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26 Jun 2019 at 01:35
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Bibliography on: Telomeres


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RJR: Recommended Bibliography 26 Jun 2019 at 01:35 Created: 


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

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Citations The Papers (from PubMed®)

RevDate: 2019-06-23

Subedi P, Nembrini S, An Q, et al (2019)

Telomere length and cancer mortality in American Indians: the Strong Heart Study.

GeroScience pii:10.1007/s11357-019-00080-4 [Epub ahead of print].

The objective of this study was to investigate whether leukocyte telomere length (LTL) predicts the risk for cancer mortality among American Indians participating in the Strong Heart Study (1989-1991). Participants (aged 45-74 years) were followed annually until December 2015 to collect information on morbidity/mortality. LTL was measured by qPCR using genomic DNA isolated from peripheral blood. The association between LTL and risk for cancer mortality was examined using a multivariable Cox proportional hazard model, adjusting for age, gender, education, study site, smoking, alcohol use, physical activity, systolic blood pressure, fasting blood glucose, obesity, and low- and high-density lipoprotein. Of 1945 participants (mean age 56.10 ± 8.17 at baseline, 57% women) followed for an average 20.5 years, 220 died of cancer. Results showed that longer LTL at baseline significantly predicts an increased risk of cancer death among females (HR 1.57, 95% CI 1.08-2.30), but not males (HR 0.74, 95% CI 0.49-1.12) (p for interaction 0.009). Specifically, compared with the women with the longest LTL (fourth quartile), those in the third, second, and first quartiles showed 53%, 41%, and 44% reduced risk for cancer death, respectively. The findings highlight the importance of sex-specific analysis in future telomere research.

RevDate: 2019-06-21

Liu B, Sun Y, Xu G, et al (2019)

Association Between Dietary Selenium Intake and Leukocyte Telomere Length in a Nationally Representative Sample of US Adults (OR11-06-19).

Current developments in nutrition, 3(Suppl 1): pii:nzz044.OR11-06-19.

Objectives: DNA damage induced by oxidative stress is implicated in accelerated telomere shortening, a biomarker of biological aging. Although selenium has antioxidant properties, its impact on telomere length is largely unknown. This study aimed to examine the association between dietary selenium intake and leukocyte telomere length in a nationally representative sample of US adults.

Methods: We included 7409 adults aged 20 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Dietary selenium intake was calculated using data collected in the 24-hour dietary recall. Leukocyte telomere length was assayed using the quantitative polymerase chain reaction method. The association between selenium intake and telomere length was estimated by weighted linear regression models adjusting for demographic, socioeconomic and lifestyle factors, body mass index, supplements intake, and leukocyte cell type composition.

Results: The average dietary selenium intake was 109.1 mg/d (standard error [SE] 1.15). We didn't find a significant association between dietary selenium intake and telomere length in US adults. The average telomere length (SE) was 1.01 (0.02), 1.01 (0.01), and 1.04 (0.01) across increasing tertiles of dietary selenium intake. However, a significant interaction was observed for age (P = 0.02). Among individuals aged 20-44 years, the β coefficient of log-transformed telomere length, compared to lowest tertile of dietary selenium intake, was -0.041 (SE 0.012, P = 0.002) and -0.033 (SE 0.018, P = 0.07) for middle tertile and the highest tertile of selenium intake, respectively. The corresponding β coefficient was 0.009 (SE 0.016, P = 0.59) and -0.001 (SE 0.012, P = 0.95), respectively, for adults 45-64 years old, and 0.017 (SE 0.015, P = 0.28) and 0.059 (SE 0.021, P = 0.01), respectively, for those aged 65 years or older. The results were not appreciably changed even after additionally adjustment for dietary intake of vitamin A, vitamin E, and zinc.

Conclusions: The association between dietary selenium intake and telomere length differed significantly by age groups, indicating that higher selenium intake may prevent telomere shortening in older adults but not in younger or middle-aged adults. Further studies about the underlying mechanisms are warranted.

Funding Sources: NA.

RevDate: 2019-06-21

Chen L, Zhu H, Gutin B, et al (2019)

Higher Chocolate Candy Intake Is Associated with Longer Telomere Length Among Adolescents (P01-018-19).

Current developments in nutrition, 3(Suppl 1): pii:nzz028.P01-018-19.

Objectives: Chocolate intake has been shown to improve lipid profiles, which is associated with longer leukocyte telomere length (LTL). But the relationship between chocolate candy intake and cellular aging has not been investigated. We aimed to examine the association between chocolate intake and LTL in adolescents with comprehensive assessments of dietary, lifestyle, and clinical risk factors.

Methods: The dietary chocolate candy intake information were available in 660 adolescents aged from 14 to 18 years (51% girls and 48% blacks). The chocolate candy intake was estimated by seven independent 24 h dietary recalls and divided into three groups, which were none, less than 2 servings/week, and 2 servings/week or more. Multiple linear regression was performed to investigate the association between chocolate intake and LTL.

Results: Among the adolescents, 383 (58%) didn't take any chocolate during dietary recall periods, 165 (25%) consumed chocolate less than 2 servings/week (1.1 ± 0.5 servings/week), and 122 (17%) consumed chocolate of 2 servings/week or more (4.7 ± 4.0 servings/week). Body mass index (BMI) or % body fat was inversely related to chocolate intake in a dose-response fashion (ps < 0.01). Chocolate consumption was also positively associated with ApoA1 (P = 0.024) and ApoA1/HDL (P = 0.036). In addition, ApoA1 and ApoA1/HDL were positively associated with LTL (ps = 0.044 and 0.003, respectively). Compared to non-consumers, adolescents who consumed chocolate of ≥2 servings/week had 0.26 standard deviation longer LTL (P = 0.016) when adjusted for age, sex and race. The association remained significant after further adjustment of BMI, energy intake, the Alternate Healthy Eating Index (AHEI), non-chocolate candy intake, physical activity, family SES and sexual development.

Conclusions: Adolescents who consume 2 servings/week or more of chocolate have longer LTL compared with non-consumers, and ApoA1-HDL pathway might be underlying the chocolate-LTL relationship. Further intervention studies are warranted to verify the beneficial effect of chocolate candy intake on the cellular aging process.

Funding Sources: Study was in part supported by the National Institute of Health, grant number HL064157.

RevDate: 2019-06-20

Nonaka K, Aida J, Takubo K, et al (2019)

Correlation between Differentiation of Adrenocortical Zones and Telomere Lengths measured by Q-FISH.

The Journal of clinical endocrinology and metabolism pii:5520382 [Epub ahead of print].

CONTEXT: Adrenocortical zonation is associated with a markedly complex developmental process, and the pathogenesis and/or etiology of many disorders of adrenocortical zonal development have remained unknown. Cells from the three adrenocortical zones are morphologically and functionally differentiated, and the mature stage of cell development or senescence has been recently reported to be correlated with telomere length. However, the telomere length of each adrenocortical zonal cell has not yet been studied in human adrenal glands.

OBJECTIVE: We aimed to study the telomere lengths of adrenocortical parenchymal cells from three different zones of the adrenal glands present during childhood, adolescence, and adulthood.

METHODS: Adrenal glands of 30 autopsied subjects, aged between 0 and 68 years, were retrieved from pathology files. The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined in the parenchymal cells of the zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR), using quantitative fluorescence in situ hybridization.

RESULTS: NTCR of ZR cells was the longest, followed in decreasing order by that of ZG and ZF cells in subjects aged 20-68 years, but no significant differences in NTCR were detected among these three zones in the group under 20 years of age. NTCR of ZR increased with age in subjects aged 20-68 years, while no significant age-dependent changes in NTCR were detected in the group under 20 years of age.

CONCLUSION: The telomere lengths for three zones in adrenal cortex were correlated with their differentiation in adulthood but not in childhood and adolescence.

RevDate: 2019-06-20

Tutton S, Deng Z, Gulve N, et al (2019)

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53.

Oncotarget, 10(38):3581-3591 pii:26980.

Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.

RevDate: 2019-06-19

Tarik M, Ramakrishnan L, Sinha S, et al (2019)

Association of birth outcomes and postnatal growth with adult leukocyte telomere length: Data from New Delhi Birth Cohort.

Maternal & child nutrition [Epub ahead of print].

Born small for gestational age due to undernutrition in utero and subsequent catchup growth is associated with risk of developing chronic diseases in adulthood. Telomere length has been shown to be a predictor of these age related diseases and may be a link between birth size, a surrogate for fetal undernutrition, and adult chronic diseases. We assessed the relationship of leukocyte telomere length in adult life with birth outcomes and serial change in BMI from birth to adulthood. Leukocyte relative telomere length (RTL) was measured by MMqPCR in 1309 subjects from New Delhi Birth Cohort (NDBC) who participated in two phases of the study between 2006-2009 (phase 6) and 2012-2015 (phase 7) at a mean age of 39.08 (±3.29) and its association with birth outcomes and conditional BMI gain at 2, 11 and 29 years was assessed in a mixed regression model. We did not find any significant association of RTL with body size at birth including birth weight, birth length and birth BMI. Gestational age was positively associated with RTL (p=0.017, multivariate model: p=0.039). Conditional BMI gain at 2 and 11 years was not associated with RTL. BMI gain at 29 year was negatively associated with RTL in multivariate model (p=0.015). Born small for gestational age was not associated with RTL in adulthood. Leukocyte telomere attrition was observed in those born before 37 week of gestational age as well as in those who gained weight as adults which may predispose to chronic diseases.

RevDate: 2019-06-18

Soumboundou M, Nkengurutse I, Dossou J, et al (2019)

Biological Dosimetry Network in Africa: Establishment of a Dose-response Curve Using Telomere and Centromere Staining.

Health physics [Epub ahead of print].

PURPOSE: Biological dosimetry, based on the relationship between the absorbed dose after exposure to ionizing radiation and the frequency of scored aberrations, has been and continues to be an important tool for estimating the dose after exposure. Dicentric chromosomes are considered to be the most specific and sensitive aberration related to radiation exposure. Here, we established the dose-response curve following in vitro irradiation of circulating lymphocytes from healthy donors from three African countries after scoring unstable chromosomal aberrations.

MATERIALS AND METHODS: Blood samples from 16 African donors were exposed to various doses (0 to 4 Gy) using an X-RAD320 x-ray system with a maximum photon energy of 250 kV at a dose rate of 0.1 Gy min. Blood lymphocytes were cultured for 48 h, and chromosomal aberrations were scored during the first mitosis by telomere and centromere staining. The distribution of dicentric chromosomes was determined.

RESULTS: No dicentric chromosomes were found after the analysis of 2,669 first-division metaphases before in vitro exposure. We established a linear-quadratic dose-response curve based on the frequency of dicentric and ring chromosomes and calculated double-strand breaks, taking into account all scored aberrations.

CONCLUSION: The generation of a specific dose-response curve for African donors will allow the practice of precise biological dosimetry in these countries. This work is the first step towards realizing an African biodosimetry network and the establishment of a biological dosimetry laboratory, which could play a major role in the application of radioprotection norms.

RevDate: 2019-06-18

Borbora D, Dutta HK, Devi KR, et al (2019)

Long telomeres cooperate with p53, MDM2, and p21 polymorphisms to elevate pediatric solid tumor risk.

Pediatrics international : official journal of the Japan Pediatric Society [Epub ahead of print].

BACKGROUND: While leukocyte telomere length has been linked with the altered risks of adult cancers, limited information is available regarding its association with the risk of pediatric solid tumors. We investigated the association of telomeric alterations with the risk of pediatric solid tumors. We also investigated, whether altered telomeres cooperated with the TP53 rs1042522, MDM2 rs2279744 and CDKN1A (p21cip1) rs1059234 single nucleotide polymorphisms to modify cancer risk.

METHODS: A total of 101 tumor cases and 202 controls were recruited for this age and gender matched case-control study. The relative telomere length (RTL) was determined in peripheral blood leukocytes using quantitative real-time PCR and the polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism technique.

RESULTS: By using median RTL in the healthy controls as a cutoff, children with longer telomeres were at an increased risk of developing a solid tumor (odds ratio [OR] 2.70; P < 0.01). When participants were categorized according to quartile RTL values of controls, a significant dose-response relation was observed (χ2 - 10.95; P < 0.001). The risk for tumors increased nearly 3-fold (P = 0.001) for the triple interaction among RTL * TP53 rs1042522 * p21 cip1 rs1059234 compared with the maximum effect of any single factor, although the interaction effect was less than additive. The MDM2 rs2279744 GG genotype reduced pediatric solid tumor risk significantly (OR 0.51).

CONCLUSION: These findings suggest that, combined analysis of telomeres and genetic polymorphisms in the TP53 pathway can provide important clues to understanding pediatric solid tumor etiology.

RevDate: 2019-06-18

Ramos-Ibeas P, Pericuesta E, Peral-Sanchez I, et al (2019)

Longitudinal analysis of somatic and germ-cell telomere dynamics in outbred mice.

Molecular reproduction and development [Epub ahead of print].

Although telomere length (TL) shortens with age in most tissues, an age-related increase in length has been described in sperm through a mechanism that is not yet fully understood. Changes in TL with age in the same individual have not been explored. This longitudinal study examines TL dynamics in somatic tissue and gametes during an entire lifespan in an outbred mouse population (from 8 to up to 114 weeks of age). Our findings indicate a reduced life expectancy in males compared to females (84.75 ± 9.23 vs. 113.16 ± 0.20 weeks) and significant variability in TL dynamics between individuals. While with aging, a clear reduction in TL was produced in somatic cells and oocytes, telomeres in sperm cells significantly lengthened. Finally, we found evidence indicating that telomere elongation in sperm during aging may be dependent on different mechanisms, such as the survival of spermatogonia with longer telomeres and the alternative lengthening of telomeres mechanism in meiotic and postmeiotic spermatogenic cells.

RevDate: 2019-06-17

Gong P, Wang H, Zhang J, et al (2019)

Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer.

Translational oncology, 12(9):1164-1176 pii:S1936-5233(19)30202-5 [Epub ahead of print].

Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.

RevDate: 2019-06-17

Guérin TM, Béneut C, Barinova N, et al (2019)

Condensin-Mediated Chromosome Folding and Internal Telomeres Drive Dicentric Severing by Cytokinesis.

Molecular cell pii:S1097-2765(19)30393-4 [Epub ahead of print].

In Saccharomyces cerevisiae, dicentric chromosomes stemming from telomere fusions preferentially break at the fusion. This process restores a normal karyotype and protects chromosomes from the detrimental consequences of accidental fusions. Here, we address the molecular basis of this rescue pathway. We observe that tandem arrays tightly bound by the telomere factor Rap1 or a heterologous high-affinity DNA binding factor are sufficient to establish breakage hotspots, mimicking telomere fusions within dicentrics. We also show that condensins generate forces sufficient to rapidly refold dicentrics prior to breakage by cytokinesis and are essential to the preferential breakage at telomere fusions. Thus, the rescue of fused telomeres results from a condensin- and Rap1-driven chromosome folding that favors fusion entrapment where abscission takes place. Because a close spacing between the DNA-bound Rap1 molecules is essential to this process, Rap1 may act by stalling condensins.

RevDate: 2019-06-16

Sutanto SSI, McLennan SV, Keech AC, et al (2019)

Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate.

Journal of cell communication and signaling pii:10.1007/s12079-019-00521-x [Epub ahead of print].

People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 μM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms.

RevDate: 2019-06-16

Miura A, A Matsuura (2019)

Phosphatase-dependent fluctuations in DNA-damage checkpoint activation at partially defective telomeres.

Biochemical and biophysical research communications pii:S0006-291X(19)31153-2 [Epub ahead of print].

Telomeres protect the ends of eukaryotic chromosomes, and telomere shortening causes irreversible cell-cycle arrest through activation of the DNA-damage checkpoint. In this study, we found that deletion of PPH3, encoding a 2A-like protein phosphatase, accelerated telomere-shortening-mediated senescence without affecting normal telomere length or the telomere erosion rate in Saccharomyces cerevisiae. Moreover, the loss of PPH3 increased sensitivity to telomere dysfunction. The detection of telomere abnormalities by DNA-damage sensors was not an all-or-none response, implying that Pph3 helps determine the border between normal and dysfunctional telomeres by suppressing premature activation of the DNA-damage checkpoint.

RevDate: 2019-06-15

Donati B, A Ciarrocchi (2019)

Telomerase and Telomeres Biology in Thyroid Cancer.

International journal of molecular sciences, 20(12): pii:ijms20122887.

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.

RevDate: 2019-06-14

Xu X, Hu H, Lin Y, et al (2019)

Differences in Leukocyte Telomere Length between Coronary Heart Disease and Normal Population: A Multipopulation Meta-Analysis.

BioMed research international, 2019:5046867.

Coronary heart disease (CHD) is one of the most common causes of death in the world. Numerous studies have shown that as the degree of atherosclerotic disease increases, leukocyte telomere length gradually decreases. Short telomeres increase the risk of all-cause death and cardiovascular death. However, the reported results are not consistent, since the experimental design method, the measurement method, and the disease outcome are different. Therefore, we searched five major literature databases (Pubmed, Web of science, Embase, CNKI, and Wangfang) and finally included 18 eligible articles (including 5,150 patients with CHD and 9341 controls). We found that telomere length in patients with CHD was significantly shorter than that in controls, and the telomere length was inversely correlated with the severity of CHD. Subgroup analysis showed that telomere shortening was the most significant in Asian patients with CHD, in CHD patients with an average age <65 years, and in men with CHD. The mechanism of shortening the telomere length leading to the occurrence and development of CHD is worthy of further study.

RevDate: 2019-06-14

Cherfils-Vicini J, E Gilson (2019)

Inhibiting TRF1 upstream signaling pathways to target telomeres in cancer cells.

EMBO molecular medicine pii:emmm.201910845 [Epub ahead of print].

RevDate: 2019-06-14

Bejarano L, Bosso G, Louzame J, et al (2019)

Multiple cancer pathways regulate telomere protection.

EMBO molecular medicine pii:emmm.201910292 [Epub ahead of print].

Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models.

RevDate: 2019-06-14

Zhang Y, Guo Y, Zhou G, et al (2019)

Regulation of Telomere Length and Atherosclerosis by Protection of Telomeres 1 Protein.

Journal of nanoscience and nanotechnology, 19(12):7953-7959.

The aim of this study was to investigate the manifestation and significance of changes in both telomere length and the expression of human telomere protective protein (hPOT1) in the peripheral blood leukocytes of patients with atherosclerosis (AS). One hundred subjects-excluding those with acute or chronic inflammation, cancer, and autoimmune diseases-were enrolled in this study and divided into two groups: the atherosclerosis group (AS group) and control group. We extracted peripheral blood leukocyte DNA along with its peripheral proteins. After purity testing, a digoxigeninlabeled telomere probe was used for Southern blotting; the length of the telomeres was obtained by image scanning and software analysis. After extracting the peripheral proteins, hPOT1 expression was detected by western blotting and scanned with an image analysis software system. We found that the telomere lengths in the peripheral blood leukocytes of AS and control groups were 7.45 ± 1.15 kb versus 8.11 ± 0.69 kb, respectively, and that the difference between them was statistically significant (p < 0.005). The expression level of hPOT1 protein in the peripheral blood leukocytes of the AS group was significantly higher than that of the control group (t = 3.77, p < 0.01). As can be determined from these results, telomere length in the peripheral blood leukocytes of AS patients was significantly shorter compared with that of the control group. The regulation of telomere length by hPOT1 by negative regulation may be one of the influencing factors in AS. Therefore, it is suggested that change in telomere length may play a role in the occurrence and development of AS.

RevDate: 2019-06-13

Zhang Y, Hua RN, Xiang D, et al (2019)

Single-molecule counting of oxidative DNA damage in telomeres from cancer cells.

Chemical communications (Cambridge, England) [Epub ahead of print].

We demonstrate for the first time the single-molecule counting of oxidative DNA damage in telomeres from a human cervical carcinoma cell line (HeLa cells). This method exhibits high sensitivity towards oxidative DNA damage with a detection limit as low as 9.3 × 10-17 M and good discrimination capability down to the 0.001% oxidative damage level. Moreover, this method can quantify the number of oxidative damaged bases (34-44) in telomeres in each HeLa cell treated with 1000 μM H2O2.

RevDate: 2019-06-13

Khan RJ, Gebreab SY, Gaye A, et al (2019)

Associations of smoking indicators and cotinine levels with telomere length: National Health and Nutrition Examination Survey.

Preventive medicine reports, 15:100895 pii:100895.

The influence of smoking exposure on telomere length with a focus on the impact of race has rarely been discussed. We performed a cross sectional analysis into the associations of smoking indicators with leukocyte telomere length (LTL) by race among 5864 nationally representative sample of US adults (≥20 years). Data from 1999 to 2002 National Health and Nutrition Examination Survey was used for the analysis. Smoking indicators were assessed by interviews and serum cotinine levels. LTL was quantified by polymerase chain reaction. Multiple linear regressions were used to assess the association with adjustment for covariates, sample weights and design effects separately for Whites, Blacks and Mexican Americans. The intensity of smoking, measured by the average number of cigarettes consumed per day, was negatively associated with LTL among Whites (β: -3.87, 95% CI: -5.98 to -1.21) and among Blacks (β: -15.46, 95% CI: -29.79 to -2.12) participants. Compared with cotinine level < 0.05 ng/ml, cotinine level ≥3 ng/ml was associated with shorter LTL (β: -77.92, 95% CI = -143.05 to -11.70) among Whites, but not among Blacks. We found increased number of cigarette consumption to be associated with shorter LTL in both Blacks and Whites, indicating that the impact of smoking on life-shortening diseases could partly be explained by telomere biology. Increased cotinine concentration however, was associated with shorter LTL only among Whites, not among Blacks. This differential relationship that we observed may have implications in interpreting cotinine as an objective biomarker of smoking exposure across races and warrant additional prospective investigation.

RevDate: 2019-06-13

Cao D, Zhao J, Nguyan LN, et al (2019)

Disruption of Telomere Integrity and DNA Repair Machineries by KML001 Induces T Cell Senescence, Apoptosis, and Cellular Dysfunctions.

Frontiers in immunology, 10:1152.

T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.

RevDate: 2019-06-13

Bürgin D, O'Donovan A, d'Huart D, et al (2019)

Adverse Childhood Experiences and Telomere Length a Look Into the Heterogeneity of Findings-A Narrative Review.

Frontiers in neuroscience, 13:490.

Background: Adverse childhood experiences (ACEs) have been associated with poor mental and somatic health. Accumulating evidence indicates that accelerated biological aging-indexed by altered telomere-related markers-may contribute to associations between ACEs and negative long-term health outcomes. Telomeres are repeated, non-coding deoxyribonucleic acid (DNA) sequences at the end of chromosomes. Telomeres shorten during repeated cell divisions over time and are being used as a marker of biological aging. Objectives: The aim of the current paper is to review the literature on the relationship between ACEs and telomere length (TL), with a specific focus on how the heterogeneity of sample and ACEs characteristics lead to varying associations between ACEs and TL. Methods: Multiple databases were searched for relevant English peer-reviewed articles. Thirty-eight papers were found to be eligible for inclusion in the current review. Results: Overall, the studies indicated a negative association between ACEs and TL, although many papers presented mixed findings and about a quarter of eligible studies found no association. Studies with smaller sample sizes more often reported significant associations than studies with larger samples. Also, studies reporting on non-clinical and younger samples more often found associations between ACEs and TL compared to studies with clinical and older samples. Reviewing the included studies based on the "Stressor Exposure Characteristics" recently proposed by Epel et al. (2018) revealed a lack of detailed information regarding ACEs characteristics in many studies. Conclusion: Overall, it is difficult to achieve firm conclusions about associations of ACEs with TL due to the heterogeneity of study and ACE characteristics and the heterogeneity in reported findings. The field would benefit from more detailed descriptions of study samples and measurement of ACEs.

RevDate: 2019-06-12

Shah A, J Shah (2019)

Concerning Greater Social Contexts in Bariatric Surgery Availability and Telomere Length Outcomes.

JAMA surgery pii:2735963 [Epub ahead of print].

RevDate: 2019-06-12

Morton J, Garg T, N Leva (2019)

Concerning Greater Social Contexts in Bariatric Surgery Availability and Telomere Length Outcomes-Reply.

JAMA surgery pii:2735964 [Epub ahead of print].

RevDate: 2019-06-12

Willis M, Staudinger UM, Factor-Litvak P, et al (2019)

Stress and Salivary Telomere Length in the Second Half of Life: A Comparison of Life-course Models.

Advances in life course research, 39:34-41.

Background: Previous research has explored the relationship between childhood and adulthood stressful life events (SLEs) and adult salivary telomere length (TL), but no research to date has tested different life-course models in which stress in adulthood may fully, partly, or not mediate the relationship between childhood stress and adult TL.

Methods: To fill this gap, we elaborate over previous work by Puterman et al. (2016) and other standard models that do not account for the temporal order of stressors in childhood and adulthood, by using structural equation modeling (SEM) for a sample of 5,754 Health and Retirement Study (HRS) participants to compare the fit of three nested life-course models-social trajectory, early critical period, and cumulative risk.

Results: Results indicated that the social trajectory model, in which the association between childhood SLEs and TL in later adulthood is fully mediated by adulthood SLEs, fit the data better than the early critical period (no mediation) and cumulative risk (partial mediation) models.

Conclusion: In the social trajectory model, childhood SLEs are related to TL in later life only through adulthood SLEs. The direct physiological effect of childhood SLEs on TL in later life would be overestimated if adulthood SLEs are overlooked.

RevDate: 2019-06-12

Weng Q, Deng K, Wu F, et al (2019)

Leukocyte telomere length, lipid parameters and gestational diabetes risk: a case-control study in a Chinese population.

Scientific reports, 9(1):8483 pii:10.1038/s41598-019-44968-9.

Telomere length (TL) is linked to various age-related diseases, but little is known about telomeres in gestational diabetes mellitus (GDM). We surveyed 509 subjects (113 GDM patients and 396 frequency matched controls) in Nanjing Drum Tower Hospital, Jiangsu province of eastern China. Relative telomere length (RTL) of genomic DNA extracted from peripheral blood leukocytes was measured using quantitative polymerase chain reaction (qPCR). Odds ratios (OR) and 95% confidence interval (CI) of GDM risk were calculated across tertiles of RTL using logistic regression model. Lipid parameters during the third trimesters of gestation (after 32 weeks) were collected from medical records. The general linear correlation test was used to explore the associations of lipid parameters with RTL. Our results showed that the RTL in GDM patients were significantly shorter than controls (0.302 ± 0.112 vs. 0.336 ± 0.164, P = 0.046). However, the GDM risk was significantly increased in subjects with median RTL (adjusted OR [aOR]: 1.936, 95% CI: 1.086, 3.453, P = 0.025) and the shortest RTL (aOR: 1.795, 95% CI: 1.004, 3.207, P = 0.048), compared to subjects with longest RTL. We also demonstrated that the lipid ratios (TC/TG, LDL/TG, HDL/TG, LDL/TC, TC/LDL) were significantly associated with RTL among controls. Overall, the present study indicated that attrition of telomeres would increase GDM risk among pregnant women, and the altered lipid levels may play an important role in RTL related GDM risk and pathogenesis.

RevDate: 2019-06-07

Vasilopoulos E, Fragkiadaki P, Kalliora C, et al (2019)

The association of female and male infertility with telomere length (Review).

International journal of molecular medicine [Epub ahead of print].

Telomere length (TL) has long been associated with aging, as telomeres serve as protective caps of chromosomes, and are thus deeply involved in the preservation of genome integrity and are vital to cellular functions. Traditionally, a strong link connects aging and infertility in both sexes, with an earlier onset in females. Over the past decade, telomeres have attracted increasing attention due to the role they play in fertility. In this review, we investigated the potential positive or negative association between relative TL and different factors of female and male infertility. A systematic search of the PubMed database was conducted. Out of the 206 studies identified, 45 were reviewed as they fulfilled the criteria of validity and relevance. Following an analysis and a comparison of the study outcomes, several clear trends were observed. The majority of female infertility factors were associated with a shorter TL, with the exception of endometriosis, premature ovarian failure and clear cell carcinoma that were associated with a longer TL and polycystic ovary syndrome (PCOS), which revealed conflicting results among several studies, leading to ambiguous conclusions. Male infertility factors were associated with a shorter TL. Although this review can provide an outline of general trends in the association of TL with infertility factors, further epidemiological and original research studies are required to focus on investigating the basis of these varying lengths of telomeres.

RevDate: 2019-06-10

Dorajoo R, Chang X, Gurung RL, et al (2019)

Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies.

Nature communications, 10(1):2491 pii:10.1038/s41467-019-10443-2.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10-8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10-7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10-4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.

RevDate: 2019-06-07

Min J, Wright WE, JW Shay (2019)

Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52.

Genes & development pii:gad.324905.119 [Epub ahead of print].

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitotic DNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to Saccharomyces cerevisiae type II ALT survivors.

RevDate: 2019-06-07

Benyelles M, Episkopou H, O'Donohue MF, et al (2019)

Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models.

EMBO molecular medicine pii:emmm.201810201 [Epub ahead of print].

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

RevDate: 2019-06-07

Myers KO, Ibrahimou B, Adegoke KK, et al (2019)

The effect of maternal vitamin C intake on fetal telomere length.

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians [Epub ahead of print].

Background: A telomere is a nucleoprotein structure that is located at the end of a chromosome. Reduced telomere length manifests as physical ailments such as increased risk of age-related illnesses. These age-related illnesses include heart disease and failure. Telomere length has been studied extensively in adults; however, limited information exists regarding maternal dietary influences on fetal telomere length. Objectives: The objective of this study was to investigate the relationship between maternal vitamin C intake and fetal telomere length. Methods: Data for this analysis were collected as part of a prospective cohort study that recruited pregnant women upon admission into labor and delivery. Umbilical cord serum was collected for 96 maternal-fetal dyads, and DNA analysis was performed using a quantitative polymerase chain reaction. The telomere to single copy gene ratio method was used to determine telomere length, and maternal vitamin C intake was measured using the Dietary History Questionnaire (DHQ). Statistical analysis was conducted using generalized linear modeling-based analyses. Results: The linear model indicates that maternal vitamin C intake (OR = 1.0032, 95%CI: 1.0014-1.0052, p ≤ 0.05) was positively associated with fetal telomere length. BMI (OR = 1.1096, 95%CI: 1.0619-1.1660, p ≤ 0.05) had a significant positive association with fetal telomere length while sodium intake was negatively associated with this outcome (OR = 0.9997, 95%CI: 0.9995-0.9998, p ≤ 0.05). Black ethnicity had a significant negative association with fetal telomere length (OR = 0.0186, 95%CI: 0.0031-0.0824, p ≤ 0.05). Conclusions: Our study shows a positive association between maternal vitamin C intake and fetal telomere length. These findings may provide a method of understanding and preventing adult-onset disease and mortality through intrauterine reprogramming.

RevDate: 2019-06-06

Araújo Carvalho AC, Tavares Mendes ML, da Silva Reis MC, et al (2019)

Telomere length and frailty in older adults. A systematic review and meta-analysis.

Ageing research reviews pii:S1568-1637(19)30037-6 [Epub ahead of print].

Telomere shortening has been proposed as a potentially useful biomarker of human ageing and age-related morbidity and mortality. We performed a systematic review and meta-analysis to summarize results from individual studies on the telomere length according to the frailty status and frailty index in older adults. We searched the PubMed, SCOPUS and Web of Science databases to identify studies that evaluated the telomere length in frail and non-frail older adults and the relationship between telomere length and frailty index score. We used the base pairs (bp) as a measure of the telomere length. Summary estimates were calculated using random-effects models. Nine studies were included in the present systematic review and a total of 10,079 older adults were analyzed. We found that the frail older adults (n = 355) had shorter telomeres than the non-frail (n = 1894) (Standardized Mean Difference [SMD] -0.41; 95% CI -0.73 to -0.09; P = 0.01; I2 = 82%). Significant differences in telomere length between frail and non-frail older adults were identified in Hispanic (SMD -1.31; 95% CI -1.71 to -0.92; P < 0.0001; I2 = 0%) but not in Non-Hispanic countries (SMD -0.13; 95% CI -0.26 to 0.00; P = 0.06; I2 = 0%). Similar results were found in the adjusted meta-analysis (SMD -0.56; 95% -1.12 to 0.00; P = 0.05; I2 = 85%). A significant but weak relationship was found between telomere length and frailty index analyzing 8244 individuals (SMD -0.06; 95% IC -0.10 to 0.01; P = 0.01; I2 = 0%). The current available evidence suggests that telomere length may be not a meaningful biomarker for frailty. Because the potential influence of ethnicity in shortening of telomeres and decline in physiologic reserves associated with aging, additional multiethnic studies are needed.

RevDate: 2019-06-06

Mantuano E, Peconi M, D Scarabino (2019)

Can leukocyte telomere shortening be a possible biomarker to track Huntington's disease progression?.

Neural regeneration research, 14(10):1709-1710.

RevDate: 2019-06-06

Bansal A, S Kukreti (2019)

The four repeat Giardia lamblia telomere forms tetramolecular G-quadruplex with antiparallel topology.

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

Guanine rich DNA sequences of regulatory genomic regions form secondary structures known as G-quadruplexes usually stabilized by tetrads of Hoogsteen hydrogen bonded guanines. The in vivo existence of G-quadruplexes ascertains their biological roles. Human telomeric repeats are the most studied G-rich sequences. The four repeat Giardia telomeric sequence (TAGGG)4 differs from its human counterpart (TTAGGG)4, by deletion of one T at the G-tract intervening site of each repeat. We show here that whilst the two repeat Giardia telomeric sequence (TAGGG)2 forms parallel and antiparallel quadruplexes with tetramolecular topology exclusively, the four repeat version (TAGGG)4 forms a tetramolecular (antiparallel) and unimolecular (parallel) quadruplexes in Na+. The tetramolecular (antiparallel) G-quadruplex formed by four repeats of Giardia telomeric sequence is stabilized by the additional Watson-Crick bonding between its intervening TA bases aligned in antiparallel fashion. Four stranded antiparallel quadruplex for four repeats of any telomeric sequence have not been characterized till date. We hypothesize that telomeric association in antiparallel fashion, (via G-overhangs to form tetramolecular quadruplex) could be a biologically relevant molecular event. Further, coexistence of Hoogsteen as well as Watson-Crick base pairing might give insight for recognition of conformationally diverse DNA structures by ligands. Communicated by Ramaswamy H. Sarma.

RevDate: 2019-06-10

Park WJ, JH Lee (2019)

Positive correlation between telomere length and mitochondrial copy number in breast cancers.

Annals of translational medicine, 7(8):183.

RevDate: 2019-06-05

Niedzwiedz CL, Katikireddi SV, Pell JP, et al (2019)

Sex differences in the association between salivary telomere length and multimorbidity within the US Health & Retirement Study.

Age and ageing pii:5511442 [Epub ahead of print].

BACKGROUND: Telomere length is associated with several physical and mental health conditions, but whether it is a marker of multimorbidity is unclear. We investigated associations between telomere length and multimorbidity by sex.

METHODS: Data from adults (N = 5,495) aged ≥50 years were taken from the US Health and Retirement Study (2008-14). Telomere length was measured in 2008 from salivary samples. The cross-sectional associations between telomere length and eight chronic health conditions were explored using logistic regression, adjusting for confounders and stratified by sex. Logistic, ordinal and multinomial regression models were calculated to explore relationships between telomere length and multimorbidity (using a binary variable and a sum of the number of health conditions) and the type of multimorbidity (no multimorbidity, physical multimorbidity, or multimorbidity including psychiatric problems). Using multilevel logistic regression, prospective relationships between telomere length and incident multimorbidity were also explored.

RESULTS: In cross-sectional analyses, longer telomeres were associated with reduced likelihood of lung disease and psychiatric problems among men, but not women. Longer telomeres were associated with lower risk of multimorbidity that included psychiatric problems among men (OR=0.521, 95% CI: 0.284 to 0.957), but not women (OR=1.188, 95% CI: 0.771 to 1.831). Prospective analyses suggested little association between telomere length and the onset of multimorbidity in men (OR=1.378, 95% CI: 0.931 to 2.038) nor women (OR=1.224, 95% CI: 0.825 to 1.815).

CONCLUSIONS: Although telomere length does not appear to be a biomarker of overall multimorbidity, further exploration of the relationships is merited particularly for multimorbidity including psychiatric conditions among men.

RevDate: 2019-06-04

Eberhard S, Valuchova S, Ravat J, et al (2019)

Molecular characterization of Chlamydomonas reinhardtii telomeres and telomerase mutants.

Life science alliance, 2(3): pii:2/3/e201900315.

Telomeres are repeated sequences found at the end of the linear chromosomes of most eukaryotes and are required for chromosome integrity. Expression of the reverse-transcriptase telomerase allows for extension of telomeric repeats to counteract natural telomere shortening. Although Chlamydomonas reinhardtii, a photosynthetic unicellular green alga, is widely used as a model organism in photosynthesis and flagella research, and for biotechnological applications, the biology of its telomeres has not been investigated in depth. Here, we show that the C. reinhardtii (TTTTAGGG)n telomeric repeats are mostly nondegenerate and that the telomeres form a protective structure, with a subset ending with a 3' overhang and another subset presenting a blunt end. Although telomere size and length distributions are stable under various standard growth conditions, they vary substantially between 12 genetically close reference strains. Finally, we identify CrTERT, the gene encoding the catalytic subunit of telomerase and show that telomeres shorten progressively in mutants of this gene. Telomerase mutants eventually enter replicative senescence, demonstrating that telomerase is required for long-term maintenance of telomeres in C. reinhardtii.

RevDate: 2019-06-10

Song L, Liu B, Zhang L, et al (2019)

Association of prenatal exposure to arsenic with newborn telomere length: Results from a birth cohort study.

Environmental research, 175:442-448 pii:S0013-9351(19)30300-7 [Epub ahead of print].

OBJECTIVES: The telomere length at birth has important implications for telomere dynamics over the lifespan; however, few studies have explored the relationship between prenatal arsenic exposure and newborn telomere length (TL). We investigated whether newborn TL is related to prenatal arsenic exposure.

METHODS: We used data from a birth cohort study of 762 mother-newborn pairs conducted between November 2013 and March 2015 in Wuhan, China. We measured relative cord blood TL using quantitative real-time polymerase chain reaction. Arsenic concentrations were measured in spot urine samples collected during three trimesters using inductively coupled plasma mass spectrometry. We applied multiple informant models to explore the relationships between prenatal urinary arsenic concentrations and cord blood TL.

RESULTS: The geometric means of urinary arsenic concentrations were 21.7 μg/g creatinine, 27.3 μg/g creatinine, and 27.1 μg/g creatinine in the first, second, and third trimesters, respectively. After adjustment for potential confounders, a doubling of maternal urinary arsenic concentration during the third trimester was related to a 5.75% (95% CI: 1.70%, 9.95%) increase in cord blood TL, particularly in female infants. Similarly, mothers in the highest quartile of urinary arsenic during the third trimester had an 11.45% (95% CI: 1.91%, 21.88%) longer cord blood TL than those in the lowest quartile. However, no significant association was found between maternal urinary arsenic concentration and cord blood TL during the first and second trimesters.

CONCLUSION: Our findings suggested that maternal arsenic exposure during the third trimester was positively associated with newborn TL. The elongation of newborn telomeres due to prenatal arsenic exposure may offer new insights into the mechanisms underlying arsenic-related disorders.

RevDate: 2019-06-03

Janovič T, Stojaspal M, Veverka P, et al (2019)

Human Telomere Repeat Binding Factor TRF1 Replaces TRF2 Bound to Shelterin Core Hub TIN2 when TPP1 Is Absent.

Journal of molecular biology pii:S0022-2836(19)30322-5 [Epub ahead of print].

Human telomeric repeat binding factors TRF1, TRF2 along with TIN2 form the core of the shelterin complex that protects chromosome ends against unwanted end-joining and DNA repair. We applied a single-molecule approach to assess TRF1-TIN2-TRF2 complex formation in solution at physiological conditions. Fluorescence Cross-Correlation Spectroscopy (FCCS) was used to describe the complex assembly by analyzing how coincident fluctuations of differently labeled TRF1 and TRF2 correlate when they move together through the confocal volume of the microscope. We observed, at the single-molecule level, that TRF1 effectively substitutes TRF2 on TIN2. We assessed also the effect of another telomeric factor TPP1 that recruits telomerase to telomeres. We found that TPP1 upon binding to TIN2 induces changes that expand TIN2 binding capacity, such that TIN2 can accommodate both TRF1 and TRF2 simultaneously. We suggest a molecular model that explains why TPP1 is essential for the stable formation of TRF1-TIN2-TRF2 core complex.

RevDate: 2019-06-10

Alnafakh RAA, Adishesh M, Button L, et al (2019)

Telomerase and Telomeres in Endometrial Cancer.

Frontiers in oncology, 9:344.

Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the "end replication problem" as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80-90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.

RevDate: 2019-06-09

Guo Y, H Yu (2019)

Leukocyte Telomere Length Shortening and Alzheimer's Disease Etiology.

Journal of Alzheimer's disease : JAD, 69(3):881-885.

BACKGROUND: Several observational studies have found leukocyte telomere length (TL) to be associated with Alzheimer's diseases (AD) or dementia. However, these findings were based on small sample sizes and cannot clarify whether this relationship was causal. Genome-wide association studies (GWAS) have identified common variants associated with TL, providing a valuable resource for examining the causal effect of TL on AD using Mendelian Randomization (MR) methods.

OBJECTIVE: To examine if TL was causally associated with AD using GWAS summary statistics.

METHODS: Using a genetic risk score comprised of seven variants associated with leukocyte TL as an instrumental variable, we tested whether shorter TL was associated with a higher risk of AD by applying an MR approach to the summarized genome-wide association study data.

RESULTS: The genetic risk score for TL was associated with higher risk of AD [log-odds ratio (OR) = 0.003 for per TL-decreasing allele; 95% confidence interval (CI): 0.001, 0.005, p = 0.005]. Moreover, the MR analysis provided support for shorter TL to be causally associated with a higher risk of AD (log-OR = 0.04 per SD-decrease of TL; 95% CI: 0.01, 0.08, p = 0.01).

CONCLUSION: We suggest that TL has a causal effect on the risk of AD.

RevDate: 2019-06-03

Aloni R, Levin Y, Uziel O, et al (2019)

Premature aging among trauma survivors - The longitudinal implications of sleep disruptions on telomere length and cognitive performance.

The journals of gerontology. Series B, Psychological sciences and social sciences pii:5510193 [Epub ahead of print].

OBJECTIVES: Sleep is necessary for brain function as well as physical and cognitive processes. Sleep disruptions, common with aging, intensify among trauma survivors. Moreover, former prisoners-of-war (ex-POWs) often experience premature aging. This study investigates the longitudinal effects of sleep disruptions for ex-POWs in relation to cognitive performance and telomere length as well as between cognition and telomeres.

METHOD: This study included Israeli veterans from the 1973 Yom Kippur War who participated in four assessments (1991, 2003, 2008, 2015): (1) ex-POWs (n=99), and (2) veterans who not were captured (controls) (n=101). Among both groups, sleep disruptions were assessed using a self-report item in all four assessments. Cognitive performance was assessed using the Montreal Cognitive Assessment (MOCA) and telomere length was assessed via total white blood cells (leukocytes) from whole blood samples using Southern blot, both were measured only among ex-POWs in 2015. We conducted descriptive statistics, repeated measures, correlations, and path analyses.

RESULTS: Sleep disruptions were related to lower cognitive performance but not to shorter telomeres. Moreover, cognitive performance and telomere length were found to be related when sleep disruptions were taken into consideration.

CONCLUSION: Interpersonal trauma was shown to be a unique experience resulting in sleep disruptions over time, leading to cognitive impairment. These findings highlight the importance of viewing trauma survivors at high-risk for sleep disruptions. Therefore, it is imperative to inquire about sleep and diagnose cognitive disorders to help identify and treat premature aging.

RevDate: 2019-06-10

Clouston SAP, Edelman NH, Aviv A, et al (2019)

Shortened leukocyte telomere length is associated with reduced pulmonary function and greater subsequent decline in function in a sample of World Trade Center responders.

Scientific reports, 9(1):8148 pii:10.1038/s41598-019-44625-1.

The objective of this study was to examine whether shorter leukocyte telomere length (LTL) is associated with more rapid pulmonary function decline in a longitudinal study of World Trade Center (WTC) responders. WTC responders (N = 284) participating in a monitoring study underwent blood sampling and were followed prospectively for spirometric outcomes. A single blood sample was taken to measure LTL using southern blotting. Outcomes included percent-predicted one-second forced expiratory volume (FEV1%), forced vital capacity (FVC%), and the FEV1/FVC ratio. In a subset, percent-predicted diffusing capacity (DLCO%) was also measured. Longitudinal modeling examined prospectively collected information over five years since blood was banked was used to examine the rate of change in pulmonary functioning over time. Severity of WTC exposure was assessed. Shorter LTL was associated with lower FEV1% and FVC% at baseline. For example, 29.9% of those with LTL <6.5 kbps had FEV1% <80% whereas only 12.4% of those with LTL ≥6.5 had FEV1% <80% (RR = 2.53, 95%CI = [1.70-3.76]). Lower DLCO% was also significantly associated with shorter LTL. Longitudinal models identified a prospective association between shorter LTL and greater yearly rates of decline in FEV1% (0.46%/year, 95%CI = [0.05-0.87]) and in the FEV1/FVC ratio (0.19%/year, 95%CI = [0.03-0.36]). There were no associations between severity of exposure and either LTL or pulmonary function. Longitudinal analyses revealed that shorter LTL, but not severity of WTC exposures, was associated with poorer pulmonary functioning and with greater subsequent decline in pulmonary functioning over time. These findings are consistent with the idea that shortened LTL may act as a biomarker for enhanced pulmonary vulnerability in the face of acute severe toxic inhalation exposures.

RevDate: 2019-06-04

Duan X, Yang Y, Zhang D, et al (2019)

Genetic polymorphisms, mRNA expression levels of telomere-binding proteins, and associates with telomere damage in PAHs-Exposure workers.

Chemosphere, 231:442-449 pii:S0045-6535(19)31046-X [Epub ahead of print].

Coke oven emissions (COEs), confirmed human carcinogens, are mainly composed of polycyclic aromatic hydrocarbons (PAHs). Telomere shortening in blood leukocytes has been associated with COEs, and polymorphisms in metabolic enzymes. However, the relationship between polymorphisms in telomere related genes and telomere shortening in COEs exposed workers has never been evaluated. Therefore, we measured telomere length and mRNA expression levels of telomere-binding proteins (TBPs) by qPCR method in leucocyte from 544 COEs exposed workers and 238 office staffs (referents). Flight mass spectrometry was used to perform the genotyping of selected functional and susceptible SNPs. The results showed that the telomere length in the exposure group 0.75(0.51,1.08) was significantly shorter than that in the control group 1.05(0.76,1.44) (P < 0.001). The mRNA expression levels of TPP1, TERF1 and TERF2 genes in the exposure group were significantly lower than those in the control group (P < 0.05), the mRNA expression level of POT1 in the exposure group was significantly higher than that in the control group (P < 0.05). We used the wild homozygous genotype as a reference, subjects carrying TERT rs2736109 AA, TERT rs3215401 CC and TERT rs2736100 GT + GG genotypes had significantly longer telomere length in the exposure group (P < 0.05). In conclusion, the workers exposed to COEs had shorter telomere length, which was regulated by the TPP1, TERF1, TERF2 and POT1 genes expression levels, and the gene polymorphisms of TERT gene were associated with the telomere length among PAHs-exposure workers.

RevDate: 2019-05-30

Grieshober L, Wactawski-Wende J, Blair RH, et al (2019)

A Cross-Sectional Analysis of Telomere Length and Sleep in the Women's Health Initiative.

American journal of epidemiology pii:5506600 [Epub ahead of print].

Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a sub-population of 3,145 postmenopausal women enrolled 1993-1998 to the Women's Health Initiative (1,796 European American (EA), 1,349 African American (AA)) with Southern-blot measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AA+EA; race-adjusted) and in race strata, as LTL differs by ancestry. Each additional hour of sleep beyond 5 hours, approximately, was associated with a 27 base pair (95% confidence interval (CI): 6, 48) longer LTL in AA+EA after covariate adjustment. Seep duration-LTL associations were strongest among AA (adjusted β = 37, 95% CI: 4, 70); a similar non-significant association was observed for EA (adjusted β = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.

RevDate: 2019-06-05

Whittemore K, Derevyanko A, Martinez P, et al (2019)

Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice.

Aging, 11(10):2916-2948.

Neurodegenerative diseases associated with old age such as Alzheimer's disease present major problems for society, and they currently have no cure. The telomere protective caps at the ends of chromosomes shorten with age, and when they become critically short, they can induce a persistent DNA damage response at chromosome ends, triggering secondary cellular responses such as cell death and cellular senescence. Mice and humans with very short telomeres owing to telomerase deficiencies have an earlier onset of pathologies associated with loss of the regenerative capacity of tissues. However, the effects of short telomeres in very low proliferative tissues such as the brain have not been thoroughly investigated. Here, we describe a mouse model of neurodegeneration owing to presence of short telomeres in the brain as the consequence of telomerase deficiency. Interestingly, we find similar signs of neurodegeneration in very old mice as the consequence of physiological mouse aging. Next, we demonstrate that delivery of telomerase gene therapy to the brain of these mice results in amelioration of some of these neurodegeneration phenotypes. These findings suggest that short telomeres contribute to neurodegeneration diseases with aging and that telomerase activation may have a therapeutic value in these diseases.

RevDate: 2019-05-29

Nguyen MT, Vryer R, Ranganathan S, et al (2019)

Telomere Length and Vascular Phenotypes in a Population-Based Cohort of Children and Midlife Adults.

Journal of the American Heart Association, 8(11):e012707.

Background Telomere length has been inversely associated with cardiovascular disease in adulthood, but its relationship to preclinical cardiovascular phenotypes across the life course remains unclear. We investigated associations of telomere length with vascular structure and function in children and midlife adults. Methods and Results Population-based cross-sectional CheckPoint (Child Health CheckPoint) study of 11- to 12-year-old children and their parents, nested within the LSAC (Longitudinal Study of Australian Children). Telomere length (telomeric genomic DNA [T]/β-globin single-copy gene [S] [T/S ratio]) was measured by quantitative polymerase chain reaction from blood-derived genomic DNA. Vascular structure was assessed by carotid intima-media thickness, and vascular function was assessed by carotid-femoral pulse-wave velocity and carotid elasticity. Mean (SD) T/S ratio was 1.09 (0.55) in children (n=1206; 51% girls) and 0.81 (0.38) in adults (n=1343; 87% women). Linear regression models, adjusted for potential confounders, revealed no evidence of an association between T/S ratio and carotid intima-media thickness, carotid-femoral pulse-wave velocity, or carotid elasticity in children. In adults, longer telomeres were associated with greater carotid elasticity (0.14% per 10-mm Hg higher per unit of T/S ratio; 95% CI, 0.04%-0.2%; P=0.007), but not carotid intima-media thickness (-0.9 μm; 95% CI, -14 to 13 μm; P=0.9) or carotid-femoral pulse-wave velocity (-0.10 m/s; 95% CI, -0.3 to 0.07 m/s; P=0.2). In logistic regression analysis, telomere length did not predict poorer vascular measures at either age. Conclusions In midlife adults, but not children, there was some evidence that telomere length was associated with vascular elasticity but not thickness. Associations between telomere length and cardiovascular phenotypes may become more evident in later life, with advancing pathological changes.

RevDate: 2019-06-10

Lu R, O'Rourke JJ, Sobinoff AP, et al (2019)

The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT).

Nature communications, 10(1):2252 pii:10.1038/s41467-019-10180-6.

The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.

RevDate: 2019-06-10

Saint-Leandre B, Nguyen SC, MT Levine (2019)

Diversification and collapse of a telomere elongation mechanism.

Genome research pii:gr.245001.118 [Epub ahead of print].

In most eukaryotes, telomerase counteracts chromosome erosion by adding repetitive sequence to terminal ends. Drosophila melanogaster instead relies on specialized retrotransposons that insert exclusively at telomeres. This exchange of goods between host and mobile element-wherein the mobile element provides an essential genome service and the host provides a hospitable niche for mobile element propagation-has been called a "genomic symbiosis." However, these telomere-specialized, jockey family retrotransposons may actually evolve to "selfishly" overreplicate in the genomes that they ostensibly serve. Under this model, we expect rapid diversification of telomere-specialized retrotransposon lineages and, possibly, the breakdown of this ostensibly symbiotic relationship. Here we report data consistent with both predictions. Searching the raw reads of the 15-Myr-old melanogaster species group, we generated de novo jockey retrotransposon consensus sequences and used phylogenetic tree-building to delineate four distinct telomere-associated lineages. Recurrent gains, losses, and replacements account for this retrotransposon lineage diversity. In Drosophila biarmipes, telomere-specialized elements have disappeared completely. De novo assembly of long reads and cytogenetics confirmed this species-specific collapse of retrotransposon-dependent telomere elongation. Instead, telomere-restricted satellite DNA and DNA transposon fragments occupy its terminal ends. We infer that D. biarmipes relies instead on a recombination-based mechanism conserved from yeast to flies to humans. Telomeric retrotransposon diversification and disappearance suggest that persistently "selfish" machinery shapes telomere elongation across Drosophila rather than completely domesticated, symbiotic mobile elements.

RevDate: 2019-06-10

Feuerbach L, Sieverling L, Deeg KI, et al (2019)

TelomereHunter - in silico estimation of telomere content and composition from cancer genomes.

BMC bioinformatics, 20(1):272 pii:10.1186/s12859-019-2851-0.

BACKGROUND: Establishment of telomere maintenance mechanisms is a universal step in tumor development to achieve replicative immortality. These processes leave molecular footprints in cancer genomes in the form of altered telomere content and aberrations in telomere composition. To retrieve these telomere characteristics from high-throughput sequencing data the available computational approaches need to be extended and optimized to fully exploit the information provided by large scale cancer genome data sets.

RESULTS: We here present TelomereHunter, a software for the detailed characterization of telomere maintenance mechanism footprints in the genome. The tool is implemented for the analysis of large cancer genome cohorts and provides a variety of diagnostic diagrams as well as machine-readable output for subsequent analysis. A novel key feature is the extraction of singleton telomere variant repeats, which improves the identification and subclassification of the alternative lengthening of telomeres phenotype. We find that whole genome sequencing-derived telomere content estimates strongly correlate with telomere qPCR measurements (r = 0.94). For the first time, we determine the correlation of in silico telomere content quantification from whole genome sequencing and whole genome bisulfite sequencing data derived from the same tumor sample (r = 0.78). An analogous comparison of whole exome sequencing data and whole genome sequencing data measured slightly lower correlation (r = 0.79). However, this is considerably improved by normalization with matched controls (r = 0.91).

CONCLUSIONS: TelomereHunter provides new functionality for the analysis of the footprints of telomere maintenance mechanisms in cancer genomes. Besides whole genome sequencing, whole exome sequencing and whole genome bisulfite sequencing are suited for in silico telomere content quantification, especially if matched control samples are available. The software runs under a GPL license and is available at https://www.dkfz.de/en/applied-bioinformatics/telomerehunter/telomerehunter.html .

RevDate: 2019-05-29

Eisenberg DTA, Lee NR, Rej PH, et al (2019)

Older paternal ages and grandpaternal ages at conception predict longer telomeres in human descendants.

Proceedings. Biological sciences, 286(1903):20190800.

Telomere length (TL) declines with age in most human tissues, and shorter TL appears to accelerate senescence. By contrast, men's sperm TL is positively correlated with age. Correspondingly, in humans, older paternal age at conception (PAC) predicts longer offspring TL. We have hypothesized that this PAC effect could persist across multiple generations, and thereby contribute to a transgenerational genetic plasticity that increases expenditures on somatic maintenance as the average age at reproduction is delayed within a lineage. Here, we examine TL data from 3282 humans together with PAC data across four generations. In this sample, the PAC effect is detectable in children and grandchildren. The PAC effect is transmitted through the matriline and patriline with similar strength and is characterized by a generational decay. PACs of more distant male ancestors were not significant predictors, although statistical power was limited in these analyses. Sensitivity analyses suggest that the PAC effect is linear, not moderated by offspring age, or maternal age, and is robust to controls for income, urbanicity and ancestry. These findings show that TL reflects the age at the reproduction of recent male matrilineal and patrilineal ancestors, with an effect that decays across generations.

RevDate: 2019-05-28

Kobayashi CR, Castillo-González C, Survotseva Y, et al (2019)

Recent emergence and extinction of the protection of telomeres 1c gene in Arabidopsis thaliana.

Plant cell reports pii:10.1007/s00299-019-02427-9 [Epub ahead of print].

KEY MESSAGE: Duplicate POT1 genes must rapidly diverge or be inactivated. Protection of telomeres 1 (POT1) encodes a conserved telomere binding protein implicated in both chromosome end protection and telomere length maintenance. Most organisms harbor a single POT1 gene, but in the few lineages where the POT1 family has expanded, the duplicate genes have diversified. Arabidopsis thaliana bears three POT1-like loci, POT1a, POT1b and POT1c. POT1a retains the ancestral function of telomerase regulation, while POT1b is implicated in chromosome end protection. Here we examine the function and evolution of the third POT1 paralog, POT1c. POT1c is a new gene, unique to A. thaliana, and was derived from a duplication event involving the POT1a locus and a neighboring gene encoding ribosomal protein S17. The duplicate S17 locus (dS17) is highly conserved across A. thaliana accessions, while POT1c is highly divergent, harboring multiple deletions within the gene body and two transposable elements within the promoter. The POT1c locus is transcribed at very low to non-detectable levels under standard growth conditions. In addition, no discernable molecular or developmental defects are associated with plants bearing a CRISPR mutation in the POT1c locus. However, forced expression of POT1c leads to decreased telomerase enzyme activity and shortened telomeres. Evolutionary reconstruction indicates that transposons invaded the POT1c promoter soon after the locus was formed, permanently silencing the gene. Altogether, these findings argue that POT1 dosage is critically important for viability and duplicate gene copies are retained only upon functional divergence.

RevDate: 2019-05-27

Patanè S (2019)

Differential effects of training on telomerase activity and telomere length: the role of microRNAs regulation.

European heart journal pii:5498945 [Epub ahead of print].

RevDate: 2019-05-27

Jiménez-Pavón D, Carbonell-Baeza A, CJ Lavie (2019)

Are changes in telomerase activity and telomere length due to different exercise modalities, intensity, or methods: intermittency?.

European heart journal pii:5498942 [Epub ahead of print].

RevDate: 2019-05-27

Inoue H, Horiguchi M, Ono K, et al (2019)

Casein kinase 2 regulates telomere protein complex formation through Rap1 phosphorylation.

Nucleic acids research pii:5498753 [Epub ahead of print].

Telomeres located at the ends of linear chromosomes play important roles in the maintenance of life. Rap1, a component of the shelterin telomere protein complex, interacts with multiple proteins to perform various functions; further, formation of shelterin requires Rap1 binding to other components such as Taz1 and Poz1, and telomere tethering to the nuclear envelope (NE) involves interactions between Rap1 and Bqt4, a nuclear membrane protein. Although Rap1 is a hub for telomere protein complexes, the regulatory mechanisms of its interactions with partner proteins are not fully understood. Here, we show that Rap1 is phosphorylated by casein kinase 2 (CK2) at multiple sites, which promotes interactions with Bqt4 and Poz1. Among the multiple CK2-mediated phosphorylation sites of Rap1, phosphorylation at Ser496 was found to be crucial for both Rap1-Bqt4 and Rap1-Poz1 interactions. These mechanisms mediate proper telomere tethering to the NE and the formation of the silenced chromatin structure at chromosome ends.

RevDate: 2019-05-26

Pusceddu I, Herrmann W, Kleber ME, et al (2019)

Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study.

European journal of nutrition pii:10.1007/s00394-019-01993-8 [Epub ahead of print].

PURPOSE: Short telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation.

METHODS: Vitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median follow-up of 9.9 years.

RESULTS: All-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28-3.37) and 0.41(95% CI 0.33-0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29-3.39) and 0.40 (95% CI 0.33-0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (r = - 0.086, p < 0.001; r = 0.04, p = 0.031, respectively), IL-6 (r = 0.148, p < 0.001; r = - 0.249, p < 0.001, respectively), and hs-CRP (r = 0.101, p < 0.001; r = - 0.320, p < 0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL.

CONCLUSIONS: In conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.

RevDate: 2019-06-10

Yu EY, Cheung IY, Feng Y, et al (2019)

Telomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma.

Neoplasia (New York, N.Y.), 21(7):689-701 pii:S1476-5586(19)30089-2 [Epub ahead of print].

Telomeres play important roles in genome stability and cell proliferation. High risk neuroblastoma (HRNB), an aggressive childhood cancer, is especially reliant on telomere maintenance. Three recurrent genetic aberrations in HRNB (MYCN amplification, TERT re-arrangements, and ATRX mutations) are mutually exclusive and each capable of promoting telomere maintenance mechanisms (i.e., through telomerase or ALT). We analyzed a panel of 5 representative HRNB cell lines and 30 HRNB surgical samples using assays that assess average telomere lengths, length distribution patterns, single-stranded DNA on the G- and C-strand, as well as extra-chromosomal circular telomeres. Our analysis pointed to substantial and variable degrees of telomere DNA damage in HRNB, including pervasive oxidative lesions. Moreover, unlike other cancers, neuroblastoma consistently harbored high levels of C-strand ssDNA overhangs and t-circles, which are consistent with active "telomere trimming". This feature is observed in both telomerase- and ALT-positive tumors and irrespective of telomere length distribution. Moreover, evidence for telomere trimming was detected in normal neural tissues, raising the possibility that TMMs in HRNB evolved in the face of a canonical developmental program of telomere shortening. Telomere trimming by itself appears to distinguish neuroectodermal derived tumors from other human cancers, a distinguishing characteristic with both biologic and therapeutic implications.

RevDate: 2019-05-25

Zhang M, Liu R, F Wang (2019)

Telomere and G-Quadruplex Colocalization Analysis by Immunofluorescence Fluorescence In Situ Hybridization (IF-FISH).

Methods in molecular biology (Clifton, N.J.), 1999:327-333.

Four-stranded G-quadruplexes consists of tracks of guanines that are stabilized by Hoogsteen base pairing. The formation of G-quadruplexes in genomic DNA contribute to numerous biological processes in vivo, including replication, transcription, and telomere maintenance. Here, we present a detailed method to detect the colocalization of G-quadruplexes with telomeres in vivo, using the BG4 antibody developed from Dr. Shankar Balasubramanian's lab.

RevDate: 2019-06-10

Gali H, Mason-Osann E, RL Flynn (2019)

Direct Visualization of DNA Replication at Telomeres Using DNA Fiber Combing Combined with Telomere FISH.

Methods in molecular biology (Clifton, N.J.), 1999:319-325.

The ability to analyze individual DNA fibers undergoing active DNA synthesis has emerged as a powerful technique in the field of DNA replication. Much of the initial analysis has focused on replication throughout the genome. However, more recent advancements in this technique have allowed for the visualization of replication patterns at distinct loci or regions within the genome. This type of locus-specific resolution will greatly enhance our understanding of the dynamics of DNA replication in regions that provide a challenge to the replication machinery. Here, we describe a protocol that will allow for the visualization of DNA replication through one of the most structurally complex regions in the human genome, the telomeric DNA.

RevDate: 2019-05-25

Fouquerel E, Barnes RP, Wang H, et al (2019)

Measuring UV Photoproduct Repair in Isolated Telomeres and Bulk Genomic DNA.

Methods in molecular biology (Clifton, N.J.), 1999:295-306.

Telomere repeats at chromosomal ends are essential for genome stability and sustained cellular proliferation but are susceptible to DNA damage. Repair of damage at telomeres is influenced by numerous factors including telomeric binding proteins, sequence and structure. Ultraviolet (UV) light irradiation induces DNA photoproducts at telomeres that can interfere with telomere maintenance. Here we describe a highly sensitive method for quantifying the formation and removal of UV photoproducts in telomeres isolated from UV irradiated cultured human cells. Damage is detected by immunospot blotting of telomeres with highly specific antibodies against UV photoproducts. This method is adaptable for measuring other types of DNA damage at telomeres as well.

RevDate: 2019-06-10

Mason-Osann E, Gali H, RL Flynn (2019)

Resolving Roadblocks to Telomere Replication.

Methods in molecular biology (Clifton, N.J.), 1999:31-57.

The maintenance of genome stability in eukaryotic cells relies on accurate and efficient replication along each chromosome following every cell division. The terminal position, repetitive sequence, and structural complexities of the telomeric DNA make the telomere an inherently difficult region to replicate within the genome. Thus, despite functioning to protect genome stability mammalian telomeres are also a source of replication stress and have been recognized as common fragile sites within the genome. Telomere fragility is exacerbated at telomeres that rely on the Alternative Lengthening of Telomeres (ALT) pathway. Like common fragile sites, ALT telomeres are prone to chromosome breaks and are frequent sites of recombination suggesting that ALT telomeres are subjected to chronic replication stress. Here, we will review the features of telomeric DNA that challenge the replication machinery and also how the cell overcomes these challenges to maintain telomere stability and ensure the faithful duplication of the human genome.

RevDate: 2019-06-05
CmpDate: 2019-06-05

Anitha A, Thanseem I, Vasu MM, et al (2019)

Telomeres in neurological disorders.

Advances in clinical chemistry, 90:81-132.

Ever since their discovery, the telomeres and the telomerase have been topics of intensive research, first as a mechanism of cellular aging and later as an indicator of health and diseases in humans. By protecting the chromosome ends, the telomeres play a vital role in preserving the information in our genome. Telomeres shorten with age and the rate of telomere erosion provides insight into the proliferation history of cells. The pace of telomere attrition is known to increase at the onset of several pathological conditions. Telomere shortening has been emerging as a potential contributor in the pathogenesis of several neurological disorders including autism spectrum disorders (ASD), schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD) and depression. The rate of telomere attrition in the brain is slower than that of other tissues owing to the low rate of cell proliferation in brain. Telomere maintenance is crucial for the functioning of stem cells in brain. Taking together the studies on telomere attrition in various neurological disorders, an association between telomere shortening and disease status has been demonstrated in schizophrenia, AD and depression, in spite of a few negative reports. But, studies in ASD and PD have failed to produce conclusive results. The cause-effect relationship between TL and neurological disorders is yet to be elucidated. The factors responsible for telomere erosion, which have also been implicated in the pathogenesis of neurological disorders, need to be explored in detail. Telomerase activation is now being considered as a potential therapeutic strategy for neurological disorders.

RevDate: 2019-05-23

He C, Jing S, Dai C, et al (2019)

Telomerase insufficiency induced telomere erosion accumulation in successive generations in dyskeratosis congenita family.

Molecular genetics & genomic medicine [Epub ahead of print].

BACKGROUND: Dyskeratosis congenita (DC) is a rare heritable bone marrow failure syndrome that is associated with telomere dysfunction, and has high genetic heterogeneity and varied features.

OBJECTIVE: This study aimed to identify the underlying genetic etiology of a DC family with more severe symptoms in the younger generation and to explore the relationship between the genetic causes and the severity of DC phenotype.

METHODS: Whole-exome sequencing was performed on the proband to screen the candidate causative gene. The protein structure was then predicted by SWISS-MODEL software. Telomere length (TL) assay was performed on family members along with large-scale population controls. The prenatal diagnosis (PND) was performed on the fetus of parents with secondary pregnancy.

RESULTS: Novel heterozygous mutations in TERT (NM_198253.2), c.1796G>A (p.Arg599Gln), c.2839T>C (p.Ser947Pro), and c.3346G>C (p.Glu1116Gln) were identified in the proband. His TL was below the first percentile of the peers, which also appeared on the fetus with epidermal dyskeratosis through PND. The TL data of large-scale population and members of the DC family implied the accumulation of telomere erosion in successive generations in this family.

CONCLUSIONS: Our study identified three clinical pathologic TERT mutations and implied that telomere erosion might be accumulated through successive generations, contributing to the severity of DC in the younger generation.

RevDate: 2019-05-23

Pan KL, Hsiao YW, Lin YJ, et al (2019)

Shorter Leukocyte Telomere Length Is Associated With Atrial Remodeling and Predicts Recurrence in Younger Patients With Paroxysmal Atrial Fibrillation After Radiofrequency Ablation.

Circulation journal : official journal of the Japanese Circulation Society [Epub ahead of print].

BACKGROUND: Telomere length is a biologic aging marker. This study investigated leukocyte telomere length (LTL) as a new biomarker to predict recurrence after paroxysmal atrial fibrillation (PAF) ablation.Methods and Results:A total of 131 participants (26 healthy individuals and 105 symptomatic PAF patients) were enrolled. PAF patients (54.1±10.8 years) who received catheter ablation therapy were divided into 2 groups: recurrent AF (n=25) and no recurrent AF after catheter ablation (n=80). Peripheral blood mononuclear cells were collected from all subjects to measure LTL. Under 50 years old, LTL in healthy individuals (n=17) was longer than in PAF patients (n=31; 7.34±0.58 kbp vs. 6.44±0.91 kbp, P=0.01). In PAF patients, LTL was positively correlated with left atrial bipolar voltage (R=0.497, P<0.001), and negatively correlated with biatrial scar area (R=-0.570, P<0.001) and left atrial diameter (R=-0.214, P=0.028). LTL was shorter in the patients with recurrent AF than in those without recurrent AF after catheter ablation (5.68±0.82 kbp vs. 6.66±0.71 kbp; P<0.001). On receiver operating characteristic curve analysis, LTL cut-off <6.14 kbp had a specificity of 0.68 and sensitivity of 0.79 to predict recurrent AF after catheter ablation.

CONCLUSIONS: Young PAF patients (≤50 years) had shorter LTL. Shorter LTL was associated with a degenerative atrial substrate and recurrence after catheter ablation in younger PAF patients.

RevDate: 2019-05-22

Chamorro CI, Muhammad A, Ekblad Å, et al (2019)

Urothelial cell senescence is not linked with telomere shortening.

Journal of tissue engineering and regenerative medicine [Epub ahead of print].

The success of regenerative medicine relies in part on the quality of the cells implanted. Cell cultures from cells isolated from bladder washes have been successfully established but molecular changes and cell characteristics have not been explored in detail. In this work, we analysed the role of telomere shortening in relation to the regenerative potential and senescence of cells isolated form bladder washes and expanded in culture. We also analysed, whether bladder washes would be a potential source for attaining stem cells or promoting stem cell proliferation by using two different substrates to support their growth: a feeder layer of growth arrested murine fibroblasts J2 3T3 cells and a xeno-free human recombinant laminin coated surface. We found no association between telomere shortening and senescence in urothelial cells in vitro. Urothelial cells had a stable telomere length and expressed mesenchymal stem cells markers but failed to differentiate into bone or adipocytes. Feeder layer showed an advantage to laminin-coated surfaces in respect to proliferative capacity with the expense of risking that feeder layer cells could persist in later passages. This emphasizes the importance of using carefully controlled culture conditions and molecular quality controls before auto-transplantation in future clinical settings. In conclusion, urothelial cells isolated by bladder washes show regenerative potential that need further understanding. Senescence in vitro might be due to cellular stress and, if so, further improvements in culture conditions may lead to longer cell life and higher proliferative capacity.

RevDate: 2019-05-22

Luu HN, Qi M, Wang R, et al (2019)

Association Between Leukocyte Telomere Length and Colorectal Cancer Risk in the Singapore Chinese Health Study.

Clinical and translational gastroenterology, 10(5):1-9.

OBJECTIVES: Telomeres and telomerase play important roles in maintaining chromosome integrity and genomic stability. To address a lack of consensus about the association between leukocyte telomere length and colorectal cancer, we investigated this association in the Singapore Chinese Health Study.

METHODS: Relative telomere length in white blood cells was quantified using a validated quantitative polymerase chain reaction method in 26,761 participants, including 776 incident colorectal cancer cases. The Cox proportional hazard regression method was used to calculate the hazard ratio and the corresponding 95% confidence interval (CI) for colorectal cancer associated with longer telomeres.

RESULTS: Longer telomeres were significantly associated with a higher risk of colorectal cancer (Ptrend = 0.02). Compared with the lowest quartile, subjects with the highest quartile of telomere length had a hazard ratio of 1.32 (95% CI: 1.08-1.62) for developing colorectal cancer. The corresponding elevation in rectal cancer risk for the highest quartile of telomere length was 71% (95% CI: 22-140, Ptrend = 0.02). There was no statistically significant association between telomere length and risk of colon cancer.

DISCUSSION: This large cohort study of Singapore Chinese, the first study using a cohort study design with more than 26,000 participants that yielded 776 incidence colorectal cancer cases during 12 years of follow-up, provides evidence in support of longer telomeres being associated with a higher risk of colorectal cancer, particularly rectal cancer.

RevDate: 2019-06-07

Tsoukalas D, Fragkiadaki P, Docea AO, et al (2019)

Association of nutraceutical supplements with longer telomere length.

International journal of molecular medicine, 44(1):218-226.

Telomeres are nucleotide tandem repeats located at the tip of eukaryotic chromosomes that maintain genomic integrity. The gradual shortening of telomeres leads to cellular senescence and apoptosis, a key mechanism of aging and age‑related chronic diseases. Epigenetic factors, such as nutrition, exercise and tobacco can affect the rate at which telomeres shorten and can modify the risk of developing chronic diseases. In this study, we evaluated the effects of a combination of nutraceutical supplements (NS) on telomere length (TL) in healthy volunteers with no medical history of any disease. Participants (n=47) were selected from healthy outpatients visiting a private clinic and were divided into the experimental group (n=16), that received the NS and the control group (n=31). We estimated the length of single telomeres in metaphase spread leukocytes, isolated from peripheral blood, using quantitative‑fluorescent in situ hybridization (Q‑FISH) analysis. The length of the whole telomere genome was significantly increased (P<0.05) for the mean, 1st quartile and median measurements in the experimental group. Similar findings were observed for short TL (20th percentile) (P<0.05) for the median and 3rd quartile measurements in the NS group, compared to the control group. The beneficial effects of the supplements on the length of short telomeres remained significant (P<0.05) following adjustment for age and sex. Telomeres were moderately longer in female patients compared to the male patients. On the whole, the findings of this study suggest that the administration of NS may be linked to sustaining the TL.

RevDate: 2019-05-22

Li N, Wang J, Ma K, et al (2019)

The dynamics of forming a triplex in an artificial telomere inferred by DNA mechanics.

Nucleic acids research pii:5494778 [Epub ahead of print].

A telomere carrying repetitive sequences ends with a single-stranded overhang. The G-rich overhang could fold back and bind in the major groove of its upstream duplex, forming an antiparallel triplex structure. The telomeric triplex has been proposed to function in protecting chromosome ends. However, we lack strategies to mechanically probe the dynamics of a telomeric triplex. Here, we show that the topological dynamics of a telomeric triplex involves 3' overhang binding at the ds/ssDNA junction inferred by DNA mechanics. Assisted by click chemistry and branched polymerase chain reaction, we developed a rescue-rope-strategy for mechanically manipulating an artificial telomeric DNA with a free end. Using single-molecule magnetic tweezers, we identified a rarely forming (5%) telomeric triplex which pauses at an intermediate state upon unzipping the Watson-Crick paired duplex. Our findings revealed that a mechanically stable triplex formed in a telomeric DNA can resist a force of 20 pN for a few seconds in a physiological buffer. We also demonstrated that the rescue-rope-strategy assisted mechanical manipulation can directly rupture the interactions between the third strand and its targeting duplex in a DNA triplex. Our single-molecule rescue-rope-strategy will serve as a general tool to investigate telomere dynamics and further develop triplex-based biotechnologies.

RevDate: 2019-06-10

Grunnet LG, Pilgaard K, Alibegovic A, et al (2019)

Leukocyte telomere length is associated with elevated plasma glucose and HbA1c in young healthy men independent of birth weight.

Scientific reports, 9(1):7639 pii:10.1038/s41598-019-43387-0.

Telomeres are protein-bound regions of repetitive nucleotide sequences (TTAGGG) at the end of human chromosomes, and their length is a marker of cellular aging. Intrauterine growth restriction is associated with shorter blood cell telomeres at birth and individuals with type 2 diabetes have shorter telomeres. Individuals with a low birth weight (LBW) have an increased risk of metabolic disease and type 2 diabetes. Therefore, we aimed to investigate the relationship between birth weight and telomere length and the association between birth weight, telomere length and cardiometabolic phenotype in adulthood. Young, healthy men with LBW (n = 55) and normal birth weight (NBW) (n = 65) were examined including blood pressure, blood samples and body composition. Leukocyte telomere length was determined using a high-throughput qPCR method. The LBW men were more insulin resistant as determined by the HOMA-IR index. There was no difference in telomere length between LBW and NBW subjects. When adjusting for birth weight and cohort effect, significant negative associations between telomere length and fasting glucose (P = 0.003) and HbA1c (P = 0.0008) were found. In conclusion, no significant difference in telomere length was found between LBW and NBW men. The telomere length was negatively associated with glucose concentrations and HbA1c levels within the normal non-diabetic range independent of birth weight.

RevDate: 2019-05-22

Giraudeau M, Heidinger B, Bonneaud C, et al (2019)

Telomere shortening as a mechanism of long-term cost of infectious diseases in natural animal populations.

Biology letters, 15(5):20190190.

Pathogens are potent selective forces that can reduce the fitness of their hosts. While studies of the short-term energetic costs of infections are accumulating, the long-term costs have only just started to be investigated. Such delayed costs may, at least in part, be mediated by telomere erosion. This hypothesis is supported by experimental investigations conducted on laboratory animals which show that infection accelerates telomere erosion in immune cells. However, the generalizability of such findings to natural animal populations and to humans remains debatable. First, laboratory animals typically display long telomeres relative to their wild counterparts. Second, unlike humans and most wild animals, laboratory small-bodied mammals are capable of telomerase-based telomere maintenance throughout life. Third, the effect of infections on telomere shortening and ageing has only been studied using single pathogen infections, yet hosts are often simultaneously confronted with a range of pathogens in the wild. Thus, the cost of an infection in terms of telomere-shortening-related ageing in natural animal populations is likely to be strongly underestimated. Here, we discuss how investigations into the links between infection, immune response and tissue ageing are now required to improve our understanding of the long-term impact of disease.

RevDate: 2019-06-10

Meier HCS, Hussein M, Needham B, et al (2019)

Cellular response to chronic psychosocial stress: Ten-year longitudinal changes in telomere length in the Multi-Ethnic Study of Atherosclerosis.

Psychoneuroendocrinology, 107:70-81 pii:S0306-4530(18)30891-6 [Epub ahead of print].

Previous studies have demonstrated an inverse association between chronic psychosocial stress and leukocyte telomere length (LTL), a potential marker of cellular aging. However, due to paucity of longitudinal data, responses of LTL and the LTL aging trajectory to changes in chronic stress exposure remain less well understood. Using data from the Stress I and II ancillary studies of the Multi-Ethnic Study of Atherosclerosis, we estimated the 10-year longitudinal (n = 1,158) associations of within-person changes in chronic stress with changes in LTL, as well as the pooled, cross-sectional associations of chronic stress and LTL (total n = 2,231). We measured chronic stress from both individual and neighborhood-environment sources. At the individual level, we calculated a summary score of each participant's rating of their ongoing (>6 months) material/social problems as moderately/very stressful on the Chronic Burden Scale. Neighborhood-level stress was measured using a summary score of reverse-coded MESA Neighborhood safety, aesthetic quality, and social cohesion scales. Quantiles of these scores were empirically categorized as high, moderate, or low stress. We then summed these individual- and neighborhood-level categorical variables for a total stress measure. Longitudinal within-person associations were estimated with fixed-effects models, which control for all time-invariant confounding, with additional control for time-varying demographics, lagged behaviors and chronic conditions, and specimen storage duration, as well as correction for regression to the mean. Change from low to high total chronic stress was associated with telomere shortening by 0.054 units [95% confidence interval: -0.095, -0.013] over 10 years. This was consistent with, though stronger in magnitude than, cross-sectional estimates. Change in individual-level stress was the primary driver of this effect. We also found suggestive evidence that 1) individuals with persistently high stress experienced the least shortening of telomeres, and 2) changes in individual-level stress were associated with stronger telomere shortening among women, whereas changes in neighborhood stress were associated with stronger shortening among men. Our findings provide longitudinal support to existing evidence, and point to interesting dynamics in telomere attrition across stress levels and genders.

RevDate: 2019-06-10

Pavanello S, Stendardo M, Mastrangelo G, et al (2019)

Higher Number of Night Shifts Associates with Good Perception of Work Capacity and Optimal Lung Function but Correlates with Increased Oxidative Damage and Telomere Attrition.

BioMed research international, 2019:8327629.

Sleep deprivation and the consequent circadian clock disruption has become an emergent health question being associated with premature aging and earlier chronic diseases onset. Night-shift work leads to circadian clock misalignment, which is linked to several age-related diseases. However, mechanisms of this association are not well understood. Aim of this study is to explore in night-shift workers early indicators of oxidative stress response and biological aging [oxidized/methylated DNA bases and leukocytes telomere length (LTL)] and late indicators of functional aging [lung function measurements (FEV1 and FVC)] in relation to personal evaluation of work capacity, measured by work ability index (WAI). One hundred fifty-five hospital workers were studied within the framework of a cross-sectional study. We collected physiological, pathological, and occupational history including pack-years, alcohol consumption, physical activity, and night shifts, together with blood and urine samples. Relationships were appraised by univariate and multivariate ordered-logistic regression models. We found that workers with good and excellent WAI present higher FEV1 (p< 0.01) and number of night-work shifts (p<0.05), but they reveal higher urinary levels of 8-oxoGua (p<0.01) and shorter LTL (p<0.05). We confirmed that higher work ability was prevalent among chronological younger workers (p<0.05), who have also a significant reduced number of diseases, particularly chronic (p<0.01) and musculoskeletal diseases (p<0.01). The new findings which stem from our work are that subjects with the highest work ability perception may have more demanding and burdensome tasks; they in fact present the highest number of night-shift work and produce unbalanced oxidative stress response that might induce premature aging.

RevDate: 2019-06-10

Zhan Y, H Song (2019)

Editorial: Telomeres and Epigenetics in Endocrinology.

Frontiers in endocrinology, 10:257.

RevDate: 2019-05-21

Shin D, Shin J, KW Lee (2019)

Effects of Inflammation and Depression on Telomere Length in Young Adults in the United States.

Journal of clinical medicine, 8(5): pii:jcm8050711.

Little is known about the associations of inflammation and depression with telomere length. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, the current study assessed the effects of inflammation and depression on telomere length in 1141 young adults in the USA. Depression status was assessed from the World Health Organization Composite International Diagnostic Interview and inflammation status was measured based on C-reactive protein (CRP) concentrations. Information on telomere length was obtained using the quantitative polymerase chain reaction method to measure telomere length relative to standard reference DNA (T/S ratio). Unadjusted and adjusted linear and logistic regression models were used to assess the relationship between the tertiles of CRP concentration and the telomere length stratified by the status of depression such as major depression or depressed affect vs. no depression. The adjusted models were controlled for age, family poverty income ratio, race/ethnicity, marital status, physical activity, body mass index, and alcohol drinking status. A significant and decreasing linear trend in telomere length was found as CRP levels increased in men, regardless of the depression status, and women with major depression or depressed affect (p values < 0.05). Among men without depression, those with an elevated CRP level had increased odds of having a shortened telomere length compared to men with low CRP levels after controlling for covariates (adjusted odds ratio 1.77, 95% confidence interval (CI) 1.09-2.90). In women, there was no association between CRP and telomere length, regardless of the depression status. In conclusion, there was a significant and inverse association between inflammation and telomere length according to the depression status in men but not in women. The present findings may be of clinical significance for the monitoring of inflammation levels and depression status as determinants of telomere length.

RevDate: 2019-05-21

Koriath M, Müller C, Pfeiffer N, et al (2019)

Relative Telomere Length and Cardiovascular Risk Factors.

Biomolecules, 9(5): pii:biom9050192.

(1) Background: Telomeres are repetitive DNA sequences located at the extremities of chromosomes that maintain genetic stability. Telomere biology is relevant to several human disorders and diseases, specifically cardiovascular disease. To better understand the link between cardiovascular disease and telomere length, we studied the effect of relative telomere length (RTL) on cardiovascular risk factors in a large population-based sample. (2) Methods: RTL was measured by a real-time quantitative polymerase chain reaction in subjects of the population-based Gutenberg Health Study (n = 4944). We then performed an association study of RTL with known cardiovascular risk factors of smoking status as well as systolic and diastolic blood pressure, body mass index (BMI), LDL cholesterol, HDL cholesterol, and triglycerides. (3) Results: A significant correlation was shown for RTL, with age as a quality control in our study (effect = -0.004, p = 3.2 × 10-47). Analysis of the relation between RTL and cardiovascular risk factors showed a significant association of RTL in patients who were current smokers (effect = -0.016, p = 0.048). No significant associations with RTL were seen for cardiovascular risk factors of LDL cholesterol (p = 0.127), HDL cholesterol (p = 0.713), triglycerides (p = 0.359), smoking (p = 0.328), diastolic blood pressure (p = 0.615), systolic blood pressure (p = 0.949), or BMI (p = 0.903). In a subsequent analysis, we calculated the tertiles of RTL. No significant difference across RTL tertiles was detectable for BMI, blood pressure, lipid levels, or smoking status. Finally, we studied the association of RTL and cardiovascular risk factors stratified by tertiles of age. We found a significant association of RTL and LDL cholesterol in the oldest tertile of age (effect = 0.0004, p = 0.006). (4) Conclusions: We determined the association of relative telomere length and cardiovascular risk factors in a population setting. An association of telomere length with age, current smoking status, as well as with LDL cholesterol in the oldest tertile of age was found, whereas no associations were observed between telomere length and triglycerides, HDL cholesterol, blood pressure, or BMI.

RevDate: 2019-05-20

Asaka S, Davis C, Lin SF, et al (2019)

Analysis of Telomere Lengths in p53 Signatures and Incidental Serous Tubal Intraepithelial Carcinomas Without Concurrent Ovarian Cancer.

The American journal of surgical pathology [Epub ahead of print].

Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable "p53 signature" lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.

RevDate: 2019-05-20

Sayed ME, Slusher AL, AT Ludlow (2019)

Droplet Digital TRAP (ddTRAP): Adaptation of the Telomere Repeat Amplification Protocol to Droplet Digital Polymerase Chain Reaction.

Journal of visualized experiments : JoVE.

The telomere repeat amplification protocol (TRAP) is the most widely used assay to detect telomerase activity within a given a sample. The polymerase chain reaction (PCR)-based method allows for robust measurements of enzyme activity from most cell lysates. The gel-based TRAP with fluorescently labeled primers limits sample throughput, and the ability to detect differences in samples is restricted to two fold or greater changes in enzyme activity. The droplet digital TRAP, ddTRAP, is a highly sensitive approach that has been modified from the traditional TRAP assay, enabling the user to perform a robust analysis on 96 samples per run and obtain absolute quantification of the DNA (telomerase extension products) input within each PCR. Therefore, the newly developed ddTRAP assay overcomes the limitations of the traditional gel-based TRAP assay and provides a more efficient, accurate, and quantitative approach to measuring telomerase activity within laboratory and clinical settings.

RevDate: 2019-05-22

Stenbäck V, Mutt SJ, Leppäluoto J, et al (2019)

Association of Physical Activity With Telomere Length Among Elderly Adults - The Oulu Cohort 1945.

Frontiers in physiology, 10:444.

Introduction: Physical activity (PA) has been associated with telomere shortening. The association of PA intensity or volume with telomere length (TL) is nonetheless unclear. The aim of our study was to investigate the associations of exercise intensity and volume with TL in elderly adults from Northern Finland (65° latitude North). Methods: Seven hundred elderly subjects born in 1945 in the Oulu region were investigated. PA was measured during a 2-week period with a wrist-worn accelerometer. In addition, a questionnaire was used to assess sedentary time and to achieve a longitudinal PA history and intensity. Relative telomere lengths (RTL) were determined from frozen whole blood samples using a qPCR-based method. Results: Relative telomere lengths were significantly longer in women than men and negatively correlated with age in both genders (men r = -0.210, p = 0.000, women r = -0.174, and p = 0.000). During the 2-week study period, women took more steps than men (p = 0.001), but the association between steps and RTL was only seen in men (p = 0.05). Total steps taken (r = 0.202 and p = 0.04) and sedentary time (r = -0.247 and p = 0.007) significantly correlated with RTLs in 70-year old subjects. Moderate PA was associated with RTL in subjects with the highest quartile of moderate PA compared to the three lower quartiles (p-values: 0.023 between 4th and 1st, 0.04 between 4th and 2nd, and 0.027 between 4th and 3rd) in the 70-year old subjects. Conclusion: Women had longer RTL and a higher step count compared to men. However, exercise volume and RTL correlated positively only in men. Surprisingly, age correlated negatively with RTL already within an age difference of 2 years. This suggests that telomere attrition rate may accelerate in older age. Moderate physical activity at the time of study was associated with RTL.

RevDate: 2019-05-18

Dlouha D, Vymetalova J, Hubacek JA, et al (2019)

Association between aortic telomere length and cardiac post-transplant allograft function.

International journal of cardiology pii:S0167-5273(18)35641-9 [Epub ahead of print].

BACKGROUND: In patients having undergone orthotopic heart transplantation, a number of complications exist that are known to be connected to both telomerase activity and telomere length. The aim of this study was to determine how telomere length in aortic DNA correlates with the subsequent post-transplantation development of the patients.

MATERIALS AND METHODS: Between 2005 and 2015, we collected aortic samples from 376 heart recipients (age 50.8 ± 11.8 years) and 383 donors (age 38.6 ± 12.2 years). Relative telomere length in aortic tissue DNA was determined using quantitative PCR.

RESULTS: Shorter telomere length was detected in heart allograft recipients compared to donors (P < 0.0001). Patients suffering acute cellular rejection had significantly shorter telomere length (P < 0.01) than patients without rejection. Shorter telomere length was observed in patients with implanted mechanical circulatory support before heart transplantation (P < 0.03), as well as in subjects with cardiac allograft vasculopathy (P < 0.05). Overall survival time after heart transplantation was associated with shorter donor telomeres (P < 0.004).

CONCLUSIONS: Telomere length differed between donors and recipients independent of the sex and age of the patients. Our findings suggest a potential new linkage between the aortic telomere length of recipients and post-heart transplant complications. Further studies focusing on epigenetic modifications and gene regulation involved in telomere maintenance in transplanted patients should verify our results.

RevDate: 2019-06-10

Fouquerel E, Barnes RP, Uttam S, et al (2019)

Targeted and Persistent 8-Oxoguanine Base Damage at Telomeres Promotes Telomere Loss and Crisis.

Molecular cell pii:S1097-2765(19)30316-8 [Epub ahead of print].

Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. Although telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological effect of this common lesion at telomeres is poorly understood because ROS have pleiotropic effects. Here we developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival. However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.

RevDate: 2019-05-18

Weale CJ, Davison GM, Hon GM, et al (2019)

Leucocyte Telomere Length and Glucose Tolerance Status in Mixed-Ancestry South Africans.

Cells, 8(5): pii:cells8050464.

Telomeres are DNA-tandem repeats situated at the ends of chromosomes and are responsible for genome stabilization. They are eroded by increased cell division, age and oxidative stress with shortened leucocyte telomeres (LTL) being associated with inflammatory disorders, including Type II diabetes. We assessed LTL in 205 participants across glucose tolerance groups at baseline and after three years in the mixed ancestry population of South Africa which have been shown to have high rates of obesity and T2DM. Baseline and follow-up data included glucose tolerance status, anthropometric measurements, lipids, insulin, γ-glutamyl transferase (GGT), cotinine, and HbA1c. Telomere length was measured using the absolute telomere q-PCR method performed on a Bio-Rad MiniOpticon Detector. No significant difference was detected in LTL across glucose tolerance groups at both time points, including in subjects who showed a deterioration of their glucose tolerance status. There was, however, a significant negative correlation between LTL and age which was more pronounced in diabetes (r = -0.18, p = 0.04) and with GGT (r = -0.16, p = 0.027). This longitudinal study has demonstrated that LTL shortening is not evident within three years, nor is it associated with glycaemia. Further studies in a larger sample and over a longer time period is required to confirm these results.

RevDate: 2019-06-07

Iberl S, Meyer AL, Müller G, et al (2019)

Effects of continuous high-dose G-CSF administration on hematopoietic stem cell mobilization and telomere length in patients with amyotrophic lateral sclerosis - a pilot study.

Cytokine, 120:192-201.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34+ hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34+ HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients' leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34+ HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.

RevDate: 2019-06-10

Farooqi A, Yang J, Sharin V, et al (2019)

Identification of patient-derived glioblastoma stem cell (GSC) lines with the alternative lengthening of telomeres phenotype.

Acta neuropathologica communications, 7(1):76 pii:10.1186/s40478-019-0732-4.

RevDate: 2019-05-16

Lin X, Zhou J, B Dong (2019)

Effect of different levels of exercise on telomere length: A systematic review and meta-analysis.

Journal of rehabilitation medicine [Epub ahead of print].

OBJECTIVE: To investigate the effect of different levels of exercise on telomere length.

METHODS: CINAHL, SPORTDiscus (EBSCO), OVID (Medline) and EMBASE databases were searched for eligible studies. Methodological quality was evaluated using the Newcastle-Ottawa Scale, and heterogeneity among the studies was assessed using the I-squared test. When heterogeneity among studies was high (I2 > 50%), a random-effects model was used (Review Manager version 5, Cochrane Collaboration, Copenhagen, Denmark); otherwise, a fixed-effects model was used.

RESULTS: Eleven eligible studies involving 15,645 participants were included in this meta-analysis. Longer telomere length was associated with physically active individuals, with a mean difference (MD) of 0.15; 95% confidence interval; 95% CI 0.05, 0.24; I2 = 99%. Longer telomere length was significantly associated with robust exercise (MD 0.08; 95% CI 0.04, 0.12); I2 = 99%, as was moderate exercise (MD 0.07; 95% CI 0.03, 0.11); I2 = 100%. Subgroup analysis revealed that longer telomere length was positively associated with exercise, regardless of sex, but was not statistically significant in elderly populations.

CONCLUSION: Compared with inactive individuals, telomere lengths were longer in active subjects, regardless of the intensity of exercise.

RevDate: 2019-05-15

Hu R, Hua XG, QC Jiang (2019)

Associations of telomere length in risk and recurrence of prostate cancer: A meta-analysis.

Andrologia [Epub ahead of print].

Over the past decades, there is an increasing number of association studies of telomere length (TL) and the risk and recurrence of prostate cancer (PCa), but the results are inconsistent. Hence, we identify the relevant studies published in English on or before 10 January 2019 conducting a literature review in the electronic databases including PubMed, EMBASE and Cochrane Library. Twelve studies (with 19 data sets) were included in this meta-analysis, five of which were associated with risk assessment, six of which reported recurrence of PCa and one of which included them. Our meta-analysis demonstrated a positive association of shorter telomeres in patients with PCa, but without statistical significance (OR, 1.23; 95% CI: 0.91-1.66). Shorter telomeres in stroma (OR, 2.40; 95% CI: 1.61-3.56) and epithelium (OR, 1.70; 95% CI: 1.33-2.16) were positively correlated with PCa, but in leucocyte (OR, 0.81; 95% CI: 0.73-0.91) had negative association with PCa. Furthermore, two studies combined yielded a pooled OR of 2.87 (95% CI: 1.22-6.76) for the association between shorter TL and metastasis. These results are novel and give further strength to formulate eligible individualising treatment and surveillance strategies.

RevDate: 2019-05-17

Gauchier M, Kan S, Barral A, et al (2019)

SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres.

Science advances, 5(5):eaav3673 pii:aav3673.

Alternative lengthening of telomeres, or ALT, is a recombination-based process that maintains telomeres to render some cancer cells immortal. The prevailing view is that ALT is inhibited by heterochromatin because heterochromatin prevents recombination. To test this model, we used telomere-specific quantitative proteomics on cells with heterochromatin deficiencies. In contrast to expectations, we found that ALT does not result from a lack of heterochromatin; rather, ALT is a consequence of heterochromatin formation at telomeres, which is seeded by the histone methyltransferase SETDB1. Heterochromatin stimulates transcriptional elongation at telomeres together with the recruitment of recombination factors, while disrupting heterochromatin had the opposite effect. Consistently, loss of SETDB1, disrupts telomeric heterochromatin and abrogates ALT. Thus, inhibiting telomeric heterochromatin formation in ALT cells might offer a new therapeutic approach to cancer treatment.

RevDate: 2019-06-10

Reddy V, Iskander A, Hwang C, et al (2019)

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death.

PloS one, 14(5):e0211090 pii:PONE-D-19-00420.

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.

RevDate: 2019-05-26

Ghanem NZ, Malla SRL, Araki N, et al (2019)

Quantitative assessment of changes in cell growth, size and morphology during telomere-initiated cellular senescence in Saccharomyces cerevisiae.

Experimental cell research, 381(1):18-28.

Telomerase-deficient cells of the budding yeast S. cerevisiae experience progressive telomere shortening and undergo senescence in a manner similar to that seen in cultured human fibroblasts. The cells exhibit a DNA damage checkpoint-like stress response, undergo changes in size and morphology, and eventually stop dividing. In this study, a new assay is described that allowed quantitation of senescence in telomerase-deficient est2 cells with applied statistics. Use of the new technique revealed that senescence was strongly accelerated in est2 mutants that had homologous recombination genes RAD51, RAD52 or RAD54 co-inactivated, but was only modestly affected when RAD55, RAD57 or RAD59 were knocked out. Additionally, a new approach for calculating population doublings indicated that loss of growth capacity occurred after approximately 64 generations in est2 cells but only 42 generations in est2 rad52 cells. Phase contrast microscopy experiments demonstrated that senescing est2 cells became enlarged in a time-dependent manner, ultimately exhibiting a 60% increase in cell size. Progressive alterations in physical properties were also observed, including striking changes in light scattering characteristics and cellular sedimentation rates. The results described herein will facilitate future studies of genetic and environmental factors that affect telomere shortening-associated cell senescence rates using the yeast model system.

RevDate: 2019-05-09

Tanpaisankit M, Hongsaprabhas C, Chareonlap C, et al (2019)

Relative telomere length and oxidative stress in musculoskeletal tumors.

Molecular biology reports pii:10.1007/s11033-019-04847-y [Epub ahead of print].

Telomeres are capped at the end of the chromosome and gradually shorten when the cell divides. When there is an oxidative stress, it can cause the DNA to be damaged. Hence, 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been shown to be an indicator for oxidative DNA damage. This study aimed to determine the relative telomere length (RTL) and 8-OHdG levels in neoplastic tissues, adjacent non-neoplastic tissues, and blood leukocytes of musculoskeletal (MS) tumor patients. Neoplastic tissues were compared to adjacent non-neoplastic tissues in MS tumor patients (n = 46). Peripheral blood leukocytes (PBLs) of MS tumor subjects were compared to those of age-matched healthy controls (n = 107). RTL was evaluated by quantitative real-time polymerase chain reaction and 8-OHdG levels were quantified by enzyme-linked immunosorbent assay. The RTL in neoplastic tissues was significantly shorter than that in non-neoplastic tissues [1.12 (0.86-1.46) vs 1.45 (1.25-1.65), P = 0.001]. PBLs had lower RTL than non-neoplastic tissues in MS tumor patients [1.04 (0.85-1.13) vs 1.45 (1.25-1.65), P < 0.001]. However, there was no significant difference between RTL in PBLs and in neoplastic tissues. In addition, PBLs of MS tumor patients had higher RTL than those of the controls [1.04 (0.85-1.13) versus 0.78 (0.68-0.90), P < 0.001]. The 8-OHdG levels in neoplastic tissues were remarkably higher than those in non-neoplastic tissues [8.14 (6.81-11.37) nM/μg/μl vs. 3.79 (2.53-6.17) nM/μg/μl, P < 0.001]. Furthermore, plasma 8-OHdG levels in MS tumor patients were markedly greater than those in the controls [102.50 (73.16-133.50) nM vs. 41.09 (6.81-11.37) nM, P < 0.001]. Area under the curve (AUC) was 0.7536 (95% confident interval (CI) 0.6602-0.8469) when the cut-off value of RTL in PBLs was 0.97. Also, plasma 8-OHdG levels depicted that when the cut-off value was 38.67 nM, the AUC was 0.7723 (95% CI 0.6920-0.8527). Moreover, ROC curve analysis showed that both RTL and 8-OHdG appeared to improve the sensitivity (85.68%) and specificity (70.91%) with the AUC 0.8639 (95% CI 0.7500-0.9500). This study suggested that blood leukocyte RTL and plasma 8-OHdG could serve as promising non-invasive biomarkers to differentiate between MS tumor patients and healthy controls. Additionally, telomere attrition and increased oxidative DNA damage might play contributory roles in the pathogenesis of MS tumors.

RevDate: 2019-05-12

Wang J, Peng X, Chen C, et al (2019)

Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors.

Frontiers in genetics, 10:358.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

RevDate: 2019-05-24
CmpDate: 2019-05-24

Niederberger C (2019)

Re: Non-Obstructive Azoospermia and Shortened Leukocyte Telomere Length: Further Evidence Linking Poor Health and Infertility.

The Journal of urology, 201(6):1040-1041.

RevDate: 2019-05-24
CmpDate: 2019-05-24

Anonymous (2019)

Re: Shorter Leukocyte Telomere Length is Associated with Risk of Nonobstructive Azoospermia.

The Journal of urology, 201(6):1040.

RevDate: 2019-06-10

Sugarman ET, Zhang G, JW Shay (2019)

In perspective: An update on telomere targeting in cancer.

Molecular carcinogenesis [Epub ahead of print].

Engaging a telomere maintenance mechanism during DNA replication is essential for almost all advanced cancers. The conversion from normal and premalignant somatic cells to advanced malignant cells often results (85%-90%) from the reactivation of the functional ribonucleoprotein holoenzyme complex, referred to as telomerase. Modulation of the human telomerase reverse transcriptase (hTERT) appears to be rate limiting to produce functional telomerase and engage a telomere maintenance mechanism. The remaining 10% to 15% of cancers overcome progressively shortened telomeres by activating an alternative lengthening of telomeres (ALT) maintenance mechanism, through a DNA recombination pathway. Exploration into the specific mechanisms of telomere maintenance in cancer have led to the development of drugs such as Imetelstat (GRN163L), BIBR1532, 6-thio-dG, VE-822, and NVP-BEZ235 being investigated as therapeutic approaches for treating telomerase and ALT tumors. The successful use of 6-thio-dG (a nucleoside preferentially recognized by telomerase) that targets and uncaps telomeres in telomerase positive but not normal telomerase silent cells has recently shown impressive effects on multiple types of cancer. For example, 6-thio-dG overcomes therapy-resistant cancers in a fast-acting mechanism potentially providing an alternative or additional route of treatment for patients with cancer. In this perspective, we provide a synopsis of the current landscape of telomeres and telomerase processing in cancer development and how this new knowledge may improve outcomes for patients with cancer.

RevDate: 2019-05-07

Huda N, Xu Y, Bates AM, et al (2019)

Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma.

Cells, 8(5): pii:cells8050414.

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.

RevDate: 2019-05-19

Song L, Zhang B, Liu B, et al (2019)

Effects of maternal exposure to ambient air pollution on newborn telomere length.

Environment international, 128:254-260.

BACKGROUND: Telomere length (TL) is considered as a surrogate of biological aging and has been related to aging-related diseases. The initial setting of newborn TL has important implications for telomere dynamics in adulthood, and is affected by the intrauterine environment. However, the effects of prenatal air pollution exposure on the initial setting of newborn TL are poor understood.

OBJECTIVES: We aimed to explore the trimester-specific relationships between maternal air pollution exposure and newborn TL.

METHODS: Between November 2013 and March 2015, a total of 762 mother-newborn pairs were recruited in a birth cohort study in Wuhan, China. Relative cord blood TL was assessed using quantitative real-time polymerase chain reaction. Maternal exposures to PM2.5, PM10, SO2, CO, and NO2, were determined using spatial-temporal land use regression models. Multiple informant models were applied to explore the trimester-specific associations of maternal air pollution exposure with cord blood TL.

RESULTS: In single-pollutant models, a 10 μg/m3 increase in PM2.5, PM10, SO2, and a 100 μg/m3 increase in CO during the third trimester were related to 3.71% (95% confidence interval [CI]: -6.06%, -1.30%), 3.24% (95% CI: -5.29%, -1.14%), 11.07% (95% CI: -18.86%, -2.53%), and 3.67% (95% CI: -6.27%, -1.00%) shorter cord blood TL, respectively. The inverse relationships between exposures to PM2.5, PM10, SO2, and CO during the third trimester and cord blood TL were more evident in male infants. In multi-pollutant models, exposures to PM2.5 and PM10 during the third trimester were both related to shorter cord blood TL, but not SO2 and CO.

CONCLUSION: This study suggested that maternal exposures to PM2.5, PM10, CO, and SO2 during the third trimester were related to shorter newborn TL, which highlights the importance of improving air quality in favor of subsequent health in later life of newborns.

RevDate: 2019-05-16

Gurugubelli Krishna R, Bhat BV, Bobby Z, et al (2019)

Are Global DNA methylation and telomere length useful biomarkers for identifying intrauterine growth restricted neonates?.

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians [Epub ahead of print].

BACKGROUND: Intrauterine growth restriction (IUGR) is manifested by decreased growth rate of fetus than its normal genetic growth potential. Global DNA methylation is a crucial investigation for identification of epigenetic changes. Epigenetic change regulates Gene transcription, maintenance of genomic stability, and telomere length.

OBJECTIVES: To investigate whether the global DNA methylation and telomere length are useful for identifying intrauterine growth restriction.

METHODS: This cohort study was conducted in the Neonatology Department of JIPMER during the period of November 2016 to December 2017. Forty (40) IUGR and forty (40) AGA neonates were recruited. Umbilical cord blood samples were collected at birth. DNA has been separated from the blood samples and using 5-mC DNA ELISA method, the percentage of genomic DNA methylated in these neonates was established. Telomere length (T/S ratio) was measured by using quantitative real time PCR. Data were expressed as a mean ± standard deviation.

RESULTS: Genomic DNA methylation varied significantly between IUGR and AGA neonates (IUGR: 3.12 ± 1.24; AGA: 4.40 ± 2.03; p: < .01). There was significant DNA hypo methylation in IUGR neonates. However, telomere length (T/S ratio) was (IUGR: 1.25 ± 0.13; AGA: 1.26 ± 0.22; p: 0.228 (NS)) similar in both groups.

CONCLUSION: Although there is no significant difference in telomere length between IUGR and AGA neonates, global DNA methylation of 3.45 would identify IUGR with a sensitivity and specificity of 69 and 65% respectively.

RevDate: 2019-05-29

Nie J, Li J, Cheng L, et al (2019)

Prenatal polycyclic aromatic hydrocarbons metabolites, cord blood telomere length, and neonatal neurobehavioral development.

Environmental research, 174:105-113.

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbon (PAH) is a potential risk factor for child neurobehavioral development. Telomere length (TL) has important implications for health over the life course.

OBJECTIVE: In this study, we aimed to investigate whether prenatal urinary PAH metabolites were associated with adverse neonatal neurobehavioral development and altered cord blood TL and to explore whether the change of TL was a predictor of neonatal neurobehavioral development.

METHOD: We enrolled 283 nonsmoking pregnant women in Taiyuan city. Eleven PAH metabolites were measured in maternal urine samples. TL in cord blood was measured by real time quantitative polymerase chain reaction. Neonatal behavioral neurological assessment (NBNA) tests were conducted when the infants were three days old. Multiple linear regression models were used to analyze the associations of maternal urinary PAH metabolites with NBNA scores and cord blood TL, and restricted cubic spline models were further used to examine the shapes of dose-response relationships. A mediation analysis was also conducted.

RESULT: We observed dose-response associations of maternal urinary 2-hydroxyfluorene (2-OHFlu) and 2-hydroxyphenanthrene (2-OH Phe) with decreased active tone scores, sum of NBNA scores, and cord blood TL (P for trend<0.05). Each 1 unit increase in urinary levels of Ln (2-OH Flu) or Ln (2-OH Phe) was associated with a 0.092 or 0.135 decrease in the active tone scores and a 0.174 or 0.199 decrease in the sum of NBNA scores. Mediation analysis showed TL could explained 21.74% of the effect of sum of NBNA scores change related to prenatal exposure to 2-OH Phe (P for mediator = 0.047).

CONCLUSION: Our data indicates maternal urinary specific PAH metabolites are inversely associated with neonatal neurobehavioral development and cord blood TL. TL mediates the associations of 2-OH Phe with neonatal neurobehavioral development and partly explains the effect of 2-OH Phe on neonatal neurobehavioral development.

RevDate: 2019-05-28

Canudas S, Hernández-Alonso P, Galié S, et al (2019)

Pistachio consumption modulates DNA oxidation and genes related to telomere maintenance: a crossover randomized clinical trial.

The American journal of clinical nutrition, 109(6):1738-1745.

BACKGROUND: Telomere attrition may play an important role in the pathogenesis and severity of type 2 diabetes (T2D), increasing the probability of β cell senescence and leading to reduced cell mass and decreased insulin secretion. Nutrition and lifestyle are known factors modulating the aging process and insulin resistance/secretion, determining the risk of T2D.

OBJECTIVES: The aim of this study was to evaluate the effects of pistachio intake on telomere length and other cellular aging-related parameters of glucose and insulin metabolism.

METHODS: Forty-nine prediabetic subjects were included in a randomized crossover clinical trial. Subjects consumed a pistachio-supplemented diet (PD, 50 E% [energy percentage] carbohydrates and 33 E% fat, including 57 g pistachios/d) and an isocaloric control diet (CD, 55 E% carbohydrates and 30 E% fat) for 4 mo each, separated by a 2-wk washout period. DNA oxidation was evaluated by DNA damage (via 8-hydroxydeoxyguanosine). Leucocyte telomere length and gene expression related to either oxidation, telomere maintenance or glucose, and insulin metabolism were analyzed by multiplexed quantitative reverse transcriptase-polymerase chain reaction after the dietary intervention.

RESULTS: Compared with the CD, the PD reduced oxidative damage to DNA (mean: -3.5%; 95% CI: -8.07%, 1.05%; P = 0.009). Gene expression of 2 telomere-related genes (TERT and WRAP53) was significantly upregulated (164% and 53%) after the PD compared with the CD (P = 0.043 and P = 0.001, respectively). Interestingly, changes in TERT expression were negatively correlated to changes in fasting plasma glucose concentrations and in the homeostatic model assessment of insulin resistance.

CONCLUSIONS: Chronic pistachio consumption reduces oxidative damage to DNA and increases the gene expression of some telomere-associated genes. Lessening oxidative damage to DNA and telomerase expression through diet may represent an intriguing way to promote healthspan in humans, reversing certain deleterious metabolic consequences of prediabetes. This study was registered at clinicaltrials.gov as NCT01441921.

RevDate: 2019-05-03

Agrusa JE, Bertuch AA, DiNardo CD, et al (2019)

Severe therapy-related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres.

Pediatric blood & cancer [Epub ahead of print].

Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to chemotherapy and radiation. We report a case of a 17-year-old female with Hodgkin lymphoma who developed severe chemotherapy-related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy-related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.

RevDate: 2019-05-19

Nettle D, Seeker L, Nussey D, et al (2019)

Consequences of measurement error in qPCR telomere data: A simulation study.

PloS one, 14(5):e0216118 pii:PONE-D-18-35272.

The qPCR method provides an inexpensive, rapid method for estimating relative telomere length across a set of biological samples. Like all laboratory methods, it involves some degree of measurement error. The estimation of relative telomere length is done subjecting the actual measurements made (the Cq values for telomere and a control gene) to non-linear transformations and combining them into a ratio (the TS ratio). Here, we use computer simulations, supported by mathematical analysis, to explore how errors in measurement affect qPCR estimates of relative telomere length, both in cross-sectional and longitudinal data. We show that errors introduced at the level of Cq values are magnified when the TS ratio is calculated. If the errors at the Cq level are normally distributed and independent of true telomere length, those in the TS ratio are positively skewed and proportional to true telomere length. The repeatability of the TS ratio declines sharply with increasing error in measurement of the Cq values for telomere and/or control gene. In simulated longitudinal data, measurement error alone can produce a pattern of low correlation between successive measures of relative telomere length, coupled with a strong negative dependency of the rate of change on initial relative telomere length. Our results illustrate the importance of reducing measurement error: a small increase in error in Cq values can have large consequences for the power and interpretability of qPCR estimates of relative telomere length. The findings also illustrate the importance of characterising the measurement error in each dataset-coefficients of variation are generally unhelpful, and researchers should report standard deviations of Cq values and/or repeatabilities of TS ratios-and allowing for the known effects of measurement error when interpreting patterns of TS ratio change over time.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

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