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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 12 Aug 2022 at 01:54 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: 2022-08-11

Lundsgaard NU, Cramp RL, CE Franklin (2022)

Early exposure to UV radiation causes telomere shortening and poorer condition later in life.

The Journal of experimental biology pii:276293 [Epub ahead of print].

Determining the contribution of elevated ultraviolet-B radiation (UVBR; 280 - 315 nm) to amphibian population declines is being hindered by a lack of knowledge about how different acute UVBR exposure regimes during early life history stages might affect post-metamorphic stages via long-term carryover effects. We acutely exposed tadpoles of the Australian green tree frog (Litoria caerulea) to a combination of different UVBR irradiances and doses in a multi-factorial laboratory experiment, and then reared them to metamorphosis in the absence of UVBR to assess carryover effects in subsequent juvenile frogs. Dose and irradiance of acute UVBR exposure influenced carryover effects into metamorphosis in somewhat opposing manners. Higher doses of UVBR exposure in larvae yielded improved rates of metamorphosis. However, exposure at a high irradiance resulted in frogs metamorphosing smaller in size and in poorer condition than frogs exposed to low and medium irradiance UVBR as larvae. We also demonstrate some of the first empirical evidence of UVBR-induced telomere shortening in vivo, which is one possible mechanism for life-history trade-offs impacting condition post-metamorphosis. These findings contribute to our understanding of how acute UVBR exposure regimes in early life affect later life-history stages, which has implications for how this stressor may shape population dynamics.

RevDate: 2022-08-11

Yu HJ, SH Koh (2022)

Is Telomere Length Shortening a Risk Factor for Neurodegenerative Disorders?.

Dementia and neurocognitive disorders, 21(3):83-92.

Telomeres are located at the end of chromosomes. They are known to protect chromosomes and prevent cellular senescence. Telomere length shortening has been considered an important marker of aging. Many studies have reported this concept in connection with neurodegenerative disorders. Considering the role of telomeres, it seems that longer telomeres are beneficial while shorter telomeres are detrimental in preventing neurodegenerative disorders. However, several studies have shown that people with longer telomeres might also be vulnerable to neurodegenerative disorders. Before these conflicting results can be explained through large-scale longitudinal clinical studies on the role of telomere length in neurodegenerative disorders, it would be beneficial to simultaneously review these opposing results. Understanding these conflicting results might help us plan future studies to reveal the role of telomere length in neurodegenerative disorders. In this review, these contradictory findings are thoroughly discussed, with the aim to better understand the role of telomere length in neurodegenerative disorders.

RevDate: 2022-08-10

Olson CL, Barbour AT, DS Wuttke (2022)

Filling in the blanks: how the C-strand catches up to the G-strand at replicating telomeres using CST.

Nature structural & molecular biology [Epub ahead of print].

RevDate: 2022-08-10

Natalini JG, England BR, Baker JF, et al (2022)

Associations between shortened telomeres and rheumatoid arthritis-associated interstitial lung disease among U.S. Veterans.

Respiratory medicine, 201:106943 pii:S0954-6111(22)00208-6 [Epub ahead of print].

BACKGROUND: Shortened telomeres are associated with several different subtypes of interstitial lung disease (ILD), although studies of telomere length and ILD in rheumatoid arthritis (RA) are lacking.

METHODS: Within the Veterans Affairs Rheumatoid Arthritis (VARA) registry, we performed cross-sectional and case-control studies of prevalent and incident ILD, respectively. We randomly selected a subset of RA patients with ILD and individually matched them to RA patients without ILD according to age, sex, and VARA enrollment date. Telomere length was measured on peripheral blood leukocytes collected at registry enrollment using quantitative PCR (T/S ratio). Short telomeres were defined as a T/S ratio in the lowest 10th percentile of the cohort.

RESULTS: Our cross-sectional study cohort was comprised of 54 RA-ILD patients and 92 RA-non-ILD patients. T/S ratios significantly differed between patients with and without prevalent ILD (1.56 [IQR 1.30, 1.78] vs. 1.96 [IQR 1.65, 2.27], p < 0.001). Similarly, prevalence of ILD was significantly higher in patients with short vs. normal-length telomeres (73.3% vs. 32.8%, p = 0.002). Short telomeres were independently associated with an increased odds of prevalent ILD compared to normal-length telomeres (adjusted OR 6.60, 95% CI 1.78-24.51, p = 0.005). In our case-control analysis, comprised of 22 incident RA-ILD cases and 36 RA-non-ILD controls, short telomeres were not associated with incident RA-ILD (adjusted OR 0.90, 95% CI 0.06-13.4, p = 0.94).

CONCLUSION: Short telomeres were strongly associated with prevalent but not incident ILD among patients with RA. Additional studies are needed to better understand telomere length dynamics among RA patients with and without ILD.

RevDate: 2022-08-10

Macha SJ, Koneru B, Burrow TA, et al (2022)

Alternative Lengthening of Telomeres in Cancer Confers a Vulnerability to Reactivation of p53 Function.

Cancer research pii:707612 [Epub ahead of print].

A subset of cancers across multiple histologies with predominantly poor outcomes use the alternative lengthening of telomeres (ALT) mechanism to maintain telomere length, which can be identified with robust biomarkers. ALT has been reported to be prevalent in high-risk neuroblastoma and certain sarcomas, and ALT cancers are a major clinical challenge that lack targeted therapeutic approaches. Here, we found ALT in a variety of pediatric and adult cancer histologies, including carcinomas. Patient-derived ALT cancer cell lines from neuroblastomas, sarcomas, and carcinomas were hypersensitive to the p53 reactivator eprenetapopt (APR-246) relative to telomerase-positive (TA+) models. Constitutive telomere damage signaling in ALT cells activated ataxia-telangiectasia mutated (ATM) kinase to phosphorylate p53, which resulted in selective ALT sensitivity to APR-246. Treatment with APR-246 combined with irinotecan achieved complete responses in mice xenografted with ALT neuroblastoma, rhabdomyosarcoma, and breast cancer and delayed tumor growth in ALT colon cancer xenografts, while the combination had limited efficacy in TA+ tumor models. A large number of adult and pediatric cancers present with the ALT phenotype, which confers a uniquely high sensitivity to reactivation of p53. These data support clinical evaluation of a combinatorial approach using APR-246 and irinotecan in ALT patients with cancer.

SIGNIFICANCE: This work demonstrates that constitutive activation of ATM in chemotherapy-refractory ALT cancer cells renders them hypersensitive to reactivation of p53 function by APR-246, indicating a potential strategy to overcome therapeutic resistance.

RevDate: 2022-08-10

Lemaître JF, Gaillard JM, E Gilson (2022)

Telomeres as a sentinel of population decline in the context of global warming.

Proceedings of the National Academy of Sciences of the United States of America, 119(35):e2211349119.

RevDate: 2022-08-09

Zhang JM, L Zou (2022)

Protocol to stimulate and delineate alternative lengthening of telomeres in human U2OS cells.

STAR protocols, 3(3):101594 pii:S2666-1667(22)00474-9.

Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe a protocol to stimulate the formation of ALT-associated PML bodies (APBs) and ALT activity by tethering PML-IV to telomeres in human U2OS cells. Through immunofluorescence, in situ hybridization, and microscopy, we analyze dynamics of telomere clustering, visualize recruitment of DNA repair proteins to APBs, and measure telomere DNA synthesis during ALT. This protocol provides a unique approach to delineate the ALT pathway. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).

RevDate: 2022-08-08

Woo JMP, Parks CG, Hyde EE, et al (2022)

Early life trauma and adult leucocyte telomere length.

Psychoneuroendocrinology, 144:105876 pii:S0306-4530(22)00217-7 [Epub ahead of print].

BACKGROUND: Telomere length, a biomarker of cell division and cellular aging, has been associated with multiple chronic disease endpoints. Experienced trauma over the life course may contribute to telomere shortening via mechanisms of stress embodiment. However, it is unclear how patterns of co-occurring trauma during sensitive periods (e.g., early life) throughout the life course may influence telomere shortening. We examine the relationship between co-occurring early life trauma on adult telomere length and the extent to which adulthood trauma, socioeconomic position, and health and lifestyle factors may mediate this relationship.

METHODS: We use data from a sample of participants in the Sister Study (N = 740, analytic sample: n = 602), a prospective cohort of U.S. self-identified females aged 35-74 years at enrollment (2003-2009) for whom leukocyte telomere length was measured in baseline blood samples. Participants reported their experience of 20 different types of trauma, from which we identified patterns of co-occurring early life trauma (before age 18) using latent class analysis. We estimated the direct and indirect effects of early life trauma on leukocyte telomere length using structural equation modeling, allowing for mediating adult pathways.

RESULTS: Approximately 47 % of participants reported early life trauma. High early life trauma was associated with shorter telomere length compared to low early life trauma (β = -0.11; 95 % CI: -0.22, -0.004) after adjusting for age and childhood socioeconomic position. The inverse association between early life trauma and adult leukocyte telomere length was largely attributable to the direct effect of early life trauma on telomere length (β = -0.12; 95 %CI: -0.23, -0.01). Mediating indirect pathways via adult trauma, socioeconomic position, and health metrics did not substantively contribute the overall association.

CONCLUSIONS: These findings highlight the role of patterns of co-occurring early life trauma on shortened telomere length independent of adult pathways.

RevDate: 2022-08-08

Dupoué A, Blaimont P, Angelier F, et al (2022)

Lizards from warm and declining populations are born with extremely short telomeres.

Proceedings of the National Academy of Sciences of the United States of America, 119(33):e2201371119.

Aging is the price to pay for acquiring and processing energy through cellular activity and life history productivity. Climate warming can exacerbate the inherent pace of aging, as illustrated by a faster erosion of protective telomere DNA sequences. This biomarker integrates individual pace of life and parental effects through the germline, but whether intra- and intergenerational telomere dynamics underlies population trends remains an open question. Here, we investigated the covariation between life history, telomere length (TL), and extinction risk among three age classes in a cold-adapted ectotherm (Zootoca vivipara) facing warming-induced extirpations in its distribution limits. TL followed the same threshold relationships with population extinction risk at birth, maturity, and adulthood, suggesting intergenerational accumulation of accelerated aging rate in declining populations. In dwindling populations, most neonates inherited already short telomeres, suggesting they were born physiologically old and unlikely to reach recruitment. At adulthood, TL further explained females' reproductive performance, switching from an index of individual quality in stable populations to a biomarker of reproductive costs in those close to extirpation. We compiled these results to propose the aging loop hypothesis and conceptualize how climate-driven telomere shortening in ectotherms may accumulate across generations and generate tipping points before local extirpation.

RevDate: 2022-08-08

Quque M, Ferreira C, Sosa S, et al (2022)

Cascading Effects of Conspecific Aggression on Oxidative Status and Telomere Length in Zebra Finches.

Physiological and biochemical zoology : PBZ, 95(5):416-429.

AbstractLiving in social groups may exacerbate interindividual competition for territory, food, and mates, leading to stress and possible health consequences. Unfavorable social contexts have been shown to elevate glucocorticoid levels (often used as biomarkers of individual stress), but the downstream consequences of socially stressful environments are rarely explored. Our study experimentally tests the mechanistic links between social aggression, oxidative stress, and somatic maintenance in captive zebra finches (Taeniopygia guttata). Over 64 d, we measured the effects of aggression (received or emitted) on the individual oxidative status, body condition, and changes in relative telomere length (rTL) of birds living in high- and low-social-density conditions. Using path analyses, we found that birds living at high social density increased their aggressive behavior. Birds receiving the highest number of aggressions exhibited the strongest activation of antioxidant defenses and highest plasmatic levels of reactive oxygen metabolites. In turn, this prevented birds from maintaining or restoring telomere length between the beginning and the end of the experiment. Received aggression also had a direct negative effect on changes in rTL, unrelated to oxidative stress. In contrast, emitted aggression had no significant effect on individual oxidative stress or changes in rTL. Body condition did not appear to affect the physiological response to aggression or oxidative stress. At low density, we found trends that were similar to those at high density but nonsignificant. Our study sheds light on the causal chain linking the social environment and aggressive behavior to individual oxidative stress and telomere length. The long-term consequences of socially induced stress on fitness remain to be characterized.

RevDate: 2022-08-08

Moazamian A, Gharagozloo P, Aitken RJ, et al (2022)

Sperm telomeres, oxidative stress, and infertility.

Reproduction (Cambridge, England) pii:REP-22-0189 [Epub ahead of print].

The maintenance of redox balance in the male reproductive tract is critical to sperm health and function. Physiological levels of reactive oxygen species (ROS) promote sperm capacitation, while excess ROS exposure, or depleted antioxidant defenses, yield a state of oxidative stress which disrupts their fertilizing capacity and DNA structural integrity. The guanine moiety is the most readily oxidized of the four DNA bases and gets converted to the mutagenic lesion 8-hydroxy-deoxyguanosine (8-OHdG). Numerous studies have also confirmed oxidative stress as a driving factor behind accelerated telomere shortening and dysfunction. Although a clear consensus has not been reached, clinical studies also appear to associate telomere integrity with fertility outcomes in the Assisted Reproductive Technology (ART) setting. Intriguingly, while sperm cellular and molecular characteristics make them more susceptible to oxidative insult than any other cell type, they are also the only cell type in which telomere lengthening accompanies aging. This article focuses on the oxidative stress response pathways to propose a mechanism in explanation of this apparent paradox.

RevDate: 2022-08-07

Paul T, S Myong (2022)

Helicase mediated vectorial folding of telomere G-quadruplex.

Methods in enzymology, 672:283-297.

The G-rich single-stranded telomere overhang can self-fold into G-quadruplex (G4) structure both in vivo and in vitro. In somatic cells, telomeres shorten progressively due to the end-replication. In stem cells, however, telomeres are replenished by a special enzyme, telomerase which synthesizes single-stranded telomere overhang. The active extension by the telomerase releases G-rich overhang segmentally in 5' to 3' direction as the overhang folds into G4 structure after successive elongation. To replicate such vectorial G4 folding process, we employed a superhelicase, Rep-X to release the G-rich sequence gradually. Using single-molecule assay we demonstrated that the folded conformation achieved by the vectorial folding is inherently different from the post-folding where the entire overhang is allowed to fold at once. In addition, the vectorially folded overhangs are less stable and more accessible to a complementary C-rich strand and the telomere binding protein, POT1 compared to the post-folded state. The higher accessibility may have implications for the facile loading of shelterin proteins after DNA replication.

RevDate: 2022-08-07

Lai X, Yuan Y, Liu M, et al (2022)

Individual and joint associations of co-exposure to multiple plasma metals with telomere length among middle-aged and older Chinese in the Dongfeng-Tongji cohort.

Environmental research pii:S0013-9351(22)01358-5 [Epub ahead of print].

Studies on associations of metals with leucocyte telomere length (LTL) were mainly limited to several most common toxic metals and single-metal effect, but the impact of other common metals and especially the overall joint associations and interactions of metal mixture with LTL are largely unknown. We included 15 plasma metals and LTL among 4906 participants from Dongfeng-Tongji cohort. Multivariable linear regression was used to estimate associations of individual metals with LTL. We also applied Bayesian kernel machine regression (BKMR) and quantile g-computation regression (Q-g) to evaluate the overall association and interactions, and identified the major contributors as well as the potential modifications by major characteristics. Multivariable linear regression found vanadium, copper, arsenic, aluminum and nickel were negatively associated with LTL, and a 2-fold change was related to 1.9%-5.1% shorter LTL; while manganese and zinc showed 3.7% and 4.0% longer LTL (all P < 0.05) in multiple-metal models. BKMR confirmed above metals and revealed a linearly inverse joint association between 15 metals and LTL. Q-g regression further indicated each quantile increase in mixture was associated with 5.2% shorter LTL (95% CI: -8.1%, -2.3%). Furthermore, manganese counteracted against aluminum and vanadium respectively (Pint<0.05). In addition, associations of vanadium, aluminum and metal mixture with LTL were more prominent in overweight participants. Our results are among the first to provide a new comprehensive view of metal mixture exposure on LTL attrition in the general population, including identifying the major components, metals interactions and the overall effects.

RevDate: 2022-08-06

Fan Y, Guo Y, Zhong J, et al (2022)

The association between visceral adiposity index and leukocyte telomere length in adults: results from National Health and Nutrition Examination Survey.

Aging clinical and experimental research [Epub ahead of print].

BACKGROUND: Leukocyte telomere length (LTL) is a robust marker of biological aging, which is associated with obesity. Recently, the visceral adiposity index (VAI) has been proposed as an indicator of adipose distribution and function.

OBJECTIVE: To evaluated the association between VAI and LTL in adult Americans.

METHODS: There were 3193 participants in U.S. National Health and Nutrition Examination Surveys (1999-2002) included in this analysis. LTL was measured using quantitative PCR (qPCR) and expressed as telomere to single-gene copy ratio (T/S ratio). We performed multiple logistic regression models to explore the association between VAI and LTL by adjusting for potential confounders.

RESULTS: Among all participants, VAI was associated with the shorter LTL (β: - 14.81, 95% CI - 22.28 to - 7.34, p < 0.001). There were significant differences of LTL in VAI tertiles (p < 0.001). Participants in the higher VAI tertile had the shorter LTL (1.26 ≤ VAI < 2.46: β = - 130.16, 95% CI [ - 183.44, - 76.87]; VAI ≥ 2.46: β = - 216.12, 95% CI [ - 216.12, - 81.42], p for trend: < 0.001) comparing with the lower VAI tertile. We also found a non-linear relationship between VAI and LTL. VAI was negatively correlated with LTL when VAI was less than 2.84.

CONCLUSIONS: The present study demonstrates that VAI is independently associated with telomere length. A higher VAI is associated with shorter LTL. The results suggest that VAI may provide prediction for LTL and account for accelerating the biological aging.

RevDate: 2022-08-06

Zheng Y, Zhang N, Wang Y, et al (2022)

Association between leucocyte telomere length and the risk of atrial fibrillation: an updated systematic review and meta-analysis.

Ageing research reviews pii:S1568-1637(22)00149-0 [Epub ahead of print].

BACKGROUND AND AIMS: Advancing age is the most important risk factor of atrial fibrillation (AF). The shortening of telomere length is a biomarker of biologic aging. There is an increasing body of evidence that leucocyte telomere length (LTL) is associated with the risk of AF development. However, the results in these studies were controversial. The current systematic review and meta-analysis was conducted to examine the role of LTL in predicting the incidence of AF.

METHODS AND RESULTS: Observational studies reporting the association between LTL and the risk of AF were retrieved through 25th June, 2022 from PubMed and Embase. A total of twelve studies including 18293 patients were included in the present analysis. Leucocyte telomere shortening was found to be an independent predictor of AF as a continuous variable in both univariate [OR:2.14; 95%CI(1.48,3.10); P<0.0001] and multivariate analyses [OR:1.41;95%CI(1.11,1.79); P=0.005], as well as categorical variable in multivariate analysis [OR:1.53; 95%CI(1.04,2.27); P=0.03]. Furthermore, leucocyte telomere shortening was significantly associated with recurrent AF [OR:4.32;95%CI(2.42,7.69); P<0.00001] but not new-onset AF [OR:1.14; 95%CI(0.90,1.45); P=0.29]. Leucocyte telomere shortening was also associated with an increased risk of persistent AF [OR:14.73;95%CI (3.16,68.67); P=0.0006] and paroxysmal AF [OR:2.74;95%CI(1.45,5.18); P=0.002]. Besides, LTL was an independent predictor for progression from paroxysmal AF to persistent AF [OR:3.2;95%CI(1.66,6.18); P=0.0005]. Differences between males [OR:1.99; 95%CI(1.29,3.06); P=0.002] and females [OR:0.86; 95%CI (0.29,2.56);P=0.79] were observed.

CONCLUSIONS: Leucocyte telomere shortening predicts the risk of AF, especially recurrent AF. The predictive value is more prominent in males than in females. Shortening in LTL can predict the progression from paroxysmal to persistent AF.

RevDate: 2022-08-06

Chik HYJ, Sparks AM, Schroeder J, et al (2022)

A meta-analysis on the heritability of vertebrate telomere length.

Journal of evolutionary biology [Epub ahead of print].

Telomere dynamics are linked with both cellular and organismal senescence, and life history, individual quality and health. Telomere dynamics, particularly telomere length, have therefore garnered much research interest in evolutionary biology. To examine the evolution of telomere length, it is important to quantify its heritability, the proportion of total variation explained by additive genetic effects. Many studies have quantified telomere length heritability, but estimates are varied, and no general conclusion has been drawn. Additionally, it is unclear whether biological and methodological factors influence telomere length heritability estimates. We present the first meta-analysis of telomere length heritability, using 104 estimates from 43 studies over 18 vertebrate species. We calculated an overall mean heritability and examined how estimates varied by study, phylogeny, species-specific ecology, environmental setting, age at sampling, laboratory methods, statistical methods, sex and repeated measurements. Overall heritability was moderate (44.9%, 95% CI: 25.2-64.7%), and there was considerable heterogeneity in heritability estimates, in particular among studies and estimates. Laboratory method influenced heritability estimates, with in-gel hybridization TRF yielding higher heritabilities than qPCR and Southern blot TRF. There was also an effect from statistical method, with twin-based and SNP-based estimates lower than correlation-based or pedigree-based estimates. Our results highlight an overall heritable basis of telomere length, and we recommend future research on a wider range of taxa, and the use of variance-partitioning methods with relatedness or SNP data over correlation methods to minimize heritability estimation bias.

RevDate: 2022-08-05

Guo Z, Zou K, Li X, et al (2022)

Relationship between miRNAs polymorphisms and peripheral blood leukocyte DNA telomere length in coke oven workers: a cross-sectional study.

Environmental toxicology and pharmacology pii:S1382-6689(22)00134-X [Epub ahead of print].

OBJECTIVE: The purpose of this study was to investigate the factors affecting telomere length (TL) in coke oven workers by analyzing the interaction between miRNAs polymorphisms and coke oven emissions (COEs) exposure.

METHODS: A total of 544 coke oven workers and 238 healthy controls were recruited. Peripheral blood was collected from the subjects, genomic DNA was extracted, leukocyte TL was detected by real-time quantitative polymerase chain reaction, and fifteen polymorphisms of eight miRNAs were genotyped by flight mass spectrometry.

RESULTS: Statistical analysis showed that the peripheral blood DNA TL in the exposure group was shorter than that in the control group (P < 0.001). Generalized linear model found that COEs-exposure [β (95%CI) = -0.427 (-0.556, -0.299), P < 0.001], genotype CC+CT for miR-612 rs1144925 [β (95%CI) = -0.367 (-0.630, -0.104), P = 0.006], and the interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure [β (95% CI) = 0.564 (0.108, 1.020), P = 0.015] were associated with the shortened TL.

CONCLUSION: COEs-exposure and miR-612 rs1144925 TT could promote telomere shortening in coke oven workers. The interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure could protect telomere. This provides clues for further mechanistic studies between miRNA and telomere damage.

RevDate: 2022-08-05

Martens DS, Sleurs H, Dockx Y, et al (2022)

Association of Newborn Telomere Length With Blood Pressure in Childhood.

JAMA network open, 5(8):e2225521 pii:2794961.

Importance: Adult telomere length (TL) is a biological marker of aging associated with vascular health. TL at birth is associated with later life TL and may contain early biological information of later life cardiovascular health and disease.

Objective: To evaluate whether newborn TL is associated with early life blood pressure differences in childhood.

This cohort study was part of the ENVIRONAGE (Environmental Influence on Aging in Early Life) study, a birth cohort of Belgian mother-child pairs with recruitment at birth and a median follow-up of 4.5 years conducted between October 2014 and July 2021. Participants included for analysis provided full data for evaluation at follow-up visit. Data analysis was conducted between August and September 2021.

Main Outcomes and Measures: Cord blood and placental average relative TL were measured at birth using quantitative polymerase chain reaction (qPCR). Systolic, diastolic, and mean arterial pressure (MAP) were evaluated at follow-up. High childhood blood pressure (standardized for child age, sex, and height) was defined following the 2017 American Academy of Pediatrics guidelines. Multivariable adjusted linear and logistic regression models were used to associate newborn TL and blood pressure indicators in childhood.

Results: This study included 485 newborn children (52.8% girls) with a mean (SD) age of 4.6 (0.4) years at the follow-up visit. Newborn TL was associated with lower blood pressure in childhood. A 1-IQR increase in cord blood TL was associated with a -1.54 mm Hg (95% CI, -2.36 to -0.72 mm Hg) lower diastolic blood pressure and -1.18 mm Hg (95% CI, -1.89 to -0.46 mm Hg) lower MAP. No association was observed with systolic blood pressure. Furthermore, a 1-IQR increase in cord blood TL was associated with lower odds of having high blood pressure at the age of 4 to 6 years (adjusted OR, 0.72; 95% CI, 0.53 to 0.98). In placenta, a 1-IQR increase in TL was associated with a -0.96 mm Hg (95% CI, -1.72 to -0.21 mm Hg) lower diastolic, -0.88 mm Hg (95% CI, -1.54 to -0.22 mm Hg) lower MAP, and a lower adjusted OR of 0.69 (95% CI, 0.52 to 0.92) for having a high blood pressure in childhood.

Conclusions and Relevance: In this prospective birth cohort study, variation in early life blood pressure at school-age was associated with TL at birth. Cardiovascular health may to some extent be programmed at birth, and these results suggest that TL entails a biological mechanism in this programming.

RevDate: 2022-08-05

Tummala H, Walne A, I Dokal (2022)

The biology and management of dyskeratosis congenita and related disorders of telomeres.

Expert review of hematology [Epub ahead of print].

BACKGROUND: Dyskeratosis congenita (DC) is a multi-system syndrome characterised by muco-cutaneous abnormalities, bone marrow failure and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders.

WHAT IS COVERED: Clinical features, genetics and biology of the different sub-types. Expert view on diagnosis, treatment of the hematological complications and future.

EXPERT VIEW: As these are very pleotropic disorders affecting multiple organs a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although, hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine based conditioning protocols. New therapies are needed where danazol/oxymetholone are ineffective and HSCT is not feasible.

RevDate: 2022-08-04

Pepke ML, Kvalnes T, Ranke PS, et al (2022)

Causes and consequences of variation in early-life telomere length in a bird metapopulation.

Ecology and evolution, 12(8):e9144 pii:ECE39144.

Environmental conditions during early-life development can have lasting effects shaping individual heterogeneity in fitness and fitness-related traits. The length of telomeres, the DNA sequences protecting chromosome ends, may be affected by early-life conditions, and telomere length (TL) has been associated with individual performance within some wild animal populations. Thus, knowledge of the mechanisms that generate variation in TL, and the relationship between TL and fitness, is important in understanding the role of telomeres in ecology and life-history evolution. Here, we investigate how environmental conditions and morphological traits are associated with early-life blood TL and if TL predicts natal dispersal probability or components of fitness in 2746 wild house sparrow (Passer domesticus) nestlings from two populations sampled across 20 years (1994-2013). We retrieved weather data and we monitored population fluctuations, individual survival, and reproductive output using field observations and genetic pedigrees. We found a negative effect of population density on TL, but only in one of the populations. There was a curvilinear association between TL and the maximum daily North Atlantic Oscillation index during incubation, suggesting that there are optimal weather conditions that result in the longest TL. Dispersers tended to have shorter telomeres than non-dispersers. TL did not predict survival, but we found a tendency for individuals with short telomeres to have higher annual reproductive success. Our study showed how early-life TL is shaped by effects of growth, weather conditions, and population density, supporting that environmental stressors negatively affect TL in wild populations. In addition, shorter telomeres may be associated with a faster pace-of-life, as individuals with higher dispersal rates and annual reproduction tended to have shorter early-life TL.

RevDate: 2022-08-03

Borges G, Criqui M, L Harrington (2022)

Tieing together loose ends: telomere instability in cancer and aging.

Molecular oncology [Epub ahead of print].

Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure, and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re-addition of G-rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.

RevDate: 2022-08-03

Gurvich C, Thomas N, Hudaib AR, et al (2022)

The relationship between cognitive clusters and telomere length in bipolar-schizophrenia spectrum disorders.

Psychological medicine pii:S0033291722002148 [Epub ahead of print].

BACKGROUND: Schizophrenia and bipolar disorder are complex mental illnesses that are associated with cognitive deficits. There is considerable cognitive heterogeneity that exists within both disorders. Studies that cluster schizophrenia and bipolar patients into subgroups based on their cognitive profile increasingly demonstrate that, relative to healthy controls, there is a severely compromised subgroup and a relatively intact subgroup. There is emerging evidence that telomere shortening, a marker of cellular senescence, may be associated with cognitive impairments. The aim of this study was to explore the relationship between cognitive subgroups in bipolar-schizophrenia spectrum disorders and telomere length against a healthy control sample.

METHODS: Participants included a transdiagnostic group diagnosed with bipolar, schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 113). Cognitive clusters within the transdiagnostic patient group, were determined using K-means cluster analysis based on current cognitive functioning (MATRICS Consensus Cognitive Battery scores). Telomere length was determined using quantitative PCRs genomic DNA extracted from whole blood. Emergent clusters were then compared to the healthy control group on telomere length.

RESULTS: Two clusters emerged within the patient group that were deemed to reflect a relatively intact cognitive group and a cognitively impaired subgroup. Telomere length was significantly shorter in the severely impaired cognitive subgroup compared to the healthy control group.

CONCLUSIONS: This study replicates previous findings of transdiagnostic cognitive subgroups and associates shorter telomere length with the severely impaired cognitive subgroup. These findings support emerging literature associating cognitive impairments in psychiatric disorders to accelerated cellular aging as indexed by telomere length.

RevDate: 2022-08-03

Vernasco BJ, HE Watts (2022)

Telomere length predicts timing and intensity of migratory behaviour in a nomadic songbird.

Biology letters, 18(8):20220176.

Our understanding of state-dependent behaviour is reliant on identifying physiological indicators of condition. Telomeres are of growing interest for understanding behaviour as they capture differences in biological state and residual lifespan. To understand the significance of variable telomere lengths for behaviour and test two hypotheses describing the relationship between telomeres and behaviour (i.e. the causation and the selective adoption hypotheses), we assessed if telomere lengths are longitudinally repeatable traits related to spring migratory behaviour in captive pine siskins (Spinus pinus). Pine siskins are nomadic songbirds that exhibit highly flexible, facultative migrations, including a period of spring nomadism. Captive individuals exhibit extensive variation in spring migratory restlessness and are an excellent system for mechanistic studies of migratory behaviour. Telomere lengths were found to be significantly repeatable (R = 0.51) over four months, and shorter pre-migratory telomeres were associated with earlier and more intense expression of spring nocturnal migratory restlessness. Telomere dynamics did not vary with migratory behaviour. Our results describe the relationship between telomere length and migratory behaviour and provide support for the selective adoption hypothesis. More broadly, we provide a novel perspective on the significance of variable telomere lengths for animal behaviour and the timing of annual cycle events.

RevDate: 2022-08-02

Huang MY, HD Madhani (2022)

Telomere transposon takeover in Cryptococcus.

Nature microbiology [Epub ahead of print].

RevDate: 2022-08-01

Passos JDC, Felisbino K, Laureano HA, et al (2022)

Occupational exposure to pesticides and its association with telomere length - A systematic review and meta-analysis.

The Science of the total environment pii:S0048-9697(22)04814-8 [Epub ahead of print].

BACKGROUND: Telomere length is a common biomarker for the cumulative effect of environmental factors on aging-related diseases, therefore an association has been hypothesized between occupational exposure to pesticides and shorter telomere length.

OBJECTIVE: This study is a systematic review and meta-analysis aiming to examine the association between telomere length and occupational exposure to pesticides.

METHODS: We systematically searched in SciELO, PubMed, Scopus, Embase, Cochrane, Lilacs, Science Direct, and Web of Science databases for all observational studies containing measurements of telomere length on groups occupationally exposed to pesticides. Data were synthesized through qualitative synthesis and meta-analysis. We estimated the associations between exposed and non-exposed groups by using the natural log of the response ratio (lnRR). Heterogeneity was quantified using the Cochran Q test and I2 statistics.

RESULTS: Six studies were included in the qualitative synthesis and meta-analysis, with a total of 480 participants exposed to pesticides. The time of exposure evaluated 391 participants that had a range of 5 to >30 years of occupational exposure. Most studies presented shorter telomere length in the occupationally exposed group. From the six studies included in the meta-analysis, three presented telomere length measurement as a single copy gene (T/S), and three presented telomere length measurement as base pairs (bp). The statistical analysis pooled estimates (log ratio of means) of the telomere length in both measurements (T/S and bp) showed a shortening of telomere length in the exposed group when compared with the non-exposed (control) group. Two of six studies reported longer telomere length in the group exposed to pesticides.

DISCUSSION: Our findings suggest an association between occupational exposure to pesticides and shorter telomere length. However, we found a small number of studies to include in our meta-analysis, being required more high-quality studies to strengthen our findings and conclusions.

RevDate: 2022-08-01

Mushtaq I, Bhat GR, Rah B, et al (2022)

Telomere Attrition With Concomitant hTERT Overexpression Involved in the Progression of Gastric Cancer May Have Prognostic and Clinical Implications in High-Risk Population Group From North India.

Frontiers in oncology, 12:919351.

Genetic instabilities exacerbated by the dysfunction of telomeres can lead to the development of cancer. Nearly 90% of all human malignancies are linked with telomere dysregulation and overexpression of telomerase, an enzyme that catalyzes the synthesis of telomeric DNA repeats at the ends of chromosomes. The burden of gastric cancer continues to inflict a deterring impact on the global health scenario, accounting for over one million new cases in 2020. The disease is asymptomatic in its early stages of progression, which is attributed to the poor prognosis and overall surge in mortality rate worldwide. Exploiting telomere physiology can provide extensive mechanistic insight into telomere-associated gastric cancer progression and its use as a target in a variety of therapeutic interventions. In this study, we aimed to evaluate the clinical implications of c-Myc, human telomerase reverse transcriptase (hTERT) expression, and telomere length in patients with gastric cancer. A total of 57 gastric cancer cases and adjacent controls were included in the study. RT-PCR and immunohistochemistry were used to assess the expression levels of c-Myc and hTERT. The relative telomere length was measured by MMQPCR using the Cawthon method. Our results indicated that the shorter telomere and increased hTERT expression were associated with gastric cancer progression. The study also highlighted the role of short telomeres and increased expression of hTERT in gastric cancer progression and its association with various etiological risk factors, transcriptional activators, and overall survival among the ethnic Kashmiri population of North India.

RevDate: 2022-08-01

Liao Q, He J, Tian FF, et al (2022)

A causal relationship between leukocyte telomere length and multiple sclerosis: A Mendelian randomization study.

Frontiers in immunology, 13:922922.

Objectives: Multiple sclerosis (MS) is a chronic inflammatory autoimmune and degenerative disorder of the central nervous system. Telomeres are protective structures located at the ends of linear chromosomes, and leukocyte telomere length (LTL) is closely connected with cell aging and senescence. However, the relationship between LTL and the risk of MS remains unknown.

Methods: We performed a two-sample Mendelian randomization (MR) to evaluate whether LTL was causally associated with MS risk.

Results: In our MR analysis, 12 LTL-related variants were selected as valid instrumental variables, and a causal relationship between LTL and MS was suggested. The risk of MS nearly doubled as the genetically predicted LTL shortened by one standard deviation (SD) under the inverse variance weighted (IVW) fixed effect model (odds ratio (OR) = 2.00, 95% confidence interval (CI): 1.52-2.62, p = 6.01e-07). Similar estimated causal effects were also observed under different MR models. The MR-Egger regression test did not reveal any evidence of directional pleiotropy (intercept = -0.005, stand error (SE) = 0.03, p = 0.87). The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis also indicated no directional pleiotropy or outliers for any LTL-related IVs (p-global test = 0.13). In addition, a leave-one-out sensitivity analysis showed similar findings, which further emphasized the validity and stability of the causal relationship.

Conclusions: Our results suggest a potential causal effect of LTL on the risk of MS. Genetically predicted shorter LTL could increase the risk of MS in the European population. LTL should be noted and emphasized in the pathogenesis and treatment of MS.

RevDate: 2022-08-01

Aviv A (2022)

The telomere tumult: meaning and metrics in population studies.

The Lancet. Healthy longevity, 3(5):e308-e309.

RevDate: 2022-07-19

Chang TR, Long X, Shastry S, et al (2022)

Single-Molecule Mechanical Analysis of Strand Invasion in Human Telomere DNA.

Biochemistry [Epub ahead of print].

Telomeres are essential chromosome end capping structures that safeguard the genome from dangerous DNA processing events. DNA strand invasion occurs during vital transactions at telomeres, including telomere length maintenance by the alternative lengthening of telomeres (ALT) pathway. During telomeric strand invasion, a single-stranded guanine-rich (G-rich) DNA invades at a complementary duplex telomere repeat sequence, forming a displacement loop (D-loop) in which the displaced DNA consists of the same G-rich sequence as the invading single-stranded DNA. Single-stranded G-rich telomeric DNA readily folds into stable, compact, structures called G-quadruplexes (GQs) in vitro and is anticipated to form within the context of a D-loop; however, evidence supporting this hypothesis is lacking. Here, we report a magnetic tweezers assay that permits the controlled formation of telomeric D-loops (TDLs) within uninterrupted duplex human telomere DNA molecules of physiologically relevant lengths. Our results are consistent with a model wherein the displaced single-stranded DNA of a TDL fold into a GQ. This study provides new insight into telomere structure and establishes a framework for the development of novel therapeutics designed to target GQs at telomeres in cancer cells.

RevDate: 2022-07-29

Son N, Cui Y, W Xi (2022)

Association Between Telomere Length and Skin Cancer and Aging: A Mendelian Randomization Analysis.

Frontiers in genetics, 13:931785 pii:931785.

Background: Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue. Methods: This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses. Results: We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168-1.0524, p = 0.01] and 1.0127 (95% CI: 1.0046-1.0209, p = 6.36E-07), respectively. Conversely, TL shortening was validated to increase the odds of skin aging (OR = 0.96, 95% CI: 0.9332-0.9956, p = 0.03). Moreover, the MR-Egger, maximum likelihood, and inverse variance weighted (IVW) methods found significant heterogeneity among instrumental variable (IV) estimates (identified as MR-Egger skin aging Q = 76.72, p = 1.36E-04; melanoma Q = 97.10, p = 1.62E-07; NMSCsQ = 82.02, p = 1.90E-05). The leave-one-out analysis also showed that the SNP sensitivity was robust to each result. Conclusion: This study found that TL shortening may promote skin aging development and reduce the risk of cutaneous melanoma and NMSCs. The results provide a reference for future research on the causal relationship between skin aging and cancer in clinical practice.

RevDate: 2022-07-28

Bae JS, Lee JW, Joung JG, et al (2022)

Clinical significance of germline telomere length and associated genetic factors in patients with neuroblastoma.

Scientific reports, 12(1):12954.

Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with germline telomere length. The germline telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative polymerase chain reaction. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density bead chip (Illumina, San Diego, CA, USA). After strict quality-control checks of the samples, an association analysis was conducted. The result showed that longer germline telomeres were significantly associated with longer event-free survival (P = 0.032). To identify significantly assocated genetic markers for germline telomere length, genome wide association analysis was performed. As a result, several single nucleotide polymorphisms located in HIVEP3, LRRTM4, ADGRV1, RAB30, and CHRNA4 genes were discovered. During gene-based analysis (VEGAS2 tool), the CNTN4 gene had the most significant association with germline telomere length (P = 1.0E-06). During gene ontology analysis, susceptible genes associated with germline telomere length were mainly distributed in neurite morphogenesis and neuron development. A longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to germline telomere length are associated with neurite morphogenesis and neuron development. Further research with larger cohorts of patients and functional investigations are needed.

RevDate: 2022-07-28

Liu Y, Liu S, Xin J, et al (2022)

Telomere Length and Hearing Loss: A Two-Sample Mendelian Randomization.

International journal of environmental research and public health, 19(15): pii:ijerph19158937.

BACKGROUND: Observational studies have suggested that there may be an association between telomere length (TL) and hearing loss (HL). However, inferring causality from observational studies is subject to residual confounding effects, reverse causation, and bias. This study adopted a two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between TL and increased risk of HL.

METHODS: A total of 16 single nucleotide polymorphisms (SNPs) associated with TL were identified from a genome-wide association study (GWAS) meta-analysis of 78,592 European participants and applied to our modeling as instrumental variables. Summary-level data for hearing loss (HL), age-related hearing loss (ARHL), and noise-induced hearing loss (NIHL) were obtained from the recent largest available GWAS and five MR analyses were used to investigate the potential causal association of genetically predicted TL with increased risk for HL, including the inverse-variance-weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode. In addition, sensitivity analysis, pleiotropy, and heterogeneity tests were also used to evaluate the robustness of our findings.

RESULTS: There was no causal association between genetically predicted TL and HL or its subtypes (by the IVW method, HL: odds ratio (OR) = 1.216, p = 0.382; ARHL: OR = 0.934, p = 0.928; NIHL: OR = 1.003, p = 0.776). Although heterogenous sites rs2736176, rs3219104, rs8105767, and rs2302588 were excluded for NIHL, the second MR analysis was consistent with the first analysis (OR = 1.003, p = 0.572).

CONCLUSION: There was no clear causal relationship between shorter TLs and increased risk of HL or its subtypes in this dataset.

RevDate: 2022-07-27

Scarabino D, Veneziano L, Fiore A, et al (2022)

Leukocyte Telomere Length Variability as a Potential Biomarker in Patients with PolyQ Diseases.

Antioxidants (Basel, Switzerland), 11(8): pii:antiox11081436.

SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.

RevDate: 2022-07-27

Quenu M, Treindl AD, Lee K, et al (2022)

Telomere-to-Telomere Genome Sequences across a Single Genus Reveal Highly Variable Chromosome Rearrangement Rates but Absolute Stasis of Chromosome Number.

Journal of fungi (Basel, Switzerland), 8(7): pii:jof8070670.

Genome rearrangements in filamentous fungi are prevalent but little is known about the modalities of their evolution, in part because few complete genomes are available within a single genus. To address this, we have generated and compared 15 complete telomere-to-telomere genomes across the phylogeny of a single genus of filamentous fungi, Epichloë. We find that the striking distinction between gene-rich and repeat-rich regions previously reported for isolated species is ubiquitous across the Epichloë genus. We built a species phylogeny from single-copy gene orthologs to provide a comparative framing to study chromosome composition and structural change through evolutionary time. All Epichloë genomes have exactly seven nuclear chromosomes, but despite this conserved ploidy, analyses reveal low synteny and substantial rearrangement of gene content across the genus. These rearrangements are highly lineage-dependent, with most occurring over short evolutionary distances, with long periods of structural stasis. Quantification of chromosomal rearrangements shows they are uncorrelated with numbers of substitutions and evolutionary distances, suggesting that different modes of evolution are acting to create nucleotide and chromosome-scale changes.

RevDate: 2022-07-27

Zimnitskaya OV, Petrova MM, Lareva NV, et al (2022)

Leukocyte Telomere Length as a Molecular Biomarker of Coronary Heart Disease.

Genes, 13(7): pii:genes13071234.

BACKGROUND: This work is a review of preclinical and clinical studies of the role of telomeres and telomerase in the development and progression of coronary heart disease (CHD).

MATERIALS AND METHODS: A search for full-text publications (articles, reviews, meta-analyses, Cochrane reviews, and clinical cases) in English and Russian was carried out in the databases PubMed, Oxford University Press, Scopus, Web of Science, Springer, and E-library electronic library using keywords and their combinations. The search depth is 11 years (2010-2021).

RESULTS: The review suggests that the relative leukocyte telomere length (LTL) is associated with the development of socially significant and widespread cardiovascular diseases such as CHD and essential hypertension. At the same time, the interests of researchers are mainly focused on the study of the relative LTL in CHD.

CONCLUSIONS: Despite the scientific and clinical significance of the analyzed studies of the relative length of human LTL as a biological marker of cardiovascular diseases, their implementation in real clinical practice is difficult due to differences in the design and methodology of the analyzed studies, as well as differences in the samples by gender, age, race, and ethnicity. The authors believe that clinical studies of the role of the relative length of leukocyte telomeres in adult patients with coronary heart disease are the most promising and require large multicenter studies with a unified design and methodology.

RevDate: 2022-07-27

Lauriola A, Davalli P, Marverti G, et al (2022)

Telomere Dysfunction Is Associated with Altered DNA Organization in Trichoplein/Tchp/Mitostatin (TpMs) Depleted Cells.

Biomedicines, 10(7): pii:biomedicines10071602.

Recently, we highlighted a novel role for the protein Trichoplein/TCHP/Mitostatin (TpMs), both as mitotic checkpoint regulator and guardian of chromosomal stability. TpMs-depleted cells show numerical and structural chromosome alterations that lead to genomic instability. This condition is a major driving force in malignant transformation as it allows for the cells acquiring new functional capabilities to proliferate and disseminate. Here, the effect of TpMs depletion was investigated in different TpMs-depleted cell lines by means of 3D imaging and 3D Structured illumination Microscopy. We show that TpMs depletion causes alterations in the 3D architecture of telomeres in colon cancer HCT116 cells. These findings are consistent with chromosome alterations that lead to genomic instability. Furthermore, TpMs depletion changes the spatial arrangement of chromosomes and other nuclear components. Modified nuclear architecture and organization potentially induce variations that precede the onset of genomic instability and are considered as markers of malignant transformation. Our present observations connect the tumor suppression ability of TpMs with its novel functions in maintaining the proper chromosomal segregation as well as the proper telomere and nuclear architecture. Further investigations will investigate the connection between alterations in telomeres and nuclear architecture with the progression of human tumors with the aim of developing personalized therapeutic interventions.

RevDate: 2022-07-26

Curtis EM, Codd V, Nelson C, et al (2022)

Telomere length and risk of incident fracture and arthroplasty: findings from UK Biobank.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [Epub ahead of print].

We investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leucocyte telomere length (LTL) was measured in baseline samples using a validated PCR method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person-years of follow-up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity and menopause (women). In further analyses we adjusted for either estimated bone mineral density from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance) or blood biomarkers, all measured at baseline (2006-2010). We studied 59,500 women and 51,895 men, mean(SD) age 56.4(8.0) and 57.0(8.3) years respectively. During follow-up there were 5,619 fractures; 5,285 hip and 4,261 knee arthroplasties. In confounder-adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men [hazard ratio/SD (95%CI): 0.93 (0.88,0.97)] and women [0.92 (0.88,0.96)] and hip arthroplasty in men [0.91 (0.87,0.95)] but not women [0.98 (0.94,1.01)]. Longer LTL was weakly associated with reduced risk of any incident fracture in women [hazard ratio/SD (95% CI): 0.96 (0.93,1.00)] with less evidence in men [0.98 (0.93,1.02)]. Associations with incident outcomes were not materially altered by adjustment for heel estimated bone mineral density, grip strength, gait speed, fat mass or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeleletal systems might influence later life musculoskeletal outcomes. This article is protected by copyright. All rights reserved.

RevDate: 2022-07-25

Topiwala A, Taschler B, Ebmeier KP, et al (2022)

Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.

Molecular psychiatry [Epub ahead of print].

Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) β = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW β = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.

RevDate: 2022-07-25

Zhan Y, X Kang (2022)

Disentangling the Causal Effect of Telomere Length in Systemic Lupus Erythematosus Using Genetic Variants as Instruments.

RevDate: 2022-07-25

Anonymous (2022)

Corrigendum to: TERT promoter C228T mutation in neural progenitors confers growth advantage following telomere shortening in vivo.

RevDate: 2022-07-25

Heaphy CM, AD Singhi (2022)

The Diagnostic and Prognostic Utility of Incorporating DAXX, ATRX, and Alternative Lengthening of Telomeres (ALT) to the Evaluation of Pancreatic Neuroendocrine Tumors (PanNETs).

Human pathology pii:S0046-8177(22)00189-7 [Epub ahead of print].

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and an ill-defined pathobiology. While many PanNETs are indolent and remain stable for years, a subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of PanNETs presents a treatment dilemma. Current prognostic systems are susceptible to interpretation errors, sampling issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to improve the prognostic stratification of patients diagnosed with a PanNET. Recent studies have identified alterations in death domain-associated protein 6 (DAXX) and alpha-thalassemia/mental retardation X-linked (ATRX), as well as alternative lengthening of telomeres (ALT), as promising prognostic biomarkers. This review summarizes the identification, clinical utility, and specific nuances in testing for DAXX/ATRX by immunohistochemistry and ALT by telomere-specific fluorescence in situ hybridization in PanNETs. Further, a discussion on diagnostic indications for DAXX, ATRX, and ALT status is provided to include the distinction between PanNETs and pancreatic neuroendocrine carcinomas (PanNECs), and determining pancreatic origin for metastatic neuroendocrine tumors in the setting of an unknown primary.

RevDate: 2022-07-21

Nadri P, Ansari-Mahyari S, Jafarpour F, et al (2022)

Melatonin accelerates the developmental competence and telomere elongation in ovine SCNT embryos.

PloS one, 17(7):e0267598 pii:PONE-D-21-33936.

SCNT embryos suffer from poor developmental competence (both in vitro and in vivo) due to various defects such as oxidative stress, incomplete epigenetic reprogramming, and flaws in telomere rejuvenation. It is very promising to ameliorate all these defects in SCNT embryos by supplementing the culture medium with a single compound. It has been demonstrated that melatonin, as a multitasking molecule, can improve the development of SCNT embryos, but its function during ovine SCNT embryos is unclear. We observed that supplementation of embryonic culture medium with 10 nM melatonin for 7 days accelerated the rate of blastocyst formation in ovine SCNT embryos. In addition, the quality of blastocysts increased in the melatonin-treated group compared with the SCNT control groups in terms of ICM, TE, total cell number, and mRNA expression of NANOG. Mechanistic studies in this study revealed that the melatonin-treated group had significantly lower ROS level, apoptotic cell ratio, and mRNA expression of CASPASE-3 and BAX/BCL2 ratio. In addition, melatonin promotes mitochondrial membrane potential and autophagy status (higher number of LC3B dots). Our results indicate that melatonin decreased the global level of 5mC and increased the level of H3K9ac in the treated blastocyst group compared with the blastocysts in the control group. More importantly, we demonstrated for the first time that melatonin treatment promoted telomere elongation in ovine SCNT embryos. This result offers the possibility of better development of ovine SCNT embryos after implantation. We concluded that melatonin can accelerate the reprogramming of telomere length in sheep SCNT embryos, in addition to its various beneficial effects such as increasing antioxidant capacity, reducing DNA damage, and improving the quality of derived blastocysts, all of which led to a higher in vitro development rate.

RevDate: 2022-07-21

Brandt M, Dörschmann H, Khraisat S, et al (2022)

Telomere Shortening in Hypertensive Heart Disease Depends on Oxidative DNA Damage and Predicts Impaired Recovery of Cardiac Function in Heart Failure.

Hypertension (Dallas, Tex. : 1979) [Epub ahead of print].

BACKGROUND: Heart failure (HF) coincides with cardiomyocyte telomere shortening. Arterial hypertension is the most prominent risk factor for HF. Both HF and arterial hypertension are associated with dysregulation of the neurohormonal axis. How neurohormonal activation is linked to telomere shortening in the pathogenesis of HF is incompletely understood.

METHODS: Cardiomyocyte telomere length was assessed in a mouse model of hypertensive HF induced by excess neurohormonal activation (AngII [angiotensin II] infusion, high-salt diet, and uninephrectomy), in AngII-stimulated cardiomyocytes and in endomyocardial biopsies from patients with HF. Superoxide (O2-)-production, expression of gp91phox/Nox2 (NADPH-oxidase 2)-NADPH-oxidase and Prdx1 (peroxiredoxin-1) and histone deacetylase-6 activity were assessed.

RESULTS: Telomere shortening occurred in vitro and in vivo, correlating with both left ventricular (LV) dilatation and LV systolic function impairment. Telomere shortening coincided with increased O2- production, increased gp91phox/Nox2 expression, increased Hdac6 (histone deacetylase-6) activity, loss of the telomere-specific antioxidant Prdx1, and increased oxidative DNA-damage. Gp91phox/Nox2 knockout prevented Prdx1 depletion, DNA-damage and telomere shortening confirming gp91phox/Nox2 as a critical source of reactive oxygen species. Cotreatment with the NOX-inhibitor apocynin ameliorated hypertensive HF and telomere shortening. Similarly, treatment with the histone deacetylase-6-inhibitor tubastatin A, which increases the peroxiredoxin-1 bioavailability, prevented telomere shortening in adult cardiomyocytes. To explore the clinical relevance of our findings, we examined endomyocardial biopsies from an all-comer population of patients with HF with reduced ejection fraction. Here, cardiomyocyte telomere length predicted the recovery of cardiac function.

CONCLUSIONS: Cardiomyocyte telomere shortening and oxidative damage in heart failure with reduced ejection fraction induced by excess neurohormonal activation depends on Nox2-derived O2- and may help to stratify HF therapy.

RevDate: 2022-07-21

Kayacık Günday Ö, Özdemir Erdoğan M, Pehlivan A, et al (2022)

The effect of metformin treatment on leukocyte telomere length in patients with polycystic ovary syndrome: a prospective case-control study.

Journal of assisted reproduction and genetics [Epub ahead of print].

PURPOSE: The study aimed to investigate the effect of metformin treatment on leukocyte telomere length (LTL) and the relationship of LTL with C-reactive protein (CRP), homocysteine, albumin, complete blood count, and HOMA-IR values in patients with polycystic ovary syndrome (PCOS).

MATERIAL AND METHOD: A prospective case-control study consisting of 30 women with PCOS and 30 healthy women without PCOS was performed. The relationship between clinical and laboratory parameters and LTL was analyzed. PCOS patients were treated with metformin (850 mg/day) for three months. Before treatment (BT) and after treatment (AT), each patient's LTL was evaluated and compared with the control group.

RESULTS: In the comparison between PCOS and control groups, the difference was significant for LTL, age, body mass index (BMI), and CRP (p = 0.002; p < 0.001; p = 0.001; p = 0.01, respectively). In PCOS patients, the difference between BT and AT, LTL was not statistically significant (BT: 6.06 ± 2.12; AT: 6.30 ± 1.93; p = 0.623; 95% C.I: - 1.22-0.74); however, the difference for weight was significant (BT: 83.78 ± 15.31; AT: 80.62 ± 15.40; p = 0.02; 95% CI: 1.34-4.99). The logistic regression model established by BMI (group 1: 21-24, group 2: 24-29, group 3: 29-34, group 4: > 34), age, and RDW, which predicted the PCOS group by affecting the LTL level, was statistically significant (p < 0.001/PPV = 96.3%; NPV = 88.5%). Each unit reduction in telomere length increased women's probability of PCOS by 0.4 times (p = 0.013; OR = 0.419, 95% CI: 0.211-0.835).

CONCLUSION: Although statistically insignificant, LTL increased after metformin use in PCOS patients, and the mean weight loss reduction was statistically significant. Telomere shortening increased the likelihood of PCOS 0.4 times.

RevDate: 2022-07-21

Lansdorp P (2022)

Telomere Length Regulation.

Frontiers in oncology, 12:943622.

The number of (TTAGGG)n repeats at the ends of chromosomes is highly variable between individual chromosomes, between different cells and between species. Progressive loss of telomere repeats limits the proliferation of pre-malignant human cells but also contributes to aging by inducing apoptosis and senescence in normal cells. Despite enormous progress in understanding distinct pathways that result in loss and gain of telomeric DNA in different cell types, many questions remain. Further studies are needed to delineate the role of damage to telomeric DNA, replication errors, chromatin structure, liquid-liquid phase transition, telomeric transcripts (TERRA) and secondary DNA structures such as guanine quadruplex structures, R-loops and T-loops in inducing gains and losses of telomere repeats in different cell types. Limitations of current telomere length measurements techniques and differences in telomere biology between species and different cell types complicate generalizations about the role of telomeres in aging and cancer. Here some of the factors regulating the telomere length in embryonic and adult cells in mammals are discussed from a mechanistic and evolutionary perspective.

RevDate: 2022-07-19

Hawks RM, Kahn LG, Fang W, et al (2022)

Prenatal phthalate exposure and placental telomere length: Prenatal DEHP exposure and placental telomere length.

RevDate: 2022-07-20

Benowitz-Fredericks ZM, Lacey LM, Whelan S, et al (2022)

Telomere length correlates with physiological and behavioural responses of a long-lived seabird to an ecologically relevant challenge.

Proceedings. Biological sciences, 289(1978):20220139.

Determinants of individual variation in reallocation of limited resources towards self-maintenance versus reproduction are not well known. We tested the hypothesis that individual heterogeneity in long-term 'somatic state' (i) explains variation in endocrine and behavioural responses to environmental challenges, and (ii) is associated with variation in strategies for allocating to self-maintenance versus reproduction. We used relative telomere length as an indicator of somatic state and experimentally generated an abrupt short-term reduction of food availability (withdrawal of food supplementation) for free-living seabirds (black-legged kittiwakes, Rissa tridactyla). Incubating male kittiwakes responded to withdrawal by increasing circulating corticosterone and losing more weight compared to continuously supplemented controls. Males with longer telomeres increased time in directed travel regardless of treatment, while experiencing smaller increases in corticosterone. Males with longer telomeres fledged more chicks in the control group and tended to be more likely to return regardless of treatment. This study supports the hypothesis that somatic state can explain variation in short-term physiological and behavioural responses to challenges, and longer-term consequences for fitness. Male kittiwakes with longer telomeres appear to have prioritized investment in self over investment in offspring under challenging conditions.

RevDate: 2022-07-20

Huang D, Lin S, He J, et al (2022)

Association between COVID-19 and telomere length: a bidirectional Mendelian randomization study.

Journal of medical virology [Epub ahead of print].

Several traditional observational studies suggested an association between COVID-19 and leukocyte telomere length (LTL), a biomarker for biological age. However, whether there was a causal association between them remained unclear. We aimed to investigate whether genetically predicted COVID-19 is related to the risk of LTL, and vice versa. We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies (GWAS) of critically ill COVID-19 (n = 1,388,342) and LTL (n = 472,174) of European ancestry. The random-effects inverse-variance weighted estimation method was applied as the primary method with several other estimators as complementary methods. Using six single-nucleotide polymorphisms (SNPs) of genome-wide significance as instrumental variables for critically ill COVID-19, we did not find a significant association of COVID-19 on LTL (β=0.0075, 95% confidence interval [CI]: -0.018-0.021, P=0.733). Likewise, using 97 SNPs of genome-wide significance as instrumental variables for LTL, we did not find a significant association of LTL on COVID-19 (odds ratio=1.00, 95% CI: 0.79-1.28, P=0.973). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. We did not find evidence to support a causal association between COVID-19 and LTL in either direction. This article is protected by copyright. All rights reserved.

RevDate: 2022-07-16

Grigoryan OR, Frolova TM, Mikheev RK, et al (2022)

[The dual role of the menopausal hormonal therapy as the enhancer of pleiotropic telomere rejuvenation and the silencer of cellular aging (literature review)].

Problemy endokrinologii, 68(3):105-112.

Present worldwide healthcare researches prove that female patients are more sensitive to the population aging. Menopause or climacteria (climax) - is not as ageing itself, but a physiological unstoppable process. The main task for a physician is to improve life quality for female despite of ageing problems. Menopausal hormone therapy (MHT) due to the estrogen component has an anti-inflammatory, antioxidant effect and promotes the expression of telomerase, which together changes the homeostasis and integrity of telomeres. The use of MHT for five years or more can not only significantly change the quality of life, but also increase its duration. Literature search was carried out in national (eLibrary, CyberLeninka.ru) and international (PubMed, Cochrane Library) databases in Russian and English. The priority was free access to the full text of articles. The choice of sources was prioritized for the period from 2019 to 2021. However, taking into account the insufficient knowledge of the chosen topic, the choice of sources dates back to 1989.

RevDate: 2022-07-15

Daios S, Anogeianaki A, Kaiafa G, et al (2022)

Telomere Length as a marker of biological aging: A critical review of recent literature.

Current medicinal chemistry pii:CMC-EPUB-125068 [Epub ahead of print].

INTRODUCTION: Aging is characterized as a syndrome of deleterious, progressive, universal, and irreversible function changes affecting every structural and functional aspect of the organism and accompanied by a generalized increase in mortality. Although a substantial number of candidates for biomarkers of aging have been proposed, none has been validated or universally accepted. Human telomeres constitute hexameric repetitive DNA sequence nucleoprotein complexes that cap chromosome ends, regulating gene expression and modulating stress-related pathways. Telomere length (TL) shortening is observed both in cellular senescence and advanced age, leading to the investigation of TL as a biomarker for aging and a risk factor indicator for the development and progression of the most common age-related diseases.

OBJECTIVE: The present review underlines the connection between TL and the pathophysiology of the diseases associated with telomere attrition.

METHODS: We performed a structured search of the PubMed database for peer-reviewed research of the literature regarding leukocyte TL and cardiovascular diseases (CVD), more specifically stroke and heart disease, and focused on the relevant articles published during the last 5 years. We also applied Hill's criteria of causation to strengthen this association.

RESULTS: We analyzed the recent literature regarding TL length, stroke, and CVD. Although approximately one-third of the available studies support the connection, the results of different studies seem to be rather conflicting as a result of different study designs, divergent methods of TL determination, small study samples, and patient population heterogeneity. After applying Hill's criteria, we can observe that the literature conforms to them weakly, with chronology being the only Hill criterion of causality that probably cannot be contested.

CONCLUSION: The present review attempted to examine the purported relation between leukocyte TL and age-related diseases such as CVD and more specific stroke and heart disease in view of the best established, comprehensive, medical and epidemiological criteria that have characterized the focused recent relevant research. Although several recommendations have been made that may contribute significantly to the field, a call for novel technical approaches and studies is mandatory to further elucidate the possible association.

RevDate: 2022-07-14

Heaphy CM, Joshu CE, Barber JR, et al (2022)

The prostate tissue-based telomere biomarker as a prognostic tool for metastasis and death from prostate cancer after prostatectomy.

The journal of pathology. Clinical research [Epub ahead of print].

Current biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells - the telomere biomarker - is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators. Here, we optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in five cohort studies of men surgically treated for clinically localized disease (N = 2,255). We estimated the relative risk (RR) of progression to metastasis (N = 311) and prostate cancer death (N = 85) using models appropriate to each study's design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights. Compared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length had 3.76 times the risk of prostate cancer death (95% confidence interval [CI] 1.37-10.3, p = 0.01) and had 2.23 times the risk of progression to metastasis (95% CI 0.99-5.02, p = 0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (grade groups 2/3: RR = 9.18, 95% CI 1.14-74.0, p = 0.037) and with PTEN protein intact tumors (RR = 6.74, 95% CI 1.46-37.6, p = 0.015). In summary, the telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically treated men.

RevDate: 2022-07-14

Bhatt SP, Misra A, Pandey RM, et al (2022)

Shortening of leucocyte telomere length is independently correlated with high body mass index and subcutaneous obesity (predominantly truncal), in Asian Indian women with abnormal fasting glycemia.

BMJ open diabetes research & care, 10(4):.

INTRODUCTION: Leucocyte telomere length (LTL) is linked to accelerate aging and premature mortality. In this research, we aimed to explore the relations between biochemical and anthropometry markers and LTL in Asian Indian women with abnormal fasting glycemia (impaired fasting glucose).

RESEARCH DESIGN AND METHODS: In this study, 797 pre-diabetic women (obese, 492; non-obese, 305) were recruited. Demographic and clinical profiles, anthropometry, and fasting blood glucose were evaluated. LTL was quantified by a quantitative PCR. LTL was expressed as the relative telomere length or telomere repeat:single copy gene (T:S) ratio. The subjects were separated into quartiles according to the LTL.

RESULTS: The average LTL was significantly decreased with increasing age. The average LTL was significantly shorter in obese women with abnormal fasting glycemia (p<0.05). R-squared (R2) statistic for multivariable linear model after adjusted for age, family income, education and hypertension showed that LTL was inversely correlated with body mass index (BMI), waist and hip circumference, waist-hip and waist-to-height ratio, truncal skinfolds (subscapular, and subscapular/triceps ratio, central and total skinfolds), fat mass (kg) and % body fat. The relationship between obesity measures and LTL (using the LTL quartile 1 as reference) identified central skinfolds (R2=0.92, p<0.0001), Σ4SF (R2=0.90, p<0.0001), BMI (R2=0.93, p<0.0001) and % body fat (R2=0.91, p<0.0001) as independent predictors of LTL.

CONCLUSIONS: Besides age, obesity and subcutaneous adiposity (predominantly truncal) are major contributors to telomere shortening in Asian Indian women with abnormal fasting glycemia (impaired fasting glucose).

RevDate: 2022-07-13

He Q, Lin X, Chavez BL, et al (2022)

Structures of the human CST-Polα-primase complex bound to telomere templates.

Nature pii:10.1038/s41586-022-05040-1 [Epub ahead of print].

The mammalian DNA polymerase-alpha/primase (pol-α/primase) is essential for DNA metabolism, providing the de novo RNA-DNA primer for several DNA replication pathways1-4 such as lagging-strand synthesis and telomere C-strand fill-in. The underlying physical mechanism of how pol-α/primase, alone or in partnership with accessory proteins, performs its complicated multistep primer synthesis function is unknown. Here, we show that CST, a single-stranded DNA-binding accessory protein complex of pol-α/primase, physically sets up the enzyme for efficient primer synthesis. Cryo-electron microscopy structures of CST-pol-α/primase preinitiation complex (PIC) bound to various types of telomere overhang reveal template-bound CST partitions the DNA and RNA catalytic centers of pol-α/primase into two separate domains and effectively arrange them in RNA-DNA synthesis order. The PIC architecture provides a single solution for the multiple structural needs for pol-α/primase RNA-DNA primer synthesis. Multiple insights into CST template-binding specificity, template requirement for CST-pol-α/primase PIC assembly, and activation are also revealed in this study.

RevDate: 2022-07-13

Wang XF, Xu WJ, Wang FF, et al (2022)

Telomere length and development of systemic lupus erythematosus: a Mendelian randomization study.

Arthritis & rheumatology (Hoboken, N.J.) [Epub ahead of print].

OBJECTIVE: Previous observational studies demonstrated that a subset of patients with systemic lupus erythematosus (SLE) have markedly short telomere length (TL) in leukocytes. The purpose of this study is to test whether leukocyte TL is causally associated with risk of SLE.

METHODS: A two-sample Mendelian randomization (TSMR) analysis was applied to estimate causality of TL on SLE in European populations. A replication TSMR study using Asian genetic data was also conducted. A backward MR analysis was then performed to test effects of SLE on TL. The autoantibodies targeting telomere-associated protein (TERF1 autoantibodies) were detected in SLE, healthy controls and rheumatoid arthritis (RA).

RESULTS: The results of inverse-variance weighted method (OR=2.96; 95% CI 1.58, 5.55; P<0.001) showed strong evidence for casual relationship between longer TL and risk of SLE in people with European ancestry. The outcomes of MR-Egger regression (OR=29.46, 95% CI 3.02, 287.60; P=0.033), and MR-PRESSO (OR=3.62; 95% CI 2.03, 6.46; P=0.002) also showed that longer TL was significantly associated with increased risk of SLE in European population. Sensitivity analyses using different methods and summary data sets showed that the results were still broadly consistent. Replication MR study using Asian genetic data yielded similar findings. However, the backward MR analysis showed that genetically predicted SLE was not causally associated with TL. In addition, we found that TERF1 autoantibodies were present in 2/40 (5.0%) patients with SLE.

CONCLUSION: In contrast with previous observational studies, MR analyses found that longer TL is significantly associated with increased risk of SLE.

RevDate: 2022-07-13

Edelson PK, Sawyer MR, Gray KJ, et al (2022)

Increase in short telomeres during the third trimester in human placenta.

PloS one, 17(7):e0271415 pii:PONE-D-22-06161.

An increase in telomere shortening in gestational tissues has been proposed as a mechanism involved in the timing for the initiation of parturition. An increase in very short telomeres with increasing gestational age has been observed in mice; this study sought to explore this phenomenon in human pregnancies. Specifically, this study addressed the hypothesis that prior to labor, the quantity of very short telomeres (<3 kilobase (kb) lengths) increases in human placental tissue as term gestation approaches. The primary outcome was the quantity of very short telomeres present in placental tissue. Quantitative measurements of very short telomeres were performed using real-time polymerase chain reaction (qPCR) adaptation of the telomere restriction fragment technique. Placental tissue from 69 pregnant individuals were included. Mean gestational age was 39.1 weeks (term) and 36.2 weeks (preterm). For term versus preterm placentas, the observed increase in very short telomeres were as follows: 500 bp telomeres increased by 1.67-fold (p < 0.03); 1 kb telomeres increased 1.67-fold (p < 0.08); and 3 kb telomeres increased 5.20-fold (p < 0.001). This study confirms a significant increase in very short telomeres in human placental tissue at term; thereby supporting the hypothesis that telomere shortening at term contributes to the mechanism that determine the length of pregnancy thereby leading to onset of parturition.

RevDate: 2022-07-13

Stock AJ, Y Liu (2021)

NAD-Linked Metabolism and Intervention in Short Telomere Syndromes and Murine Models of Telomere Dysfunction.

Frontiers in aging, 2:785171 pii:785171.

Telomeres are specialized nucleoprotein structures that form protective caps at the ends of chromosomes. Short telomeres are a hallmark of aging and a principal defining feature of short telomere syndromes, including dyskeratosis congenita (DC). Emerging evidence suggests a crucial role for critically short telomere-induced DNA damage signaling and mitochondrial dysfunction in cellular dysfunction in DC. A prominent factor linking nuclear DNA damage and mitochondrial homeostasis is the nicotinamide adenine dinucleotide (NAD) metabolite. Recent studies have demonstrated that patients with DC and murine models with critically short telomeres exhibit lower NAD levels, and an imbalance in the NAD metabolome, including elevated CD38 NADase and reduced poly (ADP-ribose) polymerase and SIRT1 activities. CD38 inhibition and/or supplementation with NAD precursors reequilibrate imbalanced NAD metabolism and alleviate mitochondrial impairment, telomere DNA damage, telomere dysfunction-induced DNA damage signaling, and cellular growth retardation in primary fibroblasts derived from DC patients. Boosting NAD levels also ameliorate chemical-induced liver fibrosis in murine models of telomere dysfunction. These findings underscore the relevance of NAD dysregulation to telomeropathies and demonstrate how NAD interventions may prove to be effective in combating cellular and organismal defects that occur in short telomere syndromes.

RevDate: 2022-07-13

Bürgin D, Varghese N, Eckert A, et al (2022)

Higher hair cortisol concentrations associated with shorter leukocyte telomere length in high-risk young adults.

Scientific reports, 12(1):11730.

Chronic stress is associated with accelerated biological aging as indexed by short age-adjusted leukocyte telomere length (LTL). Exploring links of biological stress responses with LTL has proved challenging due to the lack of biological measures of chronic psychological stress. Hair cortisol concentration (HCC) has emerged as a measure of chronic hypothalamic pituitary adrenal (HPA) axis activation, allowing the examination of relationships between aggregate cortisol concentrations over time and LTL. Our sample includes 92 participants (38% women, Mage = 26 ± 3.7 years) from a high-risk sample of young adults with previous residential care placements. Two cm hair was collected for HCC, reflecting approximately eight weeks of cortisol secretion. LTL was measured with quantitative polymerase chain reaction (qPCR) in whole blood samples. All samples for LTL were run in triplicate and assayed twice. Linear and polynomial regression models were used to describe the association between HCC and LTL, adjusting for age and sex. HCC and LTL showed negative associations (std. ß = - 0.67, 95% CI [- 0.83, - 0.52], p < .001) in age- and sex-adjusted analyses, indicating that higher HCCs are associated with shorter LTL. Using polynomial regression, we found a curvilinear relationship indicating a stronger negative association at lower cortisol concentrations. Higher HCCs were associated with shorter LTL, supporting the hypothesized involvement of prolonged cortisol secretion in telomere attrition. Thus, HCC may prove useful as a biological indicator of chronic stress associated with aging-related processes in samples exposed to high levels of stress.

RevDate: 2022-07-12

Ellis PS, Martins RR, Thompson EJ, et al (2022)

A subset of gut leukocytes has telomerase-dependent "hyper-long" telomeres and require telomerase for function in zebrafish.

Immunity & ageing : I & A, 19(1):31.

BACKGROUND: Telomerase, the enzyme capable of elongating telomeres, is usually restricted in human somatic cells, which contributes to progressive telomere shortening with cell-division and ageing. T and B-cells cells are somatic cells that can break this rule and can modulate telomerase expression in a homeostatic manner. Whereas it seems intuitive that an immune cell type that depends on regular proliferation outbursts for function may have evolved to modulate telomerase expression it is less obvious why others may also do so, as has been suggested for macrophages and neutrophils in some chronic inflammation disease settings. The gut has been highlighted as a key modulator of systemic ageing and is a key tissue where inflammation must be carefully controlled to prevent dysfunction. How telomerase may play a role in innate immune subtypes in the context of natural ageing in the gut, however, remains to be determined.

RESULTS: Using the zebrafish model, we show that subsets of gut immune cells have telomerase-dependent"hyper-long" telomeres, which we identified as being predominantly macrophages and dendritics (mpeg1.1+ and cd45+mhcII+). Notably, mpeg1.1+ macrophages have much longer telomeres in the gut than in their haematopoietic tissue of origin, suggesting that there is modulation of telomerase in these cells, in the gut. Moreover, we show that a subset of gut mpeg1.1+ cells express telomerase (tert) in young WT zebrafish, but that the relative proportion of these cells decreases with ageing. Importantly, this is accompanied by telomere shortening and DNA damage responses with ageing and a telomerase-dependent decrease in expression of autophagy and immune activation markers. Finally, these telomerase-dependent molecular alterations are accompanied by impaired phagocytosis of E. coli and increased gut permeability in vivo.

CONCLUSIONS: Our data show that limiting levels of telomerase lead to alterations in gut immunity, impacting on the ability to clear pathogens in vivo. These are accompanied by increased gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing.

RevDate: 2022-07-12

Olaya I, SM Burgess (2022)

When the anchor's away, meiotic telomeres go astray.

Developmental cell, 57(13):1563-1565.

During meiosis, microtubules emanate from the centrosome to cluster telomeres in the bouquet configuration and facilitate chromosome pairing. In a recent issue of Science, Mytlis et al. establish that a cilium in zebrafish anchors the centrosome and is important for telomere clustering and germ cell development.

RevDate: 2022-07-13
CmpDate: 2022-07-13

Inandiklioglu N, Demir V, Celik Y, et al (2022)

Leukocyte telomere length and lipid parameters in patients with myocardial infarction with non-obstructive coronary arteries.

Cellular and molecular biology (Noisy-le-Grand, France), 67(6):346-352.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is defined as stenosis of less than 50% or no stenosis on coronary angiography in a patient diagnosed with myocardial infarction. Telomere length is expressed by studies that it acts as a biomarker, especially for biological aging and cardiovascular diseases. In this study, we aimed to investigate whether there is a relationship between circulating leukocyte telomere length (LTL) and serum lipid values in MINOCA patients. Forty-five newly diagnosed patients with MINOCA were included in the study, along with 45 healthy controls who matched the patients in terms of age and gender. We determined the LTL value using the RT-PCR method. As a result of the study, we found LTL (p< 0.001) and serum lipid values (HDL-cholesterol (p< 0.001), LDL-cholesterol (p< 0.001), triglycerides (p< 0.05), and total cholesterol (p< 0.05)) to be significantly higher in the MINOCA group than in the control group. When the correlation relationship between LTL and lipid values in the MINOCA group was evaluated, a negative correlation was determined only between LTL and HDL (p=0.014, r=-0.362). This is the first study to evaluate telomere length in MINOCA patients in Turkey. Our results support the existence of short telomere length in MINOCA patients.

RevDate: 2022-07-11

Ribas-Maynou J, Llavanera M, Mateo-Otero Y, et al (2022)

Telomere length in bovine sperm is related to the production of reactive oxygen species, but not to reproductive performance.

Theriogenology, 189:290-300 pii:S0093-691X(22)00252-7 [Epub ahead of print].

Over the last decades, selection in cattle has mainly been based on milk production rather than on reproductive efficiency. While, when applied, focus on reproduction has involved females, attention has barely been paid to males and, if so, it has only looked at classical sperm quality parameters. In effect, variables such as telomere length have been missed, despite the fact that longer telomeres have been suggested to be linked to male fertility in humans. For this reason, the present study aimed to determine the length of telomeres in bovine sperm and their relationship with a) sperm quality evaluated through the conventional spermiogram and flow cytometry, and b) bull reproductive performance. For this purpose, 29 bulls were involved in this study. Sperm telomere length was evaluated through quantitative Fluorescent In Situ Hybridization (qFISH), and sperm quality was determined at 0 h and 4 h post-thaw. Bull fertility was assessed as non-return to estrus rates after 90 days of artificial insemination. Although the mean telomere length in bovine sperm was 12.06 ± 2.75 kb, the intra-individual variability in length led us to observe three different groups of telomeres in each sperm cell: short telomeres (7.14% ± 5.79% of telomeres; 8.29 ± 2.34 kb), medium telomeres (31.03% ± 12.92% of telomeres; 16.00 ± 2.72 kb) and long telomeres (61.93% ± 18.11% of telomeres; 30.13 ± 11.35 kb). Moreover, whereas reactive oxygen species (ROS) were found to be correlated to sperm telomere length (Rs = -0.492; P= 0.007), no correlation with other sperm quality parameters was found (P > 0.05). Reproductive performance after artificial insemination was not seen to be correlated to sperm telomere length (Rs = 0.123; P= 0.520). In conclusion, this study determined, for the first time, the mean telomere length in bovine sperm and also reported that there is a high variability within each sperm cell. Yet, while telomere length was found to be correlated to ROS generation, it was not related to bull reproductive performance.

RevDate: 2022-07-11

Gupta A, Hwang BJ, Benyamien-Roufaeil D, et al (2022)

Mammalian MutY Homolog (MYH or MUTYH) is Critical for Telomere Integrity under Oxidative Stress.

OBM geriatrics, 6(2):.

Telomeres consist of special features and proteins to protect the ends of each chromosome from deterioration and fusion. The telomeric DNA repeats are highly susceptible to oxidative damage that can accelerate telomere shortening and affect telomere integrity. Several DNA repair factors including MYH/MUTYH DNA glycosylase, its interacting partners Rad9/Rad1/Hus1 checkpoint clamp, and SIRT6 aging regulator, are associated with the telomeres. MYH prevents C:G to A:T mutation by removing adenine mispaired with a frequent oxidative DNA lesion, 8-oxoguanine. Here, we show that hMYH knockout (KO) human HEK-293T cells are more sensitive to H2O2 treatment, have higher levels of DNA strand breaks and shorter telomeres than the control hMYH +/+ cells. SIRT6 foci increase at both the global genome and at telomeric regions in H2O2-treated hMYH +/+ cells. However, in untreated hMYH KO HEK-293T cells, SIRT6 foci only increase at the global genome, but not at the telomeric regions. In addition, the hMYH KO HEK-293T cells have increased extra-chromosomal and intra-chromosomal telomeres compared to the control cells, even in the absence of H2O2 treatment. After H2O2 treatment, the frequency of extra-chromosomal telomeres increased in control HEK-293T cells. Remarkably, in H2O2-treated hMYH KO cells, the frequencies of extra-chromosomal telomeres, intra-chromosomal telomeres, and telomere fusions are further increased. We further found that the sensitivity to H2O2 and shortened telomeres of hMYH KO cells, are restored by expressing wild-type hMYH, and partially rescued by expressing hMYHQ324H mutant (defective in Hus1 interaction only), but not by expressing hMYHV315A mutant (defective in both SIRT6 and Hus1 interactions). Thus, MYH interactions with SIRT6 and Hus1 are critical for maintaining cell viability and telomeric stability. Therefore, the failure to coordinate 8-oxoG repair is detrimental to telomere integrity.

RevDate: 2022-07-11

Giguere DJ, Bahcheli AT, Slattery SS, et al (2022)

Telomere-to-telomere genome assembly of Phaeodactylum tricornutum.

PeerJ, 10:e13607 pii:13607.

Phaeodactylum tricornutum is a marine diatom with a growing genetic toolbox available and is being used in many synthetic biology applications. While most of the genome has been assembled, the currently available genome assembly is not a completed telomere-to-telomere assembly. Here, we used Oxford Nanopore long reads to build a telomere-to-telomere genome for Phaeodactylum tricornutum. We developed a graph-based approach to extract all unique telomeres, and used this information to manually correct assembly errors. In total, we found 25 nuclear chromosomes that comprise all previously assembled fragments, in addition to the chloroplast and mitochondrial genomes. We found that chromosome 19 has filtered long-read coverage and a quality estimate that suggests significantly less haplotype sequence variation than the other chromosomes. This work improves upon the previous genome assembly and provides new opportunities for genetic engineering of this species, including creating designer synthetic chromosomes.

RevDate: 2022-07-10

Seo SH, Shin JH, Ham DW, et al (2022)

PTEN/AKT signaling pathway related to hTERT downregulation and telomere shortening induced in Toxoplasma GRA16-expressing colorectal cancer cells.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 153:113366 pii:S0753-3322(22)00755-7 [Epub ahead of print].

This study investigated whether the molecular mechanism of granule protein 16 (GRA16), a dense granule protein of Toxoplasma gondii (T. gondii) that induces cancer cell apoptosis, results in telomere shortening in cancer cells. The molecular mechanism of GRA16 responsible for regulating telomerase reverse transcriptase (hTERT) activity and telomere shortening was investigated using GRA16-transferred HCT116 human colorectal cancer cells (GRA16-stable cells). GRA16 directly decreased hTERT expression by downregulating the expression and phosphorylation of hTERT transcriptional factors accompanied by decreased expression of shelterin complex molecules. Moreover, GRA16 resulted in cancer cell death through reduction of telomerase activity which leads to telomere shortening (decreased relative ratio of telomeric repeat-amplified sequence to that of a single-copy gene) (T/S ratio)), and at the same time gamma-H2A histone family member X (γ-H2A.X) stained nucleus was increased in the cells. The molecular mechanism between GRA16 and hTERT inactivation was revealed using inhibitors for phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A) as well as siRNAs against PTEN and PP2A. hTERT dephosphorylation was induced effectively by the signaling pathway of HAUSP/PTEN/p-AKT(S473) but not by PP2A-B55/p-AKT(T308). Inhibition of the PTEN signaling pathway increased mRNA expressions in hTERT transcriptional factors, cell cycle activating factors, and apoptosis-inhibiting factors. When HCT116 cells were infected with T. gondii, the number of γ-H2A.X-stained nuclei also increased and p-hTERT/hTERT decreased as in GRA16-stable cells. Altogether, our results emphasize that GRA16 is a novel promising telomerase inhibitor that causes telomere shortening through telomerase inactivation by inducing the activation of the tumor suppressor PTEN.

RevDate: 2022-07-09

Zou T, Sato Y, Kaneyoshi S, et al (2022)

Naphthalene Diimides Carrying Two β-Cyclodextrins Prefer Telomere RNA G-Quadruplex Recognition.

Molecules (Basel, Switzerland), 27(13): pii:molecules27134053.

Newly synthesized naphthalene diimide carrying two β-cyclodextrins (NDI-β-CyDs) showed improved specificity for the parallel G-quadruplex structure alongside the hybrid G-quadruplex structure. Specifically, the highest binding affinity of NDI-β-CyDs for the telomere RNA G-quadruplex was observed. The binding simulation indicated that β-cyclodextrins might be available for loop nucleobase inclusion under its complex.

RevDate: 2022-07-09

Zhou D, Li Z, Sun Y, et al (2022)

Early Life Stage Folic Acid Deficiency Delays the Neurobehavioral Development and Cognitive Function of Rat Offspring by Hindering De Novo Telomere Synthesis.

International journal of molecular sciences, 23(13): pii:ijms23136948.

Early life stage folate status may influence neurodevelopment in offspring. The developmental origin of health and disease highlights the importance of the period of the first 1000 days (from conception to 2 years) of life. This study aimed to evaluate the effect of early life stage folic acid deficiency on de novo telomere synthesis, neurobehavioral development, and the cognitive function of offspring rats. The rats were divided into three diet treatment groups: folate-deficient, folate-normal, and folate-supplemented. They were fed the corresponding diet from 5 weeks of age to the end of the lactation period. After weaning, the offspring rats were still fed with the corresponding diet for up to 100 days. Neurobehavioral tests, folic acid and homocysteine (Hcy) levels, relative telomere length in brain tissue, and uracil incorporation in telomere in offspring were measured at different time points. The results showed that folic acid deficiency decreased the level of folic acid, increased the level of Hcy of brain tissue in offspring, increased the wrong incorporation of uracil into telomeres, and hindered de novo telomere synthesis. However, folic acid supplementation increased the level of folic acid, reduced the level of Hcy of brain tissue in offspring, reduced the wrong incorporation of uracil into telomeres, and protected de novo telomere synthesis of offspring, which was beneficial to the development of early sensory-motor function, spatial learning, and memory in adolescence and adulthood. In conclusion, early life stage folic acid deficiency had long-term inhibiting effects on neurodevelopment and cognitive function in offspring.

RevDate: 2022-07-09

Assis V, de Sousa Neto IV, Ribeiro FM, et al (2022)

The Emerging Role of the Aging Process and Exercise Training on the Crosstalk between Gut Microbiota and Telomere Length.

International journal of environmental research and public health, 19(13): pii:ijerph19137810.

Aging is a natural process of organism deterioration, which possibly impairs multiple physiological functions. These harmful effects are linked to an accumulation of somatic mutations, oxidative stress, low-grade inflammation, protein damage, and mitochondrial dysfunction. It is known that these factors are capable of inducing telomere shortening, as well as intestinal dysbiosis. Otherwise, among the biological mechanisms triggered by physical exercise, the attenuation of pro-inflammatory mediators accompanied by redox state improvement can be the main mediators for microbiota homeostasis and telomere wear prevention. Thus, this review highlights how oxidative stress, inflammation, telomere attrition, and gut microbiota (GM) dysbiosis are interconnected. Above all, we provide a logical foundation for unraveling the role of physical exercise in this process. Based on the studies summarized in this article, exercise training can increase the biodiversity of beneficial microbial species, decrease low-grade inflammation and improve oxidative metabolism, these factors together possibly reduce telomeric shortening.

RevDate: 2022-07-09

Min S, Kwon SM, Hong J, et al (2022)

Mitoribosomal Deregulation Drives Senescence via TPP1-Mediated Telomere Deprotection.

Cells, 11(13): pii:cells11132079.

While mitochondrial bioenergetic deregulation has long been implicated in cellular senescence, its mechanistic involvement remains unclear. By leveraging diverse mitochondria-related gene expression profiles derived from two different cellular senescence models of human diploid fibroblasts, we found that the expression of mitoribosomal proteins (MRPs) was generally decreased during the early-to-middle transition prior to the exhibition of noticeable SA-β-gal activity. Suppressed expression patterns of the identified senescence-associated MRP signatures (SA-MRPs) were validated in aged human cells and rat and mouse skin tissues and in aging mouse fibroblasts at single-cell resolution. TIN2- and POT1-interaction protein (TPP1) was concurrently suppressed, which induced senescence, accompanied by telomere DNA damage. Lastly, we show that SA-MRP deregulation could be a potential upstream regulator of TPP1 suppression. Our results indicate that mitoribosomal deregulation could represent an early event initiating mitochondrial dysfunction and serve as a primary driver of cellular senescence and an upstream regulator of shelterin-mediated telomere deprotection.

RevDate: 2022-07-08

Magnano San Lio R, Maugeri A, La Rosa MC, et al (2022)

Nutrient intakes and telomere length of cell-free circulating DNA from amniotic fluid: findings from the Mamma & Bambino cohort.

Scientific reports, 12(1):11671.

Pregnancy represents a crucial period in which several exposures-and especially maternal diet-might shape children's health. Thus, identifying how maternal dietary intakes early affect biological aging in children represents a public health mission. We aimed to assess the relationship between maternal intake of nutrients in early pregnancy and telomere length of cell-free circulating DNA (cfDNA) from amniotic fluid. We used data and samples from the ongoing prospective "Mamma & Bambino" study, which recruits mother-child pairs from Catania at the first prenatal visit. Maternal nutrient intakes were assessed using a Food Frequency Questionnaire, while relative telomere length of cfDNA was assessed by real-time polymerase chain reaction. Our analysis included 174 mother-child pairs. The intakes of iron, vitamin B1, and magnesium were positively correlated with relative telomere length (p-values < 0.05). However, only the intake of magnesium was positively associated with relative telomere length, after applying a linear regression model (β = 0.002; SE = 0.001; p = 0.024). Magnesium deficiency was negatively associated with relative telomere length after adjusting for the same covariates (β = -0.467; SE = 0.176; p = 0.009). To our knowledge, this is the first evidence of a positive relationship between maternal nutrient intake and telomere length of cfDNA. Further efforts are needed for deeply investigating the effect of maternal dietary intakes on telomere length, in order to develop effective public health strategies.

RevDate: 2022-07-08

Zhou J, Chen F, Yan A, et al (2022)

Explore the molecular mechanism of angle-closure glaucoma in elderly patients induced telomere shortening of retinal ganglion cells through oxidative stress.

Nucleosides, nucleotides & nucleic acids [Epub ahead of print].

Senile glaucoma is a common ophthalmological disease in the elderly. It is a disease of visual papillary perfusion caused by elevated intraocular pressure, complicated by visual dysfunction. Glaucoma can cause serious damage to the normal vision of the elderly. Therefore, exploring the related molecular mechanisms of glaucoma is of great significance to the diagnosis and treatment of glaucoma. This is an exploratory study. Establish a mouse model and conduct experimental groupings. After one week of adaptive feeding, the mice were intraperitoneally injected with an anesthetic mixture: ketamine + xylazine. Then the mice were sacrificed by neck dissection, and the eyeball tissues were immediately dissected. HE staining was used to analyze the histopathological characteristics of the retina of each group of mice. MitoSOX fluorescent probe was used to analyze the content of ROS in retinal tissue. The ELISA analysis was used to detect the activation of β-galactosidase for the aging characteristics of retinal ganglion cells in retinal tissues. Immunohistochemistry experiments were used to analyze the expression of telomerase TERT in retinal tissues. Western blot analysis was used to determine the expression of proteins POT1, TERF1, TERF2, and TINF2 in retinal tissues. The HE staining experiment showed that the damage of retinal tissue decreased from group Glaucoma to group Old, group Old to group Young. The experimental results of MitoSOX fluorescent probe show that ROS content is positively correlated with the degree of tissue damage. ELISA analysis results showed that the expression trend of β-galactosidase was the same as the ROS content. The protein expression levels related to telomere protection (TRET, POT1, TREF1, TREF2 and TINF2) all increased from group Glaucoma to group Old, group Old to group Young. The increase in ROS content, the decrease in telomere protection-related protein expression (telomere shortening) induced by ROS, and the increase of the expression of β-galactosidase, are all potential molecular mechanisms for the occurrence of angle-closure glaucoma in elderly patients.

RevDate: 2022-07-08

Tsai LK, Ou-Yang H, Xu J, et al (2022)

Effects of Recloning on the Telomere Lengths of Mouse Terc+/- Nuclear Transfer-Derived Embryonic Stem Cells.

Stem cells and development [Epub ahead of print].

Haploinsufficiency of genes that participate in the telomere elongation and maintenance processes, such as Terc and Tert, often lead to premature aging related diseases such as dyskeratosis congenita and aplastic anemia. Previously we reported that when mouse Terc+/- tail tip fibroblasts (TTFs) were used as the donor cells for somatic cell nuclear transfer (SCNT, also known as "cloning"), the derivative embryonic stem cells (ntESCs) had elongated telomeres. In the present work, we are interested to know if an additional round of SCNT, or recloning, could bring further elongation of the telomeres. Terc+/- TTFs were used to derive the first generation (G1) ntESCs, followed by a second round SCNT using G1-Terc+/- ntESCs as donor cells to derive G2-Tert+/- ntESCs. Multiple lines of G1- and G2-Terc+/- ntESCs were efficiently established, and all expressed major pluripotent markers and supported efficient chondrocyte differentiation in vitro. Comparing to the donor TTFs, telomere lengths of G1-ntESCs were elongated to the level comparable to that in wildtype ntESCs. Interestingly, recloning did not further elongate telomere lengths of the Terc+/- ntESCs. Together, our work demonstrates that while a single round of SCNT is a viable means to reprogram Terc haploinsufficient cells to the ESC state, and to elongate these cells' telomere lengths, a second round of SCNT does not necessarily further elongate the telomeres.

RevDate: 2022-07-07

Stinus S, Bringas FRR, Wanders L, et al (2022)

Investigating the role of G-quadruplexes at Saccharomyces cerevisiae telomeres.

Microbial cell (Graz, Austria), 9(6):126-132 pii:MIC0272E112.

The G-quadruplex consensus motif G≥3NxG≥3NxG≥3NxG≥3 is found at telomeres of many species, ranging from yeast to plants to humans, but the biological significance of this fact remains largely unknown. In this study, we examine the in vivo relevance of telomeric G-quadruplexes in the budding yeast Saccharomyces cerevisiae by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant [(TG)0-4TGG]xATTTGG telomeric repeats instead of wild-type (TG)0-6TGGGTGTG(G)0-1 repeats to the distal ends of telomeres. The tlc1-tm telomere sequences lack the GGG motif present in every wild-type repeat and, therefore, are expected to be impaired in the formation of G-quadruplexes. Circular dichroism analysis of oligonucleotides consisting of tlc1-tm telomeric sequence is consistent with this hypothesis. We have previously shown that tlc1-tm cells grow similarly to wild-type cells, suggesting that the ability to form telomeric G-quadruplexes is not essential for telomere capping in S. cerevisiae cells.

RevDate: 2022-07-06

Ma Y, Wang M, Chen X, et al (2022)

Telomere length and Multiple Sclerosis: A Mendelian Randomization Study.

The International journal of neuroscience [Epub ahead of print].

PURPOSE OF THE STUDY: Previous studies have established that telomere length is associated with Multiple sclerosis(MS). However, confounding factors and reverse causality bias can impair observational research. Here, we conducted a two-sample MR study to see if telomere length is causally linked to MS using publically available GWAS summary statistics.

MATERIALS AND METHODS: We screened 13 independent single-nucleotide polymorphisms (SNPs) related to leukocyte telomere length in a recent genome-wide association meta-analysis, which was available for 78,592 samples of European ancestry. The summary statistics for MS were from the latest meta-analyses conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC), which included 115,803 European participants (47,429 MS, 68,374 controls).

RESULTS: We found that leukocyte telomere length and MS are correlated (IVW estimate of odds ratio (OR): 2.13 per 1-SD increase in genetically determined telomere length, 95% confidence interval (CI): 1.55-2.92, P =3.18 × 10-6).

CONCLUSION: Our MR study supported that leukocyte telomere length and MS have a positive causal relationship. Further researches are warranted to elucidate the physiological mechanism.

RevDate: 2022-07-05

Gao J, HA Pickett (2022)

Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies.

Nature reviews. Cancer [Epub ahead of print].

Cancer cells establish replicative immortality by activating a telomere-maintenance mechanism (TMM), be it telomerase or the alternative lengthening of telomeres (ALT) pathway. Targeting telomere maintenance represents an intriguing opportunity to treat the vast majority of all cancer types. Whilst telomerase inhibitors have historically been heralded as promising anticancer agents, the reality has been more challenging, and there are currently no therapeutic options for cancer types that use ALT despite their aggressive nature and poor prognosis. In this Review, we discuss the mechanistic differences between telomere maintenance by telomerase and ALT, the current methods used to detect each mechanism, the utility of these tests for clinical diagnosis, and recent developments in the therapeutic strategies being employed to target both telomerase and ALT. We present notable developments in repurposing established therapeutic agents and new avenues that are emerging to target cancer types according to which TMM they employ. These opportunities extend beyond inhibition of telomere maintenance, by finding and exploiting inherent weaknesses in the telomeres themselves to trigger rapid cellular effects that lead to cell death.

RevDate: 2022-07-05

Elam KK, Johnson SL, Ruof A, et al (2022)

Examining the influence of adversity, family contexts, and a family-based intervention on parent and child telomere length.

European journal of psychotraumatology, 13(1):2088935 pii:2088935.

Background: Exposure to adversity, trauma, and negative family environments can prematurely shorten telomeres, the protective caps at the ends of chromosomes. Conversely, some evidence indicates that positive environments and psychosocial interventions can buffer the shortening of telomere length (TL). However, most work has examined individual aspects of the family environment as predictive of TL with little work investigating multiple risk and protective factors. Further, most research has not examined parent TL relative to child TL despite its heritability. Objective: In the current study, we examined interparental conflict, positive parenting, alcohol use, adverse childhood experiences (ACEs), and a family-based intervention as predictive of parent TL. We also examined interparental conflict, positive parenting, ACEs, and a family-based intervention as predictive of child TL. Method: Parents and adolescents from a sample of divorced families participated in either a 10-session family-based intervention, the New Beginnings Programme (NBP), or a 2-week active control condition. Approximately six years after the intervention, a subsample of parents (n = 45) and adolescents (n = 41) were assessed for TL. Parents reported on interparental conflict, ACEs, and alcohol use. Children reported on interparental conflict, positive parenting, and ACEs. In separate models, these constructs and the NBP intervention condition were examined as predictors of parent TL and child TL. Results: Findings indicated that the family-based intervention was associated with longer TL in parents. Also, positive parenting was associated with longer TL in children. Conclusions: These findings have important implications for the role of the family and family-based preventive interventions in buffering parent and child biological stress.

HIGHLIGHTS: Across multiple indices of psychosocial functioning, we found a family-based intervention associated with longer telomere length in parents and positive parenting associated with longer telomere length in children.

RevDate: 2022-07-05

von Falkenhausen AS, Freudling R, Waldenberger M, et al (2022)

Common electrocardiogram measures are not associated with telomere length.

Aging, 14(undefined): pii:204149 [Epub ahead of print].

AIMS: Aging is accompanied by telomere shortening. Increased telomere shortening is considered a marker of premature aging. Cardiac aging results in the development of cardiac pathologies. Electrocardiogram (ECG) measures reflect cardiac excitation, conduction, and repolarization. ECG measures also prolong with aging and are associated with cardiac pathologies including atrial fibrillation. As premature prolongation of ECG measures is observed, we hypothesized that such prolongation may be associated with telomere length.

METHODS AND RESULTS: We studied the large, community-based KORA F4 Study. Of 3,080 participants enrolled between 2006 and 2007 with detailed information on demographic, anthropometric, clinical, and ECG characteristics, 2,575 presented with available data on leukocyte telomere length. Telomere length was determined by real-time quantitative PCR and expressed relative to a single copy gene. We fitted multivariable adjusted linear regression models to associate the ECG measures RR-interval, PR-interval, QRS-duration, and heart rate corrected QTc with telomere length. In our cohort, the mean age was 54.9±12.9 years and 46.6% were men. Increased age was associated with shorter telomere length (p<0.01), and men had shorter telomere length than women (p<0.05). In unadjusted models, heart rate (p=0.023), PR-interval (p<0.01), and QTc-interval (p<0.01) were significantly associated with shorter telomere length. However, no significant associations remained after accounting for age, sex, and covariates.

CONCLUSIONS: ECG measures are age-dependent, but not associated with shortened telomere length as a marker of biological aging. Further research is warranted to clarify if shortened telomeres are associated with clinical cardiac pathologies including atrial fibrillation.

RevDate: 2022-07-05

van de Crommenacker J, Hammers M, Dugdale HL, et al (2022)

Early-life conditions impact juvenile telomere length, but do not predict later life-history strategies or fitness in a wild vertebrate.

Ecology and evolution, 12(6):e8971 pii:ECE38971.

Environmental conditions experienced during early life may have long-lasting effects on later-life phenotypes and fitness. Individuals experiencing poor early-life conditions may suffer subsequent fitness constraints. Alternatively, individuals may use a strategic "Predictive Adaptive Response" (PAR), whereby they respond-in terms of physiology or life-history strategy-to the conditions experienced in early life to maximize later-life fitness. Particularly, the Future Lifespan Expectation (FLE) PAR hypothesis predicts that when poor early-life conditions negatively impact an individual's physiological state, it will accelerate its reproductive schedule to maximize fitness during its shorter predicted life span. We aimed to measure the impact of early-life conditions and resulting fitness across individual lifetimes to test predictions of the FLE hypothesis in a wild, long-lived model species. Using a long-term individual-based dataset, we investigated how early-life conditions are linked with subsequent fitness in an isolated population of the Seychelles warbler Acrocephalus sechellensis. How individuals experience early-life environmental conditions may vary greatly, so we also tested whether telomere length-shorter telomers are a biomarker of an individual's exposure to stress-can provide an effective measure of the individual-specific impact of early-life conditions. Specifically, under the FLE hypothesis, we would expect shorter telomeres to be associated with accelerated reproduction. Contrary to expectations, shorter juvenile telomere length was not associated with poor early-life conditions, but instead with better conditions, probably as a result of faster juvenile growth. Furthermore, neither juvenile telomere length, nor other measures of early-life conditions, were associated with age of first reproduction or the number of offspring produced during early life in either sex. We found no support for the FLE hypothesis. However, for males, poor early-life body condition was associated with lower first-year survival and reduced longevity, indicating that poor early-life conditions pose subsequent fitness constraints. Our results also showed that using juvenile telomere length as a measure of early-life conditions requires caution, as it is likely to not only reflect environmental stress but also other processes such as growth.

RevDate: 2022-07-05

Durand M, Nagot N, Michel L, et al (2022)

Mental Disorders Are Associated With Leukocytes Telomere Shortening Among People Who Inject Drugs.

Frontiers in psychiatry, 13:846844.

Premature biological aging, assessed by shorter telomere length (TL) and mitochondrial DNA (mtDNA) alterations, has been reported among people with major depressive disorders or psychotic disorders. However, these markers have never been assessed together among people who inject drugs (PWIDs), although mental disorders are highly prevalent in this population, which, in addition, is subject to other aggravating exposures. Diagnosis of mental disorders was performed by a psychiatrist using the Mini International Neuropsychiatric Interview test among active PWIDs in Haiphong, Vietnam. mtDNA copy number (MCN), mtDNA deletion, and TL were assessed by quantitative PCR and compared to those without any mental disorder. We next performed a multivariate analysis to identify risk factors associated with being diagnosed with a major depressive episode (MDE) or a psychotic syndrome (PS). In total, 130 and 136 PWIDs with and without psychiatric conditions were analyzed. Among PWIDs with mental disorders, 110 and 74 were diagnosed with MDE and PS, respectively. TL attrition was significantly associated with hepatitis C virus-infected PWIDs with MDE or PS (adjusted odds ratio [OR]: 0.53 [0.36; 0.80] and 0.59 [0.39; 0.88], respectively). TL attrition was even stronger when PWIDs cumulated at least two episodes of major depressive disorders. On the other hand, no difference was observed in mtDNA alterations between groups. The telomeric age difference with drug users without a diagnosis of psychiatric condition was estimated during 4.2-12.8 years according to the number of MDEs, making this group more prone to age-related diseases.

RevDate: 2022-07-01

Gampawar P, Schmidt R, H Schmidt (2022)

Telomere length and brain aging: a systematic review and meta-analysis.

Ageing research reviews pii:S1568-1637(22)00121-0 [Epub ahead of print].

The current evidence on the association of leukocyte telomere length (LTL) with age-related structural and cognitive changes in the brain is mixed. Herein conforming to PRISMA 2020 guidelines, we performed a systematic review and meta-analysis using data from 27 observational studies in non-demented individuals. We used effect size and p-value based meta-analysis methods considering marked heterogeneity among studies. We found that the longer LTL was associated with higher brain volume (β=0.43, 95%CI: 0.36%-0.50%, p=0.008, N=1102) and with higher global cognition (β=0.01; 95%CI: 0.00-0.02, p= 0.03, N=19609) by effect size based meta-analysis and with brain volume, hippocampal volume, global cognition, cognitive domains of attention/speed as well as executive functions by p-value based meta-analysis. No significant association of LTL with brain white matter hyperintensities was detected. Furthermore, the evidence strongly suggests a subgroup-specific canonical effect of telomeres, notably in older individuals and females. In conclusion, we provide meta-analytic evidence on the beneficial effect of telomeres on brain structure as well as cognition and advocate for a beneficial subgroup-specific effect that warrants further attention.

RevDate: 2022-07-01

Iannuzzi A, Albarella S, Parma P, et al (2022)

Characterization of telomere length in Agerolese cattle breed, correlating blood and milk samples.

Animal genetics [Epub ahead of print].

Studies into telomere length in cattle are relatively recent and have focused mainly on the Holstein Friesian cattle breed, making it arduous to evaluate the correlation with ageing due to the early age of culling in this breed. Telomere length provides information about the productive lifespan and the quality of farm management, complying with the 'One Health' approach. This study evaluated telomere length in Agerolese cattle, an autochthonous dairy breed characterized by a long productive lifespan (13 years). Multiplex quantitative PCR estimated telomere length in DNA extracted from blood and milk matrices. Interestingly, the results showed longer telomeres in Agerolese (compared to the Holstein Friesian cattle control group), with a negative correlation between telomere length and increasing age and a synchronous trend between blood and milk samples, with a positive correlation between them.

RevDate: 2022-06-30

Barnes RP, de Rosa M, Thosar SA, et al (2022)

Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening.

Nature structural & molecular biology [Epub ahead of print].

Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening. Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results, we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions that drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.

RevDate: 2022-06-30

Robinson H, Ali SI, Diaz-Hernandez ME, et al (2022)

Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related C9ORF72 Repeat Expansion Carriers.

Frontiers in cell and developmental biology, 10:874323 pii:874323.

The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulated DNA damage response and the generation of reactive oxygen species (ROS) have been postulated as major drivers of toxicity in C9ORF72 pathogenesis. Telomeres are tandem-repeated nucleotide sequences that are located at the end of chromosomes and protect them from degradation. Interestingly, it has been established that telomeres are sensitive to ROS. Here, we analyzed telomere length in neurons and neural progenitor cells from several induced pluripotent stem cell (iPSC) lines from control subjects and C9ORF72 repeat expansion carriers. We found an age-dependent decrease in telomere length in two-month-old iPSC-derived motor neurons from C9ORF72 carriers as compared to control subjects and a dysregulation in the protein levels of shelterin complex members TRF2 and POT1.

RevDate: 2022-06-30

Choi BE, HT Lee (2022)

DNA-RNA hybrid G-quadruplex tends to form near the 3' end of telomere overhang.

Biophysical journal pii:S0006-3495(22)00512-4 [Epub ahead of print].

Telomeric repeat-containing RNA (TERRA) has been suggested to participate in telomere maintenance. TERRA consisting of UUAGGG repeats is capable of forming intermolecular G-quadruplex (GQ) with single-stranded TTAGGG-repeat DNA in telomere 3' overhang. To explore the structural features and potential functions of this DNA-RNA hybrid GQ (HGQ), we used single-molecule FRET to study the folding patterns of DNA with four to seven telomeric tandem repeats annealed with a short RNA consisting of two or five telomeric repeats. Our data highlights that RNA prefers to form DNA-RNA HGQ near the 3' end of telomeric DNA. Furthermore, the unfolding of secondary structures by a complementary C-rich sequence was observed for DNA GQ but not for DNA-RNA HGQ, which demonstrated the enhanced stability of the telomere 3' end via hybridization with RNA. These conformational and physical properties of telomeric DNA-RNA HGQ suggest that TERRA might limit access to the 3' end of the telomeric DNA overhang which is known to be critical for the interaction with telomerase and other telomere-associated proteins.

RevDate: 2022-06-27

Buttet M, Bagheri R, Ugbolue UC, et al (2022)

Effect of a lifestyle intervention on telomere length:A systematic review and meta-analysis.

Mechanisms of ageing and development pii:S0047-6374(22)00076-8 [Epub ahead of print].

BACKGROUND: We conducted a systematic review and meta-analysis to assess the effects of lifestyle intervention on telomere length (TL).

METHOD: Four databases were searched for studies reporting TL in leukocytes, before and after a lifestyle intervention. We computed random-effects meta-analysis on TL within intervention and control group after versus before intervention, and on changes in TL between groups. Sensitivity analyses and Meta-regression were conducted.

RESULTS: We included 20 studies in the systematic review (2995 participants, mean 50.3 years old, 77% women, 2045 following an intervention and 950 controls) and 19 in the meta-analysis. TL were similar at baseline between intervention and control groups. The physical activity ± diet group had an increase in TL (Effect size 0.17, 95%CI 0.03 to 0.31, p=0.020) using changes within the intervention group, whereas TL shortened in the control group (-0.32, -0.61 to -0.02, p=0.037). TL was longer in the physical activity ± diet intervention group (0.24, 0.08 to 0.40, p=0.004) compared to controls after the intervention. Sensitivity analysis gave similar results. Meta-regressions demonstrated that combining strength and endurance exercise increased TL more than endurance alone or strength alone.

CONCLUSION: A lifestyle intervention with physical activity ± diet can increase telomere length, independently of population characteristics or baseline TL.

RevDate: 2022-06-27

Llorente H, Perez-Rivera JA, Perez-Nieto M, et al (2022)

Genetic susceptibility to telomere shortening through the rs2293607 polymorphism is associated with a greater risk of alcohol use disorder.

Mechanisms of ageing and development pii:S0047-6374(22)00075-6 [Epub ahead of print].

Telomere shortening is usually considered a biomarker of ageing. Harmful alcohol use promotes accelerated biological ageing and alcohol use disorders (AUDs) are associated with short telomere length (TL). This study was conducted to examine the relationship of TL to AUD and determine whether single nucleotide polymorphisms (SNPs) in TERC and TERT modulate this association. For this purpose, we genotyped TERC SNPs rs2293607, rs12696304, and rs16847897 and TERT SNPs rs2735940, rs2736100, and rs2736098 in 308 male patients with AUD and 255 sex-matched healthy controls and measured TL in a subset of 99 patients and 99 controls paired by age and smoking status. Our results showed that the mean TL was shorter in patients with AUD than in controls. The area under the ROC curve was 0.70 (P < 0.001). The GG genotype of TERC rs2293607 was more common among patients with AUD than among controls (9.8% vs. 5.1%; P = 0.038). No difference was found for the other SNPs. Carriers of the GG genotype of rs2293607 had shorter telomeres than did allele A carriers. In conclusion, patients with AUD had shorter telomeres. Genetic susceptibility to telomere shortening through the rs2293607 SNP is associated with a greater risk of AUD.

RevDate: 2022-06-27

Madaeva IM, Kurashova NA, Ukhinov EB, et al (2022)

[Changes in the telomeres length in patients with obstructive sleep apnea after continuous positive airway pressure therapy: a pilot study].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 122(5. Vyp. 2):52-57.

OBJECTIVE: To evaluate a relative telomere length in patients with obstructive sleep apnea (OSA) before and after a 6-month course of continuous positive airway pressure (CPAP) therapy.

MATERIAL AND METHODS: Seventy-five men participated in the study, including 50 men with OSA (the main group 1) and 25 men without OSA (the control group). The average age in the total group was 53.4±3.6 years. Thirty-five men completed the study (the main group 2). According to the design, night polysomnography (PSG) was performed for all the subjects, blood sampling to assess the length of telomeres was carried out in the morning according to the standard method. The values of the relative telomere length were obtained using the difference between the values of the threshold cycles for telomeric DNA and the reference gene albumin (∆CCt). After clarifying the diagnosis, CPAP was applied for 6 months.

RESULTS: Statistically significant indicators of PSG were revealed: a decrease in NREM 3 in patients with OSA compared to controls (89.3±15.8 versus 150±23.4 minutes), an increase in NREM1-2 in OSA (296.2±31.1 and 170.1±24.5, respectively), REM was 84.6±15.4 in the main group and 118.5±19.5 in the control group. CPAP therapy conducted for 6 months (at least 4-5 nights a week, lasting at least 5-6 hours of night sleep) demonstrated a significant improvement in the qualitative and quantitative parameters of sleep. In patients of the main group 1, there is a shortening of the telomere length compared with the control group (p<0.001). With the elimination of hypoxia and improvement of the structure of sleep after CPAP, there was an increase in the telomere lengths in the main group 1 from 0.28 [0.24-0.29] to 0.32 [0.30-0.34] in the main group 2 (p=0.03). The telomers length in the control group was 0.53 [0.50-0.55].

CONCLUSION: Intermittent hypoxia and fragmentation of sleep in OSA leads to shortening of telomeres. CPAP, by eliminating the pathophysiological triggers of OSA, contributes to an increase in telomeres lengths and can slow down the premature aging in OSA.

RevDate: 2022-06-27

Aguayo L, Ogolsky B, Teran-Garcia M, et al (2021)

From culture to chromosomes: A mother-child dyadic study of acculturation, telomere lengths and body fat.

Comprehensive psychoneuroendocrinology, 5:100029 pii:S2666-4976(21)00003-5.

Studies suggest that telomere lengths, a biomarker of aging, could also capture the physiological weathering attributable to poor health behaviors and adverse experiences, particularly those experienced in early life. For these reasons, we propose that telomere lengths may be a pivotal biomarker for measuring the heightened susceptibility to illness resulting from the cumulative exposure to acculturation to the US culture. This binational study used an Actor-Partner Interdependence Model to test if maternal acculturation to the US moderates the cross-sectional associations of telomere lengths with percentage of body fat (PBF) among Mexican women, among their children, and the intergenerational associations of mother and children telomere lengths with each other's PBF. Low income Mexican child-mother dyads (n ​= ​108 dyads) were recruited to participate in this cross-sectional study in Mexico and the US. The pooled dataset included measurements of maternal acculturation to the US, mother and children's salivary telomere lengths, PBF measured through bioelectrical impedance, and demographic characteristics. Results showed that the influences of maternal acculturation in the associations of telomere lengths with PBF were different for mothers and their children: Among mothers with higher maternal acculturation to the US, longer salivary telomere lengths were associated with lower PBF. In contrast, among mothers with lower maternal acculturation to the US, salivary telomere lengths were not associated with PBF. There were no significant associations between children's salivary telomere lengths and PBF, and the null associations did not vary across different levels of maternal acculturation to the US. Future longitudinal studies are needed to determine whether acculturation to the US (experienced through immigration or remotely) influences the association of telomere length attrition with obesity risks among immigrant and non-immigrant Mexican children and adults.

RevDate: 2022-06-24

Zhang Y, Fu J, Wang K, et al (2022)

The telomere-to-telomere gap-free genome of four rice parents reveals SV and PAV patterns in hybrid rice breeding.

Plant biotechnology journal [Epub ahead of print].

RevDate: 2022-06-24

Isehunwa OO, Warner ET, Spiegelman D, et al (2022)

Depression, religiosity, and telomere length in the Study on Stress, Spirituality, and Health (SSSH).

International journal of mental health and addiction, 20(3):1465-1484.

Prospective studies on the association between depression and telomere length have produced mixed results and have been largely limited to European ancestry populations. We examined the associations between depression and telomere length, and the modifying influence of religion and spirituality, in four cohorts, each representing a different race/ethnic population. Relative leukocyte telomere length (RTL) was measured by a quantitative polymerase chain reaction. Our result showed that depression was not associated with RTL (percent difference: 3.0 95% CI: -3.9, 10.5; p = 0.41; p-heterogeneity across studies = 0.67) overall or in cohort-specific analyses. However, in cohort-specific analyses, there was some evidence of effect modification by the extent of religiosity or spirituality, religious congregation membership, and group prayer. Further research is needed to investigate prospective associations between depression and telomere length, and the resources of resilience including dimensions of religion and spirituality that may impact such dynamics in diverse racial/ethnic populations.

RevDate: 2022-06-24

Deng Y, Liu S, Zhang Y, et al (2022)

A telomere-to-telomere gap-free reference genome of watermelon and its mutation library provide important resources for gene discovery and breeding.

Molecular plant pii:S1674-2052(22)00192-7 [Epub ahead of print].

Watermelon, Citrullus lanatus, is the world's third largest fruity crop. Reference genomes with gaps and narrow genetic base hinder functional genomics and genetic improvement of watermelon. Here, we report the assembly of a telomere-to-telomere (T2T) gap-free genome of the elite watermelon inbred G42 by incorporating the high-coverage and accurate long-read sequence data with multiple assembly strategies. All 11 chromosomes have been assembled into single contig pseudomolecules without gap, representing the highest completeness and assembly quality till now. The G42 reference genome contained a total length of 369,321,829 bp and 24,205 predicted protein-coding genes, with all 22 telomeres and 11 centromeres characterized. Over 200,000 M1 seeds from inbred G42 were generated using pollen EMS mutagenesis. In a sampling pool, 48 monogenic phenotypic mutations, selected from 223 M1 and 78 M2 mutants with morphological changes, were confirmed. The average density of mutation is 1 SNP/1.69 Mb and 1 indel/4.55 Mb per M1 plant, and 1 SNP/1.08 Mb and 1 indel/6.25 Mb per M2 plant. Taking advantage of the gap-free G42 genome, 8,039 mutations from the 32 plants sampled from M1 and M2 families were identified with 100% accuracy, whereas only 25% of the randomly selected mutations identified using 97103v2 reference genome could be confirmed. Using this library and the gap-free genome, two genes responsible for elongated fruit shape and male sterility (ClMS1) were identified, both being caused by a single base change from G to A. The validated gap-free genome and its EMS mutation library provide invaluable resources for functional genomics and genetic improvement of watermelon.

RevDate: 2022-06-24

Ebata H, Loo TM, A Takahashi (2022)

Telomere Maintenance and the cGAS-STING Pathway in Cancer.

Cells, 11(12): pii:cells11121958.

Cancer cells exhibit the unique characteristics of high proliferation and aberrant DNA damage response, which prevents cancer therapy from effectively eliminating them. The machinery required for telomere maintenance, such as telomerase and the alternative lengthening of telomeres (ALT), enables cancer cells to proliferate indefinitely. In addition, the molecules in this system are involved in noncanonical pro-tumorigenic functions. Of these, the function of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contains telomere-related molecules, is a well-known contributor to the tumor microenvironment (TME). This review summarizes the current knowledge of the role of telomerase and ALT in cancer regulation, with emphasis on their noncanonical roles beyond telomere maintenance. The components of the cGAS-STING pathway are summarized with respect to intercell communication in the TME. Elucidating the underlying functional connection between telomere-related molecules and TME regulation is important for the development of cancer therapeutics that target cancer-specific pathways in different contexts. Finally, strategies for designing new cancer therapies that target cancer cells and the TME are discussed.

RevDate: 2022-06-23

Miller JG, Buthmann JL, IH Gotlib (2022)

Hippocampal volume indexes neurobiological sensitivity to the effect of pollution burden on telomere length in adolescents.

New directions for child and adolescent development [Epub ahead of print].

Exposure to environmental pollutants has been associated with cellular aging in children and adolescents. Individuals may vary, however, in their sensitivity or vulnerability to the effects of environmental pollutants. Larger hippocampal volume has emerged as a potential index of increased sensitivity to social contexts. In exploratory analyses (N = 214), we extend work in this area by providing evidence that larger hippocampal volume in early adolescence reflects increased sensitivity to the effect of neighborhood pollution burden on telomere length (standardized β = -0.40, 95% CI[-0.65, -0.15]). In contrast, smaller hippocampal volume appears to buffer this association (standardized β = 0.02). In youth with larger hippocampal volume, pollution burden was indirectly associated with shorter telomere length approximately 2 years later through shorter telomere length at baseline (indirect standardized β = -0.25, 95% CI[-0.40, 0.10]). For these youth, living in high or low pollution-burdened neighborhoods may predispose them to develop shorter or longer telomeres, respectively, later in adolescence.

RevDate: 2022-06-23

Xiong K, Ouyang C, Liu J, et al (2022)

Chiral RuII-PtII Complexes Inducing Telomere Dysfunction against Cisplatin-Resistant Cancer Cells.

Angewandte Chemie (International ed. in English) [Epub ahead of print].

The application of G-quadruplex stabilizers presents a promising anticancer strategy. However, the molecular crowding conditions within cells diminish the potency of current G-quadruplex stabilizers. Herein, chiral Ru(II)-Pt(II) dinuclear complexes were developed as highly potent G-quadruplex stabilizers even under challenging molecular crowding conditions. The compounds were encapsulated with biotin-functionalized DNA cages to enhance sub-cellular localization and provide cancer selectivity. The nanoparticles were able to efficiently inhibit the endogenous activities of telomerase in cisplatin-resistant cancer cells and cause cell death by apoptosis. The nanomaterials demonstrated high antitumor activity towards cisplatin-resistant tumor cells as well as tumor-bearing mice. To the best of our knowledge, this study presents the first example of a Ru(II)-Pt(II) dinuclear complex as a G-quadruplex stabilizer with an anti-cancer effect towards drug-resistant tumors inside an animal model.

RevDate: 2022-06-23

Benelli R, M Weiss (2022)

Probing local chromatin dynamics by tracking telomeres.

Biophysical journal pii:S0006-3495(22)00506-9 [Epub ahead of print].

Chromatin dynamics is key for cell viability and replication. In interphase, chromatin is decondensed, allowing the transcription machinery to access a plethora of DNA loci. Yet, decondensed chromatin occupies almost the entire nucleus, suggesting that DNA molecules can hardly move. Recent reports have even indicated that interphase chromatin behaves like a solid body on mesoscopic scales. To explore the local chromatin dynamics, we have performed single-particle tracking on telomeres under varying conditions. We find that mobile telomeres feature in all conditions a strongly subdiffusive, anti-persistent motion that is consistent with the monomer motion of a Rouse polymer in viscoelastic media. In addition, telomere trajectories show intermittent accumulations in local niches at physiological conditions, suggesting the surrounding chromatin to reorganize on these time scales. Reducing the temperature or exposing cells to osmotic stress resulted in a significant reduction of mobile telomeres and the number of visited niches. Altogether, our data indicate a vivid local chromatin dynamics, akin to a semi-dilute polymer solution, unless perturbations enforce a more rigid or entangled state of chromatin.

RevDate: 2022-06-22

Mao Y, G Zhang (2022)

Publisher Correction: A complete, telomere-to-telomere human genome sequence presents new opportunities for evolutionary genomics.

RevDate: 2022-06-22

Cozzolino M, E Seli (2022)

Mitochondrial dysfunction caused by targeted deletion of Mfn1 does not result in telomere shortening in oocytes.

Zygote (Cambridge, England) pii:S0967199422000089 [Epub ahead of print].

Telomere shortening during oocyte growth and development is related to reproductive ageing and infertility. The main mechanism involved in the maintenance of telomeres is based on telomerase activity, a specialized enzyme complex, which is capable of adding TTAGGG repeats at the ends of the chromosomes. Mitochondrial dysfunction may cause progressive shortening of telomeres by promoting the generation of reactive oxygen species. Mitofusin-1 is a protein required for mitochondrial fusion. Mice with the mitofusin-1 (Mfn1) deletion in the oocyte are characterized by accelerated follicular depletion and infertility, associated with defective oocyte maturation and follicular development. We hypothesized whether mitochondrial dysfunction in oocytes with targeted deletion of Mfn1 causes telomere shortening. We analyzed telomere length in oocyte and somatic cells in 3-, 6- and 9-month-old Mfn1-/- and wild-type mice. Immunofluorescence in oocyte mice of TRF1 and H2A.X was assessed to evaluate the interplay between the end-protection functions and the response to DNA damage occurring inside the telomeric repeats. Mitochondrial dysfunction due to the deletion of Mfn1 does not seem to affect telomere length in mouse oocytes.

RevDate: 2022-06-20

Courtney MG, Roberts J, K Godde (2022)

Author Correction: How social/environmental determinants and inflammation affect salivary telomere length among middle-older adults in the health and retirement study.

Scientific reports, 12(1):10195 pii:10.1038/s41598-022-14839-x.

RevDate: 2022-06-17

Guérin C, Crestani B, Dupin C, et al (2022)

[Telomeres and lung].

Revue des maladies respiratoires pii:S0761-8425(22)00161-9 [Epub ahead of print].

Genetic studies of familial forms of interstitial lung disease (ILD) have led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) in approximately 30% of familial ILD forms. ILD patients with TRG mutation are also subject to extra-pulmonary (immune-hematological, hepatic and/or mucosal-cutaneous) manifestations. TRG mutations may be associated not only with idiopathic pulmonary fibrosis (IPF), but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis (HP). The presence of TRG mutation may also be associated with an accelerated decline of forced vital capacity (FVC) or poorer prognosis after lung transplantation, notwithstanding which, usual ILD treatments may be proposed. Lastly, patients and their relatives are called upon to reduce their exposure to environmental lung toxicity, and are likely to derive benefit from specific genetic counseling and pre-symptomatic genetic testing.

RevDate: 2022-06-20

Qin S, Chen X, Xu Z, et al (2022)

Telomere G-triplex lights up Thioflavin T for RNA detection: new wine in an old bottle.

Analytical and bioanalytical chemistry [Epub ahead of print].

Few reports are found working on the features and functions of the human telomere G-triplex (ht-G3) though the telomere G-quadruplex has been intensely studied and widely implemented to develop various biosensors. We herein report that ht-G3 lights up Thioflavin T (ThT) and establish a sensitive biosensing platform for RNA detection by introducing a target recycling strategy. An optimal condition was selected out for ht-G3 to promote ThT to generate a strong fluorescence. Accordingly, an ht-G3-based molecular beacon was successfully designed against the corresponding RNA sequence of the SARS-CoV-2 N-gene. The sensitivity for the non-amplified RNA target achieves 0.01 nM, improved 100 times over the conventional ThT-based method. We believe this ht-G3/ThT-based label-free strategy could be widely applied for RNA detection.

RevDate: 2022-06-21
CmpDate: 2022-06-21

Hu L, Zhang Q, Bai Y, et al (2022)

Triglyceride-Glucose Index Correlate With Telomere Length in Healthy Adults From the National Health and Nutrition Examination Survey.

Frontiers in endocrinology, 13:844073.

Aim: The present investigation was designed to test the association between leukocyte telomere length (LTL) and two simple markers of insulin resistance, that is, homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride-glucose (TyG) index in U.S. adults without metabolic diseases.

Methods: A total of 6489 U.S. adults without diabetes from NHANES 1999-2002 were analyzed. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. HOMA-Index was calculated as fasting plasma glucose (mmol/L) × fasting serum insulin (mU/mL)/22.5. LTL was obtained using the quantitative polymerase chain reaction method. Multivariate linear regression analysis was assessed to evaluate the association of TyG index HOMA-IR with LTL. We further conducted a generalized additive model (GAM) and a fitted smoothing curve with penalized spline method.

Results: It was found that the mean LTL was 5796.1 bp in the measured healthy adults. Overall, TyG index was significantly associated with LTL, while HOMA-IR was not. Compared with participants in tertile 1 of the TyG index, the β (95% CI) for those in the second (8.27 to 8.77) and third (≥ 8.77) were -4.31 (95% CI: -48.12~39.49) and -95.98 (95% CI: -145.08~-46.89), respectively. Subjects with TyG index ≥ 8.77 had statistically significant shorter LTL (β = -93.33, 95%CI: -134.33~-52.32), compared with TyG index < 8.77. We further explored a dose-response relation between TyG index by a decile approach [≤ 7.81 (reference), 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, 8.52-8.68, 8.68-8.83, 8.83-9.03, 9.03-9.33, and >9.33] and LTL. Five subgroups (TyG index 7.81-8.04, 8.04-8.21, 8.21-8.37, 8.37-8.52, and 8.52-8.68) did not show significant effect on LTL; while there was a significantly shorter LTL for participants with the TyG index > 8.68, supporting a threshold effect of TyG index on LTL.

Conclusions: The results suggested that higher TyG index (> 8.68) was closely related to shorter LTL and the TyG index was better associated with LTL than HOMA-IR.

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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.

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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.

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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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