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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 22 Jan 2021 at 01:50 Created: 

Telomeres

Wikipedia: A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) "end" and merοs (μέρος, root: μερ-) "part". For vertebrates, the sequence of nucleotides in telomeres is TTAGGG, with the complementary DNA strand being AATCCC, with a single-stranded TTAGGG overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans. In humans, average telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age,[3] with average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes.

Created with PubMed® Query: telomere[title] OR telomeres[title] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-01-20

Lindrose AR, McLester-Davis LWY, Tristano RI, et al (2021)

Method comparison studies of telomere length measurement using qPCR approaches: A critical appraisal of the literature.

PloS one, 16(1):e0245582 pii:PONE-D-20-35797.

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.

RevDate: 2021-01-20

Belfort MB, Qureshi F, Litt J, et al (2021)

Telomere length shortening in hospitalized preterm infants: A pilot study.

PloS one, 16(1):e0243468 pii:PONE-D-20-19370.

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.

RevDate: 2021-01-20

Barbé-Tuana FM, Grun LK, Pierdoná V, et al (2021)

Shorter telomeres in children with severe asthma, an indicative of accelerated aging.

Aging, 13: pii:202527 [Epub ahead of print].

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.

RevDate: 2021-01-20

Huang Z, Liu C, Ruan Y, et al (2021)

Dynamics of leukocyte telomere length in adults aged 50 and older: a longitudinal population-based cohort study.

GeroScience [Epub ahead of print].

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.

RevDate: 2021-01-20

Monsen RC, Chakravarthy S, Dean WL, et al (2021)

The solution structures of higher-order human telomere G-quadruplex multimers.

Nucleic acids research pii:6104436 [Epub ahead of print].

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.

RevDate: 2021-01-20

Konečná K, Sováková PP, Anteková K, et al (2021)

Distinct Responses of Arabidopsis Telomeres and Transposable Elements to Zebularine Exposure.

International journal of molecular sciences, 22(1): pii:ijms22010468.

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.

RevDate: 2021-01-19

Molbert N, Angelier F, Alliot F, et al (2021)

Fish from urban rivers and with high pollutant levels have shorter telomeres.

Biology letters, 17(1):20200819.

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.

RevDate: 2021-01-18

Vedder O, Moiron M, Bichet C, et al (2021)

Telomere length is heritable and genetically correlated with lifespan in a wild bird.

Molecular ecology [Epub ahead of print].

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 'animal models' 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.

RevDate: 2021-01-18

Samavat H, Luu HN, Beckman KB, et al (2021)

Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese Health Study.

International journal of cancer, 148(2):352-362.

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.

RevDate: 2021-01-16

Zhang JM, Genois MM, Ouyang J, et al (2021)

Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.

Molecular cell pii:S1097-2765(20)30951-5 [Epub ahead of print].

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.

RevDate: 2021-01-16

Samad MA, Saiman MZ, Abdul Majid N, et al (2021)

Berberine Inhibits Telomerase Activity and Induces Cell Cycle Arrest and Telomere Erosion in Colorectal Cancer Cell Line, HCT 116.

Molecules (Basel, Switzerland), 26(2): pii:molecules26020376.

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.

RevDate: 2021-01-15

Gala K, E Khattar (2021)

Long non-coding RNAs at work on telomeres: Functions and implications in cancer therapy.

Cancer letters pii:S0304-3835(21)00002-1 [Epub ahead of print].

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.

RevDate: 2021-01-15

Chakravarti D, LaBella KA, RA DePinho (2021)

Telomeres: history, health, and hallmarks of aging.

Cell pii:S0092-8674(20)31750-5 [Epub ahead of print].

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.

RevDate: 2021-01-15

Liddiard K, Grimstead JW, Cleal K, et al (2021)

Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response.

NAR cancer, 3(1):zcaa044.

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.

RevDate: 2021-01-15

Henslee G, Williams C, Liu P, et al (2021)

Identification and characterization of novel ACD variants: Modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.

Cold Spring Harbor molecular case studies pii:mcs.a005454 [Epub ahead of print].

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.

RevDate: 2021-01-13

Sławińska N, R Krupa (2021)

Molecular Aspects of Senescence and Organismal Ageing-DNA Damage Response, Telomeres, Inflammation and Chromatin.

International journal of molecular sciences, 22(2): pii:ijms22020590.

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.

RevDate: 2021-01-13

Selvaraju V, Phillips M, Fouty A, et al (2021)

Telomere Length as a Biomarker for Race-Related Health Disparities.

Genes, 12(1): pii:genes12010078.

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.

RevDate: 2021-01-12

Lee HH, Okuzono SS, Kim ES, et al (2020)

Optimism and telomere length among African American adults in the Jackson Heart Study.

Psychoneuroendocrinology, 125:105124 pii:S0306-4530(20)30547-3 [Epub ahead of print].

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.

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.

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.

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.

RevDate: 2021-01-12

McCulloch MJ, Ward Gauthier NA, L Vaillancourt (2021)

Use of telomere fingerprinting to identify clonal lineages of Colletotrichum fioriniae in Kentucky mixed-fruit orchards.

Plant disease [Epub ahead of print].

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.

RevDate: 2021-01-12

Lee JS, La J, Aziz S, et al (2021)

Molecular Markers of Telomere Dysfunction and Senescence are Common Findings in the Usual Interstitial Pneumonia Pattern of Lung Fibrosis.

Histopathology [Epub ahead of print].

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.

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.

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.

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.

RevDate: 2021-01-12

Evans JR, Torres-Pérez JV, Miletto Petrazzini ME, et al (2021)

Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio).

Scientific reports, 11(1):339.

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.

RevDate: 2021-01-12

Crocco P, De Rango F, Dato S, et al (2021)

Telomere length as a function of age at population level parallels human survival curves.

Aging, 13: pii:202498 [Epub ahead of print].

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.

RevDate: 2021-01-10

Martens DS, Van Der Stukken C, Derom C, et al (2021)

Newborn telomere length predicts later life telomere length: Tracking telomere length from birth to child- and adulthood.

EBioMedicine, 63:103164 pii:S2352-3964(20)30540-5 [Epub ahead of print].

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.

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.

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.

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.

FUNDING: European Research Council (ERC-StG310898) and Flemish Scientific Fund (12X9620N).

RevDate: 2021-01-10

Cheng F, Luk AO, Wu H, et al (2021)

Shortened Relative Leukocyte Telomere Length is Associated with All-cause Mortality in Type 2 Diabetes- Analysis from the Hong Kong Diabetes Register.

Diabetes research and clinical practice pii:S0168-8227(21)00002-4 [Epub ahead of print].

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.

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.

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.

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.

RevDate: 2021-01-08

Sethuram R, Bazzi AA, Salih SM, et al (2021)

Peripheral lymphocyte telomere dysfunction: a valid surrogate marker for female fertility?.

Fertility and sterility, 115(1):85-86.

RevDate: 2021-01-08

Liu X, Liu X, Shi Q, et al (2021)

Association of telomere length and telomerase methylation with n-3 fatty acids in preschool children with obesity.

BMC pediatrics, 21(1):24.

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.

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.

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.

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.

RevDate: 2021-01-07

Kalungi A, Kinyanda E, Womersley JS, et al (2021)

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.

BMC medical genomics, 14(1):15.

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).

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.

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.

RevDate: 2021-01-07

Godhamgaonkar AA, Sundrani DP, SR Joshi (2021)

Role of maternal nutrition and oxidative stress in placental telomere attrition in women with preeclampsia.

Hypertension in pregnancy [Epub ahead of print].

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.

RevDate: 2021-01-06

Fan YL, Q Ye (2020)

[A concise review of telomere and telomerase-related genetic markers in fibrotic lung diseases].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 38(12):952-956.

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.

RevDate: 2021-01-06

Elmadawy MA, Abdulah OA, El Gazzar WB, et al (2021)

Telomere length and signal joint T-cell receptor rearrangement excision circles as biomarkers for chronological age estimation.

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals [Epub ahead of print].

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.

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.

RESULTS: 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].

RevDate: 2021-01-05

Viswanath P, Batsios G, Mukherjee J, et al (2021)

Non-invasive assessment of telomere maintenance mechanisms in brain tumors.

Nature communications, 12(1):92.

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.

RevDate: 2021-01-05

Starnino L, Dupuis G, Busque L, et al (2021)

The associations of hostility and defensiveness with telomere length are influenced by sex and health status.

Biology of sex differences, 12(1):2.

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.

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.

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).

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.

RevDate: 2021-01-05

Li X, Liu J, Zhou G, et al (2021)

BDE-209 and DBDPE induce male reproductive toxicity through telomere-related cell senescence and apoptosis in SD rat.

Environment international, 146:106307.

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.

RevDate: 2021-01-04

Shah A, George M, Dhangar S, et al (2021)

Severe telomere shortening in Fanconi anemia complementation group L.

Molecular biology reports [Epub ahead of print].

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.

RevDate: 2021-01-04

Mizuno Y, Konishi S, Goto C, et al (2021)

Association between nutrient intake and telomere length in Japanese female university students.

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals [Epub ahead of print].

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.

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 fiber) 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.

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).

CONCLUSIONS: Our findings suggest that variation in vitamin A intake might influence telomere attrition in healthy individuals.

RevDate: 2021-01-04

Begus-Nahrmann Y, Hartmann D, Kraus J, et al (2021)

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis.

The Journal of clinical investigation, 131(1):.

RevDate: 2021-01-04

Remot F, Ronget V, Froy H, et al (2020)

No sex differences in adult telomere length across vertebrates: a meta-analysis.

Royal Society open science, 7(11):200548 pii:rsos200548.

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.

RevDate: 2021-01-03

Goswami A, Huda N, Yasmin T, et al (2021)

Association study of leukocyte telomere length and genetic polymorphism within hTERT promoter with type 2 diabetes in Bangladeshi population.

Molecular biology reports [Epub ahead of print].

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.

RevDate: 2021-01-03

Hautekiet P, Nawrot TS, Janssen BG, et al (2020)

Child buccal telomere length and mitochondrial DNA content as biomolecular markers of ageing in association with air pollution.

Environment international, 147:106332 pii:S0160-4120(20)32287-X [Epub ahead of print].

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.

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.

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.

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.

RevDate: 2021-01-02

Aguiar SS, Sousa CV, Santos PA, et al (2020)

Master athletes have longer telomeres than age-matched non-athletes. A systematic review, meta-analysis and discussion of possible mechanisms.

Experimental gerontology pii:S0531-5565(20)30560-X [Epub ahead of print].

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.

RevDate: 2021-01-02

Fransson S, Martinez-Monleon A, Johansson M, et al (2020)

Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance.

Scientific reports, 10(1):22432.

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.

RevDate: 2020-12-30

Salas-Huetos A, Tüttelmann F, Wyrwoll MJ, et al (2020)

Correction to: Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.

RevDate: 2020-12-29

Yu YL, H Liu (2020)

Marital Quality and Salivary Telomere Length Among Older Men and Women in the United States.

Journal of aging and health [Epub ahead of print].

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.

RevDate: 2021-01-01

Perona R (2020)

The Different Roads to Maintain Telomeres in Cancer Cells.

Genes, 11(12):.

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 [...].

RevDate: 2020-12-28

Wagner T, Pérez-Martínez L, Schellhaas R, et al (2020)

Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence.

PLoS genetics, 16(12):e1008603 pii:PGENETICS-D-20-00041 [Epub ahead of print].

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.

RevDate: 2020-12-28

Kroupa M, Rachakonda S, Vymetalkova V, et al (2020)

Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients.

Mutagenesis pii:6050628 [Epub ahead of print].

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.

RevDate: 2020-12-28

Pudas S, Josefsson M, Nordin Adolfsson A, et al (2020)

Short leukocyte telomeres, but not telomere attrition rates, predict memory decline in the 20-year longitudinal Betula study.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6053754 [Epub ahead of print].

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.

RevDate: 2020-12-28

Gadalla SM (2020)

Telomere length in hematopoietic cell transplant.

Blood, 136(26):2972-2973.

RevDate: 2020-12-29

Myllymäki M, Redd R, Reilly CR, et al (2020)

Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome.

Blood, 136(26):3070-3081.

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.

RevDate: 2020-12-28

Tomos I, Karakatsani A, Manali ED, et al (2020)

Telomere length across different UIP fibrotic-Interstitial Lung Diseases: a prospective Greek case-control study.

Pulmonology pii:S2531-0437(20)30248-8 [Epub ahead of print].

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).

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.

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).

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.

RevDate: 2021-01-01

Gupta MD, Miglani M, Bansal A, et al (2020)

Telomere length in young patients with acute myocardial infarction without conventional risk factors: A pilot study from a South Asian population.

Indian heart journal, 72(6):619-622.

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.

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.

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).

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.

RevDate: 2020-12-28

Le R, Huang Y, Zhang Y, et al (2020)

Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells.

Cell stem cell pii:S1934-5909(20)30582-8 [Epub ahead of print].

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.

RevDate: 2020-12-23

Allsopp R (2021)

Take a Ride on the Telomere-Aging Train.

The journals of gerontology. Series A, Biological sciences and medical sciences, 76(1):1-2.

RevDate: 2020-12-23

Červenák F, Sepšiová R, Nosek J, et al (2020)

Step-by-step evolution of telomeres: lessons from yeasts.

Genome biology and evolution pii:6045954 [Epub ahead of print].

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.

RevDate: 2020-12-23

Joshu CE, Heaphy CM, Barber JR, et al (2020)

Obesity is associated with shorter telomere length in prostate stromal cells in men with aggressive prostate cancer.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-20-0250 [Epub ahead of print].

In our prior studies, obesity was associated with shorter telomeres in prostate cancer associated stromal cells (CAS), and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine if 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 DAPI 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 non-aggressive 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%CI: 1.07-8.75; P-trend=0.045) when compared to normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis.

RevDate: 2020-12-23

Yu SN, Chen SQ, Fan GQ, et al (2020)

Relative Telomere Length in Peripheral Blood Cells and Hypertension Risk among Mine Workers: A Case-Control Study in Chinese Coal Miners.

BioMed research international, 2020:5681096.

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.

RevDate: 2020-12-31

Minamoto T, Nakayama K, Ishibashi T, et al (2020)

Pregnancy by Assisted Reproductive Technology Is Associated with Shorter Telomere Length in Neonates.

International journal of molecular sciences, 21(24):.

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.

RevDate: 2020-12-23

Dudinskaya EN, Tkacheva ON, Brailova NV, et al (2020)

[Telomere biology and metabolic disorders: the role of insulin resistance and type 2 diabetes].

Problemy endokrinologii, 66(4):35-44.

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 "genetic protection" of cells, which many scientists associate with replicative cellular aging.

AIMS: to study the relationship between the state of carbohydrate metabolism and markers of replicative cell aging in individuals with different sensitivity to insulin.

MATERIALS AND METHODS: The observation study included 305 patients. The parameters of glucose metabolism and telomere biology were studied.

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 "short" 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%.

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.

RevDate: 2020-12-26

Saint-Leandre B, Christopher C, MT Levine (2020)

Adaptive evolution of an essential telomere protein restricts telomeric retrotransposons.

eLife, 9:.

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.

RevDate: 2020-12-21

Li X, Wang M, Zheng W, et al (2020)

Dynamics of TRF1 organizing a single human telomere.

Nucleic acids research pii:6042956 [Epub ahead of print].

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.

RevDate: 2020-12-21

Luxton JJ, SM Bailey (2021)

Twins, Telomeres, and Aging-in Space!.

Plastic and reconstructive surgery, 147(1S-2):7S-14S.

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 "omics"-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 "out of this world" 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.

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.

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.

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.

RevDate: 2020-12-22

Simões HG, Rosa TS, Sousa CV, et al (2020)

Does Longer Leukocyte Telomere Length and Higher Physical Fitness Protect Master Athletes From Consequences of Coronavirus (SARS-CoV-2) Infection?.

Frontiers in sports and active living, 2:87.

RevDate: 2020-12-22

Goncalves T, Zoumpoulidou G, Alvarez-Mendoza C, et al (2020)

Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors.

ACS pharmacology & translational science, 3(6):1253-1264.

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.

RevDate: 2020-12-18

Ningarhari M, Caruso S, Hirsch TZ, et al (2020)

Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target.

Journal of hepatology pii:S0168-8278(20)33846-0 [Epub ahead of print].

BACKGROUND & AIMS: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. We aimed to elucidate telomere length (TL) control during liver carcinogenesis.

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.

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.

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.

RevDate: 2020-12-19

Iyengar S, Cȏté HCF, Fitch KV, et al (2020)

Relationship of Telomere Length to Fat Redistribution in HIV.

Open forum infectious diseases, 7(12):ofaa523.

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.

RevDate: 2020-12-19

Leonida SRL, Bennett NC, Leitch AR, et al (2020)

Patterns of telomere length with age in African mole-rats: New insights from quantitative fluorescence in situ hybridisation (qFISH).

PeerJ, 8:e10498.

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.

RevDate: 2020-12-17

Zarei M, Zarezadeh M, Hamedi Kalajahi F, et al (2021)

The Relationship Between Vitamin D and Telomere/Telomerase: A Comprehensive Review.

The Journal of frailty & aging, 10(1):2-9.

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.

RevDate: 2020-12-18

Gutlapalli SD, Kondapaneni V, Toulassi IA, et al (2020)

The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling.

Cureus, 12(11):e11482.

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 "Resveratrol", "Telomere", "Post Myocardial Infarction". 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.

RevDate: 2020-12-23

Yu EY, Zahid SS, Ganduri S, et al (2020)

Structurally distinct telomere-binding proteins in Ustilago maydis execute non-overlapping functions in telomere replication, recombination, and protection.

Communications biology, 3(1):777.

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.

RevDate: 2020-12-16

Oskouei Z, Mehri S, Kalalinia F, et al (2020)

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.

Phytotherapy research : PTR [Epub ahead of print].

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.

RevDate: 2020-12-19

Gao Z, Daquinag AC, Fussell C, et al (2020)

Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease.

Nature metabolism, 2(12):1482-1497.

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.

RevDate: 2020-12-16

Lee EH, Han MH, Ha J, et al (2020)

Relationship between telomere shortening and age in Korean individuals with mild cognitive impairment and Alzheimer's disease compared to that in healthy controls.

Aging, 12: pii:202206 [Epub ahead of print].

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.

RevDate: 2020-12-16

Wu F, Huang Y, Hu J, et al (2020)

Mendelian randomization study of telomere length and bone mineral density.

Aging, 12: pii:202197 [Epub ahead of print].

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.

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. "Leave-one-out" sensitivity analysis confirmed the stability of our results.

CONCLUSION: Our MR analysis did not support causal effect of telomere length on BMD.

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 "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities and stability of these genetic variants on BMD.

RevDate: 2020-12-16

Fan Y, Zheng C, Wu N, et al (2020)

Telomerase gene variants and telomere shortening in patients with silicosis or asbestosis.

Occupational and environmental medicine pii:oemed-2020-107046 [Epub ahead of print].

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.

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.

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.

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.

RevDate: 2020-12-15

Huang J, Peng X, Dong K, et al (2020)

The Association between Antidiabetic Agents and Leukocyte Telomere Length in the Novel Classification of Type 2 Diabetes Mellitus.

Gerontology pii:000511362 [Epub ahead of print].

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.

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.

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.

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.

RevDate: 2021-01-02

Solek P, Shemedyuk N, Shemedyuk A, et al (2020)

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.

Ecotoxicology and environmental safety, 209:111782 pii:S0147-6513(20)31618-3 [Epub ahead of print].

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.

RevDate: 2020-12-15

Corbo RM, Businaro R, D Scarabino (2021)

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?.

Neural regeneration research, 16(7):1397-1398.

RevDate: 2020-12-29

Alnafakh R, Choi F, Bradfield A, et al (2020)

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.

Biomedicines, 8(12):.

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.

RevDate: 2020-12-30

Zhang B, Liu L, Guo L, et al (2020)

Telomere length mediates the association between polycyclic aromatic hydrocarbons exposure and abnormal glucose level among Chinese coke oven plant workers.

Chemosphere, 266:129111 pii:S0045-6535(20)33308-7 [Epub ahead of print].

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.

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.

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.

CONCLUSIONS: Our findings suggested the effect of abnormal glucose related to PAHs exposure was mediated by telomere length in coke oven plant workers.

RevDate: 2021-01-01

Uppuluri L, Varapula D, Young E, et al (2020)

Single-molecule telomere length characterization by optical mapping in nano-channel array: Perspective and review on telomere length measurement.

Environmental toxicology and pharmacology, 82:103562 pii:S1382-6689(20)30239-8 [Epub ahead of print].

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.

RevDate: 2020-12-14

Chen L, Shivappa N, Dong X, et al (2020)

Association between appendicular skeletal muscle index and leukocyte telomere length in adults: A study from National Health and Nutrition Examination Survey (NHANES) 1999-2002.

Clinical nutrition (Edinburgh, Scotland) pii:S0261-5614(20)30652-X [Epub ahead of print].

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.

OBJECTIVE: We investigated the association of the ASMI with leukocyte telomere length in adult Americans.

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.

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.

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.

RevDate: 2020-12-22

Izano MA, Cushing LJ, Lin J, et al (2020)

The association of maternal psychosocial stress with newborn telomere length.

PloS one, 15(12):e0242064.

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.

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.

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.

CONCLUSIONS: This study is the first to examine the joint effect of multiple stressors during pregnancy on newborn TL using a flexible modeling approach.

RevDate: 2020-12-24

Li H, Wang B, Li D, et al (2021)

Roles of telomeres and telomerase in age‑related renal diseases (Review).

Molecular medicine reports, 23(2):.

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.

RevDate: 2020-12-09

Cherfils-Vicini J, É Gilson (2020)

[Longevity clocks: The promoting role of telomeres?].

Medecine sciences : M/S, 36(12):1113-1117.

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.

RevDate: 2020-12-09

Lee JJ, Lee J, H Lee (2020)

Alternative paths to telomere elongation.

Seminars in cell & developmental biology pii:S1084-9521(19)30120-X [Epub ahead of print].

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.

RevDate: 2020-12-12

Noppert GA, Feinstein L, Dowd JB, et al (2020)

Pathogen burden and leukocyte telomere length in the United States.

Immunity & ageing : I & A, 17(1):36.

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.

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.

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.

RevDate: 2020-12-08

Thomas MD, Sohail S, Mendez RM, et al (2020)

Racial Discrimination and Telomere Length in Midlife African American Women: Interactions of Educational Attainment and Employment Status.

Annals of behavioral medicine : a publication of the Society of Behavioral Medicine pii:6026577 [Epub ahead of print].

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.

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.

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.

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.

RevDate: 2020-12-11

Samuel P, Tsapekos M, de Pedro N, et al (2020)

Ergothioneine Mitigates Telomere Shortening under Oxidative Stress Conditions.

Journal of dietary supplements [Epub ahead of print].

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.

RevDate: 2020-12-19

Nayis A, Liebl K, Frost CV, et al (2020)

Targeting Telomeres: Molecular Dynamics and Free Energy Simulation of Gold-Carbene Binding to DNA.

Biophysical journal pii:S0006-3495(20)33171-4 [Epub ahead of print].

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.

RevDate: 2020-12-08

van Moorsel CHM (2020)

Putting Genetics Into Practice: Challenges Associated With the Genetics of Short Telomere Syndromes.

Chest, 158(6):2249-2250.

RevDate: 2020-12-07

Alhareeri AA, Archer KJ, Fu H, et al (2020)

Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study.

Breast cancer research : BCR, 22(1):137.

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.

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].

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).

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.

RevDate: 2020-12-30

Brown R, Hailu EM, Needham BL, et al (2020)

Neighborhood social environment and changes in leukocyte telomere length: The Multi-Ethnic Study of Atherosclerosis (MESA).

Health & place, 67:102488 pii:S1353-8292(20)31882-7 [Epub ahead of print].

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.

RevDate: 2020-12-18

Schratz KE (2020)

Extrahematopoietic manifestations of the short telomere syndromes.

Hematology. American Society of Hematology. Education Program, 2020(1):115-122.

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.

RevDate: 2020-12-04

Hanson BM, Tao X, Zhan Y, et al (2020)

Shorter telomere length of white blood cells is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization.

Fertility and sterility pii:S0015-0282(20)32505-X [Epub ahead of print].

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.

DESIGN: Prospective cohort study.

SETTING: Academic-affiliated private practice.

PATIENTS: A total of 175 infertile women undergoing in vitro fertilization (IVF) at a single center between July 2017 and December 2018.

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.

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.

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.

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.

RevDate: 2020-12-04

M'kacher R, Colicchio B, Marquet V, et al (2020)

Telomere aberrations, including telomere loss, doublets, and extreme shortening, are increased in patients with infertility.

Fertility and sterility pii:S0015-0282(20)30629-4 [Epub ahead of print].

OBJECTIVE: To test the hypothesis that telomere shortening and/or loss are risk factors for infertility.

DESIGN: Retrospective analysis of the telomere status in patients with infertility using conventional cytogenetic data collected prospectively.

SETTING: Academic centers.

PATIENT(S): Cytogenetic slides with cultured peripheral lymphocytes from 50 patients undergoing fertility treatment and 150 healthy donors, including 100 donors matched for age.

INTERVENTION(S): Cytogenetic slides were used to detect chromosomal and telomere aberrations.

MAIN OUTCOME MEASURE(S): Telomere length and telomere aberrations were analyzed after telomere and centromere staining.

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.

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.

RevDate: 2020-12-18

Liu JC, Li QJ, He MH, et al (2020)

Swc4 positively regulates telomere length independently of its roles in NuA4 and SWR1 complexes.

Nucleic acids research, 48(22):12792-12803.

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.

RevDate: 2020-12-31

Ackerson SM, Gable CI, JA Stewart (2020)

Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress.

Cell cycle (Georgetown, Tex.), 19(24):3491-3507.

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.

RevDate: 2020-12-18

Stivison EA, Young KJ, LS Symington (2020)

Interstitial telomere sequences disrupt break-induced replication and drive formation of ectopic telomeres.

Nucleic acids research, 48(22):12697-12710.

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.

RevDate: 2020-12-02

Wei H, Zhang C, P Silveyra (2020)

The Relationships Between Prenatal Smoking Exposure and Telomere Lengths in Fetuses, Infants, and Children: A Systematic Literature Review.

Journal of addictions nursing, 31(4):243-252.

OBJECTIVE: The aim of this study was to evaluate the relationships between prenatal smoking exposure and telomere lengths (TLs) in fetuses, infants, and children.

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.

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.

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.

RevDate: 2020-12-07

Eckhardt F, Pauliny A, Rollings N, et al (2020)

Stress-related changes in leukocyte profiles and telomere shortening in the shortest-lived tetrapod, Furcifer labordi.

BMC evolutionary biology, 20(1):160.

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.

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.

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.

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ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Good Beginner's Books

Although multicellular eukaryotes (MCEs) are the most visible component of the biosphere, they represent a highly derived and constrained evolutionary subset of the biosphere, unrepresentative of the vast, mostly unseen, microbial world of prokaryotic life that comprises at least half of the planet's biomass and most of its genetic diversity. The existence of telomeres is one component of the specialized biology of eukaryotes. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )