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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 26 Jan 2020 at 01:42 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.

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

Citations The Papers (from PubMed®)

RevDate: 2020-01-25

Xu J, Chang WS, Tsai CW, et al (2020)

Leukocyte telomere length is associated with aggressive prostate cancer in localized prostate cancer patients.

EBioMedicine, 52:102616 pii:S2352-3964(19)30831-X [Epub ahead of print].

BACKGROUND: Telomeres play important roles in cancer initiation and progression. The aim of this study is to investigate whether leukocyte telomere length (LTL) is associated with aggressive prostate cancer (PCa).

METHODS: We measured relative LTL in a cohort of 1,889 white PCa patients who were treated and followed up at the University of Texas MD Anderson Cancer Center and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after active treatments (radical prostatectomy and radiotherapy). We further used a Mendelian randomization (MR) approach to compute a weighted genetic risk score (GRS) predictive of LTL using 10 established LTL-associated genetic variants and determined whether this GRS is associated with aggressive PCa.

FINDINGS: LTL was significantly shorter in patients with higher Gleason scores at diagnosis. Dichotomized at the median value of LTL, patients with short LTL exhibited a 2.74-fold (95% confidence interval, 1.79-4.18, P = 3.11 × 10-6) increased risk of presenting with GS≥8 disease than those with long LTL in multivariate logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio = 1.53, 95% confidence interval, 1.01-2.34) compared to longer LTL in localized patients receiving prostatectomy or radiotherapy with a significant dose-response association (P for trend = 0.017) in multivariate Cox proportional hazards regression analysis. In MR analysis, genetically predicted short LTL was also associated with an increased risk of BCR (HR=1.73, 95% CI, 1.08-2.78).

INTERPRETATION: Our results showed for the first time that LTL was shorter in PCa patients with high Gleason scores and that short LTL and genetically predicted short LTL are associated with worse prognosis in PCa patients receiving prostatectomy or radiotherapy.

FUNDING: Cancer Prevention and Research Institute of Texas (CPRIT) grant (RP140556), National Cancer Institute Specialized Program of Research Excellence (SPORE) grant (CA140388), and MD Anderson Cancer Center start-up fund.

RevDate: 2020-01-25

Maestroni L, Reyes C, Vaurs M, et al (2020)

Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells.

Nucleic acids research pii:5715813 [Epub ahead of print].

Telomere anchoring to nuclear envelope (NE) is a key feature of nuclear genome architecture. Peripheral localization of telomeres is important for chromatin silencing, telomere replication and for the control of inappropriate recombination. Here, we report that fission yeast quiescent cells harbor predominantly a single telomeric cluster anchored to the NE. Telomere cluster association to the NE relies on Rap1-Bqt4 interaction, which is impacted by the length of telomeric sequences. In quiescent cells, reducing telomere length or deleting bqt4, both result in an increase in transcription of the telomeric repeat-containing RNA (TERRA). In the absence of Bqt4, telomere shortening leads to deep increase in TERRA level and the concomitant formation of subtelomeric rearrangements (STEEx) that accumulate massively in quiescent cells. Taken together, our data demonstrate that Rap1-Bqt4-dependent telomere association to NE preserves telomere integrity in post-mitotic cells, preventing telomeric transcription and recombination. This defines the nuclear periphery as an area where recombination is restricted, creating a safe zone for telomeres of post-mitotic cells.

RevDate: 2020-01-25

Udroiu I (2020)

On the correlation between telomere shortening rate and life span.

RevDate: 2020-01-25

Whittemore K, MA Blasco (2020)

Reply to Udroiu: Interesting mathematical analysis of telomere shortening rate and life span.

Proceedings of the National Academy of Sciences of the United States of America pii:1921935117 [Epub ahead of print].

RevDate: 2020-01-24

Mormile R (2020)

Leukocyte Telomere Length and Pancreatic Cancer Survival: a Consequence of Activation of IL-6 Signaling Pathway in the Carcinogenic Process?.

RevDate: 2020-01-24

Feng E, Batenburg NL, Walker JR, et al (2020)

CSB cooperates with SMARCAL1 to maintain telomere stability in ALT cells.

Journal of cell science pii:jcs.234914 [Epub ahead of print].

Elevated replication stress is evident at telomeres of about 10-15% of cancer cells, which maintain their telomeres via a homologous recombination (HR)-based mechanism, referred to as alternative lengthening of telomeres (ALT). How ALT cells resolve replication stress to support their growth remains incompletely characterized. Here we report that CSB promotes recruitment of HR repair proteins (MRN, BRCA1, BLM, RPA32) and POLD3 to ALT telomeres, a process that requires CSB's ATPase activity and is controlled by ATM- and CDK2-dependent phosphorylation. Loss of CSB stimulates telomeric recruitment of MUS81 and SLX4, components of the structure-specific MUS81-EME1-SLX1-SLX4 (MUS-SLX) endonuclease complex, suggesting that CSB restricts MUS-SLX-mediated processing of stalled forks at ALT telomeres. Loss of CSB coupled with depletion of SMARCAL1, a chromatin remodeler implicated in catalyzing regression of stalled forks, synergistically promotes not only telomeric recruitment of MUS81 but also the formation of fragile telomeres, the latter of which is reported to arise from fork stalling. These results altogether suggest that CSB-mediated HR repair and SMARCAL1-mediated fork regression cooperate to prevent stalled forks from being processed into fragile telomeres in ALT cells.

RevDate: 2020-01-23

Song N, Li Z, Qin N, et al (2020)

Shortened Leukocyte Telomere Length Associates with an Increased Prevalence of Chronic Health Conditions among Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-2503 [Epub ahead of print].

PURPOSE: We aimed to analyze and compare leukocyte telomere length (LTL) and age-dependent LTL attrition between childhood cancer survivors and non-cancer controls, and to evaluate the associations of LTL with treatment exposures, chronic health conditions (CHCs), and health behaviors among survivors.

EXPERIMENTAL DESIGN: We included 2,427 survivors and 293 non-cancer controls of European ancestry, drawn from the participants in St. Jude Lifetime Cohort Study (SJLIFE), a retrospective hospital-based study with prospective follow-up (2007-2016). Common non-neoplastic CHCs (59 types) and subsequent malignant neoplasms (5 types) were clinically assessed. LTL was measured with whole-genome sequencing data.

RESULTS: After adjusting for age at DNA sampling, gender, genetic risk score based on 9 SNPs known to be associated with telomere length, and eigenvectors, LTL among survivors was significantly shorter both overall (adjusted mean [AM]=6.20kb; SE=0.03kb) and across diagnoses than controls (AM=6.69kb; SE=0.07kb). Among survivors, specific treatment exposures associated with shorter LTL included chest or abdominal irradiation, glucocorticoid, and vincristine chemotherapies. Significant negative associations of LTL with 14 different CHCs, and a positive association with subsequent thyroid cancer occurring out of irradiation field were identified. Health behaviors were significantly associated with LTL among survivors aged 18-35 years (ptrend=0.03).

CONCLUSIONS: LTL is significantly shorter among childhood cancer survivors than non-cancer controls, and is associated with CHCs and health behaviors, suggesting LTL as an aging biomarker may be a potential mechanistic target for future intervention studies designed to prevent or delay onset of CHCs in childhood cancer survivors.

RevDate: 2020-01-22

Niu F, Li J, Li J, et al (2017)

Polymorphisms of telomere-length related genes in three China ethnic groups.

International journal of clinical and experimental pathology, 10(9):9654-9665.

Little is known about polymorphic distribution of telomere-length related genes among ethnicities, which play important roles in the progression of high-altitude pulmonary edema (HAPE). We genotyped 45 single nucleotide polymorphism (SNP) in 300 unrelated healthy volunteers from the following three Chinese ethnic populations: Han (n = 100), Tibetan (n = 100) and Sherpa (n = 100). We used χ2 test, pairwise FST values, and structure clustering analyses to investigate the genetic differences between these populations. Our results first indicated that rs12615793 (ACYP2), rs10936599 (TERC), rs10069690 (TERT) and rs6010620, rs4809324 (RTEL1) showed the greatest number of significant differences between Han and Tibetan, Sherpa and 11 HapMap populations. Meanwhile, we found that rs1056654 and rs1056629 (MPHOSPH6), rs2320615 (NAF1), rs6010621 (RTEL1), rs8105767 and rs2188972 (ZNF208) genotype frequencies showed considerable divergence among Tibetan and Sherpa. Besides, pairwise FST values and structure clustering analyses revealed that Han exhibited a close genetic affinity with CHD and CHB, but revealed a great genetic heterogeneity with YRI and MKK. This work greatly expanded our understanding of the distribution of telomere-length related genes in Chinese populations and may be helpful to forensic applications and population genetic studies.

RevDate: 2020-01-22

Hao F, Liu J, Zhong M, et al (2017)

Association between clincopathological characteristics and hTERT expression as well as telomere length in ameloblastoma.

International journal of clinical and experimental pathology, 10(8):8647-8653.

OBJECTIVE: This study aimed to investigate the human telomerase reverse transcriptase (hTERT) expression and telomere length in ameloblastoma, and expolre the role of hTERT in the invasiveness and recurrence of ameloblastoma.

METHODS: hTERT expression was detected by immunohistochemistry and Western blotting and telomere length by fluorescence in situ hybridization (FISH) in human ameloblastoma, normal mucosa, and oral squamous cell carcinoma (OSCC). Association between clincopathological characteristics and hTERT expression as well as telomere length in ameloblastoma was analyzed.

RESULTS: hTERT expression in ameloblastoma was higher than that in normal oral mucosa, and the highest in OSCC (P<0.05). The hTERT positive rate and expression increased with the recurrence and malignant transformation. hTERT expression was significantly different among different types of ameloblastoma. The telomere was the shortest in OSCC and the longest in normal oral mucosa.

CONCLUSION: Ameloblastoma has shortened telomere, and is positive for hTERT expression which is related to the recurrence and malignancy of ameloblastoma. These findings indicate that telomerase is involved in the occurrence and development of ameloblastoma.

RevDate: 2020-01-22

Antoun S, Atallah D, Tahtouh R, et al (2020)

Glucose restriction combined with chemotherapy decreases telomere length and cancer antigen-125 secretion in ovarian carcinoma.

Oncology letters, 19(2):1338-1350.

Although chemotherapy is the standard treatment for ovarian cancer (OC), recent studies have focused on its coupling with hypoglycemic drugs to decrease glucose availability. Similarly to cancer antigen 125 (Ca-125), telomerase, the key protein for telomere lengthening, is overexpressed in 90% of OC cases. The aim of the present study was to investigate the effect of the combination of glucose restriction and chemotherapy on telomere length and Ca-125 secretion in OC cells. SKOV-3, OVCAR-3 and Igrov-1 cells were treated with 20 µM cisplatin and 100 nM paclitaxel for 48 h in three different glucose concentrations: i) 4.5 g/l, ii) 1 g/l and iii) 0.5 g/l. The same treatment was repeated once per week for 6 consecutive weeks. The surviving cells were considered platinum-taxane escape (PTES) cells. The expression levels of telomerase and Ca-125 in treated and PTES cells were quantified by qPCR, and Ca-125 secretion by ELISA. Telomere length was evaluated by qPCR according to the Cawthon method. The modulation of Ca-125 by telomerase was assessed using inhibitors, small interfering RNA and transfection with human telomerase reverse transcriptase (hTERT) vectors. The implication of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) in Ca-125 modulation was investigated using specific inhibitors. An increase in hTERT and Ca-125 expression levels (range, 1.5-3 fold) was observed in short-term treated cells. However, an opposite effect was detected in PTES cells, where the rate of decrease in the expression levels of hTERT and Ca-125 reached 60% after treatment in 0.5 g/l glucose. Moreover, telomere length was decreased by 30% in cells treated with 0.5 g/l glucose. Inhibition of hTERT expression significantly decreased Ca-125 secretion, suggesting a potential modulation of Ca-125 by hTERT. The inhibition of the PI3K/Akt/mTOR pathway also decreased Ca-125 secretion; however, the effect of this treatment was not enhanced when coupled with telomerase inhibitors. In conclusion, the combination of chemotherapy and glucose restriction was observed to decrease Ca-125 secretion and telomerase expression leading to shortening in telomere length. Thus, decreasing glucose availability for OC cells during treatment may lead to a better clinical outcome and potentially improve the prognosis of patients with OC.

RevDate: 2020-01-22

Lew LC, Hor YY, Jaafar MH, et al (2019)

Lactobacilli modulated AMPK activity and prevented telomere shortening in ageing rats.

Beneficial microbes, 10(8):883-892.

This study aimed to evaluate the anti-ageing effects of different strains of lactobacilli putative probiotics on an ageing rat model as induced by D-galactose and a high fat diet. Male Sprague-Dawley rats were fed with high fat diet (54% kcal fat) and injected with D-galactose daily for 12 weeks to induce ageing. The effects of putative probiotic strains on age-related impairment such as telomere length, plasma lipid peroxidation, hepatic 5'adenosine monophosphate-activated protein kinase (AMPK) expression, as well as endurance performance were evaluated. Administration of statin, Lactobacillus plantarum DR7 (LP-DR7), Lactobacillus fermentum DR9 (LF-DR9), and Lactobacillus reuteri 8513d (LR-8513d) significantly reduced the shortening of telomere and increased the expression of AMPK subunit-α1 (P<0.05). Plasma lipid peroxidation was lower (P<0.05) in groups administered with statin and LF-DR9 as compared to the control. AMPK subunit-α2 was elevated in rats administered with LP-DR7 as compared to the control (P<0.05). Using an in vivo ageing rat model, the current study has illustrated the potentials of lactobacilli putative probiotics in alleviation of age-related impairment in a strain-dependent manner.

RevDate: 2020-01-21

Beijers R, Hartman S, Shalev I, et al (2020)

Testing three hypotheses about effects of sensitive-insensitive parenting on telomeres.

Developmental psychology, 56(2):237-250.

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research (n = 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differential-susceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

RevDate: 2020-01-21

Ferreira MSV, Sørensen MD, Pusch S, et al (2020)

Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.

Journal of neuro-oncology pii:10.1007/s11060-020-03394-y [Epub ahead of print].

PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance.

METHODS: We analyzed cell-specific telomere length (CS-TL) on a single cell level in 46 astrocytoma samples (WHO II-IV) by modified immune-quantitative fluorescence in situ hybridization, using endothelial cells as internal reference. In the same samples, we determined IDH1/TERT promoter mutation status and ATRX expression. The interaction of IDH1R132H mutation and CS-TL was studied in vitro using an IDH1R132H doxycycline-inducible glioma cell line system.

RESULTS: Virtually all ALTpositive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALTpositive samples had IDH1R132H mutations, resulting in a significantly longer CS-TL of IDH1R132H gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDHwildtype, ATRX expression, lack of ALT and short CS-TL. ALT, TERT promoter mutations, and CS-TL remained without prognostic significance, when correcting for IDH1 status. In vitro, overexpression of IDHR132H in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT.

CONCLUSION: ALT is the major telomere maintenance mechanism in IDHR132H mutated astrocytomas, while TERT promoter mutations were associated with IDHwildtype glioma. IDH1R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1R132H mutations, ATRX loss, and ALT.

RevDate: 2020-01-21

Boscolo-Rizzo P, Giunco S, Rampazzo E, et al (2020)

TERT promoter hotspot mutations and their relationship with TERT levels and telomere erosion in patients with head and neck squamous cell carcinoma.

Journal of cancer research and clinical oncology pii:10.1007/s00432-020-03130-z [Epub ahead of print].

PURPOSE: To evaluate the prevalence of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of the gene encoding telomerase reverse transcriptase (TERT) as well as their relationship with TERT level, telomeres length, and outcome in patients with head and neck squamous cell carcinomas (HNSCCs).

METHODS: We evaluate the prevalence of TERT promoter mutations, TERT levels, and telomere length in paired cancer tissue and adjacent mucosa (AM) in a series of HNSCCs.

RESULTS: Cancer tissue and AM specimens from 105 patients were analyzed. Telomere length and TERT mRNA levels were estimated using real-time polymerase chain reaction. TERT promoter mutations were assessed using Sanger sequencing. Out of 105 cases, 101 were considered suitable for the analysis. TERT promoter harbored mutations in 12 tumors (11.9%), with -124 C>T and -146 C>T accounting for 83.3% and 16.7% of the alterations, respectively. No mutations were detected in AM samples. The prevalence of TERT promoter mutations was significantly higher in oral cavity SCCs (10 out of 27 tumors; 37%), and telomere length in AM was shorter in patients with tumors carrying TERT promoter mutations than in patients with unmutated TERT promoter cancers (p = 0.023). TERT levels in tumor did not significantly differ according to the mutational status of TERT promoter. No significant association was found between TERT promoter status and overall survival.

CONCLUSION: TERT promoter mutations are most likely a late event in tumor development, occurring in a context of critically short telomeres, mostly in patients with oral cavity SCC. TERT levels, but not TERT promoter mutational status impact clinical outcome.

RevDate: 2020-01-20

Jimbo K, Konuma T, Mizukami M, et al (2020)

Telomere length in CD4+ and CD8+ T cells among long-term survivors of adults after single cord blood transplantation.

Telomeres are essential for maintaining genomic and cellular stability and replication. Telomere length (TL) shorten with each cell division, and its shortening is associated with aging, senescence, and replication capacity. In an allogeneic hematopoietic cell transplantation (HCT) setting, most of studies showed that leukocyte or T cell telomeres of recipients after HCT were shorter than respective donors and age-matched controls [1].

RevDate: 2020-01-20

Kemp BR, KF Ferraro (2020)

Are Biological Consequences of Childhood Exposures Detectable in Telomere Length Decades Later?.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5709676 [Epub ahead of print].

Negative early-life exposures have been linked to a host of poor adult health outcomes, but are such early exposures associated with cellular senescence decades later? This study uses data from the Health and Retirement Study to examine the association between six childhood exposure domains (e.g., socioeconomic disadvantage, risky parental behavior) and a biomarker of aging, telomere length, among 4,935 respondents. Telomere length is obtained from DNA of cells found in saliva and is measured as the telomere repeat copy number to single gene copy number ratio (T/S). Men who as children were exposed to risky parental behaviors or who reported risky adolescent behaviors have shorter telomeres (respectively: b=-0.031, p=0.052; b=-0.041, p=0.045); however, these relationships are attenuated after adjusting for adult risks and resources. Among women, parental substance abuse is associated with shorter telomeres even after adjusting for adult risks and resources (b=-0.041, p=0.005). In addition, men and women whose mother lived at least until the age of 85 have longer telomeres than those without a long-lived mother (respectively: b=0.021, p=0.045; b=0.032, p=0.005). Taken together, the ways in which early-life exposures are associated with adult telomeres vary for men and women.

RevDate: 2020-01-20

de Pedro N, Díez M, García I, et al (2020)

Analytical Validation of Telomere Analysis Technology® for the High-Throughput Analysis of Multiple Telomere-Associated Variables.

Biological procedures online, 22:2 pii:115.

Background: A large number of studies have suggested a correlation between the status of telomeres and disease risk. High-throughput quantitative fluorescence in situ hybridization (HT Q-FISH) is a highly accurate telomere measurement technique that can be applied to the study of large cell populations. Here we describe the analytical performance testing and validation of Telomere Analysis Technology (TAT®), a laboratory-developed HT Q-FISH-based methodology that includes HT imaging and software workflows that provide a highly detailed view of telomere populations.

Methods: TAT was developed for the analysis of telomeres in peripheral blood mononuclear cells (PBMCs). TAT was compared with Terminal Restriction Fragment (TRF) length analysis, and tested for accuracy, precision, limits of detection (LOD) and specificity, reportable range and reference range.

Results: Using 6 different lymphocyte cell lines, we found a high correlation between TAT and TRF for telomere length (R2 ≥ 0.99). The standard variation (assay error) of TAT was 454 base pairs, and the limit of detection of 800 base pairs. A standard curve was constructed to cover human median reportable range values and defined its lower limit at 4700 bp and upper limits at 14,400 bp. Using TAT, up to 223 telomere associated variables (TAVs) can be obtained from a single sample. A pilot, population study, of telomere analysis using TAT revealed high accuracy and reliability of the methodology.

Conclusions: Analytical validation of TAT shows that is a robust and reliable technique for the characterization of a detailed telomere profile in large cell populations. The combination of high-throughput imaging and software workflows allows for the collection of a large number of telomere-associated variables from each sample, which can then be used in epidemiological and clinical studies.

RevDate: 2020-01-18

Zhao Y, Wang B, Wang G, et al (2020)

Functional interaction between plasma phospholipid fatty acids and insulin resistance in leucocyte telomere length maintenance.

Lipids in health and disease, 19(1):11 pii:10.1186/s12944-020-1194-1.

BACKGROUND: Previous evidence suggests that plasma phospholipid fatty acids (PPFAs) and HOMA insulin resistance (HOMA-IR) are independently related to leukocyte telomere length (LTL). However, there is limited evidence of regarding the effect of their interaction on relative LTL (RLTL). Therefore, here, we aimed to determine the effect of the interaction between PPFAs and HOMA-IR on RLTL.

METHODS: We conducted a cross-sectional study, involving a total of 1246 subjects aged 25-74 years. PPFAs and RLTL were measured, and HOMA-IR was calculated. The effect of the interaction between PPFAs and HOMA-IR on RLTL was assessed by univariate analysis, adjusting for potential confounders.

RESULTS: In age-adjusted analyses, multivariate linear regression revealed a significant association of the levels of elaidic acid, HOMA-IR, monounsaturated fatty acids (MUFA) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) with RLTL. After adjustment of age and gender, race, smoking, drinking, tea, and exercise, elaidic acid, and omega-3 (n-3) PUFA were negatively associated with RLTL, and HOMA-IR and n-6 PUFA were positively associated with RLTL. These associations were not significantly altered upon further adjustment for anthropometric and biochemical indicators. Meanwhile, the effect of the interaction of elaidic acid and HOMA-IR on RLTL was significant, and remained unchanged even after adjusting for the aforementioned potential confounders. Interestingly, individuals who had the lowest HOMA-IR and the highest elaidic acid levels presented the shortest RLTL.

CONCLUSIONS: Our findings indicated that shorter RLTL was associated with lower HOMA-IR and higher elaidic acid level. These findings might open a new avenue for exploring the potential role of the interaction between elaidic acid and HOMA-IR in maintaining RLTL.

RevDate: 2020-01-17

Brandao CFC, Nonino CB, de Carvalho FG, et al (2020)

The effects of short-term combined exercise training on telomere length in obese women: a prospective, interventional study.

Sports medicine - open, 6(1):5 pii:10.1186/s40798-020-0235-7.

BACKGROUND: Telomere length is inversely associated with the senescence and aging process. Parallelly, obesity can promote telomere shortening. Evidence suggests that physical activity may promote telomere elongation.

OBJECTIVE: This study's objective is to evaluate the effects of combined exercise training on telomere length in obese women.

DESIGN AND METHODS: Twenty pre-menopausal women (BMI 30-40 kg/m2, 20-40 years) submitted to combined training (strength and aerobic exercises), but only 13 finished the protocol. Each exercise session lasted 55 min/day, three times a week, throughout 8 weeks. Anthropometric data, body composition, physical performance (Vo2max), and 8-h fasting blood samples were taken before and after 8 weeks of training. Leukocyte DNA was extracted for telomere length by RT-qPCR reaction, using the 2-ΔΔCt methodology.

RESULTS: After the training intervention, significant differences (p < 0.05) were observed in telomere length (respectively before and after, 1.03 ± 0.04 to 1.07 ± 0.04 T/S ratio), fat-free mass (46 ± 7 to 48 ± 5 kg), Vo2max (35 ± 3 to 38 ± 3 ml/kg/min), and waist circumference (96 ± 8 to 90 ± 6 cm). In addition, an inverse correlation between waist circumference and telomere length was found, before (r = - 0.536, p = 0.017) and after (r = - 0.655, p = 0.015) exercise training.

CONCLUSION: Combined exercise promoted leukocyte telomere elongation in obese women. Besides, the data suggested that greater waist circumference may predict shorter telomere length.

CLINICAL TRIAL REGISTRATION:, NCT03119350. Retrospectively registered on 18 April 2017.

RevDate: 2020-01-17

Zhang X, Wang Y, Zhao R, et al (2019)

Folic Acid Supplementation Suppresses Sleep Deprivation-Induced Telomere Dysfunction and Senescence-Associated Secretory Phenotype (SASP).

Oxidative medicine and cellular longevity, 2019:4569614.

Sleep deprivation is reported to cause oxidative stress and is hypothesized to induce subsequent aging-related diseases including chronic inflammation, Alzheimer's disease, and cardiovascular disease. However, how sleep deprivation contributes to the pathogenesis of sleep deficiency disorder remains incompletely defined. Accordingly, more effective treatment methods for sleep deficiency disorder are needed. Thus, to better understand the detailed mechanism of sleep deficiency disorder, a sleep deprivation mouse model was established by the multiple platform method in our study. The accumulation of free radicals and senescence-associated secretory phenotype (SASP) was observed in the sleep-deprived mice. Moreover, our mouse and human population-based study both demonstrated that telomere shortening and the formation of telomere-specific DNA damage are dramatically increased in individuals suffering from sleeplessness. To our surprise, the secretion of senescence-associated cytokines and telomere damage are greatly improved by folic acid supplementation in mice. Individuals with high serum baseline folic acid levels have increased resistance to telomere shortening, which is induced by insomnia. Thus, we conclude that folic acid supplementation could be used to effectively counteract sleep deprivation-induced telomere dysfunction and the associated aging phenotype, which may potentially improve the prognosis of sleeplessness disorder patients.

RevDate: 2020-01-17

Mayr FB, S Yende (2020)

Size matters! Peripheral blood leukocyte telomere length and survival after critical illness.

The European respiratory journal, 55(1): pii:55/1/1902114.

RevDate: 2020-01-17

Denham J (2019)

The association between sperm telomere length, cardiorespiratory fitness and exercise training in humans.

Biomedical journal, 42(6):430-433.

Telomeres protect genomic integrity and shorten in somatic cells due to the end replication problem. Sperm telomeres are, however, longer in older individuals and linked to semen quality. Exercise training may attenuate age-related telomere shortening in somatic cells, but the influence of exercise on sperm telomeres is unknown. Mature sperm from 34 healthy men were isolated by density gradient centrifugation and telomere length was assessed by qPCR. No significant correlations were observed between telomere length, fitness or exercise performance. Inter-individual variation in sperm telomere length responses to a 6-wk vigorous exercise training intervention (ΔT/S ratio range: -0.49 to 0.87) and a strong correlation between improvements in fitness and sperm telomere lengthening were revealed (r = 0.87, p < 0.001). These preliminary data suggest exercise training may regulate sperm telomere length and should encourage larger studies to explore the implications this may have on the health of the next generation.

RevDate: 2020-01-17

Kite E, A Forer (2020)

The role of phosphorylation in the elasticity of the tethers that connect telomeres of separating anaphase chromosomes.

Nucleus (Austin, Tex.), 11(1):19-31.

Elastic tethers, connecting telomeres of all separating anaphase chromosome pairs, lose elasticity when they lengthen during anaphase. Treatment with phosphatase inhibitor CalyculinA causes anaphase chromosomes to move backwards after they reach the poles, suggesting that dephosphorylation causes loss of tether elasticity. We added 50nM CalyculinA to living anaphase crane-fly spermatocytes with different length tethers. When tethers were short, almost all partner chromosomes moved backwards after nearing the poles. When tethers were longer, fewer chromosomes moved backwards. With yet longer tethers none moved backward. This is consistent with tether elasticity being lost by dephosphorylation. 50nM CalyculinA blocks both PP1 and PP2A. To distinguish between PP1 and PP2A we treated cells with short tethers with 50nM okadaic acid which blocks solely PP2A, or with 1µM okadaic acid which blocks both PP1 and PP2A. Only 1µM okadaic acid caused chromosomes to move backward. Thus, tether elasticity is lost because of dephosphorylation by PP1.

RevDate: 2020-01-16

Monroe DM, Goldstein RL, Teylan MA, et al (2020)

Correction: Clinical associations with telomere length in chronic spinal cord injury.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RevDate: 2020-01-15

Pineda-Pampliega J, Herrera-Dueñas A, Mulder E, et al (2020)

Antioxidant supplementation slows telomere shortening in free-living white stork chicks.

Proceedings. Biological sciences, 287(1918):20191917.

Telomere length (TL) and shortening is increasingly shown to predict variation in survival and lifespan, raising the question of what causes variation in these traits. Oxidative stress is well known to accelerate telomere attrition in vitro, but its importance in vivo is largely hypothetical. We tested this hypothesis experimentally by supplementing white stork (Ciconia ciconia) chicks with antioxidants. Individuals received either a control treatment, or a supply of tocopherol (vitamin E) and selenium, which both have antioxidant properties. The antioxidant treatment increased the concentration of tocopherol for up to two weeks after treatment but did not affect growth. Using the telomere restriction fragment technique, we evaluated erythrocyte TL and its dynamics. Telomeres shortened significantly over the 21 days between the baseline and final sample, independent of sex, mass, size and hatching order. The antioxidant treatment significantly mitigated shortening rate of average TL (-31% in shorter telomeres; percentiles 10th, 20th and 30th). Thus, our results support the hypothesis that oxidative stress shortens telomeres in vivo.

RevDate: 2020-01-14

Praveen G, Shalini T, Sivaprasad M, et al (2020)

Relative Telomere Length and Mitochondrial DNA Copy Number Variation with Age: Association with Plasma Folate and Vitamin B12.

Mitochondrion pii:S1567-7249(19)30283-1 [Epub ahead of print].

Telomere attrition and mitochondrial DNA variations are implicated in the biological aging process and genomic stability can be influenced by nutritional factors. This study aims to analyze the relative telomere length (rTL) and mitochondrial DNA copy number (mtCN) in aged individuals and their association with plasma folate and vitamin B12 levels. This community-based cross-sectional study involves 428 subjects (<60 years: 242 & ≥60 years: 186). Quantitative real-time PCR was used to measure rTL and mtCN variation, and radioimmunoassay to measure plasma folate and vitamin B12 levels. The subjects in the ≥60 years age group have significantly shorter telomeres and lower mtCN compared to the <60 years age group. A significant positive correlation was observed between the rTL and mtCN, and both of them were positively associated with plasma folate and vitamin B12 levels. In the ≥60 age group; folate and vitamin B12 positively correlated with rTL and vitamin B12 with mtCN. The study revealed a decline of rTL and mtCN with age in the Indian population and their association suggests that they may co-regulate each other with age. In conclusion, folate and vitamin B12 may delay aging by preventing the reduction in rTL length and mtCN.

RevDate: 2020-01-14

Porreca RM, Herrera-Moyano E, Skourti E, et al (2020)

TRF1 averts chromatin remodelling, recombination and replication dependent-Break Induced Replication at mouse telomeres.

eLife, 9: pii:49817 [Epub ahead of print].

Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

RevDate: 2020-01-14

Axelsson J, Wapstra E, Miller E, et al (2020)

Contrasting seasonal patterns of telomere dynamics in response to environmental conditions in the ectothermic sand lizard, Lacerta agilis.

Scientific reports, 10(1):182 pii:10.1038/s41598-019-57084-5.

Telomeres, the protective, terminal parts of the chromosomes erode during cell division and as a result of oxidative damage by reactive oxygen species (ROS). Ectotherms rely on the ambient temperature for maintaining temperature-dependent metabolic rate, regulated through behavioural thermoregulation. Their temperature-dependant metabolism, hence also the ROS production, is indirectly regulated through thermoregulation. Consequently, a potential causal chain affecting telomere length and attrition is: temperature (in particular, its deviation from a species-specific optimum) - metabolism - ROS production - anti-oxidation - telomere erosion. We measured telomere length in sand lizards (Lacerta agilis) using qPCR on blood samples from 1998-2006. Effects of climatological parameters (mean temperature and average sunshine hours) in the summer and winter preceding telomere sampling were used as predictors of telomere length in mixed model analysis. During the lizards' active period (summer), there was a largely negative effect of mean temperature and sun on telomere length, whereas a combined measure of age and size (head length) was positively related to telomere length. During the inactive period of lizards (winter), the results were largely the opposite with a positive relationship between temperature and sunshine hours and telomere length. In all four cases, thermal and age effects on telomere length appeared to be non-linear in the two sexes and seasons, with complex response surface effects on telomere length from combined age and thermal effects.

RevDate: 2020-01-14

Barg-Wojas A, Muraszko J, Kramarz K, et al (2020)

S. pombe DNA translocases Rrp1 and Rrp2 have distinct roles at centromeres and telomeres that ensure genome stability.

Journal of cell science pii:jcs.230193 [Epub ahead of print].

The regulation of telomere and centromere structure and function is essential for maintaining genome integrity. Schizosaccharomyces pombe Rrp1 and Rrp2 are orthologues of Saccharomyces cerevisiae Uls1, a SWI2/SNF2 DNA translocase and SUMO-Targeted Ubiquitin Ligase. Here we show that Rrp1 or Rrp2 overproduction leads to chromosome instability and growth defects, a reduction of global histone levels and mislocalisation of centromere-specific histone Cnp1. These phenotypes depend on putative DNA translocase activities of Rrp1 and Rrp2, suggesting that Rrp1 and Rrp2 may be involved in modulating nucleosome dynamics. Furthermore, we confirm that Rrp2, but not Rrp1, acts at telomeres, reflecting a previously described interaction between Rrp2 and Top2. In conclusion, we identify roles for Rrp1 and Rrp2 in maintaining centromere function by modulating histone dynamics, contributing to the preservation of genome stability during vegetative cell growth.

RevDate: 2020-01-13

He H, Li W, Comiskey DF, et al (2020)

A truncating germline mutation of TINF2 in individuals with thyroid cancer or melanoma results in longer telomeres.

Thyroid : official journal of the American Thyroid Association [Epub ahead of print].

BACKGROUND: Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene TINF2 gene in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here we further characterized the mutation and screened for coding variants in the six shelterin genes in 24 families.

METHODS: Sanger sequencing was performed to screen for the TINF2 mutation in the key family. Quantitative RT-PCR was used for TINF2 gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes using quantitative real-time PCR. Whole exome sequencing (WES) was performed in 7 families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed using whole genome sequencing data from 17 families and WES data from 7 families.

RESULTS: The TINF2 mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of TINF2 was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families we identified 3 missense and 1 synonymous variant(s) in two shelterin genes (TINF2 and ACD).

CONCLUSIONS: The rare frameshift mutation in the TINF2 gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.

RevDate: 2020-01-13

Chae DH, Wang Y, Martz CD, et al (2020)

Racial discrimination and telomere shortening among African Americans: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Health psychology : official journal of the Division of Health Psychology, American Psychological Association pii:2020-00718-001 [Epub ahead of print].

OBJECTIVE: Telomeres are protective sequences of DNA capping the ends of chromosomes that shorten over time. Leukocyte telomere length (LTL) is posited to reflect the replicative history of cells and general systemic aging of the organism. Chronic stress exposure leads to accelerated LTL shortening, which has been linked to increased susceptibility to and faster progression of aging-related diseases. This study examined longitudinal associations between LTL and experiences of racial discrimination, a qualitatively unique source of minority psychosocial stress, among African Americans.

METHOD: Data are from 391 African Americans in the Coronary Artery Risk Development in Young Adults (CARDIA) Telomere Ancillary Study. We examined the number of domains in which racial discrimination was experienced in relation to LTL collected in Years 15 and 25 (Y15: 2000/2001; Y25: 2010/2011). Multivariable linear regression examined if racial discrimination was associated with LTL. Latent change score analysis (LCS) examined changes in racial discrimination and LTL in relation to one another.

RESULTS: Controlling for racial discrimination at Y15, multivariable linear regression analyses indicated that racial discrimination at Y25 was significantly associated with LTL at Y25. This relationship remained robust after adjusting for LTL at Y15 (b = -.019, p = .015). Consistent with this finding, LCS revealed that increases in experiences of racial discrimination were associated with faster 10-year LTL shortening (b = -.019, p = .015).

CONCLUSIONS: This study adds to evidence that racial discrimination contributes to accelerated physiologic weathering and health declines among African Americans through its impact on biological systems, including via its effects on telomere attrition. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

RevDate: 2020-01-13

Wieczór M, J Czub (2020)

Telomere uncapping by common oxidative guanine lesions: Insights from atomistic models.

Free radical biology & medicine pii:S0891-5849(19)32325-1 [Epub ahead of print].

Oxidative damage to DNA is widely known to contribute to aging and disease. This relationship has been extensively studied for telomeres - structures that cap chromosome ends - due to their role in cell proliferation and senescence, and exceptional susceptibility to oxidation. Indeed, the repetitive telomeric DNA sequence contains the 5'-GGG-3' motif that has the lowest ionization potential of all trinucleotides. Accordingly, experiments consistently show that telomeric oxidative lesions are more abundant and persistent than elsewhere in the genome. This led to a hypothesis that telomeres act as sensors of prolonged oxidative stress and prevent carcinogenesis, as disruption of telomeric integrity triggers senescence or apoptosis. Here, we use atomistic alchemical Molecular Dynamics simulations to perform a combinatorial assessment of changes in DNA binding affinity of telomeric proteins induced by oxidative guanine lesions. We rank lesions by their effect on telomere integrity, as well as telomeric proteins by their sensitivity to DNA oxidation. While the binding of most proteins is abolished by DNA oxidation, HOT1 emerges as a notable exception, suggesting its potential role in sensing of oxidative damage. Through statistical analysis and free energy decomposition, we also identify common trends in structural responses of protein-DNA complexes that contribute to decreased binding affinity.

RevDate: 2020-01-11

Adam N, Degelman E, Briggs S, et al (2019)

Telomere analysis using 3D fluorescence microscopy suggests mammalian telomere clustering in hTERT-immortalized Hs68 fibroblasts.

Communications biology, 2(1):451 pii:10.1038/s42003-019-0692-z.

Telomere length and dynamics are central to understanding cell aging, genomic instability and cancer. Currently, there are limited guidelines for analyzing telomeric features in 3D using different cellular models. Image processing for telomere analysis is of increasing interest in many fields, however a lack of standardization can make comparisons and reproducibility an issue. Here we provide a user's guide for quantitative immunofluorescence microscopy of telomeres in interphase cells that covers image acquisition, processing and analysis. Strategies for determining telomere size and number are identified using normal human diploid Hs68 fibroblasts. We demonstrate how to accurately determine telomere number, length, volume, and degree of clustering using quantitative immunofluorescence. Using this workflow, we make the unexpected observation that hTERT-immortalized Hs68 cells with longer telomeres have fewer resolvable telomeres in interphase. Rigorous quantification indicates that this is due to telomeric clustering, leading to systematic underestimation of telomere number and overestimation of telomere size.

RevDate: 2020-01-11

Spindler MC, Redolfi J, Helmprobst F, et al (2019)

Electron tomography of mouse LINC complexes at meiotic telomere attachment sites with and without microtubules.

Communications biology, 2(1):376 pii:10.1038/s42003-019-0621-1.

Telomere movements during meiotic prophase I facilitate synapsis and recombination of homologous chromosomes. Hereby, chromosome movements depend on the dynamic attachment of meiotic telomeres to the nuclear envelope and generation of forces that actively move the telomeres. In most eukaryotes, forces that move telomeres are generated in the cytoplasm by microtubule-associated motor proteins and transduced into the nucleus through the LINC complexes of the nuclear envelope. Meiotic LINC complexes, in mouse comprised of SUN1/2 and KASH5, selectively localize to the attachment sites of meiotic telomeres. For a better understanding of meiotic telomere dynamics, here we provide quantitative information of telomere attachment sites that we have generated with the aid of electron microscope tomography (EM tomography). Our data on the number, length, width, distribution and relation with microtubules of the reconstructed structures indicate that an average number of 76 LINC complexes would be required to move a telomere attachment site.

RevDate: 2020-01-11

Mennie AK, Moser BA, Hoyle A, et al (2019)

Tpz1TPP1 prevents telomerase activation and protects telomeres by modulating the Stn1-Ten1 complex in fission yeast.

Communications biology, 2(1):297 pii:10.1038/s42003-019-0546-8.

In both mammalian and fission yeast cells, conserved shelterin and CST (CTC1-STN1-TEN1) complexes play critical roles in protection of telomeres and regulation of telomerase, an enzyme required to overcome the end replication problem. However, molecular details that govern proper coordination among shelterin, CST, and telomerase have not yet been fully understood. Here, we establish a conserved SWSSS motif, located adjacent to the Lys242 SUMOylation site in the fission yeast shelterin subunit Tpz1, as a new functional regulatory element for telomere protection and telomere length homeostasis. The SWSSS motif works redundantly with Lys242 SUMOylation to promote binding of Stn1-Ten1 at telomere and sub-telomere regions to protect against single-strand annealing (SSA)-dependent telomere fusions, and to prevent telomerase accumulation at telomeres. In addition, we provide evidence that the SWSSS motif defines an unanticipated role of Tpz1 in limiting telomerase activation at telomeres to prevent uncontrolled telomere elongation.

RevDate: 2020-01-11

da Silva GG, Morais KS, Arcanjo DS, et al (2020)

Clinical relevance of Alternative lengthening of telomeres in cancer.

Current topics in medicinal chemistry pii:CTMC-EPUB-103600 [Epub ahead of print].

The alternative lengthening of telomere (ALT) is a pathway responsible for cell immortalization in some kinds of tumors. Since the first description of ALT is relatively recent in the oncology field, its mechanism remains elusive, but recent works address ALT-related proteins or cellular structures as potential druggable targets for more specific and efficient antitumor therapies. Also, some new generation compounds for antitelomerase therapy in cancer were able to provoke acquisition of ALT phenotype in treated tumors, enhancing the importance of studies on this alternative lengthening of telomere. However, ALT has been implicated in different - sometimes opposite - outcomes, according to tumor type studied. Then, in order to design and to develop new drugs for ALT+ cancer in an effective way, it is crucial to understand its clinical implications. In this review, we gathered works published in the last two decades to highlight the clinical relevance of ALT on oncology.

RevDate: 2020-01-10

Michels KB, De Vivo I, Calafat AM, et al (2019)

In utero exposure to endocrine-disrupting chemicals and telomere length at birth.

Environmental research, 182:109053 pii:S0013-9351(19)30850-3 [Epub ahead of print].

Telomere length correlates with morbidity and mortality. While telomere length appears to be influenced by hormone levels, the potential impact of exposure to endocrine-disrupting chemicals (EDCs) has not been studied. We examined the association between maternal gestational concentrations of biomarkers of EDC exposure and telomere length at birth in the Harvard Epigenetic Birth Cohort. EDC (phenols and phthalates) biomarker concentrations were measured in maternal spot urine samples during the first trimester and telomere length in maternal and cord blood collected at delivery among 181 mother-newborn singleton dyads. Maternal and newborn telomere length exhibited a positive correlation (Spearman ρ = 0.20 (p-value< 0.01). Infant telomere length was associated with maternal biomarker concentrations of specific EDCs, and most of these associations were observed to be infant sex-specific. Prenatal exposure to triclosan, a non-paraben phenol with antimicrobial properties, was one of the most strongly associated EDCs with telomere length; telomere length was 20% (95% CI 5%-33%) shorter among boys in the highest quartile of maternal biomarker concentrations compared to the lowest quartile. In contrast, we observed longer telomere length associated with increased gestational concentrations of mono-isobutyl phthalate, and among boys, with increased concentrations of mono-2-ethylhexyl phthalate. In this birth cohort, we observed associations between maternal gestational exposure to select EDC biomarkers and telomere length, most of which were sex-specific. These findings need to be confirmed in future studies.

RevDate: 2020-01-10

Ma Y, Bellini N, Harnung Scholten R, et al (2020)

Effect of combustion-derived particles on genotoxicity and telomere length: a study on human cells and exposed populations.

Toxicology letters pii:S0378-4274(20)30002-3 [Epub ahead of print].

Particulate matter (PM) from combustion processes has been associated with oxidative stress to DNA, whereas effects related to telomere dysfunction are less investigated. We collected air-borne PM from a passenger cabin of a diesel-propelled train and at a training facility for smoke diving exercises. Effects on oxidative stress biomarkers, genotoxicity measured by the comet assay and telomere length in PM-exposed A549 cells were compared with the genotoxicity and telomere length in peripheral blood mononuclear cells (PBMCs) from human volunteers exposed to the same aerosol source. Although elevated levels of DNA strand breaks and oxidatively damaged DNA in terms of Fpg-sensitive sites were observed in PBMCs from exposed humans, the PM collected at same locations did not cause genotoxicity in the comet assay in A549 cells. Nevertheless, A549 cells displayed telomere length shortening after four weeks exposure to PM. This is in line with slightly shorter telomere length in PBMCs from exposed humans, although it was not statistically significant. In conclusion, the results indicate that genotoxic potency measured by the comet assay of PM in A549 cells may not predict genotoxicity in exposed humans, whereas telomere length measurements may be a novel indicator of genotoxic stress in cell cultures and humans.

RevDate: 2020-01-10

Chan D, Martin-Ruiz C, Saretzki G, et al (2020)

The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome.

PloS one, 15(1):e0227616 pii:PONE-D-19-23361.

BACKGROUND: Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care.

METHOD: Older patients undergoing invasive management for NSTEACS were recruited to the ICON-1 biomarker study (NCT01933581). Peripheral blood mononuclear cells (PBMC) were recovered on 153 patients. DNA was isolated and mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio (T/S ratio), and a telomere repeat amplification assay was used to assess TA during index presentation with NSTEACS. Primary clinical outcomes consisted of death, myocardial infarction (MI), unplanned revascularisation, stroke and significant bleeding recorded at 1 year. TL and TA were divided into tertile groups for analysis. Cox proportional hazards regression was performed. Ordinal regression was performed to evaluate the relationship between TL and TA and traditional cardiovascular risk factors at baseline.

RESULTS: 298 patients were recruited in the ICON-1 study of which 153 had PBMC recovered. The mean age was 81.0 ± 4.0 years (64% male). Mean telomere length T/S ratio was 0.47 ± 0.25 and mean TA was 1.52 ± 0.61 units. The primary composite outcome occurred in 44 (28.8%) patients. There was no association between short TL or low TA and incidence of the primary composite outcome (Hazard Ratio [HR] 1.50, 95% Confidence Interval [CI] 0.68-3.34, p = 0.32 and HR 1.33, 95% CI 0.52-3.36, p = 0.51 respectively).

CONCLUSION: TL and TA are not found to be associated with the incidence of adverse outcomes in older patients presenting with NSTEACS undergoing invasive care.

CLINICAL TRIAL REGISTRATION: URL: Unique identifier: NCT01933581.

RevDate: 2020-01-10

Ma TZ, Zhang MJ, Liao TC, et al (2020)

Dimers formed with the mixed-type G-quadruplex binder pyridostatin specifically recognize human telomere G-quadruplex dimers.

Organic & biomolecular chemistry [Epub ahead of print].

By choosing pyridostatin (PDS) with high thermal stabilization towards mixed-type G-quadruplexes as the monomer in dimers, three novel polyether-tethered PDS dimers (1a-c) were first synthesized and their interaction with human telomere G-quadruplex dimers (G2T1) was studied. Through the regulation of the linker length in PDS dimers, the dimer with a medium-length polyether linker (1b) showed higher binding selectivity and thermal stabilization (ΔTm = 29.5 °C) towards antiparallel G2T1 over G-quadruplex monomers (G1). Furthermore, the dimer with the longest-length polyether linker (1c) showed higher binding selectivity and thermal stabilization towards mixed-type G2T1 over mixed-type G1, c-kit 1, c-kit 2, c-myc and ds DNA. This work provides new insights into the development of G2T1 binders, especially mixed-type G2T1 binders, which could be promoted by a polymer formed with a mixed-type G-quadruplex binder. In addition, dimer 1c exhibited stronger telomerase inhibition than dimers 1a and 1b.

RevDate: 2020-01-10

Shi Y, Zhang Y, Zhang L, et al (2019)

Telomere Length of Circulating Cell-Free DNA and Gastric Cancer in a Chinese Population at High-Risk.

Frontiers in oncology, 9:1434.

Background: Telomeres have long been found to be involved in cancer development, while little was known about the dynamic changes of telomere length in carcinogenesis process. Methods: The present study longitudinally investigated telomere alterations of cell-free DNA (cfDNA) in 86 gastric cancer (GC) subjects recruited through a 16-year prospective cohort with 2-4 serums collected before each GC-diagnosis from baseline and three follow-up time-points (a total of 276 samples). As the control, 86 individual-matched cancer-free subjects were enrolled with 276 serums from the matched calendar year. Results: In the 73 pairs of baseline serums from GC and control subjects, shortened telomeres showed increased subsequent GC risk [odds ratio (OR) = 9.17, 95% CI: 2.72-31.25 for 1 unit shortening]. In each baseline gastric lesion category, higher risks of GC progression were also found with shortened cfDNA telomeres; ORs per 1 unit shortening were 6.99 (95% CI: 1.63-30.30) for mild gastric lesions, 6.06 (95% CI: 1.89-19.61) for intestinal metaplasia and 15.63 (95% CI: 1.91-125.00) for dysplasia. With all measurements from baseline and follow-up time-points, shortened telomeres also showed significant association with GC risk (OR = 7.37, 95% CI: 2.06-26.32 for 1 unit shortening). In temporal trend analysis, shortened telomeres were found in GC subjects compared to corresponding controls more than 3 years ahead of GC-diagnosis (most P < 0.05), while no significant difference was found between two groups within 3 years approaching to GC-diagnosis. Conclusion: Our findings suggest that telomere shortening may be associated with gastric carcinogenesis, which supports further etiological study and potential biomarker for risk stratification.

RevDate: 2020-01-10

Xu C, Wang Z, Su X, et al (2020)

Association between leucocyte telomere length and cardiovascular disease in a large general population in the United States.

Scientific reports, 10(1):80 pii:10.1038/s41598-019-57050-1.

Leucocyte telomere length (LTL) has been reported to be linked to ageing, cancer and cardiovascular disease (CVD). This study aimed to explore the association between LTL and CVD risk in a nationally representative sample of U.S. adults. Complex associations, including nonlinearity and interaction, were also examined. A total of 7,378 subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 were collected. Telomere length was detected from DNA samples and expressed as the mean T/S ratio (telomere repeats per single-copy gene). We performed multiple logistic regression models and interactive analysis to explore the associations between LTL and CVD risk by adjusting for potential confounders. We also performed a sensitivity analysis to investigate the robustness of our results. Among all participants, LTL was associated with the risk of CVD (OR = 0.79, 95% CI: 0.63~0.98, P = 0.033) in a linear manner rather than in a nonlinear manner (P = 0.874). Interaction effects of LTL with both education (P = 0.017) and hypertension (P = 0.007) were observed. Furthermore, using subgroup analyses, protective effects of LTL on CVD risk were found in females and in individuals who were college graduates or above, had serum cotinine >10 ng/ml, did not have hypertension, or had normal white blood cell levels. LTL is linearly inversely associated with CVD risk in the general population of the United States.

RevDate: 2020-01-09

Berei J, Eckburg A, Miliavski E, et al (2020)

Potential Telomere-Related Pharmacological Targets.

Current topics in medicinal chemistry pii:CTMC-EPUB-103579 [Epub ahead of print].

Telomeres function as protective caps at the terminal portion of chromosomes, containing non-coding nucleotide sequence repeats. As part of their protective function, telomeres preserve genomic integrity and minimize chromosomal exposure, thus limiting DNA damage responses. With continued mitotic divisions in normal cells, telomeres progressively shorten until they reach a threshold at which point they activate senescence or cell death pathways. However, the presence of the enzyme telomerase can provide functional immortality to cells that have reached or progressed past senescence. In senescent cells that amass several oncogenic mutations, cancer formation can occur due to genomic instability and the induction of telomerase activity. Telomerase has been found to be expressed in over 85% of human tumors and is labeled as a near-universal marker for cancer. Due to this feature being present in a majority of tumors but absent in most somatic cells, telomerase and telomeres have become promising targets for the development of new and effective anticancer therapeutics. In this review, we evaluate novel anticancer targets in development which aim to alter telomerase or telomere function. Additionally, we analyze the progress that has been made, including preclinical studies and clinical trials, with therapeutics directed at telomere-related targets. Furthermore, we review the potential telomere-related therapeutics that are used in combination therapy with more traditional cancer treatments. Throughout the review, topics related to medicinal chemistry are discussed, including drug bioavailability and delivery, chemical structure-activity relationships of select therapies, and the development of a unique telomere assay to analyze compounds affecting telomere elongation.

RevDate: 2020-01-09

Lara-Cerrillo S, Gual-Frau J, Benet J, et al (2020)

Microsurgical varicocelectomy effect on sperm telomere length, DNA fragmentation and seminal parameters.

Human fertility (Cambridge, England) [Epub ahead of print].

Varicocele is one of the main causes of male infertility and microsurgical varicocelectomy (MV) seems to be the best procedure for its repair and to reduce testicular oxidative stress (ROS). As ROS causes guanine modifications, we postulated that DNA damage could be more intense in telomeres due to their G-rich nature. We studied the effect of MV on sperm telomere length (TL), single- and double-strand DNA fragmentation (ssSDF and dsSDF) and seminal parameters. Sperm telomeres from 12 fertile donors and 20 varicocele patients before and nine months after MV were labelled using FITC-PNA qFISH (a new method to obtain absolute TL from relative fluorescence intensity using FITC-fluorescent spheres). Both ssSDF and dsSDF were analysed using the alkaline and neutral Comet assays, respectively. The results showed that varicocele and MV had no effect on TL. Seminal parameters, ssSDF and dsSDF of varicocele patients were altered. Although these parameters improved after MV, values did not reach those seen in fertile donors. A good estimation of absolute TL was developed based on FITC-fluorescent spheres. The results showed that TL is not affected by varicocele or surgery. However, MV is able to partially reduce altered seminal parameters, ssSDF and dsSDF values in varicocele patients.

RevDate: 2020-01-09

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

Racial difference in prostate cancer cell telomere lengths in men with higher-grade prostate cancer: a clue to the racial disparity in prostate cancer outcomes.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-19-1462 [Epub ahead of print].

BACKGROUND: Black men have worse prostate cancer outcomes following treatment than White men even accounting for prognostic factors. However, biological explanations for this racial disparity have not been fully identified. We previously showed that more variable telomere lengths among cancer cells and shorter telomere lengths in cancer-associated stromal (CAS) cells individually and together ("telomere biomarker") are associated with prostate cancer death in surgically-treated men independent of currently used prognostic indicators. Here, we hypothesize that Black-White differences in the telomere biomarker and/or in its components may help explain the racial disparity in prostate cancer outcomes.

METHODS: Black (higher-grade [Gleason >/=4+3]=34, lower-grade=93) and White (higher-grade=34, lower-grade=89) surgically-treated men were frequency matched on age, pathologic stage, and grade. We measured telomere lengths in cancer and CAS cells using a robust telomere-specific fluorescence in situ hybridization assay. Tissue microarray and grade-specific distributional cutpoints without regard to race were evaluated.

RESULTS: Among men with higher-grade disease, the proportion of Black men (47.1%) with more variable cancer cell telomere lengths was 2.3-times higher (p=0.02) than that in White men (20.6%). In contrast, among men with lower-grade disease, cancer cell telomere length variability did not differ by race. The proportion of men with shorter CAS cell telomeres did not differ by race for either higher- or lower-grade disease.

CONCLUSIONS: A greater proportion of Black men with higher-grade disease have an adverse prostate cancer cell telomere phenotype than White men with higher-grade disease.

IMPACT: Our findings suggest a possible explanation for the racial disparity in prostate cancer outcomes.

RevDate: 2020-01-09

Peters-Hall JR, Min J, Tedone E, et al (2020)

Proliferation of adult human bronchial epithelial cells without a telomere maintenance mechanism for over 200 population doublings.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34(1):386-398.

To date, there is no direct evidence of telomerase activity in adult lung epithelial cells, but typical culture conditions only support cell proliferation for 30-40 population doublings (PD), a point at which telomeres remain relatively long. Here we report that in in vitro low stress culture conditions consisting of a fibroblast feeder layer, rho-associated coiled coil protein kinase inhibitor (ROCKi), and low oxygen (2%), normal human bronchial epithelial basal progenitor cells (HBECs) divide for over 200 PD without engaging a telomere maintenance mechanism (almost four times the "Hayflick limit"). HBECs exhibit critically short telomeres at 200 PD and the population of cells start to undergo replicative senescence. Subcloning these late passage cells to clonal density, to mimic lung injury in vivo, selects for rare subsets of HBECs that activate low levels of telomerase activity to maintain short telomeres. CRISPR/Cas9 knockout of human telomerase reverse transcriptase or treatment with the telomerase-mediated telomere targeting agent 6-thio-2'deoxyguanosine abrogates colony growth in these late passage cultures (>200 PD) but not in early passage cultures (<200 PD). To our knowledge, this is the first study to report such long-term growth of HBECs without a telomere maintenance mechanism. This report also provides direct evidence of telomerase activation in HBECs near senescence when telomeres are critically short. This novel cell culture system provides an experimental model to understand how telomerase is regulated in normal adult tissues.

RevDate: 2020-01-08

Steiner B, Ferrucci LM, Mirabello L, et al (2020)

Association between coffee drinking and telomere length in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

PloS one, 15(1):e0226972 pii:PONE-D-19-12491.

Mounting evidence indicates that coffee, a commonly consumed beverage worldwide, is inversely associated with various chronic diseases and overall mortality. Few studies have evaluated the effect of coffee drinking on telomere length, a biomarker of chromosomal integrity, and results have been inconsistent. Understanding this association may provide mechanistic insight into associations of coffee with health. The aim of our study was to test the hypothesis that heavier coffee intake is associated with greater likelihood of having above-median telomere length. We evaluated the cross-sectional association between coffee intake and relative telomere length using data from 1,638 controls from four previously conducted case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Coffee intake was assessed using a food frequency questionnaire, and relative telomere length was measured from buffy-coat, blood, or buccal cells. We used unconditional logistic regression models to generate multivariable-adjusted, study-specific odds ratios for the association between coffee intake and relative telomere length. We then conducted a random-effects meta-analysis to determine summary odds ratios. We found that neither summary continuous (OR = 1.01, 95% CI = 0.99-1.03) nor categorical (OR <3 cups/day vs. none = 1.37, 95% CI = 0.71-2.65; OR ≥3 cups/day vs. none = 1.47, 95% CI = 0.81-2.66) odds ratio estimates of coffee drinking and relative telomere length were statistically significant. However, in the largest of the four contributing studies, moderate (<3 cups/day) and heavy coffee drinkers (≥3 cups/day) were 2.10 times (95% CI = 1.25, 3.54) and 1.93 times as likely (95% CI = 1.17, 3.18) as nondrinkers to have above-median telomere length, respectively. In conclusion, we found no evidence that coffee drinking is associated with telomere length. Thus, it is unlikely that telomere length plays a role in potential coffee-disease associations.

RevDate: 2020-01-07

van Batenburg AA, Kazemier KM, van Oosterhout MFM, et al (2020)

From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis.

PloS one, 15(1):e0226785 pii:PONE-D-19-27797.

RATIONALE: A subset of patients with idiopathic pulmonary fibrosis (IPF) contains short leukocyte telomeres or telomere related mutations. We previously showed that alveolar type 2 cells have short telomeres in fibrotic lesions. Our objectives were to better understand how telomere shortening associates with fibrosis in IPF lung and identify a subset of patients with telomere-related disease.

METHODS: Average telomere length was determined in multiple organs, basal and apical lung, and diagnostic and end-stage fibrotic lung biopsies. Alveolar type 2 cells telomere length was determined in different areas of IPF lungs.

RESULTS: In IPF but not in controls, telomere length in lung was shorter than in other organs, providing rationale to focus on telomere length in lung. Telomere length did not correlate with age and no difference in telomere length was found between diagnostic and explant lung or between basal and apical lung, irrespective of the presence of a radiological apicobasal gradient or fibrosis. Fifteen out of 28 IPF patients had average lung telomere length in the range of patients with a telomerase (TERT) mutation, and formed the IPFshort group. Only in this IPFshort and TERT group telomeres of alveolar type 2 cells were extremely short in fibrotic areas. Additionally, whole exome sequencing of IPF patients revealed two genetic variations in RTEL1 and one in PARN in the IPFshort group.

CONCLUSIONS: Average lung tissue telomere shortening does not associated with fibrotic patterns in IPF, however, approximately half of IPF patients show excessive lung telomere shortening that is associated with pulmonary fibrosis driven by telomere attrition.

RevDate: 2020-01-07

Udroiu I, A Sgura (2019)

Alternative Lengthening of Telomeres and Chromatin Status.

Genes, 11(1): pii:genes11010045.

Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some authors describe them as heterochromatic, while for others, they are euchromatic. Similarly, ALT activity should be characterized by the loss (according to most researchers) or formation (as claimed by a minority) of heterochromatin in telomeres. Besides reviewing the main works in this field and the most recent findings, some hypotheses involving the role of telomere non-canonical sequences and the possible spatial heterogeneity of telomeres are given.

RevDate: 2020-01-07

Ock J, Kim J, YH Choi (2019)

Organophosphate insecticide exposure and telomere length in U.S. adults.

The Science of the total environment, 709:135990 pii:S0048-9697(19)35985-6 [Epub ahead of print].

BACKGROUND: Organophosphate insecticides have been widely used for >30 years, and are reported to be associated with various age-related chronic diseases. While shortening of telomere length has been considered as a marker of cellular aging, only a few small studies have been conducted to examine any difference of telomere length in workers exposed to organophosphates versus controls. Epidemiologic studies of the dose-response associations between environmental organophosphate exposure and telomere length in the general population are few.

OBJECTIVE: This study aimed to evaluate the association between levels of organophosphate insecticide exposure and telomere length in the general population.

METHODS: We analyzed data for 1724 participants aged 20 years or more from the National Health and Nutrition Examination Survey 1999-2002. Organophosphate insecticide exposure was estimated using measures of urinary concentrations for 3,5,6-trichloro-2-pyridinol (TCPY) and six non-specific dialkyl phosphate metabolites, e.g., diethyl thiophosphate (DETP). Multiple linear regression was conducted to assess the association between organophosphate exposure and telomere length.

RESULTS: After controlling for sociodemographic and physical factors and urinary creatinine, participants in the second quartile for urinary TCPY had 0.06 (95% CI: 0.02-0.10) T/S ratio shorter telomere length than those in the lowest quartile. By contrast, participants in the second and third tertiles of urinary DETP had 0.08 (95% CI: 0.02-0.14) and 0.06 (95% CI, 0.01-0.11) T/S ratio longer telomere length than those in the lowest tertile. For other five metabolites, there was no association with telomere length.

CONCLUSIONS: Levels of environmental exposures to certain organophosphate insecticides may be linked to altered telomere length in adults in the general population. Although our findings may need to be replicated, we provide the first evidence that environmental exposure to organophosphates may contribute to the alteration of telomere length, which is potentially related to biological aging and to the development of various chronic diseases.

RevDate: 2020-01-06

Yuan X, Dai M, D Xu (2020)


Current topics in medicinal chemistry pii:CTMC-EPUB-103506 [Epub ahead of print].

Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far. To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and the identified mechanisms include the aberrant activation of telomerase or the alternative-lengthening of telomere pathway responsible for telomere elongation, dysregulation and mutation of telomere-associated factors, and other telomere homeostasis-related signaling nodes. In the present review, we summarize these various strategies employed by malignant cells to regulate their telomere length, structure and function, and discuss potential implications of these findings in the rational development of telomere-based cancer therapy and other clinical applications for precision oncology.

RevDate: 2020-01-06

Schutte NS, Malouff JM, SL Keng (2020)

Meditation and telomere length: a meta-analysis.

Psychology & health [Epub ahead of print].

Objective: Telomeres are the caps at the end of chromosomes. Short telomeres are a biomarker for worsening health and early death.Design: The present study consolidated research on meditation and telomere length through a meta-analysis of results of studies examining the effect of meditation on telomere length by comparing the telomere length of meditating participants with participants in control conditions.Results: A search of the literature identified 11 studies reporting 12 comparisons of meditating individuals with individuals in control conditions. An overall significant weighted effect size of g =.40 indicated that the individuals in meditation conditions had longer telomeres. When an outlier effect size was trimmed from the analysis, the effect size was smaller, g =.16. Across studies, a greater number of hours of meditation among participants in meditation conditions was associated with larger effect sizes.Conclusion: These findings provide tentative support for the hypothesis that participants in meditation conditions have longer telomeres than participants in comparison conditions, and that a greater number of hours of meditation is associated with a greater impact on telomere biology. The results of the meta-analysis have potential clinical significance in that they suggest that meditation-based interventions may prevent telomere attrition or increase telomere length.

RevDate: 2020-01-06

Mazidi M, Mikhailidis DP, Banach M, et al (2019)

Impact of serum 25-hydroxyvitamin D 25(OH) on telomere attrition: A Mendelian Randomization study.

Clinical nutrition (Edinburgh, Scotland) pii:S0261-5614(19)33177-2 [Epub ahead of print].

BACKGROUND: Conventional observational studies have suggested that 25-hydroxyvitamin D (25(OH)D) is inversely associated with telomere shortening. We aimed to apply two-sample Mendelian randomization (MR) to assess the causal association between serum 25(OH) D and telomere length (TL).

METHODS: MR was implemented by using summary-level data from the largest genome-wide association studies (GWAS) on vitamin D (n = 73 699) and TL (n = 37 684). Inverse variance weighted method (IVW) was used to estimate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out were applied as sensitivity analysis.

RESULTS: The results of MR demonstrated no effect of 25(OH)D on TL (IVW = β:-0.104, p = 0.219, WM = β:-0.109, p = 0.188; MR Egger = β:-0.127, p = 0.506). None of the 25(OH)D-related single nucleotide polymorphisms (SNPs) were significantly associated with TL. Heterogeneity tests did not detect heterogeneity. Furthermore, MR pleiotropy residual sum and outlier (MR-PRESSO) did not highlight any outliers (p = 0.424). Results of leave-one-out method demonstrated that the links are not driven because of the single SNPs.

CONCLUSIONS: Our study does not support any causal effect of 25(OH) D on TL.

RevDate: 2020-01-05

Hiam D, Smith C, Voisin S, et al (2020)

Aerobic capacity and telomere length in human skeletal muscle and leukocytes across the lifespan.

Aging, 11: pii:102627 [Epub ahead of print].

A reduction in aerobic capacity and the shortening of telomeres are hallmarks of the ageing process. We examined whether a lower aerobic capacity is associated with shorter TL in skeletal muscle and/or leukocytes, across a wide age range of individuals. We also tested whether TL in human skeletal muscle (MTL) correlates with TL in leukocytes (LTL). Eighty-two recreationally active, healthy men from the Gene SMART cohort (31.4±8.2 years; body mass index (BMI)=25.3±3.3kg/m2), and 11 community dwelling older men (74.2±7.5years-old; BMI=28.7±2.8kg/m2) participated in the study. Leukocytes and skeletal muscle samples were collected at rest. Relative telomere length (T/S ratio) was measured by RT-PCR. Associations between TL, aerobic capacity (VO2 peak and peak power) and age were assessed with robust linear models. Older age was associated with shorter LTL (45% variance explained, P<0.001), but not MTL (P= 0.7). Aerobic capacity was not associated with MTL (P=0.5), nor LTL (P=0.3). MTL and LTL were correlated across the lifespan (rs=0.26, P=0.03). In healthy individuals, age explain most of the variability of LTL and this appears to be independent of individual aerobic capacity. Individuals with longer LTL also have a longer MTL, suggesting that there might be a shared molecular mechanism regulating telomere length.

RevDate: 2020-01-04

Rentscher KE, Carroll JE, C Mitchell (2020)

Psychosocial Stressors and Telomere Length: A Current Review of the Science.

Annual review of public health [Epub ahead of print].

A growing literature suggests that exposure to adverse social conditions may accelerate biological aging, offering one mechanism through which adversity may increase risk for age-related disease. As one of the most extensively studied biological markers of aging, telomere length (TL) provides a valuable tool to understand potential influences of social adversity on the aging process. Indeed, a sizeable literature now links a wide range of stressors to TL across the life span. The aim of this article is to review and evaluate this extant literature with a focus on studies that investigate psychosocial stress exposures and experiences in early life and adulthood. We conclude by outlining potential biological and behavioral mechanisms through which psychosocial stress may influence TL, and we discuss directions for future research in this area. Expected final online publication date for the Annual Review of Public Health, Volume 41 is April 1, 2020. Please see for revised estimates.

RevDate: 2020-01-03

Márquez-Ruiz AB, González-Herrera L, Luna JD, et al (2020)

DNA methylation levels and telomere length in human teeth: usefulness for age estimation.

International journal of legal medicine pii:10.1007/s00414-019-02242-7 [Epub ahead of print].

In the last decade, increasing knowledge of epigenetics has led to the development of DNA methylation-based models to predict age, which have shown high predictive accuracy. However, despite the value of teeth as forensic samples, few studies have focused on this source of DNA. This study used bisulfite pyrosequencing to measure the methylation levels of specific CpG sites located in the ELOVL2, ASPA, and PDE4C genes, with the aim of selecting the most age-informative genes and determining their associations with age, in 65 tooth samples from individuals 15 to 85 years old. As a second aim, methylation data and measurements of relative telomere length in the same set of samples were used to develop preliminary age prediction models to evaluate the accuracy of both biomarkers together and separately in estimating age from teeth for forensic purposes. In our sample, several CpG sites from ELOVL2 and PDE4C genes, as well as telomere length, were significantly associated with chronological age. We developed age prediction quantile regression models based on DNA methylation levels, with and without telomere length as an additional variable, and adjusted for type of tooth and sex. Our results suggest that telomere length may have limited usefulness as a supplementary marker for DNA methylation-based age estimation in tooth samples, given that it contributed little improvement in the prediction errors of the models. In addition, even at older ages, DNA methylation appeared to be more informative in predicting age than telomere length when both biomarkers were evaluated separately.

RevDate: 2020-01-03

Chan R, Leung J, Tang N, et al (2020)

Dietary patterns and telomere length in community-dwelling Chinese older men and women: a cross-sectional analysis.

European journal of nutrition pii:10.1007/s00394-019-02168-1 [Epub ahead of print].

PURPOSE: Environmental and lifestyle factors that affect oxidative stress and inflammation may influence telomere length (TL). There are limited data to relate dietary patterns with TL. This study examined the association of various dietary patterns with TL in Chinese older adults.

METHODS: We conducted a cross-sectional analysis and performed multivariate linear regression analyses using available data from 1981 (965 men, 1016 women) community-dwelling Chinese adults aged 65 years and over in Hong Kong. The interviewer administered questionnaires that covered dietary intake estimation and dietary pattern generation from the food frequency questionnaire, demographic and lifestyle factors, and self-reported medical history. TL was measured by quantitative real-time polymerase chain reaction.

RESULTS: None of the dietary pattern scores including the Diet Quality Index-International (DQI-I) score, the Dietary Approaches to Stop Hypertension (DASH) score, the Mediterranean-DASH Intervention for Neurodegenerative Delay Diet (MIND) score, the Mediterranean Diet Score (MDS), the Okinawan diet score, as well as the "vegetables-fruits" pattern score, the "snacks-drinks-milk" pattern score, and the "meat-fish" pattern score were associated with TL in the age- and sex-adjusted model and the multivariate adjusted model.

CONCLUSION: Our findings suggest a minimal role of dietary patterns in telomere length in community-dwelling Chinese older adults.

RevDate: 2020-01-02

Todendi PF, Martínez JA, Reuter CP, et al (2019)

Biochemical profile, eating habits, and telomere length among Brazilian children and adolescents.

Nutrition (Burbank, Los Angeles County, Calif.), 71:110645 pii:S0899-9007(19)30228-X [Epub ahead of print].

OBJECTIVES: Lifestyle, obesity, and eating habits are emerging as determinants for the instability of telomeres. The increase in childhood and adolescent obesity and the association of biochemical profiles and dietary components with telomere length (TL) makes it an important issue in nutritional research. The aim of the present study was to investigate TL and its association with ethnic background, adiposity, clinical and biochemical parameters, and dietary patterns among Brazilian children and adolescents.

METHODS: A cross-sectional study encompassing 981 children and adolescents between 7 and 17 y of age was performed. Dietary intake habits, anthropometry, and clinical data were collected. TL analysis was performed by quantitative polymerase chain reaction.

RESULTS: Children presented significantly longer TL than adolescents (P = 0.046). Participants who self-declared as black, mulatto, or brown (P < 0.001) also showed longer TL than those who were white. Regarding biochemical parameters, individuals with altered glucose levels had shorter TL than normoglycemic participants in the total sample (P = 0.014). Such difference remained statistically significant in adolescents (P = 0.019). Participants who reported eating fruits and vegetables regularly had longer TL than those who did not (P < 0.001).

CONCLUSION: The results suggested that both biochemical parameters and the intake of antioxidant-rich food, such as fruits and vegetables, are associated with the stability of telomere biology among young Brazilians.

RevDate: 2020-01-02

Wang Z, Li J, Liu J, et al (2020)

Molecular insights into the selective binding mechanism of the negatively charged stabilizer to human telomere G-quadruplex.

Clinical and experimental pharmacology & physiology [Epub ahead of print].

The single-stranded overhang of human telomere DNA intramolecularly forms a high-order nucleic acid structure named as G-quadruplex (G4) under physiological conditions. Stabilization of telomere G4 prevents telomere lengthening by the over-activated telomerase in cancer cells and thus represents a promising strategy in cancer therapy. Using molecular docking and molecular dynamics (MD) simulations, specific binding of the anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) to the human hybrid (3 + 1) G4s was investigated at the atomic level. For the first time, APC was showed to prefer the end-stacking binding with the telomere hybrid type II (hybrid-II) G4 to the groove binding with the hybrid type I (hybrid-I) G4, with remarkable stabilizing effect besides much more favorable binding free energies. The groove binding that usually represents the most stable binding mode of double-stranded DNA and its ligand was found inferior in binding with hybrid G4, elucidating the selective binding mechanism of APC towards telomere G4. Non-covalent interaction analysis and decomposition of the binding free energy revealed that van der Waals interaction played a leading role in the binding of APC and telomere hybrid G4s, with the most energetically favorable model presenting most extensive van der Waals interactions through the end-stacking binding mode. These findings provide evidence to shed new light on designs of selective stabilizers targeting telomere G4.

RevDate: 2020-01-01

Epel ES (2020)

Can Childhood Adversity Affect Telomeres of the Next Generation? Possible Mechanisms, Implications, and Next-Generation Research.

The American journal of psychiatry, 177(1):7-9.

RevDate: 2019-12-31

Mahoney ER, Dumitrescu L, Seto M, et al (2019)

Telomere length associations with cognition depend on Alzheimer's disease biomarkers.

Alzheimer's & dementia (New York, N. Y.), 5:883-890 pii:S2352-8737(19)30089-7.

Introduction: While telomere shortening, a marker of cellular aging, may impact the progression of age-related neurodegenerative diseases, its association with cognition is unclear, particularly in the context of Alzheimer's disease (AD) pathology.

Methods: Telomere, cognitive, and CSF data from 482 participants in the AD Neuroimaging Initiative (148 cognitively normal, 283 mild cognitive impairment, 51 AD) was leveraged to assess telomere length associations with cognition (measured by memory and executive function) and interactions with CSF amyloid-β, tau, and APOE-ε4. Secondary analyses assessed brain volume and thickness outcomes.

Results: Longer telomeres at baseline were associated with faster executive function decline. Amyloid-β and tau interacted with telomere length on cognition, with longer telomeres related to faster decline among biomarker-positive individuals.

Discussion: Telomere associations with cognition shift with AD progression, with longer telomeres related to worse outcomes as pathology increases, highlighting the need for further investigation of telomere length along the AD neuropathological cascade.

RevDate: 2019-12-30

Gu D, Li J, Little J, et al (2020)

Associations between Serum Sex Hormone Concentrations and Telomere Length among U.S. Adults, 1999-2002.

The journal of nutrition, health & aging, 24(1):48-54.

BACKGROUND AND OBJECTIVES: Sex hormone concentrations and telomere length are age related responses of human body, while whether there is a direct relation between sex hormone and telomere length is uncertain. Therefore, we used the data of National Health and Nutrition Examination Survey (NHANES) to quantify their direct association.

RESEARCH DESIGN AND METHODS: A total of 710 women aged 35-60 years and 539 men aged 20-85 years were included from two cycles of the NHANES (1999-2002). Telomere length relative to standard reference DNA (T/S ratio) was measured using quantitative polymerase chain reaction method. Seven hormones in serum (5 in men and 2 in women) were assayed. Logistic regressions were used to calculate the odds ratios to evaluate the telomere length-sex hormones association.

RESULTS: Men with vigorous physical activity (71.1%) and without history of cardiovascular diseases, diabetes, and lipid-lowering drugs using tended to have a longer telomere length (all P-values < 0.05); while women with longer sedentary time, smaller pregnant or live birth, and with older ages of firth/last birth were likely with longer telomere length (all P-values < 0.05). After adjusted for potential confounders, only anti-Mullerian hormone was positively and stably associated with short leukocytes telomere length in men (OR: 1.098; 95% CI: 1.034, 1.165). We did not detect any significant association of short telomere length with sex hormones in men and women. Discussion and Implications: Serum anti-Mullerian hormone in men was positively and stably associated with telomere length. More large-scaled and well-designed prospective studies are warranted to reconfirm our conclusions.

RevDate: 2019-12-30

Shen G, Huang JY, Huang YQ, et al (2020)

The Relationship between Telomere Length and Cancer Mortality: Data from the 1999-2002 National Healthy and Nutrition Examination Survey (NHANES).

The journal of nutrition, health & aging, 24(1):9-15.

OBJECTIVES: The association between telomeres length (TL) and cancer mortality is uncertain. We tested the hypotheses that long TL are associated with reduced cancer mortality.

DESIGN: Prospective cohort study.

SETTING: the National Health and Nutrition Survey (NHANES, 1999-2002).

PARTICIPANTS: The analytic sample included adults (n = 7183) who had TL measurements.

MEASUREMENTS: DNA was obtained via blood samples. Telomere length was assessed using the quantitative polymerase chain reaction method.

RESULTS: During follow-up (0.08-12.7 person-years, median = 9.5 years), we observed 195 participants had cancer as causes of death. TL was negatively corelated with age, body mass index (BMI), systolic blood pressure (SBP), C-reactive protein (CRP), race, diabetes, hypertension, cardiovascular diseases (CVD) and cancer mortality, conversely, positively corelated with alcohol use, but not related to diastolic blood pressure (DBP) and smoking. Kaplan-Meier analysis revealed that TL was significantly associated with cancer mortality (log-rank, P <0.001).

CONCLUSIONS: Our study expands upon previous evidence of a relationship between TL and cancer mortality. TL may be a useful tool for evaluating risk of cancer mortality in American adults.

RevDate: 2019-12-28

Li M, K Liu (2019)

Protection of the shelterin complex is key for tethering telomeres to the nuclear envelope during meiotic prophase I.

Biology of reproduction pii:5688711 [Epub ahead of print].

RevDate: 2019-12-28

Kalstad AA, Tveit S, Myhre PL, et al (2019)

Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients.

BMC geriatrics, 19(1):376 pii:10.1186/s12877-019-1383-9.

BACKGROUND: Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients.

METHODS: The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70-82 years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2-8 weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used.

RESULTS: Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75 years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r = 0.139, p = 0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p = 0.073). No associations were found between LTL and CVD risk factors or features of MI.

CONCLUSIONS: In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging.

TRIAL REGISTRATION: Clinical trials no. NCT01841944, registration date April 29, 2013.

RevDate: 2019-12-27

Normando P, Santos-Rebouças C, Leung C, et al (2019)

Variants in gene encoding for vitamin D binding protein were associated with leukocyte telomere length: The Pró-Saúde Study.

Nutrition (Burbank, Los Angeles County, Calif.), 71:110618 pii:S0899-9007(19)30201-1 [Epub ahead of print].

OBJECTIVE: The aim of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) in vitamin D metabolic pathway genes, serum 25-hydroxyvitamin D [25(OH)D] concentrations, and leukocyte telomere length (LTL) in Brazilian adults.

METHODS: The study population comprised 461 participants (33-79 y of age; 51% women) from the Pró-Saúde Study, a cohort of civil servants at a university campus in Rio de Janeiro, Brazil. LTL, genotypes of vitamin D-related SNPs (rs12785878, rs10741657, rs6013897, and rs2282679), and serum 25(OH)D concentrations were determined cross-sectionally. Differences in age- and sex-adjusted LTL means by categories of genotypes and 25(OH)D serum concentrations were evaluated. LTL associations with genotypes and 25(OH)D were investigated using multiple linear regression models adjusted for sociodemographic characteristics and markers of health behavior.

RESULTS: Participants with CC genotype (rs2282679) had shorter age- and sex-adjusted mean LTL than those with AC and AA genotypes (mean ± SE: 0.51 ± 0.03, 0.58 ± 0.01 and 0.5 ± 0.01, respectively, P < 0.05). In adjusted analyses, the CC genotype (rs2282679) was inversely associated with LTL (β = -0.061; 95% confidence interval, -0.120 to -0.001). Other vitamin D-related SNPs and serum 25(OH)D concentrations were not associated with LTL.

CONCLUSIONS: Genetic variations in the gene encoding vitamin D binding protein (GC - rs2282679) were associated with LTL, suggesting an influence of vitamin D status on telomere length that may start early in life.

RevDate: 2019-12-27

Bonetti D, Rinaldi C, Vertemara J, et al (2019)

DNA binding modes influence Rap1 activity in the regulation of telomere length and MRX functions at DNA ends.

Nucleic acids research pii:5687828 [Epub ahead of print].

The cellular response to DNA double-strand breaks (DSBs) is initiated by the Mre11-Rad50-Xrs2 (MRX) complex that has structural and catalytic functions. MRX association at DSBs is counteracted by Rif2, which is known to interact with Rap1 that binds telomeric DNA through two tandem Myb-like domains. Whether and how Rap1 acts at DSBs is unknown. Here we show that Rif2 inhibits MRX association to DSBs in a manner dependent on Rap1, which binds to DSBs and promotes Rif2 association to them. Rap1 in turn can negatively regulate MRX function at DNA ends also independently of Rif2. In fact, a characterization of Rap1 mutant variants shows that Rap1 binding to DNA through both Myb-like domains results in formation of Rap1-DNA complexes that control MRX functions at both DSBs and telomeres primarily through Rif2. By contrast, Rap1 binding to DNA through a single Myb-like domain results in formation of high stoichiometry complexes that act at DNA ends mostly in a Rif2-independent manner. Altogether these findings indicate that the DNA binding modes of Rap1 influence its functional properties, thus highlighting the structural plasticity of this protein.

RevDate: 2019-12-27

Guachalla LM, Ju Z, Koziel R, et al (2019)

Correction for: Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice.

Aging, 11(23):11793-11794.

RevDate: 2019-12-24

Bhala S, Best AF, Giri N, et al (2019)

CNS manifestations in patients with telomere biology disorders.

Neurology. Genetics, 5(6):370 pii:NG2019010843.

Objective: We systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.

Methods: Forty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board-approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.

Results: In this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.

Conclusions: Structural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.

RevDate: 2019-12-24

Powell-Wiley TM, Gebreab SY, Claudel SE, et al (2020)

The relationship between neighborhood socioeconomic deprivation and telomere length: The 1999-2002 National Health and Nutrition Examination Survey.

SSM - population health, 10:100517 pii:100517.

Socioeconomically disadvantaged neighborhoods have been associated with poor health outcomes. Little is known about the biological mechanism by which deprived neighborhood conditions exert negative influences on health. Data from the 1999-2002 National Health and Nutrition Examination Surveys (NHANES) were used to assess the relationship between neighborhood deprivation index (NDI) and log-transformed leukocyte telomere length (LTL) via multilevel modeling to control for census tract level clustering. Models were constructed using tertiles of NDI (ref = low NDI). NDI was calculated using census tract level socioeconomic indicators from the 2000 U.S. Census. The sample (n = 5,106 adults) was 49.8% female and consisted of 82.9% non-Hispanic whites, 9.4% non-Hispanic blacks, and 7.6% Mexican Americans. Mean age was 45.8 years. Residents of neighborhoods with high NDI were younger, non-white, had lower educational attainment, and had a lower poverty to income ratio (all p < 0.0001). Neighborhood deprivation was inversely associated with LTL among individuals living in neighborhoods with medium NDI (β = -0.043, SE = 0.012, p = 0.0005) and high NDI (β = -0.039, SE = 0.013, p = 0.003). Among men, both medium (β = -0.042, SE = 0.015, p = 0.006) and high (β = -0.047, SE = 0.015, p = 0.001) NDI were associated with shorter LTL. Among women, only medium NDI (β = -0.020, SE = 0.016, p = 0.009) was associated with shorter LTL. After controlling for individual characteristics, including individual-level socioeconomic status, increasing neighborhood socioeconomic deprivation is associated with shorter LTL among a nationally representative sample of US adults. This suggests that telomere shortening may be a mechanism through which neighborhood deprivation results in poor health outcomes.

RevDate: 2019-12-23

Rej PH, HEAT Steering Committee, Gravlee CC, et al (2019)

Shortened telomere length is associated with unfair treatment attributed to race in African Americans living in Tallahassee, Florida.

American journal of human biology : the official journal of the Human Biology Council [Epub ahead of print].

OBJECTIVES: Experiences of interpersonal discrimination are pervasive stressors in the lives of African Americans. Increased discrimination stress may cause premature aging. Telomere length (TL) is a plastic genetic trait that is an emerging indicator of cellular health and aging. Short TL is a risk factor for the earlier onset of disease. TL shortens with age, a process that may be accelerated by psychosocial stress. Our study explores the relationship between TL and experiences of discrimination in the form of self-reported unfair treatment (UT).

METHODS: Using a qPCR-based method, we measured TL in DNA from saliva samples provided by 135 African American adults from Tallahassee, FL. We developed discrimination measures using a modified survey that explores nine social domains of self-reported unfair treatment experienced both directly and indirectly. We used multiple regression to examine associations between UT and TL.

RESULTS: We found that racial discrimination in the form of self-reported unfair treatment attributed to race (UT-Race-Self) is inversely associated with TL.

CONCLUSIONS: The significant association between increased UT-Race-Self and shorter telomeres supports the hypothesis that psychosocial stress stemming from racial discrimination may affect TL. The potential impact of discrimination on TL may contribute to premature biological aging and racial health inequalities seen in African Americans.

RevDate: 2019-12-21

Li W, Ma Y, Li Z, et al (2019)

Folic Acid Decreases Astrocyte Apoptosis by Preventing Oxidative Stress-Induced Telomere Attrition.

International journal of molecular sciences, 21(1): pii:ijms21010062.

Astrocytes are the most widely distributed cells in the brain, and astrocyte apoptosis may play an important role in the pathogenesis of neurodegenerative diseases. Folate is required for the normal development of the nervous system, but its effect on astrocyte apoptosis is unclear. In this study, we hypothesized that folic acid (the therapeutic form of folate) decreases astrocyte apoptosis by preventing oxidative stress-induced telomere attrition. Primary cultures of astrocytes were incubated for 12 days with various concentrations of folic acid (0-40 μmol/L), then cell proliferation, apoptosis, intracellular folate concentration, intracellular homocysteine (Hcy) concentration, intracellular reactive oxygen species (ROS) levels, telomeric DNA oxidative damage, and telomere length were determined. The results showed that folic acid deficiency decreased intracellular folate, cell proliferation, and telomere length, whereas it increased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In contrast, folic acid dose-dependently increased intracellular folate, cell proliferation, and telomere length but it decreased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In conclusion, folic acid inhibited apoptosis in astrocytes. The underlying mechanism for this protective effect may be that folic acid decreased oxidative stress and thereby prevented telomeric DNA oxidative damage and telomere attrition.

RevDate: 2019-12-20

Luo M, Teng X, Wang B, et al (2019)

Protection of telomeres 1 (POT1) of Pinus tabuliformis bound the telomere ssDNA.

Tree physiology pii:5681426 [Epub ahead of print].

Protection of telomeres 1 (POT1) is a telomeric protein that binds to the telomere single-stranded (ss) region. It plays an essential role in maintaining genomic stability in both plants and animals. In this study, we investigated the properties of POT1 in Pinus tabuliformis (PtPOT1) through electrophoretic mobility shift assay. PtPOT1 harbored affinity for telomeric ssDNA, and could bind plant- and mammalian-type ssDNA sequences. Notably, there were two oligonucleotide/oligosaccharide binding (OB) folds, and OB1 or OB2 alone, or both together, could bind ssDNA, which is significantly different from human POT1. Based on our data, we hypothesized that the two OB folds of PtPOT1 bound the same ssDNA. This model not only provides new insight into the ssDNA binding of PtPOT1, but also sheds light on the functional divergence of POT1 proteins in gymnosperms and humans.

RevDate: 2019-12-20

Groer M, Louis-Jacques A, Szalacha L, et al (2019)

Relationship of Anxiety, Inflammation, and Telomere Length in Postpartum Women: A Pilot Study.

Biological research for nursing [Epub ahead of print].

BACKGROUND: The postpartum period can be a vulnerable time during which many women are prone to mood disturbances. Since telomere length (TL) is known to be associated with dysphoric moods, inflammation, and stress in many populations, this study's objective was to assess the relationships among TL, dysphoric moods, stress, and inflammation during the postpartum period.

METHOD: This cross-sectional pilot study is a secondary analysis of data collected in a larger parent study of anti-thyroid peroxidase (TPO) enzyme antibody positive versus negative women. The parent study followed selected mothers every month for 6 postpartum months. From this parent study, a random sample of preserved peripheral blood mononuclear cells from 97 participants collected at 2-4 months postpartum were measured for TL. Data were available on the production of interleukin-6 (IL-6), an inflammatory cytokine, in stimulated ex vivo cultures for 59 of these women. Dysphoric moods and stress were measured. Pearson correlations and linear regressions were performed, controlling for postpartum thyroiditis status and age.

RESULTS: There were no statistically significant relationships between TL and demographic factors, stress, depression, or TPO status. There were significant negative correlations between TL and anxiety and a trend for a relationship between TL and IL-6 levels. IL-6 levels were significantly, positively associated with negative moods.

CONCLUSIONS: Higher anxiety scores and inflammation were associated with shorter TL. Inflammation was related to anxiety and other dysphoric moods and was marginally associated with shorter TLs.

RevDate: 2019-12-18

Peker Eyüboğlu İ, Yenmiş G, Bingöl EN, et al (2019)

Next-Generation Sequencing Identifies BRCA1 and/or BRCA2 Mutations in Women at High Hereditary Risk for Breast Cancer with Shorter Telomere Length.

Omics : a journal of integrative biology [Epub ahead of print].

Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation (p = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.

RevDate: 2019-12-18

Amir M, Ahamad S, Mohammad T, et al (2019)

Investigation of conformational dynamics of Tyr89Cys mutation in protection of telomeres 1 gene associated with familial melanoma.

Journal of biomolecular structure & dynamics [Epub ahead of print].

Protection of telomeres 1 (POT1) is a component of the shelterin complex which is crucial for the regulation of telomere length and maintenance. Many naturally occurring mutations in the POT1 gene have been found to be associated with cardiac angiosarcoma, glioma, familial melanoma, and chronic lymphocytic leukemia. In particular, Y89C is a naturally occurring mutation of POT1, responsible for familial melanoma, and the molecular basis of this mutation is unexplored. In this study, we have extensively analyzed the structure of WT and Y89C mutants of POT1 to see the change in the conformational dynamics, free energy landscape, molecular motions and configurational frustration using molecular dynamics (MD) and other bioinformatics approaches. Y89C mutation shows a significant in the backbone orientation, compactness, residual fluctuation, solvent accessibility, and hydrogen bonding, suggesting an overall destabilization of protein structure. In addition, essential dynamics, conformational, magnitude and direction of motion and frustration analysis further suggesting the structural loss in POT1 due to Y89C mutation. Free energy landscape analysis also indicates the presence of a single well-defined free-energy minima in case of WT compared to compare to multiple wells defined free energy minima observed in Y89C, clearly suggesting that this mutation leads to reduce the stability of POT1. This study possibly provides a valuable path to understand the molecular basis of Y89C-mediated development of cancer.

RevDate: 2019-12-17

Aschacher T, Wolf B, Aschacher O, et al (2019)

Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells.

Neoplasia (New York, N.Y.), 22(2):61-75 pii:S1476-5586(19)30296-9 [Epub ahead of print].

Malignant cells ensure telomere maintenance by the alternative lengthening of telomeres (ALT) in the absence of telomerase activity (TA). The retrotransposons "long interspersed nuclear element-1" (LINE-1, L1) are expressed in malignant cells and are primarily known to contribute to complex karyotypes. Here we demonstrate that LINE-1 ribonucleoprotein particles (L1-RNPs) expression is significantly higher in ALT+- versus in TA+-human glioma. Analyzing a role of L1-RNP in ALT, we show that L1-RNPs bind to telomeric repeat containing RNA (TERRA), which is critical for telomere stabilization and which is overexpressed in ALT+ cells. In turn, L1-RNP knockdown (KD) abrogated the nuclear retention of TERRA, resulted in increased telomeric DNA damage, decreased cell growth and reduced expression of ALT characteristics such as c-circles and PML-bodies. L1-RNP KD also decreased the expression of Shelterin- and the ALT-regulating protein Topoisomerase IIIα (TopoIIIα) indicating a more general role of L1-RNPs in supporting telomeric integrity in ALT. Our findings suggest an impact of L1-RNP on telomere stability in ALT+ dependent tumor cells. As L1-RNPs are rarely expressed in normal adult human tissue those elements might serve as a novel target for tumor ablative therapy.

RevDate: 2019-12-17

Eisenberg DTA, Rej PH, Duazo P, et al (2019)

Testing for paternal influences on offspring telomere length in a human cohort in the Philippines.

American journal of physical anthropology [Epub ahead of print].

OBJECTIVES: Telomeres, emerging biomarkers of aging, are comprised of DNA repeats located at chromosomal ends that shorten with cellular replication and age in most human tissues. In contrast, spermatocyte telomeres lengthen with age. These changes in telomere length (TL) appear to be heritable, as older paternal ages of conception (PAC) predict longer offspring TL. Mouse-model studies raise questions about the potential for effects of paternal experiences on human offspring TL, as they suggest that smoking, inflammation, DNA damage, and stressors all shorten sperm TL. Here, we examined whether factors from the paternal environment predict offspring TL as well as interact with PAC to predict offspring TL.

MATERIALS AND METHODS: Using data from the Philippines, we tested if smoking, psychosocial stressors, or shorter knee height (a measure of early life adversity) predict shorter offspring TL. We also tested if these interacted with PAC in predicting offspring TL.

RESULTS: While we did not find the predicted associations, we observed a trend toward fathers with shorter knee height having offspring with longer TL. In addition, we found that knee height interacted with PAC to predict offspring TL. Specifically, fathers with shorter knee heights showed a stronger positive effect of PAC on offspring TL.

DISCUSSION: While the reasons for these associations remain uncertain, shorter knee height is characteristic of earlier puberty. Since spermatocyte TL increases with the production of sperm, we speculate that individuals with earlier puberty, and its concomitant commencement of production of sperm, had more time to accumulate longer sperm telomeres.

RevDate: 2019-12-16

Powolny T, Bassin N, Crini N, et al (2019)

Corticosterone mediates telomere length in raptor chicks exposed to chemical mixture.

The Science of the total environment, 706:135083 pii:S0048-9697(19)35075-2 [Epub ahead of print].

Stressors experience early in life by animals may have carry over impacts on life-traits over the life cycle. Accelerated telomere attrition induced by stress during development and growth could play a role in such delayed effects. Among stressors, exposure to chemicals may modify telomere dynamic but, to date, the trends evidenced between exposure and telomere shortening remains inconsistent. Moreover, the role of corticosterone as a possible mediator of chemical impact on telomere is not yet clearly established. Here, we investigated in wild populations of Red kite whether nestling exposure to metals and pesticides was related to corticosterone concentrations in feathers and telomere length measured in 47 individuals. Lead and mercury concentrations in blood ranged from 2.3 to 59.0 µg L-1 and to 1.4 to 115.7 µg L-1, respectively, and were below the toxicity thresholds proposed for wildlife. Rodenticides were detected in 30% of the chicks. Corticosterone increased with mercury and lead in interaction, showing a synergistic effect of these 2 non-essential metals on this stress hormone. Telomere length was not linked to metals and/or rodenticide exposure while it was related negatively to corticosterone. The relationship between telomere and corticosterone was modulated by nestling's age, which suggests that the rate of telomere shortening is higher when corticosterone increases. Our findings propose an effect of low exposure of Red Kite nestlings to mercury and lead mixture to raise baseline corticosterone in feathers. The relationships established suggest the hypothesis that telomere attrition could be an indirect consequence of metal exposure mediated by corticosterone.

RevDate: 2019-12-16

Shvaiko LI, Bazyka KD, Sushko VO, et al (2019)


Problemy radiatsiinoi medytsyny ta radiobiolohii, 24:503-515.

OBJECTIVE: The objective was to study the relationship between functional status of bronchopulmonary system and telomere length in clean-up workers of Chornobyl NPP accident in a remote post-accident period.

MATERIALS AND METHODS: A study was performed in 113 clean-up workers of Chornobyl NPP accident. Individual do- cumented doses of irradiation in clean-up workers ranged from 1,0 to 880 mSv (330.4 ± 317.7 (M ± SD)). The aver- age age of the Chornobyl NPP participants was (62.21 ± 6.99) years. A complex of functional pulmonary tests (spirometry, body plethysmography, examination of lung diffusion capacity) was performed. Relative telomere length (RTL) was analysed by flow-FISH.

RESULTS: There was a tendency to decrease the relative telomere length in clean-up workers with COPD I-II stage and COPD III-IV, compared with patients with the absence of bronchopulmonary diseases (RTL 15,2 ± 2,7). Significantly shorter telomeres were observed in patients with COPD who were exposed to radiation at a dose of more than 500 mSv (13.6 ± 2.5) compared with COPD patients who were exposed at a dose <10 mSv (RTL 15.3 ± 2.3). When analyzing the correlation relationships of the studied indicators, no significant associations were found with the relative telomere length. At this stage of the study no association of relative telomere length with age, body mass index, and functional criteria (FEV1 (l), intrathoracic pressure (ITGV), total lung capacity (TLC), diffusion lung capac- ity (DLCO)) was detected.

CONCLUSIONS: The analyzed telomere length relationship from liquidators of the Chernobyl found no direct associa- tion with indicators of lung function tests, however, showed a trend towards reducing the relative telomere length in clean-up workers who suffer from COPD and exposed to doses from 100 to 500 mSv and above 500 mSv.

RevDate: 2019-12-16

Bichet C, Bouwhuis S, Bauch C, et al (2019)

Telomere length is repeatable, shortens with age and reproductive success, and predicts remaining lifespan in a long-lived seabird.

Molecular ecology [Epub ahead of print].

Telomeres are protective caps at the end of chromosomes, and their length is positively correlated with individual health and lifespan across taxa. Longitudinal studies have provided mixed results regarding the within-individual repeatability of telomere length. While some studies suggest telomere length to be highly dynamic and sensitive to resource-demanding or stressful conditions, others suggest that between-individual differences are mostly present from birth and relatively little affected by the later environment. This dichotomy could arise from differences between species, but also from methodological issues. In our study, we used the highly reliable Terminal Restriction Fragment analysis method to measure telomeres over a 10-year period in adults of a long-lived seabird, the common tern (Sterna hirundo). Telomeres shortened with age within individuals. The individual repeatability of age-dependent telomere length was high (> 0.53), and independent of the measurement interval (i.e. 1 vs. 6 years). A small (R2 = 0.01), but significant part of the between-individual variation in telomere length was, however, explained by the number of fledglings produced in the previous year, while reproduction in years prior to the previous year had no effect. We confirmed that age-dependent telomere length predicted an individual's remaining lifespan. Overall, our study suggests that the majority of between-individual variation in adult telomere length is consistent across adult life, and that a smaller part of the variation can be explained by dynamic factors, such as reproduction.

RevDate: 2019-12-16

Fani L, Hilal S, Sedaghat S, et al (2019)

Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study.

Journal of Alzheimer's disease : JAD pii:JAD190759 [Epub ahead of print].

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.

RevDate: 2019-12-15

Bhattacharjee P, Das A, Giri AK, et al (2019)

Epigenetic regulations in alternative telomere lengthening: Understanding the mechanistic insight in arsenic-induced skin cancer patients.

The Science of the total environment pii:S0048-9697(19)35381-1 [Epub ahead of print].

Telomere integrity is considered to be one of the primary mechanisms during malignant transformation. Arsenic, a group 1 carcinogenic metalloid, has been reported to cause telomere lengthening in a telomerase-independent manner. Recent studies suggest a significant role for epigenetic modifications in regulating telomeric length and integrity. Here, we have explored the role of epigenetic deregulation in alternative lengthening of telomeres (ALT) in arsenic-exposed skin cancer tissues and corresponding non-tumor tissues. The relative telomere length (RTL) was analyzed by qRT-PCR using 2-ΔΔCt method. The subtelomeric methylation pattern of the four chromosomes (7q, 18p, 21q and XpYp) were analysed by Methylation Specific PCR (MSP) in 40 pairs of arsenic exposed skin cancer tissues and its corresponding control. The role of constitutive heterochromatin histone marks in the regulation of telomere length (TL) was analyzed by targeted ELISA. A 2-fold increase of relative telomere length in 85% of the arsenic-induced skin cancer tissues was observed. Among the four chromosomes, subtelomere of XpYp was found to be hypermethylated (p < 0.001) whereas 18p was hypomethylated (p < 0.01). Additionally, the level of H4K20me3, a heterochromatic mark was found to be significantly down-regulated (p < 0.0003), and inversely correlated with telomere length indicating loss of heterochromatinization of telomeric DNA. These observations highlight the novel role of epigenetic regulation in the maintenance of constitutive heterochromatin structure at telomere. Alteration in subtelomeric DNA methylation patterns and depletion of H4K20me3 might lead to loss of heterochromatinization resulting in arsenic-induced telomeric elongation. We provide novel data indicating possible alternative determinants of telomere elongation through epigenetic modifications during arsenic-induced skin carcinogenesis which could be used as early 'epimarkers' in the near future. The findings provide new insights about the mechanism of arsenic-induced carcinogenesis.

RevDate: 2019-12-14

Storti CB, de Oliveira RA, de Carvalho M, et al (2019)

Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC).

Experimental and molecular pathology pii:S0014-4800(19)30746-4 [Epub ahead of print].

In the past decade, research efforts were made to identify molecular biomarkers useful as therapeutic targets in Non-Small Cell Lung Cancer (NSCLC), the most frequent type of lung carcinoma. NSCLC presents different histological subtypes being the most prevalent LUSC (Lung Squamous Cell Cancer) and LUAD (Lung Adenocarcinoma), and only a subset of LUAD patients' present tumors expressing known targetable genetic alterations. Telomeres and its components, including telomerase, the enzyme that replenishes telomeres, have been considered potential cancer biomarkers due to their crucial role in cell proliferation and genome stability. Our study aims to quantify expression changes affecting telomere-associated genes and ncRNAs associated with telomere regulation and maintenance in NSCLC. We first assessed the transcriptome (RNA-Seq) data of NSCLC patients from The Cancer Genome Atlas (TCGA) and then we tested the expression of telomere-associated genes and telomeric ncRNAs (TERC, telomerase RNA component, and TERRA, telomere repeat-containing RNA) in Brazilian NCSLC patient samples by quantitative RT-PCR, using matched normal adjacent tissue samples as the control. We also estimated the mean size of terminal restriction fragments (TRF) of some Brazilian NSCLC patients using telomeric Southern blot. The TCGA analysis identified alterations in the expression profile of TERT and telomere damage repair genes, mainly in the LUSC subtype. The study of Brazilian NSCLC samples by RT-qPCR showed that LUSC and LUAD express high amounts of TERT and that although the mean TRF size of tumor samples was shorter compared to normal cells, telomeres in NSCLC are probably maintained by telomerase. Also, the expression analysis of Brazilian NSCLC samples identified statistically significant alterations in the expression of genes involved with telomere damage repair, as well as in TERC and TERRA, mainly in the LUSC subtype. We, therefore, concluded that telomere maintenance genes are significantly deregulated in NSCLC, representing potential biomarkers in the LUSC subtype.

RevDate: 2019-12-14

Pan X, Chen Y, Biju B, et al (2019)

FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops.

Scientific reports, 9(1):19110 pii:10.1038/s41598-019-55537-5.

Cancer cells maintain their telomeres by either re-activating telomerase or adopting the homologous recombination (HR)-based Alternative Lengthening of Telomere (ALT) pathway. Among the many prominent features of ALT cells, C-circles (CC) formation is considered to be the most specific and quantifiable biomarker of ALT. However, the molecular mechanism behind the initiation and maintenance of CC formation in ALT cells is still largely unknown. We reported previously that depletion of the FANCM complex (FANCM-FAAP24-MHF1&2) in ALT cells induced pronounced replication stress, which primarily takes place at their telomeres. Here, we characterized the changes in ALT associated phenotypes in cells deficient of the FANCM complex. We found that depletion of FAAP24 or FANCM, but not MHF1&2, induces a dramatic increase of CC formation. Most importantly, we identified multiple DNA damage response (DDR) and DNA repair pathways that stimulate the dramatic increase of CC formation in FANCM deficient cells, including the dissolvase complex (BLM-TOP3A-RMI1/2, or BTR), DNA damage checkpoint kinases (ATR and Chk1), HR proteins (BRCA2, PALB2, and Rad51), as well as proteins involved in Break-Induced Replication (BIR) (POLD1 and POLD3). In addition, FANCD2, another Fanconi Anemia (FA) protein, is also required for CC formation, likely through promoting the recruitment of BLM to the replication stressed ALT telomeres. Finally, we demonstrated that TERRA R-loops accumulate at telomeres in FANCM deficient ALT cells and downregulation of which attenuates the ALT-associated PML bodies (APBs), replication stress and CC formation. Taken together, our data suggest that FANCM prevents replisomes from stalling/collapsing at ALT telomeres by disrupting TERRA R-loops.

RevDate: 2019-12-14

Zhao S, Wang F, L Liu (2019)

Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells.

Genes, 10(12): pii:genes10121030.

A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telomere length heterogeneity. In this review, we focus on the mechanisms of the ALT pathway and potential clinical implications. We also discuss the characteristics of telomeres in PSCs, thereby shedding light on the therapeutic significance of telomere length regulation in age-related diseases and regenerative medicine.

RevDate: 2019-12-13

Adamusová K, Khosravi S, Fujimoto S, et al (2019)

Two combinatorial patterns of telomere histone marks in plants with canonical and non-canonical telomere repeats.

The Plant journal : for cell and molecular biology [Epub ahead of print].

Telomeres, nucleoprotein structures at the ends of linear eukaryotic chromosomes, are crucial for the maintenance of genome integrity. In most plants, telomeres consist of conserved tandem repeat units comprising the TTTAGGG motif. Recently, non-canonical telomeres were described in several plants and plant taxons, including the carnivorous plant Genlisea hispidula (TTCAGG/TTTCAGG), the genus Cestrum (Solanaceae; TTTTTTAGGG), and plants from the Asparagales order with either a vertebrate-type telomere repeat TTAGGG or Allium genus-specific CTCGGTTATGGG repeat. We analyzed epigenetic modifications of telomeric histones in plants with canonical and non-canonical telomeres, and further in telomeric chromatin captured from leaves of Nicotiana benthamiana transiently transformed by telomere CRISPR-dCas9-eGFP, and of Arabidopsis thaliana stably transformed with TALE_telo C-3 × GFP. Two combinatorial patterns of telomeric histone modifications were identified: (i) an Arabidopsis-like pattern (A. thaliana, G. hispidula, Genlisea nigrocaulis, Allium cepa, Narcissus pseudonarcissus, Petunia hybrida, Solanum tuberosum, Solanum lycopersicum) with telomeric histones decorated predominantly by H3K9me2; (ii) a tobacco-like pattern (Nicotiana tabacum, N. benthamiana, C. elegans) with a strong H3K27me3 signal. Our data suggest that epigenetic modifications of plant telomere-associated histones are related neither to the sequence of the telomere motif nor to the lengths of the telomeres. Nor the phylogenetic position of the species plays the role; representatives of the Solanaceae family are included in both groups. Since both patterns of histone marks are compatible with fully functional telomeres in respective plants, we conclude that the described specific differences in histone marks are not critical for telomere functions.

RevDate: 2019-12-13

Karere GM, Mahaney MC, Newman DE, et al (2019)

Diet-induced leukocyte telomere shortening in a baboon model for early stage atherosclerosis.

Scientific reports, 9(1):19001 pii:10.1038/s41598-019-55348-8.

Reported associations between leukocyte telomere length (LTL) attrition, diet and cardiovascular disease (CVD) are inconsistent. This study explores effects of prolonged exposure to a high cholesterol high fat (HCHF) diet on LTL in a baboon model of atherosclerosis. We measured LTL by qPCR in pedigreed baboons fed a chow (n = 105) or HCHF (n = 106) diet for 2 years, tested for effects of diet on LTL, and association between CVD risk factors and atherosclerotic lesions with LTL. Though not different at baseline, after 2 years median LTL is shorter in HCHF fed baboons (P < 0.0001). Diet predicts sex- and age-adjusted LTL and LTL attrition (P = 0.0009 and 0.0156, respectively). Serum concentrations of CVD biomarkers are associated with LTL at the 2-year endpoint and LTL accounts approximately 6% of the variance in aortic lesions (P = 0.04). Although heritable at baseline (h2 = 0.27, P = 0.027) and after 2 years (h2 = 0.46, P = 0.0038), baseline LTL does not predict lesion extent after 2 years. Atherogenic diet influences LTL, and LTL is a potential biomarker for early atherosclerosis. Prolonged exposure to an atherogenic diet decreases LTL and increases LTL attrition, and shortened LTL is associated with early-stage atherosclerosis in pedigreed baboons.

RevDate: 2019-12-12

Everson F, Martens DS, Nawrot TS, et al (2019)

Personal exposure to NO2 and benzene in the Cape Town region of South Africa is associated with shorter leukocyte telomere length in women.

Environmental research, 182:108993 pii:S0013-9351(19)30790-X [Epub ahead of print].

Air pollution exposure is a major global health concern and has been associated with molecular aging. Unfortunately, the situation has not received much attention in the African region. The aim of this study was to investigate whether current personal ambient NO2 and benzene, toluene, ethyl-benzene and xylenes (ortho (o)-, meta (m)- and para (p)-xylene (BTEX) exposure is associated with leukocyte telomere length (LTL), a marker of molecular ageing, in apparently healthy women (mean ± SD age: 42.5 ± 13.4 years) residing in the Cape Town region of South Africa. The repeated measures study collected data from 61 women. Seven-day median (interquartile range (IQR)) personal NO2 and BTEX exposure levels were determined via compact passive diffusion samplers carried on the person prior to baseline (NO2: 14.2 (9.4-17.2) μg/m³; Benzene: 3.1 (2.1-5.3) μg/m³) and 6-month follow-up (NO2: 10.6 (6.6-13.6) μg/m³; Benzene: 2.2 (1.3-4.9) μg/m³) visits. LTL was measured at baseline and follow-up using a real-time PCR method. Multiple linear mixed model analyses (adjusting for age, body mass index, smoking, employment status, level of education and assessment visit) showed that each IQR increment increase in NO2 (7.0 μg/m³) and benzene (3.3 μg/m³) was associated with -7.30% (95% CI: -10.98 to -3.46%; p < 0.001) and -6.78% (95% CI: -11.88 to -1.39%; p = 0.015) difference in LTL, respectively. The magnitude of these effects of NO2 and benzene corresponds to the effect of an increase of 10.3- and 6.0-year in chronological age on LTL. Our study shows that personal exposures to NO2 and benzene are associated with molecular ageing as indicated by LTL in healthy women residing in the Cape Town region.

RevDate: 2019-12-12

Davé A, Pai CC, Durley SC, et al (2019)

Homologous recombination repair intermediates promote efficient de novo telomere addition at DNA double-strand breaks.

Nucleic acids research pii:5673631 [Epub ahead of print].

The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stability.

RevDate: 2019-12-11

Rai R, Gu P, Broton C, et al (2019)

The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function.

Cell reports, 29(11):3708-3725.e5.

Telomeres use shelterin to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), repressing ataxia-telangiectasia, mutated (ATM) and ATM and Rad3-related (ATR) dependent DNA damage checkpoint responses. The MRE11 nuclease is thought to be essential for the resection of the 5' C-strand to generate the microhomologies necessary for alternative non-homologous end joining (A-NHEJ) repair. In the present study, we uncover DNA damage signaling and repair pathways engaged by components of the replisome complex to repair dysfunctional telomeres. In cells lacking MRN, single-stranded telomeric overhangs devoid of POT1-TPP1 do not recruit replication protein A (RPA), ATR-interacting protein (ATRIP), and RAD 51. Rather, components of the replisome complex, including Claspin, Proliferating cell nuclear antigen (PCNA), and Downstream neighbor of SON (DONSON), initiate DNA-PKcs-mediated p-CHK1 activation and A-NHEJ repair. In addition, Claspin directly interacts with TRF2 and recruits EXO1 to newly replicated telomeres to promote 5' end resection. Our data indicate that MRN is dispensable for the repair of dysfunctional telomeres lacking POT1-TPP1 and highlight the contributions of the replisome in telomere repair.

RevDate: 2019-12-11

Lincz LF, Scorgie FE, Garg MB, et al (2019)

A simplified method to calculate telomere length from Southern blot images of terminal restriction fragment lengths.

BioTechniques [Epub ahead of print].

Southern blotting of DNA terminal restriction fragment lengths is the gold standard for measuring mean telomere length. Analysis of the final image is a crucial step in this process, however, current techniques are cumbersome and prone to error. Here we present a simple and accurate method for analyzing telomere smears. Basic 2D gel imaging software was used to automatically subtract background, generate standard curves and calculate net intensity and MW at each position (i) along the telomere smear. Our method required no statistical software or major data manipulation and correctly classified >80% of 18 samples as having short, medium or long telomeres compared with 33-72% using other methods.

RevDate: 2019-12-11

Bateson M, Eisenberg DTA, D Nettle (2019)

Controlling for baseline telomere length biases estimates of the rate of telomere attrition.

Royal Society open science, 6(10):190937 pii:rsos190937.

Longitudinal studies have sought to establish whether environmental exposures such as smoking accelerate the attrition of individuals' telomeres over time. These studies typically control for baseline telomere length (TL) by including it as a covariate in statistical models. However, baseline TL also differs between smokers and non-smokers, and telomere attrition is spuriously linked to baseline TL via measurement error and regression to the mean. Using simulated datasets, we show that controlling for baseline TL overestimates the true effect of smoking on telomere attrition. This bias increases with increasing telomere measurement error and increasing difference in baseline TL between smokers and non-smokers. Using a meta-analysis of longitudinal datasets, we show that as predicted, the estimated difference in telomere attrition between smokers and non-smokers is greater when statistical models control for baseline TL than when they do not, and the size of the discrepancy is positively correlated with measurement error. The bias we describe is not specific to smoking and also applies to other exposures. We conclude that to avoid invalid inference, models of telomere attrition should not control for baseline TL by including it as a covariate. Many claims of accelerated telomere attrition in individuals exposed to adversity need to be re-assessed.

RevDate: 2019-12-11

Martínez-Ezquerro JD, Rodríguez-Castañeda A, Ortiz-Ramírez M, et al (2019)


Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion, 71(6):393-401.

Background: A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. In this field, oxidative stress and telomere length have been suggested as biomarkers of aging.

Objective: The objective of the study was to study the association of oxidative stress, telomere length, and frailty in an old age population.

Methods: We conducted a cross-sectional study based on 2015 data from 202 members of a cohort of older adults (n = 202; F/M gender ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species were measured by dichlorofluorescein diacetate and lipid peroxidation by malondialdehyde. Telomere length was determined using quantitative polymerase chain reaction with SYBR Green Master Mix.

Results: Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress and telomere length or frailty.

Conclusions: Telomere length could eventually be used as a marker to differentiate between healthy and unhealthy aging as expressed by frailty phenotype; oxidative stress seemed merely a biological process of aging.

RevDate: 2019-12-11

Clemente DBP, Maitre L, Bustamante M, et al (2019)

Obesity is associated with shorter telomeres in 8 year-old children.

Scientific reports, 9(1):18739 pii:10.1038/s41598-019-55283-8.

Telomere length is considered a biomarker of biological aging. Shorter telomeres and obesity have both been associated with age-related diseases. To evaluate the association between various indices of obesity with leukocyte telomere length (LTL) in childhood, data from 1,396 mother-child pairs of the multi-centre European birth cohort study HELIX were used. Maternal pre-pregnancy body mass index (BMI) and 4 adiposity markers in children at age 8 (6-11) years were assessed: BMI, fat mass, waist circumference, and skinfold thickness. Relative LTL was obtained. Associations of LTL with each adiposity marker were calculated using linear mixed models with a random cohort effect. For each 1 kg/m² increment in maternal pre-pregnancy BMI, the child's LTL was 0.23% shorter (95%CI: 0.01,0.46%). Each unit increase in child BMI z-score was associated with 1.21% (95%CI: 0.30,2.11%) shorter LTL. Inverse associations were observed between waist circumference and LTL (-0.96% per z-score unit; 95%CI: -2.06,0.16%), and skinfold thickness and LTL (-0.10% per z-score unit; 95%CI: -0.23,0.02%). In conclusion, this large multicentric study suggests that higher child adiposity indicators are associated with short telomeres in children, and that associations are stronger for child BMI than for maternal pre-pregnancy BMI.

RevDate: 2019-12-11

Nersisyan L, Nikoghosyan M, Arakelyan A, et al (2019)

WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene.

Scientific reports, 9(1):18758 pii:10.1038/s41598-019-55109-7.

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother's, and, to a lesser extent, with father's TL having the strongest influence on the offspring. In this cohort, mother's, but not father's age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

RevDate: 2019-12-11

Tesmer VM, Smith EM, Danciu O, et al (2019)

Combining conservation and species-specific differences to determine how human telomerase binds telomeres.

Proceedings of the National Academy of Sciences of the United States of America pii:1911912116 [Epub ahead of print].

Telomerase catalyzes telomeric DNA synthesis at chromosome ends to allow for continued cell division. The telomeric protein TPP1 is essential for enhancing the processivity of telomerase and recruiting the enzyme to telomeres. The telomerase interaction surface on human TPP1 has been mapped to 2 regions of the N-terminal oligosaccharide/oligonucleotide-binding (OB) domain, namely the TPP1 glutamate (E) and leucine (L)-rich (TEL) patch and the N terminus of TPP1-oligosaccharide/oligonucleotide-binding (NOB) region. To map the telomerase side of the interface, we exploited the predicted structural similarities for human and Tetrahymena thermophila telomerase as well as the species specificity of human and mouse telomerase for their cognate TPP1 partners. We show that swapping in the telomerase essential N-terminal (TEN) and insertions in fingers domain (IFD)-TRAP regions of the human telomerase catalytic protein subunit TERT into the mouse TERT backbone is sufficient to bias the species specificity toward human TPP1. Employing a structural homology-based mutagenesis screen focused on surface residues of the TEN and IFD regions, we identified TERT residues that are critical for contacting TPP1 but dispensable for other aspects of telomerase structure or function. We present a functionally validated structural model for how human telomerase engages TPP1 at telomeres, setting the stage for a high-resolution structure of this interface.

RevDate: 2019-12-09

Markova DN, Christensen SM, E Betrán (2019)

Telomere-Specialized Retroelements in Drosophila: Adaptive Symbionts of the Genome, Neutral, or in Conflict?.

BioEssays : news and reviews in molecular, cellular and developmental biology [Epub ahead of print].

Linear chromosomes shorten in every round of replication. In Drosophila, telomere-specialized long interspersed retrotransposable elements (LINEs) belonging to the jockey clade offset this shortening by forming head-to-tail arrays at Drosophila telomere ends. As such, these telomeric LINEs have been considered adaptive symbionts of the genome, protecting it from premature decay, particularly as Drosophila lacks a conventional telomerase holoenzyme. However, as reviewed here, recent work reveals a high degree of variation and turnover in the telomere-specialized LINE lineages across Drosophila. There appears to be no absolute requirement for LINE activity to maintain telomeres in flies, hence the suggestion that the telomere-specialized LINEs may instead be neutral or in conflict with the host, rather than adaptive.

RevDate: 2019-12-09

Adam N, Degelman E, Briggs S, et al (2019)

Telomere analysis using 3D fluorescence microscopy suggests mammalian telomere clustering in hTERT-immortalized Hs68 fibroblasts.

Communications biology, 2:451 pii:692.

Telomere length and dynamics are central to understanding cell aging, genomic instability and cancer. Currently, there are limited guidelines for analyzing telomeric features in 3D using different cellular models. Image processing for telomere analysis is of increasing interest in many fields, however a lack of standardization can make comparisons and reproducibility an issue. Here we provide a user's guide for quantitative immunofluorescence microscopy of telomeres in interphase cells that covers image acquisition, processing and analysis. Strategies for determining telomere size and number are identified using normal human diploid Hs68 fibroblasts. We demonstrate how to accurately determine telomere number, length, volume, and degree of clustering using quantitative immunofluorescence. Using this workflow, we make the unexpected observation that hTERT-immortalized Hs68 cells with longer telomeres have fewer resolvable telomeres in interphase. Rigorous quantification indicates that this is due to telomeric clustering, leading to systematic underestimation of telomere number and overestimation of telomere size.

RevDate: 2019-12-09

Li Y, Li X, Cao M, et al (2019)

Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence.

Signal transduction and targeted therapy, 4:50 pii:78.

Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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Good Beginner's Books

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

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Papers in Classical Genetics

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

Digital Books

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


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 )