells. DNA damage starts to accumulate in non-replicating cells, leading to senescence and aging. DNA damage is linked with genetic and epigenetic factors, but the development of cancer is favored by telomerase activity. Evidence indicates that telomere length is affected by chronic inflammations, alterations of mitochondrial DNA, and various environmental factors. Emotional stress also influences telomere length. Chronic inflammation can cause oxidative DNA damage. Oxidative stress, in turn, can trigger mitochondrial changes, which ultimately alter nuclear gene expression. This vicious cycle has led several scientists to view cancer as a metabolic disease. We have proposed complex personalized treatments that seek to correct multiple changes simultaneously using a psychological approach to reduce chronic stress, immune checkpoint therapy with reduced doses of chemo and radiotherapy, minimal surgical intervention, if any, and mitochondrial metabolic reprogramming protocols supplemented by intermittent fasting and personalized dietary plans without interfering with the other therapies.},
}
@article {pmid32903138,
year = {2020},
author = {Boyle, JM and Hennick, KM and Regalado, SG and Vogan, JM and Zhang, X and Collins, K and Hockemeyer, D},
title = {Telomere length set point regulation in human pluripotent stem cells critically depends on the shelterin protein TPP1.},
journal = {Molecular biology of the cell},
volume = {31},
number = {23},
pages = {2583-2596},
pmid = {32903138},
issn = {1939-4586},
support = {R01 CA196884/CA/NCI NIH HHS/United States ; R01 HL079585/HL/NHLBI NIH HHS/United States ; },
abstract = {Telomere maintenance is essential for the long-term proliferation of human pluripotent stem cells, while their telomere length set point determines the proliferative capacity of their differentiated progeny. The shelterin protein TPP1 is required for telomere stability and elongation, but its role in establishing a telomere length set point remains elusive. Here, we characterize the contribution of the shorter isoform of TPP1 (TPP1S) and the amino acid L104 outside the TEL patch, TPP1's telomerase interaction domain, to telomere length control. We demonstrate that cells deficient for TPP1S (TPP1S knockout [KO]), as well as the complete TPP1 KO cell lines, undergo telomere shortening. However, TPP1S KO cells are able to stabilize short telomeres, while TPP1 KO cells die. We compare these phenotypes with those of TPP1L104A/L104A mutant cells, which have short and stable telomeres similar to the TPP1S KO. In contrast to TPP1S KO cells, TPP1L104A/L104A cells respond to increased telomerase levels and maintain protected telomeres. However, TPP1L104A/L104A shows altered sensitivity to expression changes of shelterin proteins suggesting the mutation causes a defect in telomere length feedback regulation. Together this highlights TPP1L104A/L104A as the first shelterin mutant engineered at the endogenous locus of human stem cells with an altered telomere length set point.},
}
@article {pmid32900359,
year = {2020},
author = {Lee, KH and Kimmel, M},
title = {Analysis of two mechanisms of telomere maintenance based on the theory of g-Networks and stochastic automata networks.},
journal = {BMC genomics},
volume = {21},
number = {Suppl 9},
pages = {587},
pmid = {32900359},
issn = {1471-2164},
abstract = {*: Background Telomeres, which are composed of repetitive nucleotide sequences at the end of chromosomes, behave as a division clock that measures replicative senescence. Under the normal physiological condition, telomeres shorten with each cell division, and cells use the telomere lengths to sense the number of divisions. Replicative senescence has been shown to occur at approximately 50-70 cell divisions, which is termed the Hayflick's limit. However, in cancer cells telomere lengths are stabilized, thereby allowing continual cell replication by two known mechanisms: activation of telomerase and Alternative Lengthening of Telomeres (ALT). The connections between the two mechanisms are complicated and still poorly understood. *: Results In this research, we propose that two different approaches, G-Networks and Stochastic Automata Networks, which are stochastic models motivated by queueing theory, are useful to identify a set of genes that play an important role in the state of interest and to infer their previously unknown correlation by obtaining both stationary and joint transient distributions of the given system. Our analysis using G-Network detects five statistically significant genes (CEBPA, FOXM1, E2F1, c-MYC, hTERT) with either mechanism, contrasted to normal cells. A new algorithm is introduced to show how the correlation between two genes of interest varies in the transient state according not only to each mechanism but also to each cell condition. *: Conclusions This study expands our existing knowledge of genes associated with mechanisms of telomere maintenance and provides a platform to understand similarities and differences between telomerase and ALT in terms of the correlation between two genes in the system. This is particularly important because telomere dynamics plays a major role in many physiological and disease processes, including hematopoiesis.},
}
@article {pmid32899298,
year = {2020},
author = {Bradfield, A and Button, L and Drury, J and Green, DC and Hill, CJ and Hapangama, DK},
title = {Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer.},
journal = {Methods and protocols},
volume = {3},
number = {3},
pages = {},
pmid = {32899298},
issn = {2409-9279},
support = {RG2137//Wellbeing of Women/ ; MRes Studentship//North West Cancer Research Fund/ ; Alice Bradfield//NHS bursary/ ; },
abstract = {Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.},
}
@article {pmid32894749,
year = {2021},
author = {Dhillon, VS and Deo, P and Chua, A and Thomas, P and Fenech, M},
title = {Telomere Length in Healthy Adults Is Positively Associated With Polyunsaturated Fatty Acids, Including Arachidonic Acid, and Negatively With Saturated Fatty Acids.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {3-6},
doi = {10.1093/gerona/glaa213},
pmid = {32894749},
issn = {1758-535X},
abstract = {Lymphocyte telomere length (LTL) is a biomarker of aging that may be modified by dietary factors including fat. Red blood cell fatty acid status is a well-validated indicator of long-term dietary intake of fat from various sources. Recent findings from epidemiological studies of LTL in relation to fatty acids in red blood cells are not conclusive. The present study was carried out to investigate if red blood cell fatty acid status in 174 healthy older South Australians is associated with LTL. Lymphocyte telomere length was measured by real-time qPCR and fatty acid content in red blood cells was measured by gas chromatography. Our results indicate that the majority of saturated fatty acids and monounsaturated fatty acids are negatively associated with LTL, whereas polyunsaturated fatty acids are positively associated with LTL. Multiple regression analysis revealed that arachidonic acid (C20:4n-6) is significantly, independently, positively correlated with LTL (β = 0.262; p = .000). The significant association of fatty acids, particularly C20:4n-6, with telomere length warrants further research.},
}
@article {pmid32890403,
year = {2020},
author = {Leal, AZ and Schwebs, M and Briggs, E and Weisert, N and Reis, H and Lemgruber, L and Luko, K and Wilkes, J and Butter, F and McCulloch, R and Janzen, CJ},
title = {Genome maintenance functions of a putative Trypanosoma brucei translesion DNA polymerase include telomere association and a role in antigenic variation.},
journal = {Nucleic acids research},
volume = {48},
number = {17},
pages = {9660-9680},
pmid = {32890403},
issn = {1362-4962},
support = {104111/WT_/Wellcome Trust/United Kingdom ; },
mesh = {*Antigenic Variation ; Cell Line ; Cell Nucleus/enzymology/genetics ; Chromosome Segregation ; DNA Replication ; DNA-Directed DNA Polymerase/genetics/*metabolism ; Gene Expression Regulation ; Genome, Protozoan ; Humans ; Protozoan Proteins/genetics/metabolism ; RNA Interference ; Telomere/*genetics/metabolism ; Trypanosoma brucei brucei/*genetics/metabolism/pathogenicity ; Variant Surface Glycoproteins, Trypanosoma/genetics ; },
abstract = {Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of one putative translesion Pol in African trypanosomes, which we now name TbPolIE. Previously, we demonstrated that TbPolIE is associated with telomeric sequences and here we show that RNAi-mediated depletion of TbPolIE transcripts results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. We also show that TbPolIE displays pronounced localization at the nuclear periphery, and that its depletion leads to chromosome segregation defects and increased levels of endogenous DNA damage. Finally, we demonstrate that TbPolIE depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this putative translesion DNA polymerase to host immune evasion by antigenic variation.},
}
@article {pmid32887908,
year = {2020},
author = {Sonnenberg, ASM and Sedaghat-Telgerd, N and Lavrijssen, B and Ohm, RA and Hendrickx, PM and Scholtmeijer, K and Baars, JJP and van Peer, A},
title = {Telomere-to-telomere assembled and centromere annotated genomes of the two main subspecies of the button mushroom Agaricus bisporus reveal especially polymorphic chromosome ends.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {14653},
pmid = {32887908},
issn = {2045-2322},
abstract = {Agaricus bisporus, the most cultivated edible mushroom worldwide, is represented mainly by the subspecies var. bisporus and var. burnettii. var. bisporus has a secondarily homothallic life cycle with recombination restricted to chromosome ends, while var. burnettii is heterothallic with recombination seemingly equally distributed over the chromosomes. To better understand the relationship between genomic make-up and different lifestyles, we have de novo sequenced a burnettii homokaryon and synchronised gene annotations with updated versions of the published genomes of var. bisporus. The genomes were assembled into telomere-to-telomere chromosomes and a consistent set of gene predictions was generated. The genomes of both subspecies were largely co-linear, and especially the chromosome ends differed in gene model content between the two subspecies. A single large cluster of repeats was found on each chromosome at the same respective position in all strains, harbouring nearly 50% of all repeats and likely representing centromeres. Repeats were all heavily methylated. Finally, a mapping population of var. burnettii confirmed an even distribution of crossovers in meiosis, contrasting the recombination landscape of var. bisporus. The new findings using the exceptionally complete and well annotated genomes of this basidiomycete demonstrate the importance for unravelling genetic components underlying the different life cycles.},
}
@article {pmid32883756,
year = {2020},
author = {Compton, A and Liang, J and Chen, C and Lukyanchikova, V and Qi, Y and Potters, M and Settlage, R and Miller, D and Deschamps, S and Mao, C and Llaca, V and Sharakhov, IV and Tu, Z},
title = {The Beginning of the End: A Chromosomal Assembly of the New World Malaria Mosquito Ends with a Novel Telomere.},
journal = {G3 (Bethesda, Md.)},
volume = {10},
number = {10},
pages = {3811-3819},
pmid = {32883756},
issn = {2160-1836},
abstract = {Chromosome level assemblies are accumulating in various taxonomic groups including mosquitoes. However, even in the few reference-quality mosquito assemblies, a significant portion of the heterochromatic regions including telomeres remain unresolved. Here we produce a de novo assembly of the New World malaria mosquito, Anopheles albimanus by integrating Oxford Nanopore sequencing, Illumina, Hi-C and optical mapping. This 172.6 Mbps female assembly, which we call AalbS3, is obtained by scaffolding polished large contigs (contig N50 = 13.7 Mbps) into three chromosomes. All chromosome arms end with telomeric repeats, which is the first in mosquito assemblies and represents a significant step toward the completion of a genome assembly. These telomeres consist of tandem repeats of a novel 30-32 bp Telomeric Repeat Unit (TRU) and are confirmed by analyzing the termini of long reads and through both chromosomal in situ hybridization and a Bal31 sensitivity assay. The AalbS3 assembly included previously uncharacterized centromeric and rDNA clusters and more than doubled the content of transposable elements and other repetitive sequences. This telomere-to-telomere assembly, although still containing gaps, represents a significant step toward resolving biologically important but previously hidden genomic components. The comparison of different scaffolding methods will also inform future efforts to obtain reference-quality genomes for other mosquito species.},
}
@article {pmid32883681,
year = {2020},
author = {Yang, Z and Takai, KK and Lovejoy, CA and de Lange, T},
title = {Break-induced replication promotes fragile telomere formation.},
journal = {Genes &amp; development},
volume = {34},
number = {19-20},
pages = {1392-1405},
pmid = {32883681},
issn = {1549-5477},
support = {R01 AG016642/AG/NIA NIH HHS/United States ; R56 AG016642/AG/NIA NIH HHS/United States ; },
abstract = {TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres-structures that resemble common fragile sites (CFSs)-but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.},
}
@article {pmid32881625,
year = {2020},
author = {Hernando, B and Gil-Barrachina, M and Tomás-Bort, E and Martinez-Navarro, I and Collado-Boira, E and Hernando, C},
title = {The effect of long-term ultra-endurance exercise and SOD2 genotype on telomere shortening with age.},
journal = {Journal of applied physiology (Bethesda, Md. : 1985)},
volume = {129},
number = {4},
pages = {873-879},
doi = {10.1152/japplphysiol.00570.2020},
pmid = {32881625},
issn = {1522-1601},
support = {//Fundacion Trinidad Alfonso/ ; //Vithas-Nisa Hospital Group/ ; //Sociedad Deportiva Correcaminos/ ; },
abstract = {Telomere shortening, a well-known biomarker of aging, is a complex process influenced by several intrinsic and lifestyle factors. Although habitual exercise may promote telomere length maintenance, extreme endurance exercise has been also associated with increased oxidative stress-presumed to be the major cause of telomere shortening. Therefore, the pace of telomere shortening with age may also depend on antioxidant system efficiency, which is, in part, genetically determined. In this study, we aimed to evaluate the impact of ultra-endurance exercise and oxidative stress susceptibility (determined by the rs4880 polymorphism in the superoxide dismutase 2 (SOD2) gene) on telomere length. Genomic DNA was obtained from 53 sedentary individuals (34 females, 19-67 yr) and 96 ultra-trail runners (31 females, 23-58 yr). Indeed, blood samples before and after finishing a 107-km-trail race were collected from 69 runners to measure c-reactive protein (CRP) levels and, thus, analyze whether acute inflammation response is modulated by the SOD2 rs4880 polymorphism. Our results revealed that telomere length was better preserved in ultra-trail runners compared with controls, especially in elderly runners who have been regularly training for many years. Carrying the SOD2 rs4880*A allele was significantly associated with having shorter telomeres, as well as with having increased CRP levels after the ultra-trail race. In conclusion, habitual ultra-endurance exercise had a beneficial effect on telomere length maintenance, especially at older ages. This study also suggested that the SOD2 rs4880 polymorphism may also have an impact on acute and chronic oxidative-related damage (inflammatory response and telomere length) after an ultra-trail race.NEW &amp; NOTEWORTHY Habitual ultra-endurance exercise seems to promote telomere length maintenance, especially at older ages. In addition, the beneficial effect of ultra-endurance training on biological aging is higher in ultra-trail runners who have been engaged to ultra-endurance training during many years. Finally, and for the first time, this study shows that the SOD2 rs4880 polymorphism has a significant impact on telomere length, as well as on acute inflammatory response to a 107-km trail race.},
}
@article {pmid32880939,
year = {2020},
author = {Tsilingiris, D and Tentolouris, A and Eleftheriadou, I and Tentolouris, N},
title = {Telomere length, epidemiology and pathogenesis of severe COVID-19.},
journal = {European journal of clinical investigation},
volume = {50},
number = {10},
pages = {e13376},
doi = {10.1111/eci.13376},
pmid = {32880939},
issn = {1365-2362},
mesh = {Apoptosis/immunology ; Betacoronavirus ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; COVID-19 ; Cellular Senescence/immunology ; Coronavirus Infections/*immunology/metabolism/physiopathology ; Humans ; Lymphocytes/*immunology/metabolism ; Lymphopenia/*immunology ; Mitochondria/metabolism ; NAD/metabolism ; Pandemics ; Pneumonia, Viral/*immunology/metabolism/physiopathology ; Risk Factors ; SARS-CoV-2 ; Severity of Illness Index ; Sirtuins/metabolism ; T-Lymphocytes/immunology ; Telomere/*metabolism ; Telomere Homeostasis ; Telomere Shortening/*immunology ; },
}
@article {pmid32876842,
year = {2020},
author = {Lulkiewicz, M and Bajsert, J and Kopczynski, P and Barczak, W and Rubis, B},
title = {Telomere length: how the length makes a difference.},
journal = {Molecular biology reports},
volume = {47},
number = {9},
pages = {7181-7188},
pmid = {32876842},
issn = {1573-4978},
support = {2016/21/B/NZ7/01079//Narodowym Centrum Nauki (PL)/ ; },
abstract = {Telomerase is perceived as an immortality enzyme that might provide longevity to cells and whole organisms. Importantly, it is generally inactive in most somatic cells of healthy, adult men. Consequently, its substrates, i.e. telomeres, get shorter in most human cells with time. Noteworthy, cell life limitation due to telomere attrition during cell divisions, may not be as bad as it looks since longer cell life means longer exposition to harmful factors. Consequently, telomere length (attrition rate) becomes a factor that is responsible for inducing the signaling that leads to the elimination of cells that lived long enough to acquire severe damage. It seems that telomere length that depends on many different factors (including telomerase activity but also genetic factors, a hormonal profile that reflects sex, etc.) might become a useful marker of aging and exposition to stress. Thus in the current paper, we review the factors that affect telomere length in human cells focusing on sex that all together with different environmental and hormonal regulations as well as parental aspect affect telomere attrition rate. We also raise some limitations in the assessment of telomere length that hinders a trustworthy meta-analysis that might lead to acknowledgment of the real value of this parameter.},
}
@article {pmid32873778,
year = {2020},
author = {Giaccherini, M and Macauda, A and Sgherza, N and Sainz, J and Gemignani, F and Maldonado, JMS and Jurado, M and Tavano, F and Mazur, G and Jerez, A and Góra-Tybor, J and Gołos, A and Mohedo, FH and Lopez, JM and Várkonyi, J and Spadano, R and Butrym, A and Canzian, F and Campa, D},
title = {Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms.},
journal = {Blood cancer journal},
volume = {10},
number = {8},
pages = {89},
pmid = {32873778},
issn = {2044-5385},
abstract = {Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the &quot;teloscore&quot; in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10-3, comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (ORallelic = 1.43; 95% CI 1.15-1.77; P = 1.35 × 10-3). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.},
}
@article {pmid32871095,
year = {2020},
author = {Ojeda-Rodríguez, A and Morell-Azanza, L and Martín-Calvo, N and Zalba, G and Chueca, M and Azcona-Sanjulian, MC and Marti, A},
title = {Association between favourable changes in objectively measured physical activity and telomere length after a lifestyle intervention in pediatric patients with abdominal obesity.},
journal = {Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme},
volume = {},
number = {},
pages = {},
doi = {10.1139/apnm-2020-0297},
pmid = {32871095},
issn = {1715-5320},
abstract = {The purpose of this study was to assess the effect of physical activity (PA) changes, measured by accelerometry, on telomere length (TL) in pediatric patients with abdominal obesity after a lifestyle intervention. 121 children with abdominal obesity (7-16 years old) were randomized to the intervention (moderately hypocaloric Mediterranean Diet) or usual care group (standard pediatrics recommendations) for 22 months (a 2-month intensive phase and a subsequent 20-month follow-up). Both groups were encouraged to accumulate extra 200 min/week of PA. TL was measured by MMqPCR. Data were analyzed in 102 subjects after 2-month and 64 subjects at the first 10 months of follow-up. Light PA level decreased in both groups after 12-month of intervention. At month 2, moderate-to-vigorous PA (MVPA) incremented in the intervention group (+5.4 min/day, p=0.035) and so did sedentary time in the usual care group (+49.7 min/day, p=0.010). TL changes were positively associated (p<0.050) with metabolic equivalents (METs), MVPA level and number of steps; and inversely associated with sedentary and light PA levels in the intervention group after the intensive phase. In conclusion, favourable changes in PA levels in the intensive phase of a lifestyle intervention could contribute to TL maintenance in pediatric population with abdominal obesity. Novelty: • Changes in physical activity levels had a direct effect on telomere length, a biomarker of cellular aging and oxidative stress. • PA advice based on The American College of Sports Medicine included in this intervention is easy to implement in primary care.},
}
@article {pmid32861877,
year = {2020},
author = {Fathi, E and Farahzadi, R and Javanmardi, S and Vietor, I},
title = {L-carnitine Extends the Telomere Length of the Cardiac Differentiated CD117+- Expressing Stem Cells.},
journal = {Tissue &amp; cell},
volume = {67},
number = {},
pages = {101429},
doi = {10.1016/j.tice.2020.101429},
pmid = {32861877},
issn = {1532-3072},
abstract = {Stem cell-based therapy has emerged as an attractive method for regenerating and repairing the lost heart organ. On other hand, poor survival and maintenance of the cells transferred into the damaged heart tissue are broadly accepted as serious barriers to enhance the efficacy of the regenerative therapy. For this reason, external factors, such as antioxidants are used as a favorite strategy by the investigators to improve the cell survival and retention properties. Therefore, the present study was conducted to investigate the In -vitro effect of L-carnitine (LC) on the telomere length and human telomerase reverse transcriptase (hTERT) gene expression in the cardiac differentiated bone marrow resident CD117+ stem cells through Wnt3/β-catenin and ERK1/2 pathways. To do this, bone marrow resident CD117+ stem cells were enriched by the magnetic-activated cell sorting (MACS) method, and were differentiated to the cardiac cells in the absence (-LC) and presence of the LC (+LC). Also, characterization of the enriched c-kit+ cells was performed using the flow cytometry and immunocytochemistry. At the end of the treatment period, the cells were subjected to the real-time PCR technique along with western blotting assay for measurement of the telomere length and assessment of mRNA and protein, respectively. The results showed that 0.2 mM LC caused the elongation of the telomere length and increased the hTERT gene expression in the cardiac differentiated CD117+ stem cells. In addition, a significant increase was observed in the mRNA and protein expression of Wnt3, β-catenin and ERK1/2 as key components of these pathways. It can be concluded that the LC can increase the telomere length as an effective factor in increasing the cell survival and maintenance of the cardiac differentiated bone marrow resident CD117+ stem cells via Wnt3/β-catenin and ERK1/2 signaling pathway components.},
}
@article {pmid32856217,
year = {2021},
author = {Uysal, F and Kosebent, EG and Toru, HS and Ozturk, S},
title = {Decreased expression of TERT and telomeric proteins as human ovaries age may cause telomere shortening.},
journal = {Journal of assisted reproduction and genetics},
volume = {38},
number = {2},
pages = {429-441},
pmid = {32856217},
issn = {1573-7330},
support = {TUBITAK; Grant no. 117S258//The Scientific and Technological Research Council of Turkey/ ; },
abstract = {OBJECTIVE: Telomeres are repetitive sequences localized at the ends of eukaryotic chromosomes comprising noncoding DNA and telomere-binding proteins. TRF1 and TRF2 both bind to the double-stranded telomeric DNA to regulate its length throughout the lifespan of eukaryotic cells. POT1 interacts with single-stranded telomeric DNA and contributes to protecting genomic integrity. Previous studies have shown that telomeres gradually shorten as ovaries age, coinciding with fertility loss. However, the molecular background of telomere shortening with ovarian aging is not fully understood.<br><br>METHODS: The present study aimed to determine the spatial and temporal expression levels of the TERT, TRF1, TRF2, and POT1 proteins in different groups of human ovaries: fetal (n = 11), early postnatal (n = 10), premenopausal (n = 12), and postmenopausal (n = 14). Also, the relative telomere signal intensity of each group was measured using the Q-FISH method.<br><br>RESULTS: We found that the telomere signal intensities decreased evenly and significantly from fetal to postmenopausal groups (P < 0.05). The TERT, TRF1, TRF2, and POT1 proteins were localized in the cytoplasmic and nuclear regions of the oocytes, granulosa and stromal cells. Furthermore, the expression levels of these proteins reduced significantly from fetal to postmenopausal groups (P < 0.05).<br><br>CONCLUSION: These findings suggest that decreased TERT and telomere-binding protein expression may underlie the telomere shortening of ovaries with age, which may be associated with female fertility loss. Further investigations are required to elicit the molecular mechanisms regulating the gradual decrease in the expression of TERT and telomere-binding proteins in human oocytes and granulosa cells during ovarian aging.},
}
@article {pmid32856116,
year = {2020},
author = {Hussien, MT and Shaban, S and Temerik, DF and Helal, SR and Mosad, E and Elgammal, S and Mostafa, A and Hassan, E and Ibrahim, A},
title = {Impact of DAXX and ATRX expression on telomere length and prognosis of breast cancer patients.},
journal = {Journal of the Egyptian National Cancer Institute},
volume = {32},
number = {1},
pages = {34},
doi = {10.1186/s43046-020-00045-1},
pmid = {32856116},
issn = {2589-0409},
abstract = {BACKGROUND: Telomere stability is one of the hallmarks of cancer that promotes cellular longevity, the accumulation of genetic alterations, and tumorigenesis. The loss of death domain-associated protein (DAXX) and α-thalassemia/mental retardation X-linked protein (ATRX) plays a role in telomere lengthening and stability. This study aims to evaluate the prognostic significance of telomere length (TL) and its association with DAXX and ATRX proteins in breast cancer (BC). Our study used the FISH technique to detect peptide nucleic acid (PNA) in the peripheral blood cells of a cohort of BC patients (n = 220) and a control group of apparently healthy individuals (n = 100). Expression of DAXX and ATRX proteins was evaluated using immunohistochemistry (IHC) in all BC tissues.<br><br>RESULTS: Patients with a shorter TL had worse disease-free survival (DFS) and overall survival (OS). There were significant associations between shorter TL and advanced disease stages, lymph node metastasis, and positive HER2/neu expression. DAXX protein expression was significantly correlated with TL. Lower DAXX expression was significantly with shorter DFS.<br><br>CONCLUSION: Assessing TL can be used as a worthy prognostic indicator in BC patients. Specifically, short TL had a poor impact on the prognosis of BC patients. Low DAXX expression is associated with poor outcomes in BC. Further mechanistic studies are warranted to reveal the underlying mechanisms of these associations.},
}
@article {pmid32853653,
year = {2020},
author = {Maleki, M and Khelghati, N and Alemi, F and Bazdar, M and Asemi, Z and Majidinia, M and Sadeghpoor, A and Mahmoodpoor, A and Jadidi-Niaragh, F and Targhazeh, N and Yousefi, B},
title = {Stabilization of telomere by the antioxidant property of polyphenols: Anti-aging potential.},
journal = {Life sciences},
volume = {259},
number = {},
pages = {118341},
doi = {10.1016/j.lfs.2020.118341},
pmid = {32853653},
issn = {1879-0631},
mesh = {Animals ; Antioxidants/*pharmacology ; Drug Combinations ; Humans ; Plantago/*drug effects ; Polyphenols/*pharmacology ; Senna Extract ; Telomere/*drug effects ; Telomere Shortening/drug effects ; },
abstract = {Aging is a form of a gradual loss of physiological integrity that results in impaired cellular function and ultimately increased vulnerability to disease and death. This process is a significant risk factor for critical age-related disorders such as cancer, diabetes, cardiovascular disease, and neurological conditions. Several mechanisms contribute to aging, most notably progressive telomeres shortening, which can be counteracted by telomerase enzyme activity and increasing in this enzyme activity associated with partly delaying the onset of aging. Individual behaviors and environmental factors such as nutrition affect the life-span by impact the telomerase activity rate. Healthy eating habits, including antioxidant intakes, such as polyphenols, can have a positive effect on telomere length by this mechanism. In this review, after studying the underlying mechanisms of aging and understanding the relationships between telomeres, telomerase, and aging, it has been attempted to explain the effect of polyphenols on reversing the oxidative stress and aging process.},
}
@article {pmid32842933,
year = {2020},
author = {Stier, A and Metcalfe, NB and Monaghan, P},
title = {Pace and stability of embryonic development affect telomere dynamics: an experimental study in a precocial bird model.},
journal = {Proceedings. Biological sciences},
volume = {287},
number = {1933},
pages = {20201378},
pmid = {32842933},
issn = {1471-2954},
mesh = {Adult ; Animals ; *Coturnix ; *Embryonic Development ; Female ; Glucocorticoids ; Humans ; Pregnancy ; *Telomere ; Telomere Shortening ; Temperature ; },
abstract = {Prenatal effects on telomere length are increasingly recognized as a potential contributor to the developmental origin of health and adult disease. While it is becoming clear that telomere length is influenced by prenatal conditions, the factors affecting telomere dynamics during embryogenesis remain poorly understood. We manipulated both the pace and stability of embryonic development through varying incubation temperature and its stability in Japanese quail. We investigated the impact on telomere dynamics from embryogenesis to adulthood, together with three potential drivers of telomere shortening, growth rate, oxidative damage and prenatal glucocorticoid levels. Telomere length was not affected by our prenatal manipulation for the first 75% of embryogenesis, but was reduced at hatching in groups experiencing faster (i.e. high temperature) or less stable embryonic development. These early life differences in telomere length persisted until adulthood. The effect of developmental instability on telomere length at hatching was potentially mediated by an increased secretion of glucocorticoid hormones during development. Both the pace and the stability of embryo development appear to be key factors determining telomere length and dynamics into adulthood, with fast and less stable development leading to shorter telomeres, with the potential for adverse associated outcomes in terms of reduced longevity.},
}
@article {pmid32841635,
year = {2020},
author = {Colicino, E and Cowell, W and Bozack, A and Foppa Pedretti, N and Joshi, A and Niedzwiecki, MM and Bollati, V and Berin, C and Wright, RO and Wright, RJ},
title = {Association between prenatal immune phenotyping and cord blood leukocyte telomere length in the PRISM pregnancy cohort.},
journal = {Environmental research},
volume = {191},
number = {},
pages = {110113},
pmid = {32841635},
issn = {1096-0953},
support = {UG3 OD023337/OD/NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; T32 HD049311/HD/NICHD NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R01 HL114396/HL/NHLBI NIH HHS/United States ; },
mesh = {*Air Pollutants ; Bayes Theorem ; Child ; Female ; *Fetal Blood ; Humans ; Infant, Newborn ; Leukocytes ; Pregnancy ; Telomere/genetics ; },
abstract = {BACKGROUND: Environmental exposures including air pollutants, toxic metals, and psychosocial stress have been associated with shorter telomere length (TL) in newborns. These exposures have in turn been linked to an enhanced inflammatory immune response. Increased inflammation during pregnancy may be a central biological pathway linking environmental factors with reduced TL at birth. Approaches that more comprehensively characterize the prenatal inflammatory milieu rather than targeting specific individual cytokines in relation to newborn TL may better elucidate inflammatory mechanisms.<br><br>METHODS: Analyses included 129 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured 92 inflammation related proteins during pregnancy in maternal serum using the Olink protein array and quantified cord blood relative leukocyte TL (rLTL) via qPCR. We leveraged a tree-based machine learning algorithm to select the most important inflammatory related proteins jointly associated with rLTL. We then evaluated the combined association between the selected proteins with rLTL using Bayesian Weighted Quantile Sum (BWQS) Regression. Analyses were adjusted for gestational week of serum collection, maternal race/ethnicity, age, and education, and fetal sex. We evaluated major biological function of the identified proteins by using the UniProtKB, a centralized repository of curated functional information.<br><br>RESULTS: Three proteins were negatively and linearly associated with rLTL (CASP8 β: -0.22 p = 0.008, BNGF β: -0.43 p = 0.033, TRANCE β: 0.38 p = 0.004). Results from BWQS regression showed a significant overall decrease in rLTL (β: -0.26 95%CrI: -0.43, -0.07) per quartile increase of the mixture, with CASP8 contributing the greatest weight (CASP8 50%; BNGF 27%, and TRANCE 23%). The identified proteins were involved in the regulation of apoptotic processes and cell proliferation.<br><br>CONCLUSIONS: This proteomics approach identifies novel maternal prenatal inflammatory protein biomarkers associated with shortened rLTL in newborns.},
}
@article {pmid32840794,
year = {2021},
author = {Simon, MN and Churikov, D and Géli, V},
title = {Analysis of Recombination at Yeast Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2153},
number = {},
pages = {395-402},
doi = {10.1007/978-1-0716-0644-5_27},
pmid = {32840794},
issn = {1940-6029},
abstract = {Upon telomerase inactivation telomeres are getting shorter at each round of DNA replication and progressively lose capping functions and hence protection against homologous recombination. In addition, telomerase-minus cells undergo a round of stochastic DNA damage before the bulk of telomeres become critically short because telomeres are difficult regions to replicate. Although most of the cells will enter finally replicative senescence, those that unleash recombination can eventually recover functional telomeres and growth capacity. Formation of these survivors in yeast depends on various recombination mechanisms. Here, we present assays that we developed to analyze and quantify recombination at telomeres.},
}
@article {pmid32829966,
year = {2021},
author = {Chen, R and Zhan, Y},
title = {Association between telomere length and Parkinson's disease: a Mendelian randomization study.},
journal = {Neurobiology of aging},
volume = {97},
number = {},
pages = {144.e9-144.e11},
doi = {10.1016/j.neurobiolaging.2020.07.019},
pmid = {32829966},
issn = {1558-1497},
abstract = {In this study, we examined the potential association of telomere length with Parkinson's disease (PD) using the publicly available genome-wide association study summary statistics from the International Parkinson's Disease Genomics Consortium involving up to 37,688 patients with PD and 449,056 controls in Mendelian randomization framework. The Mendelian randomization approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and reverse causation that often present in conventional epidemiological studies. We did not find that longer telomeres were associated with higher risks of PD (odds ratio: 1.18, 95% confidence interval: 0.94, 1.48, p = 0.15). Our study, therefore, did not provide evidence to support a potential causal relationship between telomere length and PD.},
}
@article {pmid32825843,
year = {2020},
author = {Fattet, AJ and Toupance, S and Thornton, SN and Monnin, N and Guéant, JL and Benetos, A and Koscinski, I},
title = {Telomere length in granulosa cells and leukocytes: a potential marker of female fertility? A systematic review of the literature.},
journal = {Journal of ovarian research},
volume = {13},
number = {1},
pages = {96},
pmid = {32825843},
issn = {1757-2215},
support = {ANR-15-IDEX-04-LUE//Agence Nationale de la Recherche/ ; },
abstract = {In the context of a continuously increased delay of motherhood and of an increase of the incidence of premature ovarian failure, it is of the greatest interest to dispose of a predictive marker of the duration of the fertility window. Unfortunately, current available markers of women's fertility (hormonal rates or echography count of small follicles) have a poor predictive value of premature ovarian failure. In the last ten years, some studies have suggested that telomere length may be correlated with premature ovarian failure, but the results of these studies are contradictory.In accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this systematic review of the literature selected studies evaluating telomere length or telomerase activity in granulosa cells and/or in leukocytes as a premature ovarian failure marker.Five publications (252 premature ovarian failure patients) were included in this review of experimental evidence. Two of them studied telomere length and/or telomerase activity in granulosa cells and 4 in leukocytes in women with premature ovarian failure. For each study, authors determined if there was a positive or a negative correlation between telomeric parameters and premature ovarian failure.3 studies (178 premature ovarian failure patients) found shorter telomere length in granulosa cells and/or leukocytes and/or lower telomerase activity in premature ovarian failure patients. 2 studies (74 premature ovarian failure patients) presented contradictory results about the correlation of leucocyte telomere length with premature ovarian failure.Shorter telomeres and diminished telomerase activity in granulosa cells appear to be associated with ovarian insufficiency. However, the number of studies and of subjects within are low and the methodology questionable. The confirmation of these results is essential with more subjects, better defined populations and more adapted methodology, in order to consider telomere length in granulosa cells and/or in leucocytes as an early and reliable marker for the decline of ovarian function.},
}
@article {pmid32824789,
year = {2020},
author = {Bernabeu-Wittel, M and Gómez-Díaz, R and González-Molina, Á and Vidal-Serrano, S and Díez-Manglano, J and Salgado, F and Soto-Martín, M and Ollero-Baturone, M and On Behalf Of The Proteo Researchers, },
title = {Oxidative Stress, Telomere Shortening, and Apoptosis Associated to Sarcopenia and Frailty in Patients with Multimorbidity.},
journal = {Journal of clinical medicine},
volume = {9},
number = {8},
pages = {},
pmid = {32824789},
issn = {2077-0383},
abstract = {BACKGROUND: The presence of oxidative stress, telomere shortening, and apoptosis in polypathological patients (PP) with sarcopenia and frailty remains unknown.<br><br>METHODS: Multicentric prospective observational study in order to assess oxidative stress markers (catalase, glutathione reductase (GR), total antioxidant capacity to reactive oxygen species (TAC-ROS), and superoxide dismutase (SOD)), absolute telomere length (aTL), and apoptosis (DNA fragmentation) in peripheral blood samples of a hospital-based population of PP. Associations of these biomarkers to sarcopenia, frailty, functional status, and 12-month mortality were analyzed.<br><br>RESULTS: Of the 444 recruited patients, 97 (21.8%), 278 (62.6%), and 80 (18%) were sarcopenic, frail, or both, respectively. Oxidative stress markers (lower TAC-ROS and higher SOD) were significantly enhanced and aTL significantly shortened in patients with sarcopenia, frailty or both syndromes. No evidence of apoptosis was detected in blood leukocytes of any of the patients. Both oxidative stress markers (GR, p = 0.04) and telomere shortening (p = 0.001) were associated to death risk and to less survival days.<br><br>CONCLUSIONS: Oxidative stress markers and telomere length were enhanced and shortened, respectively, in blood samples of polypathological patients with sarcopenia and/or frailty. Both were associated to decreased survival. They could be useful in the clinical practice to assess vulnerable populations with multimorbidity and of potential interest as therapeutic targets.},
}
@article {pmid32823549,
year = {2020},
author = {Bryan, TM},
title = {G-Quadruplexes at Telomeres: Friend or Foe?.},
journal = {Molecules (Basel, Switzerland)},
volume = {25},
number = {16},
pages = {},
pmid = {32823549},
issn = {1420-3049},
abstract = {Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures.},
}
@article {pmid32821950,
year = {2020},
author = {Hunt, SC and Hansen, MEB and Verhulst, S and McQuillan, MA and Beggs, W and Lai, TP and Mokone, GG and Mpoloka, SW and Meskel, DW and Belay, G and Nyambo, TB and Abnet, CC and Yeager, M and Chanock, SJ and Province, MA and Williams, SM and Aviv, A and Tishkoff, SA},
title = {Genetics and geography of leukocyte telomere length in sub-Saharan Africans.},
journal = {Human molecular genetics},
volume = {29},
number = {18},
pages = {3014-3020},
pmid = {32821950},
issn = {1460-2083},
support = {R35 GM134957/GM/NIGMS NIH HHS/United States ; T32 ES019851/ES/NIEHS NIH HHS/United States ; },
abstract = {Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramifications for LTL-associated diseases.},
}
@article {pmid32814800,
year = {2020},
author = {Ämmälä, AJ and Vitikainen, EIK and Hovatta, I and Paavonen, J and Saarenpää-Heikkilä, O and Kylliäinen, A and Pölkki, P and Porkka-Heiskanen, T and Paunio, T},
title = {Maternal stress or sleep during pregnancy are not reflected on telomere length of newborns.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {13986},
pmid = {32814800},
issn = {2045-2322},
mesh = {Female ; Humans ; Infant, Newborn ; Linear Models ; Male ; Pregnancy ; Pregnancy Complications/*physiopathology ; Prenatal Exposure Delayed Effects/*diagnosis/genetics/physiopathology ; Self Report ; Sleep Wake Disorders/*physiopathology ; Stress, Psychological/*physiopathology ; Surveys and Questionnaires ; Telomere/genetics/metabolism ; Telomere Homeostasis/*genetics ; },
abstract = {Telomeres play an important role in maintaining chromosomal integrity. With each cell division, telomeres are shortened and leukocyte telomere length (LTL) has therefore been considered a marker for biological age. LTL is associated with various lifetime stressors and health-related outcomes. Transgenerational effects have been implicated in newborns, with maternal stress, depression, and anxiety predicting shorter telomere length at birth, possibly reflecting the intrauterine growth environment. Previous studies, with relatively small sample sizes, have reported an effect of maternal stress, BMI, and depression during pregnancy on the LTL of newborns. Here, we attempted to replicate previous findings on prenatal stress and newborn LTL in a sample of 1405 infants using a qPCR-based method. In addition, previous research has been expanded by studying the relationship between maternal sleep quality and LTL. Maternal prenatal stress, anxiety, depression, BMI, and self-reported sleep quality were evaluated with self-reported questionnaires. Despite sufficient power to detect similar or even considerably smaller effects than those previously reported in the literature, we were unable to replicate the previous correlation between maternal stress, anxiety, depression, or sleep with LTL. We discuss several possible reasons for the discrepancies between our findings and those previously described.},
}
@article {pmid32807581,
year = {2020},
author = {Öngel, ME and Yıldız, C and Akpınaroğlu, C and Yilmaz, B and Özilgen, M},
title = {Why women may live longer than men do? A telomere-length regulated and diet-based entropic assessment.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clnu.2020.07.030},
pmid = {32807581},
issn = {1532-1983},
abstract = {BACKGROUND &amp; AIMS: Empirical analyses of the data available around the word concluded that women have longer life span now, when compared to the men. Available literature unfortunately could not offer full answers to this observation. The &quot;entropic age&quot; concept suggests that ageing related changes in the body, such as loss of molecular functions and overwhelming of the maintenance systems, may be explained in terms of entropy generation.<br><br>METHODS: Telomere-length regulated entropic assessment based on metabolic activity with four different diets carried out.<br><br>RESULTS: Estimates of the life expectancy of the women on all of these diets is longer than those of the men. Faster shortening of the telomere lengths in men was the major reason of the shorter life expectancy. The highest and the lowest life expectancy for women were estimated with Mediterranean and the vegetarian diets, respectively; men were estimated to have the longest life span with the vegetarian diet and the shortest life span with the ketogenic diet.<br><br>CONCLUSIONS: A higher rate of metabolism causes higher entropy generation and hints correlations that can be helpful in future ageing research. Faster shortening of the telomere lengths in men was the major reason of the estimation of the shorter life span for men.},
}
@article {pmid32807015,
year = {2020},
author = {Piekna-Przybylska, D and Bambara, RA and Maggirwar, SB and Dewhurst, S},
title = {G-quadruplex ligands targeting telomeres do not inhibit HIV promoter activity and cooperate with latency reversing agents in killing latently infected cells.},
journal = {Cell cycle (Georgetown, Tex.)},
volume = {19},
number = {18},
pages = {2298-2313},
pmid = {32807015},
issn = {1551-4005},
support = {R01 NS066801/NS/NINDS NIH HHS/United States ; R21 AI131961/AI/NIAID NIH HHS/United States ; },
abstract = {Altered telomere maintenance mechanism (TMM) is linked to increased DNA damage at telomeres and telomere uncapping. We previously showed that HIV-1 latent cells have altered TMM and are susceptible to ligands that target G-quadruplexes (G4) at telomeres. Susceptibility of latent cells to telomere targeting could potentially be used to support approaches to eradicate HIV reservoirs. However, G4 ligands also target G-quadruplexes in promoters blocking gene transcription. Since HIV promoter sequence can form G-quadruplexes, we investigated whether G4 ligands interfere with HIV-1 promoter activity and virus reactivation from latency, and whether telomere targeting could be combined with latency reversing agents (LRAs) to promote elimination of HIV reservoirs. Our results indicate that Sp1 binding region in HIV-1 promoter can adopt G4 structures in duplex DNA, and that in vitro binding of Sp1 to G-quadruplex is blocked by G4 ligand, suggesting that agents targeting telomeres interfere with virus reactivation. However, our studies show that G4 agents do not affect HIV-1 promoter activity in cell culture, and do not interfere with latency reversal. Importantly, primary memory CD4 + T cells infected with latent HIV-1 are more susceptible to combined treatment with LRAs and G4 ligands, indicating that drugs targeting TMM may enhance killing of HIV reservoirs. Using a cell-based DNA repair assay, we also found that HIV-1 infected cells have reduced efficiency of DNA mismatch repair (MMR), and base excision repair (BER), suggesting that altered TMM in latently infected cells could be associated with accumulation of DNA damage at telomeres and changes in telomeric caps.},
}
@article {pmid32804988,
year = {2020},
author = {Leisen, T and Bietz, F and Werner, J and Wegner, A and Schaffrath, U and Scheuring, D and Willmund, F and Mosbach, A and Scalliet, G and Hahn, M},
title = {CRISPR/Cas with ribonucleoprotein complexes and transiently selected telomere vectors allows highly efficient marker-free and multiple genome editing in Botrytis cinerea.},
journal = {PLoS pathogens},
volume = {16},
number = {8},
pages = {e1008326},
pmid = {32804988},
issn = {1553-7374},
mesh = {Botrytis/*physiology ; *CRISPR-Cas Systems ; *Gene Editing ; Genetic Vectors/administration &amp; dosage/genetics ; Oryza/genetics/*microbiology ; Plant Diseases/genetics/*microbiology ; Ribonucleoproteins/*antagonists &amp; inhibitors/genetics ; Telomere/*genetics ; },
abstract = {CRISPR/Cas has become the state-of-the-art technology for genetic manipulation in diverse organisms, enabling targeted genetic changes to be performed with unprecedented efficiency. Here we report on the first establishment of robust CRISPR/Cas editing in the important necrotrophic plant pathogen Botrytis cinerea based on the introduction of optimized Cas9-sgRNA ribonucleoprotein complexes (RNPs) into protoplasts. Editing yields were further improved by development of a novel strategy that combines RNP delivery with cotransformation of transiently stable vectors containing telomeres, which allowed temporary selection and convenient screening for marker-free editing events. We demonstrate that this approach provides superior editing rates compared to existing CRISPR/Cas-based methods in filamentous fungi, including the model plant pathogen Magnaporthe oryzae. Genome sequencing of edited strains revealed very few additional mutations and no evidence for RNP-mediated off-targeting. The high performance of telomere vector-mediated editing was demonstrated by random mutagenesis of codon 272 of the sdhB gene, a major determinant of resistance to succinate dehydrogenase inhibitor (SDHI) fungicides by in bulk replacement of the codon 272 with codons encoding all 20 amino acids. All exchanges were found at similar frequencies in the absence of selection but SDHI selection allowed the identification of novel amino acid substitutions which conferred differential resistance levels towards different SDHI fungicides. The increased efficiency and easy handling of RNP-based cotransformation is expected to accelerate molecular research in B. cinerea and other fungi.},
}
@article {pmid32804179,
year = {2020},
author = {Yamaguchi, I and Ooe, R and Wang, A},
title = {Water-soluble oligofluorenes bearing N1-alkylcytosine side chains as turn-on and turn-off materials in telomere DNA length sensing.},
journal = {Chemical communications (Cambridge, England)},
volume = {56},
number = {74},
pages = {10914-10917},
doi = {10.1039/d0cc05153e},
pmid = {32804179},
issn = {1364-548X},
abstract = {Water-soluble cationic and anionic oligofluorenes bearing N1-alkylcytosine side chains, namely OF-1 and OF-2, were synthesized. The photoluminescence (PL) intensity of an aqueous solution of OF-1 decreased on the addition of (TTAGGG)m as telomere DNA models. In contrast, the PL intensity of OF-2 increased on the addition of DNA.},
}
@article {pmid32799224,
year = {2020},
author = {Koroleva, AG and Evtushenko, EV and Vershinin, AV and Zaytseva, EP and Timoshkin, OA and Kirilchik, SV},
title = {[Age Dynamics of Telomere Length in Endemic Baikal Planarians].},
journal = {Molekuliarnaia biologiia},
volume = {54},
number = {4},
pages = {616-625},
doi = {10.31857/S0026898420040072},
pmid = {32799224},
issn = {0026-8984},
mesh = {Animals ; Lakes ; Phylogeny ; *Planarians/genetics/physiology ; Russia ; Species Specificity ; *Telomerase/metabolism ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {Age-related changes in telomere length (TL) in somatic tissues are not limited only to shortening. It is known that many organisms show different TL dynamics. Such species specificity indicates the complexity of the mechanisms involved in the regulation of TL. Owing to their morphological, physiological, and ecological features, Baikal planarians are an interesting model for studying the TL dynamics and the factors influencing it in comparison with species living outside Baikal. In this work, we investigated telomerase activity and age-related changes in TL in three endemic species of planarians from the Dendrocoelidae family. Two species are giant deep-water species (7-12 cm long, Sorocelis hepatizon and Rimacephalus arecepta), and one is a coastal shallow species (1 cm long, Baikalobia guttata). In addition, we investigated the telomere biology in another small Siberian species from the Planariidae family (2 cm in length, Phagocata sibirica), which is not found in Baikal. TL and telomerase activity were determined using real-time PCR and the TRAP method. Three types of age-related TL dynamics were detected with active telomerase: (1) TL shortening at the juvenile stage of development and subsequent maintenance (R. arecepta, Ph. sibirica), (2) gradual TL shortening during ontogeny (S. hepatizon) and (3) cyclic dynamics of TL (B. guttata). Thus, the changes of TL in the studied planarians does not have an obvious connection with body size, habitat depth, phylogenetic relationship and is probably a consequence of species features in the regulation of telomerase activity.},
}
@article {pmid32792056,
year = {2020},
author = {Huang, Z and Zhao, X and Zhang, H and Liang, G and Qi, H and He, X and Zhu, C and Ge, S and Zhang, J},
title = {The association between mitochondrial DNA copy number, telomere length, and tubal pregnancy.},
journal = {Placenta},
volume = {97},
number = {},
pages = {108-114},
doi = {10.1016/j.placenta.2020.06.017},
pmid = {32792056},
issn = {1532-3102},
abstract = {Growing evidence has demonstrated association between the occurrence of tubal ectopic pregnancy (TP) and oxidative stress (OS) status, in which mitochondria and telomeres play important roles. However, little is known about the underlying correlation between TP and the mitochondrial DNA copy number (mtDNAcn) or telomere length (TL) abnormalities. In this study, we found OS level was elevated in TP patients. We hierarchically detected the relative mtDNAcn and TL of villi from normal pregnancy (NP) and TP samples according to different gestational age, fetal sex, maternal age, and BMI. The results revealed that the relative mtDNAcn was significantly lower in the villi in the TP group compared with the NP cohort, which was negatively correlated with OS status. In the NP group, the mtDNAcn in the female subgroup was apparently lower than that in the male subgroup, while no statistical difference was found in the mtDNAcn in the TP group between the female and male subgroups. Moreover, the relative TL in the TP group was at a similar level to the NP group, and no statistical correlation was observed between relative TL and OS level. In summary, our findings indicate that the abnormal level of mtDNAcn rather than TL is correlated with TP, which provides new insights into the mechanism of TP.},
}
@article {pmid32792055,
year = {2020},
author = {Kohlrausch, FB and Keefe, DL},
title = {Telomere erosion as a placental clock: From placental pathologies to adverse pregnancy outcomes.},
journal = {Placenta},
volume = {97},
number = {},
pages = {101-107},
doi = {10.1016/j.placenta.2020.06.022},
pmid = {32792055},
issn = {1532-3102},
abstract = {The placenta provides nutritional and gas exchange between fetus and mother. Early in pregnancy, placental trophoblasts proliferate rapidly and invade aggressively. As pregnancy progresses, placental cells begin to age. Indeed, pregnancy itself has a tightly regulated duration, determined in large part by placental lifespan. Late in pregnancy, placental cells reach a senescent apoptotic state, activated by a number of intrinsic and extrinsic factors, including oxidative stress (OS), and DNA damage. Pregnancy complications, stillbirths and neonatal deaths have been related to OS and abnormal placental aging. Telomeres, the protective nucleoprotein structures at the ends of linear chromosomes, shorten both from cell replication and from exposure to OS. When telomeres become critically short they trigger cell cycle arrest and eventually cell death. Telomere attrition thus provide an intrinsic mechanism to explain tissue senescence and aging. Mounting evidence suggests that senescence of placental and fetal membrane cells results from telomere attrition. We review the studies that have addressed the role of telomere length (TL) in placentas from normal and complicated pregnancies, including pre-eclampsia, intrauterine growth restriction, gestational diabetes, and stillbirth. To date studies have uncovered associations between TL and a number of obstetrical complications. Future research is needed to determine whether these associations are causative, i.e. whether these clinical conditions result from telomere dysfunction, and whether particular features of telomeres, e.g. mean or shortest length, etc. could serve as clinically useful biomarkers of placental health.},
}
@article {pmid32784588,
year = {2020},
author = {Sung, JY and Lim, HW and Joung, JG and Park, WY},
title = {Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity.},
journal = {Cancers},
volume = {12},
number = {8},
pages = {},
pmid = {32784588},
issn = {2072-6694},
support = {NRF-2018R1D1A1B07048531//Ministry of Science and ICT, South Korea/ ; },
abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.},
}
@article {pmid32781627,
year = {2020},
author = {Sharma, R and Martins, N},
title = {Telomeres, DNA Damage and Ageing: Potential Leads from Ayurvedic Rasayana (Anti-Ageing) Drugs.},
journal = {Journal of clinical medicine},
volume = {9},
number = {8},
pages = {},
pmid = {32781627},
issn = {2077-0383},
abstract = {Ageing, while a relentless, unidirectional and pleiotropic phenomenon of life, is a key trigger for several age-related disorders, such as cancer, cataract, osteoporosis, hypertension, cardiovascular (CV), metabolic and even neurodegenerative ailments, including Alzheimer's (AD) and Parkinson's (PD) disease [1] [...].},
}
@article {pmid32781553,
year = {2020},
author = {Herrmann, W and Herrmann, M},
title = {The Importance of Telomere Shortening for Atherosclerosis and Mortality.},
journal = {Journal of cardiovascular development and disease},
volume = {7},
number = {3},
pages = {},
pmid = {32781553},
issn = {2308-3425},
abstract = {Telomeres are the protective end caps of chromosomes and shorten with every cell division. Short telomeres are associated with older age and adverse lifestyle factors. Leucocyte telomere length (LTL) has been proposed as a biomarker of biological age. The shortening of LTL with age is the result of the end-replication problem, environmental, and lifestyle-related factors. Epidemiologic studies have shown that LTL predicts cardiovascular disease, all-cause mortality, and death from vascular causes. Age appears to be an important co-variate that explains a substantial fraction of this effect. Although it has been proposed that short telomeres promote atherosclerosis and impair the repair of vascular lesions, existing results are inconsistent. Oxidative stress and chronic inflammation can both accelerate telomere shortening. Multiple factors, including homocysteine (HCY), vitamin B6, and vitamin B12 modulate oxidative stress and inflammation through direct and indirect mechanisms. This review provides a compact overview of telomere physiology and the utility of LTL measurements in atherosclerosis and cardiovascular disease. In addition, it summarizes existing knowledge regarding the impact of oxidative stress, inflammation, HCY, and B-vitamins on telomere function.},
}
@article {pmid32777275,
year = {2020},
author = {Cowell, W and Colicino, E and Tanner, E and Amarasiriwardena, C and Andra, SS and Bollati, V and Kannan, S and Ganguri, H and Gennings, C and Wright, RO and Wright, RJ},
title = {Prenatal toxic metal mixture exposure and newborn telomere length: Modification by maternal antioxidant intake.},
journal = {Environmental research},
volume = {190},
number = {},
pages = {110009},
pmid = {32777275},
issn = {1096-0953},
support = {R01 HD082078/HD/NICHD NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R21 ES021318/ES/NIEHS NIH HHS/United States ; UG3 OD023337/OD/NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; R01 ES030302/ES/NIEHS NIH HHS/United States ; T32 HD049311/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; *Antioxidants ; Boston ; Female ; Humans ; Infant, Newborn ; Maternal Exposure/adverse effects ; New York City ; Pregnancy ; *Telomere ; },
abstract = {BACKGROUND: Telomere length (TL) predicts the onset of cellular senescence and correlates with longevity and age-related disease risk. While telomeres erode throughout life, adults display fixed ranking and tracking of TL, supporting the importance of the early environment in determining inter-individual variability across the life course. Given their guanine-rich structure, telomeres are highly susceptible to oxidative stress (OS). We examined maternal metal exposure, which can induce OS, in relation to newborn TL. We also considered the modifying role of maternal antioxidant intake.<br><br>METHODS: Analyses included 100 mother-newborn pairs enrolled in the Boston and New York City-based PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured As, Ba, Cd, Ni, and Pb in maternal late-pregnancy urine by ICP-MS and quantified relative leukocyte TL (rLTL) in cord blood using qPCR. We used Weighted Quantile Sum (WQS) regression to estimate the metal mixture - rLTL association and conducted repeated holdout validation to improve the stability of estimates across data partitions. We examined models stratified by high (>median) versus low (≤median) maternal antioxidant intake, estimated from Block98 Food Frequency Questionnaires. We considered urinary creatinine, week of urine collection, maternal age, and race/ethnicity as covariates.<br><br>RESULTS: In adjusted models, urinary metals were inversely associated with newborn rLTL (βWQS = -0.50, 95% CI: -0.78, -0.21). The top metals contributing to the negative association included Ba (weight: 35.4%), Cd (24.5%) and Pb (26.9%). In models stratified by antioxidant intake, the significant inverse association between metals and rLTL remained only among mothers with low antioxidant intake (low: βWQS = -0.92, 95% CI: -1.53, -0.30; high: βWQS = -0.03, 95% CI: -0.58, 0.52). Results were similar in unadjusted models.<br><br>CONCLUSIONS: Relative LTL was shorter among newborns of mothers with higher exposure to metals during pregnancy. Higher maternal antioxidant intake may mitigate the negative influence of metals on newborn rLTL.},
}
@article {pmid32776370,
year = {2020},
author = {Liu, J and Hong, X and Liang, CY and Liu, JP},
title = {Simultaneous visualisation of the complete sets of telomeres from the MmeI generated terminal restriction fragments in yeasts.},
journal = {Yeast (Chichester, England)},
volume = {37},
number = {11},
pages = {585-595},
doi = {10.1002/yea.3517},
pmid = {32776370},
issn = {1097-0061},
support = {31501110//National Natural Science Foundation of China/ ; 81530039//National Natural Science Foundation of China/ ; 91649205//National Natural Science Foundation of China/ ; 91949207//National Natural Science Foundation of China/ ; 2018YFC2000100//National Key Research and Development Program of China/ ; 2018QDL010//Start-up Research Program of Hangzhou Normal University/ ; 2014M551470//China Postdoctoral Science Foundation/ ; 2014KIP305//Postdoctoral Research Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/ ; },
abstract = {Telomere length is measured using Southern blotting of the chromosomal terminal restriction fragments (TRFs) released by endonuclease digestion in cells from yeast to human. In the budding yeast Saccharomyces cerevisiae, XhoI or PstI is applied to cut the subtelomere Y' element and release TRFs from the 17 subtelomeres. However, telomeres from other 15 X-element-only subtelomeres are omitted from analysis. Here, we report a method for measuring all 32 telomeres in S. cerevisiae using the endonuclease MmeI. Based on analyses of the endonuclease cleavage sites, we found that the TRFs generated by MmeI displayed two distinguishable bands in the sizes of ~500 and ~700 bp comprising telomeres (300 bp) and subtelomeres (200-400 bp). The modified MmeI-restricted TRF (mTRF) method recapitulated telomere shortening and lengthening caused by deficiencies of YKu and Rif1 respectively in S. cerevisiae. Furthermore, we found that mTRF was also applicable to telomere length analysis in S. paradoxus strains. These results demonstrate a useful tool for simultaneous detection of telomeres from all chromosomal ends with both X-element-only and Y'-element subtelomeres in S. cerevisiae species.},
}
@article {pmid32774788,
year = {2020},
author = {Aramburu, T and Plucinsky, S and Skordalakes, E},
title = {POT1-TPP1 telomere length regulation and disease.},
journal = {Computational and structural biotechnology journal},
volume = {18},
number = {},
pages = {1939-1946},
pmid = {32774788},
issn = {2001-0370},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; },
abstract = {Telomeres are DNA repeats at the ends of linear chromosomes and are replicated by telomerase, a ribonucleoprotein reverse transcriptase. Telomere length regulation and chromosome end capping are essential for genome stability and are mediated primarily by the shelterin and CST complexes. POT1-TPP1, a subunit of shelterin, binds the telomeric overhang, suppresses ATR-dependent DNA damage response, and recruits telomerase to telomeres for DNA replication. POT1 localization to telomeres and chromosome end protection requires its interaction with TPP1. Therefore, the POT1-TPP1 complex is critical to telomere maintenance and full telomerase processivity. The aim of this mini-review is to summarize recent POT1-TPP1 structural studies and discuss how the complex contributes to telomere length regulation. In addition, we review how disruption of POT1-TPP1 function leads to human disease.},
}
@article {pmid32768567,
year = {2020},
author = {Utyro, O and Perła-Kaján, J and Kubalska, J and Graban, A and Jakubowski, H},
title = {Telomere length and mtDNA copy number in human cystathionine β-synthase deficiency.},
journal = {Free radical biology &amp; medicine},
volume = {160},
number = {},
pages = {219-226},
doi = {10.1016/j.freeradbiomed.2020.07.036},
pmid = {32768567},
issn = {1873-4596},
abstract = {Telomere shortening and mitochondrial DNA (mtDNA) copy number are associated with human disease and a reduced life span. Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step in metabolic conversion of homocysteine (Hcy) to cysteine. Mutations in the CBS gene cause CBS deficiency, a rare recessive metabolic disease, manifested by severe hyperhomocysteinemia (HHcy) and thromboembolism, which ultimately reduces the life span. However, it was not known whether telomere shortening or mtDNA is involved in the pathology of human CBS deficiency. We quantified leukocyte telomere length (TL), mtDNA copy number, and plasma Hcy levels in CBS-/- patients (n = 23) and in sex- and age-matched unaffected CBS+/+ control individuals (n = 28) 0.08-57 years old. We found that TL was significantly increased in severely HHcy CBS-/- female patients but unaffected in severely HHcy CBS-/- male patients, relative to the corresponding CBS+/+ controls who had normal plasma Hcy levels. In multiple regression analysis TL was associated with CBS genotype in women but not in men. MtDNA copy number was not significantly affected by the CBS-/- genotype. Taken together, these findings identify the CBS gene as a new locus in human DNA that affects TL in women and illustrate a concept that a housekeeping metabolic gene can be involved in telomere biology. Our findings suggest that neither telomere shortening nor reduced mtDNA copy number contribute to the reduced life span in CBS-/- patients.},
}
@article {pmid32767207,
year = {2020},
author = {Lopes, AC and Oliveira, PF and Pinto, S and Almeida, C and Pinho, MJ and Sá, R and Rocha, E and Barros, A and Sousa, M},
title = {Discordance between human sperm quality and telomere length following differential gradient separation/swim-up.},
journal = {Journal of assisted reproduction and genetics},
volume = {37},
number = {10},
pages = {2581-2603},
pmid = {32767207},
issn = {1573-7330},
abstract = {BACKGROUND: Strong evidence has suggested an important role of telomeres in meiosis, fertilization, and embryo development.<br><br>PURPOSE: To determine if sperm telomere length (STL) in sperm purified by differential gradient centrifugation followed by swim-up (selected STL) is correlated with sperm quality and clinical outcomes.<br><br>METHODS: Relative selected STL was assessed by quantitative polymerase chain reaction (Q-PCR) in 78 consecutive assisted reproductive technology (ART) treatments during 2017. Statistical analyses were performed in the totality of patients, and in normozoospermic and non-normozoospermic patients. These included correlations between selected STL and sperm quality parameters, embryological parameters (multivariable linear regression), and clinical parameters (multivariable logistic regression).<br><br>RESULTS: No significant correlations were found between selected STL and sperm quality in the total population. However, selected STL was significantly correlated with total sperm count (r = 0.361; P = 0.039) and sperm DNA fragmentation-post-acrosomal region pattern (r = - 0.464; P = 0.030) in normozoospermic patients. No relation was observed between selected STL and clinical outcomes in any clinical group.<br><br>CONCLUSIONS: As the correlations observed in normozoospermic patients were not representative of the whole heterogeneous population, differences in the sperm characteristics of the study population may lead to discrepant results when evaluating the association of STL with sperm quality. Since the total population selected STL was not related with sperm quality and with clinical outcomes, results do not support the use of selected STL measurement to evaluate the reproductive potential of the male patient or to predict the success rates of ART treatments.},
}
@article {pmid32766884,
year = {2020},
author = {Ajaykumar, A and Wong, GC and Yindom, LM and McHugh, G and Dauya, E and Majonga, E and Mujuru, H and Ferrand, RA and Rowland-Jones, SL and Côté, HCF},
title = {Shorter granulocyte telomeres among children and adolescents with perinatally-acquired HIV infection and chronic lung disease in Zimbabwe.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {},
number = {},
pages = {},
doi = {10.1093/cid/ciaa1134},
pmid = {32766884},
issn = {1537-6591},
abstract = {BACKGROUND: Chronic lung disease (CLD) has been reported among African children with perinatally-acquired HIV infection (C-PHIV), despite combination antiretroviral therapy (cART). In adults, shorter telomere length (TL) has been reported in association with both CLD and HIV. As little is known in children, our objective was to compare TL in HIV+ (cART-naïve or treated) and HIV-negative children with and without CLD.<br><br>METHODS: Participants included Zimbabwean C-PHIV, aged 6-16, who were either newly diagnosed and cART-naïve, or on cART for >6 months, and HIV-negative controls of similar age and sex. Packed blood cell (granulocyte) TL from 621 children were compared cross-sectionally between groups. For a subset of newly diagnosed C-PHIV, changes in TL following cART initiation was evaluated.<br><br>RESULTS: C-PHIV had shorter granulocyte TL compared to uninfected peers, regardless of cART. Among 255 C-PHIV without CLD, TL was shorter in cART-naïve participants. In multivariable analyses adjusted for age, sex, CLD, and HIV/cART status, shorter TL was independently associated with older age, being HIV+, and having reduced forced vital capacity (FVC). Lastly, cART initiation increased TL.<br><br>CONCLUSIONS: In this cohort, C-PHIV and those with reduced FVC have shorter granulocyte TL, possibly the result of increased immune activation and cellular turnover due to long-standing HIV infection with delayed cART initiation.},
}
@article {pmid32765866,
year = {2020},
author = {Manoy, P and Yuktanandana, P and Tanavalee, A and Tanpowpong, T and Ittipanichpong, T and Honsawek, S},
title = {Telomere shortening is associated with poor physical performance in knee osteoarthritis.},
journal = {Biomedical reports},
volume = {13},
number = {4},
pages = {27},
pmid = {32765866},
issn = {2049-9434},
abstract = {Telomere length is a hallmark characteristic of ageing and age-related diseases. Osteoarthritis (OA) is the most common cause of joint pain and physical disability in the elderly. Previous studies have revealed the role of telomere shortening in OA; however, the relationship between telomere length, muscle strength and physical performance in knee OA patients remains unknown. The aim of the present study was to investigate the association of telomere length and physical performance in patients with knee OA. A total of 202 patients with knee OA and 60 healthy controls were enrolled in the study. The quality of life was assessed using Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and Short Form Health Survey. The skeletal muscle mass was examined using bioelectrical impedance analysis, while the muscle strength was analyzed using hand grip force and isometric knee extension force. The physical performance of patients with knee OA was also investigated using gait speed, Timed up and go test (TUGT), Sit to stand test and 6-min walk test (6MWT). Blood leukocyte relative telomere length (RTL) was assessed using real time quantitative PCR. The mean blood leukocyte RTL in knee OA subjects was significantly lower compared with healthy controls (P<0.001). Knee OA patients with RTL values in the lowest quartile had a slow gait speed (P=0.006) and prolonged TUGT time (P=0.03). Multivariate regression analyses and multiple logistic regression analyses adjusted for age, sex, waist circumference, body mass index, fat mass, skeletal muscle index and the total WOMAC demonstrated that gait speed, TUGT and 6MWT were associated with longer RTL (P-trend<0.05). These findings suggested that poorer physical performance was associated with shorter RTL. Therefore, leukocyte telomere length and physical performance tests, especially gait speed, TUGT and 6MWT, could predict the health status and quality of life in patients with knee OA.},
}
@article {pmid32763773,
year = {2020},
author = {Miri, M and de Prado-Bert, P and Alahabadi, A and Najafi, ML and Rad, A and Moslem, A and Aval, HE and Ehrampoush, MH and Bustamante, M and Zare Sakhvidi, MJ and Nawrot, T and Sunyer, J and Dadvand, P},
title = {Association of greenspace exposure with telomere length in preschool children.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {266},
number = {Pt 1},
pages = {115228},
doi = {10.1016/j.envpol.2020.115228},
pmid = {32763773},
issn = {1873-6424},
mesh = {Aging ; Child ; Child, Preschool ; *Environment ; Humans ; Iran ; Leukocytes ; *Telomere ; },
abstract = {Exposure to greenspace has been associated with a wide range of health benefits; however, the available evidence on the association of this exposure with telomere length (TL), an early marker of ageing, is still scarce. We investigated the association of greenspace exposure with TL in a sample of 200 preschool children (aged 5-7 years) residing in Sabzevar, Iran (2017). We comprehensively characterized different aspects of greenspace exposure encompassing residential, kindergarten, and total (including both residential and kindergarten) surrounding greenspace (using satellite-derived Normalized Difference Vegetation Index), residential and kindergarten distance to green spaces, time spent in private gardens and public green spaces, and the number of plant pots at home. Relative leukocyte TL (LTL) in blood samples of the study participants was measured using quantitative polymerase chain reaction (qPCR). We applied mixed effects linear regression models with kindergarten and qPCR plate as random effects, to estimate the association of indicators of greenspace exposure (one at a time) with LTL, controlled for relevant covariates. We observed an inverse association between distance from home and kindergarten to green spaces larger than 5000 m2 and LTL. Moreover, higher total surrounding greenspace at 300m and 500m buffers and higher surrounding greenspace at 300m buffer around kindergarten and home were associated with longer LTL. Furthermore, longer time spent (h/week) in the public green spaces was associated with longer LTL. Our findings for residential and kindergarten distance to any green space (regardless of the size), residential surrounding greenspace at 100m and 500m buffers, kindergarten surrounding greenspace at 100m buffer, time spent in private gardens (h/week) and the number of plant pots at home were not conclusive. Our findings were generally suggestive for a positive association between greenspace exposure and LTL in preschool children. More studies are needed to confirm these findings in other settings with different climates and populations.},
}
@article {pmid32762107,
year = {2021},
author = {Hudon, SF and Palencia Hurtado, E and Beck, JD and Burden, SJ and Bendixsen, DP and Callery, KR and Sorensen Forbey, J and Waits, LP and Miller, RA and Nielsen, ÓK and Heath, JA and Hayden, EJ},
title = {Primers to highly conserved elements optimized for qPCR-based telomere length measurement in vertebrates.},
journal = {Molecular ecology resources},
volume = {21},
number = {1},
pages = {59-67},
doi = {10.1111/1755-0998.13238},
pmid = {32762107},
issn = {1755-0998},
support = {2018-SB-2842//Semiconductor Research Corporation/ ; 1145552//National Science Foundation/ ; 1263167//National Science Foundation/ ; 1807809//National Science Foundation/ ; 1826801//National Science Foundation/ ; 80NSSC17K0738/NASA/NASA/United States ; 80NSSC17K0738/NASA/NASA/United States ; },
abstract = {Telomere length dynamics are an established biomarker of health and ageing in animals. The study of telomeres in numerous species has been facilitated by methods to measure telomere length by real-time quantitative PCR (qPCR). In this method, telomere length is determined by quantifying the amount of telomeric DNA repeats in a sample and normalizing this to the total amount of genomic DNA. This normalization requires the development of genomic reference primers suitable for qPCR, which remains challenging in nonmodel organism with genomes that have not been sequenced. Here we report reference primers that can be used in qPCR to measure telomere lengths in any vertebrate species. We designed primer pairs to amplify genetic elements that are highly conserved between evolutionarily distant taxa and tested them in species that span the vertebrate tree of life. We report five primer pairs that meet the specificity and reproducibility standards of qPCR. In addition, we demonstrate an approach to choose the best primers for a given species by testing the primers on multiple individuals within a species and then applying an established computational tool. These reference primers can facilitate qPCR-based telomere length measurements in any vertebrate species of ecological or economic interest.},
}
@article {pmid32761187,
year = {2021},
author = {Yeap, BB and Hui, J and Knuiman, MW and Flicker, L and Divitini, ML and Arscott, GM and Twigg, SM and Almeida, OP and Hankey, GJ and Golledge, J and Norman, PE and Beilby, JP},
title = {U-Shaped Relationship of Leukocyte Telomere Length With All-Cause and Cancer-Related Mortality in Older Men.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {76},
number = {1},
pages = {164-171},
doi = {10.1093/gerona/glaa190},
pmid = {32761187},
issn = {1758-535X},
abstract = {BACKGROUND: Telomeres are essential DNA-protein complexes whose attrition results in cellular dysfunction and senescence. Leukocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However, its predictive value for mortality risk, and for cardiovascular versus cancer deaths, in older adults remains uncertain.<br><br>METHOD: We studied 3608 community-dwelling men aged 77.0 ± 3.6 years. Leukocyte telomere length was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD), and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors, and prevalent disease.<br><br>RESULTS: There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.77-0.97, p = .012; Q3 vs Q1 HR = 0.88, CI 0.79-0.99, p = .032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR = 0.73, CI 0.59-0.90, p = .004; Q3 vs Q1, HR = 0.75, CI 0.61-0.92, p = .007).<br><br>CONCLUSIONS: In older men, both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.},
}
@article {pmid32760251,
year = {2020},
author = {Levstek, T and Kozjek, E and Dolžan, V and Trebušak Podkrajšek, K},
title = {Telomere Attrition in Neurodegenerative Disorders.},
journal = {Frontiers in cellular neuroscience},
volume = {14},
number = {},
pages = {219},
pmid = {32760251},
issn = {1662-5102},
abstract = {Telomere attrition is increased in various disorders and is therefore a potential biomarker for diagnosis and/or prognosis of these disorders. The contribution of telomere attrition in the pathogenesis of neurodegenerative disorders is yet to be fully elucidated. We are reviewing the current knowledge regarding the telomere biology in two common neurodegenerative disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). Furthermore, we are discussing future prospective of telomere research in these disorders. The majority of studies reported consistent evidence of the accelerated telomere attrition in AD patients, possibly in association with elevated oxidative stress levels. On the other hand in PD, various studies reported contradictory evidence regarding telomere attrition. Consequently, due to the low specificity and sensitivity, the clinical benefit of telomere length as a biomarker of neurodegenerative disease development and progression is not yet recognized. Nevertheless, longitudinal studies in large carefully selected cohorts might provide further elucidation of the complex involvement of the telomeres in the pathogenesis of neurodegenerative diseases. Telomere length maintenance is a complex process characterized by environmental, genetic, and epigenetic determinants. Thus, in addition to the selection of the study cohort, also the selection of analytical methods and types of biological samples for evaluation of the telomere attrition is of utmost importance.},
}
@article {pmid32755577,
year = {2020},
author = {Segura-Bayona, S and Villamor-Payà, M and Attolini, CS and Koenig, LM and Sanchiz-Calvo, M and Boulton, SJ and Stracker, TH},
title = {Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres.},
journal = {Cell reports},
volume = {32},
number = {5},
pages = {107983},
pmid = {32755577},
issn = {2211-1247},
support = {/WT_/Wellcome Trust/United Kingdom ; FC0010048/CRUK_/Cancer Research UK/United Kingdom ; FC0010048/MRC_/Medical Research Council/United Kingdom ; FC0010048/WT_/Wellcome Trust/United Kingdom ; },
abstract = {The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone and influence cell cycle progression and genome maintenance, yet the mechanisms underlying TLK-mediated genome stability remain uncertain. Here, we show that TLK loss results in severe chromatin decompaction and altered genome accessibility, particularly affecting heterochromatic regions. Failure to maintain heterochromatin increases spurious transcription of repetitive elements and induces features of alternative lengthening of telomeres (ALT). TLK depletion culminates in a cGAS-STING-TBK1-mediated innate immune response that is independent of replication-stress signaling and attenuated by the depletion of factors required to produce extra-telomeric DNA. Analysis of human cancers reveals that chromosomal instability correlates with high TLK2 and low STING levels in many cohorts. Based on these findings, we propose that high TLK levels contribute to immune evasion in chromosomally unstable and ALT+ cancers.},
}
@article {pmid32748415,
year = {2021},
author = {Fang, B and Yan, E and Tung, K and Liu, Z and Ip, P},
title = {Association between elder abuse and telomere shortening in older adults: A 2-year prospective study.},
journal = {International journal of geriatric psychiatry},
volume = {36},
number = {1},
pages = {54-63},
doi = {10.1002/gps.5390},
pmid = {32748415},
issn = {1099-1166},
abstract = {BACKGROUNDS: Elder abuse is a public health issue associated with increased morbidity and mortality. Its impact on victims' health at the cellular level, however, remains unknown. This study assessed the association between abuse exposure and shortening of telomere length (TL), a promising molecular marker for biological aging, in older victims.<br><br>SETTING: The geriatric departments of three Grade-A hospitals in the People's Republic of China (PRC).<br><br>PARTICIPANTS: Six hundred Chinese older adults, including 300 abused victims and 300 non-abused controls were randomly drawn respectively from a larger sample of 467 abused and 518 non-abused older adults recruited at baseline. Participants were assessed for physical and psychological abuse exposure at baseline between September 2015 and February 2016 and assessed for TL 2 years after the abuse assessment.<br><br>MEASUREMENTS: TL was quantified using a quantitative PCR method and expressed as T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Physical and psychological abuse was measured using the Revised Conflicts Tactics Scale.<br><br>RESULTS: Adjusting for demographic, medical, and behavioral confounders, physical and psychological abuse exposure at baseline were independently associated with shorter TL at follow-up. The association was the most significant between multiple forms of abuse (physical and psychological) exposure and shorter TL.<br><br>CONCLUSION: This study provides the first evidence on the relationship between abuse and shortened TL in older victims, implying the potential effect of elder abuse on accelerated cellular aging. The findings suggest the importance of routinely assessing and intervening abuse in older adults by healthcare professionals, to promote and maintain physical health in older adults.},
}
@article {pmid32745307,
year = {2020},
author = {Seeker, LA},
title = {Telomere shortening correlates with harsh weather conditions in the bat species Myotis myotis.},
journal = {Molecular ecology},
volume = {29},
number = {16},
pages = {2951-2953},
doi = {10.1111/mec.15580},
pmid = {32745307},
issn = {1365-294X},
mesh = {Animals ; Cellular Senescence ; *Chiroptera/genetics ; Humans ; Telomere/genetics ; *Telomere Shortening ; Weather ; },
abstract = {The relationship of telomere shortening and cellular ageing in cultured cells such as fibroblasts is straightforward: telomeres shorten with an increasing number of cell divisions until they trigger replicative senescence which prevents further mitotic cycles. But studies investigating the relationship between telomere shortening and ageing in whole organisms show contrasting results: while there is a clear decline in telomere length (TL) with chronological age in some species such as humans, no such decline is observed in others. In this issue of Molecular Ecology, Foley et al. (2020) show that experiencing harsh weather conditions correlates with longitudinal telomere shortening in the bat species Myotis myotis, whereas chronological age does not (Foley et al., 2020). Further, the authors investigated whether genetics influence TL and find a low heritability (h2 = 0.01-0.06) again suggesting that environmental effects are the dominant drivers of variation in TL in this species. These are important findings as there is disagreement in the literature about the relative magnitude of genetic and environmental effects contributing to TL variation in different species. This paper investigating the impact of environmental effects makes a novel and important contribution to the literature on TL in free-living mammals.},
}
@article {pmid32744739,
year = {2020},
author = {Kirschner, M and Vieri, M and Kricheldorf, K and Ferreira, MSV and Wlodarski, MW and Schwarz, M and Balabanov, S and Rolles, B and Isfort, S and Koschmieder, S and Höchsmann, B and Panse, J and Brümmendorf, TH and Beier, F},
title = {Androgen derivatives improve blood counts and elongate telomere length in adult cryptic dyskeratosis congenita.},
journal = {British journal of haematology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bjh.16997},
pmid = {32744739},
issn = {1365-2141},
abstract = {Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome-related mutations. Seven TERC or TERT-mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS-related mutations were detected. Pending longer follow-up, treatment with AD seems to represent an efficient and safe therapy for DKC patients.},
}
@article {pmid32742684,
year = {2020},
author = {Olsson, M and Geraghty, NJ and Wapstra, E and Wilson, M},
title = {Telomere length varies substantially between blood cell types in a reptile.},
journal = {Royal Society open science},
volume = {7},
number = {6},
pages = {192136},
pmid = {32742684},
issn = {2054-5703},
abstract = {Telomeres are repeat sequences of non-coding DNA-protein molecules that cap or intersperse metazoan chromosomes. Interest in telomeres has increased exponentially in recent years, to now include their ongoing dynamics and evolution within natural populations where individuals vary in telomere attributes. Phylogenetic analyses show profound differences in telomere length across non-model taxa. However, telomeres may also differ in length within individuals and between tissues. The latter becomes a potential source of error when researchers use different tissues for extracting DNA for telomere analysis and scientific inference. A commonly used tissue type for assessing telomere length is blood, a tissue that itself varies in terms of nuclear content among taxa, in particular to what degree their thrombocytes and red blood cells (RBCs) contain nuclei or not. Specifically, when RBCs lack nuclei, leucocytes become the main source of telomeric DNA. RBCs and leucocytes differ in lifespan and how long they have been exposed to 'senescence' and erosion effects. We report on a study in which cells in whole blood from individual Australian painted dragon lizards (Ctenophorus pictus) were identified using flow cytometry and their telomere length simultaneously measured. Lymphocyte telomeres were on average 270% longer than RBC telomeres, and in azurophils (a reptilian monocyte), telomeres were more than 388% longer than those in RBCs. If this variation in telomere length among different blood cell types is a widespread phenomenon, and DNA for comparative telomere analyses are sourced from whole blood, evolutionary inference of telomere traits among taxa may be seriously complicated by the blood cell type comprising the main source of DNA.},
}
@article {pmid32742450,
year = {2020},
author = {Li, Z and Song, Y and Xu, Y and Shen, Y and Zhang, N and Yang, M and Yu, D},
title = {Identification of Leukocyte telomere length-related genetic variants contributing to predisposition of Esophageal Squamous Cell Carcinoma.},
journal = {Journal of Cancer},
volume = {11},
number = {17},
pages = {5025-5031},
pmid = {32742450},
issn = {1837-9664},
abstract = {Background: Cancers may arise from cells with dysregulated telomeric functions due to shorten telomere length. We and others previously found that short leukocyte telomere length was associated with markedly evaluated risk of esophageal squamous cell carcinoma (ESCC). Hence, we hypothesized that single nucleotide polymorphisms (SNPs) associated with shorter telomere length may contribute to ESCC predisposition. Methods: We systematically evaluated association between seven candidate seven SNPs (CXCR4 rs6430612, TERT rs13172201, TERT rs10069690, TERT rs2853676, TERT rs451360, OBFC1 rs4387287, and VPS34 rs2162440) and ESCC risk in two case-control sets consisting of 1588 ESCC cases and 1600 controls. Logistic regression models were utilized to estimate associations between SNPs and ESCC susceptibility and odds ratios (ORs) and their 95% confidence intervals (95% CIs) were computed. Results: We firstly identified three SNPs (rs6430612, rs13172201 and rs4387287) which are significantly associated with telomere length in Chinese populations (all P<0.05). Importantly, CXCR4 rs6430612 and OBFC1 rs4387287 polymorphisms significantly confer reduced risk of ESCC (P=1.7×10-7 and P=3.9×10-5). On the contrary, we observed an evidently increased risk for ESCC development associated with TERT rs13172201 genetic variant (P=2.2×10-4). Conclusions: In summary, rs6430612, rs13172201 and rs4387287 might be key genetic components in complicated regulation of telomere length and contributing to ESCC predisposition. Our results elucidate the prevalent involvement of genetic variants in telomere biology and further provide pathogenic insights into the role of telomeres in cancer development.},
}
@article {pmid32742149,
year = {2020},
author = {Davis, SK and Xu, R and Khan, RJ and Gaye, A},
title = {Adiposity and Leukocyte Telomere Length in US Adults by Sex-Specific Race/Ethnicity: National Health and Nutrition Examination Survey.},
journal = {Ethnicity &amp; disease},
volume = {30},
number = {3},
pages = {441-450},
pmid = {32742149},
issn = {1945-0826},
abstract = {Objective: Little is known about the relationship between adiposity and telomere length in the United States population. The objective of our research was to examine this relationship in a representative, socioeconomically and sex-specific, diverse racial/ethnic population in the United States.<br><br>Methods: Body mass index (BMI), % total body fat (TBF) and waist circumference (WC) with leukocyte telomere length (LTL) were examined according to sex-specific race/ethnicity using separate adjusted multivariate linear regressions on a sample of 4,919 respondents aged 20-84 years from the National Health and Nutrition Examination Survey's 1999-2002 data.<br><br>Results: LTL was shortened .41%, .44%, and .16% in African American (AA) women and was associated with increasing BMI, %TBF, and WC, (β:-.0041, 95%CI: -.0070, -.0012; P=.007; β:-.0044, 95% CI: -.0081, -.0007; P=.02; β:-.0016, 95%CI: -.0031, -.0001; P=.04, respectively). LTL was shortened .29% in White women and was associated with increasing %TBF (β:-.0029, 95%CI: -.0048, -.0009; P=.006). There were no associations among AA men, White men or Mexican American men and women.<br><br>Conclusions: LTL is associated with an obesity phenotype in AA women. Tailored intervention is needed to ameliorate the burden of excess adiposity and subsequent cellular aging.},
}
@article {pmid32741725,
year = {2020},
author = {Peña, E and Powell, TR and Arenas, C and Cardoner, N and Rebasa, P and Luna, A and Caixàs, A and Rosa, A},
title = {Longitudinal changes in telomere length in a cohort of obese patients submitted to bariatric surgery: a 2-year follow-up.},
journal = {Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery},
volume = {16},
number = {11},
pages = {1794-1801},
doi = {10.1016/j.soard.2020.06.027},
pmid = {32741725},
issn = {1878-7533},
abstract = {BACKGROUND: Telomere length (TL) is one biomarker of cell aging used to explore the effects of the environment on age-related pathologies. Obesity and high body mass index have been identified as a risk factors for shortened TL.<br><br>OBJECTIVE: To evaluate TL in different subtypes of obese patients, and to examine changes in TL in relation to weight loss after bariatric surgery.<br><br>SETTING: University Hospital in Spain.<br><br>METHODS: A cohort of 94 patients submitted to bariatric surgery were followed-up during 24 months (t24m: lost to follow-up = 0%). All patients were evaluated before surgery (t0) and during the postoperative period (t6m, t12m, and t24m) for body mass index and metabolic variables. We assessed TL at each timepoint using quantitative polymerase chain reactions and the telomere sequence to single-copy gene sequence ratio method.<br><br>RESULTS: Patients with class III obesity showed significantly shorter TL at baseline than those patients with class II obesity (P = .027). No differences in TL were found between patients with or without type 2 diabetes or metabolic syndrome. Longitudinal analysis did not show an effect of time, type of surgery, age, or sex on TL. However, a generalized estimating equation model showed that TL was shorter amongst class III obesity patients across the time course (P = .008). Comparison between patients with obesity class II and class III showed differences in TL at t6m (adjusted P = .024), whereby class II patients had longer TL. However, no difference was observed at the other evaluated times.<br><br>CONCLUSION: Obesity severity may have negative effects on TL independently of type 2 diabetes or metabolic syndrome. Although TL is significantly longer in class II obesity patients relative to class III 6 months after bariatric surgery. This difference is not apparent after 24 months.},
}
@article {pmid32734707,
year = {2020},
author = {Heidinger, BJ and Young, RC},
title = {Cross-Generational Effects of Parental Age on Offspring Longevity: Are Telomeres an Important Underlying Mechanism?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {42},
number = {9},
pages = {e1900227},
doi = {10.1002/bies.201900227},
pmid = {32734707},
issn = {1521-1878},
support = {1656194//National Science Foundation/International ; },
abstract = {Parental age at offspring conception often influences offspring longevity, but the mechanisms underlying this link are poorly understood. One mechanism that may be important is telomeres, highly conserved, repetitive sections of non-coding DNA that form protective caps at chromosome ends and are often positively associated with longevity. Here, the potential pathways by which the age of the parents at the time of conception may impact offspring telomeres are described first, including direct effects on parental gamete telomeres and indirect effects on offspring telomere loss during pre- or post-natal development. Then a surge of recent studies demonstrating the effects of parental age on offspring telomeres in diverse taxa are reviewed. In doing so, important areas for future research and experimental approaches that will enhance the understanding of how and when these effects likely occur are highlighted. It is concluded by considering the potential evolutionary consequences of parental age on offspring telomeres.},
}
@article {pmid32733650,
year = {2020},
author = {Achrem, M and Szućko, I and Kalinka, A},
title = {The epigenetic regulation of centromeres and telomeres in plants and animals.},
journal = {Comparative cytogenetics},
volume = {14},
number = {2},
pages = {265-311},
pmid = {32733650},
issn = {1993-0771},
abstract = {The centromere is a chromosomal region where the kinetochore is formed, which is the attachment point of spindle fibers. Thus, it is responsible for the correct chromosome segregation during cell division. Telomeres protect chromosome ends against enzymatic degradation and fusions, and localize chromosomes in the cell nucleus. For this reason, centromeres and telomeres are parts of each linear chromosome that are necessary for their proper functioning. More and more research results show that the identity and functions of these chromosomal regions are epigenetically determined. Telomeres and centromeres are both usually described as highly condensed heterochromatin regions. However, the epigenetic nature of centromeres and telomeres is unique, as epigenetic modifications characteristic of both eu- and heterochromatin have been found in these areas. This specificity allows for the proper functioning of both regions, thereby affecting chromosome homeostasis. This review focuses on demonstrating the role of epigenetic mechanisms in the functioning of centromeres and telomeres in plants and animals.},
}
@article {pmid32733163,
year = {2020},
author = {Yu, J and Liu, H and He, S and Li, P and Ma, C and Ma, M and Liu, Y and Lv, L and Ping, F and Zhang, H and Li, W and Sun, Q and Xu, L and Li, Y},
title = {Corrigendum to &quot;Dietary Magnesium Intake and Leukocyte Telomere Attrition in Adults: The Regulatory Role of Serum Tumor Necrosis Factor α&quot;.},
journal = {Mediators of inflammation},
volume = {2020},
number = {},
pages = {2594730},
pmid = {32733163},
issn = {1466-1861},
abstract = {[This corrects the article DOI: 10.1155/2020/7610436.].},
}
@article {pmid32731419,
year = {2020},
author = {Molina-Carrión, S and Brochado-Kith, Ó and González-García, J and Berenguer, J and Díez, C and Llop, E and Hontañón, V and Ibañez-Samaniego, L and Montes, ML and Resino, S and Fernández-Rodríguez, A and Jiménez-Sousa, MÁ},
title = {Telomere Length Increase in HIV/HCV-Coinfected Patients with Cirrhosis after HCV Eradication with Direct-Acting Antivirals.},
journal = {Journal of clinical medicine},
volume = {9},
number = {8},
pages = {},
pmid = {32731419},
issn = {2077-0383},
support = {1.010.932//Universidad Alfonso X el Sabio/ ; CP17CIII/00007//Instituto de Salud Carlos III/ ; PI18CIII/00028//Instituto de Salud Carlos III/ ; PI18CIII/00020//Instituto de Salud Carlos III/ ; PI15CIII/00031//Instituto de Salud Carlos III/ ; PI14/01094//Instituto de Salud Carlos III/ ; PI17/00657//Instituto de Salud Carlos III/ ; PI17/00903//Instituto de Salud Carlos III/ ; PI14CIII/00011//Instituto de Salud Carlos III/ ; PI17CIII/00003//Instituto de Salud Carlos III/ ; },
abstract = {INTRODUCTION: Human immunodeficiency virus (HIV) infection and cirrhosis are associated with a senescent phenotype that decreases telomere length. We evaluated the impact of hepatitis C virus (HCV) elimination on telomere length in patients with advanced HCV-related cirrhosis after sustained virological response (SVR), with all-oral direct-acting antiviral agents (DAAs).<br><br>METHODS: Prospective study of 60 HIV/HCV-coinfected and 30 HCV-monoinfected patients with advanced HCV cirrhosis (liver decompensation or liver stiffness measurement (LSM) ≥ 25 kPa, hepatic liver pressure gradient (HVPG) ≥ 10 mmHg, or Child-Pugh-Turcotte (CPT) ≥ 7). The relative telomere length (RTL) was quantified by real-time multiplex PCR (MMqPCR) on peripheral blood mononuclear cells at baseline and 48 weeks after HCV treatment. Generalized linear models (GLMs) adjusted for the most relevant clinical and epidemiological variables and mixed GLMs were used.<br><br>RESULTS: In comparison with HCV-monoinfected patients, HIV/HCV-coinfected patients were younger (p < 0.001), had lower body mass index (BMI) (p = 0.002), and had been exposed less frequently to interferons (p = 0.011). In addition, they were more frequently men (p = 0.011), smokers (p = 0.005), prior intravenous drug users (IVDUs) (p < 0.001), and alcohol abusers (p = 0.005). RTL was significantly lower in HIV/HCV-coinfected patients than in HCV-monoinfected patients, both at baseline (p < 0.001), and at the end of follow-up (p = 0.032). A significant RTL increase over time was found only for HIV/HCV-coinfected patients (p < 0.001), especially in those patients with compensated cirrhosis (p < 0.001).<br><br>CONCLUSION: HCV eradication with all-oral DAAs was associated with an increase in telomere length in HIV/HCV-coinfected patients with advanced cirrhosis, particularly in compensated patients. This finding suggests that HCV clearance may have implications in age-related conditions in this population group.},
}
@article {pmid32730558,
year = {2020},
author = {Canudas, S and Becerra-Tomás, N and Hernández-Alonso, P and Galié, S and Leung, C and Crous-Bou, M and De Vivo, I and Gao, Y and Gu, Y and Meinilä, J and Milte, C and García-Calzón, S and Marti, A and Boccardi, V and Ventura-Marra, M and Salas-Salvadó, J},
title = {Mediterranean Diet and Telomere Length: A Systematic Review and Meta-Analysis.},
journal = {Advances in nutrition (Bethesda, Md.)},
volume = {11},
number = {6},
pages = {1544-1554},
pmid = {32730558},
issn = {2156-5376},
abstract = {Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.},
}
@article {pmid32728890,
year = {2020},
author = {McAninch, D and Bianco-Miotto, T and Gatford, KL and Leemaqz, SY and Andraweera, PH and Garrett, A and Plummer, MD and Dekker, GA and Roberts, CT and Smithers, LG and Grieger, JA},
title = {The metabolic syndrome in pregnancy and its association with child telomere length.},
journal = {Diabetologia},
volume = {63},
number = {10},
pages = {2140-2149},
doi = {10.1007/s00125-020-05242-0},
pmid = {32728890},
issn = {1432-0428},
support = {GNT1174971//National Health and Medical Research Council/International ; GNT1090778//National Health and Medical Research Council, Peter Doherty Early Career Fellowship/International ; GNT 161305//Channel 7 Children's Research Foundation/International ; },
abstract = {AIMS/HYPOTHESIS: The aim of this study was to determine whether presence of the metabolic syndrome in pregnancy associates with child telomere length or child anthropometry (weight, BMI) and BP, measured at 10 years of age.<br><br>METHODS: The Screening for Pregnancy Endpoints study (SCOPE) was a multicentre, international prospective cohort of nulliparous pregnant women recruited from Australia, New Zealand, Ireland and the UK (N = 5628). The current analysis is a 10 year follow-up of SCOPE pregnant women and their children, from the Australian cohort. Clinical data collected at 14-16 weeks' gestation during the SCOPE study were used to diagnose the metabolic syndrome using IDF criteria. Telomere length, a biomarker of ageing, was assessed by quantitative PCR from children's saliva collected at 10 years of age.<br><br>RESULTS: In women who completed follow-up (n = 255), 20% had the metabolic syndrome in pregnancy. After adjusting for a range of confounders, children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers without the metabolic syndrome in pregnancy (mean difference -0.36 [95% CI -0.74, 0.01]). Height- and weight-for-age, and BMI z scores were similar in children of mothers who did and did not have the metabolic syndrome during pregnancy.<br><br>CONCLUSIONS/INTERPRETATION: Children of mothers who had the metabolic syndrome in pregnancy have shorter telomeres, a biomarker of accelerated ageing. These findings warrant further studies in larger cohorts of children, as well as investigations into whether telomere length measured in cord blood associates with telomere length in childhood.},
}
@article {pmid32725240,
year = {2020},
author = {Engel, T and Raffenberg, M and Schoepf, IC and Kootstra, NA and Reiss, P and Thorball, CW and Hasse, B and Hirzel, C and Wissel, K and Roth, JA and Bernasconi, E and Darling, KEA and Calmy, A and Fellay, J and Kouyos, RD and Günthard, HF and Ledergerber, B and Tarr, PE and , },
title = {Telomere Length, Traditional Risk Factors, HIV-related Factors and Coronary Artery Disease Events in Swiss Persons Living with HIV.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {},
number = {},
pages = {},
doi = {10.1093/cid/ciaa1034},
pmid = {32725240},
issn = {1537-6591},
abstract = {BACKGROUND: Leukocyte telomere length (TL) shortens with age and is associated with coronary artery disease (CAD) events in the general population. Persons living with HIV (PLWH) may have accelerated atherosclerosis and shorter TL than the general population. It is unknown whether TL is associated with CAD in PLWH.<br><br>METHODS: We measured TL by quantitative PCR in white Swiss HIV Cohort Study participants. Cases had a first CAD event during 01.01.2000-31.12.2017. We matched 1-3 PLWH controls without CAD events on sex, age, and observation time. We obtained univariable and multivariable odds ratios (OR) for CAD from conditional logistic regression analyses.<br><br>RESULTS: We included 333 cases (median age 54 years; 14% women; 83% with suppressed HIV RNA) and 745 controls. Median time (interquartile range) of TL measurement was 9.4 (5.9-13.8) years prior to CAD event. Compared to the 1st (shortest) TL quintile, participants in the 5th (longest) TL quintile had univariable and multivariable CAD event OR=0.56 (95% confidence interval, 0.35-0.91) and OR=0.54 (0.31-0.96). Multivariable OR for current smoking was 1.93 (1.27-2.92), dyslipidemia OR=1.92 (1.41-2.63), and for recent abacavir, cumulative lopinavir, indinavir, and darunavir exposure was OR=1.82 (1.27-2.59), OR=2.02 (1.34-3.04), OR=3.42 (2.14-5.45), and OR=1.66 (1.00-2.74), respectively. The TL-CAD association remained significant when adjusting only for Framingham risk score, when excluding TL outliers, and when adjusting for CMV-seropositivity, HCV-seropositivity, time spent with detectable HIV viremia, and injection drug use.<br><br>CONCLUSION: In PLWH, TL measured >9 years before, is independently associated with CAD events after adjusting for multiple traditional and HIV-related factors.},
}
@article {pmid32724340,
year = {2020},
author = {Trybek, T and Kowalik, A and Góźdź, S and Kowalska, A},
title = {Telomeres and telomerase in oncogenesis.},
journal = {Oncology letters},
volume = {20},
number = {2},
pages = {1015-1027},
pmid = {32724340},
issn = {1792-1074},
abstract = {Telomeres are located at the ends of chromosomes and protect them from degradation. Suppressing the activity of telomerase, a telomere-synthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. This leads to the progressive shortening of telomeres and inhibition of cell growth in a process called replicative senescence. Most types of primary cancer exhibit telomerase activation, which allows uncontrolled cell proliferation. Previous research indicates that TERT activation also affects cancer development through activities other than the canonical function of mediating telomere elongation. Recent studies have improved the understanding of the structure and function of telomeres and telomerase as well as key mechanisms underlying the activation of TERT and its role in oncogenesis. These advances led to a search for drugs that inhibit telomerase as a target for cancer therapy. The present review article summarizes the organization and function of telomeres, their role in carcinogenesis, and advances in telomerase-targeted therapy.},
}
@article {pmid32722302,
year = {2020},
author = {In der Stroth, L and Tharehalli, U and Günes, C and Lechel, A},
title = {Telomeres and Telomerase in the Development of Liver Cancer.},
journal = {Cancers},
volume = {12},
number = {8},
pages = {},
pmid = {32722302},
issn = {2072-6694},
support = {GRK2254/C3 - HEIST//Deutsche Forschungsgemeinschaft/ ; GU 569/6-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Liver cancer is one of the most common cancer types worldwide and the fourth leading cause of cancer-related death. Liver carcinoma is distinguished by a high heterogeneity in pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequent in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which represent the two most common types of liver tumors. Both tumor types are characterized by telomere shortening and reactivation of telomerase during carcinogenesis. Continuous cell proliferation, e.g., by oncogenic mutations, can cause extensive telomere shortening in the absence of sufficient telomerase activity, leading to dysfunctional telomeres and genome instability by breakage-fusion-bridge cycles, which induce senescence or apoptosis as a tumor suppressor mechanism. Telomerase reactivation is required to stabilize telomere functionality and for tumor cell survival, representing a genetic risk factor for the development of liver cirrhosis and liver carcinoma. Therefore, telomeres and telomerase could be useful targets in hepatocarcinogenesis. Here, we review similarities and differences between HCC and iCCA in telomere biology.},
}
@article {pmid32719516,
year = {2020},
author = {Maciejowski, J and Chatzipli, A and Dananberg, A and Chu, K and Toufektchan, E and Klimczak, LJ and Gordenin, DA and Campbell, PJ and de Lange, T},
title = {APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis.},
journal = {Nature genetics},
volume = {52},
number = {9},
pages = {884-890},
pmid = {32719516},
issn = {1546-1718},
support = {R35 CA210036/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; ZIA ES103266/ImNIH/Intramural NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R00 CA212290/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromothripsis ; Cytidine Deaminase/*genetics ; Cytosine Deaminase/genetics ; Exodeoxyribonucleases/*genetics ; Genomic Instability/genetics ; Humans ; Mutation/genetics ; Neoplasms/genetics ; Phosphoproteins/*genetics ; Telomere/*genetics ; U937 Cells ; },
abstract = {Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1-5. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.},
}
@article {pmid32710419,
year = {2020},
author = {Khosravi, S and Dreissig, S and Schindele, P and Wolter, F and Rutten, T and Puchta, H and Houben, A},
title = {Live-Cell CRISPR Imaging in Plant Cells with a Telomere-Specific Guide RNA.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2166},
number = {},
pages = {343-356},
doi = {10.1007/978-1-0716-0712-1_20},
pmid = {32710419},
issn = {1940-6029},
abstract = {Chromatin organization is highly dynamic in living cells. Therefore, it might have a regulatory role over biological mechanisms like transcription, replication, and DNA repair. To elucidate how these mechanisms are regulated, it is required to establish imaging methods to visualize the chromatin dynamic in living cells. Here, we provide a protocol for a live plant cell imaging technique based on application of two orthologs of the bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) from Streptococcus pyogenes and Staphylococcus aureus. This technique uses the inactive variants of Cas9 combined with different fluorescent proteins (GFP and mRuby) and telomere-specific guide RNA to target telomeric repeats in Nicotiana benthamiana. Our immuno-FISH data revealed that signals arising from the CRISPR/dCas9 method are specifically belonging to telomeric regions.},
}
@article {pmid32709557,
year = {2020},
author = {Wilson, SH},
title = {Telomeres come to life thanks to an exciting review article in this issue.},
journal = {DNA repair},
volume = {94},
number = {},
pages = {102904},
doi = {10.1016/j.dnarep.2020.102904},
pmid = {32709557},
issn = {1568-7856},
mesh = {Cellular Senescence ; Molecular Biology ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; },
}
@article {pmid32708340,
year = {2020},
author = {Armendáriz-Castillo, I and López-Cortés, A and García-Cárdenas, J and Guevara-Ramírez, P and Leone, PE and Pérez-Villa, A and Yumiceba, V and Zambrano, AK and Guerrero, S and Paz-Y-Miño, C},
title = {TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes.},
journal = {Genes},
volume = {11},
number = {7},
pages = {},
pmid = {32708340},
issn = {2073-4425},
abstract = {Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.},
}
@article {pmid32705188,
year = {2020},
author = {Razgonova, MP and Zakharenko, AM and Golokhvast, KS and Thanasoula, M and Sarandi, E and Nikolouzakis, K and Fragkiadaki, P and Tsoukalas, D and Spandidos, DA and Tsatsakis, A},
title = {Telomerase and telomeres in aging theory and chronographic aging theory (Review).},
journal = {Molecular medicine reports},
volume = {22},
number = {3},
pages = {1679-1694},
pmid = {32705188},
issn = {1791-3004},
abstract = {The current review focuses on the connection of telomerase and telomeres with aging. In this review, we describe the changes in telomerase and telomere length (TEL) during development, their role in carcinogenesis processes, and the consequences of reduced telomerase activity. More specifically, the connection of TEL in peripheral blood cells with the development of aging‑associated diseases is discussed. The review provides systematic data on the role of telomerase in mitochondria, the biology of telomeres in stem cells, as well as the consequences of the forced expression of telomerase (telomerization) in human cells. Additionally, it presents the effects of chronic stress exposure on telomerase activity, the effect of TEL on fertility, and the effect of nutraceutical supplements on TEL. Finally, a comparative review of the chronographic theory of aging, presented by Olovnikov is provided based on currently available scientific research on telomere, telomerase activity, and the nature of aging by multicellular organisms.},
}
@article {pmid32703912,
year = {2020},
author = {Hsieh, AYY and Kimmel, E and Pick, N and Sauvé, L and Brophy, J and Kakkar, F and Bitnun, A and Murray, MCM and Côté, HCF},
title = {Inverse relationship between leukocyte telomere length attrition and blood mitochondrial DNA content loss over time.},
journal = {Aging},
volume = {12},
number = {15},
pages = {15196-15221},
pmid = {32703912},
issn = {1945-4589},
support = {//CIHR/Canada ; },
abstract = {Leukocyte telomere length (LTL) and whole blood mitochondrial DNA (WB mtDNA) content are aging markers impacted by chronic diseases such as human immunodeficiency virus (HIV) infection. We characterized the relationship between these two markers in 312 women ≥12 years of age living with HIV and 300 HIV-negative controls. We found no relationship between the two markers cross-sectionally. In multivariable models, age, ethnicity, HIV, and tobacco smoking were independently associated with shorter LTL, and the former three with lower WB mtDNA. Longitudinally, among a subgroup of 228 HIV participants and 68 HIV-negative controls with ≥2 biospecimens ≥1 year apart, an inverted pattern was observed between the rates of change in LTL and WB mtDNA content per year, whereby faster decline of one was associated with the preservation of the other. Furthermore, if HIV viral control was not maintained between visits, increased rates of both LTL attrition and WB mtDNA loss were observed. We describe a novel relationship between two established aging markers, whereby rates of change in LTL and WB mtDNA are inversely related. Our findings highlight the importance of maintaining HIV viral control, the complementary longitudinal relationship between the two markers, and the need to consider both in aging studies.},
}
@article {pmid32702724,
year = {2020},
author = {Maremanda, KP and Sundar, IK and Li, D and Rahman, I},
title = {Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {32702724},
abstract = {Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 &amp; 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 &amp; 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.},
}
@article {pmid32699404,
year = {2020},
author = {Gao, Y and Wang, T and Yu, X and , and Zhao, H and Zeng, P},
title = {Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {12184},
pmid = {32699404},
issn = {2045-2322},
support = {MR/L501542/1/MRC_/Medical Research Council/United Kingdom ; MC_U123160651/MRC_/Medical Research Council/United Kingdom ; G0701075/MRC_/Medical Research Council/United Kingdom ; MC_UU_00024/1/MRC_/Medical Research Council/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; P30 AG062422/AG/NIA NIH HHS/United States ; G0400074/MRC_/Medical Research Council/United Kingdom ; MR/N026004/1/MRC_/Medical Research Council/United Kingdom ; G0901254/MRC_/Medical Research Council/United Kingdom ; MR/K01417X/1/MRC_/Medical Research Council/United Kingdom ; G-0907/PUK_/Parkinson's UK/United Kingdom ; P30 AG066462/AG/NIA NIH HHS/United States ; G0502157/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Amyotrophic Lateral Sclerosis/genetics/*pathology ; Asian Continental Ancestry Group/genetics ; Cholesterol/blood ; European Continental Ancestry Group/genetics ; *Frontotemporal Dementia/genetics/pathology ; Genome-Wide Association Study ; Humans ; Leukocytes/cytology/*metabolism ; Lipoproteins, LDL/blood ; *Mendelian Randomization Analysis ; Odds Ratio ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Telomerase/genetics ; Telomere/*physiology ; Telomere Shortening ; },
abstract = {We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.},
}
@article {pmid32699327,
year = {2020},
author = {Adams, CD and Boutwell, BB},
title = {A Mendelian randomization study of telomere length and blood-cell traits.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {12223},
pmid = {32699327},
issn = {2045-2322},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blood Cells/*metabolism ; Female ; Genome-Wide Association Study/methods ; Germ-Line Mutation/genetics ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Phenotype ; Polymorphism, Single Nucleotide/*genetics ; Risk Factors ; Telomere/*genetics/*metabolism ; Telomere Homeostasis/genetics ; Young Adult ; },
abstract = {Whether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n = 9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n ~ 173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell and white blood cell counts, decreased mean corpuscular hemoglobinand mean cell volume, and had no observable impact on mean corpuscular hemoglobin concentration, red cell distribution width, hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to germline mutations in telomere biology genes leading to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population.},
}
@article {pmid32697083,
year = {2020},
author = {Wang, CX and Zhang, ZL and Yin, QK and Tu, JL and Wang, JE and Xu, YH and Rao, Y and Ou, TM and Huang, SL and Li, D and Wang, HG and Li, QJ and Tan, JH and Chen, SB and Huang, ZS},
title = {Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors.},
journal = {Journal of medicinal chemistry},
volume = {63},
number = {17},
pages = {9752-9772},
doi = {10.1021/acs.jmedchem.0c00917},
pmid = {32697083},
issn = {1520-4804},
mesh = {Apoptosis/drug effects ; Cell Proliferation/drug effects ; Chemistry Techniques, Synthetic ; *DNA Damage ; *Drug Design ; Drug Synergism ; HCT116 Cells ; Humans ; Models, Molecular ; Poly(ADP-ribose) Polymerase Inhibitors/*pharmacology ; Protein Conformation ; Quinazolinones/*chemical synthesis/chemistry/*pharmacology ; RecQ Helicases/*antagonists &amp; inhibitors/chemistry ; Structure-Activity Relationship ; Telomere/*genetics ; },
abstract = {DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.},
}
@article {pmid32696640,
year = {2020},
author = {Sebastiano, M and Angelier, F and Blévin, P and Ribout, C and Sagerup, K and Descamps, S and Herzke, D and Moe, B and Barbraud, C and Bustnes, JO and Gabrielsen, GW and Chastel, O},
title = {Exposure to PFAS is Associated with Telomere Length Dynamics and Demographic Responses of an Arctic Top Predator.},
journal = {Environmental science &amp; technology},
volume = {54},
number = {16},
pages = {10217-10226},
doi = {10.1021/acs.est.0c03099},
pmid = {32696640},
issn = {1520-5851},
mesh = {Animals ; Arctic Regions ; Cross-Sectional Studies ; Demography ; *Environmental Pollutants/analysis/toxicity ; Female ; *Fluorocarbons/analysis/toxicity ; Male ; Svalbard ; Telomere/chemistry ; },
abstract = {Environmental factors that can influence telomeres are diverse, but the association between telomeres and exposure to environmental contaminants is yet to be elucidated. To date, prior studies have focused on legacy persistent chlorinated pollutants (POPs), while the effects of poly- and perfluoroalkyl substances (PFAS) have been poorly documented. Here, we investigated the associations among PFAS congeners, absolute telomere length (cross-sectional approach), and telomere dynamics (rate of telomere length change over time, longitudinal approach) in one of the most contaminated arctic top predators, the glaucous gull Larus hyperboreus from Svalbard. We further estimated the effect of PFAS on apparent survival rates and re-sighting probabilities using a 10-year capture/recapture dataset (2010-2019). We found that birds exposed to higher concentrations of perfluorononadecanoate (PFNA) (median of 1565 pg/mL of ww in males and 1370 pg/mL of ww in females) and perfluorotetradecanoate (PFTeDA) (median of 370 pg/mL of ww in males and 210 pg/mL of ww in females) showed the slowest rate of telomere shortening. We also found that high blood concentrations of perfluorooctanoate (PFOA) (median of 120 pg/mL of ww in males and 150 pg/mL of ww in females) and perfluorohexanesulfonate (PFHxS) (median of 495 pg/mL of ww in males and 395 pg/mL of ww in females) were positively associated with higher re-sighting probabilities and apparent survival in males but not in females. Our work is the first to report an association between single PFAS compounds and telomeres, and the first to link PFAS exposure with survival probabilities, suggesting that the effect of PFAS exposure might be more tied to the type of compound rather than the total concentration of PFAS.},
}
@article {pmid32688270,
year = {2020},
author = {Miranda, DM and Rosa, DV and Costa, BS and Nicolau, NF and Magno, LAV and de Paula, JJ and Romano-Silva, MA},
title = {Telomere shortening in patients with drug-resistant epilepsy.},
journal = {Epilepsy research},
volume = {166},
number = {},
pages = {106427},
doi = {10.1016/j.eplepsyres.2020.106427},
pmid = {32688270},
issn = {1872-6844},
abstract = {Epilepsy affects about 1 % of the world population. Mesial temporal lobe epilepsy (mTLE) presents with seizures initiated in hippocampus and is the most frequent form of epilepsy. About 30 % of individuals with mTLE do not respond to conventional medications maintaining seizures and consequently new lesions on a daily basis. Treatment-resistant epilepsy has a huge social and individual burden due to impaired quality of life and increased mortality rate. There are many reasons for telomere shortening in individuals with mTLE, such as a chronic mitochondrial oxidative stress and increased levels of pro-inflammatory mediators. In the past 10 years, there was a boom of studies establishing association between telomere length and chronic/complex disorders. Telomeres are essential for the maintenance of genomic integrity. Telomere length has been assumed as a biological marker for stress and cellular ageing. Here we hypothesized that individuals affected with treatment-resistant mTLE would course with a shorter telomere than controls. So, we measured leucocytes telomere length in a sample of 89 individuals, 48 treatment-resistant mTLE compared to 41 healthy controls. As expected, we observed a significant shorter telomere in the peripheral cell leukocytes of treatment-resitant mTLE group. Telomere length was not associated with sex, side of hippocampal sclerosis, family history, etiology of seizures, duration of disease or the Engel score. Our results points towards the need of further investigation to shed light on the relation of telomeres shortening and the outcomes and impacts of epilepsy.},
}
@article {pmid32687724,
year = {2020},
author = {Maeda, T and Horiuchi, T and Makino, N},
title = {Telomere shortening velocity of patients administered with hypnotics is accelerated in a gender-differential manner.},
journal = {Canadian journal of physiology and pharmacology},
volume = {},
number = {},
pages = {1-6},
doi = {10.1139/cjpp-2020-0291},
pmid = {32687724},
issn = {1205-7541},
abstract = {The telomere length and its distribution were compared between patients administered with and without hypnotics to see if regular administration of hypnotics is associated with their aging-related somatic telomere shortening. Male patients presented significant shortening of telomere length of circulating leukocytes in association with age (-41.9 bp/year, p = 0.045) in contrast with controls (-18.3 kb/year, p = 0.155). On the other hand, female patients presented no significant shortening of telomere length with aging (-16.4 bp/year, p = 0.372) in contrast with controls (-55.9 bp/year, p = 0.00005). These results suggested that regular administration of hypnotics is associated with aging progression in a gender-related manner. The administration of hypnotics could be an indicator as the somatic aging status and for the screening of background lifestyle-associated diseases promoting biological aging.},
}
@article {pmid32687062,
year = {2020},
author = {Li, T and Luo, Z and Lin, S and Li, C and Dai, S and Wang, H and Huang, J and Ma, W and Songyang, Z and Huang, Y},
title = {MiR-185 targets POT1 to induce telomere dysfunction and cellular senescence.},
journal = {Aging},
volume = {12},
number = {14},
pages = {14791-14807},
pmid = {32687062},
issn = {1945-4589},
abstract = {Protection of telomere 1 (POT1), the telomeric single-stranded DNA (ssDNA)-binding protein in the shelterin complex, has been implicated in the DNA damage response, tumorigenesis and aging. Telomere dysfunction induced by telomere deprotection could accelerate cellular senescence in primary human cells. While previous work demonstrated the biological mechanism of POT1 in aging and cancer, how POT1 is posttranscriptionally regulated remains largely unknown. To better understand the POT1 regulatory axis, we performed bioinformatic prediction, and selected candidates were further confirmed by dual-luciferase reporter assay. Collectively, our results revealed that miR-185 can significantly reduce POT1 mRNA and protein levels by directly targeting the POT1 3'-untranslated region (3'-UTR). Overexpression of miR-185 increased telomere dysfunction-induced foci (TIF) signals in both cancer cells and primary human fibroblasts. Elevated miR-185 led to telomere elongation in the telomerase-positive cell line HTC75, which was phenotypically consistent with POT1 knocking down. Moreover, miR-185 accelerated the replicative senescence process in primary human fibroblasts in a POT1-dependent manner. Interestingly, increased serum miR-185 could represent a potential aging-related biomarker. Taken together, our findings reveal miR-185 as a novel aging-related miRNA that targets POT1 and provide insight into the telomere and senescence regulatory network at both the intracellular and extracellular levels.},
}
@article {pmid32681489,
year = {2020},
author = {Schořová, Š and Fajkus, J and Schrumpfová, PP},
title = {Optimized Detection of Protein-Protein and Protein-DNA Interactions, with Particular Application to Plant Telomeres.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2175},
number = {},
pages = {139-167},
doi = {10.1007/978-1-0716-0763-3_11},
pmid = {32681489},
issn = {1940-6029},
abstract = {Characterization of protein-protein and protein-DNA interactions is critical to understand mechanisms governing the biology of cells. Here we describe optimized methods and their mutual combinations for this purpose: bimolecular fluorescence complementation (BiFC), co-immunoprecipitation (Co-IP), yeast two-hybrid systems (Y2H), and chromatin immunoprecipitation (ChIP). These improved protocols detect trimeric complexes in which two proteins of interest interact indirectly via a protein sandwiched between them. They also allow isolation of low-abundance chromatin proteins and confirmation that proteins of interest are associated with specific DNA sequences, for example telomeric tracts. Here we describe these methods and their application to map interactions of several telomere- and telomerase-associated proteins and to purify a sufficient amount of chromatin from Arabidopsis thaliana for further investigations (e.g., next-generation sequencing, hybridization).},
}
@article {pmid32679078,
year = {2020},
author = {Barroso-González, J and García-Expósito, L and Hoang, SM and Lynskey, ML and Roncaioli, JL and Ghosh, A and Wallace, CT and de Vitis, M and Modesti, M and Bernstein, KA and Sarkar, SN and Watkins, SC and O'Sullivan, RJ},
title = {RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.},
journal = {Molecular cell},
volume = {79},
number = {2},
pages = {359},
doi = {10.1016/j.molcel.2020.06.026},
pmid = {32679078},
issn = {1097-4164},
support = {R01 CA207209/CA/NCI NIH HHS/United States ; },
}
@article {pmid32678440,
year = {2020},
author = {Vahter, M and Broberg, K and Harari, F},
title = {Placental and Cord Blood Telomere Length in Relation to Maternal Nutritional Status.},
journal = {The Journal of nutrition},
volume = {150},
number = {10},
pages = {2646-2655},
pmid = {32678440},
issn = {1541-6100},
mesh = {Body Composition ; Body Mass Index ; Female ; *Fetal Blood ; Humans ; Maternal Nutritional Physiological Phenomena ; Nutritional Status ; Placenta/*metabolism ; Pregnancy ; *Telomere ; *Telomere Homeostasis ; Vitamin B 12/blood ; },
abstract = {BACKGROUND: The uterine environment may be important for the chromosomal telomere length (TL) at birth, which, in turn, influences disease susceptibility throughout life. However, little is known about the importance of specific nutritional factors.<br><br>OBJECTIVES: We assessed the impact of multiple maternal nutritional factors on TL in placenta and cord blood.<br><br>METHODS: In a population-based mother-child cohort in northwestern Argentina, we measured maternal weight, BMI, body fat percentage (BFP), and several nutrients [selenium, magnesium, calcium, zinc, manganese, iodine, vitamin B-12, folate, 25-hydroxycholecalciferol (25(OH)D3)], hemoglobin, and homocysteine in maternal whole blood, serum, plasma, or urine during pregnancy (mean gestational week 27). We measured the relative TL (rTL) in placenta (n = 99) and cord blood (n = 98) at delivery by real-time PCR. Associations were evaluated by multivariable-adjusted linear regression.<br><br>RESULTS: The women's prepregnancy BMI (kg/m2; mean ± SD: 23.7 ± 4.1), body weight (55.4 ± 9.9 kg), and BFP (29.9 ± 5.5%), but not height (153 ± 5.3 cm), were inversely associated with placental rTL (P < 0.01 for all), with ∼0.5 SD shorter rTL for an IQR increase in prepregnancy body weight, BMI, or BFP. Also, impedance-based BFP, but not lean body mass, in the third trimester was associated with shorter placental rTL. In addition, serum vitamin B-12 (232 ± 96 pmol/L) in pregnancy (P = 0.038), but not folate or homocysteine, was associated with shorter placental rTL (0.2 SD for an IQR increase). In contrast, plasma 25(OH)D3 (46 ± 15 nmol/L) was positively associated with placental rTL (P < 0.01), which increased by 0.4 SD for an IQR increase in 25(OH)D3. No clear associations of the studied maternal nutritional factors were found with cord blood rTL.<br><br>CONCLUSIONS: Maternal BMI, BFP, and vitamin B-12 were positively associated, whereas 25(OH)D3 was inversely associated, with placental TL. No association was observed with cord blood TL. Future studies should elucidate the role of placental TL for child health.},
}
@article {pmid32674474,
year = {2020},
author = {Fernandes, SG and Dsouza, R and Pandya, G and Kirtonia, A and Tergaonkar, V and Lee, SY and Garg, M and Khattar, E},
title = {Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential.},
journal = {Cancers},
volume = {12},
number = {7},
pages = {},
pmid = {32674474},
issn = {2072-6694},
support = {(No. BT/RLF/Re-entry/06/2015//Department of Biotechnology, Ministry of Science and Technology, India/ ; (ECR/2018/002117//Science and Engineering Research Board/ ; BT/RLF/Re-entry/24/2014//Department of Biotechnology, Ministry of Science and Technology, India/ ; ECR/2016/001519//Science and Engineering Research Board/ ; },
abstract = {Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects them from being identified as DNA damage sites. Telomeres are transcribed by RNA polymerase II, and generate a long noncoding RNA called telomeric repeat-containing RNA (TERRA), which plays a key role in regulating subtelomeric gene expression. Replicative immortality and genome instability are hallmarks of cancer and to attain them cancer cells exploit telomere maintenance and telomere protection mechanisms. Thus, understanding the role of telomeres and their associated proteins in cancer initiation, progression and treatment is very important. The present review highlights the critical role of various telomeric components with recently established functions in cancer. Further, current strategies to target various telomeric components including human telomerase reverse transcriptase (hTERT) as a therapeutic approach in human malignancies are discussed.},
}
@article {pmid32673712,
year = {2020},
author = {Wang, J and Liu, Y and Xia, Q and Xia, Q and Wang, B and Yang, C and Liang, J and Liu, X},
title = {Potential roles of telomeres and telomerase in neurodegenerative diseases.},
journal = {International journal of biological macromolecules},
volume = {163},
number = {},
pages = {1060-1078},
doi = {10.1016/j.ijbiomac.2020.07.046},
pmid = {32673712},
issn = {1879-0003},
abstract = {Telomeres, protective DNA-protein complexes at the end of eukaryotic linear chromosomes, play pivotal roles in the maintenance of genomic stability during cell division. When telomeres are severely shortened, cells stop dividing and die, consequently leading to tissues degeneration. Concretely, replicative senescence and genomic damage are generally accompanied with telomere shortening, which may be a potential contributor in the pathogenesis of neurological disorders. Regardless of occasional negative findings, accelerated telomere erosion is routinely found in neurodegenerative diseases and has been believed to be positively correlated with the severity of neurodegenerative diseases. As considerable knowledge of telomeres and telomerase continues to accumulate, telomerase is increasingly being recognized as a promising therapeutic target for neurodegenerative disease. Until now, strong evidence has accumulated that activated telomerase is responsible for telomere elongation that may be sufficient to prevent &quot;mother cells&quot; from replicative aging, and besides, telomerase activators exhibit remarkable neuroprotective effects through the prolongation of telomere length and the promotion of neuronal survival as well as proliferation. Therefore, a consensus is emerging that the activation of telomerase, promoted by peptides, natural herbal extracts, small molecules compounds and others, represents a novel promising treatment strategy for neurodegenerative diseases.},
}
@article {pmid32673551,
year = {2020},
author = {Sánchez-Montes, G and Martínez-Solano, Í and Díaz-Paniagua, C and Vilches, A and Ariño, AH and Gomez-Mestre, I},
title = {Telomere attrition with age in a wild amphibian population.},
journal = {Biology letters},
volume = {16},
number = {7},
pages = {20200168},
pmid = {32673551},
issn = {1744-957X},
mesh = {Animals ; Bufonidae ; Cross-Sectional Studies ; Male ; *Telomere/genetics ; *Telomere Shortening ; },
abstract = {Telomere shortening with age has been documented in many organisms, but few studies have reported telomere length measurements in amphibians, and no information is available for growth after metamorphosis, nor in wild populations. We provide both cross-sectional and longitudinal evidence of net telomere attrition with age in a wild amphibian population of natterjack toads (Epidalea calamita). Based on age-estimation by skeletochronology and qPCR telomere length measurements in the framework of an individual-based monitoring programme, we confirmed telomere attrition in recaptured males. Our results support that toads experience telomere attrition throughout their ontogeny, and that most attrition occurs during the first 1-2 years. We did not find associations between telomere length and inbreeding or body condition. Our results on telomere length dynamics under natural conditions confirm telomere shortening with age in amphibians and provide quantification of wide telomere length variation within and among age-classes in a wild breeding population.},
}
@article {pmid32669102,
year = {2020},
author = {Abid, HZ and McCaffrey, J and Raseley, K and Young, E and Lassahn, K and Varapula, D and Riethman, H and Xiao, M},
title = {Single-molecule analysis of subtelomeres and telomeres in Alternative Lengthening of Telomeres (ALT) cells.},
journal = {BMC genomics},
volume = {21},
number = {1},
pages = {485},
pmid = {32669102},
issn = {1471-2164},
support = {R21HG007205 and R21CA177395/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Telomeric DNA is typically comprised of G-rich tandem repeat motifs and maintained by telomerase (Greider CW, Blackburn EH; Cell 51:887-898; 1987). In eukaryotes lacking telomerase, a variety of DNA repair and DNA recombination based pathways for telomere maintenance have evolved in organisms normally dependent upon telomerase for telomere elongation (Webb CJ, Wu Y, Zakian VA; Cold Spring Harb Perspect Biol 5:a012666; 2013); collectively called Alternative Lengthening of Telomeres (ALT) pathways. By measuring (TTAGGG) n tract lengths from the same large DNA molecules that were optically mapped, we simultaneously analyzed telomere length dynamics and subtelomere-linked structural changes at a large number of specific subtelomeric loci in the ALT-positive cell lines U2OS, SK-MEL-2 and Saos-2.<br><br>RESULTS: Our results revealed loci-specific ALT telomere features. For example, while each subtelomere included examples of single molecules with terminal (TTAGGG) n tracts as well as examples of recombinant telomeric single molecules, the ratio of these molecules was subtelomere-specific, ranging from 33:1 (19p) to 1:25 (19q) in U2OS. The Saos-2 cell line shows a similar percentage of recombinant telomeres. The frequency of recombinant subtelomeres of SK-MEL-2 (11%) is about half that of U2OS and Saos-2 (24 and 19% respectively). Terminal (TTAGGG) n tract lengths and heterogeneity levels, the frequencies of telomere signal-free ends, and the frequency and size of retained internal telomere-like sequences (ITSs) at recombinant telomere fusion junctions all varied according to the specific subtelomere involved in a particular cell line. Very large linear extrachromosomal telomere repeat (ECTR) DNA molecules were found in all three cell lines; these are in principle capable of templating synthesis of new long telomere tracts via break-induced repair (BIR) long-tract DNA synthesis mechanisms and contributing to the very long telomere tract length and heterogeneity characteristic of ALT cells. Many of longest telomere tracts (both end-telomeres and linear ECTRs) displayed punctate CRISPR/Cas9-dependent (TTAGGG) n labeling patterns indicative of interspersion of stretches of non-canonical telomere repeats.<br><br>CONCLUSION: Identifying individual subtelomeres and characterizing linked telomere (TTAGGG) n tract lengths and structural changes using our new single-molecule methodologies reveals the structural consequences of telomere damage, repair and recombination mechanisms in human ALT cells in unprecedented molecular detail and significant differences in different ALT-positive cell lines.},
}
@article {pmid32668770,
year = {2020},
author = {Panasiak, L and Dobosz, S and Ocalewicz, K},
title = {Telomere Dynamics in the Diploid and Triploid Rainbow Trout (Oncorhynchus mykiss) Assessed by Q-FISH Analysis.},
journal = {Genes},
volume = {11},
number = {7},
pages = {},
pmid = {32668770},
issn = {2073-4425},
abstract = {Changes of telomere length with age were assessed in diploid and triploid rainbow trout (Oncorhynchus mykiss) females in the cross-sectional study using Q-FISH technique. Triploid trout as sterile do not invest an energy in gametogenesis and continue to grow, whereas fertile diploid individuals suffer from declines in growth and survival during sexual maturation. However, triploid and diploid specimens exhibited similar patterns of telomere dynamics. Telomere length in the embryos, larvae and one-year-old juveniles did not change significantly. In the second year after hatching, subadults exhibited substantially shortened telomeres, while significant increase of the telomere length was reported in the three-year-old adults. On the other hand, correlation between telomere length and body size was observed in the triploid, but not in the diploid rainbow trout. Telomere shortening observed in two-year-old subadults may have been associated with the premature period of the fast growth in rainbow trout. Similar pattern of the telomere dynamics reported in the fertile diploids and sterile triploids indicated processes related to reproduction did not affect telomere dynamics in this species. Unexpected increase of the telomere length reported during the third year of life confirmed that in rainbow trout telomeric DNA shortens and lengthens, depending on the developmental stage.},
}
@article {pmid32666074,
year = {2021},
author = {Frati, G and Versaci, F and Sciarretta, S},
title = {A novel signalling mechanism regulating telomere length in cardiomyocytes.},
journal = {Cardiovascular research},
volume = {117},
number = {1},
pages = {13-14},
doi = {10.1093/cvr/cvaa210},
pmid = {32666074},
issn = {1755-3245},
}
@article {pmid32666011,
year = {2020},
author = {Tatsi, C and Flippo, C and Faucz, FR and Sinaii, N and Stratakis, CA},
title = {Telomere Length Changes in Children With Cushing Disease: A Pilot Study.},
journal = {Journal of the Endocrine Society},
volume = {4},
number = {7},
pages = {bvaa067},
pmid = {32666011},
issn = {2472-1972},
abstract = {Context: Changes in telomere length (TL) have been linked to certain diseases. Studies on the effect of cortisol on TL have not led to conclusive results.<br><br>Objective: To determine whether TL is affected in pediatric patients with Cushing disease (CD) through an exploratory study.<br><br>Design: We studied 10 pediatric patients [mean age: 13.3 (2.6) years, 7 females], diagnosed and treated successfully for CD. TL was measured before and approximately 1 year after treatment. TL was compared with controls adjusting for age, and associations with disease characteristics were assessed.<br><br>Results: Adjusting for age, total lymphocyte TL of patients did not differ from controls during active disease (P = 0.13) but was shorter than controls at follow-up (P = 0.031). Total lymphocyte TL during active CD and at follow-up did not correlate with markers of hypercortisolemia. There was strong inverse correlation between TL during active disease and at follow-up with triglyceride levels at active disease (adjusted [Adj] R2 = 0.64; P = 0.02 and Adj R2 = 0.5; P = 0.036, respectively), suggesting that the higher the triglycerides, the shorter the TL in patients with CD. The change of TL between active disease and follow-up was positively correlated with systolic blood pressure (Adj R2 = 0.76; P = 0.006).<br><br>Conclusions: In this pilot study, TL is shorter in children with hypercortisolemia, a difference that becomes detectable only after cure of CD. Triglycerides and blood pressure appear to be factors that are associated with TL in these patients. Further studies are required to confirm these results.},
}
@article {pmid32663838,
year = {2020},
author = {Miga, KH and Koren, S and Rhie, A and Vollger, MR and Gershman, A and Bzikadze, A and Brooks, S and Howe, E and Porubsky, D and Logsdon, GA and Schneider, VA and Potapova, T and Wood, J and Chow, W and Armstrong, J and Fredrickson, J and Pak, E and Tigyi, K and Kremitzki, M and Markovic, C and Maduro, V and Dutra, A and Bouffard, GG and Chang, AM and Hansen, NF and Wilfert, AB and Thibaud-Nissen, F and Schmitt, AD and Belton, JM and Selvaraj, S and Dennis, MY and Soto, DC and Sahasrabudhe, R and Kaya, G and Quick, J and Loman, NJ and Holmes, N and Loose, M and Surti, U and Risques, RA and Graves Lindsay, TA and Fulton, R and Hall, I and Paten, B and Howe, K and Timp, W and Young, A and Mullikin, JC and Pevzner, PA and Gerton, JL and Sullivan, BA and Eichler, EE and Phillippy, AM},
title = {Telomere-to-telomere assembly of a complete human X chromosome.},
journal = {Nature},
volume = {585},
number = {7823},
pages = {79-84},
pmid = {32663838},
issn = {1476-4687},
support = {2U41HG007234/HG/NHGRI NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; R21 HG010548/HG/NHGRI NIH HHS/United States ; R21 CA238758/CA/NCI NIH HHS/United States ; HG002385/NH/NIH HHS/United States ; R01 HG009190/HG/NHGRI NIH HHS/United States ; R01 HG002385/HG/NHGRI NIH HHS/United States ; HG010169/NH/NIH HHS/United States ; R01 GM124041/GM/NIGMS NIH HHS/United States ; U01 1U01HG010971/NH/NIH HHS/United States ; U01 HL137183/HL/NHLBI NIH HHS/United States ; DP2 MH119424/MH/NIMH NIH HHS/United States ; U54 1U54HG007990/NH/NIH HHS/United States ; T32 LM012419/LM/NLM NIH HHS/United States ; U01 1U01HL137183/HL/NHLBI NIH HHS/United States ; 1F32GM134558-01/NH/NIH HHS/United States ; 212965/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; /HHMI/Howard Hughes Medical Institute/United States ; F32 GM134558/GM/NIGMS NIH HHS/United States ; R01 HG010169/HG/NHGRI NIH HHS/United States ; U41 HG007234/HG/NHGRI NIH HHS/United States ; R01 CA181308/CA/NCI NIH HHS/United States ; U01 HG010971/HG/NHGRI NIH HHS/United States ; U54 HG007990/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R44 HG008118/HG/NHGRI NIH HHS/United States ; },
mesh = {Centromere/genetics ; Chromosomes, Human, X/*genetics ; CpG Islands/genetics ; DNA Methylation ; DNA, Satellite/genetics ; Female ; Genome, Human/*genetics ; Humans ; Hydatidiform Mole/genetics ; Male ; Pregnancy ; Reproducibility of Results ; Telomere/*genetics ; Testis/metabolism ; },
abstract = {After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.},
}
@article {pmid32661422,
year = {2020},
author = {Ge, Y and Wu, Z and Chen, H and Zhong, Q and Shi, S and Li, G and Wu, J and Lei, M},
title = {Structural insights into telomere protection and homeostasis regulation by yeast CST complex.},
journal = {Nature structural &amp; molecular biology},
volume = {27},
number = {8},
pages = {752-762},
doi = {10.1038/s41594-020-0459-8},
pmid = {32661422},
issn = {1545-9985},
mesh = {Crystallography, X-Ray ; DNA, Fungal/chemistry/metabolism ; Fungal Proteins/chemistry/*metabolism ; Kluyveromyces/chemistry/*metabolism ; Models, Molecular ; Protein Conformation ; Protein Multimerization ; Telomere/chemistry/*metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/chemistry/*metabolism ; },
abstract = {Budding yeast Cdc13-Stn1-Ten1 (CST) complex plays an essential role in telomere protection and maintenance. Despite extensive studies, only structural information of individual domains of CST is available; the architecture of CST still remains unclear. Here, we report crystal structures of Kluyveromyces lactis Cdc13-telomeric-DNA, Cdc13-Stn1 and Stn1-Ten1 complexes and propose an integrated model depicting how CST assembles and plays its roles at telomeres. Surprisingly, two oligonucleotide/oligosaccharide-binding (OB) folds of Cdc13 (OB2 and OB4), previously believed to mediate Cdc13 homodimerization, actually form a stable intramolecular interaction. This OB2-OB4 module of Cdc13 is required for the Cdc13-Stn1 interaction that assembles CST into an architecture with a central ring-like core and multiple peripheral modules in a 2:2:2 stoichiometry. Functional analyses indicate that this unique CST architecture is essential for both telomere capping and homeostasis regulation. Overall, our results provide fundamentally valuable structural information regarding the CST complex and its roles in telomere biology.},
}
@article {pmid32661111,
year = {2020},
author = {Cheng, F and Luk, AO and Tam, CHT and Fan, B and Wu, H and Yang, A and Lau, ESH and Ng, ACW and Lim, CKP and Lee, HM and Chow, E and Kong, AP and Keech, AC and Joglekar, MV and So, WY and Jenkins, AJ and Chan, JCN and Hardikar, AA and Ma, RCW},
title = {Shortened Relative Leukocyte Telomere Length Is Associated With Prevalent and Incident Cardiovascular Complications in Type 2 Diabetes: Analysis From the Hong Kong Diabetes Register.},
journal = {Diabetes care},
volume = {43},
number = {9},
pages = {2257-2265},
doi = {10.2337/dc20-0028},
pmid = {32661111},
issn = {1935-5548},
abstract = {OBJECTIVE: Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes.<br><br>RESEARCH DESIGN AND METHODS: Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code.<br><br>RESULTS: Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P < 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P < 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P < 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195-1.311], P < 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084-1.200], P < 0.001).<br><br>CONCLUSIONS: rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.},
}
@article {pmid32660821,
year = {2020},
author = {Hu, X and Guo, X and Ni, J and Wang, H and Cao, N and Liang, Z and Wang, X},
title = {High homocysteine promotes telomere dysfunction and chromosomal instability in human neuroblastoma SH-SY5Y cells.},
journal = {Mutation research},
volume = {854-855},
number = {},
pages = {503197},
doi = {10.1016/j.mrgentox.2020.503197},
pmid = {32660821},
issn = {1873-135X},
mesh = {Apoptosis/genetics ; Cell Death/genetics ; Cell Division/genetics ; Cell Line, Tumor ; Chromosomal Instability/*genetics ; Cytokinesis/genetics ; DNA Damage/genetics ; Homocysteine/*genetics ; Humans ; Micronuclei, Chromosome-Defective ; Micronucleus Tests/methods ; Necrosis/genetics ; Neuroblastoma/*genetics ; Telomerase/genetics ; Telomere/*genetics ; },
abstract = {Telomeres, specialized structures at the ends of linear chromosomes, protect chromosome ends from degradation, recombination, and mis-repair. Critically short telomere length (TL) may result in chromosome instability (CIN), causing tumor promotion and, at higher levels, cell death and tumor suppression. Homocysteine (Hcy) is a sulfur-containing amino acid involved in one-carbon metabolism. Elevated plasma Hcy is a cancer risk factor. Human SH-SY5Y neuroblastoma cells were treated with pathophysiological concentrations of Hcy (15-120 μM) for 14 and 28 days. The cytokinesis-block micronucleus cytome assay was used to determine cytostasis (nuclear division index, NDI), cell death (apoptosis and necrosis), and CIN (micronuclei, nucleoplasmic bridges, and nuclear buds in binucleated cells). Quantitative PCR was used to measure TL and the expression of hTERT, the gene encoding the catalytic subunit of telomerase for TL elongation. The results showed that Hcy induced elongation of TL and fluctuating changes in expression of hTERT. TL elongation was associated with increased CIN. Hcy decreased the NDI and increased cell death. This study shows that there is cross-talk between Hcy and TL in tumor cells and supports the concept that high Hcy inhibits cell division and promotes the death of tumor cells by abnormal elongation of TL and elevation of CIN.},
}
@article {pmid32658923,
year = {2020},
author = {Collin, V and Gravel, A and Kaufer, BB and Flamand, L},
title = {The Promyelocytic Leukemia Protein facilitates human herpesvirus 6B chromosomal integration, immediate-early 1 protein multiSUMOylation and its localization at telomeres.},
journal = {PLoS pathogens},
volume = {16},
number = {7},
pages = {e1008683},
pmid = {32658923},
issn = {1553-7374},
support = {MOP_123214//CIHR/Canada ; PJT_156118//CIHR/Canada ; },
mesh = {Cell Line ; Herpesvirus 6, Human/genetics/*metabolism ; Humans ; Immediate-Early Proteins/*metabolism ; Phosphoproteins/*metabolism ; Promyelocytic Leukemia Protein/*metabolism ; Roseolovirus Infections/genetics/*metabolism ; Sumoylation ; Telomere/*virology ; Virus Latency/genetics ; },
abstract = {Human herpesvirus 6B (HHV-6B) is a betaherpesvirus capable of integrating its genome into the telomeres of host chromosomes. Until now, the cellular and/or viral proteins facilitating HHV-6B integration have remained elusive. Here we show that a cellular protein, the promyelocytic leukemia protein (PML) that forms nuclear bodies (PML-NBs), associates with the HHV-6B immediate early 1 (IE1) protein at telomeres. We report enhanced levels of SUMOylated IE1 in the presence of PML and have identified a putative SUMO Interacting Motif (SIM) within IE1, essential for its nuclear distribution, overall SUMOylation and association with PML to nuclear bodies. Furthermore, using PML knockout cell lines we made the original observation that PML is required for efficient HHV-6B integration into host chromosomes. Taken together, we could demonstrate that PML-NBs are important for IE1 multiSUMOylation and that PML plays an important role in HHV-6B integration into chromosomes, a strategy developed by this virus to maintain its genome in its host over long periods of time.},
}
@article {pmid32650286,
year = {2020},
author = {Stroik, S and Hendrickson, EA},
title = {Telomere replication-When the going gets tough.},
journal = {DNA repair},
volume = {94},
number = {},
pages = {102875},
doi = {10.1016/j.dnarep.2020.102875},
pmid = {32650286},
issn = {1568-7856},
abstract = {Telomeres consist of repetitive tracts of DNA that shield a chromosome's contents from erosion and replicative attrition. However, telomeres are also late-replicating regions of the genome in which a myriad of replicative obstructions reside. The obstacles contained within telomeres, as well as their genomic location, drive replicative stalling and subsequent fork collapse in these regions. Consequently, large scale deletions, under-replicated DNA, translocations, and fusion events arise following telomere replication failure. Further, under-replicated DNA and telomere fusions that are permitted to enter mitosis will produce mitotic DNA bridges - known drivers of genetic loss and chromothripsis. Thus, aberrant telomere replication promotes genomic instability, which, in turn leads either to cellular death, senescence or oncogenic transformation. The importance of these issues for organismal well-being necessitates a need for resolute telomere maintenance. Here, we describe recent advances in identifying and understanding the molecular mechanisms that are in place in human cells to escort the replisome through the telomere's unwieldy structures and repetitive sequences. Finally, we review the pathways that combat the deleterious outcomes that occur when telomeric replication forks do collapse.},
}
@article {pmid32641227,
year = {2020},
author = {Fazzini, F and Lamina, C and Raschenberger, J and Schultheiss, UT and Kotsis, F and Schönherr, S and Weissensteiner, H and Forer, L and Steinbrenner, I and Meiselbach, H and Bärthlein, B and Wanner, C and Eckardt, KU and Köttgen, A and Kronenberg, F and , },
title = {Results from the German Chronic Kidney Disease (GCKD) study support association of relative telomere length with mortality in a large cohort of patients with moderate chronic kidney disease.},
journal = {Kidney international},
volume = {98},
number = {2},
pages = {488-497},
doi = {10.1016/j.kint.2020.02.034},
pmid = {32641227},
issn = {1523-1755},
abstract = {Telomere length is known to be inversely associated with aging and has been proposed as a marker for aging-related diseases. Telomere attrition can be accelerated by oxidative stress and inflammation, both commonly present in patients with chronic kidney disease. Here, we investigated whether relative telomere length is associated with mortality in a large cohort of patients with chronic kidney disease stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. Relative telomere length was quantified in peripheral blood by a quantitative PCR method in 4,955 patients from the GCKD study, an ongoing prospective observational cohort. Complete four-year follow-up was available from 4,926 patients in whom we recorded 354 deaths. Relative telomere length was a strong and independent predictor of all-cause mortality. Each decrease of 0.1 relative telomere length unit was highly associated with a 14% increased risk of death (hazard ratio1.14 [95% confidence interval 1.06-1.22]) in a model adjusted for age, sex, baseline eGFR, urine albumin/creatinine ratio, diabetes mellitus, prevalent cardiovascular disease, LDL-cholesterol, HDL-cholesterol, smoking, body mass index, systolic and diastolic blood pressure, C-reactive protein and serum albumin. This translated to a 75% higher risk for those in the lowest compared to the highest quartile of relative telomere length. The association was mainly driven by 117 cardiovascular deaths (1.20 [1.05-1.35]) as well as 67 deaths due to infections (1.27 [1.07-1.50]). Thus, our findings support an association of shorter telomere length with all-cause mortality, cardiovascular mortality and death due to infections in patients with moderate chronic kidney disease.},
}
@article {pmid32637486,
year = {2020},
author = {Ren, JC and Liu, H and Zhang, GH and Wang, T and Li, J and Dong, T and Wu, H and Xia, ZL},
title = {Dataset on the effect of Benzene exposure on genetic damage, hematotoxicity, telomere length and polymorphisms in metabolic and DNA repair genes.},
journal = {Data in brief},
volume = {31},
number = {},
pages = {105869},
pmid = {32637486},
issn = {2352-3409},
abstract = {In this paper, we present an occupational dataset to evaluate benzene exposure on the effective biomarkers of genetic damage, indicated as cytokinesis-block micronucleus (MN) frequency, hematotoxicity, indicated as white blood cells (WBC) counts, and molecular marker of telomere length (TL). And we further to eliminate the mechanism of benzene induced damage. Then evaluate the effects of sites polymorphism in environmental response genes, including 18 sites in metabolic and DNA repair genes, and the interaction between gene polymorphism and benzene exposure. This dataset is supplementary to the submitted research by [1] focused on the biomarkers TL, and a detailed description of the subjects sampling, biomarkers detection, data analysis and discussion are discussed in detail.},
}
@article {pmid32632978,
year = {2020},
author = {Antkowiak, M and Green, RM},
title = {Telomeres, p53, Hepatocyte Nuclear Factor 4α, and Liver Disease.},
journal = {Hepatology (Baltimore, Md.)},
volume = {72},
number = {4},
pages = {1166-1168},
doi = {10.1002/hep.31454},
pmid = {32632978},
issn = {1527-3350},
}
@article {pmid32620872,
year = {2020},
author = {Azarm, K and Bhardwaj, A and Kim, E and Smith, S},
title = {Persistent telomere cohesion protects aged cells from premature senescence.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {3321},
pmid = {32620872},
issn = {2041-1723},
support = {R01 CA200751/CA/NCI NIH HHS/United States ; F31 CA221162/CA/NCI NIH HHS/United States ; },
mesh = {Base Sequence ; Cell Line ; Cell Line, Tumor ; Cellular Senescence/genetics ; DNA Damage ; HEK293 Cells ; Heterochromatin/genetics/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Mutation ; RNA Interference ; Tankyrases/metabolism ; Telomere/*genetics/metabolism ; Telomere Shortening/*genetics ; Telomeric Repeat Binding Protein 1/deficiency/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/deficiency/*genetics/metabolism ; },
abstract = {Human telomeres are bound by the telomere repeat binding proteins TRF1 and TRF2. Telomere shortening in human cells leads to a DNA damage response that signals replicative senescence. While insufficient loading of TRF2 at shortened telomeres contributes to the DNA damage response in senescence, the contribution of TRF1 to senescence induction has not been determined. Here we show that counter to TRF2 deficiency-mediated induction of DNA damage, TRF1 deficiency serves a protective role to limit induction of DNA damage induced by subtelomere recombination. Shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion. Our findings suggest that the persistent cohesion protects short telomeres from inappropriate recombination. Ultimately, in the final division, telomeres are no longer able to maintain cohesion and subtelomere copying ensues. Thus, the gradual loss of TRF1 and concomitant persistent cohesion that occurs with telomere shortening ensures a measured approach to replicative senescence.},
}
@article {pmid32619407,
year = {2020},
author = {Mender, I and Zhang, A and Ren, Z and Han, C and Deng, Y and Siteni, S and Li, H and Zhu, J and Vemula, A and Shay, JW and Fu, YX},
title = {Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity.},
journal = {Cancer cell},
volume = {38},
number = {3},
pages = {400-411.e6},
pmid = {32619407},
issn = {1878-3686},
support = {C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; T32 CA124334/CA/NCI NIH HHS/United States ; },
abstract = {Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells. Here, we show that treatment with a telomere-targeting drug, 6-thio-2'-deoxyguanosine (6-thio-dG), leads to tumor regression through innate and adaptive immune-dependent responses in syngeneic and humanized mouse models of telomerase-expressing cancers. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/interferon I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8+ T cell activation. Moreover, 6-thio-dG overcomes resistance to checkpoint blockade in advanced cancer models. Our results unveil how telomere stress increases innate sensing and adaptive anti-tumor immunity and provide strong rationales for combining telomere-targeting therapy with immunotherapy.},
}
@article {pmid32618906,
year = {2020},
author = {},
title = {The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons: Erratum.},
journal = {Psychosomatic medicine},
volume = {82},
number = {6},
pages = {631},
doi = {10.1097/PSY.0000000000000831},
pmid = {32618906},
issn = {1534-7796},
}
@article {pmid32617831,
year = {2020},
author = {Vahidi, S and Norollahi, SE and Agah, S and Samadani, AA},
title = {DNA Methylation Profiling of hTERT Gene Alongside with the Telomere Performance in Gastric Adenocarcinoma.},
journal = {Journal of gastrointestinal cancer},
volume = {51},
number = {3},
pages = {788-799},
doi = {10.1007/s12029-020-00427-7},
pmid = {32617831},
issn = {1941-6636},
abstract = {PURPOSE: Epigenetic modification including of DNA methylation, histone acetylation, histone methylation, histon phosphorylation and non-coding RNA can impress the gene expression and genomic stability and cause different types of malignancies and also main human disorder. Conspicuously, the epigenetic alteration special DNA methylation controls telomere length, telomerase activity and also function of different genes particularly hTERT expression. Telomeres are important in increasing the lifespan, health, aging, and the development and progression of some diseases like cancer.<br><br>METHODS: This review provides an assessment of the epigenetic alterations of telomeres, telomerase and repression of its catalytic subunit, hTERT and function of long non-coding RNAs such as telomeric-repeat containing RNA (TERRA) in carcinogenesis and tumorgenesis of gastric cancer.<br><br>RESULTS: hTERT expression is essential and indispensable in telomerase activation through immortality and malignancies and also plays an important role in maintaining telomere length. Telomeres and telomerase have been implicated in regulating epigenetic factors influencing certain gene expression. Correspondingly, these changes in the sub telomere and telomere regions are affected by the shortening of telomere length and increased telomerase activity and hTERT gene expression have been observed in many cancers, remarkably in gastric cancer.<br><br>CONCLUSION: Epigenetic alteration and regulation of hTERT gene expression are critical in controlling telomerase activity and its expression. Graphical Abstract.},
}
@article {pmid32614411,
year = {2020},
author = {Tsai, CW and Chang, WS and Xu, J and Xu, Y and Huang, M and Pettaway, C and Bau, DT and Gu, J},
title = {Leukocyte telomere length is associated with aggressive prostate cancer in localized African American prostate cancer patients.},
journal = {Carcinogenesis},
volume = {41},
number = {9},
pages = {1213-1218},
doi = {10.1093/carcin/bgaa070},
pmid = {32614411},
issn = {1460-2180},
abstract = {Telomeres play important roles in cancer initiation and progression. Leukocyte telomere length (LTL) has been associated with the risk and prognosis of several cancers, but its association with prostate cancer (PCa) prognosis in African Americans (AAs) has not been reported. In this study, we measured relative LTL from 317 AA PCa patients and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after radical prostatectomy and radiotherapy. LTL was shorter in patients with higher Gleason scores (GS) at diagnosis. Dichotomized into short and long LTL groups, patients with short LTL exhibited a 1.91-fold (95% confidence interval, CI, 1.14-3.20, P = 0.013) increased risk of being diagnosed with high-risk disease (GS =7 [4 + 3] and GS ≥8) than those with long LTL in multivariable logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio = 1.68, 95% CI, 1.18-11.44, P = 0.024) compared with longer LTL in localized patients receiving prostatectomy or radiotherapy in multivariable Cox analysis. Kaplan-Meier survival analysis showed patients with short LTL had significantly shorter BCR-free survival time than patients with long LTL (Log rank P = 0.011). In conclusion, our results showed for the first time that LTL was shorter in PCa patients with higher GS and short LTL was associated with worse prognosis in AA PCa patients receiving prostatectomy or radiotherapy.},
}
@article {pmid32613841,
year = {2020},
author = {Sun, Y and Wang, W and Jiao, YR and Ren, J and Gao, L and Li, Y and Hu, P and Ren, TY and Han, QF and Chen, C and Yao, HC},
title = {Leukocyte telomere length: a potential biomarker for the prognosis of coronary artery disease.},
journal = {Biomarkers in medicine},
volume = {14},
number = {11},
pages = {933-941},
doi = {10.2217/bmm-2020-0171},
pmid = {32613841},
issn = {1752-0371},
abstract = {Aim: This study aimed to explore the prognostic value of leukocyte telomere length (LTL) in patients with coronary artery disease (CAD). Materials &amp; methods: We enrolled 366 CAD patients and 76 healthy subjects in this study. LTL was measured. All subjects were followed up for 6 months for further analysis regarding major adverse cardiac events (MACEs). Results: CAD patients had a significantly shortened LTL compared with healthy subjects (p < 0.05). The area under the curve for LTL prediction of MACEs was 0.769 (p < 0.001), with a shorter LTL being an independent predictor of MACEs (Cox proportional hazards regression, hazard ratio: 2.866; p < 0.001). Conclusion: LTL could be considered as an independent predictor of short-term MACEs in CAD.},
}
@article {pmid32612998,
year = {2020},
author = {Kahl, VFS and Allen, JAM and Nelson, CB and Sobinoff, AP and Lee, M and Kilo, T and Vasireddy, RS and Pickett, HA},
title = {Telomere Length Measurement by Molecular Combing.},
journal = {Frontiers in cell and developmental biology},
volume = {8},
number = {},
pages = {493},
pmid = {32612998},
issn = {2296-634X},
abstract = {Telomeres are repetitive regions of DNA bound by specialized proteins at the termini of linear chromosomes that prevent the natural chromosome ends from being recognized as DNA double strand breaks. Telomeric DNA is gradually eroded with each round of cell division, resulting in the accumulation of critically short or dysfunctional telomeres that eventually trigger cellular senescence. Consequently, telomere length is indicative of the proliferative capacity of a cell. Multiple methods exist to measure telomere length and telomere content, but a simple and reliable technique to accurately measure individual telomere lengths is currently lacking. We have developed the Telomere length Combing Assay (TCA) to measure telomere length on stretched DNA fibers. We used TCA to measure telomere erosion in primary human fibroblasts, and to detect telomere lengthening in response to activation of telomere maintenance pathways. TCA was also used to accurately measure telomere length in healthy individuals, and to identify critically short telomeres in patients with telomere biology disorders. TCA is performed on isolated DNA, negating the need for cycling cells. TCA is amenable to semi-automated image analysis, and can be fully automated using the Genomic Vision molecular combing platform. This not only precludes sampling bias, but also provides the potential for high-throughput applications and clinical development. TCA is a simple and versatile technique to measure the distribution of individual telomere lengths in a cell population, offering improved accuracy, and more detailed biological insight for telomere length measurement applications.},
}
@article {pmid32606142,
year = {2020},
author = {Jumatovaite, Z and Kriauciunas, A and Vilkeviciute, A and Gedvilaite, G and Liutkevicius, V and Uloza, V and Smalinskiene, A and Liutkeviciene, R},
title = {Association of Leukocyte Telomere Length and Genes Involved in its Regulation With Oral Carcinoma.},
journal = {In vivo (Athens, Greece)},
volume = {34},
number = {4},
pages = {1739-1747},
pmid = {32606142},
issn = {1791-7549},
abstract = {BACKGROUND/AIM: This study aimed to determine the relationship between the relative leukocyte telomere length (RLTL) and gene polymorphisms involved in its regulation with the occurrence of oral squamous cell carcinoma (OSCC).<br><br>PATIENTS AND METHODS: Patients with OSCC and healthy subjects were examined. Genotyping and RLTL measurement were carried out using rPCR.<br><br>RESULTS: The OSCC group had longer telomeres than controls (p=0.001). Minor allele T at TERF1rs1545827 may increase RLTL shortening (p=0.047). TNKS2rs10509639 A/G and A/G+G/G genotypes were associated with a 2.6-fold increased odd (p=0.012) and a 2.4-fold increased odd (p=0.019) of RLTL elongation compared to A/A genotype. The A/G genotype was associated with a 2.6-fold increased odd (p=0.011) compared to the A/A+G/G genotypes. Each G allele was associated with a 2.1-fold increased odd of longer RLTL (p=0.036).<br><br>CONCLUSION: Longer telomeres were found in patients with OSCC than in controls. The TERF1 rs1545827 and the TNKS2 rs10509639 polymorphisms were associated with an increase in RLTL.},
}
@article {pmid32604805,
year = {2020},
author = {Valera-Gran, D and Prieto-Botella, D and Peral-Gómez, P and Hurtado-Pomares, M and Sánchez-Pérez, A and Navarrete-Muñoz, EM},
title = {Bibliometric Analysis of Research on Telomere Length in Children: A Review of Scientific Literature.},
journal = {International journal of environmental research and public health},
volume = {17},
number = {12},
pages = {},
pmid = {32604805},
issn = {1660-4601},
mesh = {Asia ; *Bibliometrics ; Child ; Europe ; Humans ; Publications ; *Telomere ; *Telomere Homeostasis ; *Telomere Shortening ; United States ; },
abstract = {Telomere length in early life has been recently associated with biological aging and development of negative consequences in later adult life. A relevant area of research has emerged to understand the factors that impact telomere length in children. We conducted a bibliometric analysis to track research output and identify global trends and gaps in the knowledge of telomere length in children. Bibliographic data were retrieved from the Web of Science database and then analyzed by using Bibliometrix R package. A total of 840 publications were yielded from 1991 to 2019. The references were prominently published in journals, with 20 high ranked journals contributing to 30% of literature on telomere length in children. The USA was the most productive country (35.7%), followed by Europe (12.1%), and Asia (11.9%). A knowledge map of telomere length in children through keyword analyses revealed that there were two potential main lines of research based on two different approaches: genomic research and epidemiological research. This study shows that telomere length in children is a topic of research that has gained significant relevance in the last decade. This bibliometric study may be helpful in identifying research trends and finding research hot spots and gaps in this research field.},
}
@article {pmid32603955,
year = {2020},
author = {Coimbra, BM and Carvalho, CM and Ota, VK and Vieira-Fonseca, T and Bugiga, A and Mello, AF and Mello, MF and Belangero, SI},
title = {A systematic review on the effects of social discrimination on telomere length.},
journal = {Psychoneuroendocrinology},
volume = {120},
number = {},
pages = {104766},
doi = {10.1016/j.psyneuen.2020.104766},
pmid = {32603955},
issn = {1873-3360},
abstract = {Discrimination is unfair treatment against a certain group based on race, age, gender, sexual orientation, or other social identities. Discrimination is pervasive in society, elevates psychosocial stress, and is associated with negative mental and physical health outcomes. However, more research is needed to understand the biological mechanisms underlying discrimination-related health disparities. Telomere science may contribute to elucidate some of these aspects. Telomeres are protein-DNA complexes that shorten after cell division and are valuable markers of cellular aging. Short telomeres have been associated with the onset of age-related diseases. Evidence shows that chronic psychological stress may accelerate telomere shortening. Since discrimination can lead to psychological strain with cumulative impact on general health, we hypothesized that groups that report more discrimination show reduced telomere length (TL) as a consequence of psychosocial stress elevation. Through a systematic review of the literature we found 12 articles that met our criteria. Eligible studies measured racial, gender, unfair policing, and multiple forms of discrimination in association with TL. Our review showed mixed results, suggesting that there is weak evidence of a main association between discrimination and TL. However, discrimination may interact with several variables (such as depressive symptoms, acculturation, higher socioeconomic status, internalization of negative racial bias, and not discussing discrimination experiences with others) and contribute to shorten telomeres. Discrimination is a complex social construct composed of a vast sum of experiences, impressions, and contexts that in combination with other sources of stress may have an impact on TL. Telomeres may be a plausible pathway to investigate health discrepancies in discriminated groups in society, but more evidence is needed to investigate the potential harm of discrimination on cells.},
}
@article {pmid32599751,
year = {2020},
author = {Ogłuszka, M and Te Pas, MFW and Poławska, E and Nawrocka, A and Stepanow, K and Pierzchała, M},
title = {Omega-3 Alpha-Linolenic Fatty Acid Affects the Level of Telomere Binding Protein TRF1 in Porcine Skeletal Muscle.},
journal = {Animals : an open access journal from MDPI},
volume = {10},
number = {6},
pages = {},
pmid = {32599751},
issn = {2076-2615},
support = {RG 2/2016//NUTRICIA Foundation/ ; 2015/17/N/NZ9/01105//National Science Centre/ ; },
abstract = {Omega-3 fatty acids are health-promoting nutrients that contribute to the amelioration of age-related diseases. Recent studies have reported the role of these fatty acids in the aging process, explicitly impacting telomere biology. The shelterin protein complex, located at the extremities of chromosomes, ensures telomere protection and length regulation. Here, we analyzed the impact of dietary omega-3 alpha-linolenic fatty acid from linseed oil on skeletal muscle telomere biology using an animal model of female pigs. Fifteen animals were supplemented with linseed oil for nine weeks and an equal number of individuals were fed with a control diet. Linseed-oil-supplemented animals showed an increased level of alpha-linolenic acid in skeletal muscles compared to control animals. There was no difference between groups in the telomere length measured in leukocytes and muscles. However, muscles of the linseed-oil-supplemented pigs showed lower levels of the shelterin TRF1 protein compared to the control group. Our results suggest that omega-3 linolenic acid counteracts the elevation of TRF1 levels, which increase with age and due to the presence of reactive oxygen species in muscle. The observed effect may be due to attenuation of oxidative stress.},
}
@article {pmid32597753,
year = {2020},
author = {Shubin, CB and Greider, CW},
title = {The role of Rif1 in telomere length regulation is separable from its role in origin firing.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {32597753},
issn = {2050-084X},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; DGE-1746891//National Science Foundation/International ; },
abstract = {To examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ∆N-Dbf4 and Cdc7 increased DDK activity and activated telomeric origins, yet telomere length was unchanged. We tested a third mechanism to activate origins using the sld3-A mcm5-bob1 mutant that de-regulates the pre-replication complex, and again saw no change in telomere length. Finally, we tested whether mutations in RIF1 that cause telomere elongation would affect origin firing. We found that neither rif1-∆1322 nor rif1HOOK affected firing of telomeric origins. We conclude that telomeric origin firing does not cause telomere elongation, and the role of Rif1 in regulating origin firing is separable from its role in regulating telomere length.},
}
@article {pmid32594585,
year = {2020},
author = {Martínez-González, K and Islas-Hernández, A and Martínez-Ezquerro, JD and Bermúdez-Rattoni, F and Garcia-delaTorre, P},
title = {Telomere length and oxidative stress variations in a murine model of Alzheimer's disease progression.},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.14877},
pmid = {32594585},
issn = {1460-9568},
support = {179594//Consejo Nacional de Ciencia y Tecnología/ ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, and ageing is its major risk factor. Changes in telomere length have been associated with ageing and some degenerative diseases. Our aim was to explore some of the molecular changes caused by the progression of AD in a transgenic murine model (3xTg-AD; B6; 129-Psen1 <tm1Mpm> Tg (APPSwe, tauP301L) 1Lfa). Telomere length was assessed by qPCR in both brain tissue and peripheral blood cells and compared between three age groups: 5, 9 and 13 months. In addition, a possible effect of oxidative stress on telomere length and AD progression was explored. Shorter telomeres were found in blood cells of older transgenic mice compared to younger and wild-type mice but no changes in telomere length in the hippocampus. An increase in oxidative stress with age was found for all strains, but no correlation was found between oxidative stress and shorter telomere length for transgenic mice. Telomere length and oxidative stress are affected by AD progression in the 3xTg-AD murine model. Changes in blood cells are more noticeable than changes in brain tissue, suggesting that systemic changes can be detected early in the disease in this murine model.},
}
@article {pmid32589715,
year = {2020},
author = {Peska, V and Mátl, M and Mandáková, T and Vitales, D and Fajkus, P and Fajkus, J and Garcia, S},
title = {Human-like telomeres in Zostera marina reveal a mode of transition from the plant to the human telomeric sequences.},
journal = {Journal of experimental botany},
volume = {71},
number = {19},
pages = {5786-5793},
doi = {10.1093/jxb/eraa293},
pmid = {32589715},
issn = {1460-2431},
abstract = {A previous study describing the genome of Zostera marina, the most widespread seagrass in the Northern hemisphere, revealed some genomic signatures of adaptation to the aquatic environment such as the loss of stomatal genes, while other functions such as an algal-like cell wall composition were acquired. Beyond these, the genome structure and organization were comparable with those of the majority of plant genomes sequenced, except for one striking feature that went unnoticed at that time: the presence of human-like instead of the expected plant-type telomeric sequences. By using different experimental approaches including fluorescence in situ hybridization (FISH), genome skimming by next-generation sequencing (NGS), and analysis of non-coding transcriptome, we have confirmed its telomeric location in the chromosomes of Z. marina. We have also identified its telomerase RNA (TR) subunit, confirming the presence of the human-type telomeric sequence in the template region. Remarkably, this region was found to be very variable even in clades with a highly conserved telomeric sequence across their species. Based on this observation, we propose that alternative annealing preferences in the template borders can explain the transition between the plant and human telomeric sequences. The further identification of paralogues of TR in several plant genomes led us to the hypothesis that plants may retain an increased ability to change their telomeric sequence. We discuss the implications of this occurrence in the evolution of telomeres while introducing a mechanistic model for the transition from the plant to the human telomeric sequences.},
}
@article {pmid32588935,
year = {2021},
author = {Millan, AL and Trobo, SI and de Dios, A and Cerrato García, M and Pérez, MS and Cerrone, GE and Frechtel, GD and López, AP},
title = {MODY patients exhibit shorter telomere length than non-diabetic subjects.},
journal = {Diabetes/metabolism research and reviews},
volume = {37},
number = {2},
pages = {e3374},
doi = {10.1002/dmrr.3374},
pmid = {32588935},
issn = {1520-7560},
support = {2018//Sociedad Argentina de Diabetes/ ; 20720170200027BA//Universidad de Buenos Aires/ ; },
abstract = {BACKGROUND: Given the increasing evidence supporting the association between telomere shortening and diabetes, the aim of the present work was to establish whether MODY patients suffer a reduction in telomere lenght (TL) due to oxidative stress produced by chronic hyperglycemia, despite not presenting insulin resistance or inflammation.<br><br>METHODS: We analysed clinical and biochemical parameters in 35 MODY2 and 12 MODY3 patients compared with 48 control subjects. The absolute telomere length (aTL) of peripheral blood leukocytes was measured using the quantitative polymerase chain reaction (qPCR).<br><br>RESULTS: A significant negative correlation was observed between aTL and age in the whole population, among MODY patients and in each subtype studied, MODY2 and MODY3, which allowed us to validate the method. We found, for the first time, that MODY patients have shorter aTL with respect to non-diabetic controls (6.49 ± 3.31 kbp vs 11.13 ± 7.82 kbp, p = .006). However, no differences were found between MODY2 and MODY3. In addition, aTL showed a negative correlation with duration of the disease and fasting plasma glucose (FPG) levels in MODY patients in general and also with HbA1c in MODY2 patients in particular.<br><br>CONCLUSIONS: Both MODY2 and MODY3 types present telomere shortening, which, at least partly, responds to HbA1c and FPG levels. These findings suggest comparable mechanisms underlying the attrition of TL. Taken together, our results on aTL in MODY patients may provide a parameter relatively easy and inexpensive to quantify in order to measure the impact of high glucose levels and potentially carry out antidiabetic treatment with stricter targets.},
}
@article {pmid32588833,
year = {2020},
author = {Vysotskaya, OV and Glukhov, AI and Semochkina, YP and Gordeev, SA and Moskaleva, EY},
title = {[Telomerase activity, mTert gene expression and the telomere length in mouse mesenchymal stem cells in the late period after γ- and γ,n-irradiation and in the tumors developed from these cells].},
journal = {Biomeditsinskaia khimiia},
volume = {66},
number = {3},
pages = {265-273},
doi = {10.18097/PBMC20206603265},
pmid = {32588833},
issn = {2310-6972},
mesh = {Animals ; Cell Line ; Fibrosarcoma/pathology ; *Gamma Rays ; *Mesenchymal Stem Cells ; Mice ; *Telomerase/genetics/metabolism ; *Telomere/genetics ; },
abstract = {In proliferating normal and tumor cells, the telomere length (TL) is maintained by high telomerase activity (TA). In the absence of TA the TL maintenance involves a mechanism of alternative lengthening of telomeres (ALT). The aim of this study was to investigate the level of TA, the mTert expression and TL in cultured normal and transformed by γ- and γ,n-irradiation mesenchymal stem cells (MSCs) from mouse bone marrow, in sarcomas that developed after the transplantation of these cells into syngeneic mice, and in fibrosarcoma cell lines obtained from these tumors to find out the role of AT or ALT in maintaining TL in these cells. During prolonged cultivation of normal and transformed under the influence of γ- (1 Gy and 6 Gy) and γ,n-irradiation (0.05 Gy, 0.5 Gy, and 2 Gy) MSCs from mouse bone marrow, a decrease in TA was detected in irradiated cells. Even deeper decrease in TA was found in sarcomas developed after administration of transformed MSCs to syngeneic mice and in fibrosarcoma cell lines isolated from these tumors in which TA was either absent or was found to be at a very low level. TL in three of the four lines obtained was halved compared to the initial MSCs. With absent or low TA and reduced TL, the cells of all the obtained fibrosarcoma lines successfully proliferated without signs of a change in survival. The mechanism of telomere maintainance in fibrosarcoma cell lines in the absence of TA needs further investigation and it can be assumed that it is associated with the use of the ALT. The detected decrease or absence of TA in transformed under the action of irradiation MSCs with the preservation or even an increase in the telomerase gene expression may be associated with the formation of inactive splicing variants, and requires further study. The obtained lines of transformed MSCs and fibrosarcomas with TA and without the activity of this enzyme can be a useful model for studying the efficacy of TA and ALT inhibitors in vitro and in vivo.},
}
@article {pmid32587985,
year = {2020},
author = {Maremanda, KP and Sundar, IK and Li, D and Rahman, I},
title = {Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2020.06.14.20129957},
pmid = {32587985},
abstract = {Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 &amp; 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 &amp; 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.},
}
@article {pmid32586834,
year = {2020},
author = {Yin, H and Hardikar, S and Lindstroem, S and Hsu, L and Anderson, KE and Banbury, BL and Berndt, SI and Chan, AT and Giovanucci, EL and Harrison, TA and Joshi, AD and Nan, H and Potter, JD and Sakoda, LC and Slattery, ML and Schoen, RE and White, E and Peters, U and Newcomb, PA},
title = {Telomere Maintenance Variants and Survival after Colorectal Cancer: Smoking- and Sex-Specific Associations.},
journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {29},
number = {9},
pages = {1817-1824},
doi = {10.1158/1055-9965.EPI-19-1507},
pmid = {32586834},
issn = {1538-7755},
support = {P30 CA015704/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated.<br><br>METHODS: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction.<br><br>RESULTS: The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men.<br><br>CONCLUSIONS: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted.<br><br>IMPACT: Our study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.},
}
@article {pmid32586523,
year = {2020},
author = {Koss, KJ and Schneper, LM and Brooks-Gunn, J and McLanahan, S and Mitchell, C and Notterman, DA},
title = {Early Puberty and Telomere Length in Preadolescent Girls and Mothers.},
journal = {The Journal of pediatrics},
volume = {222},
number = {},
pages = {193-199.e5},
pmid = {32586523},
issn = {1097-6833},
support = {R01 HD036916/HD/NICHD NIH HHS/United States ; R01 HD076592/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Child ; *Child Development ; Female ; Humans ; Menarche/*genetics ; *Mothers ; Puberty/*genetics ; Retrospective Studies ; Telomere/*genetics ; Telomere Homeostasis/*physiology ; Young Adult ; },
abstract = {OBJECTIVE: To test the association between early puberty and telomere length in preadolescent girls and mothers from a large representative sample of US females.<br><br>STUDY DESIGN: We analyzed data from 1194 preadolescent girls and 2421 mothers from the Fragile Families and Child Wellbeing Study. Participants were from a population-based birth cohort (1998-2000) born in large US cities. Telomere length was assessed by quantitative polymerase chain reaction from saliva samples provided by preadolescent girls and mothers of preadolescent youth. Mothers completed a questionnaire about their child's pubertal development to determine concurrent Tanner stages and provided self-reports of her own age at menarche. Linear regression models were used to estimate the association between pubertal development (status and timing) and telomere length.<br><br>RESULTS: Early pubertal timing but not pubertal status was associated with shorter telomere length in preadolescent girls (P < .01). Early age at menarche was associated with shorter telomere length in a sample of mothers of preadolescent youth (P < .05).<br><br>CONCLUSIONS: Results provide evidence for the association between early puberty and shorter telomeres evidenced by associations in both preadolescent girls and mothers. Future research should address the limitations of this study by using longitudinal measurements of pubertal development assessed through medical examinations and repeated assessments of telomere length to capture telomere attrition.},
}
@article {pmid32583791,
year = {2020},
author = {Vakili, SA and George, A and Ayatollahi, SA and Martorell, M and Ostrander, EA and Salehi, B and Martins, N and Sharifi-Rad, J},
title = {Phenolic compounds, saponins and alkaloids on cancer progression: emphasis on p53 expression and telomere length.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {66},
number = {4},
pages = {110-119},
pmid = {32583791},
issn = {1165-158X},
mesh = {Alkaloids/*pharmacology ; Animals ; *Disease Progression ; Humans ; Neoplasms/*pathology ; Phenols/*pharmacology ; Saponins/*pharmacology ; Telomere Homeostasis/*drug effects ; Tumor Suppressor Protein p53/*metabolism ; },
abstract = {Telomere length is correlated with cell proliferation, and cancer cells are characterized by an uncontrolled cell cycle. Being apoptosis one of the checks and balances incorporated into cells cycle, due to its characteristics, cancer cells are able to overcome this process. In particular, the tumour suppressor protein p53 loss or inactivation can lead to activation of telomerase enzyme, which can make cells unable to detect DNA damages that spurs apoptosis. Some bioactive compounds, in particular phenolic compounds, saponins and alkaloids have revealed good abilities to affect p53 expression and indirectly control the telomere length. In this sense, this review gives a key emphasis to the ability of these compounds in blocking cancer progression by acting on p53 expression and controlling telomere length. As main findings, phenolic compounds, saponins and alkaloids interfere with cancer progression by stimulating p53 expression, which can cause pro-apoptotic onset and restrict the anti-apoptotic activity, in addition to preventing telomerase enzyme activity.},
}
@article {pmid32583532,
year = {2020},
author = {Fang, C and Huang, H and Zhang, Q and Wang, N and Jing, X and Guo, J and Ferianc, M and Xu, Z},
title = {Relation between sex hormones and leucocyte telomere length in men with idiopathic pulmonary fibrosis.},
journal = {Respirology (Carlton, Vic.)},
volume = {25},
number = {12},
pages = {1265-1273},
pmid = {32583532},
issn = {1440-1843},
support = {2016YFC0905700//National Key R&amp;D Program of China:/ ; 81670061//National Natural Science Foundation of China/ ; 2016YFC0905700//National Key R&amp;D Program of China/ ; },
abstract = {BACKGROUND AND OBJECTIVE: IPF is an ageing-related lung disorder featuring progressive lung scarring. IPF patients are frequently identified with short telomeres but coding mutations in telomerase can only explain a minority of cases. Sex hormones regulate telomerase activity in vitro and levels of sex hormones are related to LTL. The objective of this study was to explore whether sex hormones were associated with LTL, whether they interacted with genetic variants in telomerase and whether polymorphisms in the exon of androgen metabolism genes were associated with plasma testosterone concentrations in male IPF patients.<br><br>METHODS: A case-control study was performed on 101 male IPF subjects and 51 age-matched healthy controls. Early morning plasma sex hormones were quantified, and whole-exome sequencing was used to identify rare protein-altering variants of telomerase and SNP in the exon of androgen metabolism genes. LTL was analysed by PCR and expressed as a T/S ratio.<br><br>RESULTS: LTL, testosterone and DHT were decreased significantly in the IPF group. After adjustments for age and variant status in telomerase-related genes, only testosterone was positively associated with LTL (P = 0.001). No significant interaction (P = 0.661) was observed between rare protein-altering variants of telomerase and testosterone. No coding SNP in androgen metabolism genes were significantly associated with testosterone concentrations.<br><br>CONCLUSION: Plasma testosterone is associated with LTL independent of age or rare protein-altering variants of telomerase. No genetic variations of androgen-related pathway genes are associated with androgen concentrations. Further studies are warranted to examine whether hormonal interventions might retard telomere loss in male IPF patients.},
}
@article {pmid32581523,
year = {2020},
author = {Mir, SM and Samavarchi Tehrani, S and Goodarzi, G and Jamalpoor, Z and Asadi, J and Khelghati, N and Qujeq, D and Maniati, M},
title = {Shelterin Complex at Telomeres: Implications in Ageing.},
journal = {Clinical interventions in aging},
volume = {15},
number = {},
pages = {827-839},
pmid = {32581523},
issn = {1178-1998},
mesh = {Aging/genetics/*metabolism ; DNA Replication ; Humans ; *Oxidative Stress ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere-Binding Proteins/genetics/*metabolism ; },
abstract = {Different factors influence the development‎ and control of ageing. It is well known that progressive telomere shorting is one of the molecular mechanisms underlying ageing. The shelterin complex consists of six telomere-specific proteins which are involved in the protection of chromosome ends. More particularly, this vital complex protects the telomeres from degradation, prevents from activation of unwanted repair systems, regulates the activity of telomerase, and has a crucial role in cellular senescent and ageing-related pathologies. This review explores the organization and function of telomeric DNA along with the mechanism of telomeres during ageing, followed by a discussion of the critical role of shelterin components and their changes during ageing.},
}
@article {pmid32581228,
year = {2020},
author = {Zhang, Y and Zhou, Q and Yang, R and Hu, C and Huang, Z and Zheng, C and Liang, Q and Gong, R and Zhu, X and Gong, H and Yuan, H and Chen, C and Li, X and Zhang, N and Yang, Z and Sun, L},
title = {Serum branched-chain amino acids are associated with leukocyte telomere length and frailty based on residents from Guangxi longevity county.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {10252},
pmid = {32581228},
issn = {2045-2322},
mesh = {Adult ; Aged ; Aged, 80 and over ; Amino Acids, Branched-Chain/*blood ; China ; Chromatography, Liquid ; Cross-Sectional Studies ; Female ; Frailty/*blood/metabolism ; Humans ; Leukocytes/*chemistry ; Male ; Middle Aged ; Tandem Mass Spectrometry ; Telomere/*metabolism ; Telomere Homeostasis ; },
abstract = {Branched-chain amino acids (BCAAs) and telomere length are biologically associated with healthy aging. However, the association between them and their interaction on frailty remain unclear in humans. Here, a cross-sectional study based on residents from Guangxi longevity county was conducted to investigate the association of serum BCAAs, peripheral leukocyte telomere length (LTL) and frailty. A total of 1,034 subjects aged 20 to 110 years were recruited in the study. The real-time qPCR method and a targeted metabolomics approach based on isotope dilution liquid chromatography tandem mass spectrometry (LC/MS/MS) method were used for measurement of LTL and BCAAs, respectively. A frailty score defined as the proportion of accumulated deficits based on 24 aging-related items was used assess the health status of elderly subjects. First, we found that a higher concentration of BCAAs was significantly associated with longer LTL only in middle-aged subjects, independent of age and BMI (P < 0.05). In the oldest-old subjects, we identified a significantly inverse association between BCAAs and frailty score (P < 0.001), even after adjustment for age and BMI (P < 0.05). Additionally, we recognized a statistically significant synergetic interaction between BCAAs and LTL on frailty score in the oldest-old subjects by the general linear model (P = 0.042), although we did not find any significant association between LTL and frailty score. In summary, our findings suggest a potentially protective effect of circulating BCAAs on LTL and frailty based on the subjects from longevity county in East Asia and indicate a potential synergetic interaction between BCAAs and LTL in healthy aging.},
}
@article {pmid32579791,
year = {2020},
author = {Seimiya, H},
title = {Crossroads of telomere biology and anticancer drug discovery.},
journal = {Cancer science},
volume = {111},
number = {9},
pages = {3089-3099},
pmid = {32579791},
issn = {1349-7006},
support = {N/A//Nippon Foundation/ ; 19H03523//Japan Society for the Promotion of Science/ ; 20H04789//Japan Society for the Promotion of Science/ ; 20ck0106476h0002 and N/A//Japan Agency for Medical Research and Development/ ; },
mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Cell Transformation, Neoplastic/genetics ; *Drug Discovery ; G-Quadruplexes/drug effects ; Genetic Therapy ; Humans ; Ligands ; Neoplasms/drug therapy/genetics/pathology ; Oncolytic Virotherapy ; Promoter Regions, Genetic ; RNA, Untranslated/genetics ; Telomerase/genetics/metabolism ; Telomere/*drug effects/genetics ; Telomere Shortening/drug effects ; },
abstract = {The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5'-TTAGGG-3' repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination-based mechanism to maintain telomeres and exhibit immortality. As the most frequent non-coding mutations in cancer, gain-of-function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere-directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter-driven oncolytic adenoviruses. Tankyrase poly(ADP-ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt-driven cancer. Meanwhile, telomeric nucleic acids form a higher-order structure called a G-quadruplex (G4). G4s are formed genome-wide and their dynamics affect various events, including replication, transcription, and translation. G4-stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.},
}
@article {pmid32579423,
year = {2020},
author = {Zhang, H and Zhao, R and Tones, J and Liu, M and Dilley, RL and Chenoweth, DM and Greenberg, RA and Lampson, MA},
title = {Nuclear body phase separation drives telomere clustering in ALT cancer cells.},
journal = {Molecular biology of the cell},
volume = {31},
number = {18},
pages = {2048-2056},
pmid = {32579423},
issn = {1939-4586},
support = {K22 CA237632/CA/NCI NIH HHS/United States ; R01 CA174904/CA/NCI NIH HHS/United States ; R01 GM101149/GM/NIGMS NIH HHS/United States ; U54 CA193417/CA/NCI NIH HHS/United States ; R35 GM122475/GM/NIGMS NIH HHS/United States ; R01 GM118510/GM/NIGMS NIH HHS/United States ; },
abstract = {Telomerase-free cancer cells employ a recombination-based alternative lengthening of telomeres (ALT) pathway that depends on ALT-associated promyelocytic leukemia nuclear bodies (APBs), whose function is unclear. We find that APBs behave as liquid condensates in response to telomere DNA damage, suggesting two potential functions: condensation to enrich DNA repair factors and coalescence to cluster telomeres. To test these models, we developed a chemically induced dimerization approach to induce de novo APB condensation in live cells without DNA damage. We show that telomere-binding protein sumoylation nucleates APB condensation via interactions between small ubiquitin-like modifier (SUMO) and SUMO interaction motif (SIM), and that APB coalescence drives telomere clustering. The induced APBs lack DNA repair factors, indicating that APB functions in promoting telomere clustering can be uncoupled from enriching DNA repair factors. Indeed, telomere clustering relies only on liquid properties of the condensate, as an alternative condensation chemistry also induces clustering independent of sumoylation. Our findings introduce a chemical dimerization approach to manipulate phase separation and demonstrate how the material properties and chemical composition of APBs independently contribute to ALT, suggesting a general framework for how chromatin condensates promote cellular functions.},
}
@article {pmid32578161,
year = {2020},
author = {Sasamoto, N and Yland, J and Vitonis, AF and Cramer, DW and Titus, LJ and De Vivo, I and Missmer, SA and Terry, KL},
title = {Peripheral Blood Leukocyte Telomere Length and Endometriosis.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {27},
number = {10},
pages = {1951-1959},
pmid = {32578161},
issn = {1933-7205},
support = {R01 HD094842/HD/NICHD NIH HHS/United States ; Trainee Award//Boston Center for Endometriosis (US)/International ; Liz Tilberis Award//Ovarian Cancer Research Fund (US)/International ; },
mesh = {Adult ; Algorithms ; Case-Control Studies ; Endometriosis/*metabolism ; Female ; Humans ; Leukocytes, Mononuclear/*metabolism ; Middle Aged ; Nutrition Surveys ; *Telomere ; },
abstract = {Endometriosis is a common gynecologic disease defined by the presence of endometrial-like tissue outside the uterine cavity. While its etiology is largely unknown, accumulating evidence suggests that inflammation plays a major role. Our objective was to investigate the association between peripheral blood leukocyte telomere length (LTL) and endometriosis using data from two large population-based studies, the New England Case-Control Study (NEC; n = 877) and the National Health and Nutrition Examination Survey (NHANES; n = 2268). NEC control participants were identified through a combination of random digit dialing, drivers' license lists, and town resident lists. In NHANES, selection algorithms were used to identify a nationally representative sample. Blood samples and demographic, reproductive, and health-related information were available from both data sources. Endometriosis was defined as self-reported of physician-diagnosed endometriosis. LTL was measured using quantitative polymerase chain reaction. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between LTL and endometriosis. Shorter LTL was associated with greater odds of history of endometriosis. In NEC, women with the shortest LTL tertile compared with the longest had a 2.5-fold greater odds of endometriosis (ORT3/T1 = 2.56, 95% CI = 1.16-5.63; p value, test for linear trend = 0.02). The association was stronger among women who usually experienced moderate or severe menstrual pain (OR T3/T1 = 3.50, 95% CI = 1.12-10.97). In NHANES, the data suggested a similar but attenuated association (ORT3/T1 = 1.29, 95% CI = 0.85-1.96). The observed associations in NEC suggest that shorter LTL may be associated with greater odds of endometriosis. A better understanding of how LTL influences endometriosis risk could elucidate novel disease pathophysiology.},
}
@article {pmid32577419,
year = {2020},
author = {Courtwright, AM and Lamattina, AM and Takahashi, M and Trindade, AJ and Hunninghake, GM and Rosas, IO and Agarwal, S and Raby, BA and Goldberg, HJ and El-Chemaly, S},
title = {Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival.},
journal = {ERJ open research},
volume = {6},
number = {2},
pages = {},
pmid = {32577419},
issn = {2312-0541},
abstract = {Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease. This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival. Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1-3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03-1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01-1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05-15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27-7.01, p=0.70). Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease.},
}
@article {pmid32577134,
year = {2020},
author = {Huang, P and Li, R and Shen, L and He, W and Chen, S and Dong, Y and Ma, J and Chen, X and Xu, M},
title = {Single nucleotide polymorphisms in telomere length-related genes are associated with hepatocellular carcinoma risk in the Chinese Han population.},
journal = {Therapeutic advances in medical oncology},
volume = {12},
number = {},
pages = {1758835920933029},
pmid = {32577134},
issn = {1758-8340},
abstract = {Background: Single nucleotide polymorphisms (SNPs) in telomere-related genes are associated with a high risk of hepatocellular carcinoma (HCC). In this study, we investigated the SNPs of telomere length-related genes and their correlation with HCC risk in the Chinese Han population.<br><br>Materials and methods: A total of 473 HCC patients and 564 healthy volunteers were recruited. Overall, 42 SNPs distributed in telomere-related genes were selected and identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.<br><br>Results: We found rs6713088 (OR = 1.27, 95% CI = 1.07-1.52, p = 0.007), rs843711 (OR = 1.29, 95% CI = 1.09-1.54, p = 0.004) and rs843706 (OR = 1.30, 95% CI = 1.09-1.55, p = 0.003) in the ACYP2 gene, rs10936599 (OR = 1.21, 95% CI = 1.02-1.44, p = 0.032) in the TERC gene and rs7708392 (OR = 1.24, 95% CI = 1.00-1.52, p = 0.042) in the TNIP1 gene were associated with high HCC risk (OR > 1). In contrast, rs1682111 (OR = 0.77, 95% CI = 0.64-0.94, p = 0.008) in the ACYP2 gene, rs2320615 (OR = 0.79, 95% CI = 0.64-0.99, p = 0.038) in the NAF1 gene, rs10069690 (OR = 0.75, 95% CI = 0.59-0.96, p = 0.021) and rs2242652 (OR = 0.70, 95% CI = 0.55-0.90, p = 0.004) in the TERT gene were associated with low HCC risk (OR < 1). Based on genotype frequency distributions, rs6713088, rs843645, rs843711 and rs843706 located in the ACYP2 gene as well as rs10936599 in the TERC gene were associated with a high incidence of HCC (p < 0.05). In addition, SNPs in these genes could form a linkage imbalance haplotype. Specifically, the haploid 'GC' formed by rs10069690 and rs2242652 within the TERT gene increased the risk of HCC (p < 0.05).<br><br>Conclusion: SNPs in ACYP2, TERC, TERT and other genes were correlated with HCC risk in the Chinese Han population. These data may provide new insights into early diagnosis and screening of HCC.},
}
@article {pmid32576588,
year = {2020},
author = {Vaiciulis, P and Liutkeviciene, R and Liutkevicius, V and Vilkeviciute, A and Gedvilaite, G and Uloza, V},
title = {Association of Relative Leucocyte Telomere Length and Gene Single Nucleotide Polymorphisms (TERT, TRF1, TNKS2) in Laryngeal Squamous Cell Carcinoma.},
journal = {Cancer genomics &amp; proteomics},
volume = {17},
number = {4},
pages = {431-439},
pmid = {32576588},
issn = {1790-6245},
mesh = {Biomarkers, Tumor/*genetics ; Case-Control Studies ; Female ; Follow-Up Studies ; Genetic Predisposition to Disease ; Head and Neck Neoplasms/genetics/pathology ; Humans ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Prognosis ; Squamous Cell Carcinoma of Head and Neck/genetics/*pathology ; Tankyrases/*genetics ; Telomerase/*genetics ; Telomere Homeostasis/*genetics ; Telomere-Binding Proteins/*genetics ; },
abstract = {BACKGROUND/AIM: The study aimed to evaluate associations of relative leukocyte telomere length (LTL) and polymorphisms of telomere length-associated genes TERT (rs2736098), TERT-CLPTM1L (rs401681), TRF1 (rs1545827, rs10107605) and TNKS2 (rs10509637, rs10509639) in patients with laryngeal squamous cell carcinoma (LSCC).<br><br>MATERIALS AND METHODS: The study consisted of 300 patients with LSCC and 369 healthy control subjects. Genotyping and relative LTL measuring were carried out using qPCR.<br><br>RESULTS: Relative LTL was statistically significantly shorter in the G3 (tumor differentiation grade) subgroup of patients with LSCC compared to the G1 and G2 subgroups. Significant differences were found in genotype distributions of TERT rs401681 and TNKS2 rs10509639 between the study groups. TERT rs401681 C/T and T/T genotypes were associated with approximately 30% decreased odds of LSCC development.<br><br>CONCLUSION: LTL was shorter in the G3 subgroup compared to the G2 and G1 subgroups of LSCC patients. TERT rs401681 and its C/T and T/T genotypes were associated with decreased odds of overall LSCC development.},
}
@article {pmid32575418,
year = {2020},
author = {Posch, A and Hofer-Zeni, S and Klieser, E and Primavesi, F and Naderlinger, E and Brandstetter, A and Filipits, M and Urbas, R and Swiercynski, S and Jäger, T and Winkelmann, P and Kiesslich, T and Lu, L and Neureiter, D and Stättner, S and Holzmann, K},
title = {Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns.},
journal = {Cancers},
volume = {12},
number = {6},
pages = {},
pmid = {32575418},
issn = {2072-6694},
abstract = {Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN.},
}
@article {pmid32575077,
year = {2020},
author = {Semeraro, MD and Smith, C and Kaiser, M and Levinger, I and Duque, G and Gruber, HJ and Herrmann, M},
title = {Physical activity, a modulator of aging through effects on telomere biology.},
journal = {Aging},
volume = {12},
number = {13},
pages = {13803-13823},
pmid = {32575077},
issn = {1945-4589},
abstract = {Aging is a complex process that is not well understood but involves finite changes at the genetic and epigenetic level. Physical activity is a well-documented modulator of the physiological process of aging. It has been suggested that the beneficial health effects of regular exercise are at least partly mediated through its effects on telomeres and associated regulatory pathways. Telomeres, the region of repetitive nucleotide sequences functioning as a &quot;cap&quot; at the chromosomal ends, play an important role to protect genomic DNA from degradation. Telomeres of dividing cells progressively shorten with age. Leucocyte telomere length (TL) has been associated with age-related diseases. Epidemiologic evidence indicates a strong relationship between physical activity and TL. In addition, TL has also been shown to predict all-cause and cardiovascular mortality. Experimental studies support a functional link between aerobic exercise and telomere preservation through activation of telomerase, an enzyme that adds nucleotides to the telomeric ends. However, unresolved questions regarding exercise modalities, pathomechanistic aspects and analytical issues limit the interpretability of available data. This review provides an overview about the current knowledge in the area of telomere biology, aging and physical activity. Finally, the capabilities and limitations of available analytical methods are addressed.},
}
@article {pmid32575070,
year = {2020},
author = {Honkonen, M and Vääräniemi, K and Saijonmaa, O and Nyman, A and Tikkakoski, AJ and Koskela, J and Lehtimäki, T and Kähönen, M and Mustonen, J and Fyhrquist, F and Pörsti, I},
title = {Leukocyte telomere length is inversely associated with arterial wave reflection in 566 normotensive and never-treated hypertensive subjects.},
journal = {Aging},
volume = {12},
number = {12},
pages = {12376-12392},
pmid = {32575070},
issn = {1945-4589},
abstract = {Telomeres are short segments in chromosome ends, the length of which is reduced during cell lifecycles. We examined the association of mean leukocyte telomere length (LTL) and short telomere proportion (STP) with hemodynamic variables in normotensive and never-treated hypertensive volunteers (n=566, 19-72 years). STP and mean LTL were determined using Southern blotting, and supine hemodynamics recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. The analyses were adjusted for age, body mass index (BMI), alcohol use, smoking, plasma chemistry, and estimated glomerular filtration rate (eGFR). In univariate analyses, mean LTL and STP both correlated with age, BMI, eGFR, aortic blood pressure, augmentation index, and pulse wave velocity (p<0.05 for all). Mean LTL also correlated with systemic vascular resistance (p<0.05). In linear regression analyses of all hemodynamic variables, mean LTL was only an independent explanatory factor for augmentation index (Beta -0.006, p=0.032), while STP was not an explanatory factor for any of the hemodynamic variables, in contrast to age, BMI and several cardiovascular risk factors. To conclude, augmentation index was predominantly related with chronological aging, but also with mean LTL, suggesting that this variable of central wave reflection is a modest marker of vascular biological aging.},
}
@article {pmid32571415,
year = {2020},
author = {Keng, SL and Yim, OS and Lai, PS and Chew, SH and Ebstein, RP},
title = {Correction to: Association among dispositional mindfulness, self-compassion, and leukocyte telomere length in Chinese adults.},
journal = {BMC psychology},
volume = {8},
number = {1},
pages = {65},
pmid = {32571415},
issn = {2050-7283},
abstract = {An amendment to this paper has been published and can be accessed via the original article.},
}
@article {pmid32565730,
year = {2020},
author = {Yu, J and Liu, H and He, S and Li, P and Ma, C and Ma, M and Liu, Y and Lv, L and Ping, F and Zhang, H and Li, W and Sun, Q and Xu, L and Li, Y},
title = {Dietary Magnesium Intake and Leukocyte Telomere Attrition in Adults: The Regulatory Role of Serum Tumor Necrosis Factor α.},
journal = {Mediators of inflammation},
volume = {2020},
number = {},
pages = {7610436},
pmid = {32565730},
issn = {1466-1861},
abstract = {Objectives: In this study, we assessed the effects of dietary magnesium on leukocyte telomere length (LTL).<br><br>Designs: The current cross-sectional analysis was based on data collected within a type 2 diabetes project. Settings. Dietary magnesium intake is associated with peripheral blood leukocyte telomere length (LTL). However, few epidemiological studies have evaluated the effects of magnesium on LTL in the clinical setting. Participants. This cross-sectional analysis included 467 participants (34.8% men). Measurements. Serum blood lipid profile, HbA1c, oxidative stress, and proinflammatory mediator levels were measured. Detailed dietary data were obtained using a 24 h food recall. LTL was assessed using a real-time PCR assay. Regression models and simple regulatory models were used for data analysis.<br><br>Results: There was an inverse relationship between dietary magnesium and LTL (P < 0.001), with a between-extreme-quarter difference of -0.55. Conversely, there was a positive relationship between dietary magnesium and serum tumor necrosis factor (TNF) α, with an interquarter difference of 3.79 pmol/mL (P for trend = 0.006). Multivariate regression analysis revealed that the odds ratios (ORs) for shorter LTL and higher serum TNFα increased with magnesium intake, and the ORs of the differences between extreme quartiles were 2.60 (95% confidence interval (CI): 1.31-5.36; P = 0.003) and 1.98 (95% CI: 1.09-3.59; P = 0.008). There was a direct negative effect of dietary magnesium intake on LTL (B = -0.002; P = 0.001), which appeared to be indirectly influenced by TNFα (-0.002 to -0.0005).<br><br>Conclusions: Dietary magnesium intake may be a critical component of the cellular aging process, and its effect could be partly mediated by TNFα.},
}
@article {pmid32565330,
year = {2020},
author = {Aguado, J and d'Adda di Fagagna, F and Wolvetang, E},
title = {Telomere transcription in ageing.},
journal = {Ageing research reviews},
volume = {62},
number = {},
pages = {101115},
doi = {10.1016/j.arr.2020.101115},
pmid = {32565330},
issn = {1872-9649},
mesh = {Aging/genetics ; Cellular Senescence/genetics ; Genomic Instability ; Humans ; RNA, Untranslated/genetics ; *Telomere/genetics ; },
abstract = {Telomeres, the ends of eukaryotic chromosomes, play a central role in the control of cellular senescence and organismal ageing and need to be protected in order to avoid being recognised as damaged DNA and activate DNA damage response pathways. Dysfunctional telomeres arise from critically short telomeres or altered telomere structures, which ultimately lead to replicative cellular senescence and chromosome instability: both hallmarks of ageing. The observation that telomeres are transcribed led to the discovery that telomeric transcripts play important roles in chromosome end protection and genome stability maintenance. Recent evidence indicates that particular long non-coding (nc)RNAs transcribed at telomeres, namely TElomeric Repeat-containing RNA (TERRA) and telomeric damage-induced long ncRNAs (tdilncRNA), play key roles in age-related pathways by actively orchestrating the mechanisms known to regulate telomere length, chromosome end protection and DNA damage signalling. Here, we provide a comprehensive overview of the telomere transcriptome, outlining how it functions as a regulatory platform with essential functions in safeguarding telomere integrity and stability. We next review emerging antisense oligonucleotides therapeutic strategies that target telomeric ncRNAs and discuss their potential for ameliorating ageing and age-related diseases. Altogether, this review provides insights on the biological relevance of telomere transcription mechanisms in human ageing physiology and pathology.},
}
@article {pmid32564008,
year = {2020},
author = {Habib, R and Kim, R and Neitzel, H and Demuth, I and Chrzanowska, K and Seemanova, E and Faber, R and Digweed, M and Voss, R and Jäger, K and Sperling, K and Walter, M},
title = {Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome.},
journal = {Aging},
volume = {12},
number = {12},
pages = {12342-12375},
pmid = {32564008},
issn = {1945-4589},
abstract = {BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy.<br><br>RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity.<br><br>CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis.<br><br>METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.},
}
@article {pmid32560940,
year = {2020},
author = {Liu, Z and Han, R and Zhu, W and Xiu, J and Shen, Y and Xu, Q},
title = {Inverse changes in telomere length between the blood and brain in depressive-like mice.},
journal = {Journal of affective disorders},
volume = {273},
number = {},
pages = {453-461},
doi = {10.1016/j.jad.2020.01.089},
pmid = {32560940},
issn = {1573-2517},
mesh = {Animals ; Brain/metabolism ; *Depressive Disorder, Major/genetics ; Humans ; Mice ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; },
abstract = {BACKGROUND: Telomeres are nucleoprotein complexes located at the end of chromosomes. Previous studies have confirmed that telomere length is reduced in the peripheral blood of depression patients. However, studies regarding whether telomere length is altered in brain regions associated with depression are limited. It remains unclear whether the peripheral blood telomere length indicates telomere variation in the brain.<br><br>METHODS: Using quantitative PCR, we measured telomere length in five brain regions (prefrontal cortex, amygdala, nucleus accumbens, paraventricular nucleus, and hippocampus) from depressive-like mice and in peripheral blood from depressive-like mice and major depressive disorder (MDD) patients. We also examined the expression of telomerase- and alternative lengthening of telomere (ALT)-related genes in the prefrontal cortex and amygdala of depressive-like mice.<br><br>RESULTS: Telomeres were shortened in the peripheral blood of depressive-like mice and MDD patients, but were elongated in the prefrontal cortex and amygdala compared with healthy controls. We also observed that the expression of ALT-related genes increased in the prefrontal cortex and amygdala.<br><br>LIMITATIONS: The amount of human sample was limited. The mechanism of telomere lengthening in the brain of depressive-like mice was not well explained. Mice and humans have inherently different telomere and telomere maintenance systems.<br><br>CONCLUSION: These findings illustrate that the telomere length in the peripheral blood may not indicate the dynamics of telomere length in the brain. They offer a new perspective on variable telomere length in different brain regions affected in depression and provide a new basis for understanding the relationship between variable telomere length and MDD.},
}
@article {pmid32558886,
year = {2020},
author = {Rahnama, M and Novikova, O and Starnes, JH and Zhang, S and Chen, L and Farman, ML},
title = {Transposon-mediated telomere destabilization: a driver of genome evolution in the blast fungus.},
journal = {Nucleic acids research},
volume = {48},
number = {13},
pages = {7197-7217},
pmid = {32558886},
issn = {1362-4962},
mesh = {Evolution, Molecular ; Magnaporthe/*genetics ; Plant Diseases/*microbiology ; Retroelements/*genetics ; Telomere/*genetics ; },
abstract = {The fungus Magnaporthe oryzae causes devastating diseases of crops, including rice and wheat, and in various grasses. Strains from ryegrasses have highly unstable chromosome ends that undergo frequent rearrangements, and this has been associated with the presence of retrotransposons (Magnaporthe oryzae Telomeric Retrotransposons-MoTeRs) inserted in the telomeres. The objective of the present study was to determine the mechanisms by which MoTeRs promote telomere instability. Targeted cloning, mapping, and sequencing of parental and novel telomeric restriction fragments (TRFs), along with MinION sequencing of genomic DNA allowed us to document the precise molecular alterations underlying 109 newly-formed TRFs. These included truncations of subterminal rDNA sequences; acquisition of MoTeR insertions by 'plain' telomeres; insertion of the MAGGY retrotransposons into MoTeR arrays; MoTeR-independent expansion and contraction of subtelomeric tandem repeats; and a variety of rearrangements initiated through breaks in interstitial telomere tracts that are generated during MoTeR integration. Overall, we estimate that alterations occurred in approximately sixty percent of chromosomes (one in three telomeres) analyzed. Most importantly, we describe an entirely new mechanism by which transposons can promote genomic alterations at exceptionally high frequencies, and in a manner that can promote genome evolution while minimizing collateral damage to overall chromosome architecture and function.},
}
@article {pmid32558330,
year = {2020},
author = {Ojeda-Rodríguez, A and Morell-Azanza, L and Zalba, G and Zazpe, I and Azcona-Sanjulian, MC and Marti, A},
title = {Associations of telomere length with two dietary quality indices after a lifestyle intervention in children with abdominal obesity: a randomized controlled trial.},
journal = {Pediatric obesity},
volume = {15},
number = {11},
pages = {e12661},
doi = {10.1111/ijpo.12661},
pmid = {32558330},
issn = {2047-6310},
mesh = {Adiposity ; Adolescent ; Body Composition ; Body Mass Index ; Child ; *Diet, Healthy ; Diet, Mediterranean ; Female ; *Healthy Lifestyle ; Humans ; Male ; Obesity, Abdominal/*genetics ; Spain ; Telomere Homeostasis/*physiology ; },
abstract = {BACKGROUND: Dietary factors seem to influence telomere length. Moreover, associations between changes in adiposity indices and telomere length (TL) have been found in intervention studies.<br><br>OBJECTIVE: We evaluated changes in two diet quality indices and their association with TL in children with abdominal obesity in a 12-month lifestyle intervention.<br><br>METHODS: Eighty-seven participants (7-16 years old) were assigned to the intervention (moderate hypocaloric Mediterranean diet) or usual care group (standard paediatric recommendations) for a 2-month intensive phase and a subsequent 10-month follow-up. Diet quality was assessed using the Diet Quality Index for Adolescents (DQI-A) and the Healthy Lifestyle Diet Index (HLD-I). TL was measured by monochrome multiplex real-time quantitative PCR. The intra-class correlation coefficient for TL was 0.793 (95% CI 0.707, 0.857).<br><br>RESULTS: After a 12-month lifestyle intervention, a significant reduction in BMI-SDS (-0.57 and -0.49 for the intervention and usual care groups, respectively) and fat mass was observed in all subjects without differences between groups. Changes in DQI-A (+12.36% vs +5.53%, P = .005) and HLD-I (+4.43 vs +1.09, P < .001) were higher in the intervention subjects compared with usual care subjects after 2 months. Interestingly, we observed a positive change in TL between 2 and 12 months (P = .025), which was associated with higher scores on the DQI-A (β = 0.008, R2 = 0.088, P = .010) and HLD-I (β = 0.022, R2 = 0.198, P = .015), in the intervention group after the 2-month intensive phase.<br><br>CONCLUSION: Favourable changes in diet quality indices could contribute to telomere integrity in children with abdominal obesity enrolled in an intensive lifestyle intervention.},
}
@article {pmid32554492,
year = {2020},
author = {Lex, K and Maia Gil, M and Lopes-Bastos, B and Figueira, M and Marzullo, M and Giannetti, K and Carvalho, T and Ferreira, MG},
title = {Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {26},
pages = {15066-15074},
pmid = {32554492},
issn = {1091-6490},
support = {/HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Disease Models, Animal ; Humans ; Melanoma/genetics/immunology/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Telomere Shortening ; Tumor Necrosis Factor-alpha/genetics/immunology ; Zebrafish/genetics/immunology/*metabolism ; Zebrafish Proteins/genetics/metabolism ; },
abstract = {Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-α (TNF1-α) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.},
}
@article {pmid32551854,
year = {2020},
author = {Naikawadi, RP and Green, G and Jones, KD and Achtar-Zadeh, N and Mieleszko, JE and Arnould, I and Kukreja, J and Greenland, JR and Wolters, PJ},
title = {Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction.},
journal = {American journal of respiratory cell and molecular biology},
volume = {63},
number = {4},
pages = {490-501},
pmid = {32551854},
issn = {1535-4989},
support = {I01 CX002011/CX/CSRD VA/United States ; IK2 CX001034/CX/CSRD VA/United States ; R01 HL139897/HL/NHLBI NIH HHS/United States ; R01 HL151552/HL/NHLBI NIH HHS/United States ; },
mesh = {Allografts/metabolism/*pathology ; Alveolar Epithelial Cells/metabolism/*pathology ; Animals ; Biomarkers/metabolism ; Cellular Senescence/genetics ; Humans ; Lung/metabolism/*physiology ; Lung Transplantation/methods ; Mice ; Pulmonary Fibrosis/genetics/metabolism/pathology ; Telomere/*genetics ; Uteroglobin/genetics/metabolism ; },
abstract = {Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (β-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1F/F (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated β-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.},
}
@article {pmid32551387,
year = {2020},
author = {Nickels, M and Mastana, S and Hunter, D and Denniff, M and Codd, V and Akam, E},
title = {The effect of a 12-week resistance training intervention on leukocyte telomere length.},
journal = {Heliyon},
volume = {6},
number = {6},
pages = {e04151},
pmid = {32551387},
issn = {2405-8440},
abstract = {Telomere dynamics are an active biological process and positive lifestyle factors such as exercise are proposed to potentiate their length. The aim of this study was to investigate the effect of a low-resistance, high-repetition resistance training intervention on leukocyte telomere length (LTL) and associated health parameters. 23 sedentary middle-aged adults volunteered for this study (16 female/7 male; age = 51.5 ± 4.9 years) and performed two one-hour sessions of Les Mills BODYPUMP™ per week for 12 weeks. Outcome measures were taken at baseline, after the training intervention and at 12-month follow-up. LTL remained unchanged following the training intervention (pre 0.819 ± 0.121 vs post 0.812 ± 0.114, p = 0.420), despite a borderline significant increase in hTERT expression (p = 0.050). Circulating levels of tumour necrosis factor alpha were reduced after the intervention (p = 0.001). At 12-month follow-up, subjects who returned to a sedentary lifestyle (n = 10) displayed shorter telomeres compared to their pre (p = 0.036) values. In conclusion, no changes were observed in LTL following the 12-week training intervention, despite improvements in molecular parameters associated with telomere dynamics. It appears continued long-term exercise (>12 months) is necessary to preserve LTL in previously sedentary individuals.},
}
@article {pmid32547557,
year = {2020},
author = {Trindade, AJ and Thaniyavarn, T and Townsend, K and Klasek, R and Tsveybel, KP and Kennedy, JC and Goldberg, HJ and El-Chemaly, S},
title = {Alemtuzumab as a Therapy for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients With Short Telomeres.},
journal = {Frontiers in immunology},
volume = {11},
number = {},
pages = {1063},
pmid = {32547557},
issn = {1664-3224},
support = {R01 HL130275/HL/NHLBI NIH HHS/United States ; },
abstract = {Alemtuzumab, a monoclonal antibody targeting CD52 that causes lymphocyte apoptosis, is a form of advanced immunosuppression that is currently used as a therapy for refractory acute cellular rejection and chronic lung allograft dysfunction in lung transplant recipients (1-3). Side effects of alemtuzumab include bone marrow suppression, infection, and malignancy. Whether alemtuzumab can be safely used in allograft recipients that have an increased propensity for bone marrow suppression due to telomeropathies is unknown. In a retrospective case series, we report outcomes associated with alemtuzumab in three lung allograft recipients with short telomere lengths, comparing endpoints such as leukopenia, transfusion needs, infection, hospitalization and survival to those of 17 patients without known telomeropathies that received alemtuzumab. We show that the use of alemtuzumab in lung transplant recipients with short telomeres is safe, though is associated with an increased incidence of neutropenia, thrombocytopenia and anemia requiring packed red blood cell transfusions. Alemtuzumab appears to be an acceptable advanced immunosuppressive therapy in patients with telomeropathies, though given the design and scope of this study, the actual clinical effect needs further evaluation in larger trials.},
}
@article {pmid32541825,
year = {2020},
author = {Maasen, K and James, PT and Prentice, AM and Moore, SE and Fall, CH and Chandak, GR and Betts, M and Silver, MJ and Buxton, JL},
title = {Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7-9 year old rural Gambian children.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {9675},
pmid = {32541825},
issn = {2045-2322},
support = {MC-A760- 5QX00/MRC_/Medical Research Council/United Kingdom ; MR/N006208/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_12011/3/MRC_/Medical Research Council/United Kingdom ; G0400519/MRC_/Medical Research Council/United Kingdom ; MC_UP_A620_1016/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Child ; Child, Preschool ; Cross-Sectional Studies ; Female ; Fertilization ; Gambia ; Humans ; Leukocytes/*metabolism ; Male ; Regression Analysis ; Seasons ; Telomere/*metabolism ; *Telomere Shortening ; },
abstract = {Early life exposures are important predictors of adult disease risk. Although the underlying mechanisms are largely unknown, telomere maintenance may be involved. This study investigated the relationship between seasonal differences in parental exposures at time of conception and leukocyte telomere length (LTL) in their offspring. LTL was measured in two cohorts of children aged 2 yrs (N = 487) and 7-9 yrs (N = 218). The association between date of conception and LTL was examined using Fourier regression models, adjusted for age, sex, leukocyte cell composition, and other potential confounders. We observed an effect of season in the older children in all models [likelihood ratio test (LRT) χ²2 = 7.1, p = 0.03; fully adjusted model]. LTL was greatest in children conceived in September (in the rainy season), and smallest in those conceived in March (in the dry season), with an effect size (LTL peak-nadir) of 0.60 z-scores. No effect of season was evident in the younger children (LRT χ²2 = 0.87, p = 0.65). The different results obtained for the two cohorts may reflect a delayed effect of season of conception on postnatal telomere maintenance. Alternatively, they may be explained by unmeasured differences in early life exposures, or the increased telomere attrition rate during infancy.},
}
@article {pmid32540968,
year = {2020},
author = {Abdisalaam, S and Bhattacharya, S and Mukherjee, S and Sinha, D and Srinivasan, K and Zhu, M and Akbay, EA and Sadek, HA and Shay, JW and Asaithamby, A},
title = {Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase.},
journal = {The Journal of biological chemistry},
volume = {295},
number = {32},
pages = {11144-11160},
pmid = {32540968},
issn = {1083-351X},
support = {R01 HL115275/HL/NHLBI NIH HHS/United States ; P30 CA142543/CA/NCI NIH HHS/United States ; C06 RR030414/RR/NCRR NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 AG053341/AG/NIA NIH HHS/United States ; },
abstract = {Defective DNA damage response (DDR) signaling is a common mechanism that initiates and maintains the cellular senescence phenotype. Dysfunctional telomeres activate DDR signaling, genomic instability, and cellular senescence, but the links among these events remains unclear. Here, using an array of biochemical and imaging techniques, including a highly regulatable CRISPR/Cas9 strategy to induce DNA double strand breaks specifically in the telomeres, ChIP, telomere immunofluorescence, fluorescence in situ hybridization (FISH), micronuclei imaging, and the telomere shortest length assay (TeSLA), we show that chromosome mis-segregation due to imperfect DDR signaling in response to dysfunctional telomeres creates a preponderance of chromatin fragments in the cytosol, which leads to a premature senescence phenotype. We found that this phenomenon is caused not by telomere shortening, but by cyclic GMP-AMP synthase (cGAS) recognizing cytosolic chromatin fragments and then activating the stimulator of interferon genes (STING) cytosolic DNA-sensing pathway and downstream interferon signaling. Significantly, genetic and pharmacological manipulation of cGAS not only attenuated immune signaling, but also prevented premature cellular senescence in response to dysfunctional telomeres. The findings of our study uncover a cellular intrinsic mechanism involving the cGAS-mediated cytosolic self-DNA-sensing pathway that initiates premature senescence independently of telomere shortening.},
}
@article {pmid32533363,
year = {2020},
author = {Albizua, I and Chopra, P and Allen, EG and He, W and Amin, AS and Sherman, SL},
title = {Study of telomere length in men who carry a fragile X premutation or full mutation allele.},
journal = {Human genetics},
volume = {139},
number = {12},
pages = {1531-1539},
doi = {10.1007/s00439-020-02194-8},
pmid = {32533363},
issn = {1432-1203},
support = {NS091859//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {5' Untranslated Regions/genetics ; Adult ; Aged ; Alleles ; Ataxia/*genetics/pathology ; Fragile X Mental Retardation Protein/*genetics ; Fragile X Syndrome/*genetics/pathology ; Humans ; Male ; Middle Aged ; Mutation/genetics ; Telomere/*genetics/pathology/ultrastructure ; Telomere Homeostasis/genetics ; Tremor/*genetics/pathology ; Trinucleotide Repeat Expansion/genetics ; Young Adult ; },
abstract = {The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5' UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are &quot;biologically older&quot;, as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are &quot;biologically older&quot; than men carrying the normal size allele in the same age group.},
}
@article {pmid32532864,
year = {2020},
author = {Casagrande, S and Stier, A and Monaghan, P and Loveland, JL and Boner, W and Lupi, S and Trevisi, R and Hau, M},
title = {Increased glucocorticoid concentrations in early life cause mitochondrial inefficiency and short telomeres.},
journal = {The Journal of experimental biology},
volume = {223},
number = {Pt 15},
pages = {},
doi = {10.1242/jeb.222513},
pmid = {32532864},
issn = {1477-9145},
abstract = {Telomeres are DNA structures that protect chromosome ends. However, telomeres shorten during cell replication and at critically low lengths can reduce cell replicative potential, induce cell senescence and decrease fitness. Stress exposure, which elevates glucocorticoid hormone concentrations, can exacerbate telomere attrition. This phenomenon has been attributed to increased oxidative stress generated by glucocorticoids ('oxidative stress hypothesis'). We recently suggested that glucocorticoids could increase telomere attrition during stressful periods by reducing the resources available for telomere maintenance through changes in the metabolic machinery ('metabolic telomere attrition hypothesis'). Here, we tested whether experimental increases in glucocorticoid levels affected telomere length and mitochondrial function in wild great tit (Parus major) nestlings during the energy-demanding early growth period. We monitored resulting corticosterone (Cort) concentrations in plasma and red blood cells, telomere lengths and mitochondrial metabolism (metabolic rate, proton leak, oxidative phosphorylation, maximal mitochondrial capacity and mitochondrial inefficiency). We assessed oxidative damage caused by reactive oxygen species (ROS) metabolites as well as the total non-enzymatic antioxidant protection in plasma. Compared with control nestlings, Cort-nestlings had higher baseline corticosterone, shorter telomeres and higher mitochondrial metabolic rate. Importantly, Cort-nestlings showed increased mitochondrial proton leak, leading to a decreased ATP production efficiency. Treatment groups did not differ in oxidative damage or antioxidants. Hence, glucocorticoid-induced telomere attrition is associated with changes in mitochondrial metabolism, but not with ROS production. These findings support the hypothesis that shortening of telomere length during stressful periods is mediated by glucocorticoids through metabolic rearrangements.},
}
@article {pmid32532801,
year = {2020},
author = {Aklilu, BB and Peurois, F and Saintomé, C and Culligan, KM and Kobbe, D and Leasure, C and Chung, M and Cattoor, M and Lynch, R and Sampson, L and Fatora, J and Shippen, DE},
title = {Functional Diversification of Replication Protein A Paralogs and Telomere Length Maintenance in Arabidopsis.},
journal = {Genetics},
volume = {215},
number = {4},
pages = {989-1002},
pmid = {32532801},
issn = {1943-2631},
support = {R01 GM065383/GM/NIGMS NIH HHS/United States ; },
abstract = {Replication protein A (RPA) is essential for many facets of DNA metabolism. The RPA gene family expanded in Arabidopsis thaliana with five phylogenetically distinct RPA1 subunits (RPA1A-E), two RPA2 (RPA2A and B), and two RPA3 (RPA3A and B). RPA1 paralogs exhibit partial redundancy and functional specialization in DNA replication (RPA1B and RPA1D), repair (RPA1C and RPA1E), and meiotic recombination (RPA1A and RPA1C). Here, we show that RPA subunits also differentially impact telomere length set point. Loss of RPA1 resets bulk telomeres at a shorter length, with a functional hierarchy for replication group over repair and meiosis group RPA1 subunits. Plants lacking RPA2A, but not RPA2B, harbor short telomeres similar to the replication group. Telomere shortening does not correlate with decreased telomerase activity or deprotection of chromosome ends in rpa mutants. However, in vitro assays show that RPA1B2A3B unfolds telomeric G-quadruplexes known to inhibit replications fork progression. We also found that ATR deficiency can partially rescue short telomeres in rpa2a mutants, although plants exhibit defects in growth and development. Unexpectedly, the telomere shortening phenotype of rpa2a mutants is completely abolished in plants lacking the RTEL1 helicase. RTEL1 has been implicated in a variety of nucleic acid transactions, including suppression of homologous recombination. Thus, the lack of telomere shortening in rpa2a mutants upon RTEL1 deletion suggests that telomere replication defects incurred by loss of RPA may be bypassed by homologous recombination. Taken together, these findings provide new insight into how RPA cooperates with replication and recombination machinery to sustain telomeric DNA.},
}
@article {pmid32531916,
year = {2020},
author = {Slusher, AL and Kim, JJ and Ludlow, AT},
title = {The Role of Alternative RNA Splicing in the Regulation of hTERT, Telomerase, and Telomeres: Implications for Cancer Therapeutics.},
journal = {Cancers},
volume = {12},
number = {6},
pages = {},
pmid = {32531916},
issn = {2072-6694},
support = {R00 CA197672/CA/NCI NIH HHS/United States ; CA197672-01A1//National Institutes of Health/ National Cancer Institute/ ; },
abstract = {Alternative RNA splicing impacts the majority (>90%) of eukaryotic multi-exon genes, expanding the coding capacity and regulating the abundance of gene isoforms. Telomerase (hTERT) is a key example of a gene that is alternatively spliced during human fetal development and becomes dysregulated in nearly all cancers. Approximately 90% of human tumors use telomerase to synthesize de novo telomere repeats and obtain telomere-dependent cellular immortality. Paradigm shifting data indicates that hTERT alternative splicing, in addition to transcription, plays an important role in the regulation of active telomerase in cells. Our group and others are pursuing the basic science studies to progress this emerging area of telomerase biology. Recent evidence demonstrates that switching splicing of hTERT from the telomerase activity producing full-length hTERT isoform to alternatively spliced, non-coding isoforms may be a novel telomerase inhibition strategy to prevent cancer growth and survival. Thus, the goals of this review are to detail the general roles of telomerase in cancer development, explore the emerging regulatory mechanisms of alternative RNA splicing of the hTERT gene in various somatic and cancer cell types, define the known and potential roles of hTERT splice isoforms in cancer cell biology, and provide insight into new treatment strategies targeting hTERT in telomerase-positive cancers.},
}
@article {pmid32531572,
year = {2020},
author = {Louzon, M and Zahn, S and Capelli, N and Massemin, S and Coeurdassier, M and Pauget, B and Gimbert, F and de Vaufleury, A},
title = {Impact of ageing and soil contaminants on telomere length in the land snail.},
journal = {Ecotoxicology and environmental safety},
volume = {201},
number = {},
pages = {110766},
doi = {10.1016/j.ecoenv.2020.110766},
pmid = {32531572},
issn = {1090-2414},
mesh = {Animals ; Environmental Pollution ; Helix, Snails ; Mercury ; Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; Snails/drug effects/*physiology ; Soil ; Soil Pollutants/analysis/*toxicity ; Telomere/*drug effects ; },
abstract = {Telomeres (TLs) are non-coding DNA sequences that are usually shortened with ageing and/or chemical exposure. Bioindicators such as the land snail can be used to assess the environmental risk of contaminated soils. As for most invertebrates, the evolution of TLs with ageing or exposure to contaminants is unknown in this mollusc. The aims of this study were to explore the relationships between ageing, contaminant exposure, sublethal effects and TL length in the terrestrial gastropod Cantareus aspersus. TL length was investigated in haemocytes from five age classes of C. aspersus. The impact of contaminants on sub-adult snails exposed to Cd, Hg or a mixture of polycyclic aromatic hydrocarbons (PAHs) in soils for one or two months was studied. Bioaccumulation, growth, sexual maturity and TLs were measured. TL attrition was significant for the juvenile and sub-adult stages, but not later. Exposure to Cd increased the mortality (around 30%). Exposure to polluted soils inhibited growth (19-40%) and sexual maturity (6-100%). Although the health of the snails exposed to Cd, Hg and PAHs was altered, TL length in haemocytes was not disturbed, suggesting a high capacity of this snail species to maintain its TLs in haemocytes under chemical stress. These results first address TL length in snails and reveal that the relationship commonly proposed for vertebrates between TL shortening and ageing or exposure to contaminants cannot be generalized.},
}
@article {pmid32526789,
year = {2020},
author = {Penrice, DD and Simonetto, DA},
title = {Short Telomeres: Cause and Consequence in Liver Disease.},
journal = {Seminars in liver disease},
volume = {},
number = {},
pages = {},
doi = {10.1055/s-0040-1713007},
pmid = {32526789},
issn = {1098-8971},
abstract = {Short telomere syndrome is a genetically inherited syndrome resulting in premature telomere shortening. This premature shortening of telomeres can result in hematologic, pulmonary, vascular, gastrointestinal, and hepatic manifestations of disease. Identifying patients with short telomere syndrome can be a clinical challenge due to the multitude of potential manifestations and lack of widely available diagnostic tests. In this review, we will highlight hepatic manifestations of short telomere syndrome with a focus on diagnosis, testing, and potential treatments.},
}
@article {pmid32522626,
year = {2020},
author = {Burraco, P and Comas, M and Reguera, S and Zamora-Camacho, FJ and Moreno-Rueda, G},
title = {Telomere length mirrors age structure along a 2200-m altitudinal gradient in a Mediterranean lizard.},
journal = {Comparative biochemistry and physiology. Part A, Molecular &amp; integrative physiology},
volume = {247},
number = {},
pages = {110741},
doi = {10.1016/j.cbpa.2020.110741},
pmid = {32522626},
issn = {1531-4332},
abstract = {The timing of organisms' senescence is developmentally programmed but also shaped by the interaction between environmental inputs and life-history traits. In ectotherms, ageing dynamics are still poorly understood even though their body temperature, metabolism, or growth trajectory are very sensitive to environmental changes. Here, we investigated the role of life-history traits such as age, sex, body size, body condition, and tail autotomy (i.e self-amputation) in shaping telomere length in six populations of the Algerian sand lizard (Psammodromus algirus) distributed along an elevational gradient from 300 to 2500 m above the sea level. Additionally, we compiled the available information on reptiles' telomere length in a review table. Our cross-sectional study shows that older lizards have longer telomeres, which might be mostly linked to the selective disappearance of individuals with shorter telomeres or, alternatively, mediated by a higher expression of telomerase across their life. In fact, variation in telomere length across elevation was explained by age structure of lizards; thus, in contrast to our predictions, altitude had no effect on telomere length in this study system. Telomere length was unaffected by tail regeneration and was sex-independent, but positively correlated with body condition, which might be linked to high somatic investment. Hence, our results suggest that life-history traits such as age or body condition can be major drivers of telomere dynamics for this species, whereas environmental conditions apparently had scarce or no effects on lizard telomeres. Our findings emphasize the relevance of understanding species' life histories for fully disentangling the causes and consequences of differences in ageing in ectotherms.},
}
@article {pmid32516515,
year = {2020},
author = {Munroe, M and Niero, EL and Fok, WC and Vessoni, AT and Jeong, HC and Brenner, KA and Batista, LFZ},
title = {Telomere Dysfunction Activates p53 and Represses HNF4α Expression Leading to Impaired Human Hepatocyte Development and Function.},
journal = {Hepatology (Baltimore, Md.)},
volume = {72},
number = {4},
pages = {1412-1429},
pmid = {32516515},
issn = {1527-3350},
support = {//Alvin J. Siteman Cancer Center/ ; //V Foundation for Cancer Research/ ; BM160054//U.S. Department of Defense/ ; //Edward Mallinckrodt, Jr. Foundation/ ; 1R01HL137793/HL/NHLBI NIH HHS/United States ; //American Federation for Aging Research/ ; P30 DK052574/DK/NIDDK NIH HHS/United States ; HL007088/HL/NHLBI NIH HHS/United States ; //American Cancer Society/ ; R01 HL137793/HL/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND AND AIMS: Telomere attrition is a major risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo.<br><br>APPROACH AND RESULTS: Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-regulation, immediately after endoderm differentiation and completely absent in in vitro-derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening prevents the up-regulation and activation of human hepatocyte nuclear factor 4 alpha (HNF4α) in a p53-dependent manner. Both reactivation of telomerase and silencing of p53 rescued hepatocyte formation in telomerase mutants. Likewise, the conditional expression (doxycycline-controlled) of HNF4α, even in cells that retained short telomeres, accrued DNA damage, and exhibited p53 stabilization, successfully restored hepatocyte formation from hESCS.<br><br>CONCLUSIONS: Our data show that telomere dysfunction acts as a major regulator of HNF4α during hepatocyte development, pointing to a target in the treatment of liver disease in telomere-syndrome patients.},
}
@article {pmid32515222,
year = {2020},
author = {Khalangot, M and Krasnienkov, D and Vaiserman, A},
title = {Telomere length in different metabolic categories: Clinical associations and modification potential.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {245},
number = {13},
pages = {1115-1121},
pmid = {32515222},
issn = {1535-3699},
abstract = {IMPACT STATEMENT: Metabolic disorders are known to be associated with accelerated telomere attrition. Their pathophysiological heterogeneity suggests the importance of multiple tests in examining these associations. However, oral glucose tolerance test (OGTT) has rarely been performed in such studies to date. There are few studies aimed at determining leukocyte telomere length (LTL) in different categories of impaired glucose tolerance (IGT), and those that do exist do not take into account the impaired fasting glucose (IFG)/IGT categorization. Therefore, we believe our study, when the OGTT was used, is important to the field. This testing made it possible to determine whether LTLs are associated with glucose levels in different hyperglycemic categories. Our data indicate that relationships between LTLs and IFG/IGT levels are not the same. This distinction can potentially be used in categorization of metabolic disorders and in determining the effectiveness of interventions aimed at treating diabetes and other metabolic abnormalities.},
}
@article {pmid32512904,
year = {2020},
author = {Shanta, K and Nakayama, K and Ishikawa, M and Ishibashi, T and Yamashita, H and Sato, S and Sasamori, H and Sawada, K and Kurose, S and Mahmud, HM and Razia, S and Iida, K and Ishikawa, N and Kyo, S},
title = {Prognostic Value of Peripheral Blood Lymphocyte Telomere Length in Gynecologic Malignant Tumors.},
journal = {Cancers},
volume = {12},
number = {6},
pages = {},
pmid = {32512904},
issn = {2072-6694},
support = {18K09229 and 18K09291//JSPS KAKENHI/ ; },
abstract = {Background: Lymphocyte telomere length is strongly correlated with patient prognosis in several malignant tumor types and is thought to be related to tumor immunity. However, this correlation has not been studied in gynecological cancers. We determined the prognostic significance of peripheral blood lymphocyte telomere length in gynecologic cancers. Methods: Telomere length of lymphocytes from patients with gynecological malignant tumors (ovarian cancer (OC), N = 72; cervical cancer (CC), N = 63; endometrial cancer (EC), N = 87) was examined by quantitative reverse-transcription PCR of isolated mononuclear cells. Kaplan-Meier and Cox proportional hazard analyses were used to determine the association between lymphocyte telomere length and clinicopathological factors. Results: The overall survival (OS) and progression-free survival (PFS) of patients were based on the dichotomized lymphocyte telomere length using the median as a threshold (OC: 0.75, CC: 1.94, and EC: 1.09). A short telomere length was significantly correlated with residual tumors (≥1 cm) in OC and with advanced stage (III and IV) of CC. In OC and CC, patients with shorter relative lymphocyte telomere length (RLT) had significantly poorer OS and PFS than patients with longer RLT (p = 0.002, p = 0.003, and p = 0.001, p = 0.001, respectively). However, in EC, RLT was not significantly associated with OS or PFS (p = 0.567 and p = 0.304, log-rank test). Multivariate analysis showed that shorter RLT was a significant independent prognostic factor of PFS and OS for OC (p = 0.03 and p = 0.04, respectively) and CC (p = 0.02 and p = 0.03, respectively). Conclusions: Patients with OC and CC with shorter lymphocyte telomeres have significantly reduced survival; therefore, the peripheral blood lymphocyte telomere length is a prognostic biomarker in OC and CC.},
}
@article {pmid32512652,
year = {2020},
author = {Bloom, SI and Tuluca, A and Ives, SJ and Reynolds, TH},
title = {High-fat diet induced obesity and age influence the telomere shelterin complex and telomerase gene expression in mouse adipose tissue.},
journal = {Physiological reports},
volume = {8},
number = {11},
pages = {e14461},
pmid = {32512652},
issn = {2051-817X},
support = {R15 AG053790/AG/NIA NIH HHS/United States ; T32 HL139451/HL/NHLBI NIH HHS/United States ; T32 5T32HL139451-02/NH/NIH HHS/United States ; R15 AG053790-01/AG/NIA NIH HHS/United States ; },
abstract = {Obesity and aging are linked to inflammation and increased risk of chronic disease. Telomeres are the endcaps of chromosomes that are regulated by telomerase, the enzyme that elongates telomeres, as well as a protein complex known as shelterin. Telomere dysfunction is associated with inflammation, aging, and disease. However, the effect of high-fat diet (HFD) induced obesity and advancing age on the shelterin complex and telomerase in adipose tissue is unknown. The present study investigated the effects of obesity and aging on C57BL/6J mice adipose tissue mRNA expression of shelterin complex genes. Young (YG) mice (3 mo) were randomly assigned to be fed either a high-fat diet (YG + HFD; 60% kcal from fat) or a low-fat diet (YG + LFD; 10% kcal from fat). A subset of mice were aged until 16 months. Body weight and epididymal white adipose tissue (EWAT) weight increased with age or a HFD. There was a trend for increased Terf2 expression, as expression was increased in HFD + YG by ~47% and aged mice by ~80%. Pot1b expression was increased in aged mice by ~35%-60% compared to YG, independent of diet. mTert, the gene that codes for the catalytic subunit of telomerase, was significantly elevated in aged mice. Changes in telomere associated gene expression was accompanied by changes in expression of inflammatory markers Mcp1 and Tnfα. These findings suggest obesity and age impact expression of shelterin complex and telomerase related genes in adipose, perhaps altering telomere function in adipose tissue thereby increasing inflammation and risk of chronic disease.},
}
@article {pmid32512281,
year = {2020},
author = {Guan, X and Fu, W and Wei, W and Li, G and Wu, X and Bai, Y and Feng, Y and Meng, H and Li, H and Li, M and Fu, M and Zhang, X and He, M and Guo, H},
title = {Mediation of the association between polycyclic aromatic hydrocarbons exposure and telomere attrition by oxidative stress: A prospective cohort study.},
journal = {Journal of hazardous materials},
volume = {399},
number = {},
pages = {123058},
doi = {10.1016/j.jhazmat.2020.123058},
pmid = {32512281},
issn = {1873-3336},
abstract = {Previous studies have reported associations between polycyclic aromatic hydrocarbons (PAHs) exposure and telomere attrition, but the underlying mechanisms remain to be elucidated. This study aimed to explore the mediation role of oxidative stress on the effects of PAHs exposure on telomere attrition in a cohort study of 1180 coke-oven workers. We determined baseline urinary concentrations of ten urinary PAH metabolites, two oxidative stress biomarkers [8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-isoPGF2α)] and peripheral leukocytes telomere length (TL) in both baseline and follow-up visits. Mediation analysis was applied to assess effects of oxidative stress biomarkers on the PAHs-TL attrition associations. The baseline 8-OHdG had a significant dose-response relationship with TL decline [β(95 %CI) = 0.07(0.03-0.12), P = 0.001] and TL ratio [β(95 %CI)]=0.07 (0.02-0.12), P = 0.003]. Mediation analyses indicated that 8-OHdG mediated a separate 39.1 %, 47.0 %, 43.3 %, and 58.0 % of the associations between 1-hydroxynaphthalene (1-OHNa), 2-OHNa, ΣOHNa, 1-hydroxypyrene (1-OHP) and TL decline (P = 0.016, 0.008, 0.012, and 0.014, respectively). Additionally, 8-OHdG mediated a separate 44.8 %, 49.4 %, 49.2 %, and 35.5 % of the associations between 1-OHNa, 2-OHNa, ΣOHNa, 1-OHP and TL ratio (P = 0.012, 0.008, 0.012, and 0.046, respectively). Our study proposed the positive association of 8-OHdG with TL attrition and revealed the mediation roles of 8-OHdG in PAHs-TL attrition associations.},
}
@article {pmid32511191,
year = {2020},
author = {Wysocki, K and Seibert, D},
title = {Genomics of aging: Genes, adducts, and telomeres.},
journal = {Journal of the American Association of Nurse Practitioners},
volume = {32},
number = {6},
pages = {419-422},
doi = {10.1097/JXX.0000000000000455},
pmid = {32511191},
issn = {2327-6924},
abstract = {Genomics influences the aging process in many different ways. This 10-part series of articles describes what is known about genetics and aging, including genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown. This first article explores gene adducts as an epigenetic &quot;sludge,&quot; the influence of telomeres and other mutations that contribute to DNA dysfunction, cell stress, and premature aging. Factors that contribute to adduct formation and reduced telomere length are presented along with some changes in behavior, environmental exposure, food/supplement use, weight, sleep, and exercise that have been found to reduce damage, potentially increasing longevity. Adherence to a Mediterranean diet that contains fruits and whole grains along with fiber, antioxidants (e.g., beta-carotene, vitamins C and E), omega-3 fatty acids, and soy protein may reduce DNA adducts and protect telomeres. So providers may want to recommend these simple but key clinical and individual changes to enhance DNA health, wellness, and longevity.},
}
@article {pmid32504677,
year = {2020},
author = {Miga, KH},
title = {Centromere studies in the era of 'telomere-to-telomere' genomics.},
journal = {Experimental cell research},
volume = {394},
number = {2},
pages = {112127},
doi = {10.1016/j.yexcr.2020.112127},
pmid = {32504677},
issn = {1090-2422},
mesh = {Centromere/*metabolism ; DNA, Satellite/genetics ; *Genomics ; Humans ; Reproducibility of Results ; Tandem Repeat Sequences/genetics ; Telomere/*metabolism ; },
abstract = {We are entering into an exciting era of genomics where truly complete, high-quality assemblies of human chromosomes are available end-to-end, or from 'telomere-to-telomere' (T2T). This technological advance offers a new opportunity to include endogenous human centromeric regions in high-resolution, sequence-based studies. These emerging reference maps are expected to reveal a new functional landscape in the human genome, where centromere proteins, transcriptional regulation, and spatial organization can be examined with base-level resolution across different stages of development and disease. Such studies will depend on innovative assembly methods of extremely long tandem repeats (ETRs), or satellite DNAs, paired with the development of new, orthogonal validation methods to ensure accuracy and completeness. This review reflects the progress in centromere genomics, credited by recent advancements in long-read sequencing and assembly methods. In doing so, I will discuss the challenges that remain and the promise for a new period of scientific discovery for satellite DNA biology and centromere function.},
}
@article {pmid32502401,
year = {2020},
author = {Reddel, RR and MacKenzie, KL and Bryan, TM},
title = {End Products of Telomere Research.},
journal = {Cell stem cell},
volume = {26},
number = {6},
pages = {804-805},
doi = {10.1016/j.stem.2020.05.006},
pmid = {32502401},
issn = {1875-9777},
mesh = {Humans ; Stem Cells/metabolism ; *Telomerase/metabolism ; *Telomere/genetics/metabolism ; Telomere Shortening ; },
abstract = {Most rare inherited telomere biology disorders and some common aging-related diseases are associated with shortened telomeres. In this issue of Cell Stem Cell, insights into one of the rarest genetic causes of these disorders led to the discovery (Nagpal et al., 2020) of small molecules that lengthen telomeres.},
}
@article {pmid32502208,
year = {2020},
author = {Wu, S and Ge, Y and Li, X and Yang, Y and Zhou, H and Lin, K and Zhang, Z and Zhao, Y},
title = {BRM-SWI/SNF chromatin remodeling complex enables functional telomeres by promoting co-expression of TRF2 and TRF1.},
journal = {PLoS genetics},
volume = {16},
number = {6},
pages = {e1008799},
pmid = {32502208},
issn = {1553-7404},
mesh = {Chromosomal Proteins, Non-Histone/*metabolism ; Genomic Instability ; HEK293 Cells ; HeLa Cells ; Hep G2 Cells ; Heterochromatin/metabolism ; Humans ; Promoter Regions, Genetic ; Telomere/*metabolism ; Telomeric Repeat Binding Protein 1/*genetics/metabolism ; Telomeric Repeat Binding Protein 2/*genetics/metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {TRF2 and TRF1 are a key component in shelterin complex that associates with telomeric DNA and protects chromosome ends. BRM is a core ATPase subunit of SWI/SNF chromatin remodeling complex. Whether and how BRM-SWI/SNF complex is engaged in chromatin end protection by telomeres is unknown. Here, we report that depletion of BRM does not affect heterochromatin state of telomeres, but results in telomere dysfunctional phenomena including telomere uncapping and replication defect. Mechanistically, expression of TRF2 and TRF1 is jointly regulated by BRM-SWI/SNF complex, which is localized to promoter region of both genes and facilitates their transcription. BRM-deficient cells bear increased TRF2-free or TRF1-free telomeres due to insufficient expression. Importantly, BRM depletion-induced telomere uncapping or replication defect can be rescued by compensatory expression of exogenous TRF2 or TRF1, respectively. Together, these results identify a new function of BRM-SWI/SNF complex in enabling functional telomeres for maintaining genome stability.},
}
@article {pmid32502020,
year = {2020},
author = {Lili, M and Yuxiang, F and Zhongcheng, H and Ying, S and Ru, C and Rong, X and Jiang, L},
title = {Genetic variations associated with telomere length affect the risk of gastric carcinoma.},
journal = {Medicine},
volume = {99},
number = {23},
pages = {e20551},
doi = {10.1097/MD.0000000000020551},
pmid = {32502020},
issn = {1536-5964},
mesh = {Case-Control Studies ; China/epidemiology ; DNA-Binding Proteins/*genetics ; Female ; *Genetic Predisposition to Disease ; Haplotypes ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Real-Time Polymerase Chain Reaction ; Stomach Neoplasms/*genetics ; Telomerase/*genetics ; Telomere/*genetics ; Telomere Homeostasis ; },
abstract = {This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to gastric carcinoma (GC) and investigate the association between genetic polymorphisms in the telomere length related genes and GC risk.RTL was measured using the real-time quantitative polymerase chain reaction from 1000 patients and 1100 healthy controls. Genotyping was performed using the Agena MassARRAY platform. The statistical analysis was performed using the chi-square/ Welch T tests, Mann-Whitney U test, and logistic regression analysis.The association analysis of telomere length and GC showed that the RTL in the case group was shorter than in the controls, and the shorter RTL was associated with an increased risk of GC. The association analysis between telomere length related genes polymorphisms and genetic susceptibility to GC indicated that: In the allele models and genetic models, TERT (rs10069690, rs2242652 and rs2853676) and TN1F1 (rs7708392 and rs10036748) were significantly associated with an increased risk of GC. In addition, the haplotype 'Grs10069690Crs2242652&quot; of TERT and the haplotype 'Grs7708392Trs10036748&quot; of TNIP1 were associated with an increased risk of GCOur results suggested that shorter RTL was associated with an increased risk of GC; The association analysis have identified that the TERT (rs10069690, rs2242652 and rs2853676) and TN1P1 (rs7708392 and rs10036748) were associated with GC risk.},
}
@article {pmid32500358,
year = {2020},
author = {AlDehaini, DMB and Al-Bustan, SA and Ali, ME and Malalla, ZHA and Sater, M and Giha, HA},
title = {Shortening of the leucocytes' telomeres length in T2DM independent of age and telomerase activity.},
journal = {Acta diabetologica},
volume = {57},
number = {11},
pages = {1287-1295},
pmid = {32500358},
issn = {1432-5233},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Blood Glucose/metabolism ; Body Mass Index ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/genetics/*metabolism/physiopathology ; Female ; Humans ; Insulin Resistance ; Leukocytes/*metabolism ; Male ; Middle Aged ; Risk Factors ; Telomerase/*metabolism ; Telomere/*metabolism ; Telomere Shortening ; },
abstract = {AIMS: This study aimed to examine the role of plasma telomerase (TE), plasma insulin, patient's age and disease duration in determination of the leucocytes' telomeres length (LTL) in T2DM.<br><br>METHODS: Blood samples from Kuwaiti patients with T2DM (110) and non-diabetic subjects (94) were analyzed by SYBR Green Quantitative PCR for estimation of the Absolute Human Telomere Length and by ELISA for estimation of the TE activity and insulin level. The body mass index (BMI) and HOMA-IR were calculated.<br><br>RESULTS: The results revealed marked shortening of the LTL in T2DM compared with the non-diabetic subjects (6.068, 2.276-11.652 vs. 10.979, 6.495-23.402 kb), p < 0.001, while the TE concentration was comparable between the two groups (3.16, 0.00-6.02 vs. 4.16, 1.38-7.94 U/L, respectively), p 0.100. Importantly, in T2DM the LTL did not vary significantly with the disease duration (1 month to 40 years), p 0.959, and did not correlate with age, BMI, insulin-resistance, or glycemic parameters. Interestingly, there was a positive correlation between the LTL and insulin levels in T2DM (CC 0.211, p 0.0419). Finally, in non-diabetic subjects, HbA1c ≥ 6% was associated significantly with shorter LTL, this observation together with the lack of association of the LTL with the disease duration, suggests a causal role of short telomeres in T2DM development.<br><br>CONCLUSIONS: This study confirmed the LTL shortening in T2DM in Kuwaiti Arabs, and showed that the LTL was independent of age and TE activity but positively influenced by insulin levels. Furthermore, the study suggested that telomeres shortening could be a risk factor for T2DM.},
}
@article {pmid32499315,
year = {2020},
author = {Lambing, C and Kuo, PC and Tock, AJ and Topp, SD and Henderson, IR},
title = {ASY1 acts as a dosage-dependent antagonist of telomere-led recombination and mediates crossover interference in Arabidopsis.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {24},
pages = {13647-13658},
pmid = {32499315},
issn = {1091-6490},
support = {BB/M004937/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/metabolism ; *Crossing Over, Genetic ; DNA-Binding Proteins/genetics/*metabolism ; *Recombination, Genetic ; Telomere/*genetics/metabolism ; },
abstract = {During meiosis, interhomolog recombination produces crossovers and noncrossovers to create genetic diversity. Meiotic recombination frequency varies at multiple scales, with high subtelomeric recombination and suppressed centromeric recombination typical in many eukaryotes. During recombination, sister chromatids are tethered as loops to a polymerized chromosome axis, which, in plants, includes the ASY1 HORMA domain protein and REC8-cohesin complexes. Using chromatin immunoprecipitation, we show an ascending telomere-to-centromere gradient of ASY1 enrichment, which correlates strongly with REC8-cohesin ChIP-seq data. We mapped crossovers genome-wide in the absence of ASY1 and observe that telomere-led recombination becomes dominant. Surprisingly, asy1/+ heterozygotes also remodel crossovers toward subtelomeric regions at the expense of the pericentromeres. Telomeric recombination increases in asy1/+ occur in distal regions where ASY1 and REC8 ChIP enrichment are lowest in wild type. In wild type, the majority of crossovers show interference, meaning that they are more widely spaced along the chromosomes than expected by chance. To measure interference, we analyzed double crossover distances, MLH1 foci, and fluorescent pollen tetrads. Interestingly, while crossover interference is normal in asy1/+, it is undetectable in asy1 mutants, indicating that ASY1 is required to mediate crossover interference. Together, this is consistent with ASY1 antagonizing telomere-led recombination and promoting spaced crossover formation along the chromosomes via interference. These findings provide insight into the role of the meiotic axis in patterning recombination frequency within plant genomes.},
}
@article {pmid32497584,
year = {2020},
author = {Hagman, M and Werner, C and Kamp, K and Fristrup, B and Hornstrup, T and Meyer, T and Böhm, M and Laufs, U and Krustrup, P},
title = {Reduced telomere shortening in lifelong trained male football players compared to age-matched inactive controls.},
journal = {Progress in cardiovascular diseases},
volume = {63},
number = {6},
pages = {738-749},
doi = {10.1016/j.pcad.2020.05.009},
pmid = {32497584},
issn = {1873-1740},
mesh = {Adolescent ; Adult ; Age Factors ; Aged ; *Athletes ; Case-Control Studies ; *Cellular Senescence ; Cross-Sectional Studies ; Humans ; Male ; *Physical Fitness ; *Soccer ; Telomere/*genetics ; *Telomere Shortening ; Young Adult ; },
abstract = {AIMS: Current evidence points to cellular anti-ageing effects of regular endurance training which may differ from other sport modalities. Effects of football training on markers of cell senescence have not been tested.<br><br>METHODS: One hundred and forty healthy, non-smoking men participated in the study, including young elite football players aged 18-30 years (YF, n = 35, 21.6 ± 0.5 yrs), elderly football players aged 65-80 years (EF, n = 35, 71.9 ± 0.5 yrs), untrained young controls (YC, n = 35, 24.3 ± 0.6 yrs) and elderly controls (EC, n = 35, 70.1 ± 0.7 yrs). Besides body composition (DXA scan), resting heart rate (RHR), blood pressure (BP) and selected fasting blood variables, mononuclear cells (MNC) were isolated. MNC telomere length was determined by flow-fluorescence in-situ hybridization (FISH) and polymerase chain reaction (PCR). Telomerase activity was quantified using telomerase repeat amplification protocol (TRAP) assay. mRNA expression of anti- and pro-senescent factors was measured with real-time PCR.<br><br>RESULTS: EF showed 2.5% higher (p = 0.047) granulocyte telomere length and 1.3% higher (p = 0.009) lymphocyte telomere length compared to EC. EF had 37% lower (p = 0.025) mRNA expression of the pro-senescent factor p16 compared to EC. No significant between-group differences (p > 0.050) were observed in telomerase activity or anti-senescent factors (TRF2, Ku70 and POT1a) for EF vs EC. YF had higher telomerase activity (4.2-fold, p = 0.001), telomere repeat binding factor (TRF) 2 mRNA expression (3.2-fold, p = 0.003), Ku70 mRNA expression (2.3-fold, p < 0.001) and POT1a mRNA expression (2.2-fold, p = 0.002) compared to YC, but there was no significant between-group difference in telomere length.<br><br>CONCLUSION: This study is the first cross-sectional, controlled trial showing effects of lifelong football participation on telomere shortening and senescence markers in circulating cells, suggesting that football induces cellular anti-senescence mechanisms implying positive long-term cardiovascular health effects.},
}
@article {pmid32497497,
year = {2020},
author = {Laprade, H and Querido, E and Smith, MJ and Guérit, D and Crimmins, H and Conomos, D and Pourret, E and Chartrand, P and Sfeir, A},
title = {Single-Molecule Imaging of Telomerase RNA Reveals a Recruitment-Retention Model for Telomere Elongation.},
journal = {Molecular cell},
volume = {79},
number = {1},
pages = {115-126.e6},
doi = {10.1016/j.molcel.2020.05.005},
pmid = {32497497},
issn = {1097-4164},
support = {PJT-162156//CIHR/Canada ; },
mesh = {Clustered Regularly Interspaced Short Palindromic Repeats ; Coiled Bodies/*metabolism ; DNA, Single-Stranded/genetics/*metabolism ; Gene Editing ; HeLa Cells ; Humans ; Mutation ; RNA/genetics/*metabolism ; Single Molecule Imaging/*methods ; Telomerase/genetics/*metabolism ; Telomere/genetics/*metabolism ; *Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; },
abstract = {Extension of telomeres is a critical step in the immortalization of cancer cells. This complex reaction requires proper spatiotemporal coordination of telomerase and telomeres and remains poorly understood at the cellular level. To understand how cancer cells execute this process, we combine CRISPR genome editing and MS2 RNA tagging to image single molecules of telomerase RNA (hTR). Real-time dynamics and photoactivation experiments of hTR in Cajal bodies (CBs) reveal that hTERT controls the exit of hTR from CBs. Single-molecule tracking of hTR at telomeres shows that TPP1-mediated recruitment results in short telomere-telomerase scanning interactions, and then base pairing between hTR and telomere ssDNA promotes long interactions required for stable telomerase retention. Interestingly, POT1 OB-fold mutations that result in abnormally long telomeres in cancers act by enhancing this retention step. In summary, single-molecule imaging unveils the life cycle of telomerase RNA and provides a framework to reveal how cancer-associated mutations mechanistically drive defects in telomere homeostasis.},
}
@article {pmid32496827,
year = {2020},
author = {Furtado, CLM and Iannetta, R and Ferriani, RA and Rosa E Silva, ACJS and Martinelli, CE and Calado, RT and Dos Reis, RM},
title = {Telomere length is not altered in girls with idiopathic central precocious puberty treated with a GnRH analog - leuprolide acetate.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {36},
number = {12},
pages = {1119-1123},
doi = {10.1080/09513590.2020.1770212},
pmid = {32496827},
issn = {1473-0766},
abstract = {BACKGROUND: Idiopathic central precocious puberty (iCPP) presents a disproportionate advancement of bone age and maturation, as well as metabolic and endocrinological changes that may be related to effects on telomere biology.<br><br>OBJECTIVE: To investigate the telomere length in iCPP girls treated with GnRHa.<br><br>STUDY DESIGN: Observational case-control study with 85 girls, including 45 iCPP treated with GnRHa and 40 controls. It was analyzed age, height, weight and body mass index (BMI), insulin, triglycerides, testosterone, insulin resistance by HOMA, and telomere length by real-time PCR. Statistical analyses were determined by Wilcoxon test and Spearman correlation was carried out.<br><br>RESULTS: Weight, BMI, insulin level and HOMA index were higher in the iCPP than in the control group (p < .01); without difference between mean ages. The telomere length did not differ between iCPP and control group. However, a negative correlation was observed between the telomere length and age in iCPP (p = .0009) and control group (p = .014), and weight in the iCPP (p = .017).<br><br>CONCLUSIONS: We did not observe any difference in the telomere length in the iCPP and control group. Even though, some characteristics of the disease, such as increased weight and body fat, negatively influence the telomere biology.},
}
@article {pmid32489697,
year = {2020},
author = {Zhang, S and Li, R and Yang, Y and Chen, Y and Yang, S and Li, J and Wu, C and Kong, T and Liu, T and Cai, J and Fu, L and Zhao, Y and Hui, R and Zhang, W},
title = {Longitudinal Association of Telomere Attrition with the Effects of Antihypertensive Treatment and Blood Pressure Lowering.},
journal = {Aging and disease},
volume = {11},
number = {3},
pages = {494-508},
pmid = {32489697},
issn = {2152-5250},
abstract = {Leukocytes telomere length has been associated with hypertension, but, whether longitudinal telomeres change could serve as a useful predictive tool in hypertension remains uncertain. This study aimed to examine the longitudinal trajectory of leukocytes telomere length in a population-based prospective study of 1,108 individuals with hypertension. Leukocytes telomere length were measured at baseline and again after a median 2.2 (range 1.5-2.4) years of follow-up. Age as an independent predictor was inversely associated with baseline telomeres and follow-up telomeres. Annual telomere attrition rate was calculated as (follow-up telomeres-baseline telomeres)/follow-up years, and participants were categorized into the shorten and the lengthen groups. Results showed that telomere lengthening was significantly correlated with decreased systolic blood pressure (SBP) (β=-3.28; P=0.02) and pulse pressure (PP) (β=-2.53; P=0.02), and the differences were respectively -3.3 mmHg (95%CI, -6.2 to -0.3; P=0.03) in ∆SBP and -2.4 mmHg (95%CI, -4.9 to -0.1; P=0.04) in ∆PP between two groups after adjustment for vascular risk factors and baseline blood pressures. When stratified by age and gender, the correlations were observed in women and patients ≤60 years. Furthermore, among patients using calcium channel blocker (CCB) and angiotensin receptor blocker (ARB), those with telomeres lengthening showed a significantly lower level of ∆SBP and ∆PP. There was no correlation between telomere attrition and incidence of cardiovascular events. Our data indicated that increased telomere length of leukocytes was associated with decreased SBP and PP, particularly for patients who received CCB and ARB, supporting that telomere attrition may provide new sight in clinical intervention for hypertension.},
}
@article {pmid32488018,
year = {2020},
author = {Nichuguti, N and Fujiwara, H},
title = {Essential factors involved in the precise targeting and insertion of telomere-specific non-LTR retrotransposon, SART1Bm.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {8963},
pmid = {32488018},
issn = {2045-2322},
mesh = {3' Untranslated Regions ; Animals ; Base Sequence ; Bombyx/genetics ; Cloning, Molecular/*methods ; Repetitive Sequences, Nucleic Acid ; Retroelements/*genetics/physiology ; Telomere/metabolism ; Telomere Homeostasis/*genetics/physiology ; Terminal Repeat Sequences/genetics/physiology ; },
abstract = {Telomere length maintenance is essential for most eukaryotes to ensure genome stability and integrity. A non-long terminal repeat (LTR) retrotransposon, SART1Bm, targets telomeric repeats (TTAGG)n of the silkworm Bombyx mori and is presumably involved in telomere length maintenance. However, how many telomeric repeats are required for its retrotransposition and how reverse transcription is initiated at the target site are not well understood. Here, using an ex vivo and trans-in vivo recombinant baculovirus retrotransposition system, we demonstrated that SART1Bm requires at least three (TTAGG) telomeric repeats and a longer poly(A) tail for its accurate retrotransposition. We found that SART1Bm retrotransposed only in the third (TTAGG) tract of three repeats and that the A residue of the (TTAGG) unit was essential for its retrotransposition. Interestingly, SART1Bm also retrotransposed into telomeric repeats of other species, such as human (TTAGGG)n repeats, albeit with low retrotransposition efficiency. We further showed that the reverse transcription of SART1Bm occurred inaccurately at the internal site of the 3' untranslated region (UTR) when using a short poly(A) tail but at the accurate site when using a longer poly(A) tail. These findings promote our understanding of the general mechanisms of site-specific retrotransposition and aid the development of a site-specific gene knock-in tool.},
}
@article {pmid32487251,
year = {2020},
author = {Nanthatanti, N and Tantiworawit, A and Piriyakhuntorn, P and Rattanathammethee, T and Hantrakool, S and Chai-Adisaksopha, C and Rattarittamrong, E and Norasetthada, L and Tuntiwechapikul, W and Fanhchaksai, K and Charoenkwan, P and Kumfu, S and Chattipakorn, N},
title = {Leukocyte telomere length in patients with transfusion-dependent thalassemia.},
journal = {BMC medical genomics},
volume = {13},
number = {1},
pages = {73},
pmid = {32487251},
issn = {1755-8794},
support = {FUND-2559-03967//Chiang Mai University/International ; },
abstract = {BACKGROUND: Thalassemia is a hereditary hemolytic anemia with a severity ranging from mild, non-transfusion dependent to severe chronic anemia requiring lifelong transfusion. Transfusional iron overload is a major complication in patients with transfusion-dependent thalassemia (TDT). Telomeres are sequences of nucleotides forming the end caps of chromosomes that act as a DNA repair system. Iron overload in thalassemia can cause increased oxidative stress which leads to cellular damage and senescence. This may result in telomere length shortening. The degree of telomere length shortening may reflect the severity of thalassemia.<br><br>METHODS: This research aimed to study the leukocyte telomere length in patients with TDT in comparison to non-thalassemic individuals and to identify the clinical and laboratory parameters that are associated with telomere length. We conducted a cross-sectional study in patients with TDT aged ≥18 years. Leukocyte telomere length was measured by real-time quantitative PCR.<br><br>RESULTS: Sixty-five patients with TDT were enrolled onto the study. There were 37 female patients (54.4%). The median age was 27 (18-57) years, and mean pre-transfusion hemoglobin level was 7.1 (± 1.07) g/dL. The mean telomere to single copy gene (T/S) ratios of patients with TDT and the controls were 0.72 ± 0.18 and 0.99 ± 0.25, respectively (p < 0.0001). There was a significant correlation between the T/S ratio and age (p = 0.0002), and hemoglobin level (p = 0.044). There was no correlation between telomere length and other factors.<br><br>CONCLUSIONS: Our study showed that TDT patients had shorter leukocyte telomere length compared with controls. Leukocyte telomere shortening in TDT was an aging-dependent process and associated with lower hemoglobin level.},
}
@article {pmid32486379,
year = {2020},
author = {Toupance, S and Stathopoulou, MG and Petrelis, AM and Gorenjak, V and Labat, C and Lai, TP and Visvikis-Siest, S and Benetos, A},
title = {TERC Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model.},
journal = {Cells},
volume = {9},
number = {6},
pages = {},
pmid = {32486379},
issn = {2073-4409},
abstract = {Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.},
}
@article {pmid32482456,
year = {2020},
author = {Brenner, KA and Nandakumar, J},
title = {Small Molecules Restore Telomeres in Patient Stem Cells.},
journal = {Trends in pharmacological sciences},
volume = {41},
number = {8},
pages = {506-508},
pmid = {32482456},
issn = {1873-3735},
support = {R01 AG050509/AG/NIA NIH HHS/United States ; R01 GM120094/GM/NIGMS NIH HHS/United States ; },
mesh = {*Dyskeratosis Congenita ; Humans ; RNA ; Stem Cells/metabolism ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; },
abstract = {Genetic defects in telomere maintenance result in stem cell exhaustion and a spectrum of telomere biology diseases. Systemic treatments beyond organ transplantation are lacking for these diseases. Nagpal and colleagues identified small molecules that restore telomere maintenance in patient-derived stem cells, offering a promising therapy for telomere biology diseases.},
}
@article {pmid32479352,
year = {2020},
author = {Thierry, AD},
title = {Association between telomere length and neighborhood characteristics by race and region in US midlife and older adults.},
journal = {Health &amp; place},
volume = {62},
number = {},
pages = {102272},
pmid = {32479352},
issn = {1873-2054},
support = {T32 AG000029/AG/NIA NIH HHS/United States ; },
abstract = {Disadvantaged neighborhoods are correlated with worse health outcomes, particularly among US Blacks. However, less is known about the link between neighborhood characteristics and biomarkers of cellular age, such as telomere length (TL), which may be implicated in racial health inequities. Moreover, this relationship may vary across US region given patterns of racial segregation across the US. Therefore, this study analyzed 2008 Health and Retirement Study data on 3,869 US-born white and Black adults >50 years old to examine race differences in the relationship between salivary TL and (1) neighborhood safety, cleanliness, and social cohesion and (2) interactions between neighborhood characteristics and US region. Neighborhood characteristics were not associated with TL in whites. However, significant associations were found among Blacks with variation by region. Blacks living in less clean neighborhoods in the Northeast (b = -0.03, SE = 0.01, p < 0.05), Midwest (b = -0.04, SE = 0.01, p < 0.01), and South (b = -0.05, SE = 0.01, p < 0.01) as well as those reporting less neighborhood safety and social cohesion in the Midwest (b = -0.03, SE = 0.02, p < 0.05 and b = -0.03, SE = 0.01, p < 0.05) and South (b = -0.03, SE = 0.01, p < 0.05 for both characteristics) had shorter TL than Blacks in the West. Therefore, exposure to neighborhood level historical discrimination and neglect may be detrimental to TL in Blacks. Future research should further examine how neighborhoods contribute to aging disparities.},
}
@article {pmid32474316,
year = {2020},
author = {Lee, AG and Cowell, W and Kannan, S and Ganguri, HB and Nentin, F and Wilson, A and Coull, BA and Wright, RO and Baccarelli, A and Bollati, V and Wright, RJ},
title = {Prenatal particulate air pollution and newborn telomere length: Effect modification by maternal antioxidant intakes and infant sex.},
journal = {Environmental research},
volume = {187},
number = {},
pages = {109707},
pmid = {32474316},
issn = {1096-0953},
support = {R21 ES021318/ES/NIEHS NIH HHS/United States ; UG3 OD023337/OD/NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; T32 HD049311/HD/NICHD NIH HHS/United States ; K23 HL135349/HL/NHLBI NIH HHS/United States ; UH3 OD023337/OD/NIH HHS/United States ; R01 HL095606/HL/NHLBI NIH HHS/United States ; R01 HL114396/HL/NHLBI NIH HHS/United States ; },
mesh = {*Air Pollutants/analysis ; *Air Pollution/analysis ; Antioxidants ; Bayes Theorem ; Child ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Maternal Exposure/adverse effects ; Particulate Matter/analysis ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Telomere ; },
abstract = {BACKGROUND: Evidence links gestational exposure to particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) with changes in leukocyte telomere length in cord blood with some studies showing sex-specific effects. PM2.5 exposure in utero increases oxidative stress, which can impact telomere biology. Thus, maternal antioxidant intakes may also modify the particulate air pollution effects.<br><br>METHODS: We examined associations among prenatal PM2.5 exposure and newborn relative leukocyte telomere length (rLTL), and the modifying effects of maternal antioxidant intake and infant sex. We estimated daily PM2.5 exposures over gestation using a validated spatiotemporally resolved satellite-based model. Maternal dietary and supplemental antioxidant intakes over the prior three months were ascertained during the second trimester using the modified Block98 food frequency questionnaire; high and low antioxidant intakes were categorized based on a median split. We employed Bayesian distributed lag interaction models (BDLIMs) to identify both sensitive windows of exposure and cumulative effect estimates for prenatal PM2.5 exposure on newborn rLTL, and to examine effect modification by maternal antioxidant intakes. A 3-way interaction between PM2.5, maternal antioxidant intake and infant sex was also explored.<br><br>RESULTS: For the main effect of PM2.5, BDLIMs identified a sensitive window at 12-20 weeks gestation for the association between increased prenatal PM2.5 exposure and shorter newborn rLTL and a cumulative effect of PM2.5 over gestation on newborn telomere length [cumulative effect estimate (CEE) = -0.29 (95% CI -0.49 to -0.10) per 1μg/m3 increase in PM2.5]. In models examining maternal antioxidant intake effects, BDLIMs found that children born to mothers reporting low antioxidant intakes were most vulnerable [CEE of low maternal antioxidant intake = -0.31 (95% CI -0.55 to -0.06) vs high maternal antioxidant intake = -0.07 (95% CI -0.34 to 0.17) per 1μg/m3 increase in PM2.5]. In exploratory models examining effect modification by both maternal antioxidant intakes and infant sex, the cumulative effect remained significant only in boys whose mothers reported low antioxidant intakes [CEE = -0.38 (95% CI -0.80 to -0.004)]; no sensitive windows were identified in any group.<br><br>CONCLUSIONS: Prenatal PM2.5 exposure in mid-gestation was associated with reduced infant telomere length. Higher maternal antioxidant intakes mitigated these effects.},
}
@article {pmid32472076,
year = {2020},
author = {de Krijger, I and van der Torre, J and Peuscher, MH and Eder, M and Jacobs, JJL},
title = {H3K36 dimethylation by MMSET promotes classical non-homologous end-joining at unprotected telomeres.},
journal = {Oncogene},
volume = {39},
number = {25},
pages = {4814-4827},
pmid = {32472076},
issn = {1476-5594},
mesh = {Animals ; Cells, Cultured ; DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; Embryo, Mammalian/cytology ; Fibroblasts/cytology/metabolism ; HEK293 Cells ; Histone-Lysine N-Methyltransferase/genetics/*metabolism ; Histones/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Mice, Knockout ; RNA Interference ; Repressor Proteins/genetics/*metabolism ; Telomere/genetics/*metabolism ; },
abstract = {The epigenetic environment plays an important role in DNA damage recognition and repair, both at DNA double-strand breaks and at deprotected telomeres. To increase understanding on how DNA damage responses (DDR) at deprotected telomeres are regulated by modification and remodeling of telomeric chromatin we screened 38 methyltransferases for their ability to promote telomere dysfunction-induced genomic instability. As top hit we identified MMSET, a histone methyltransferase (HMT) causally linked to multiple myeloma and Wolf-Hirschhorn syndrome. We show that MMSET promotes non-homologous end-joining (NHEJ) at deprotected telomeres through Ligase4-dependent classical NHEJ, and does not contribute to Ligase3-dependent alternative NHEJ. Moreover, we show that this is dependent on the catalytic activity of MMSET, enabled by its SET-domain. Indeed, in absence of MMSET H3K36-dimethylation (H3K36me2) decreases, both globally and at subtelomeric regions. Interestingly, the level of MMSET-dependent H3K36me2 directly correlates with NHEJ-efficiency. We show that MMSET depletion does not impact on recognition of deprotected telomeres by the DDR-machinery or on subsequent recruitment of DDR-factors acting upstream or at the level of DNA repair pathway choice. Our data are most consistent with an important role for H3K36me2 in more downstream steps of the DNA repair process. Moreover, we find additional H3K36me2-specific HMTs to contribute to NHEJ at deprotected telomeres, further emphasizing the importance of H3K36me2 in DNA repair.},
}
@article {pmid32469808,
year = {2020},
author = {He, S and Li, J and Wang, Z and Wang, L and Liu, L and Sun, X and Shohaib, SA and Koenig, HG},
title = {Early-life exposure to famine and late-life depression: Does leukocyte telomere length mediate the association?.},
journal = {Journal of affective disorders},
volume = {274},
number = {},
pages = {223-228},
doi = {10.1016/j.jad.2020.05.082},
pmid = {32469808},
issn = {1573-2517},
mesh = {Adult ; China/epidemiology ; Cross-Sectional Studies ; Depression/epidemiology ; Famine ; Female ; Humans ; Leukocytes ; Middle Aged ; Pregnancy ; *Prenatal Exposure Delayed Effects ; *Starvation ; Telomere ; },
abstract = {BACKGROUND: A positive association between early-life famine exposure and depression has been demonstrated. However, the mechanisms by which famine exposure in early life leads to late-life depression remains unclear. The present study examines the impact of leukocyte telomere length (LTL) and/or religiosity on the relationship between early-life famine exposure and late-life depression in a Chinese minority sample.<br><br>METHODS: A cross-sectional study of community-dwelling adults aged 55 or older was conducted in the Ningxia province of western China from 2013 to 2016. Multivariate ordinal logistic regression was used to examine the association between famine exposure and depression status, and a series mediation model was constructed to identify the mediation role of LTL and religiosity.<br><br>RESULTS: Compared with famine exposure during adulthood, fetal famine exposure was associated with a higher risk of late-life depression (adjusted odds ratio of 3.17, 95% CI: 1.36-7.38). A cumulative effect of fetal famine exposure on the risk of late-life depression was observed. Participants born in 1961 (the third year of the famine) had the strongest association with late-life depression. LTL played a mediating role in the association between famine exposure and depression which accounted for 21% of the total effect.<br><br>LIMITATIONS: The cross-sectional design prevents causal inferences regarding the relationships between famine and depression.<br><br>CONCLUSIONS: Fetal famine exposure was associated with an increased risk of late-life depression in a Chinese minority community-dwelling population. Telomere shortening partially mediated this association.},
}
@article {pmid32468974,
year = {2020},
author = {Savoy, CD and Schmidt, LA and McGowan, PO and Saigal, S and Van Lieshout, RJ},
title = {Extremely low birth weight influences the relationship between stress and telomere length in adulthood.},
journal = {Journal of developmental origins of health and disease},
volume = {},
number = {},
pages = {1-7},
doi = {10.1017/S2040174420000409},
pmid = {32468974},
issn = {2040-1752},
abstract = {This study examined the link between two biological markers of stress vulnerability at 22-26 years of age and telomere length at 30-35 among extremely low birth weight (ELBW; <1000 g) survivors and normal birth weight (NBW; >2500 g) control participants. Sixteen ELBW and 22 NBW participants provided baseline afternoon salivary cortisol samples and resting frontal electroencephalogram (EEG) alpha asymmetry data at 22-26 years. Buccal cells were assayed for telomere length at 30-35 years. Analyses controlled for sex, postnatal steroid exposure, childhood socioeconomic status, time of cortisol sample collection, and body mass index at 22-26 years. Salivary cortisol and frontal asymmetry at age 22-26 independently predicted telomere length at age 30-35, such that relatively higher cortisol and greater relative right frontal asymmetry at rest predicted telomere shortening among NBW controls, but not among ELBW survivors. However, similar associations were not noted in ELBW survivors, suggesting that ELBW survivors may have different mechanisms of stress coping as a result of their early-life exposures. These findings offer preliminary evidence in support of the role of stress in the genesis of cellular senescence at least among those born at NBW, but that these links may differ in those born preterm.},
}
@article {pmid32468620,
year = {2020},
author = {Park, MK and Lee, JC and Lee, JW and Kang, S and Kim, J and Park, MH and Hwang, SJ and Lee, M},
title = {Effects of fermented rice bran on DEN-induced oxidative stress in mice: GSTP1, LINE-1 methylation, and telomere length ratio.},
journal = {Journal of food biochemistry},
volume = {44},
number = {7},
pages = {e13274},
doi = {10.1111/jfbc.13274},
pmid = {32468620},
issn = {1745-4514},
support = {520160310//Kangwon National University/ ; },
abstract = {N-diethylnitrosamine (DEN), a well-known carcinogen, not only induces excessive reactive oxygen species but also suppresses DNA methylation. This study investigated the effect of fermented rice bran (FRB) treatment on DEN-induced oxidative stress through DNA methylation and telomere length analysis. To evaluate the potential protective role of FRB in oxidative stress, two different doses of FRB, DEN, and their combination were administered to mice that were preadapted or not to FRB. Glutathione-S-transferase P1 (GSTP1) methylation levels significantly decreased at 2 and 24 hr after FRB and DEN co-administration in mice with and without pre-adaptation. Moreover, GSTP1 mRNA was upregulated under DEN-induced oxidative stress. Furthermore, changes in long interspersed nuclear element-1 methylation were observed from the viewpoint of genomic instability. In addition, FRB preadapted mice displayed a lower telomere length ratio than the non-adapted mice, suggesting that FRB adaptation offers advantages over the non-adapted conditions in terms of inflammation suppression. PRACTICAL APPLICATIONS: DEN induces excessive ROS, which is associated with oxidative stress on DNA and other cellular components, resulting in inflammation. This study shows that FRB may alleviate DEN-triggered oxidative stress, based on changes in GSTP1, LINE-1 methylation, and telomere length ratios, thereby, revealing the potential of dietary intervention during inflammation. Furthermore, this study furthers the current understanding of DNA methylation mechanisms underlying the antioxidant and anti-inflammatory effects of functional food components. These results indicate that dietary inclusion of FRB may help decrease oxidative DNA damage and its associated inflammation at early stages of a disease.},
}
@article {pmid32467172,
year = {2020},
author = {Wu, J and Crowe, DL},
title = {Telomere DNA Damage Signaling Regulates Prostate Cancer Tumorigenesis.},
journal = {Molecular cancer research : MCR},
volume = {18},
number = {9},
pages = {1326-1339},
doi = {10.1158/1541-7786.MCR-19-1129},
pmid = {32467172},
issn = {1557-3125},
abstract = {Telomere shortening has been demonstrated in benign prostatic hypertrophy (BPH), which is associated with prostate epithelial cell senescence. Telomere shortening is the most frequently observed genetic alteration in prostatic intraepithelial neoplasia, and is associated with poor clinical outcomes in prostate cancer. Gene expression database analysis revealed decreased TRF2 expression during malignant progression of the prostate gland. We reasoned that reduced TRF2 expression in prostate epithelium, by activating the telomere DNA damage response, would allow us to model both benign and malignant prostate disease. Prostate glands with reduced epithelial TRF2 expression developed age- and p53-dependent hypertrophy, senescence, ductal dilation, and smooth muscle hyperplasia similar to human BPH. Prostate tumors with reduced TRF2 expression were classified as high-grade androgen receptor-negative adenocarcinomas, which exhibited decreased latency, increased proliferation, and distant metastases. Prostate cancer stem cells with reduced TRF2 expression were highly tumorigenic and maintained telomeres both by telomerase and alternative lengthening (ALT). Telomerase inhibition in prostate glands with reduced TRF2 expression produced significant reduction in prostate tumor incidence by halting progression at intraepithelial neoplasia (PIN). These lesions were highly differentiated, exhibited low proliferation index, and high apoptotic cell fraction. Prostate tumors with reduced TRF2 expression and telomerase inhibition failed to metastasize and did not exhibit ALT. IMPLICATIONS: Our results demonstrate that the telomere DNA damage response regulates BPH, PIN, and prostate cancer and may be therapeutically manipulated to prevent prostate cancer progression.},
}
@article {pmid32464172,
year = {2020},
author = {Kosebent, EG and Uysal, F and Ozturk, S},
title = {The altered expression of telomerase components and telomere-linked proteins may associate with ovarian aging in mouse.},
journal = {Experimental gerontology},
volume = {138},
number = {},
pages = {110975},
doi = {10.1016/j.exger.2020.110975},
pmid = {32464172},
issn = {1873-6815},
abstract = {Telomeres are repetitive DNA sequences localized at the ends of eukaryotic chromosomes, and shorten during ovarian aging. The molecular background of telomere shortening during ovarian aging is not fully understood. As the telomerase components (TERT and Terc) and telomere-associated proteins (TRF1, TRF2, and POT1a) play key roles in the elongation and maintenance of telomeres, we aimed to determine their spatial and temporal expression and cellular localization in the mouse ovaries at the different ages of postnatal life. For this purpose, five groups were generated based on the ovarian histological changes in the postnatal mouse ovaries as follows: young (1- and 2-week-old; n = 3 from each week), prepubertal (3- and 4-week-old; n = 3 from each week), pubertal (5- and 6-week-old; n = 3 from each week), postpubertal (16- and 18-week-old; n = 3 from each week) and aged (52-, 60- and 72-week-old, n = 3 from each week). We found significant changes for the Tert, Terc, Trf1, Trf2, and Pot1a genes expression in the postnatal ovary groups from young to aged (P < 0.05) as well as in the follicles from primordial to antral stages and their oocytes and granulosa cells. Also, we have detected gradually decreasing telomere length from young to aged groups (P < 0.001). In conclusion, the altered Tert, Terc, Trf2, and Pot1a genes expression compatible with telomere shortening may be associated with ovarian aging.},
}
@article {pmid32462419,
year = {2020},
author = {Benati, M and Montagnana, M and Danese, E and Mazzon, M and Paviati, E and Garzon, S and Laganà, AS and Casarin, J and Giudici, S and Raffaelli, R and Ghezzi, F and Franchi, M and Lippi, G},
title = {Aberrant Telomere Length in Circulating Cell-Free DNA as Possible Blood Biomarker with High Diagnostic Performance in Endometrial Cancer.},
journal = {Pathology oncology research : POR},
volume = {26},
number = {4},
pages = {2281-2289},
pmid = {32462419},
issn = {1532-2807},
abstract = {To investigate the diagnostic performance of relative telomere length (RTL) in cell-free DNA (cfDNA) for endometrioid endometrial cancer (EC). We measured RTL in cfDNA of 40 EC patients (65 ± 12 years) and 31 healthy controls (HC) (63 ± 13 years), excluding in both groups other oncologic and severe non-oncologic diseases to limit confounders. Circulating cfDNA was extracted from serum using the QIAamp DNA Blood Mini kit (Qiagen, Hilden, Germany). After the quantitative real-time polymerase chain reaction, telomere repeat copy number to single-gene copy number ratio was calculated. RTL in cfDNA was found to be significantly lower in EC patients than in HC (p < 0.0001). The diagnostic performance of cfDNA RTL was estimated with receiver operating characteristics (ROC) curve analysis, which showed a diagnostic accuracy for EC of 0.87 (95% CI: 0.79-0.95, p < 0.0001). The cutoff cfDNA RTL value of 2.505 (T/S copy ratio) reported a sensitivity of 80.0% (95% CI: 64.35-90.95) and a specificity of 80.65% (95% CI: 62.53-92.55). Significant differences of RTL among EC stages or grades (p = 0.85 and p = 0.89, respectively) were not observed. Our results suggest that cfDNA RTL analysis may be a diagnostic tool for EC detection since the early stage, whilst its diagnostic performance seems unsatisfactory for cancer progression, staging, and grading. However, further studies are needed to confirm these preliminary findings. In particular, future investigations should focus on high-risk patients (such as those with atypical endometrial hyperplasia) that may benefit from this tool, because TL shortening is not specific for EC and is influenced by other oncologic and non-oncologic diseases.},
}
@article {pmid32458497,
year = {2020},
author = {Viblanc, VA and Schull, Q and Stier, A and Durand, L and Lefol, E and Robin, JP and Zahn, S and Bize, P and Criscuolo, F},
title = {Foster rather than biological parental telomere length predicts offspring survival and telomere length in king penguins.},
journal = {Molecular ecology},
volume = {29},
number = {16},
pages = {3155-3167},
doi = {10.1111/mec.15485},
pmid = {32458497},
issn = {1365-294X},
abstract = {Because telomere length and dynamics relate to individual growth, reproductive investment and survival, telomeres have emerged as possible markers of individual quality. Here, we tested the hypothesis that, in species with parental care, parental telomere length can be a marker of parental quality that predicts offspring phenotype and survival. In king penguins (Aptenodytes patagonicus), we experimentally swapped the single egg of 66 breeding pairs just after egg laying to disentangle the contribution of prelaying parental quality (e.g., genetics, investment in the egg) and/or postlaying parental quality (e.g., incubation, postnatal feeding rate) on offspring growth, telomere length and survival. Parental quality was estimated through the joint effects of biological and foster parent telomere length on offspring traits, both soon after hatching (day 10) and at the end of the prewinter growth period (day 105). We expected that offspring traits would be mostly related to the telomere lengths (i.e., quality) of biological parents at day 10 and to the telomere lengths of foster parents at day 105. Results show that chick survival up to 10 days was negatively related to biological fathers' telomere length, whereas survival up to 105 days was positively related to foster fathers' telomere lengths. Chick growth was not related to either biological or foster parents' telomere length. Chick telomere length was positively related to foster mothers' telomere length at both 10 and 105 days. Overall, our study shows that, in a species with biparental care, parents' telomere length is foremost a proxy of postlaying parental care quality, supporting the &quot;telomere - parental quality hypothesis.&quot;},
}
@article {pmid32454945,
year = {2020},
author = {Lyu, L and He, S and Zhang, H and Li, W and Zeng, J and Ping, F and Li, YX},
title = {TNFα Mediates the Interaction of Telomeres and Mitochondria Induced by Hyperglycemia: A Rural Community-Based Cross-Sectional Study.},
journal = {Oxidative medicine and cellular longevity},
volume = {2020},
number = {},
pages = {8235873},
pmid = {32454945},
issn = {1942-0994},
mesh = {Biomarkers/metabolism ; Blood Glucose/metabolism ; Cross-Sectional Studies ; DNA, Mitochondrial/genetics ; Fasting/blood ; Female ; Glucose Tolerance Test ; Glycated Hemoglobin A/metabolism ; Humans ; Hyperglycemia/blood/*metabolism ; Inflammation Mediators/metabolism ; Interleukin-6/metabolism ; Leukocytes/metabolism ; Male ; Middle Aged ; Mitochondria/*metabolism ; *Rural Population ; Superoxide Dismutase/metabolism ; Telomere/*metabolism ; Telomere Shortening ; Tumor Necrosis Factor-alpha/*metabolism ; },
abstract = {This study is aimed at evaluating the relationship between leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in a noninterventional rural community of China with different glucose tolerance statuses. In addition, we investigate whether the indicators of oxidative stress and inflammation were involved and identify mediators among them. A total of 450 subjects in rural China were included and divided into two groups according to a 75 g oral glucose tolerance test (OGTT): the abnormal glucose metabolism (AGM, n = 257, 57.1%) group and the normal glucose tolerance (NGT, n = 193, 42.9%) group. Indicators of oxidative stress (superoxide dismutase (SOD) and glutathione reductase (GR)) and inflammatory indices (tumor necrosis factor α (TNFα) and interleukin-6 (IL-6)) were all determined by ELISA. LTL and mtDNAcn were measured using a real-time PCR assay. Linear regressions were used to adjust for covariates that might affect the relationship between LTL and mtDNAcn. Mediation analyses were utilized to evaluate the mediators. In the AGM, LTL was correlated with mtDNAcn (r = 0.214, p = 0.001), but no correlation was found in the NGT. The association between LTL and mtDNAcn was weakened after adjusting for inflammatory factors in the AGM (p = 0.087). LTL and mtDNAcn were both inversely related to HbA1c, IL-6, TNFα, and SOD activity. Mediation analysis demonstrated that TNFα was a significant mediator in the telomere-mitochondrial interactome in the AGM. This result suggests that inflammation and oxidative stress may play a vital role in telomere shortening as well as mitochondrial dysfunction. In the subjects with hyperglycemia, a significant positive correlation is observed between LTL and mtDNAcn, which is probably mediated by TNFα. TNFα may be considered a potential therapeutic target against aging-related disease in hyperglycemia.},
}
@article {pmid32447915,
year = {2020},
author = {Gao, YY and Guo, JY and Zhang, Z and Han, ZC and Lei, LJ and Sun, CM and Huang, JJ and Wang, T},
title = {[Relationship of telomere length, mitochondrial DNA copy number of peripheral blood with hypertension in coal miners].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {41},
number = {5},
pages = {727-732},
doi = {10.3760/cma.j.cn112338-20190930-00714},
pmid = {32447915},
issn = {0254-6450},
support = {81872701//National Natural Science Foundation of China/ ; 2016JD24//Shanxi Provincial Foundation For Talent Training in Joint Postgraduate Training Base/ ; },
mesh = {Case-Control Studies ; Coal ; DNA Copy Number Variations ; *DNA, Mitochondrial ; Humans ; *Hypertension/genetics ; Telomere ; },
abstract = {Objective: To explore the relationship of telomere length, mitochondrial DNA copy number of peripheral blood with hypertension and the interaction between telomere length and mtDNA-CN on hypertension in coal miners. Methods: A case control study was conducted in a coal mine of Shanxi province from July to December of 2013, in which 325 healthy workers were selected as the control group and 378 workers with hypertension as the case group. The information about general demographic characteristics and life behavior habits of the subjects were collected through questionnaire. Levels of telomere length and mtDNA-CN in peripheral blood were detected by real-time PCR. Unconditional logistic regression was used to examine the association between hypertension and telomere length, mtDNA-CN. The interaction test between telomere length and mtDNA-CN on hypertension was performed by adding the interaction term in the corresponding model. Results: The mean telomere length of the workers in the case group was (1.50±0.55) kb, and that of the control group was (2.01±0.62) kb, the difference between two groups was significant (t=11.68, P<0.001). The correlation analysis showed that telomere length was positively correlated with mtDNA-CN (r=0.157, P=0.002) in the case group. Multivariate analysis showed that telomere length (OR=4.408, 95%CI: 3.012-6.452), age (OR=0.417, 95%CI: 0.284-0.613), BMI (OR=1.357, 95%CI: 1.162-1.584), monthly household income level (OR=0.656, 95%CI: 0.553-0.778) and work duration (OR=1.249, 95%CI: 1.100-1.417) were influencing factors of hypertension. The multiply interaction between telomere length and mtDNA-CN was significant on hypertension (OR=1.267, 95%CI: 1.094-1.468). Conclusions: The results suggest shorter telomere length is a risk factor of hypertension. There is a multiply interaction between telomere length and mtDNA-CN on hypertension. However, the association between mtDNA-CN and hypertension was not found.},
}
@article {pmid32447718,
year = {2020},
author = {Vita, GL and Aguennouz, M and Sframeli, M and Sanarica, F and Mantuano, P and Oteri, R and Polito, F and Licata, N and Romeo, S and Distefano, MG and La Rosa, M and Bonanno, C and Nicocia, G and Vita, G and De Luca, A and Messina, S},
title = {Effect of exercise on telomere length and telomere proteins expression in mdx mice.},
journal = {Molecular and cellular biochemistry},
volume = {470},
number = {1-2},
pages = {189-197},
doi = {10.1007/s11010-020-03761-3},
pmid = {32447718},
issn = {1573-4919},
support = {MIUR PRIN 2015 to ADL [n. 2015MJBEM2_005].//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {Animals ; Disease Models, Animal ; Genotype ; Mice ; Mice, Inbred mdx ; Muscle, Skeletal/metabolism ; Muscular Dystrophy, Duchenne/*metabolism ; *Physical Conditioning, Animal ; Poly (ADP-Ribose) Polymerase-1/*genetics ; Signal Transduction ; Telomerase/*genetics ; Telomere/*metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 1/*genetics ; },
abstract = {In Duchenne muscular dystrophy (DMD), telomere shortening has been postulated to contribute to the failure of regenerative activity promoting the premature senescence of satellite cells. The aim of the present study was to investigate the telomere length and the expression of telomeric repeat-binding factor-1 (TRF1), poly (ADP-ribose) polymerase-1 (PARP1) and mouse telomerase reverse transcriptase (MTERT) in gastrocnemius, tibialis anterior and diaphragm muscles of the murine model of DMD, the mdx mouse and whether a chronic protocol of forced exercise impacts on them. Our results confirmed a telomere shortening in mdx muscles, more evident in the diaphragm, in which exercise induced a greater shortening than in wild-type mice. Moreover, we showed for the first time in mdx an increased TRF1 and PARP1 expression and an augmented activity of MTERT, further enhanced by exercise. These results reinforce the hypothesis that a deregulation of mechanisms involved in telomere length occurs and may pave the way for the test of compounds targeting proteins modulating telomere maintenance as a novel strategy to treat dystrophinopathies.},
}
@article {pmid32444498,
year = {2020},
author = {Vinayagamurthy, S and Ganguly, A and Chowdhury, S},
title = {Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness.},
journal = {The Journal of biological chemistry},
volume = {295},
number = {30},
pages = {10245-10254},
pmid = {32444498},
issn = {1083-351X},
mesh = {Aging/genetics/*metabolism/pathology ; *Cell Differentiation ; DNA Damage ; Humans ; Myocytes, Cardiac/metabolism/pathology ; Neurodegenerative Diseases/genetics/*metabolism/pathology ; Pluripotent Stem Cells/*metabolism/pathology ; Telomere/genetics/*metabolism/pathology ; Telomere Homeostasis ; Telomeric Repeat Binding Protein 2/metabolism ; },
abstract = {Telomeres comprise specialized nucleic acid-protein complexes that help protect chromosome ends from DNA damage. Moreover, telomeres associate with subtelomeric regions through looping. This results in altered expression of subtelomeric genes. Recent observations further reveal telomere length-dependent gene regulation and epigenetic modifications at sites spread across the genome and distant from telomeres. This regulation is mediated through the telomere-binding protein telomeric repeat-binding factor 2 (TRF2). These observations suggest a role of telomeres in extra-telomeric functions. Most notably, telomeres have a broad impact on pluripotency and differentiation. For example, cardiomyocytes differentiate with higher efficacy from induced pluripotent stem cells having long telomeres, and differentiated cells obtained from human embryonic stem cells with relatively long telomeres have a longer lifespan. Here, we first highlight reports on these two seemingly distinct research areas: the extra-telomeric role of telomere-binding factors and the role of telomeres in pluripotency/stemness. On the basis of the observations reported in these studies, we draw attention to potential molecular connections between extra-telomeric biology and pluripotency. Finally, in the context of the nonlocal influence of telomeres on pluripotency and stemness, we discuss major opportunities for progress in molecular understanding of aging-related disorders and neurodegenerative diseases.},
}
@article {pmid32443982,
year = {2020},
author = {Pasquier, E and Wellinger, RJ},
title = {In vivo chromatin organization on native yeast telomeric regions is independent of a cis-telomere loopback conformation.},
journal = {Epigenetics &amp; chromatin},
volume = {13},
number = {1},
pages = {23},
pmid = {32443982},
issn = {1756-8935},
support = {FDN 154315//CIHR/Canada ; Telomere Biology//Canada Research Chairs/International ; },
abstract = {BACKGROUND: DNA packaging into chromatin regulates all DNA-related processes and at chromosomal ends could affect both essential functions of telomeres: protection against DNA damage response and telomere replication. Despite this primordial role of chromatin, little is known about chromatin organization, and in particular about nucleosome positioning on unmodified subtelomere-telomere junctions in Saccharomyces cerevisiae.<br><br>RESULTS: By ChEC experiments and indirect end-labeling, we characterized nucleosome positioning as well as specialized protein-DNA associations on most subtelomere-telomere junctions present in budding yeast. The results show that there is a relatively large nucleosome-free region at chromosome ends. Despite the absence of sequence homologies between the two major classes of subtelomere-telomere junctions (i.e.: Y'-telomeres and X-telomeres), all analyzed subtelomere-telomere junctions show a terminal nucleosome-free region just distally from the known Rap1-covered telomeric repeats. Moreover, previous evidence suggested a telomeric chromatin fold-back structure onto subtelomeric areas that supposedly was implicated in chromosome end protection. The in vivo ChEC method used herein in conjunction with several proteins in a natural context revealed no evidence for such structures in bulk chromatin.<br><br>CONCLUSIONS: Our study allows a structural definition of the chromatin found at chromosome ends in budding yeast. This definition, derived with direct in vivo approaches, includes a terminal area that is free of nucleosomes, certain positioned nucleosomes and conserved DNA-bound protein complexes. This organization of subtelomeric and telomeric areas however does not include a telomeric cis-loopback conformation. We propose that the observations on such fold-back structures may report rare and/or transient associations and not stable or constitutive structures.},
}
@article {pmid32439486,
year = {2020},
author = {Davis, SK and Xu, R and Khan, RJ and Gaye, A},
title = {Modifiable mediators associated with the relationship between adiposity and leukocyte telomere length in US adults: The National Health and Nutrition Examination Survey.},
journal = {Preventive medicine},
volume = {138},
number = {},
pages = {106133},
doi = {10.1016/j.ypmed.2020.106133},
pmid = {32439486},
issn = {1096-0260},
support = {ZIA HG200393/ImNIH/Intramural NIH HHS/United States ; ZIA HG200404/ImNIH/Intramural NIH HHS/United States ; },
abstract = {Obesity is associated with age-related health conditions and telomere attrition - a marker of cellular aging. Obesity is attributable to adverse modifiable lifestyle factors. Little is known about the mediation effect of lifestyle factors associated with the relationship between obesity and telomere length. Our objective was to examine this association in the US. Pack years smoked, drinking level per day, physical activity (PA) per week and diet based on Healthy Eating Index (HEI) were assessed as mediators associated with the relationship between adiposity measures and leukocyte telomere length (LTL); adiposity measures included body mass index (BMI), % total body fat (TBF) and waist circumference (WC). Separate adjusted linear regressions and mediation analysis were conducted on a total of 4919 respondents aged 20-84 years using cross-sectional 1999-2002 data from the US National Health and Nutrition Examination Survey. Inadequate PA correlated with 1.28% shorter LTL and was a factor accounting for 35% of the relationship between BMI and LTL (β = -0.0128, 95% CI = 0.0259, 0.0004, p = .05). Smoking 30-≥59 pack years correlated with 4% shorter LTL and accounted for 21% of the relationship between %TBF and LTL (β = -0.0386, 95% CI = -0.0742, -0.0030, p = .03). Improvement in diet correlated with 0.11% longer LTL and contributed 25% of the association between %TBF and LTL (β = 0.0011, 95%CI =0.0004, 0.0018, p = .01). Diet correlated with 0.11% longer LTL and correspond to 28% of the relationship between WC and LTL (β = 0.0011, 95%CI = 0.0004, 0.0018, p = .03). Interventions to improve modifiable behaviors may ameliorate cellular aging and aging related health conditions due to obesity among US adults.},
}
@article {pmid32439402,
year = {2020},
author = {Kang, JI and Mueller, SG and Wu, GWY and Lin, J and Ng, P and Yehuda, R and Flory, JD and Abu-Amara, D and Reus, VI and Gautam, A and , and Hammamieh, R and Doyle, FJ and Jett, M and Marmar, CR and Mellon, SH and Wolkowitz, OM},
title = {Effect of Combat Exposure and Posttraumatic Stress Disorder on Telomere Length and Amygdala Volume.},
journal = {Biological psychiatry. Cognitive neuroscience and neuroimaging},
volume = {5},
number = {7},
pages = {678-687},
doi = {10.1016/j.bpsc.2020.03.007},
pmid = {32439402},
issn = {2451-9030},
abstract = {BACKGROUND: Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined.<br><br>METHODS: Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging.<br><br>RESULTS: A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates.<br><br>CONCLUSIONS: These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.},
}
@article {pmid32433826,
year = {2020},
author = {Li, Y and Gu, J and Ding, Y and Gao, H and Li, Y and Sun, Y and He, M and Zhang, W and Yin, J and Bai, C and Gao, Y},
title = {A small molecule compound IX inhibits telomere and attenuates oncogenesis of drug-resistant leukemia cells.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {34},
number = {7},
pages = {8843-8857},
doi = {10.1096/fj.201902651RR},
pmid = {32433826},
issn = {1530-6860},
support = {//Ministry of Science and Technology of the People's Republic of China/ ; 81870083//National Natural Science Foundation of China/ ; 81430004//National Natural Science Foundation of China/ ; 81421002//National Natural Science Foundation of China/ ; 81970105//National Natural Science Foundation of China/ ; 2016-I2M-3-008//CAMS Innovation Fund for Medical Sciences/ ; 2016-I2M-1-017//CAMS Innovation Fund for Medical Sciences/ ; 18ZXXYSY00010//Tianjin Science and Technology Planning Project/ ; //Central Research Institute/ ; //SKLEH-Pilot Research Grant/ ; },
abstract = {Drug resistance is a common obstacle in leukemia treatment and failing to eradicate leukemia stem cells is the main cause of leukemia relapse. Previous studies have demonstrated that telomerase activity is associated with deregulated self-renewal of leukemia stem cells (LSCs). Here, we identified a novel compound IX, an imatinib derivative with a replacement fragment of a telomerase inhibitor, which can effectively eradicate LSCs but had no influence on normal hematopoietic stem cells (HSCs) survival. We showed that compound IX can decrease the viability of drug-resistant K562/G cells and blast crisis CML primary patient cells. Besides, IX can affect LSC survival, inhibit the colony-forming ability, and reduce LSC frequency. In vivo results showed that IX can relieve the tumor burden in patient-derived xenograft (PDX) model and prolong the lifespan. We observed that compound IX can not only decrease telomerase activity, but also affect the alternative lengthening of telomeres. In addition, IX can inhibit both the canonical and non-canonical Wnt pathways. Our data suggested this novel compound IX as a promising candidate for drug-resistant leukemia therapy.},
}
@article {pmid32430098,
year = {2020},
author = {Vecoli, C and Borghini, A and Andreassi, MG},
title = {The molecular biomarkers of vascular aging and atherosclerosis: telomere length and mitochondrial DNA4977 common deletion.},
journal = {Mutation research},
volume = {784},
number = {},
pages = {108309},
doi = {10.1016/j.mrrev.2020.108309},
pmid = {32430098},
issn = {1873-135X},
mesh = {Aging/genetics/metabolism/*pathology ; Animals ; Atherosclerosis/*diagnosis/genetics/metabolism ; Biomarkers/*analysis ; DNA, Mitochondrial/*genetics ; *Gene Deletion ; Humans ; Mitochondria/genetics/*pathology ; Risk Factors ; Telomere Shortening/*genetics ; },
abstract = {Age is the dominant risk factor for the most prevalent atherosclerotic vascular diseases, including coronary artery disease, myocardial infarction, cerebrovascular disease and stroke. In human, telomere erosion and mitochondrial DNA (mtDNA) damage play a central role in the mechanisms leading to cellular aging decline. This review summarizes the most relevant findings on the role of telomere shortening and the common mtDNA4977 deletion in the progression and evolution of atherosclerosis by combining insight from experimental models and human clinical studies. The current evidence shows a link between telomere erosion and compromised mitochondrial function and provides a new perspective regarding their potential role as clinical biomarkers and therapeutic targets.},
}
@article {pmid32429809,
year = {2020},
author = {Noguera, JC and Velando, A},
title = {Gull chicks grow faster but lose telomeres when prenatal cues mismatch the real presence of sibling competitors.},
journal = {Proceedings. Biological sciences},
volume = {287},
number = {1927},
pages = {20200242},
pmid = {32429809},
issn = {1471-2954},
mesh = {Animals ; Charadriiformes/*physiology ; Clutch Size ; Cues ; Siblings ; Social Environment ; *Telomere ; },
abstract = {During embryonic life, individuals should adjust their phenotype to the conditions that they will encounter after birth, including the social environment, if they have access to (social) cues that allow them to forecast future conditions. In birds, evidence indicates that embryos are sensitive to cues from clutch mates, but whether embryos adjust their development to cope with the expected level of sibling competition has not hitherto been investigated. To tackle this question, we performed a 'match versus mismatch' experimental design where we manipulated the presence of clutch mates (i.e. clutch size manipulation) and the real (postnatal) level of sibling competition (i.e. brood size manipulation) in the yellow-legged gull (Larus michahellis). We provide evidence that the prenatal cues of sibling presence induced developmental changes (such as epigenetic profiles) that had programming effects on chick begging behaviour and growth trajectories after hatching. While receiving mismatching information favoured chick begging and growth, this came at the cost of reduced antioxidant defences and a premature loss of telomeres. Our findings highlight the role of the prenatal social environment in developmental plasticity and suggest that telomere attrition may be an important physiological cost of phenotype-environment mismatch.},
}
@article {pmid32427758,
year = {2020},
author = {Gerritsen, L and Hägg, S and Reynolds, CA and Pedersen, NL},
title = {The Association of Individual Changes in Stressful Life Events and Telomere Length Over Time in Twins 50 Years and Older.},
journal = {Psychosomatic medicine},
volume = {82},
number = {6},
pages = {614-622},
doi = {10.1097/PSY.0000000000000826},
pmid = {32427758},
issn = {1534-7796},
abstract = {OBJECTIVE: Exposure to adverse stressors has been associated with shortening of leukocyte telomere length (LTL). The present longitudinal study investigates the time course of exposure to life events and LTL to determine whether increases in exposure to life events are related to subsequent accelerated LTL shortening.<br><br>METHODS: In the Swedish Adoption/Twin Study of Aging, we assessed late-life stressful events and LTL in 543 individual participants (mean age = 68.4 years, 40% men, including 48 complete monozygotic twin pairs and 167 complete dizygotic twin pairs) in up to five separate measurements over a period of 25 years. LTL was measured using quantitative polymerase chain reaction. Longitudinal analyses were conducted using time-varying mixed modeling, corrected for life-style factors and depressive symptoms.<br><br>RESULTS: When adjusting for differences in genetic makeup by looking only in monozygotic twins, we found that an increase in life stressors within an individual was related to decreased LTL over time (B = -0.02; 95% confidence interval = -0.04 to 0.01; p = .002). None of the findings were significant when only looking at dizygotic twins (all, p > .05).<br><br>CONCLUSIONS: Our findings in an older population show a causal relation between increase in life stress and accelerated LTL shortening by using intraindividual time-varying analysis.},
}
@article {pmid32427393,
year = {2020},
author = {Aviv, A},
title = {Telomeres and COVID-19.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {34},
number = {6},
pages = {7247-7252},
pmid = {32427393},
issn = {1530-6860},
support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; ES562296//Norwegian Research Council/International ; U01AG066529//HHS | NIH | National Institute on Aging (NIA)/International ; },
mesh = {*Betacoronavirus ; Biomarkers ; Bone Marrow/pathology ; COVID-19 ; Cell Division ; Coronavirus Infections/genetics/immunology/mortality/*pathology ; Disease Progression ; Hematopoietic Stem Cells/pathology ; Humans ; Lymphocyte Activation ; Lymphocyte Count ; Lymphopenia/*etiology/pathology ; Lymphopoiesis ; *Models, Biological ; Pandemics ; Pneumonia, Viral/genetics/immunology/mortality/*pathology ; Prognosis ; Risk ; SARS-CoV-2 ; T-Lymphocyte Subsets/*ultrastructure ; Telomere/*ultrastructure ; *Telomere Shortening ; },
abstract = {The medical, public health, and scientific communities are grappling with monumental imperatives to contain COVID-19, develop effective vaccines, identify efficacious treatments for the infection and its complications, and find biomarkers that detect patients at risk of severe disease. The focus of this communication is on a potential biomarker, short telomere length (TL), that might serve to identify patients more likely to die from the SARS-CoV-2 infection, regardless of age. The common thread linking these patients is lymphopenia, which largely reflects a decline in the numbers of CD4/CD8 T cells but not B cells. These findings are consistent with data that lymphocyte TL dynamics impose a limit on T-cell proliferation. They suggest that T-cell lymphopoiesis might stall in individuals with short TL who are infected with SARS-CoV-2.},
}
@article {pmid32427102,
year = {2020},
author = {El Maï, M and Marzullo, M and de Castro, IP and Ferreira, MG},
title = {Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {32427102},
issn = {2050-084X},
support = {PTDC/SAU-ORG/116826/2010//Fundação para a Ciência e a Tecnologia/International ; PJA 20161205137//Fondation ARC pour la Recherche sur le Cancer/International ; Installation Grant: Action 2 - 2019//Université Côte d'Azur - Académie 4/International ; IECS/HHMI/Howard Hughes Medical Institute/United States ; Postdoctoral fellowship//Ville de Nice/International ; },
abstract = {Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence.},
}
@article {pmid32425970,
year = {2020},
author = {van der Spek, A and Warner, SC and Broer, L and Nelson, CP and Vojinovic, D and Ahmad, S and Arp, PP and Brouwer, RWW and Denniff, M and van den Hout, MCGN and van Rooij, JGJ and Kraaij, R and van IJcken, WFJ and Samani, NJ and Ikram, MA and Uitterlinden, AG and Codd, V and Amin, N and van Duijn, CM},
title = {Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length.},
journal = {Frontiers in genetics},
volume = {11},
number = {},
pages = {337},
pmid = {32425970},
issn = {1664-8021},
support = {U54 HG003067/HG/NHGRI NIH HHS/United States ; },
abstract = {Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10-7, minor allele frequency of 0.2-0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10-6), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10-4) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.},
}
@article {pmid32422075,
year = {2020},
author = {Morais, M and Dias, F and Resende, T and Nogueira, I and Oliveira, J and Maurício, J and Teixeira, AL and Medeiros, R},
title = {Leukocyte telomere length and hTERT genetic polymorphism rs2735940 influence the renal cell carcinoma clinical outcome.},
journal = {Future oncology (London, England)},
volume = {16},
number = {18},
pages = {1245-1255},
doi = {10.2217/fon-2019-0795},
pmid = {32422075},
issn = {1744-8301},
mesh = {Adult ; Aged ; Biomarkers, Tumor ; Carcinoma, Renal Cell/*genetics/*mortality/pathology ; Case-Control Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Kidney Neoplasms/*genetics/*mortality/pathology ; Leukocytes/*metabolism ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; *Polymorphism, Single Nucleotide ; Prognosis ; Proportional Hazards Models ; Telomerase/*genetics ; Telomere Homeostasis ; },
abstract = {Aim: Analysis of the genetic hTERT-1327 C>T (rs2735940) influence on leukocyte telomere length (LTL) and tumor development, progression and overall survival in renal cell carcinoma (RCC) patients. Materials &amp; methods: Using leukocyte DNA of RCC patients and healthy individuals, LTL measurement and allelic discrimination of rs2735940 was performed by real-time PCR. Results: RCC patients showed shorter LTL than healthy individuals and LTL increased with clinical stage. CC+TC genotypes healthy carriers' presented shorter LTL. However, no statistical association between the different genotypes and RCC risk. Nevertheless, CC homozygous presented a reduced time to disease progression and a lower overall survival. The use of hTERT-1327 single nucleotide polymorphism information increased the capacity to predict risk for RCC progression. Conclusion: In fact, in healthy individuals, hTERT-1327 CC+TC genotypes were associated with shorter LTL, and this single nucleotide polymorphism was associated with time to disease progression, being a promising potential prognosis biomarker to be used in the future.},
}
@article {pmid32417614,
year = {2020},
author = {Wang, C and Wolters, PJ and Calfee, CS and Liu, S and Balmes, JR and Zhao, Z and Koyama, T and Ware, LB},
title = {Long-term ozone exposure is positively associated with telomere length in critically ill patients.},
journal = {Environment international},
volume = {141},
number = {},
pages = {105780},
pmid = {32417614},
issn = {1873-6750},
support = {K24 HL103836/HL/NHLBI NIH HHS/United States ; R01 HL135849/HL/NHLBI NIH HHS/United States ; R35 HL140026/HL/NHLBI NIH HHS/United States ; },
mesh = {*Air