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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 25 Sep 2022 at 02:11 Created: 


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.

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Citations The Papers (from PubMed®)


RevDate: 2022-09-23

Revy P, Kannengiesser C, AA Bertuch (2022)

Genetics of human telomere biology disorders.

Nature reviews. Genetics [Epub ahead of print].

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.

RevDate: 2022-09-23

Wight DJ, Aimola G, Beythien G, et al (2022)

Impact of Host Telomere Length on HHV-6 Integration.

Viruses, 14(9): pii:v14091864.

Human herpesvirus 6A and 6B are two closely related viruses that infect almost all humans. In contrast to most herpesviruses, HHV-6A/B can integrate their genomes into the telomeres during the infection process. Both viruses can also integrate in germ cells and subsequently be inherited in children. How HHV-6A/B integrate into host telomeres and the consequences of this remain a subject of active research. Here, we developed a method to measure telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. This method was validated using a panel of HeLa cells having short or long telomeres. These cell lines were infected with HHV-6A, revealing that the virus could efficiently integrate into telomeres independent of their length. Furthermore, we assessed the telomere lengths after HHV-6A integration and found that the virus-containing telomeres display a variety of lengths, suggesting that either telomere length is restored after integration or telomeres are not shortened by integration. Our results highlight new aspects of HHV-6A/B biology and the role of telomere length on virus integration.

RevDate: 2022-09-23

Ogłuszka M, Lipiński P, RR Starzyński (2022)

Effect of Omega-3 Fatty Acids on Telomeres-Are They the Elixir of Youth?.

Nutrients, 14(18): pii:nu14183723.

Telomeres are complexes consisting of tandem repeat DNA combined with associated proteins that play a key role in protecting the ends of chromosomes and maintaining genome stability. They are considered a biological clock, as they shorten in parallel with aging. Furthermore, short telomeres are associated with several age-related diseases. However, the variability in telomere shortening independent of chronological age suggests that it is a modifiable factor. In fact, it is regulated inter alia by genetic damage, cell division, aging, oxidative stress, and inflammation. A key question remains: how can we prevent accelerated telomere attrition and subsequent premature replicative senescence? A number of studies have explored the possible impact of omega-3 fatty acids on telomere shortening. This review summarizes published cross-sectional studies, randomized controlled trials, and rodent studies investigating the role of omega-3 fatty acids in telomere biology. It also covers a broad overview of the mechanism, currently favored in the field, that explains the impact of omega-3 fatty acids on telomeres-the food compound's ability to modulate oxidative stress and inflammation. Although the results of the studies performed to date are not consistent, the vast majority indicate a beneficial effect of omega-3 fatty acids on telomere length.

RevDate: 2022-09-23

Liutkeviciene R, Mikalauskaite R, Gedvilaite G, et al (2022)

Relative Leukocyte Telomere Length and Telomerase Complex Regulatory Markers Association with Leber's Hereditary Optic Neuropathy.

Medicina (Kaunas, Lithuania), 58(9): pii:medicina58091240.

Background and Objectives: To evaluate the association of relative leukocyte telomere length (RLTL) and telomerase complex regulatory markers with Leber's hereditary optic neuropathy (LHON). Material and Methods: A case-control study was performed in patients with LHON (≥18 years) and healthy subjects. The diagnosis of LHON was based on a genetic blood test (next-generation sequencing with Illumina MiSeq, computer analysis: BWA2.1 Illumina BaseSpace, Alamut, and mtDNA Variant analyzer 1000 were performed) and diagnostic criteria approved by the LHON disease protocol. Statistical analysis was performed using the standard statistical software package, IBM SPSS Statistics 27. Statistically significant results were considered when p < 0.05. Results: Significantly longer RLTL was observed in LHON patients than in healthy controls (p < 0.001). RLTL was significantly longer in women and men with LOHN than in healthy women and men in the control group (p < 0.001 and p = 0.003, respectively). In the elderly group (>32 years), RLTL was statistically significantly longer in LHON patients compared with healthy subjects (p < 0.001). The GG genotype of the TERC rs12696304 polymorphism was found to be statistically significantly higher in the LHON group (p = 0.041), and the C allele in the TERC rs12696304 polymorphism was found to be statistically significantly less common in the LHON group (p < 0.001). The RLTL of LHON patients was found to be statistically significantly longer in the TERC rs12696304 polymorphism in all tested genotypes (CC, p = 0.005; CG, p = 0.008; GG, p = 0.025), TEP1 rs1760904 polymorphism in the GA genotype (p < 0.001), and TEP1 gene rs1713418 in the AA and AG genotypes (p = 0.011 and p < 0.001, respectively). Conclusions: The RLTL in LHON patients was found to be longer than in healthy subjects regardless of treatment with idebenone. The TERC rs12696304 polymorphism, of all studied polymorphisms, was the most significantly associated with changes in LHON and telomere length.

RevDate: 2022-09-23

Jenner LP, Peska V, Fulnečková J, et al (2022)

Telomeres and Their Neighbors.

Genes, 13(9): pii:genes13091663.

Telomeres are essential structures formed from satellite DNA repeats at the ends of chromosomes in most eukaryotes. Satellite DNA repeat sequences are useful markers for karyotyping, but have a more enigmatic role in the eukaryotic cell. Much work has been done to investigate the structure and arrangement of repetitive DNA elements in classical models with implications for species evolution. Still more is needed until there is a complete picture of the biological function of DNA satellite sequences, particularly when considering non-model organisms. Celebrating Gregor Mendel's anniversary by going to the roots, this review is designed to inspire and aid new research into telomeres and satellites with a particular focus on non-model organisms and accessible experimental and in silico methods that do not require specialized equipment or expensive materials. We describe how to identify telomere (and satellite) repeats giving many examples of published (and some unpublished) data from these techniques to illustrate the principles behind the experiments. We also present advice on how to perform and analyse such experiments, including details of common pitfalls. Our examples are a selection of recent developments and underexplored areas of research from the past. As a nod to Mendel's early work, we use many examples from plants and insects, especially as much recent work has expanded beyond the human and yeast models traditional in telomere research. We give a general introduction to the accepted knowledge of telomere and satellite systems and include references to specialized reviews for the interested reader.

RevDate: 2022-09-23

Konstantinidou F, Budani MC, Marconi GD, et al (2022)

The Aftermath of Long-Term Cigarette Smoking on Telomere Length and Mitochondrial DNA Copy Number in Human Cumulus Cells Prior to In Vitro Fertilization-A Pilot Study.

Antioxidants (Basel, Switzerland), 11(9): pii:antiox11091841.

Cigarette smoking among women of reproductive age is known to take a toll on systemic health and fertility potential by severely impacting ovarian tissues and cells, such as granulosa and cumulus cells (CCs). The purpose of this study was to determine the potential damage caused by tobacco smoke at a molecular level in the CCs of females who had undergone in vitro fertilization. The level of intracellular damage was determined by estimating the average telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN), as well as the expression profile of telomere maintenance genes TERF1, TERF2, POT1 and microRNAs miR-155, miR-23a and miR-185. Western blotting analysis was performed to detect consequent protein levels of TERF1, TERF2 and POT1. Our results evidenced significantly lower relative TL and mtDNA-CN and a down-regulation pattern for all three described genes and corresponding proteins in the CCs of smokers compared with controls (p < 0.05). No significant differences were found in the miRNAs' modulation. Combined, our data add another piece to the puzzle of the complex regulatory molecular networks controlling the general effects of tobacco smoke in CCs. This pilot study extends the until now modest number of studies simultaneously investigating the mtDNA-CN and TL pathways in the human CCs of smoking women.

RevDate: 2022-09-22

Chandyo RK, Schwinger C, Kvestad I, et al (2022)

The association between household biomass fuel use and leukocyte telomere length among toddlers in Bhaktapur, Nepal.

Journal of exposure science & environmental epidemiology [Epub ahead of print].

BACKGROUND: Biomass fuels are still in use for cooking by many households in resource poor countries such as Nepal and is a major source of household air pollution (HAP). Chronic exposure to HAP has been shown to be associated with shorter telomere length in adults.

OBJECTIVES: To measure the association between exposure related to household biomass fuel in infancy and leukocyte telomere length (LTL) at 18-23 months of age among 497 children from Bhaktapur, Nepal.

METHODS: In a prospective cohort study design, we have collected information on household cooking fuel use and several clinical, anthropometric, demographic, and socioeconomic variables. We estimated the association between biomass fuel use and the relative LTL in multiple linear regression models.

RESULTS: Most of the families (78%) reported liquified petroleum gas (LPG) as the primary cooking fuel, and 18.7% used biomass. The mean relative (SD) LTL was 1.03 (0.19). Children living in households using biomass fuel had on average 0.09 (95% CI: 0.05 to 0.13) units shorter LTL than children in households with no biomass fuel use. The observed association was unaltered after adjusting for relevant confounders. The association between LTL and biomass use was strongest among children from households with ≤2 rooms and without separate kitchen.

SIGNIFICANCE: Exposure to biomass fuel use in early life might have consequences for longevity, and risk of chronic illnesses reflected in shortening of the telomeres. Our findings support the ongoing effort to reduce exposure to biomass fuel in low-resource settings.

IMPACT STATEMENTS: Biomass for cooking is a leading source of household air pollution in low and middle-income countries, contributing to many chronic diseases and premature deaths. Chronic exposure to biomass fuel through oxidative stress and inflammation has been associated with a shortening of the telomeres, a "biological marker" of longevity. This prospective cohort study describes the association between household biomass fuel use and leukocyte telomere length among 497 toddlers. Leukocyte telomere length was significantly shorter among children living in households with biomass fuel than in children from homes where mainly LPG was used for cooking.

CLINICAL TRIAL REGISTRATION: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014).

RevDate: 2022-09-22

Verma AK, Singh P, Al-Saeed FA, et al (2022)

Unravelling the role of telomere shortening with ageing and their potential association with diabetes, cancer, and related lifestyle factors.

Tissue & cell, 79:101925 pii:S0040-8166(22)00197-5 [Epub ahead of print].

Telomeres are often considered as the 'ageing clock' that determines the lifespan at the cellular level, forming the ends of a chromosome, which shorten each time the cell divides itself to the point where they become so short the cell is unable to divide itself further. Telomere length alteration is often linked with lifestyle factors such as age, obesity, exposure to pesticides and pollution, depression, unhealthy diet, lack of exercise, and stress. The current review discusses the mechanism of telomere shortening in relation to ageing and lifestyle factors in general and its association with chronic diseases like diabetes which may influence the health and lifespan of an individual by increasing telomere shortening. Accelerated or excessive telomere shortening is also associated with the early onset of age-related disorders globally and, hence, reduced lifespan of individuals. Upregulated Telomerase activity and reactivation of telomeres is observed in > 70 % of cancer patients by TERT point mutations, rearrangements, DNA amplifications, and transcript fusions, making it a useful marker in diagnosis and prognosis of various cancers. The study presents a systematic review of the unregulated Telomere activity with progression of various cancer and extrapolation of suitable pathways and prognostic information correlated with mRNA levels of TERT, which are critical among thymic epithelial tumors (TETs). In most cancers, unlimited proliferation is due to the reactivation of reverse transcriptase gene TERT. All these observations are comprehensively presented in the paper and might be useful for researchers working in the field of telomere dynamics and finding the correlation of age shortening with mRNA expression profiling.

RevDate: 2022-09-22

Chico-Sordo L, Polonio AM, Córdova-Oriz I, et al (2022)

Telomeres and oocyte maturation rate are not reduced by COVID-19 except in severe cases.

Reproduction (Cambridge, England) pii:REP-22-0243 [Epub ahead of print].

The coronavirus SARS-CoV-2 causes the COVID-19 disease and affects primarily the lungs, but also other organs, causing accelerated cell aging. One of main pathways involved in aging is telomere attrition, which ultimately leads to defective tissue regeneration and organ dysfunction. Indeed, short telomeres in aged people aggravate the COVID-19 symptoms and, COVID-19 survivors showed shorter telomeres in blood cells. The SARS-CoV-2 has been detected in testis, but the ovaries, which express the viral entry factors, have not been fully explored. Our objective was the analysis of telomeres and reproductive outcomes in women who had COVID-19 and controls. In this prospective cohort study, granulosa cells (GCs) and blood were collected from 65 women. Telomere length (TL) was measured by high-throughput in situ hybridization. Mean TL of GCs and peripheral blood mononuclear cells (PBMCs) was alike in control and mild cases. However, mean TL of GCs was lower in severe cases compared to controls (p=0.017). Control and COVID groups had similar ovarian reserve and number of total oocytes after puncture. However, the oocyte maturation rate was lower in severe cases (p= 0.018). Interestingly, a positive correlation between the oocyte maturation rate and TL of GCs was found in the control group (p=0.024). Our findings point to a potential impact of the coronavirus infection on telomeres and reproductive outcomes in severe cases. This might be considered upon possible new SARS-CoV threats, to favor treatments that enhance oocyte maturation in women severely affected by coronavirus undergoing ART.

RevDate: 2022-09-21

McKinney AM, Mathur R, Stevers NO, et al (2022)

GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer.

Cell reports, 40(12):111344.

Telomerase activation counteracts senescence and telomere erosion caused by uncontrolled proliferation. Epidermal growth factor receptor (EGFR) amplification drives proliferation while telomerase reverse transcriptase promoter (TERTp) mutations underlie telomerase reactivation through recruitment of GA-binding protein (GABP). EGFR amplification and TERTp mutations typically co-occur in glioblastoma, the most common and aggressive primary brain tumor. To determine if these two frequent alterations driving proliferation and immortality are functionally connected, we combine analyses of copy number, mRNA, and protein data from tumor tissue with pharmacologic and genetic perturbations. We demonstrate that proliferation arrest decreases TERT expression in a GABP-dependent manner and elucidate a critical proliferation-to-immortality pathway from EGFR to TERT expression selectively from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and GABP upregulation. EGFR-AMPK signaling promotes telomerase activity and maintains telomere length. These results define how the tumor cell immortality mechanism keeps pace with persistent oncogene signaling and cell cycling.

RevDate: 2022-09-21

Seo B, Yang K, Kahe K, et al (2022)

Association of omega-3 and omega-6 fatty acid intake with leukocyte telomere length in US males.

The American journal of clinical nutrition pii:6708365 [Epub ahead of print].

BACKGROUND: Omega-3 (n-3) and omega-6 (n-6) fatty acids may contribute to oxidative stress and inflammation, which are related to telomere shortening. Evidence supporting an association between intake of n-3 or n-6 fatty acids and leukocyte telomere length (LTL) in males has been limited.

OBJECTIVE: We conducted a cross-sectional study to examine the associations of total or individual n-3 or total n-6 fatty acid intake with LTL in US males.

METHODS: We included 2,494 US males with LTL measurement from 4 nested case-control studies within the Health Professionals Follow-up Study. Individuals with previous histories of cancers, diabetes, and cardiovascular diseases at or prior to blood collection were excluded. Blood collection was performed between 1993 and 1995, and relevant information including n-3 and n-6 intake was collected in 1994 by questionnaire. The LTL was log-transformed and Z scores of the LTL were calculated for statistical analyses by standardizing the LTL in comparison with the mean within each selected nested case-control study.

RESULTS: We found that consumption of docosahexaenoic acid (DHA) was positively associated with LTL. In the multivariable-adjusted model, compared to individuals who had the lowest intake of DHA (i.e., first quartile group), the percentage differences [95% confidence intervals (CIs)] of LTL were -3.7 (-13.7, 7.5), 7.0 (-4.3, 19.7), and 8.2 (-3.5, 21.3) for individuals in the second, third, and fourth quartiles of consumption, respectively (P for trend = 0.0498). We did not find significant associations between total n-3 or total n-6 fatty acid intakes and LTL. Additionally, we found that males who consumed canned tuna had longer LTL than those who did not; in the multivariable-adjusted model, the percentage difference (95% CI) of LTL was 10.5 (1.3, 20.4) (P value = 0.02).

CONCLUSIONS: Our results suggest that higher intakes of DHA and canned tuna consumption are associated with longer LTL.

RevDate: 2022-09-20

Foley JF (2022)

Telomeres to go.

Science signaling, 15(752):eade9136.

By acquiring telomeres from antigen-presenting cells, some T cells are protected from senescence.

RevDate: 2022-09-20

Tian C, Heng D, Zhao N, et al (2022)

Short telomeres impede germ cell specification by upregulating MAPK and TGFβ signaling.

Science China. Life sciences [Epub ahead of print].

Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFβ and MAPK/ERK signaling for somatic cell differentiation. Notably, elevated Fst expression in TGFβ pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Re-elongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFβ and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFβ and MAPK signaling.

RevDate: 2022-09-20

Park HS, Son BR, J Kwon (2022)

Usefulness of Genetic Aberration and Shorter Telomere Length in Myelodysplastic Syndrome: A Pilot Study.

Laboratory medicine pii:6705954 [Epub ahead of print].

OBJECTIVE: We aimed to evaluate the clinical usefulness of genetic aberration and shorter telomere length (TL) in individuals with myelodysplastic syndrome (MDS).

METHODS: A targeted sequencing panel with 49 genes and TL measurement by quantitative real-time polymerase chain reaction were performed for 46 subjects.

RESULTS: According to the revised International Prognostic Scoring System (IPSS-R) subtypes, the mutation frequency was 33.3%, 57.9%, and 100% in the very low/low, intermediate, and very high/high risk groups, respectively. A shorter telomere was detected in 43.5%. We defined group 1 as IPSS-R-high or -very high risk, group 2 as having 1 or more genetic aberrations, group 3 as having a shorter TL, and group 4 as having a longer TL than the age-matched reference. Group 1 and group 2 showed an adverse prognosis. The TL was not strongly correlated with MDS prognosis. However, it may be related to a poor long-term prognosis.

CONCLUSION: Genetic variation and shorter TL may be helpful in reclassifying non-high-risk groups.

RevDate: 2022-09-19

Silva B, Arora R, CM Azzalin (2022)

The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted.

Proceedings of the National Academy of Sciences of the United States of America, 119(39):e2208669119.

A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy.

RevDate: 2022-09-20

Sharqawi M, Hantisteanu S, Bilgory A, et al (2022)

The Impact of Lifestyle on Sperm Function, Telomere Length, and IVF Outcomes.

American journal of men's health, 16(5):15579883221119931.

Many risk factors can potentially influence sperm quality. Telomeres confer stability on the chromosome and their dysfunction has been implicated in conditions such as cancer, aging, and lifestyle. The impact of lifestyle on sperm cell telomeres is unclear. The objectives of this study were to evaluate the impact of lifestyle behaviors on telomere length in sperm and to follow the correlation with pregnancy outcomes in patients undergoing in vitro fertilization (IVF). In this prospective observational study, sperm was analyzed for telomere length (TL). Men were asked to report lifestyle behaviors including occupation (physical or sedentary), smoking duration and amount, physical activity, dietary habits, and where they keep their cellular phone (bag, pants, or shirt pocket). Correlations among semen analysis, TL, men's habits, and embryo quality and pregnancy outcomes were evaluated. Among 34 patients recruited, 12 had longer TL and 13 shorter TL. Sperm motility was negatively correlated with TL (Pearson correlation = -.588, p = .002). Smoking adversely affected native sperm motility (53% motility in nonsmokers vs. 37% in smokers; p = .006). However, there was no significant impact on TL. The group with longer telomeres demonstrated significant association with healthy diet (10/12 vs. 6/13; p = .05) and a trend toward more sports activity, weekly (16/84 vs. 7/91; p = .04) compared with the shorter telomeres group. This study suggests that lifestyle, healthy diet, and sports activity are associated with long telomeres in sperm. Sperm quality is also influenced by patients' habits. The study strongly recommends maintaining a healthy lifestyle to preserve general health and fertility.

RevDate: 2022-09-20

Kazantseva AV, Davydova YD, Enikeeva RF, et al (2022)

Individual Differences in Relative Telomere Length in Mentally Healthy Subjects: The Effect of TERT Gene Polymorphism and Urban Residency.

Russian journal of genetics, 58(9):1135-1144.

The changes in the telomere length caused by the terminal underreplication in the existing literature are related to depressive disorders. However, the use of the telomere length as a biomarker of depressive states is ambiguous, which is due to the effect of various environmental factors on both the psychoemotional state and cellular aging of an organism. In order to identify the possible use of the relative telomere length (RTL) measured in peripheral blood leukocytes as a biomarker of enhanced liability to depression prior to the clinical symptoms, as well as to determine the link between telomere length, sociodemographic factors, allelic variants of the genes involved in the regulation of telomere elongation, and depression level, the association analysis of reverse transcriptase (TERT rs7726159), telomerase RNA component (TERC rs1317082), and the CST complex encoding protein (OBFC1 rs2487999) gene polymorphisms was performed with RTL and depression level in mentally healthy individuals (N = 1065) aged 18-25 years. Together with genetic variants, the examined regression models included various sociodemographic parameters as predictors. As a result of statistical analysis, we failed to observe the association between RTL and individual differences in depression level in the studied sample. Nevertheless, multiple regression analysis allowed us to construct a statistically significant model of individual variance in RTL (P = 4.3е-4; r 2 = 0.018), which included rs7726159 in the TERT gene (P = 0.020; β = 0.078) and such environmental predictors as age (P = 0.001; β = -0.027) and place of residence in childhood (urban/rural area) (P = 0.048; β = 0.063). The data obtained confirm the involvement of TERT gene variants and age in telomere length in mentally healthy individuals aged 18-25 years and indicate a negative effect of urban residency on telomere length shortening, which reflects the cellular aging of an organism.

RevDate: 2022-09-18

Saini D, Jain V, B Das (2022)

Evaluation of natural chronic low dose radiation exposure on telomere length and transcriptional response of shelterin complex in individuals residing in Kerala coast, India.

Mutation research, 825:111797 pii:S0027-5107(22)00024-0 [Epub ahead of print].

The high level natural radiation areas (HLNRA) of Kerala coast provide unique opportunity to study the biological effect of chronic low dose ionizing radiation (LDIR) on human population below 100 mSv. The radiation level in this area varies from < 1.0-45 mGy /year due to patchy distribution of monazite in the sand, which contains 232Th (8-10%), 238U (0.3%), and their decay products. Telomere length attrition has been correlated to DNA damage due to genotoxic agents. The objective of the present study is to evaluate the effect of natural chronic LDIR exposure on telomere length and transcriptional response of telomere specific and DNA damage repair genes in peripheral blood mononuclear cells (PBMCs) of individuals from normal level natural radiation areas (NLNRA) and HLNRA of Kerala coast, southwest India. Blood samples were collected from 71 random male donors (24-80 years) from NLNRA (≤1.50 mGy/year; N = 19) and two HLNRA dose groups [1.51-10 mGy/year (N = 17); > 10 mGy/year, (N = 35)]. Genomic DNA was isolated from PBMCs and relative telomere length (RTL) was determined using real time q-PCR. Radio-adaptive response (RAR) study was carried out in PBMCs of 40 random males from NLNRA (N = 20) and HLNRA (>10 mGy/year; N = 20), where PBMCs were given a challenged dose of 2.0 Gy gamma radiation at 4 h. Transcriptional profile of telomere specific (TRF1, TRF2, POT1, TIN2, TPP1, RAP1), DNA damage response (RAD17, ATM, CHEK1) and base excision repair pathway (BER) (OGG1, XRCC1, NTH1, NEIL1, MUTYH, MBD4) genes were analysed at basal level and after a challenge dose of 2.0 Gy at 4 h. Our results did not show any significant effect of chronic LDR on RTL among the individuals from NLNRA and two HLNRA groups (p = 0.195). However, influence of age on RTL was clearly evident among NLNRA and HLNRA individuals. At basal level, TRF1, TRF2, TIN2, MBD4, NEIL1 and RAD17 showed significant up-regulation, whereas XRCC1 was significantly down regulated in HLNRA individuals. After a challenge dose of 2.0 Gy, significant transcriptional up-regulation was observed at telomere specific (TRF2, POT1) and BER (MBD4, NEIL1) genes in HLNRA individuals as compared to NLNRA suggesting their role in RAR. In conclusion, elevated level of natural chronic LDR exposure did not have any adverse effect on telomere length in Kerala coast. Significant transcriptional response at TRF2, MBD4 and NEIL1 at basal level and with a challenge dose of 2.0 Gy suggested their active involvement in efficient repair and telomere maintenance in individuals from HLNRA of Kerala coast.

RevDate: 2022-09-17

Panelli DM, Diwan M, Cruz GI, et al (2022)

An exploratory analysis of leukocyte telomere length among pregnant and non-pregnant people.

Brain, behavior, & immunity - health, 25:100506.

Background: Leukocyte telomere length (LTL) is a biomarker that is affected by older age, psychosocial stress, and medical comorbidities. Despite the relevance of these factors to obstetric practice, little is known about LTL in pregnancy. Our study explored longitudinal LTL dynamics in pregnant and non-pregnant people.

Objective: This pilot study compares changes in LTL between pregnant and non-pregnant people over time, explores potential correlations between LTL and mental health measures, and investigates associations between short first-trimester LTL and adverse pregnancy outcomes.

Study design: This was a prospective pilot cohort study of nulliparous pregnant and non-pregnant people between ages 18 and 50 who presented for care at a single institution from January to November 2020. Pregnant people were enrolled between 10 and 14 weeks gestation. Participants had two blood samples drawn for LTL; the first on the day of enrollment and the second on postpartum day 1 (pregnant cohort) or 7 months later (non-pregnant cohort). LTL was measured using quantitative PCR. The primary outcome was the difference between pregnant and non-pregnant people in LTL change between the two timepoints (basepair difference per 30-day period). Secondary outcomes included differences in responses to the Patient Health Questionnaire-9 (PHQ-9) and a survey about stress related to COVID-19. Differences in LTL were tested using t-tests and linear regression models, both crude and adjusted for age. A subgroup analysis was conducted within the pregnant cohort to examine whether shorter first-trimester LTL was associated with adverse pregnancy outcomes. We conducted t-tests to compare LTL between people with and without each categorical outcome and computed Pearson correlation coefficients between LTL and continuous outcomes such as gestational age at delivery.

Results: 46 pregnant and 30 non-pregnant people were enrolled; 44 pregnant and 18 non-pregnant people completed all LTL assessments. There were no between-group differences in LTL change (-4.2 ± 22.2 bp per 30 days pregnant versus -6.4 ± 11.2 bp per 30 days non-pregnant, adjusted beta 2.1, 95% CI -9.0-13.2, p = 0.60). The prevalence of depression and pandemic-related stress were both low overall. The two groups did not differ in PHQ-9 scores, and no correlations were significant between LTL and PHQ-9 scores. Among the 44 pregnant people, shorter first-trimester LTL was significantly correlated with earlier gestational age at delivery (r = 0.35, p = 0.02).

Conclusion: In this exploratory pilot cohort of reproductive-aged people with low levels of psychological stress, we described baseline changes in LTL over time in pregnant and non-pregnant participants. We found a correlation between shorter first-trimester LTL and earlier gestational age at delivery, which warrants further investigation in a larger cohort.

RevDate: 2022-09-15

Lanna A, Vaz B, D'Ambra C, et al (2022)

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.

Nature cell biology [Epub ahead of print].

The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.

RevDate: 2022-09-18
CmpDate: 2022-09-16

Bowyer P, Currin A, Delneri D, et al (2022)

Telomere-to-telomere genome sequence of the model mould pathogen Aspergillus fumigatus.

Nature communications, 13(1):5394.

The pathogenic fungus Aspergillus fumigatus is a major etiological agent of fungal invasive and chronic diseases affecting tens of millions of individuals worldwide. Draft genome sequences of two clinical isolates (Af293 and A1163) are commonly used as reference genomes for analyses of clinical and environmental strains. However, the reference sequences lack coverage of centromeres, an accurate sequence for ribosomal repeats, and a comprehensive annotation of chromosomal rearrangements such as translocations and inversions. Here, we used PacBio Single Molecule Real-Time (SMRT), Oxford Nanopore and Illumina HiSeq sequencing for de novo genome assembly and polishing of two laboratory reference strains of A. fumigatus, CEA10 (parental isolate of A1163) and its descendant A1160. We generated full length chromosome assemblies and a comprehensive telomere-to-telomere coverage for CEA10 and near complete assembly of A1160 including ribosomal repeats and the sequences of centromeres, which we discovered to be composed of long transposon elements. We envision these high-quality reference genomes will become fundamental resources to study A. fumigatus biology, pathogenicity and virulence, and to discover more effective treatments against diseases caused by this fungus.

RevDate: 2022-09-14

Barbosa ARC, Nunes DP, Lima DB, et al (2022)

Association of social support network with telomere length: A cross-sectional study with community-dwelling older adults.

Rejuvenation research [Epub ahead of print].

Considering that telomere length can be determined not only by issues related to cell biology, but also by aspects related to social factors and environmental exposures, studies on the relationship between social aspects and telomere length can help to better understand the still little-known aspects of the human aging process. Thus, this research seeks to verify whether social support network is associated with telomere length in older adults. This is a cross-sectional study conducted with 448 individuals aged 60 years or older living in the urban area of a municipality in Brazil's countryside. The relative quantification of telomere length was obtained through real-time qPCR. Social support was assessed through the Medical Outcomes Study Social Support Scale. Descriptive statistics and multiple logistic regression were used in the data analysis. The evaluated social support networks for older adults are composed, on average, of 16.4 people and the percentage of older adults who reported up to five members in the network was 27.75%. The shorter telomere length was identified in 25% of the participants, and older adults who reported having up to five members in the support network were more likely to have shorter telomere length than the ones who reported more numerous networks (OR: 1.89, p=0.011), regardless of gender, age, household arrangement, cognitive decline and dependence for basic and instrumental activities of daily life, which suggests that measures that stimulate the creation and maintenance of social support networks should be implemented in order to improve the health of the older adults.

RevDate: 2022-09-21

Liu Z, Wei X, Gao Y, et al (2022)

Zbtb34 promotes embryonic stem cell proliferation by elongating telomere length.

Aging, 14(17):7126-7136.

Zbtb34 is a novel zinc finger protein, which is revealed by biological software analysis to have 3 zinc fingers, but its functions remain unknown. In this study, mouse Zbtb34 cDNA was amplified by PCR and inserted into the plasmid pEGFP-N1 to generate Zbtb34-EGFP fusion protein. The upregulation of Zbtb34 in mouse embryonic stem cells promoted telomere elongation and increased cell proliferation. In order to understand the above phenomena, the telomere co-immunoprecipitation technique was employed to investigate the relationship between Zbtb34 and telomeres. The results indicated that Zbtb34 could bind to the DNA sequences of the telomeres. Alanine substitution of the third zinc finger abolished such binding. Since Pot1 is the only protein binding to the single-stranded DNA at the end of the telomeres, we further investigated the relationship between Zbtb34 and Pot1. The results revealed that the upregulation of Zbtb34 decreased the binding of Pot1b to the telomeres. Through the upregulation of Pot1b, the binding of Zbtb34 to the telomeres was also reduced. In conclusion, we showed that the main biological function of Zbtb34 was to bind telomere DNA via its third ZnF, competing with Pot1b for the binding sites, resulting in telomere elongation and cell proliferation.

RevDate: 2022-09-13

Fiesco-Roa MÓ, García-de Teresa B, Leal-Anaya P, et al (2022)

Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability.

Frontiers in oncology, 12:949435.

Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.

RevDate: 2022-09-13
CmpDate: 2022-09-13

Svyryd Y, Pascual-Ramos V, Contreras-Yañez I, et al (2022)

Telomeres Length Variations in a Rheumatoid Arthritis Patients Cohort at Early Disease Onset and after Follow-Up.

Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion, 74(4):202-211.

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial joint inflammation, progressive disability, premature immune aging, and telomere length (TL) shortening.

Objectives: The objective of the study was to study TL changes in patients at early disease onset and after follow-up.

Methods: Relative leukocyte TL (rLTL) was measured by quantitative polymerase chain reaction (qPCR) in 88 at-admission patients (AAP) with < 1 year of symptoms onset, self-compared after follow-up, and a reference group of sex- and age-matched healthy individuals. Correlations between rLTL percentage change after variable disease exposure time (DET) and clinical laboratory disease activity markers and treatments were assessed. Non-parametrical statistics were applied, considering < 0.05 p-value significant.

Results: The median (p25, p75) rLTL was lower in patients after DET (0.61, 0.49-0.70) than in AAP (0.64, 0.50-0.77), p = 0.017. Furthermore, telomeres at early stages of RA were shorter than in the reference group (0.77, 0.59-0.92; p = 0.003). HLA-DRB1*04 allele carrier status did not significantly affect rLTL at an early stage and after follow-up. The patients' rLTL shortening was mainly associated with longer at-admission telomeres (OR 16.2, 95%CI: 3.5-74.4; p < 0.0001).

Conclusions: At follow-up, RA patients showed significantly shorter rLTL than AAP, particularly in those AAP with longer telomeres, disregarding disease activity and treatments, denoting an rLTL shortening effect influenced by age, DET, and native rLTL.

RevDate: 2022-09-12

Qureshi F, Aris IM, Rifas-Shiman SL, et al (2022)

Associations of cord blood leukocyte telomere length with adiposity growth from infancy to adolescence.

Pediatric obesity [Epub ahead of print].

OBJECTIVE: Leukocyte telomere length (LTL) may be a biomarker for chronic disease susceptibility, but no work has tested this hypothesis directly. Our study investigated associations of LTL at birth with markers of adiposity growth that are linked with cardiometabolic health later in life.

METHODS: Participants were 375 children in Project Viva (48% female, 71% White). Body mass index (BMI) trajectories from birth to 18 years were tracked using repeated measures of BMI collected in physical examinations and via medical records, then used to predict age (months) and magnitude (kg/m2) of BMI peak and rebound. LTL was measured from cord blood via duplex quantitative PCR. A binary variable indicating LTL shorter than the reference population average was the primary exposure.

RESULTS: LTL was unrelated to BMI at peak or rebound, but associations were apparent with the timing of BMI growth milestones. Short LTL was related to a later age of peak for females (β = 0.99, 95% CI = 0.16, 1.82; psex interaction = 0.015) and an earlier age of rebound for both males and females (βcombined = -5.26, 95% CI = -9.44, -1.08).

CONCLUSION: LTL at birth may be an early biomarker of altered adiposity growth. Newborn telomere biology may shed new insight into the developmental origins of health and disease.

RevDate: 2022-09-13
CmpDate: 2022-09-13

Montiel Ishino FA, Rowan CE, Villalobos K, et al (2022)

A Time-Varying Effect Model (TVEM) of the Complex Association of Tobacco Use and Smoke Exposure on Mean Telomere Length: Differences between Racial and Ethnic Groups Assessed in the National Health and Nutrition Examination Survey.

International journal of environmental research and public health, 19(17): pii:ijerph191711069.

Telomere length is affected by lifestyle and environmental factors and varies between racial and ethnic groups; however, studies are limited, with mixed findings. This study examined the effects of tobacco use and smoke exposure on mean telomere length to identify critical age periods by race/ethnicity. We used time-varying effect modeling on the National Health and Nutrition Examination Survey for continuous years 1999-2002 to observe the effects of active tobacco use and environmental tobacco smoke-measured through serum cotinine-and mean telomere length for adults 19 to 85 and older (N = 7826). Models were run for Mexican American, other Hispanic, non-Hispanic White, non-Hispanic Black, and other/multi-race categories to allow for time-varying group differences, and controlled for biological sex, socioeconomic status, education, and ever-smoker status. Serum cotinine was found to have an increasing effect on telomere length from age 37 to approximately age 74 among Mexican Americans. Among other/multi-race individuals serum cotinine was found to have a decreasing effect at approximately age 42, and among Blacks, it had an overall decreasing effect from age 61 to 78. Findings reveal a further need to focus additional support and resources to intervene regarding disparate health effects from tobacco use and environmental smoke exposure for already vulnerable groups at particular ages.

RevDate: 2022-09-13
CmpDate: 2022-09-12

Jitjumnong M, Chalermkitpanit P, Suantawee T, et al (2022)

Telomere Shortening and Increased Oxidative Stress in Lumbar Disc Degeneration.

International journal of molecular sciences, 23(17):.

Lumbar disc degeneration (LDD) contributes to low back pain. This study aimed to determine relative telomere length (RTL), oxidative stress status, and antioxidant levels and examine the relationships between RTL, oxidative stress, and the severity in LDD patients. A total of 100 subjects, 50 LDD patients and 50 healthy controls, were enrolled in the case-control study. Blood leukocyte RTL was analyzed using quantitative real-time polymerase chain reaction. Lipid peroxidation was determined by malondialdehyde (MDA) assay. Plasma 8-hydroxy 2'-deoxyguanosine (8-OHdG) values were determined using enzyme-linked immunosorbent assay. Total antioxidant capacity (TAC) and ferric reducing antioxidant power (FRAP) in plasma were also measured. The LDD patients had significantly shorter telomeres than the healthy controls (p = 0.04). Blood leukocyte RTL was inversely correlated with the LDD severity (r = -0.41, p = 0.005). Additionally, plasma MDA and 8-OHdG levels were markedly greater in LDD patients than in the controls (p = 0.01 and p = 0.002, respectively). Furthermore, the plasma MDA level showed a positive correlation with the radiographic severity (r = 0.49, p = 0.001). There was a positive correlation between plasma 8-OHdG and the severity (r = 0.60, p < 0.001). Moreover, plasma TAC and FRAP levels were significantly lower in LDD patients than in the controls (p = 0.04). No significant differences in plasma TAC and FRAP were observed among the three groups of LDD severity. We found that RTL was negatively correlated with the severity while plasma MDA and 8-OHdG levels were positively correlated with the severity. These findings suggest that blood leukocyte RTL, plasma MDA, and 8-OHdG may have potential as noninvasive biomarkers for the assessment of severity in LDD.

RevDate: 2022-09-13
CmpDate: 2022-09-13

Andrés V, J Díez (2022)

Failing Hypertensive Heart: a Question of Altered Telomere Biology?.

Hypertension (Dallas, Tex. : 1979), 79(10):2185-2187.

RevDate: 2022-09-08

Pölönen J, Pinola P, Ronkainen J, et al (2022)

Polycystic ovary syndrome and leukocyte telomere length: cross-sectional and longitudinal changes.

European journal of endocrinology pii:EJE-22-0462 [Epub ahead of print].

Objective Telomeres are DNA-protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular ageing. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardio-metabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population. Design Population-based cohort study: women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (PCOS) (age 31:N=190; age 46:N=207) and referent women (age 31:N=1054; age 46:N=1324) with data on LTL. Methods The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age. Results Women with PCOS had similar mean LTL at ages 31 and 46 (P>0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P=0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P<0.001), but not in women with PCOS (P=0.96). Conclusions This finding may suggest a difference in LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms.

RevDate: 2022-09-13

Faingelernt Y, Nassar R, Ling G, et al (2022)

Early-life liver cirrhosis and variable clinical presentation in telomere disease.

Acta paediatrica (Oslo, Norway : 1992) [Epub ahead of print].

AIM: Telomeres are DNA sequences of tandem TTAGGG repeats that protect chromosome ends from degradation and instability. Constitutional loss-of-function telomerase mutations result in rapid telomere shortening, premature senescence and cell death. Liver cirrhosis is rare and has only been reported in adults. We present five family members of Bedouin-Muslim origin, all of which carry the same mutation, and yet demonstrate an extremely variable phenotypical presentation, including liver cirrhosis during early childhood.

METHODS: A multidisciplinary long-term follow-up of two healthy and three affected patients was analysed. The mutation (r.95G>C) was identified in all patients using Sanger sequencing. Telomere length samples were obtained and analysed.

RESULTS: Clinical phenotypes were extremely variable, including age at first symptoms, organ involvement, disease severity and patient prognosis. The most prominent clinical phenotype is liver involvement, including end-stage liver disease early in life, which affects three members of the family. Affected patients had markedly shorter telomeres.

CONCLUSION: We describe an unusual presentation of early liver failure in telomere disease patients. Little, if any, is known about the association between the genotype and phenotype among children with telomere disease and whether the mutation we have described (r.95G>C) is predisposed to early severe hepatic involvement.

RevDate: 2022-09-21
CmpDate: 2022-09-08

Young RC, Westneat DF, Vangorder-Braid J, et al (2022)

Stressors interact across generations to influence offspring telomeres and survival.

Proceedings. Biological sciences, 289(1982):20220868.

Parental stress often has long-term consequences for offspring. However, the mechanisms underlying these effects and how they are shaped by conditions offspring subsequently experience are poorly understood. Telomeres, which often shorten in response to stress and predict longevity, may contribute to, and/or reflect these cross-generational effects. Traditionally, parental stress is expected to have negative effects on offspring telomeres, but experimental studies in captive animals suggest that these effects may depend on the subsequent conditions that offspring experience. Yet, the degree to which parental stress influences and interacts with stress experienced by offspring to affect offspring telomeres and survival in free-living organisms is unknown. To assess this, we experimentally manipulated the stress exposure of free-living parent and offspring house sparrows (Passer domesticus). We found a weak, initial, negative effect of parental stress on offspring telomeres, but this effect was no longer evident at the end of post-natal development. Instead, the effects of parental stress depended on the natural sources of stress that offspring experienced during post-natal development whereby some outcomes were improved under more stressful rearing conditions. Thus, the effects of parental stress on offspring telomeres and survival are context-dependent and may involve compensatory mechanisms of potential benefit under some circumstances.

RevDate: 2022-09-19

Assavanopakun P, Sapbamrer R, Kumfu S, et al (2022)

Effects of air pollution on telomere length: Evidence from in vitro to clinical studies.

Environmental pollution (Barking, Essex : 1987), 312:120096 pii:S0269-7491(22)01310-0 [Epub ahead of print].

Air pollution remains the major environmental problem globally. There is extensive evidence showing that the variety of air pollutants from environmental and occupational exposures cause adverse effects to our health. The clinical symptoms of those effects may present at a late stage, so surveillance is difficult to manage. Several biomarkers have been used for the early detection of health issues following exposure to air pollution, including the use of telomere length which indicates cellular senescence in response to oxidative stress. Oxidative stress is one of the most plausible mechanisms associated with exposure to air pollutants. Some specific contexts including age groups, gender, ethnicity, occupations, and health conditions, showed significant alterations in telomere length after exposure to air pollutants. Several reports demonstrated both negative and positive associations between telomere length and air pollution, the studies using different concentrations and exposure times to air pollution on the study of telomere lengths. Surprisingly, some studies reported that low levels of exposure to air pollutants (lower than regulated levels) caused the alterations in telomere length. Those findings suggest that telomere length could be one of most practical biomarkers in air pollution surveillance. Therefore, this review aimed to summarize and discuss the relationship between telomere length and exposure to air pollution. The knowledge from this review will be beneficial for the planning of public health to reduce health problems in the general population, particularly in vulnerable people, who still live in areas with high air pollution.

RevDate: 2022-09-12
CmpDate: 2022-09-08

Kato TA (2023)

Nontraditional Method for Telomere Staining by PNA Probes.

Methods in molecular biology (Clifton, N.J.), 2519:111-116.

The standard FISH uses DNA probes to hybridize to the designated complementary strands. This is DNA-DNA interaction, and it usually takes much longer time to obtain detectable signals compared to other reactions such as immunochemical reactions and simple chemical reactions. Certain proteins bind to specific DNA sequences and regulate the biological function of DNA. These DNA-binding proteins have specific domains to interact with single- or double-stranded DNA. Some of telomere proteins apparently bind to telomere sequence and form nucleoprotein complex to protect chromosome ends. Using telomere PNA probes, probes can be accumulated at the telomere sites in a non-hybridization manner. This chapter introduces nontraditional PNA telomere staining protocol without DNA-DNA hybridization to visualize telomere locations on metaphase chromosomes.

RevDate: 2022-09-12
CmpDate: 2022-09-08

Kato TA (2023)

Telomere Aberration Detection by PNA FISH Probe.

Methods in molecular biology (Clifton, N.J.), 2519:105-110.

Telomere is a structure of the end cap of chromosomes. Telomere gets shorter as cell aging and progressing cell division. Shorter telomere may cause telomere fusion, thus inducing genomic instability. Telomere dysfunction can be visualized by PNA FISH probe against telomere repeat sequence (TTAGGG)n. PNA probes have higher hybridization affinity than DNA probes. The traditional FISH or modified FISH protocol can stain telomere relatively easier than whole-chromosome painting probes. This chapter introduces PNA telomere FISH protocol to visualize telomere signals on metaphase chromosomes.

RevDate: 2022-09-13
CmpDate: 2022-09-08

Ghoussaini R, Tamim H, Elbejjani M, et al (2022)

C-peptide is a predictor of telomere shortening: A five-year longitudinal study.

Frontiers in endocrinology, 13:978747.

Aim: Relative telomere length (RTL) predicts the development of many age-related diseases. Yet, few studies have evaluated their longitudinal effect on RTL. We investigated longitudinally the association between cardiometabolic risk factors and RTL.

Methods: This was a longitudinal study with a 5-year follow-up period, based on data collected in 2014 and 2019. Of 478 participants in 2014, 198 consented to be followed-up in 2019. The associations between RTL and risk factors were analyzed using t-test, ANOVA or simple linear regression as applicable.

Results: RTL was significantly shortened after 5 years (P<0.001). Older age (P=0.018) and gender (P=0.05) were significantly associated with shorter RTL at follow-up. Higher baseline C-peptide correlated with shorter RTL (P=0.04) and shortening of RTL (P=0.03) after 5 years. Multivariate linear regression including both age and gender revealed a significant trend for C-peptide and change in RTL after 5 years (P=0.04). Interestingly, there was a trend of shorter RTL at follow-up with diabetes, though the findings were not statistically significant.

Conclusions: Higher C-peptide level contributes to telomere shortening over time, suggesting that metabolic dysregulation may play a role in early aging. Further understanding of this relationship and addressing high C-peptide levels can be important to prevent premature aging.

RevDate: 2022-09-05

Pan L, Tormey D, Bobon N, et al (2022)

Rap1 prevents fusions between long telomeres in fission yeast.

The EMBO journal [Epub ahead of print].

The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length regulation. Previous studies have addressed how fission yeast Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a mutagenesis screen in combination with high-throughput sequencing to identify several amino acid positions in Rap1 that have key roles in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner, whereby longer telomeres are prone to undergoing end fusions, while telomeres within the normal length range are sufficiently protected. The protection of long telomeres is in part dependent on their nuclear envelope attachment mediated by the Rap1-Bqt4 interaction. Our data demonstrate that long telomeres represent a challenge for the maintenance of genome integrity, thereby providing an explanation for species-specific upper limits on telomere length.

RevDate: 2022-09-10

Schellnegger M, Lin AC, Hammer N, et al (2022)

Physical Activity on Telomere Length as a Biomarker for Aging: A Systematic Review.

Sports medicine - open, 8(1):111.

BACKGROUND: Overall life expectancy continues to rise, approaching 80 years of age in several developed countries. However, healthy life expectancy lags far behind, which has, in turn, contributed to increasing costs in healthcare. One way to improve health and attenuate the socio-economic impact of an aging population is to increase overall fitness through physical activity. Telomere attrition or shortening is a well-known molecular marker in aging. As such, several studies have focused on whether exercise influences health and aging through telomere biology. This systematic review examines the recent literature on the effect of physical activity on telomere length (TL) and/or telomerase activity as molecular markers of aging.

METHODS: A focused search was performed in the databases PubMed and Web of Science for retrieving relevant articles over the past ten years. The search contained the following keywords: exercise, sport, physical activity, fitness, sedentary, physical inactivity, telomere, telomere length, t/s ratio, and telomerase. PRISMA guidelines for systematic reviews were observed.

RESULTS: A total of 43 articles were identified and categorized into randomized controlled trials (RCT), observational or interventional studies. RCTs (n = 8) showed inconsistent findings of increased TL length with physical activity in, e.g. obese, post-menopausal women. In comparison with a predominantly sedentary lifestyle, observational studies (n = 27) showed significantly longer TL with exercise of moderate to vigorous intensity; however, there was no consensus on the duration and type of physical activity and training modality. Interventional studies (n = 8) also showed similar findings of significantly longer TL prior to exercise intervention; however, these studies had smaller numbers of enrolled participants (mostly of high-performance athletes), and the physical activities covered a range of exercise intensities and duration. Amongst the selected studies, aerobic training of moderate to vigorous intensity is most prevalent. For telomere biology analysis, TL was determined mainly from leukocytes using qPCR. In some cases, especially in RCT and interventional studies, different sample types such as saliva, sperm, and muscle biopsies were analyzed; different leukocyte cell types and potential genetic markers in regulating telomere biology were also investigated.

CONCLUSIONS: Taken together, physical activity with regular aerobic training of moderate to vigorous intensity appears to help preserve TL. However, the optimal intensity, duration of physical activity, as well as type of exercise still need to be further elucidated. Along with TL or telomerase activity, participants' fitness level, the type of physical activity, and training modality should be assessed at different time points in future studies, with the plan for long-term follow-up. Reducing the amount of sedentary behavior may have a positive effect of preserving and increasing TL. Further molecular characterization of telomere biology in different cell types and tissues is required in order to draw definitive causal conclusions on how physical activity affects TL and aging.

RevDate: 2022-09-10
CmpDate: 2022-09-08

Porrazzo A, Cipressa F, De Gregorio A, et al (2022)

Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious.

Communications biology, 5(1):905.

It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute γ-irradiation, is considerably reduced when flies are previously exposed to a protracted dose of 0.4 Gy delivered at a dose rate of 2.5 mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TFs frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and in the epigenetic routes involved in radioresistance.

RevDate: 2022-09-03

Batista LFZ, Dokal I, R Parker (2022)

Telomere biology disorders: time for moving towards the clinic?.

Trends in molecular medicine pii:S1471-4914(22)00202-7 [Epub ahead of print].

Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and pharmacological agents targeting the poly(A) polymerase PAPD5, which adds 3'-oligoadenosine tails to hTR to promote hTR degradation, and TGS1, which modifies the 5'-cap structure of hTR to enhance degradation, as possible therapeutic approaches. Critical next steps will be clinical trials to establish the effectiveness and potential side effects of these compounds in TBD patients.

RevDate: 2022-09-20
CmpDate: 2022-09-20

Seibt KD, Ghaffari MH, Scheu T, et al (2022)

Effects of different feeding levels during a 14-week preweaning phase in dairy heifer calves on telomere length and mitochondrial DNA copy number in blood.

Journal of dairy science, 105(10):8509-8522.

Telomeres cap the ends of eukaryotic chromosomes, and the telomere length (TL) is related to cellular age. The mitochondrial DNA copy number (mtDNAcn) reflects the abundance of mitochondria in a cell. In addition to generating energy, mitochondria are also the main producers of reactive oxygen species, which in turn can accelerate TL attrition and impair mitochondrial function. Nutrition in early life could influence mtDNAcn and TL in later life. In the present study, we investigated the effects of feeding different levels of milk replacer (MR) on TL shortening and energetic status by examining mtDNAcn of heifers during their first year of life. In this study, whole blood samples were obtained from German Holstein heifer calves 36 to 48 h after birth (wk 1) and at wk 12 and wk 16 of life (n = 37), as well as from 31 calves when reaching 1 yr of age. Calves were fed either a high level of MR (14% solids) at 10 L/d (1.4 kg of MR/d; n = 18) or a restrictive low level at 5.7 L/d (0.8 kg of MR/d; n = 19) until linear weaning in wk 13 to 14 of life. Additional whole blood samples were taken from their respective dams 36 to 48 h after calving. Relative TL (qT) and mtDNAcn in cells from whole blood were measured by multiplex quantitative PCR. The greatest qT values were observed in neonates (36-48 h after birth), with decreasing qT values thereafter. Delta qT values were calculated as ΔqT = qT (first year of life) - initial qT (36-48 h after birth). We found no effect of the feeding regimen on qT values, but qT decreased with age. The mtDNAcn was lowest in neonates, increased until wk 12 of life, and then remained at a constant level until after weaning (wk 16). After the first year of life, mtDNAcn was decreased and returned to levels comparable to those of the neonatal stage. No differences in mtDNAcn were detectable between feeding groups within each time point. When comparing the values of qT and mtDNAcn between the calves and their dams after calving (36-48 h after birth and after calving), greater values were observed in calves than in dams. Delta qT values were negative in all but 2 calves (on the restricted diet), indicating that the change in TL with age was not uniform among individual animals, whereas no difference in mean ΔqT values occurred between the feeding groups. Additional analyses of the correlation between qT, mtDNAcn, and various indicators of oxidative status from birth until wk 16 of life did not indicate major interactions between oxidative status, qT and mtDNAcn. The results of this study support an age-dependent decrease of TL in calves independent of the MR feeding level and show the dynamic changes of mtDNAcn in early life.

RevDate: 2022-09-20

Chen L, Dickerhoff J, Sakai S, et al (2022)

DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting.

Accounts of chemical research, 55(18):2628-2646.

ConspectusDNA G-quadruplex secondary structures formed in guanine-rich human telomeres and oncogene promoters are functionally important and have emerged as a promising new class of cancer-specific drug targets. These globular intramolecular structures are stabilized by K+ or Na+ and form readily under physiological solution conditions. Moreover, G-quadruplexes are epigenetic features and can alter chromatin structure and function together with interactive proteins. Here, we discuss our efforts over the last two decades to understand the structures and functions of DNA G-quadruplexes formed in key oncogene promoters and human telomeres and their interactions with small molecules. Using high-field NMR spectroscopy, we determined the high-resolution structures of physiologically relevant telomeric G-quadruplexes in K+ solution with a major form (hybrid-2) and a minor form (hybrid-1), as well as a two-tetrad intermediate. The intrinsic structural polymorphism of telomeric DNA may be important for the biology of human telomeres, and we proposed a model for the interconversion. More recently, we have worked on G-quadruplexes of MYC, BCL2, PDGFR-β, VEGF, and k-RAS oncogene promoters. We determined the structure of the major G-quadruplex formed in the MYC promoter, a prototype for parallel G-quadruplexes. It is the first example of the parallel-stranded G3NG3 structure motif with a 1-nt loop, which is prevalent in promoter sequences and likely evolutionarily selected to initiate folding. Remarkably, the parallel MYC promoter G-quadruplexes are highly stable. Additionally, we determined the molecular structures of G-quadruplexes formed in human BCL2, VEGF, and PDGFR-β promoters, each adopting a unique structure. For example, the BCL2 promoter contains distinct interchangeable G-quadruplexes in two adjacent regions, suggesting precise regulation by different proteins. The PDGFR-β promoter adopts unique "broken-strand" and vacancy G-quadruplexes, which can be recognized by cellular guanine metabolites for a potential regulatory role.Structural information on G-quadruplexes in complex with small-molecules is critical for understanding specific recognition and structure-based rational drug design. Our studies show that many G-quadruplexes contain unique structural features such as capping and loop structures, allowing specific recognition by drugs and protein. This represents a paradigm shift in understanding DNA as a drug target: Rather than a uniform, nonselective binding site in duplex DNA, the G-quadruplex is being pursued as a new class of selectively targetable drug receptors. We focus on targeting the biologically relevant MYC promoter G-quadruplex (MycG4) with small molecules and have determined its first and additional drug complex structures. Very recently, we have discovered clinically tested indenoisoquinolines as strong MycG4 binders and potent MYC inhibitors. We have also discovered drugs targeting the unique dGMP-bound-vG4 formed in the PDGFR-β promoter. Moreover, we determined the complex structures of the first small molecules that specifically recognize the physiologically relevant human telomeric G-quadruplexes. Unlike the previously recognized dogma that the optimal G-quadruplex ligands are large aromatic or cyclic compounds, our results suggest that smaller asymmetric compounds with appropriate functional groups are better choices to specifically bind G-quadruplexes. This body of work lays a strong foundation for future work aimed at understanding the cellular functions of G-quadruplexes and G-quadruplex-targeted drug design.

RevDate: 2022-09-03

Rodríguez-Fernández B, Gispert JD, Guigo R, et al (2022)

Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy.

Computational and structural biotechnology journal, 20:4251-4256.

Telomere length (TL) is a biomarker of biological aging. Shorter telomeres have been associated with mortality and increased rates of age-related diseases. However, observational studies are unable to conclude whether TL is causally associated with those outcomes. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. The objective of this study was to test the potential causal role of TL in neurodegenerative disorders and life expectancy through MR analysis. Summary level data were extracted from the most recent genome-wide association studies for TL, Alzheimer's disease (AD), Parkinson's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, Progressive Supranuclear Palsy and life expectancy. MR estimates revealed that longer telomeres inferred a protective effect on risk of AD (OR = 0.964; adjusted p-value = 0.039). Moreover, longer telomeres were significantly associated with increased life expectancy (βIVW = 0.011; adjusted p-value = 0.039). Sensitivity analyses suggested evidence for directional pleiotropy in AD analyses. Our results showed that genetically predicted longer TL may increase life expectancy and play a protective causal effect on AD. We did not observe significant causal relationships between longer TL and other neurodegenerative diseases. This suggests that the involvement of TL on specific biological mechanisms might differ between AD and life expectancy, with respect to that in other neurodegenerative diseases. Moreover, the presence of pleiotropy may reflect the complex interplay between TL homeostasis and AD pathophysiology. Further observational studies are needed to confirm these results.

RevDate: 2022-09-08
CmpDate: 2022-09-08

Coukos A, Daccord C, Lazor R, et al (2022)

[Short telomere syndrome in adults: a rare entity that should be evoked].

Revue medicale suisse, 18(793):1606-1613.

Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.

RevDate: 2022-09-21

Dey A, Pandav K, Nath M, et al (2022)

Molecular rec§ognition of telomere DNA sequence by 2, 6 anthraquinone derivatives leads to thermal stabilization and induces apoptosis in cancer cells.

International journal of biological macromolecules, 221:355-370 pii:S0141-8130(22)01859-1 [Epub ahead of print].

According to current research, anti-cancer anthraquinones impact telomere disruption and may interact with G-quadruplex DNA that triggers signaling to apoptosis. The present study represents the biophysical investigation of oxidative stress, late apoptosis, and induced senescence among cancer cells after binding laboratory synthesized piperidine-based anthraquinone derivatives, 2, 6- Bis [(3-piperidino)acetamido)]anthracene-9,10-dione (N1P) and 2, 6-Bis [piperidino)propionamido]anthracene-9,10-dione (N2P), with G-quadruplex DNA. We employed biophysical approaches to explore the interaction of synthetic anthraquinone derivatives with quadruplex DNA sequences to influence biological activities in the presence of K+ and Na+ cations. The binding affinity for N2P and N1P are Kb = 5.8 × 106 M-1 and Kb = 1.0 × 106 M-1, respectively, leading to hypo-/hyper-chromism with 5-7 nm red shift and significant fluorescence quenching and changes in ellipticity resulting in external binding of both the ligands to G-quadruplex DNA. Ligand binding induced enhancement of thermostability of G4 DNA is greater in Na+ environment (ΔTm = 34 °C) as compared to that in K+ environment (ΔTm = 21 °C), thereby restricting telomerase binding access to telomeres. Microscopic images of treated cells indicated cellular shape, nuclear condensation, and fragmentation alterations. The findings pave the path for therapeutic research, given the great potential of modifying anthraquinone substituent groups towards improved efficacy, ROS generation, and G-quadruplex DNA selectivity.

RevDate: 2022-09-02
CmpDate: 2022-08-31

Kille B, Balaji A, Sedlazeck FJ, et al (2022)

Multiple genome alignment in the telomere-to-telomere assembly era.

Genome biology, 23(1):182.

With the arrival of telomere-to-telomere (T2T) assemblies of the human genome comes the computational challenge of efficiently and accurately constructing multiple genome alignments at an unprecedented scale. By identifying nucleotides across genomes which share a common ancestor, multiple genome alignments commonly serve as the bedrock for comparative genomics studies. In this review, we provide an overview of the algorithmic template that most multiple genome alignment methods follow. We also discuss prospective areas of improvement of multiple genome alignment for keeping up with continuously arriving high-quality T2T assembled genomes and for unlocking clinically-relevant insights.

RevDate: 2022-09-16
CmpDate: 2022-08-31

Fohringer C, Hoelzl F, Allen AM, et al (2022)

Large mammal telomere length variation across ecoregions.

BMC ecology and evolution, 22(1):105.

BACKGROUND: Telomere length provides a physiological proxy for accumulated stress in animals. While there is a growing consensus over how telomere dynamics and their patterns are linked to life history variation and individual experience, knowledge on the impact of exposure to different stressors at a large spatial scale on telomere length is still lacking. How exposure to different stressors at a regional scale interacts with individual differences in life history is also poorly understood. To better understand large-scale regional influences, we investigated telomere length variation in moose (Alces alces) distributed across three ecoregions. We analyzed 153 samples of 106 moose representing moose of both sexes and range of ages to measure relative telomere lengths (RTL) in white blood cells.

RESULTS: We found that average RTL was significantly shorter in a northern (montane) and southern (sarmatic) ecoregion where moose experience chronic stress related to severe summer and winter temperatures as well as high anthropogenic land-use compared to the boreal region. Our study suggests that animals in the northern boreal forests, with relatively homogenous land use, are less disturbed by environmental and anthropogenic stressors. In contrast, animals in areas experiencing a higher rate of anthropogenic and environmental change experience increased stress.

CONCLUSION: Although animals can often adapt to predictable stressors, our data suggest that some environmental conditions, even though predictable and ubiquitous, can generate population level differences of long-term stress. By measuring RTL in moose for the first time, we provide valuable insights towards our current understanding of telomere biology in free-ranging wildlife in human-modified ecosystems.

RevDate: 2022-09-20
CmpDate: 2022-09-20

Jentsch A, Hoferichter F, Raufelder D, et al (2022)

The relation between sensory processing sensitivity and telomere length in adolescents.

Brain and behavior, 12(9):e2751.

BACKGROUND: In the present study, we investigated the association between sensory processing sensitivity (SPS) and telomere length (TL), which is considered a biomarker of cellular aging. SPS is an individual characteristic describing increased perception and procession of inner or outer stimuli, and is positively related to self-perceived stress.

METHODS: We recruited 82 healthy adolescents aged 13-16 from secondary schools in Germany. SPS was measured with the Highly Sensitive Person Scale, and TL was determined by a multiplex quantitative PCR method.

RESULTS: Our results show that students with higher values of SPS are likely to have shorter telomeres (β = 0.337, p = .001), when adjusting for sex, socioeconomic status, age, and body mass index. These findings are also independent of the negative impact of stress students might have perceived shortly before data collection.

CONCLUSIONS: Our analysis suggests that students who struggle with low sensory threshold are likely to have shorter telomeres.

RevDate: 2022-08-29

Salisbury ML, Markin CR, Wu P, et al (2022)

Peripheral Blood Telomere Attrition in Persons at Risk for Familial Pulmonary Fibrosis.

American journal of respiratory and critical care medicine [Epub ahead of print].

RevDate: 2022-08-29

Khalil D, Giurgescu C, Misra DP, et al (2022)

Psychosocial Factors and Telomere Length Among Parents and Infants of Immigrant Arab American Families.

Biological research for nursing [Epub ahead of print].

Background: Immigrant Arab American families face multiple stressors related to migration and resettlement. Telomere length (TL) is an established biomarker of aging and psychosocial stress. No published studies have concurrently examined the association between maternal and paternal psychosocial factors and infants' TL. The purpose of this study was to: (1) compare mother, father, and infant TLs; (2) explore the association of maternal and paternal psychosocial factors (acculturative stress and depressive symptoms) with maternal and paternal TL; and (3) explore the association of maternal and paternal psychosocial factors with infants' TL among Arab American immigrants. Method: Using a cross-sectional exploratory design, a sample of 52 immigrant Arab American mother-father-infant triads were recruited from community centers. Data were collected in a single home visit when the infant was 6-24 months old. Each parent completed the study questionnaires addressing their psychosocial factors (acculturative stress, and depressive symptoms), then parents and infants provided buccal cell for TL measurement. Results: Maternal TL was positively correlated to infants' TL (r = .31, p = .04) and significantly shorter (p < .001). Paternal TL was not correlated with infant TL but was significantly shorter than infant's TL (p < .001). Maternal depression was significantly correlated with mothers' TL (r = .4, p = .007). Higher levels of maternal depressive symptoms were significantly associated with shorter infant TL when controlling for background characteristics. Conclusions: Our pilot study is the first study to examine maternal and paternal psychosocial factors related to migration and infants' TL. More research is needed to advance our understanding of the effects of immigration on the intergenerational transfer of stress and trauma.

RevDate: 2022-09-20
CmpDate: 2022-08-30

Wang Y, Ferrucci L, Seidman MM, et al (2022)

An optimized proximity ligation assay to detect telomere dysfunction induced foci in human and mouse cells.

STAR protocols, 3(3):101610.

Telomere dysfunction-induced foci (TIF) can be measured by immunofluorescence, combined with telomere-fluorescent in situ hybridization. We modified this approach by combining the proximity ligation assay (PLA), which detects colocalization of two molecules in proximity through a signal amplification step and improves the fidelity and sensitivity of TIF detection in human and mouse cells. The protocol includes cell preparation, permeabilization, fixation, and blocking PLA detection of DNA damage response proteins within proximity with telomeres and optional PLA verification by immunofluorescence-based technique.

RevDate: 2022-08-29

Maher TM (2022)

A clinical short-cut to identifying short telomeres in idiopathic pulmonary fibrosis?.

RevDate: 2022-09-06
CmpDate: 2022-08-30

Yu EY, Cheung NV, NF Lue (2022)

Connecting telomere maintenance and regulation to the developmental origin and differentiation states of neuroblastoma tumor cells.

Journal of hematology & oncology, 15(1):117.

A cardinal feature that distinguishes clinically high-risk neuroblastoma from low-risk tumors is telomere maintenance. Specifically, neuroblastoma tumors with either active telomerase or alternative lengthening of telomeres exhibit aggressive growth characteristics that lead to poor outcomes, whereas tumors without telomere maintenance can be managed with observation or minimal treatment. Even though the need for cancer cells to maintain telomere DNA-in order to sustain cell proliferation-is well established, recent studies suggest that the neural crest origin of neuroblastoma may enforce unique relationships between telomeres and tumor malignancy. Specifically in neuroblastoma, telomere structure and telomerase activity are correlated with the adrenergic/mesenchymal differentiation states, and manipulating telomerase activity can trigger tumor cell differentiation. Both findings may reflect features of normal neural crest development. This review summarizes recent advances in the characterization of telomere structure and telomere maintenance mechanisms in neuroblastoma and discusses the findings in the context of relevant literature on telomeres during embryonic and neural development. Understanding the canonical and non-canonical roles of telomere maintenance in neuroblastoma could reveal vulnerabilities for telomere-directed therapies with potential applications to other pediatric malignancies.

RevDate: 2022-08-30
CmpDate: 2022-08-30

Tan KT, Slevin MK, Meyerson M, et al (2022)

Identifying and correcting repeat-calling errors in nanopore sequencing of telomeres.

Genome biology, 23(1):180.

Nanopore long-read sequencing is an emerging approach for studying genomes, including long repetitive elements like telomeres. Here, we report extensive basecalling induced errors at telomere repeats across nanopore datasets, sequencing platforms, basecallers, and basecalling models. We find that telomeres in many organisms are frequently miscalled. We demonstrate that tuning of nanopore basecalling models leads to improved recovery and analysis of telomeric regions, with minimal negative impact on other genomic regions. We highlight the importance of verifying nanopore basecalls in long, repetitive, and poorly defined regions, and showcase how artefacts can be resolved by improvements in nanopore basecalling models.

RevDate: 2022-09-12
CmpDate: 2022-08-29

Opstad TB, Alexander J, Aaseth JO, et al (2022)

Selenium and Coenzyme Q10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality-Sub-Study of a Randomized Clinical Trial.

Nutrients, 14(16):.

Short telomeres have been associated with ageing and cardiovascular disease. The influence on leukocyte telomere length (LTL) of long-term intervention with combined selenium and coenzyme Q10 is unknown. Our aim was to determine whether 42 months of selenium and coenzyme Q10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium (n = 118), aged 70-80 years, were included. Intervention time was 4 years, with 10 years' follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group (p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. -0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL (p < 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival (p = 0.03). To conclude, preservation of LTL after selenium and coenzyme Q10 supplementation associated with reduced cardiovascular mortality.

RevDate: 2022-09-15
CmpDate: 2022-08-29

Oudrhiri N, M'kacher R, Chaker D, et al (2022)

Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome.

Genes, 13(8):.

Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (CTC1). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1-STN1-TEN1 which promotes telomere DNA synthesis and inhibits telomerase-mediated telomere elongation. However, it is unclear how CTC1 mutations may have an effect on telomere structure and function. For that purpose, we established the very first induced pluripotent stem cell lines (iPSCs) from a compound heterozygous patient with CP carrying deleterious mutations in both alleles of CTC1. Telomere dysfunction and chromosomal instability were assessed in both circulating lymphocytes and iPSCs from the patient and from healthy controls of similar age. The circulating lymphocytes and iPSCs from the CP patient were characterized by their higher telomere length heterogeneity and telomere aberrations compared to those in control cells from healthy donors. Moreover, in contrast to iPSCs from healthy controls, the high levels of telomerase were associated with activation of the alternative lengthening of telomere (ALT) pathway in CP-iPSCs. This was accompanied by inappropriate activation of the DNA repair proteins γH2AX, 53BP1, and ATM, as well as with accumulation of DNA damage, micronuclei, and anaphase bridges. CP-iPSCs presented features of cellular senescence and increased radiation sensitivity. Clonal dicentric chromosomes were identified only in CP-iPSCs after exposure to radiation, thus mirroring the role of telomere dysfunction in their formation. These data demonstrate that iPSCs derived from CP patients can be used as a model system for molecular studies of the CP syndrome and underscores the complexity of telomere dysfunction associated with the defect of DNA repair machinery in the CP syndrome.

RevDate: 2022-08-30
CmpDate: 2022-08-29

Derevyanko A, Skowronska A, Skowronski MT, et al (2022)

The Interplay between Telomeres, Mitochondria, and Chronic Stress Exposure in the Aging Egg.

Cells, 11(16):.

While at the organismal level, biological aging can be estimated by telomere length and DNA methylation signatures, reliable biomarkers that can predict reproductive age are much needed to gauge the quality of an oocyte. Reproductive medicine and fertility centers often merely quantitate the ovarian reserve to predict the likelihood of fertilization and pregnancy in women of advanced reproductive age. It is highly important to address the level of age-related decline in oocyte quality since it leads to an increased risk of miscarriages and aneuploidy. Conversely, the pathways behind oocyte aging remain, in large part, elusive. Telomere shortening upon chronic stress exposure regulates mitochondria function and biogenesis by various pathways; therefore, establishing a link between these two important players and extrapolating them for the aging of oocytes will be the purpose of our commentary.

RevDate: 2022-08-30

Opstad TB, Solheim S, Pettersen AR, et al (2022)

TERT and TET2 Genetic Variants Affect Leukocyte Telomere Length and Clinical Outcome in Coronary Artery Disease Patients-A Possible Link to Clonal Hematopoiesis.

Biomedicines, 10(8):.

Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme reverse transcriptase (TERT) (rs7705526) and the epigenetic regulator ten-eleven translocation 2 (TET2) (rs2454206), were investigated in 1001 patients with stable coronary artery disease (CAD) (mean age 62 years, 22% women), with regards to cardiovascular outcome, comorbidities, and leukocyte telomere length. Over 2 years, mutated TERT increased the risk two-fold for major clinical events (MACEs) in all patients (p = 0.004), acute myocardial infarction (AMI) in male patients (p = 0.011), and stroke in female patients (p < 0.001). Mutated TET2 correlated with type 2 diabetes (p < 0.001), the metabolic syndrome (p = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (p = 0.032, p = 0.003, and p = 0.016, respectively). In conclusion, our results from stable CAD patients highlight TERTs' role in CVD, and underline TET2s' role in the epigenetic regulation of lifestyle-related diseases.

RevDate: 2022-09-02
CmpDate: 2022-08-29

Sharaf R, Frampton GM, LA Albacker (2022)

Mutations in the TERC template sequence can be incorporated into the telomeres of human tumors.

PloS one, 17(8):e0272707.

Telomerase-mediated lengthening is a mechanism by which some cancer cells avoid senescence-mediated cell cycle arrest due to shortened telomeres. By reverse transcribing an RNA template, encoded by TERC, the enzyme telomerase synthesizes the elongation of telomeric DNA using the 3' end of the chromosome as a primer. TERC harbors a highly conserved template region consisting of 11 nucleotides spanning hg19 coordinates chr3:169482793-169482803. In human cell lines, when TERC was mutated to alter its template region, telomerase generated the predicted mutant telomeric repeats. However, it is unknown if this can occur in human clinical samples. Here, we report on the rare occurrence of two tumor samples where TERC template mutations were reflected in telomeric repeats.

RevDate: 2022-08-27

Tacheva T, Zienolddiny-Narui S, Dimov D, et al (2022)

The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease.

Current issues in molecular biology, 44(8):3757-3769.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.

RevDate: 2022-08-26

Retuerto M, Lledó A, Fernandez-Varas B, et al (2022)

Shorter telomere length is associated with COVID-19 hospitalization and with persistence of radiographic lung abnormalities.

Immunity & ageing : I & A, 19(1):38.

BACKGROUND: Age and comorbidity are the main determinants of COVID-19 outcome. Shorter leukocyte telomere length (TL), a hallmark of biological aging, has been associated with worse COVID-19 outcomes. We sought to determine TL in patients with severe COVID-19 requiring hospitalization to analyze whether clinical outcomes and post-COVID-19 manifestations are associated with shorter TL.

RESULTS: We analyzed 251 patients with PCR-confirmed COVID-19, hospitalized in the first months of the pandemics. We determined TL in PBL at admission by quantitative-PCR (qPCR) analysis in patients. A healthy cohort from the same area with a similar age range (n = 169) was used to calculate TL Z-scores. After hospital discharge, 144 COVID-19 survivors were followed-up for persistent COVID-19 manifestations. A second TL determination was performed in a smaller group of 63 patients 1 year later and compared with baseline TL. Hospitalized COVID-19 patients had a decreased baseline age-adjusted TL Z-score compared to the reference group. No differences in Z-scores were observed in patients with different COVID-19 outcomes, classified as WHO ordinal scores. In 144 patients, followed for a median of 8 months, post-COVID manifestations were not associated to differences in TL. Persistence of lung radiographic abnormalities was associated with shorter baseline TL. In patients with a second TL determination, further telomere shortening (TS) was observed in 35% and telomere lengthening in 49%. Patients with further TS had suffered a more severe disease.

CONCLUSION: Shorter TL is associated with COVID-19 hospitalization but not with hospital clinical outcomes nor with persistent post-COVID-19 manifestations. Delayed resolution of radiographic lung abnormalities was also associated with shorter TL.

RevDate: 2022-08-23

Li JH, Tao YF, Shen CH, et al (2022)

Integrated multi-omics analysis identifies ENY2 as a predictor of recurrence and a regulator of telomere maintenance in hepatocellular carcinoma.

Frontiers in oncology, 12:939948.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a high recurrence rate. Accurate prediction of recurrence risk is urgently required for tailoring personalized treatment programs for individual HCC patients in advance. In this study, we analyzed a gene expression dataset from an HCC cohort with 247 samples and identified five genes including ENY2, GPAA1, NDUFA4L2, NEDD9, and NRP1 as the variables for the prediction of HCC recurrence, especially the early recurrence. The Cox model and risks score were validated in two public HCC cohorts (GSE76427 and The Cancer Genome Atlas (TCGA)) and one cohort from Huashan Hospital, which included a total of 641 samples. Moreover, the multivariate Cox regression analysis revealed that the risk score could serve as an independent prognostic factor in the prediction of HCC recurrence. In addition, we found that ENY2, GPAA1, and NDUFA4L2 were significantly upregulated in HCC of the two validation cohorts, and ENY2 had significantly higher expression levels than another four genes in malignant cells, suggesting that ENY2 might play key roles in malignant cells. The cell line analysis revealed that ENY2 could promote cell cycle progression, cell proliferation, migration, and invasion. The functional analysis of the genes correlated with ENY2 revealed that ENY2 might be involved in telomere maintenance, one of the fundamental hallmarks of cancer. In conclusion, our data indicate that ENY2 may regulate the malignant phenotypes of HCC via activating telomere maintenance.

RevDate: 2022-09-06

Lynn SE, Kern MD, Serrurier B, et al (2022)

Chill out: Environmentally relevant cooling challenge does not increase telomere loss during early life.

General and comparative endocrinology, 329:114108 pii:S0016-6480(22)00133-2 [Epub ahead of print].

In vertebrates, exposure to diverse stressors during early life activates a stress response that can initiate compensatory mechanisms or promote cellular damage with long-term fitness consequences. A growing number of studies associate exposure to stressors during early life with increased damage to telomeres (i.e., promoting the shortening of these highly conserved, repeating sequences of non-coding DNA at chromosome ends). However, some studies show no such relationship, suggesting that the nature, timing, and context of these challenges may determine the degree to which physiological mediators of the stress response act in a damage-mitigating or damage promoting way in relation to telomere dynamics. In free-living eastern bluebirds (Sialia sialis), we have previously demonstrated that bouts of offspring cooling that occur when brooding females leave the nest increase at least one such physiological mediator of the stress response (circulating glucocorticoids), suggesting that variation in patterns of maternal brooding may result in different impacts on telomere dynamics at a young age. Here we experimentally tested whether repeated bouts of ecologically relevant offspring cooling affected telomere dynamics during post-natal development. Rates of telomere shortening during the nestling stage were not affected by experimental cooling, but they were affected by brood size and the rate of growth during the nestling stage. Our data suggest that the effects of developmental stress exposure on offspring telomeres are often context-dependent and that not all challenges that increase physiological mediators of stress result in damage to telomeres. Under some conditions, physiological mediators of stress may instead act as protective regulators, allowing for optimization of fitness outcomes in the face of environmental challenges.

RevDate: 2022-08-26
CmpDate: 2022-08-23

Wang T, Jia Z, Li S, et al (2022)

The association between leukocyte telomere length and chronic obstructive pulmonary disease is partially mediated by inflammation: a meta-analysis and population-based mediation study.

BMC pulmonary medicine, 22(1):320.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the major health issues worldwide. Pathophysiological changes in COPD are mainly reflected in the deterioration of lung function with aging.

METHODS: Considering that telomere length is a hallmark of biological aging, we first performed a meta-analysis to summarize the current knowledge about the relationship between telomere length and COPD and then employed individual-level data from the continuous National Health and Nutrition Examination Survey (NHANES) to investigate whether telomere length could reflect accelerated aging in COPD and serve as an independent predictor. A mediation study was further performed to examine whether the association between telomeres and COPD could be mediated by inflammation, as one of the most important etiologies and characteristics of COPD.

RESULTS: The four studies included in our meta-analysis were with high heterogeneity (I2 = 95.7%, Phet < 0.001), and the pooled relative risk for COPD comparing the shortest tertile versus the longest tertile was 4.06 (95% CI = 1.38 to 11.96). Of the 6,378 subjects in the individual-level data analyses using NHANES, 455 were diagnosed with COPD, and multivariable-adjusted logistic regression also indicated that short telomere length was associated with COPD. Consistently, cubic regression spline analyses showed that long telomeres exhibited a significant association with a decreased risk of COPD. In the subsequent mediation analyses, C-reactive protein concentration, white blood cells count and blood neutrophil count, as inflammatory biomarkers, showed a significant indirect effect on the relationship between telomere length and COPD.

CONCLUSION: Accelerated aging in COPD could be characterized by excessive telomere shortening, and inflammatory response might be involved in the underlying mechanisms of COPD pathogenesis promoted by short telomere length. Telomere length measurement may facilitate clinical translational research and targeted therapy of COPD.

RevDate: 2022-08-20

Zafirovic S, Macvanin M, Stanimirovic J, et al (2022)

Association between telomere length and cardiovascular risk: Pharmacological treatments affecting telomeres and telomerase activity.

Current vascular pharmacology pii:CVP-EPUB-125665 [Epub ahead of print].

Telomeres represent the ends of chromosomes, and they are composed of an extensive number of - TTAGGG nucleotide sequence repeats in humans. Telomeres prevent chromosome degradation, participate in stabilization, and regulate the DNA repair system. Inflammation and oxidative stress have been identified as important processes causing cardiovascular disease and accelerating telomere shortening rate. This review investigates the link between telomere length and pathological vascular conditions from experimental and human studies. Also, we discuss pharmacological treatments affecting telomeres and telomerase activity.

RevDate: 2022-08-20

Hoffmann J, Tabata N, Mas-Peiro S, et al (2022)

Longer leukocyte telomere length is associated with myeloid inflammation and increased mortality after transcatheter aortic valve replacement.

European heart journal open, 2(4):oeac045.

Aims: Inflammatory activation of leukocytes may limit prognosis of patients (pts) with severe aortic valve stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Leukocyte telomere length (LTL) is a marker of proliferative capacity and inflammatory responsiveness but the impact of LTL on the prognosis in AS remains elusive. The aim of this study was to analyse the association of LTL with inflammatory markers and prognosis of pts undergoing TAVR.

Methods and results: LTL was analysed using quantitative real-time PCR in 285 consecutive pts (median age 82 years) undergoing TAVR and correlated with 18-month all-cause mortality. C-reactive protein was significantly elevated in pts with the longest LTL (P = 0.017), paralleled by increased procalcitonin (PCT) serum levels (P = 0.0006). This inflammatory reaction was accompanied by increased myeloid cells in the highest LTL tertile, mainly a rise in circulating neutrophils (P = 0.0025) and monocytes (P = 0.01). Multivariate analysis revealed LTL (HR 2.6, 95%CI 1.4-5.1, P= 0.004) and PCT levels (HR 4.3, 95%CI 1.7-11.0, P = 0.003) as independent predictors of mortality.

Conclusions: Longer LTL is associated with increased mortality after TAVR. This might be explained by enhanced proliferative capacity of cells resulting in myeloid and systemic inflammation. Our findings suggest that targeting the specific inflammation pathways could present a novel strategy to augment survival in selected patients with degenerative aortic stenosis.

RevDate: 2022-08-26
CmpDate: 2022-08-19

Romero-Haro AÁ, Morger J, Haussmann MF, et al (2022)

Reproductive Strategies Affect Telomere Dynamics across the Life Course.

The American naturalist, 200(3):373-382.

AbstractBecause parental care has a heritable basis, the benefits of receiving increased parental provisioning early in life are genetically linked to the costs of providing increased parental provisioning at adulthood. Reproductive strategies thus result in distinct cost-benefit syndromes across the life course that may shape individual health and aging trajectories. Here we used an artificial selection approach in Japanese quail (Coturnix japonica) to test how reproductive strategies affect telomere length, a biomarker of somatic state, at different life stages. We show that males but not females from lines selected for low maternal investment (i.e., developing in a relatively small egg) had shorter telomeres at birth. These patterns were still weakly present at the end of the juvenile growth period. In contrast, significantly shorter telomeres were found in reproductively active adult birds from the high-investment lines, suggesting that telomere attrition was accelerated in these individuals once they had become reproductively active. Our study shows that reproductive strategies differentially affect telomere dynamics across the life course, highlighting the role of cross-generational constraints in shaping individual aging trajectories.

RevDate: 2022-08-16

Petermann-Rocha F, Valera-Gran D, Fernández-Pires P, et al (2022)

Children who sleep more may have longer telomeres: evidence from a longitudinal population study in Spain.

Pediatric research [Epub ahead of print].

BACKGROUND: Inadequate sleep duration has been suggested as a chronic stressor associated with changes in telomere length (TL). This study aimed to explore the association between sleep duration and TL using the INMA birth cohort study data.

METHODS: A total of 1014 children were included in this study (cross-sectional: 686; longitudinal: 872). Sleep duration (h/day) was reported by caregivers at 4 years and classified into tertiles (7-10 h/day; >10-11 h/day; >11-14 h/day). Leucocyte TL at 4 and 7-9 years were measured using quantitative PCR methods. Multiple robust linear regression models, through log-level regression models, were used to report the % of difference among tertiles of sleep duration.

RESULTS: In comparison to children who slept between >10 and 11 h/day, those in the highest category (more than 11 h/day) had 8.5% (95% CI: 3.56-13.6) longer telomeres at 4 years. Longitudinal analysis showed no significant association between sleep duration at 4 years and TL at 7-9 years.

CONCLUSION: Children who slept more hours per day had longer TL at 4 years independently of a wide range of confounder factors. Environmental conditions, such as sleep duration, might have a major impact on TL during the first years of life.

IMPACT: Telomere length was longer in children with longer sleep duration (>11 h/day) independently of a wide range of confounder factors at age 4 and remained consistent by sex. Sleep routines are encouraged to promote positive child development, like the number of hours of sleep duration. Considering the complex biology of telomere length, future studies still need to elucidate which biological pathways might explain the association between sleep duration and telomere length.

RevDate: 2022-08-16

Maroon JC (2022)

The effect of hyperbaric oxygen therapy on cognition, performance, proteomics, and telomere length-The difference between zero and one: A case report.

Frontiers in neurology, 13:949536.

Introduction: Hyperbaric oxygen (HBO2) therapy has recently been suggested for the treatment of different brain injuries as well as for physical and cognitive enhancement. The author recently carried out a self-experiment to obtain objective information on the effects of HBO2 therapy on neurocognition, cardiopulmonary function, neuroimaging and its effect on novel biomarkers such as telomere length and proteomics. In the following case report, the author will present and discuss the results and the differences between zero and one.

Methods: This is a personal case report on a single subject, myself, who underwent a protocol of 60 daily HBO2 therapy sessions within 3 months. Pre- and post-therapy objective evaluation measured included computerized cognitive assessment, brain imaging, cardiopulmonary exercise test, physical assessments and blood tests including telomere length and proteomics.

Results: Neurocognitive results showed a 3.1-3.8% improvements in global cognitive function as well as all other cognitive function domains. In the perfusion MRI, there was a relative increase ranging from 43.3 to 52.3% in cerebral perfusion in various areas subserving memory, coordination, and visual motor cortex function. Similar improvements in cerebral perfusion were seen in the SPECT scans, which ranged from 8.79 to 16.12% increased perfusion in the temporal pole and entorhinal cortex subserving memory, as well as in the subcallosal area and lingual gyrus. MRI-DTI showed prominent increases in fractional anisotropy in several white matter areas including 9% in the body of the corpus callosum, 16.85% in for the fornix and 22.06% in the tapetum. In the physical domains, there were improvements in both anaerobic threshold, exercise endurance, muscle strength, gait speed and grip strength in the 7-15% range. The telomeres length was doubled and clusters of inflammatory proteins dropped around the 40th session and remained low at the 60th session.

Conclusion: The difference between zero and one in this single case study of HBO2 therapy confirmed improvement in objective biomarkers which measured cognition, memory, brain processing speed, athletic performance and neuroimaging modalities measuring cerebral perfusion, blood flow and tractography. Additional studies with larger sample size and randomized clinical trials using similar biomarkers are needed to confirm the results and to delineate the longevity of these improvements.

RevDate: 2022-08-17
CmpDate: 2022-08-15

Byrjalsen A, Bygum A, Lautrup CK, et al (2022)

[Telomere biology disorders].

Ugeskrift for laeger, 184(28):.

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

RevDate: 2022-09-07
CmpDate: 2022-08-15

Kim S, Chowdhury T, Yu HJ, et al (2022)

The telomere maintenance mechanism spectrum and its dynamics in gliomas.

Genome medicine, 14(1):88.

BACKGROUND: The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues.

METHODS: Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups.

RESULTS: We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression.

CONCLUSIONS: This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies.

RevDate: 2022-09-08
CmpDate: 2022-09-08

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, 225(17):.

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: 2022-08-13

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: 2022-08-15
CmpDate: 2022-08-15

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, 29(8):730-733.

RevDate: 2022-09-19
CmpDate: 2022-09-13

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.

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: 2022-09-19
CmpDate: 2022-09-19

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, 82(18):3345-3358.

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: 2022-09-03
CmpDate: 2022-08-12

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: 2022-09-20
CmpDate: 2022-08-10

Zhang JM, L Zou (2022)

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

STAR protocols, 3(3):101594.

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: 2022-09-14
CmpDate: 2022-09-08

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

Early life trauma and adult leucocyte telomere length.

Psychoneuroendocrinology, 144:105876.

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: 2022-08-26
CmpDate: 2022-08-10

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: 2022-08-10
CmpDate: 2022-08-10

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: 2022-08-15
CmpDate: 2022-08-09

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: 2022-09-14
CmpDate: 2022-09-14

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, 214(Pt 3):114031.

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: 2022-09-13
CmpDate: 2022-09-13

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, 34(9):2177-2183.

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: 2022-09-20

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, 81:101707 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 18,293 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: 2022-09-18

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, 95:103941 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: 2022-09-04
CmpDate: 2022-08-09

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.

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: 2022-09-20
CmpDate: 2022-09-13

Tummala H, Walne A, I Dokal (2022)

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

Expert review of hematology, 15(8):685-696.

BACKGROUND: Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous 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 subtypes. 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 is ineffective and HSCT is not feasible.

RevDate: 2022-08-05

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.

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: 2022-09-21

Borges G, Criqui M, L Harrington (2022)

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

Molecular oncology, 16(18):3380-3396.

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: 2022-08-09

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: 2022-09-14
CmpDate: 2022-08-08

Huang MY, HD Madhani (2022)

Telomere transposon takeover in Cryptococcus.

Nature microbiology, 7(8):1108-1109.

RevDate: 2022-08-30

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, 849:157715 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: 2022-08-02

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: 2022-08-18
CmpDate: 2022-08-02

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: 2022-08-30
CmpDate: 2022-08-30

Aviv A (2022)

The telomere tumult: meaning and metrics in population studies.

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

RevDate: 2022-07-31

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.

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.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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Good Beginner's Books

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

Electronic Scholarly Publishing
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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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