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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 22 Sep 2018 at 01:43 Created: 

Telomeres

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

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

Citations The Papers (from PubMed®)

RevDate: 2018-09-20

Rathore M, J Abraham (2018)

Implication of Asana, Pranayama and Meditation on Telomere Stability.

International journal of yoga, 11(3):186-193.

Telomeres, the repetitive sequences that protect the ends of chromosomes, help to maintain genomic integrity and are of key importance to human health. Telomeres progressively shorten throughout life and a number of studies have shown shorter telomere length to be associated with lifestyle disorders. Previous studies also indicate that yoga and lifestyle-based intervention have significant role on oxidative DNA damage and cellular aging. However, very few publications investigate telomere stability and its implication from the point of view of asana, pranayama, and meditation. In this context, a review was conducted to systematically assess the available data on the effectiveness of asana, pranayama, and meditation in maintaining telomere and telomerase. Literature search was performed using the following electronic databases: Cochrane Library, NCBI, PubMed, Google Scholar, EMBASE, and Web of Science. We explored the possible mechanisms of how asana, pranayama, and meditation might be affecting telomere length and telomerase. Moreover, results showed that asana and pranayama increase the oxygen flow to the cells and meditation reduces the stress level by modulating the hypothalamic-pituitary-adrenal axis. Summing up the result, it can be concluded that practice of asana, pranayama, and meditation can help to maintain genomic integrity and are of key importance to human health and lifestyle disorders.

RevDate: 2018-09-19

Zhu Y, Liu X, Ding X, et al (2018)

Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction.

Biogerontology pii:10.1007/s10522-018-9769-1 [Epub ahead of print].

Aging is a biological process characterized by a progressive functional decline in tissues and organs, which eventually leads to mortality. Telomeres, the repetitive DNA repeat sequences at the end of linear eukaryotic chromosomes protecting chromosome ends from degradation and illegitimate recombination, play a crucial role in cell fate and aging. Due to the mechanism of replication, telomeres shorten as cells proliferate, which consequently contributes to cellular senescence and mitochondrial dysfunction. Cells are the basic unit of organismal structure and function, and mitochondria are the powerhouse and metabolic center of cells. Therefore, cellular senescence and mitochondrial dysfunction would result in tissue or organ degeneration and dysfunction followed by somatic aging through multiple pathways. In this review, we summarized the main mechanisms of cellular senescence, mitochondrial malfunction and aging triggered by telomere attrition. Understanding the molecular mechanisms involved in the aging process may elicit new strategies for improving health and extending lifespan.

RevDate: 2018-09-18

Brosnan-Cashman JA, Yuan M, Graham MK, et al (2018)

ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner.

PloS one, 13(9):e0204159 pii:PONE-D-18-12176.

Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.

RevDate: 2018-09-18

Pepper GV, Bateson M, D Nettle (2018)

Telomeres as integrative markers of exposure to stress and adversity: a systematic review and meta-analysis.

Royal Society open science, 5(8):180744 pii:rsos180744.

Telomeres have been proposed as a biomarker that integrates the impacts of different kinds of stress and adversity into a common currency. There has as yet been no overall comparison of how different classes of exposure associate with telomeres. We present a meta-analysis of the literature relating telomere measures to stresses and adversities in humans. The analysed dataset contained 543 associations from 138 studies involving 402 116 people. Overall, there was a weak association between telomere variables and exposures (greater adversity, shorter telomeres: r = -0.15, 95% CI -0.18 to -0.11). This was not driven by any one type of exposure, because significant associations were found separately for physical diseases, environmental hazards, nutrition, psychiatric illness, smoking, physical activity, psychosocial and socioeconomic exposures. Methodological features of the studies did not explain any substantial proportion of the heterogeneity in association strength. There was, however, evidence consistent with publication bias, with unexpectedly strong negative associations reported by studies with small samples. Restricting analysis to sample sizes greater than 100 attenuated the overall association substantially (r = -0.09, 95% CI -0.13 to -0.05). Most studies were underpowered to detect the typical association magnitude. The literature is dominated by cross-sectional and correlational studies which makes causal interpretation problematic.

RevDate: 2018-09-18

Jokhun DS, Shang Y, GV Shivashankar (2018)

Actin Dynamics Couples Extracellular Signals to the Mobility and Molecular Stability of Telomeres.

Biophysical journal pii:S0006-3495(18)30983-4 [Epub ahead of print].

Genome regulatory programs such as telomere functioning require extracellular signals to be transmitted from the microenvironment to the nucleus and chromatin. Although the cytoskeleton has been shown to directly transmit stresses, we show that the intrinsically dynamic nature of the actin cytoskeleton is important in relaying extracellular signals to telomeres. Interestingly, this mechanical pathway not only transmits physical stimuli but also chemical stimuli. The cytoskeletal network continuously reorganizes and applies dynamic forces on the nucleus and feeds into the regulation of telomere dynamics. We further found that distal telomeres are mechanically coupled in a length- and timescale-dependent manner and identified nesprin 2G as well as lamin A/C as being essential to regulate their translational dynamics. Finally, we demonstrated that such mechanotransduction events impinge on the binding dynamics of critical telomere binding proteins. Our results highlight an overarching physical pathway that regulates positional and molecular stability of telomeres.

RevDate: 2018-09-18

Zhao K, Y Li (2018)

Can telomere length predict contrast-induced nephropathy?.

International journal of cardiology, 271:350.

RevDate: 2018-09-17

Wulaningsih W, Hardy R, Wong A, et al (2018)

Parental age and offspring leukocyte telomere length and attrition in midlife: Evidence from the 1946 British birth cohort.

Experimental gerontology pii:S0531-5565(17)30677-0 [Epub ahead of print].

BACKGROUND: There is evidence that paternal age may influence offspring telomere length, but the joint effects of father's and mother's age are unclear. We evaluated whether parental ages, individually and jointly, were associated with offspring telomere length and shortening.

METHODS: We included 2305 British birth cohort participants with measured leukocyte telomere length (LTL) at age 53, among whom 941 had a second measurement at age 60-64. Linear regressions were performed to assess the associations of father's and mother's age at birth and the parental age gap, i.e. the difference between maternal and paternal age with LTL and LTL change.

RESULTS: A one year increase in father's age corresponded to a 0.26% (95% CI: 0.04-0.47%) increase in offspring LTL at age 53 in the sex-adjusted model. No association was observed for mother's age. Associations of father's or mother's age with offspring LTL at age 53 went to opposite directions when both parental ages were included together. For the difference in parental age, every year that fathers were older than mothers corresponded to a 0.94% (95% CI, 0.38-1.50%) increase in LTL at age 53 after adjustment for potential confounders. Neither parental ages nor the difference in parental ages were correlated with LTL change.

CONCLUSION: There was a joint effect of parental ages on offspring telomere length, further denoting a complex role of reproductive age in offspring health and ageing.

RevDate: 2018-09-17

Esch T, Kream RM, GB Stefano (2018)

Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length.

Medical science monitor basic research, 24:134-140 pii:911786.

Stress affects cellular aging and inflammatory and chromosomal processes, including telomere length, thereby potentially compromising health and facilitating disease onset and progression. Stress-related diseases and strategies to manage stress usually require integrative or behavioral therapeutic approaches that also operate on cellular levels. Mind-body medicine (MBM) uses the interaction between the mind, body, behavior, and the environment to correct physical and psychological malfunctions, thus ameliorating disease states and improving health. The relaxation response (RR) is a physiological opponent of stress and the stress response (SR) (i.e., fight-or-flight response), also invoking molecular anti-stress processes. Techniques that elicit the RR are at the core of practically all MBM interventions. We surmise that these techniques can also affect chromosomal and telomere processes, molecular aging, and the modulation of inflammatory states on cellular levels.

RevDate: 2018-09-15

Thriveni K, Raju A, Kumar RV, et al (2018)

Patterns of Relative Telomere Length is Associated With hTERT Gene Expression in the Tissue of Patients With Breast Cancer.

Clinical breast cancer pii:S1526-8209(18)30372-0 [Epub ahead of print].

BACKGROUND: Homeostasis of telomere in breast cancer might be altered as a result of cumulative effects of various factors causing genomic instability and affecting prognosis. This study aimed to compare the relative telomere length (RTL) and hTERT mRNA expression in the tissue of patients with breast cancer along with the clinicopathologic parameters.

PATIENTS AND METHODS: Frozen tumor tissues and adjacent normal breast tissue from 98 patients with invasive ductal breast cancer were used for the analysis. RTL and hTERT mRNA expression were measured using quantitative real time polymerase chain reaction.

RESULTS: Among the 98 cases, 51% had an early-stage carcinoma, 66% were tumor size < 5 cm, 30% were node-negative, and 20% were low-grade tumors. In this study, 63% of cases showed higher hTERT gene expression with an odds ratio of 2.77 (P = .02). The median RTL for elongated telomere was 3.49, and the value was significantly elevated when compared with the shorter telomere. Shortened RTL was present in 60% of early-stage cancer cases, 55% where the tumor size was < 5 cm, 72% of the lymph node-negative cases, and 68% of low-grade carcinoma. Significantly elongated RTL, with median 4.22, 3.19, 3.17, and 3.28 was observed (P < .05) in the advanced stage, larger tumor size, node-positive, and high-grade cases respectively.

CONCLUSION: In this study, shortened telomere was observed in early-stage cancer, and elongated telomere was found in advanced diseases. However, 13% of patients with lower hTERT gene expression showed elongated telomeres, indicating relative telomere length measurement in tissue is different from blood leukocyte, showing the dynamic process of tumorigenesis in tissue.

RevDate: 2018-09-14

Zhao B, Vo HQ, Johnston FH, et al (2018)

Air pollution and telomere length: a systematic review of 12,058 subjects.

Cardiovascular diagnosis and therapy, 8(4):480-492.

Background: Over recent decades, adverse effects of ambient air pollution on the cardiovascular system have been clearly demonstrated. However, the underlying mechanisms are not fully elucidated. Air pollution may accelerates biological aging and thereby the susceptibility to cardiovascular diseases (CVDs). Telomeres are tandem repetitive DNA complexes that play a critical role in maintaining chromosome stability. There are, however, heterogeneities among the reported effects of air pollution on telomere. This study sought to evaluate the existing literature on the association between air pollution and telomere length (TL).

Methods: Two reviewers independently searched on electronic databases including PUBMED, EMBASE, SCOPUS, WEB OF SCIENCE and Ovid. The key terms were "air pollution" and "telomere" without language restriction. Articles relating to tobacco smoke were excluded.

Results: A total of 12,058 subjects from 25 articles remained for final review. All were observational studies: 14 cross-sectional, 6 cohort and 5 case-control studies. Nineteen (76%) assessed leukocyte telomere length (LTL) of which 15 found associations between air pollution and shorter TL, 2 with longer TL, 1 had mixed results, and a study of patients with type 2 diabetes found non-significant associations with TL. One found longer TL from saliva. The remaining studies were of placental cells, buccal cells or sperm and all reported shorter TL associated with air pollution. Particulate matter (PM) was investigated in 8 articles, and the remainder assessed black carbon (BC), benzene, lead, cadmium and polycyclic aromatic hydrocarbon (PAH). Geographically, 11 studies were conducted in Europe, with 10 in Asia and 4 in North America. While all followed Cawthon's protocol for TL assessment, discordance in the reporting formats did not allow us to perform a quantitative meta-analysis.

Conclusions: Most of the studies support the association of shorter TL with air pollution. Uniform reporting format would be warranted for future studies to estimate true effect size of air pollution on TL.

RevDate: 2018-09-13

Wang F, Sheng JF, Cai L, et al (2018)

The Telomerase and Alternative Lengthening of Telomeres Mechanisms Regulate Laryngeal Cancer Cell Apoptosis via the PI3K/Akt Pathway.

ORL; journal for oto-rhino-laryngology and its related specialties pii:000489461 [Epub ahead of print].

PURPOSE: To investigate the possible telomerase and alternative lengthening of telomeres (ALT) mechanisms influencing the apoptosis of laryngeal squamous cells.

MATERIALS AND METHODS: The effects of the telomerase mechanism were observed by knockdown of human telomerase reverse transcriptase (hTERT). The ALT mechanism was induced by silencing related genes including TRF2, RAD51, and NBS1. Effects of telomerase and ALT mechanisms on tumor development were confirmed by xenograft tumors model. Tumor cell apoptosis was investigated by flow cytometry and Hoechst staining. Caspase-3 activity assay and Western blot were performed to investigate the possible mechanisms.

RESULTS: After silencing ALT- and telomerase mechanism-related genes, Bax and Bcl-2 were increased, and nuclear factor (NF)-κB translocation and PI3K/Akt phosphorylation were inhibited.

CONCLUSIONS: The inhibition of telomere-related genes inhibited the growth of laryngeal squamous cell carcinoma by promoting cell apoptosis via the PI3K/Akt pathway.

RevDate: 2018-09-13

Tsamou M, Martens DS, Cox B, et al (2018)

Sex-specific associations between telomere length and candidate miRNA expression in placenta.

Journal of translational medicine, 16(1):254 pii:10.1186/s12967-018-1627-z.

BACKGROUND: In the early-life environment, proper development of the placenta is essential for both fetal and maternal health. Telomere length at birth has been related to life expectancy. MicroRNAs (miRNAs) as potential epigenetic determinants of telomere length at birth have not been identified. In this study, we investigate whether placental miRNA expression is associated with placental telomere length at birth.

METHODS: We measured the expression of seven candidate miRNAs (miR-16-5p, -20a-5p, -21-5p, -34a-5p, 146a-5p, -210-3p and -222-3p) in placental tissue at birth in 203 mother-newborn (51.7% girls) pairs from the ENVIRONAGE birth cohort. We selected miRNAs known to be involved in crucial cellular processes such as inflammation, oxidative stress, cellular senescence related to aging. Placental miRNA expression and relative average placental telomere length were measured using RT-qPCR.

RESULTS: Both before and after adjustment for potential covariates including newborn's ethnicity, gestational age, paternal age, maternal smoking status, maternal educational status, parity, date of delivery and outdoor temperature during the 3rd trimester of pregnancy, placental miR-34a, miR-146a, miR-210 and miR-222 expression were significantly (p ≤ 0.03) and positively associated with placental relative telomere length in newborn girls. In newborn boys, only higher expression of placental miR-21 was weakly (p = 0.08) associated with shorter placental telomere length. Significant miRNAs explain around 6-8% of the telomere length variance at birth.

CONCLUSIONS: Placental miR-21, miR-34a, miR-146a, miR-210 and miR-222 exhibit sex-specific associations with telomere length in placenta. Our results indicate miRNA expression in placental tissue could be an important determinant in the process of aging starting from early life onwards.

RevDate: 2018-09-12

de Lange T (2018)

Shelterin-Mediated Telomere Protection.

Annual review of genetics [Epub ahead of print].

For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3' overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain. Expected final online publication date for the Annual Review of Genetics Volume 52 is November 23, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

RevDate: 2018-09-11

Rachakonda S, Kong H, Srinivas N, et al (2018)

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk.

Genes, chromosomes & cancer [Epub ahead of print].

Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10-10) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10-5) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.

RevDate: 2018-09-11

Chen B, Zhang Y, Yang Y, et al (2018)

Involvement of telomerase activity inhibition and telomere dysfunction in silver nanoparticles anticancer effects.

Nanomedicine (London, England) [Epub ahead of print].

AIM: To investigate the possible mechanisms of telomerase and telomere underlying the anticancer effects of silver nanoparticles (AgNPs).

MATERIALS & METHODS: 25nm polyvinylpyrrolidone-coated AgNPs were used. The telomerase activity and telomere function were evaluated. The anticancer effects of AgNPs were gauged with cell viability assay under different statement of telomerase and telomere.

RESULTS & CONCLUSION: AgNPs could inhibit telomerase activity and lead to telomere shortening and dysfunction. Overexpression of telomerase attenuated the anticancer activity of AgNPs, whereas downregulation of telomerase activity or dysfunction of the telomere enhanced the cytotoxicity of AgNPs in HeLa cells. Our findings provided strong evidence that the anticancer effects of AgNPs were mediated via interference with the telomerase/telomere.

RevDate: 2018-09-10

Stein JY, Levin Y, Lahav Y, et al (2018)

Perceived social support, loneliness, and later life telomere length following wartime captivity.

Health psychology : official journal of the Division of Health Psychology, American Psychological Association pii:2018-44127-001 [Epub ahead of print].

OBJECTIVES: Telomere length (TL) is a robust indicator of cellular aging. TL erosion has been associated with exposure to social and traumatic stressors. Loneliness and perceived social support are strongly linked to increased morbidity and mortality, but have yet to be investigated in relation to TL after extreme stress. The present study examined whether loneliness and lack of perceived social support following wartime captivity may be associated with TL as repatriated prisoners of war (ex-POWs) enter old age and contribute to its prediction.

METHOD: A cohort of Israeli ex-POWs from the 1973 Yom Kippur War (n = 83) were assessed. Questionnaires were utilized to assess loneliness and perceived social support 18 years after the repatriation (T1), and Southern blotting was used to measure TL 24 years later (T2). A zero-order Pearson correlation test and a hierarchical regression analysis were utilized in order to examine the research questions.

RESULTS: Loneliness and lack of perceived social support each significantly predicted shorter TL in later life, and together added 25.8% to the overall explained variance.

CONCLUSIONS: This is the first study to empirically demonstrate that loneliness and lack of perceived social support in early adulthood may be associated with shorter TL during transition to old age in a population that has endured extreme stress. Although the study design precludes causal inferences, several psychobiological mechanisms may explain the findings. The potential clinical significance of social deficits for longevity and heath in related populations is therefore addressed, and an agenda for future investigations is suggested. (PsycINFO Database Record

RevDate: 2018-09-10

Piekna-Przybylska D, SB Maggirwar (2018)

CD4+ memory T cells infected with latent HIV-1 are susceptible to drugs targeting telomeres.

Cell cycle (Georgetown, Tex.) [Epub ahead of print].

The population of HIV reservoir in infected person is very small, but extremely long-lived and is a major obstacle for an HIV cure. We previously showed that cells with established HIV latency have deficiencies in DNA damage response (DDR). Here, we investigated ability of HIV-1 to interfere with telomere maintenance, and the effects of targeting telomeres on latently infected cells. Our results show that telomeres are elongated in cultured primary memory CD4+T cells (TCM) after HIV-1 infection and when virus latency is established. Similarly, much longer telomeres were found in several Jurkat-derived latently infected cell lines, indicating that virus stimulates telomere elongation. Exposing primary CD4+TCM cells to BRACO19, an agent targeting telomeres, resulted in a higher rate of apoptosis for infected cultures at day 3 post-infection, during HIV-1 latency and for PMA-stimulated cultures with low level of HIV-1 reactivation. Importantly, BRACO19 induced apoptosis in infected cells with potency similar to etoposide and camptothecin, whereas uninfected cells were less affected by BRACO19. We also determined that apoptosis induced by BRACO19 is not caused by telomeres shortening, but is related to formation of gamma-H2AX, implicating DNA damage or uncapping of telomeres, which triggers genome instability. In conclusion, our results indicate that HIV-1 stimulates telomere elongation during latency, suggesting that HIV reservoir has greater capacity for clonal expansion and extended lifespan. Higher rates of apoptosis in response to BRACO19 treatment suggest that HIV reservoirs are more susceptible to targeting telomere maintenance and to inhibitors targeting DDR, which is also involved in stabilizing telomeres.

RevDate: 2018-09-10

Yang Q, Luo X, Bai R, et al (2018)

Shorter leukocyte telomere length is associated with risk of nonobstructive azoospermia.

Fertility and sterility, 110(4):648-654.e1.

OBJECTIVE: To determine the association between leukocyte telomere length and the risk of nonobstructive azoospermia (NOA).

DESIGN: The mean leukocyte telomere length (LTL) among men with NOA, obstructive azoospermia (OA), and normospermic subjects was determined by quantitative polymerase chain reaction (PCR). We used logistic regression to investigate the association between LTL and the risk of NOA after adjustment for age and body mass index (BMI). Partial correlation analysis was also used to evaluate the relationship of clinical parameters with the mean LTL among men with OA and NOA.

SETTING: Reproductive medicine center.

PATIENTS(S): A total of 866 men, including 270 normospermic controls, 247 OA and 349 NOA patients.

INTERVENTION(S): None.

MAIN OUTCOME MEASURE(S): Leukocyte telomere length.

RESULT(S): The mean relative LTL of men with NOA was significantly shorter than that of those with OA and in normospermic controls (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.64-0.98 vs. OR 0.92, 95% CI 0.70-1.24 vs. OR 0.99, 95% CI 0.83-1.22), respectively). Subjects with shorter telomeres (lowest tertile) had a significantly higher risk of NOA than those with longer telomeres (highest tertile). Interestingly, we also found that a low relative LTL was associated with poor efficiency of spermatogenesis using the Johnsen score after testis biopsy and histopathology in azoospermic patients, after adjusting for patient age and BMI.

CONCLUSION(S): This is the first report that short LTL is associated with NOA, shedding light on an important biological pathway involved in the etiology of this form of male factor infertility.

RevDate: 2018-09-10

Kohn TP, AW Pastuszak (2018)

Non-obstructive azoospermia and shortened leukocyte telomere length: further evidence linking poor health and infertility.

Fertility and sterility, 110(4):629-630.

RevDate: 2018-09-07

Booth SA, Wadley GD, Marques FZ, et al (2018)

Fetal growth restriction shortens cardiac telomere length but this is attenuated by exercise in early life.

Physiological genomics [Epub ahead of print].

BACKGROUND AND AIMS: Fetal and postnatal growth restriction predispose to cardiovascular disease (CVD) in adulthood. Telomeres are repetitive DNA-protein structures that protect chromosome ends, and the loss of these repeats (a reduction in telomere length) is associated with CVD. As exercise preserves telomere length and cardiovascular health, the aim of this study was to determine the effects of growth restriction and exercise training on cardiac telomere length and telomeric genes.

METHODS AND RESULTS: Pregnant Wistar Kyoto rats underwent bilateral uterine vessel ligation to induce uteroplacental insufficiency and fetal growth restriction ('Restricted'). Sham operated rats had either intact litters ('Control') or their litters reduced to five pups with slowed postnatal growth ('Reduced'). Control, Restricted, and Reduced male rats were assigned to Sedentary, Early exercise (5-9 weeks of age) or Late exercise (20-24 weeks of age) groups. Hearts were excised at 24 weeks of age for telomere length and gene expression measurements by qPCR. Growth restriction shortened cardiac telomere length (P<0.001) but this was rescued by early exercise (P<0.001). Early and Late exercise increased cardiac weight index (P<0.001) but neither this nor telomere length was associated with expression of the telomeric genes Tert, Terc, Trf2, Pnuts, or Sirt1.

DISCUSSION AND CONCLUSIONS: Growth restriction shortens cardiac telomere length, reflecting the cardiac pathologies associated with low birth weight. Exercise in early life may offer long-term protective effects on cardiac telomere length which could help prevent CVD in later life.

RevDate: 2018-09-07

Rodriguez FJ, Brosnan-Cashman JA, Allen SJ, et al (2018)

Alternative lengthening of telomeres, ATRX loss and h3-k27m mutations in histologically defined pilocytic astrocytoma with anaplasia.

Brain pathology (Zurich, Switzerland) [Epub ahead of print].

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3-75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas. This article is protected by copyright. All rights reserved.

RevDate: 2018-09-07

Schrank Z, Khan N, Osude C, et al (2018)

Oligonucleotides Targeting Telomeres and Telomerase in Cancer.

Molecules (Basel, Switzerland), 23(9): pii:molecules23092267.

Telomeres and telomerase have become attractive targets for the development of anticancer therapeutics due to their involvement in cancer cell immortality. Currently, several therapeutics have been developed that directly target telomerase and telomeres, such as telomerase inhibitors and G-quadruplex stabilizing ligands. Telomere-specific oligonucleotides that reduce telomerase activity and disrupt telomere architecture are also in development as novel anticancer therapeutics. Specifically, GRN163L and T-oligos have demonstrated promising anticancer activity in multiple cancers types via induction of potent DNA damage responses. Currently, several miRNAs have been implicated in the regulation of telomerase activity and may prove to be valuable targets in the development of novel therapies by reducing expression of telomerase subunits. Targeting miRNAs that are known to increase expression of telomerase subunits may be another strategy to reduce carcinogenesis. This review aims to provide a comprehensive understanding of current oligonucleotide-based anticancer therapies that target telomeres and telomerase. These studies may help design novel therapeutic approaches to overcome the challenges of oligonucleotide therapy in a clinical setting.

RevDate: 2018-09-06

Sulastri D, Lestari Y, Afriwardi , et al (2017)

Relationship Between Body Composition and Smoking Habit with Telomere Length of Minangkabau Ethnicity Men, in West Sumatera, Indonesia.

Pakistan journal of biological sciences : PJBS, 20(10):516-522.

BACKGROUND AND OBJECTIVE: An increase in body composition and smoking habit are risk factors for high free radical levels in the body. This can lead to oxidative stress, due to the imbalance of pro-oxidants and oxidants in the body that leads to telomere shortening. The purpose of this research was to investigate the correlation between body composition and smoking habit with telomere length of men in West Sumatera, Indonesia.

MATERIALS AND METHODS: This cross-sectional study was conducted in Padang City using a sample of 130 Minangkabau ethnic district civil servant men aged between 40-50 years. The smoking habit were collected using a questionnaire, body composition data with bioelectrical impedance analysis (BIA) and blood sample analysis using O'Callaghan and Fenech's technique to measure telomere length.

RESULTS: This research indicated an average telomere length was 580.37±323.58 bp, BMI was 25.01±4.15 and percentage body fat was 22.06±6.16%. The proportion of subjects who smoke is 58.5% with heavy smoker 26.3%. The average length of smoked cigarettes was 25.2±7.3 years and the average of cigarette consumption is 270.58±343.18. There were no correlations between BMI and body fat percentage with telomere length (p>0.005). There is a negative correlation were significantly between smoking duration with telomere length (r = -0.270, p = 0.020). Telomere loss was 94.39 bp throughout the life-span equivalent to losing 3.4-3.8 years.

CONCLUSION: Body composition is not a risk factor but smoking duration is a risk factor for telomere shortening in ethnic Minangkabau men.

RevDate: 2018-09-06

Hirvonen EAM, Peuhkuri S, Norberg A, et al (2018)

Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation.

Leukemia pii:10.1038/s41375-018-0243-5 [Epub ahead of print].

RevDate: 2018-09-06

Zeiger AM, White MJ, Eng C, et al (2018)

Genetic Determinants of Telomere Length in African American Youth.

Scientific reports, 8(1):13265 pii:10.1038/s41598-018-31238-3.

Telomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining genetic associations with TL in diverse pediatric populations such as African Americans.

RevDate: 2018-09-06

Nguyen LN, Zhao J, Cao D, et al (2018)

Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection.

Cell death & disease, 9(9):900 pii:10.1038/s41419-018-0897-y.

T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus (HCV) infection. We found that naïve CD4 T cells in chronically HCV-infected patients (HCV T cells) were significantly reduced due to apoptosis compared with age-matched healthy subjects (HSs). These HCV T cells were not only senescent, as demonstrated by overexpression of aging markers and particularly shortened telomeres; but also DNA damaged, as evidenced by increased dysfunctional telomere-induced foci (TIF). Mechanistically, the telomere shelterin protein, in particular telomeric repeat binding factor 2 (TRF2) that functions to protect telomeres from DNA damage, was significantly inhibited posttranscriptionally via the p53-dependent Siah-1a ubiquitination. Importantly, knockdown of TRF2 in healthy T cells resulted in increases in telomeric DNA damage and T-cell apoptosis, whereas overexpression of TRF2 in HCV T cells alleviated telomeric DNA damage and T-cell apoptosis. To the best of our knowledge, this is the first report revealing that inhibition of TRF2 promotes T-cell telomere attrition and telomeric DNA damage that accelerates T-cell senescent and apoptotic programs, which contribute to naïve T-cell loss during viral infection. Thus, restoring the impaired T-cell telomeric shelterin machinery may offer a new strategy to improve immunotherapy and vaccine response against human viral diseases.

RevDate: 2018-09-05

Dorado-Correa AM, Zollinger SA, Heidinger B, et al (2018)

Timing matters: traffic noise accelerates telomere loss rate differently across developmental stages.

Frontiers in zoology, 15:29 pii:275.

Background: Noise pollution is one of the leading environmental health risks for humans, linked to a myriad of stress-related health problems. Yet little is known about the long-term effects of noise on the health and fitness of wildlife. We experimentally investigated the direct and cross-generational effects of traffic noise on telomeres; a measure of cellular ageing that is predictive of disease and longevity in humans and other organisms. We exposed zebra finches (Taenopygia guttata) to three different treatment groups: 1) parents were exposed to traffic noise before and during breeding, together with their nestling young, 2) fledged juveniles but not their parents were exposed to traffic noise, and 3) control group birds were never exposed to traffic noise.

Results: Although there was no significant effect of traffic noise exposure at early (pre-fledging) stages of offspring telomere length or loss rate, traffic noise exposure accelerated telomere loss in older (post-fledging) juveniles.

Conclusions: The age-dependent differences found in this study in telomere loss could occur if parents buffer younger offspring against the detrimental effects of noise exposure and/or if younger offspring are less sensitive to noise exposure. Telomere length during early life has been shown to be positively related to lifespan and the observed noise-induced increase of telomere attrition rate could reduce the fitness of the affected birds and potentially alter the population dynamics of birds in noise polluted areas. Our data highlight the need to consider the developmental stage of an organism to better understand the ecological consequences of anthropogenic change.

RevDate: 2018-09-05

Chow TT, Shi X, Wei JH, et al (2018)

Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection.

Nature communications, 9(1):3583 pii:10.1038/s41467-018-05840-y.

Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.

RevDate: 2018-09-04

Wagner CL, Hanumanthu VS, Talbot CC, et al (2018)

Short telomere syndromes cause a primary T cell immunodeficiency.

The Journal of clinical investigation pii:120216 [Epub ahead of print].

The mechanisms that drive T cell aging are not understood. We report children and adult telomerase mutation carriers with short telomere length (TL) develop a T cell immunodeficiency that can manifest in the absence of bone marrow failure and causes life-threatening opportunistic infections. Mutation carriers shared T cell aging phenotypes seen in adults five decades older including depleted naïve T cells, increased apoptosis, and restricted T cell repertoire. T cell receptor excision circles (TRECs) were also undetectable or low, suggesting newborn screening may identify individuals with germline telomere maintenance defects. Telomerase null mice with short TL showed defects throughout T cell development including increased apoptosis of stimulated thymocytes, their intra-thymic precursors, in addition to depleted hematopoietic reserves. When we examined the transcriptional programs of T cells from telomerase mutation carriers, we found they diverged from older adults with normal TL. Short telomere T cells up-regulated DNA damage and intrinsic apoptosis pathways, while older adult T cells up-regulated extrinsic apoptosis pathways and PD-1 expression. T cells from mice with short TL also showed an active DNA damage response, in contrast to old wild-type mice, despite their shared propensity to apoptosis. Our data suggest there are telomere length-dependent and telomere length-independent mechanisms that differentially contribute to distinct molecular programs of T cell apoptosis with aging.

RevDate: 2018-09-04

Farmery JHR, Smith ML, NIHR BioResource - Rare Diseases, et al (2018)

Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Scientific reports, 8(1):13376 pii:10.1038/s41598-018-31524-0.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

RevDate: 2018-09-03

Behravan E, Moallem SA, Kalalinia F, et al (2018)

Telomere shortening associated with increased levels of oxidative stress in sulfur mustard-exposed Iranian veterans.

Mutation research, 834:1-5.

Sulfur Mustard (SM) is the most widely used chemical weapon. It was used in World War 1 and in the more recent Iran-Iraq conflict. Genetic toxicity and DNA alkylation effects of SM in molecular and animal experiments are well documented. In this study, lymphocytic telomere lengths and serum levels of isoprostane F2α were measured using q-PCR and enzyme immunoassay-based methods in 40 Iranian veterans who had been exposed to SM between 1983-88 and 40 non-exposed healthy volunteers. The relative telomere length in SM-exposed individuals was found to be significantly shorter than the non-exposed individuals. In addition, the level of 8-isoprostane F2α was significantly higher in the SM-exposed group compared to controls. Oxidative stress can be caused by defective antioxidant responses following gene mutations or altered activities of antioxidant enzymes. Chronic respiratory diseases and infections may also increaseoxidative stress. The novel finding of this study was a the identification of 'premature ageing phenotype'. More specifically, telomere shortening which occurs naturally with aging is accelerated in SM-exposed individuals. Oxidative stress, mutations in DNA repair genes and epimutaions may be among the major mechanisms of telomere attrition. These findings may help for a novel therapeutic strategy by telomere elongation or for validation of an exposure biomarker for SM toxicity.

RevDate: 2018-09-02

McAlindon T, Roberts M, Driban J, et al (2018)

Incident hand oa is strongly associated with reduced peripheral blood leukocyte telomere length.

Osteoarthritis and cartilage pii:S1063-4584(18)31431-6 [Epub ahead of print].

OBJECTIVE: To evaluate the relationship of telomere length to the prevalence and incidence of hand osteoarthritis in a longitudinal cohort.

DESIGN: We conducted a cross-sectional and longitudinal analysis of data from a subset of participants in the Osteoarthritis Initiative recruited between February 2004 and May 2006. 274 individuals were eligible for the study based on availability of both baseline and 48-month hand radiographs and peripheral blood leucocyte telomere length data. Mean telomere length of PBLs from the DNA samples was determined using a validated quantitative PCR-based assay, and hand radiographs were analyzed and graded using the Kellgren-Lawrence scale.

RESULTS: In joint -level analyses, prevalent IPJOA was significantly associated with PBL telomere length in the baseline sample in unadjusted analyses (RR=2.84; 95% CI:0.87-9.29) or in models adjusted for age, sex, and body mass index (aRR=1.10; 95% CI: 0.96-1.27). The association in crude and adjusted analyses appeared slightly stronger with incident IPJOA, especially in the subset with normal hands at baseline (aRR=1.62; 95% CI: 1.02-2.57). PBL telomere length was also associated with prevalent HOA at baseline (significant in unadjusted analysis: RR=1.22; 95% CI 1.06-1.42), but not after adjusting for covariates: aRR=1.12; 95% CI: 0.96-1.30). The magnitude of association was stronger for incident HOA, especially incident symptomatic HOA (aRR=1.53; 95% CI: 1.09-2.15).

CONCLUSIONS: In summary, the results of this exploratory analysis are confirmatory of previous work showing a cross-sectional relationship between telomere length and HOA and add to the field by demonstrating an even stronger association with incident IPJOA, both radiographic and symptomatic.

RevDate: 2018-08-31

Higgs C, Crow YJ, Adams DM, et al (2018)

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Angiogenesis pii:10.1007/s10456-018-9640-7 [Epub ahead of print].

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.

RevDate: 2018-08-31

Kouprina N, Lee HS, Carmena M, et al (2018)

Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy.

Cancer research pii:0008-5472.CAN-18-0894 [Epub ahead of print].

The targeting of telomerase and telomere maintenance mechanisms represents a promising therapeutic approach for various types of cancer. In this work, we designed a new protocol to screen for and rank the efficacy of compounds specifically targeting telomeres and telomerase. This approach used two isogenic cell lines containing a circular human artificial chromosome (HAC, lacking telomeres) and a linear HAC (containing telomeres) marked with the EGFP transgene: compounds that target telomerase or telomeres should preferentially induce loss of the linear HAC but not the circular HAC. Our assay allowed quantification of chromosome loss by routine flow cytometry. We applied this dual-HAC assay to rank a set of known and newly developed compounds, including G-quadruplex (G4) ligands. Among the latter group, two compounds -Cu-ttpy and Pt-ttpy- induced a high rate of linear HAC loss with no significant effect on the mitotic stability of a circular HAC. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges in late mitosis and cytokinesis as well as UFB (Ultrafine Bridges). Chromosome loss after Pt-ttpy or Cu-ttpy treatment correlated with the induction of telomere-associated DNA damage. Overall, this platform enables identification and ranking of compounds that greatly increase chromosome mis-segregation rates as a result of telomere dysfunction and may expedite the development of new therapeutic strategies for cancer treatment.

RevDate: 2018-08-30

Banach M, Mazidi M, Mikhailidis DP, et al (2018)

Association between phenotypic familial hypercholesterolaemia and telomere length in US adults: results from a multi-ethnic survey.

European heart journal pii:5077832 [Epub ahead of print].

Aims: Familial hypercholesterolaemia (FH) accelerates atherosclerotic cardiovascular disease (ASCVD) and accordingly is the most potent hereditary cause of premature coronary heart disease. The association between telomere length (TL), a biological index of ageing, and FH has not been hitherto investigated. We addressed this question using data from the US National Health and Education National Surveys (NHANES, 1999-2002).

Methods and results: We included individuals, who had TL measurements (with quantitative polymerase chain reaction method) and a phenotypic diagnosis of FH based on the Dutch Lipid Clinic Network (DLCN) criteria. Sample weights were applied for unequal probabilities of selection, non-response bias, and oversampling by complex sample analysis. The adult prevalence of FH in NHANES was 0.43% [95% confidence interval (95% CI) 0.33-0.57]. The frequencies of probable FH (mean DLCN score: 6.2) and definite FH (mean DLCN score: 8.9) were 0.42% (95% CI 0.32-0.48) and 0.03% (95% CI 0.02-0.06), respectively. Subjects with FH had a higher prevalence of non-communicable diseases (hypertension, diabetes 2 type, and obesity) and early atherosclerosis (2.9% in overall population vs. 42.2% in FH). Overall, the mean TL in the non-FH population was 1.09 (95% CI 1.06-1.12) (T/S ratio) and 1.09 (95% CI 1.03-1.12) [(T/S ratio) for total FH]. Telomere length adjusted for age, sex, race, and body mass index was shorter in FH compared with healthy subjects (FH 0.89, 95% CI 0.84-0.93 vs. healthy: 1.05, 95% CI 0.97-1.11 T/S ratio; P < 0.001). Subjects with longer TL (highest quartile) had 12% less chance of having FH compared with those with TL in the lowest quartile (Q1, 95% CI 0.78-0.93).

Conclusions: These preliminary data suggest an association between TL, an index of biological age, and the presence of FH, the most common inherited cause of premature ASCVD. Given our relatively low sample size, the findings need confirmation in larger studies.

RevDate: 2018-08-30

McGovern JM, Singhi AD, Borhani AA, et al (2018)

CT Radiogenomic Characterization of the Alternative Lengthening of Telomeres Phenotype in Pancreatic Neuroendocrine Tumors.

AJR. American journal of roentgenology [Epub ahead of print].

OBJECTIVE: The objective of this study was to identify imaging characteristics in patients with known pancreatic neuroendocrine tumors (PanNETs) that predict the alternative lengthening of telomeres (ALT) phenotype by blinded retrospective review of preoperative multiphasic CT scans.

MATERIALS AND METHODS: For this retrospective study of 121 preoperative CT examinations of patients with resected PanNETs, two radiologists independently reviewed the CT examinations for tumor characteristics including size, shape, cystic or necrotic elements, calcifications, invasion of adjacent organs and vessels, biliary duct dilatation, pancreatic duct dilatation, and hepatic metastases. Univariate analysis of association of CT characteristics with ALT phenotype was performed with Fisher exact tests or t tests, and multivariate analysis was assessed by multiple logistic regression.

RESULTS: Univariate analysis showed that the following CT features were significantly associated with the ALT phenotype: lobulated or irregular tumor shape (p = 0.001), tumor necrosis (p = 0.002), vascular invasion (p < 0.001), pancreatic duct dilatation (p < 0.001), and hepatic metastasis (p < 0.001). Multivariate analysis found that the combination of pancreatic duct dilatation, hepatic metastasis, and size of tumor ≥ 3 cm was a strong predictor of ALT phenotype (odds ratio = 20.3; 95% CI = 2.3-176.3; AUC = 0.58; p = 0.006).

CONCLUSION: This study showed that several preoperative CT features of PanNETs are associated with the ALT phenotype, which is known to predict poor prognosis. Additionally, CT findings of intratumoral calcifications and metastases predicted poor survival independent of the ALT status.

RevDate: 2018-08-30

Greenland JR (2018)

Where the Chromosome Ends: Telomeres and CMV Risk in Lung Transplant Recipients.

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

RevDate: 2018-08-28

Gao X, Zhang Y, Mons U, et al (2018)

Leukocyte telomere length and epigenetic-based mortality risk score: associations with all-cause mortality among older adults.

Epigenetics [Epub ahead of print].

Telomere length (TL) has been established as a biomarker of aging and aging-related health outcomes, but showed only a weak or inconsistent association with all-cause mortality in previous epidemiological studies. Recently, an epigenetic "mortality risk score" (MS) based on whole blood DNA methylation at 10 mortality-related CpG sites has been demonstrated to be strongly related to all-cause mortality at the population level. This study aimed to address the association between TL and this MS, and to assess and compare their associations with all-cause mortality. The MS was derived from the DNA methylation profiles measured by Illumina Human Methylation450K Beadchip and TL was measured by quantitative PCR at baseline among 1517 participants aged 50 - 75 of the German ESTHER cohort study. In cross-sectional bi- and multivariable analyses, the MS was strongly associated and showed monotonic dose-response relationships with TL (p-values <0.05). However, only the MS but not TL was associated with all-cause mortality during a median follow-up of 12.5 years. After controlling for potential covariates and TL, hazard ratios (95% CI) for all-cause mortality for low, moderate and high levels of the MS defined by 1, 2 - 5 and >5 CpG sites with aberrant methylation were 2.24 (1.13 - 4.41), 3.31 (1.76 - 6.22) and 6.33 (3.22 - 12.41) compared to a MS of 0, respectively. Our investigation shows that the epigenetic-based MS is strongly associated with TL, a broadly accepted aging biomarker, and at the same time shows much stronger associations with all-cause mortality than the latter.

RevDate: 2018-08-28

Chang ACY, Chang ACH, Kirillova A, et al (2018)

Telomere shortening is a hallmark of genetic cardiomyopathies.

Proceedings of the National Academy of Sciences of the United States of America pii:1714538115 [Epub ahead of print].

This study demonstrates that significantly shortened telomeres are a hallmark of cardiomyocytes (CMs) from individuals with end-stage hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) as a result of heritable defects in cardiac proteins critical to contractile function. Positioned at the ends of chromosomes, telomeres are DNA repeats that serve as protective caps that shorten with each cell division, a marker of aging. CMs are a known exception in which telomeres remain relatively stable throughout life in healthy individuals. We found that, relative to healthy controls, telomeres are significantly shorter in CMs of genetic HCM and DCM patient tissues harboring pathogenic mutations: TNNI3, MYBPC3, MYH7, DMD, TNNT2, and TTN Quantitative FISH (Q-FISH) of single cells revealed that telomeres were significantly reduced by 26% in HCM and 40% in DCM patient CMs in fixed tissue sections compared with CMs from age- and sex-matched healthy controls. In the cardiac tissues of the same patients, telomere shortening was not evident in vascular smooth muscle cells that do not express or require the contractile proteins, an important control. Telomere shortening was recapitulated in DCM and HCM CMs differentiated from patient-derived human-induced pluripotent stem cells (hiPSCs) measured by two independent assays. This study reveals telomere shortening as a hallmark of genetic HCM and DCM and demonstrates that this shortening can be modeled in vitro by using the hiPSC platform, enabling drug discovery.

RevDate: 2018-08-27

Naka KH, Matsu-Ura A, Tachibana A, et al (2001)

Introduction of Telomerase to Ataxia Teleangiectasia Cells Can Extend Shortend Telomere and Bypass Replicative Senescence.

TheScientificWorldJournal, 1:70 pii:543609.

RevDate: 2018-08-27

Manning EL, G Van Zant (2001)

Role of Telomerase in Maintaining Hematopoietic Stem Cell Telomere Length during Replicative Stress and Aging.

TheScientificWorldJournal, 1:69 pii:905941.

RevDate: 2018-08-27

Freitas-Simoes TM, Ros E, A Sala-Vila (2018)

Telomere length as a biomarker of accelerated aging: is it influenced by dietary intake?.

Current opinion in clinical nutrition and metabolic care [Epub ahead of print].

PURPOSE OF REVIEW: There is increasing interest in exploring whether age-related diseases can be prevented by dietary means through nutrients or food bioactives, whole foods, or specific dietary patterns. Because of the slow nature of the aging process, biomarkers such as telomere length are helpful for this purpose. Here we update the developments in the area during the last 2 years.

RECENT FINDINGS: Most data stem from epidemiologic studies, often cross-sectional in design. Recent articles strengthened the link between consumption of sugar-sweetened beverages and telomere shortening, whereas a novel association between telomere length and drinking coffee has been uncovered. Controversy on meat consumption and telomere length persists, mostly because of the presumed different effects of total meat and processed meat. In general terms, increasing consumption of antioxidant-rich plant foods relates to maintained telomere length. Feeding intervention trials with outcomes on telomere length are few and thus far have contributed little to further knowledge on this topic.

SUMMARY: Epidemiologic studies provide support for the putative effects of diet components on telomere length and on the aging process in general. Dietary associations with telomere length should be confirmed with adequately powered randomized controlled trials.

RevDate: 2018-08-27

Montiel Rojas D, Nilsson A, Ponsot E, et al (2018)

Short Telomere Length Is Related to Limitations in Physical Function in Elderly European Adults.

Frontiers in physiology, 9:1110.

The present study aims to explore the potential influence of leucocyte telomere length (LTL) on both a single indicator and a composite construct of physical functioning in a large European population of elderly men and women across diverse geographical locations. A total of 1,221 adults (65-79 years) were recruited from five European countries within the framework of NU-AGE study. The physical functioning construct was based on the 36-item Short Form Health Survey. Handgrip strength was used as a single indicator of muscle function and LTL was assessed using quantitative real-time PCR. Women had significantly longer (p < 0.05) LTL than men. Participants in Poland had significantly shorter LTL than in the other study centers, whereas participants in the Netherlands had significantly longer LTL than most of the other centers (p < 0.01). An analysis of LTL as a continuous outcome against physical functioning by using linear models revealed inconsistent findings. In contrast, based on an analysis of contrasting telomere lengths (first vs. fifth quintile of LTL), a significant odds ratio (OR) of 1.7 (95% CI: 1.1 - 2.6; p < 0.05) of having functional limitation was observed in those belonging to the first LTL quintile compared to the fifth. Interestingly, having the shortest LTL was still related to a higher likelihood of having physical limitation when compared to all remaining quintiles (OR: 1.5, 95% CI: 1.1 - 2.1; p < 0.05), even after adjustment by study center, age, sex, and overweight status. Collectively, our findings suggest that short LTL is an independent risk factor that accounts for functional decline in elderly European populations. The influence of LTL on functional limitation seems driven by the detrimental effect of having short telomeres rather than reflecting a linear dose-response relationship.

RevDate: 2018-08-25

Seeker LA, Ilska JJ, Psifidi A, et al (2018)

Bovine telomere dynamics and the association between telomere length and productive lifespan.

Scientific reports, 8(1):12748 pii:10.1038/s41598-018-31185-z.

Average telomere length (TL) in blood cells has been shown to decline with age in a range of vertebrate species, and there is evidence that TL is a heritable trait associated with late-life health and mortality in humans. In non-human mammals, few studies to date have examined lifelong telomere dynamics and no study has estimated the heritability of TL, despite these being important steps towards assessing the potential of TL as a biomarker of productive lifespan and health in livestock species. Here we measured relative leukocyte TL (RLTL) in 1,328 samples from 308 Holstein Friesian dairy cows and in 284 samples from 38 female calves. We found that RLTL declines after birth but remains relatively stable in adult life. We also calculated the first heritability estimates of RLTL in a livestock species which were 0.38 (SE = 0.03) and 0.32 (SE = 0.08) for the cow and the calf dataset, respectively. RLTL measured at the ages of one and five years were positively correlated with productive lifespan (p < 0.05). We conclude that bovine RLTL is a heritable trait, and its association with productive lifespan may be used in breeding programmes aiming to enhance cow longevity.

RevDate: 2018-08-23

Pantesco EJ, Leibel DK, Ashe JJ, et al (2018)

Multiple forms of discrimination, social status, and telomere length: Interactions within race.

Psychoneuroendocrinology, 98:119-126 pii:S0306-4530(18)30163-X [Epub ahead of print].

Previous research has demonstrated inverse associations between experiences of interpersonal discrimination and telomere length, a marker of cellular aging. Here, we investigate within-race interactions between multiple indices of interpersonal discrimination and sociodemographic characteristics in relation to telomere length in African American and White adults. Participants were from the Healthy Aging in Neighborhoods of Diversity across the Life Span study (Baltimore, Maryland). Ages ranged from 30 to 64 years old and all self-identified as either African American (n = 176) or White (n = 165). Using linear regression, three patterns were observed within African Americans: (1) women reporting greater lifetime burden of discrimination (p = .02), racial (p = .03), or gender (p = .01) discrimination; (2) those with higher socioeconomic status reporting greater lifetime burden (p = .03) or racial discrimination (p = .02); and (3) younger adults reporting greater exposure to multiple sources of discrimination (p = .03) had shorter telomere length. Among Whites, younger and older men reporting greater racial discrimination had shorter and longer telomeres, respectively (p = .02). Findings demonstrate within-race patterns of interpersonal discrimination and cellular aging, which may contribute to racial health disparities.

RevDate: 2018-08-23

Vetter VM, Antje M, Karbasiyan M, et al (2018)

Epigenetic clock and relative telomere length represent largely different aspects of aging in the Berlin Aging Study II (BASE-II).

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5076188 [Epub ahead of print].

DNA methylation age (DNAm age; 'epigenetic clock') has recently been described as highly correlated with chronological age. Several studies suggest that DNAm age reflects, at least in part, biological age. Here we adapted a recently published methylation-sensitive single nucleotide primer extension method (MS-SNuPE) for epigenetic age estimation and calculated the DNAm age based on only seven CpG sites in 1,895 DNA samples of the Berlin Aging Study II (BASE-II). In a second step we explored the relationship between this new potential measure of biological age with an established marker of biological age, relative leukocyte telomere length (rLTL), in the same cohort.Our results showed a positive and significant correlation between DNAm age estimation and chronological age (N=1,895, Rs2=0.47), which persisted after adjustment for covariates (sex, leukocyte distribution, alcohol and smoking).We found a significant but weak negative association between DNAm age acceleration and rLTL in linear regression analysis adjusted for age, sex, alcohol and smoking (β=-0.002, p=0.007). Therefore, DNAm age appears to be a promising biomarker in the analysis of phenotypes of aging, which are not (only) related to pathways associated with mitotic age as measured by rLTL.

RevDate: 2018-08-23

Pauliny A, Miller E, Rollings N, et al (2018)

Effects of male telomeres on probability of paternity in sand lizards.

Biology letters, 14(8):.

Standardized swim-up trials are used in in vitro fertilization clinics to select particularly motile spermatozoa in order to increase the probability of a successful fertilization. Such trials demonstrate that sperm with longer telomeres have higher motility and lower levels of DNA damage. Regardless of whether sperm motility, and successful swim-up to fertilization sites, is a direct or correlational effect of telomere length or DNA damage, covariation between telomere length and sperm performance predicts a relationship between telomere length and probability of paternity in sperm competition, a prediction that for ethical reasons cannot be tested on humans. Here, we test this prediction in sand lizards (Lacerta agilis) using experimental data from twice-mated females in a laboratory population, and telomere length in blood from the participating lizards. Female identity influenced paternity (while the mechanism was not identified), while relatively longer male telomeres predicted higher probability of paternity. We discuss potential mechanisms underpinning this result.

RevDate: 2018-08-22

Manczak EM, IH Gotlib (2018)

Relational Victimization and Telomere Length in Adolescent Girls.

Journal of research on adolescence : the official journal of the Society for Research on Adolescence [Epub ahead of print].

An emerging body of research suggests that telomere length (TL)-a measure of cellular aging-is inversely associated with experiences of childhood stress. Given the salience of peer relationships in childhood and adolescence, we tested whether relational victimization is a unique and specific predictor of salivary TL in girls. Results examining 122 girls (ages 9-15) revealed that greater relational victimization was related to shorter TL but that similar associations were not evident for other measures of social relationships nor accounted for by factors related to depression, life stress, or 5-HTTLPR genotype. The present findings suggest that relational victimization is uniquely associated with TL in adolescence, revealing a link between key aspects of social relationships and biological processes.

RevDate: 2018-08-21

Tennyson RL, Gettler LT, Kuzawa CW, et al (2018)

Lifetime socioeconomic status and early life microbial environments predict adult blood telomere length in the Philippines.

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

OBJECTIVES: Psychosocial stress is postulated to hasten senescence in part by accelerating the shortening of telomere length (TL). One pathway through which this may happen is via increasing inflammation and innate immune system activation-a pathway which recent studies suggest acts more strongly for those who grew up in low microbial environments. Thus, we hypothesized that: (1) Psychosocial stress will be inversely associated with TL, (2) early life microbial environments will predict TL, and (3) microbial environments will moderate the association between psychosocial stress and TL.

METHODS: We utilized data from the Cebu Longitudinal Health and Nutrition Survey based in the Philippines (N = 1410). We determined early life microbial environments by season of birth and exposure to animal feces. Psychosocial stress measures included perceived stress in adulthood, lifetime socioeconomic status (SES), and parental instability in childhood. TL was measured in blood from young adults by qPCR.

RESULTS: Contrary to predictions, we found that higher SES was associated with shorter TL and no association of TL with the other stress variables. Individuals born in the higher microbial exposure season had shorter TL, but early life microbial environments did not moderate the association between psychosocial stress and TL.

CONCLUSIONS: The unexpected inverse association between SES and TL suggests that higher SES, while indexing lower psychosocial stress, may impact TL more strongly through nonstress factors in the Philippines, such as unhealthy behavior. The inverse association between microbial environments and TL is consistent with other evidence connecting early life infections to decreased life expectancies.

RevDate: 2018-08-21

Sováková PP, Magdolenová A, Konečná K, et al (2018)

Telomere elongation upon transfer to callus culture reflects the reprogramming of telomere stability control in Arabidopsis.

Plant molecular biology pii:10.1007/s11103-018-0765-2 [Epub ahead of print].

KEY MESSAGE: Standard pathways involved in the regulation of telomere stability do not contribute to gradual telomere elongation observed in the course of A. thaliana calli propagation. Genetic and epigenetic changes accompanying the culturing of plant cells have frequently been reported. Here we aimed to characterize the telomere homeostasis during long term callus propagation. While in Arabidopsis thaliana calli gradual telomere elongation was observed, telomeres were stable in Nicotiana tabacum and N. sylvestris cultures. Telomere elongation during callus propagation is thus not a general feature of plant cells. The long telomere phenotype in Arabidopsis calli was correlated neither with changes in telomerase activity nor with activation of alternative mechanisms of telomere elongation. The dynamics of telomere length changes was maintained in mutant calli with loss of function of important epigenetic modifiers but compromised in the presence of epigenetically active drug zebularine. To examine whether the cell culture-induced disruption of telomere homeostasis is associated with the modulated structure of chromosome ends, epigenetic properties of telomere chromatin were analysed. Albeit distinct changes in epigenetic modifications of telomere histones were observed, these were broadly stochastic. Our results show that contrary to animal cells, the structure and function of plant telomeres is not determined significantly by the epigenetic character of telomere chromatin. Set of differentially transcribed genes was identified in calli, but considering the known telomere- or telomerase-related functions of respective proteins, none of these changes per se was apparently related to the elongated telomere phenotype. Based on our data, we propose that the disruption in telomere homeostasis in Arabidopsis calli arises from the interplay of multiple factors, as a part of reprogramming of plant cells to long-term culture conditions.

RevDate: 2018-08-20

Damiao Gouveia AC, Skovman A, Jensen A, et al (2018)

Telomere shortening and aortic plaque progression in Apoliprotein E knockout mice after pulmonary exposure to candle light combustion particles.

Mutagenesis pii:5074426 [Epub ahead of print].

Particles from burning candles contribute to the overall indoor exposure to particulate matter (PM). However, little is known about the effects of indoor sources of particles on cardiovascular disease endpoints. This study investigated the effect of pulmonary exposure to particles from combustion of candles and progression of atherosclerosis. Telomere shortening was assessed in tissues due to its relationship to risk of cardiovascular diseases. The particles were collected from burning candles and used for toxicological studies in cultured endothelial cells and apolipoprotein E (ApoE) knockout mice. Three hours exposure to particles increased the production of reactive oxygen species in endothelial cells, whereas there was no effect on cytotoxicity. Intratracheal instillation of particles (0.5 or 5 mg/kg) once a week for 5 weeks in ApoE-/- mice was associated with an accelerated progression of atherosclerosis in aorta and telomere shortening in the lung and spleen, whereas there was no effect on inflammation in the lungs (i.e. cell numbers), cell damage (i.e. lactate dehydrogenase) and lung barrier damage (i.e. protein concentration) as measured in bronchoalveolar lavage fluid. The results indicate that particles from burning candles are hazardous and this indoor emission source is an important contribution to the health risk of exposure to PM.

RevDate: 2018-08-17

Liu H, Xie Y, Zhang Z, et al (2018)

Telomeric Recombination Induced by DNA Damage Results in Telomere Extension and Length Heterogeneity.

Neoplasia (New York, N.Y.), 20(9):905-916 pii:S1476-5586(18)30272-0 [Epub ahead of print].

About 15% of human cancers counteract telomere loss by alternative lengthening of telomeres (ALT), which is attributed to homologous recombination (HR)-mediated events. But how telomeric HR leads to length elongation is poorly understood. Here, we explore telomere clustering and telomeric HR induced by double-stranded breaks (DSBs). We show that telomere clustering could occur at G1 and S phase of cell cycle and that three types of telomeric HR occur based on the manner of telomeric DNA exchange: equivalent telomeric sister chromatin exchange (T-SCE), inequivalent T-SCE, and No-SCE. While inequivalent T-SCE increases telomere length heterogeneity with no net gain of telomere length, No-SCE, which is presumably induced by interchromatid HR and/or break-induced replication, results in telomere elongation. Accordingly, cells subjected to long-term telomeric DSBs display increased heterogeneity of length and longer telomeres. We also demonstrate that DSBs-induced telomere elongation is telomerase independent. Moreover, telomeric recombination induced by DSBs is associated with formation of ALT-associated PML body and C-circle. Thus, DNA damage triggers recombination mediated elongation, leading to the induction of multiple ALT phenotypes.

RevDate: 2018-08-17

Trotta L, Norberg A, Taskinen M, et al (2018)

Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders.

Orphanet journal of rare diseases, 13(1):139 pii:10.1186/s13023-018-0864-9.

BACKGROUND: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.

METHODS: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.

RESULTS: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.

CONCLUSIONS: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.

RevDate: 2018-08-15

Klegarth AR, DTA Eisenberg (2018)

Mammalian chromosome-telomere length dynamics.

Royal Society open science, 5(7):180492 pii:rsos180492.

Individual chromosome arms have specific individual telomere lengths (TLs). Past studies within species have shown strong positive correlations between individual chromosome length and TL at that chromosome. While the reasons for these associations are unclear, the strength and consistency of the associations across disparate taxa suggest that this is important to telomere biology and should be explored further. If TL is primarily determined by chromosome length, then chromosome length should be considered and controlled for in cross-species analyses of TL. Here, we employ a cross-species approach to explore whether the chromosome length-TL association observed intraspecifically is a determinant of mean TL across species. Data were compiled from two studies characterizing TL across a range of mammalian taxa and analysed in a phylogenetic framework. We found no significant relationship between TL and chromosome size across mammals or within mammalians orders. The pattern trends in the expected direction and we suggest may be masked by evolutionary lag effects.

RevDate: 2018-08-14

Wilson SJ, Woody A, Padin AC, et al (2018)

Loneliness and Telomere Length: Immune and Parasympathetic Function in Associations With Accelerated Aging.

Annals of behavioral medicine : a publication of the Society of Behavioral Medicine pii:5071789 [Epub ahead of print].

Background: Lonely people's heightened risks for chronic health conditions and early mortality may emerge in part through cellular aging. Lonelier people have more severe sympathetic responses to acute stress, increasing their risk for herpesvirus reactivation, a possible path to shorter telomeres. Parasympathetic function may modulate this risk.

Purpose: The current study aimed to examine the associations among loneliness, herpesvirus reactivation, and telomere length, with parasympathetic activity as a moderator, in healthy middle-aged and older adults.

Methods: A sample of 113 healthy men and women of ages 40-85 provided blood samples that were assayed for telomere length, as well as the latent herpesviruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). They also provided heart rate variability (HRV), a measure of parasympathetic activity, and reported on their feelings of loneliness.

Results: Lonelier people with lower HRV (i.e., lower parasympathetic activity) had greater CMV reactivation and shorter telomeres compared with their less lonely counterparts, above and beyond demographics, health behaviors, resting heart rate, and social network size. However, loneliness was not associated with viral reactivation or telomere length among those with higher HRV. In turn, greater CMV and EBV reactivation was associated with shorter telomeres.

Conclusions: Taken together, these data implicate parasympathetic function in novel links between loneliness and accelerated cellular aging.

RevDate: 2018-08-14

Lin Z, Gao H, Wang B, et al (2018)

Dietary Copper Intake and Its Association With Telomere Length: A Population Based Study.

Frontiers in endocrinology, 9:404.

Background: Telomere is regarded as the fundamental aspect of cellular aging and copper is recognized as one of the most essential trace elements. The role of dietary copper intake in telomere length maintenance is seldom examined. This study aims to investigate if telomere length is to be associated with daily dietary copper intake. Methods: We used epidemiological data from a large national population-based health and nutrition survey. Dietary intake was assessed during the 24-h period before the interview date when blood sample was collected. Telomere length was measured from blood leukocyte using PCR method. The relationship between telomere length and dietary copper intake was assessed using multivariable linear regression models. We also examined if obesity, measured by body mass index, could modify the observed association. Results: There are 7,324 participants had both leukocyte telomere length measured and dietary copper intake assessed, around 48.0% of them were men. Telomere length was longer in women than that in men (1.05 ± 0.26 vs. 1.00 ± 0.26 T/S ratio), while dietary copper intake was less in women than that in men (1.12 ± 0.80 vs. 1.51 ± 1.61 mg). After controlling for age, sex, ethnicity, physical activity, current smoking status, hypertension, cardiovascular diseases, and body mass index in the multivariable linear regression models, one unit increase of log-transformed dietary copper intake was significantly associated with longer telomere length (β = 0.02, 95% confidence interval: 0.01, 0.04). We did not find a significant sex difference for this association. Conclusions: Dietary copper intake was significantly associated telomere length.The role of copper in human health might be involved in biological aging process.

RevDate: 2018-08-12

Miranda-Furtado CL, Luchiari HR, Chielli Pedroso DC, et al (2018)

Skewed X-chromosome inactivation and shorter telomeres associate with idiopathic premature ovarian insufficiency.

Fertility and sterility, 110(3):476-485.e1.

OBJECTIVE: To analyze whether telomere length, X-chromosome inactivation (XCI), and androgen receptor (AR) GAG polymorphism are related to idiopathic premature ovarian insufficiency (POI).

DESIGN: Case-control study.

SETTING: University hospital.

PATIENT(S): A total of 121 women, including 46 nonsyndromic POI and 75 controls.

INTERVENTION(S): None.

MAIN OUTCOME MEASURE(S): Age, weight, height, body mass index (BMI), systolic and diastolic arterial pressure, E2, androstenedione, T, and C-reactive protein were assessed. Telomere length was estimated by quantitative real-time polymerase chain reaction, XCI was measured using the Human Androgen Receptor and X-linked retinitis pigmentosa 2 (RP2) methylation assays. AR and FMR1 polymorphism was assessed by quantitative fluorescent polymerase chain reaction and sequencing.

RESULT(S): Premature ovarian insufficiency women had a higher mean age, weighed less, and exhibited lower C-reactive protein, E2, and androstenedione levels. The AR polymorphism did not differ between the groups. Four patients had premutation (55-200 CGG repeats), and none displayed a full mutation in the FMR1 gene. However, patients with POI showed shorter telomere length and higher frequency of skewed XCI. Extreme skewing (≥90%) was observed in 15% of women with POI, and shorter telomeres correlated with XCI skewing in both groups.

CONCLUSION(S): Skewed XCI and shortened telomere length were associated with idiopathic POI, despite no alterations in the AR and FMR1 genes. Additionally, there is a tendency for women with short telomeres to exhibit skewed XCI.

RevDate: 2018-08-11

Aida S, Aida J, Naoi M, et al (2018)

Measurement of telomere length in cells from pleural effusion: Asbestos exposure causes telomere shortening in pleural mesothelial cells.

Pathology international [Epub ahead of print].

We estimated the telomere lengths of neoplastic and non-neoplastic mesothelial cells and examined their correlation with asbestos exposure and the expression of markers of mesothelial malignancy. Cell blocks of pleural effusion obtained from 35 cases of non-neoplastic disease (NN), 12 cases of malignant mesothelioma (MM) and 12 cases of carcinomatous effusion due to lung adenocarcinoma (LA) were examined. Fifteen of the 35 NN cases had pleural plaques (NNpp+) suggestive of asbestos exposure, and the other 20 cases had no pleural plaques (NNpp-). Telomere length was measured using the tissue quantitative fluorescence in situ hybridization method, and expressed as normalized telomere-to-centromere ratio. NN cases had significantly longer telomeres than MM (P < 0.001) and LA (P < 0.001) cases. Telomeres in NNpp+ cases were slightly shorter than those of NNpp- cases (P = 0.047). MM and LA showed almost the same telomere length. NN cases with shorter telomeres tended to show aberrant expression of epithelial membrane antigen (EMA), CD146, glucose transporter 1 (GLUT1) and IGF-II messenger RNA-binding protein 3 (IMP3). These results suggest that telomere shortening and subsequent genetic instability play an important role in the development of MM. Measurement of telomere length of cells in pleural effusion might be helpful for earlier detection of MM.

RevDate: 2018-08-11

Fu W, Chen Z, Bai Y, et al (2018)

The interaction effects of polycyclic aromatic hydrocarbons exposure and TERT- CLPTM1L variants on longitudinal telomere length shortening: A prospective cohort study.

Environmental pollution (Barking, Essex : 1987) pii:S0269-7491(17)34793-0 [Epub ahead of print].

Telomere length (TL) is an index of cellular aging and can predict the incidences of many age-related diseases. Change of TL might be affected by environmental pollution and individual's genetic background. In this cohort study, we aimed to evaluate the associations between polycyclic aromatic hydrocarbons (PAHs) exposure and longitudinal TL shortening, and investigate whether genetic variations in TERT-CLPTM1L can modify these associations. We measured the baseline concentrations of twelve urinary PAH metabolites and genotyped six variants at TERT-CLPTM1L among 1243 coke-oven workers. The relative leukocyte TL was detected in both baseline and follow-up (4 years later) visits. The TL shortening were estimated by TL decline and TL ratio. We found that the urinary level of 1-hydroxypyrene (1-OHP) had significant dose-response relationships with increased TL decline [β(95%CI) = 0.078(0.023, 0.133), P = 0.005] and TL ratio [β(95%CI) = 0.096(0.037, 0.155), P = 0.002]. Besides, urinary 1-hydroxynaphthalene (1-OHNa) was marginally dose-related with elevated TL decline [β(95%CI) = 0.053(-0.001, 0.107), P = 0.055] and TL ratio [β(95%CI) = 0.057(-0.002, 0.116), P = 0.058]. Analyses of TERT-CLPTM1L variants showed that the rs401681 and rs465498 could modify the effect of 1-OHP on increasing TL decline (Pinteraction = 0.012 and 0.035, respectively) and TL ratio (Pinteraction = 0.014 and 0.067, respectively), which were pronounced among rs401681TT and rs465498CC carriers, but not seen among rs401681TC + CC and rs465498CT + TT carriers. In conclusion, elevated exposure to PAHs can accelerate the TL shortening and this effect can be modified by TERT-CLPTM1L variants. These results may add potential evidence for gene-environment interactions on dynamic changes of telomere length. Further studies are warranted to validate these findings and uncover the underlying mechanisms.

RevDate: 2018-08-10

Tomita KI, Aida J, Izumiyama-Shimomura N, et al (2018)

Changes in telomere length with aging in human neurons and glial cells revealed by quantitative fluorescence in situ hybridization analysis.

Geriatrics & gerontology international [Epub ahead of print].

AIM: The telomere is a structure present at the ends of chromosomes, and is known to shorten with aging and successive rounds of cell division. However, very little is known about telomere attrition in post-mitotic cells, such as neurons.

METHODS: Using our originally developed quantitative fluorescence in situ hybridization method, we analyzed age-dependent alterations of telomere length in three types of cells in the human cerebrum: neurons and glial cells in both the gray and white matter.

RESULTS: In adults, telomeres were significantly longer in neurons than in glial cells, whereas in infants, telomere lengths did not differ among the three cell types. No aging-related telomere attrition was evident in neurons. However, the telomeres of glial cells were shorter in older individuals than in younger individuals, and attrition was more rapid in the white matter than in the gray matter.

CONCLUSIONS: The present results suggest that the telomeres of neurons remain stable throughout life, whereas telomeres in white matter glial cells become significantly shorter with age. Examination of adults showed no significant correlation between telomere length and age in the three cell types. Although the present study was cross-sectional, the results suggest that telomere shortening before adolescence contributes to the significant decrease of telomere length in white matter glial cells. The present findings in normal cerebral tissues will be informative for future studies of telomere stability in the diseased brain. Geriatr Gerontol Int 2018; ••: ••-••.

RevDate: 2018-08-10

Danese E, G Lippi (2018)

Telomere length: is the future in our "ends"?.

Annals of translational medicine, 6(13):280.

Telomeres, repetitive nucleotide sequences located at the end of each chromosome, play the important function of preserving chromosome stability and preventing molecular contact with neighboring chromosomes. Albeit the concept that telomere length may be a marker of health and disease seems hence counterintuitive, the translation of this clear-cut concept from the bench to the beside has appeared so far less straightforward. In particular, controversial evidence has emerged so far about the fact that telomere length may actually predict morbidity and mortality across many clinical settings. This uncertainty is actually due to a kaleidoscope of biological and technical factors, including preanalytical issues (e.g., sample matrix), poor standardization of techniques used for their assessment, and dependence of telomere structure upon genetics, epigenetics, environment and behavioral attitudes, which may be present at a variable extent in various physiological or pathological conditions. Therefore, although it is now undeniable that our future is largely in our "hands" (i.e., genotype, diet, exposure to environmental factors and so forth), larger and more solid evidence will be necessary before concluding that the future is also written in our (chromosome) "ends".

RevDate: 2018-08-10

De Meyer T, Nawrot T, Bekaert S, et al (2018)

Telomere Length as Cardiovascular Aging Biomarker: JACC Review Topic of the Week.

Journal of the American College of Cardiology, 72(7):805-813.

Telomeres shorten with age, the major risk factor for atherosclerotic cardiovascular disease (aCVD). The observation of shorter telomeres in aCVD patients thus suggested that critical telomere shortening may contribute to premature biological aging and aCVD. Therefore, telomere length often is suggested as a causal aCVD risk factor, a proposal supported by recent Mendelian randomization studies; however, epidemiological research has shown disappointingly low effect sizes. It therefore remains uncertain whether telomere shortening is a cause of aCVD or merely a consequence. The authors argue that elucidating the mechanistic foundation of these findings is essential for any possible translation of telomere biology to the clinic. Here, they critically evaluate evidence for causality in animal models and human studies, and review popular hypotheses and discuss their clinical implications. The authors identify 4 key questions that any successful mechanistic theory should address, and they discuss how atherosclerosis-associated local telomere attrition may provide the answers.

RevDate: 2018-08-08

Popescu I, Mannem H, Winters SA, et al (2018)

Impaired CMV Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres.

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

RATIONALE: CMV-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high-risk for CMV complications and effective immunity are incompletely understood.

OBJECTIVES: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control.

METHODS: We studied IPF-LTRs (n=42) and age-matched non-IPF-LTRs (n=42) and assessed CMV outcomes. We measured lymphocyte telomere length (TL), DNA sequencing and assessed CMV-specific T-cell immunity in LTRs at high-risk for CMV events, using flow cytometry and flowFISH.

MEASUREMENTS AND MAIN RESULTS: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared to non-IPF-LTRs (69% vs. 31%, Odds ratio=4.98; 95% CI: 1.95-12.50; P<0.001). Within this subset, IPF-LTRs who had short telomeres had the highest risk of CMV complications (P<0.01) including relapsing-viremia episodes, end-organ disease and CMV resistance to therapy, as well as shorter time to viremia versus age-match non-IPF controls (P<0.001). The short telomere defect in IPF-LTRs was associated with significantly impaired CMV-specific proliferative responses, T cell effector functions and induction of the major Type-1 transcription factor, T-bet.

CONCLUSIONS: As the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of lung transplant recipients has implications for risk assessment, management and potential strategies for averting posttransplant CMV morbidities.

RevDate: 2018-08-07

Renner W, Krenn-Pilko S, Gruber HJ, et al (2018)

Relative telomere length and prostate cancer mortality.

Prostate cancer and prostatic diseases pii:10.1038/s41391-018-0068-3 [Epub ahead of print].

PURPOSE: Telomeres are essential for the maintenance of chromosomal integrity and telomere length has been associated with cancer risk and development. Aim of the present study was to analyze the prognostic value of leukocyte relative telomere (RTL) length in long-term prostate cancer (PCa) mortality.

METHODS: Blood samples of PCa patients were obtained before initiation of radiotherapy. RTL of peripheral blood leukocytes was determined by a quantitative polymerase chain reaction method in 533 patients with PCa. Main outcome was overall mortality.

RESULTS: During a median follow-up time of 149 months, 188 (35.3%) patients died. In a univariate Cox regression analysis, RTL quartiles (longer RTL) were significantly associated with higher overall mortality (hazard ration (HR) = 1.20; 95% confidence interval (CI): 1.05-1.36; p = 0.006). In a multivariate Cox regression model including age at diagnosis, androgen deprivation therapy, and risk group (based on PSA level, GS, and T stage), RTL quartiles remained a significant predictor of higher overall mortality (HR = 1.22; 95% CI: 1.07-1.39; p = 0.003).

CONCLUSIONS: Longer leukocyte RTL predicts higher overall mortality in patients with PCa.

RevDate: 2018-08-07

Kratz K, T de Lange (2018)

Both Protection of Telomeres 1 proteins POT1a and POT1b can repress ATR signaling by RPA exclusion but binding to CST limits ATR repression by POT1b.

The Journal of biological chemistry pii:RA118.004598 [Epub ahead of print].

Comprised of telomeric TTAGGG repeats and shelterin, telomeres ensure that the natural ends of chromosomes remain impervious to the DNA damage response. Telomeres carry a long constitutive 3' overhang that can bind Replication Protein A (RPA) and activate the ATR Ser/Thr kinase, which induces cell cycle arrest. A single-stranded (ss) TTAGGG repeat binding protein in mouse shelterin, POT1a, has been proposed to repress ATR signaling by preventing RPA binding. Repression of ATR at telomeres requires tethering of POT1a to the other shelterin subunits situated on the double-stranded (ds) telomeric DNA. The simplest model of ATR repression, the "tethered exclusion model", suggests that the only critical features of POT1a are its connection to shelterin and its binding to ss telomeric DNA.In agreement with the model, we show here that a shelterin-tethered variant of RPA70 (lacking the ATR recruitment domain) can repress ATR signaling at telomeres that lack POT1a. However, arguing against the tethered exclusion model, the nearly identical POT1b subunit of shelterin has been shown to be much less proficient than POT1a in repression of ATR. We now show that POT1b has the intrinsic ability to fully repress ATR, but is prevented from doing so when bound to the Ctc1, Stn1, Ten1 (CST), the complex needed for telomere end processing. These results establish that shelterin represses ATR with a tethered ssDNA-binding domain that excludes RPA from the 3' overhang and also reveal an unexpected effect of CST on the ability of POT1b to repress ATR.

RevDate: 2018-08-06

Polito F, Cucinotta M, Abbritti RV, et al (2018)

Silencing of telomere-binding protein adrenocortical dysplasia (ACD) homolog enhances radiosensitivity in glioblastoma cells.

Translational research : the journal of laboratory and clinical medicine pii:S1931-5244(18)30106-3 [Epub ahead of print].

Adrenocortical dysplasia (ACD) is a shelterin protein involved in the maintenance of telomere length and in cancer radioresistance. This study investigated the expression profile of ACD in human gliomas and its role in radioresistance of glioma cells. The expression of ACD was analyzed in 62 different grades of glioma tissues and correlated with prognosis. A radioresistant cell line was generated from U87MG cells. For mechanistic studies, ACD was inhibited by small interfering RNA-targeting ACD and the effect on cell radioresistance, telomerase activity, cyclinD1, caspase-3, hTERT, and BIRC1 was evaluated. Clonogenic assay was performed after irradiation, to investigate the effect of ACD silencing on radiation sensitivity. ACD expression appeared strongly upregulated in higher grade gliomas, and its expression was significantly correlated to grading and poor prognosis. In glioma cell lines, ACD expression pattern was similar to those observed in glioma tissues. In irradiated cells, ACD expression was increased in an ionizing radiation dose-dependent manner. A higher expression of ACD was observed in the radioresistant clones than parental cells. Silencing of ACD led to the enhanced radiation sensitivity, decreased telomerase activity and cyclin D1 expression, reduced expression of BIRC1, and finally to the upregulation of caspase-3. This study represents the first report, which demonstrated the expression pattern of ACD in gliomas and its prognostic value. Our results suggested that ACD is involved in glioblastoma radioresistance, likely through the modulation of telomerase activity, proliferation, and apoptosis. ACD might represent a potential molecular biomarker and a novel therapeutic target in glioblastoma.

RevDate: 2018-08-05

Conklin QA, King BG, Zanesco AP, et al (2018)

Corrigendum to "Insight meditation and telomere biology: The effects of intensive retreat and the moderating role of personality" [Brain Behav. Immun. 70 (2018) 233-245].

RevDate: 2018-08-04

Buschiazzo LM, Caraballo DA, Cálcena E, et al (2018)

Integrative analysis of chromosome banding, telomere localization and molecular genetics in the highly variable Ctenomys of the Corrientes group (Rodentia; Ctenomyidae).

Genetica pii:10.1007/s10709-018-0032-0 [Epub ahead of print].

The genus Ctenomys comprises about 70 species with great chromosome diversity. The Corrientes group is one of the most chromosomally variable lineages in the genus, where the diploid number (2n) varies from 41 to 70. In this group, three nominal species and numerous polymorphic and polytypic populations have been described. In order to get insight into the chromosomal evolution of this species complex, we applied different banding and molecular cytogenetic techniques. The results were interpreted in an evolutionary context, based on mitochondrial cytochrome b analyses. Studied samples are representative of the broad chromosomal variability in the group, including specimens with 2n = 42 to 2n = 70. Heterochromatin was scarce but concentrated in a few chromosomes. Centromeric DAPI-negative heterochromatin was observed in some autosomal pairs, which differed among populations. Location and amount of DAPI-neutral heterochromatin within the Y chromosome varied among populations. The variable distribution of heterochromatin indicates its dynamic behavior. NORs were detected in one pair of autosomes, which also differed among some populations. Telomeric FISH signals were observed in all complements only at the chromosome ends. The Corrientes group belongs to a clade that also includes C. pearsoni, C. lami, C. minutus, C. ibicuiensis and C. torquatus. Almost all of these species are variable at the chromosomal level, suggesting that this is the ancestral condition of the clade. Within the Corrientes group, the observed low genetic divergence, in contrast with its high chromosomal variability, is indicative of decoupling between the rates of chromosomal and mitochondrial evolution.

RevDate: 2018-08-03

Friedenreich CM, Wang Q, Ting NS, et al (2018)

Effect of a 12-month exercise intervention on leukocyte telomere length: Results from the ALPHA Trial.

Cancer epidemiology, 56:67-74 pii:S1877-7821(18)30378-3 [Epub ahead of print].

BACKGROUND: Short telomeres may indicate a higher risk of cancer and other chronic diseases. Some observational studies show positive associations between leukocyte telomere length (LTL) and physical activity levels. We hypothesized, therefore, that exercise may be one strategy for slowing telomere attrition.

METHODS: We conducted an ancillary analysis of blood from a year-long, two-centred, two-armed (1:1) randomized controlled trial of aerobic exercise versus usual inactivity. The analysis included 212 physically inactive, disease-free, non-smoking, postmenopausal women (n = 99 exercisers, n = 113 controls) in Alberta, Canada (2003-2006). The exercise prescription was aerobic exercise five days/week (supervised three days/week), 45 min/session, achieving 70-80% heart rate reserve. Baseline and 12-month LTL were analyzed using quantitative real-time polymerase chain reactions (qPCR). The primary statistical analysis was intention-to-treat, comparing the ratio of mean LTLs (12-months:baseline) for exercisers versus controls from a general linear model. Secondary analyses included a per-protocol analysis (≥90% adherence) and analyses stratified by baseline LTL, age, body mass index, and fitness level, respectively.

RESULTS: Participants were overweight at baseline (mean BMI = 29 kg/m2). The primary analysis showed no evidence that LTL change differed between groups (12-month mean LTL change for the exercise group: -13% (95% CI: -32%, 11%) versus controls: -8% (95%CI: -27%, 15%); treatment effect ratio (TER, Exercise/Control) = 0.95 (95% CI: 0.68, 1.32). Per-protocol results were similar (TER = 0.87, 95% CI: 0.59, 1.30). In stratified models, TERs ranged from 0.68 to 1.35 across strata and P-interaction > 0.05).

CONCLUSION: We found no evidence to suggest that one year of aerobic exercise alters telomere attrition significantly in healthy postmenopausal women.

RevDate: 2018-08-02

Arts MHL, Collard RM, Comijs HC, et al (2018)

Leucocyte telomere length is no molecular marker of physical frailty in late-life depression.

Experimental gerontology pii:S0531-5565(18)30212-2 [Epub ahead of print].

BACKGROUND: Although average life-expectancy is still increasing worldwide, ageing processes markedly differ between individuals, which has stimulated the search for biomarkers of biological ageing.

OBJECTIVES: Firstly, to explore the cross-sectional and longitudinal association between leucocyte telomere length (LTL) as molecular marker of ageing and the physical frailty phenotype (PFP) as a clinical marker of ageing and secondly, to examine whether these associations are moderated by the presence of a depressive disorder, as depression can be considered a condition of accelerated ageing.

METHODS: Among 378 depressed older patients (according to DSM-IV criteria) and 132 non-depressed older persons participating in the Netherlands Study of Depression in Older persons, we have assessed the physical frailty phenotype and LTL. The PFP was defined according to Fried's criteria and its components were reassessed at two-year follow-up.

RESULTS: LTL was neither associated with the PFP at baseline by Spearman rank correlation tests, nor did it predict change in frailty parameters over a two-year follow-up using regression analyses adjusted for potential confounders.

CONCLUSION: LTL is not associated with frailty; neither in non-depressed nor in depressed older persons. As LTL and physical frailty appear to represent different aspects of ageing, they may complement each other in future studies.

RevDate: 2018-08-01

Torrance V, D Lydall (2018)

Overlapping open reading frames strongly reduce human and yeast STN1 gene expression and affect telomere function.

PLoS genetics, 14(8):e1007523 pii:PGENETICS-D-18-00661 [Epub ahead of print].

The levels of telomeric proteins, such as telomerase, can have profound effects on telomere function, cell division and human disease. Here we demonstrate how levels of Stn1, a component of the conserved telomere capping CST (Cdc13, Stn1, Ten1) complex, are tightly regulated by an upstream overlapping open reading frame (oORF). In budding yeast inactivation of the STN1 oORF leads to a 10-fold increase in Stn1 levels, reduced telomere length, suppression of cdc13-1 and enhancement of yku70Δ growth defects. The STN1 oORF impedes translation of the main ORF and reduces STN1 mRNA via the nonsense mediated mRNA decay (NMD) pathway. Interestingly, the homologs of the translation re-initiation factors, MCT-1Tma20/DENRTma22 also reduce Stn1 levels via the oORF. Human STN1 also contains oORFs, which reduce expression, demonstrating that oORFs are a conserved mechanism for reducing Stn1 levels. Bioinformatic analyses of the yeast and human transcriptomes show that oORFs are more underrepresented than upstream ORFs (uORFs) and associated with lower protein abundance. We propose that oORFs are an important mechanism to control expression of a subset of the proteome.

RevDate: 2018-08-01

Ridout KK, Khan M, SJ Ridout (2018)

Adverse Childhood Experiences Run Deep: Toxic Early Life Stress, Telomeres, and Mitochondrial DNA Copy Number, the Biological Markers of Cumulative Stress.

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

This manuscript reviews recent evidence supporting the utility of telomeres and mitochondrial DNA copy number (mtDNAcn) in detecting the biological impacts of adverse childhood experiences (ACEs) and outlines mechanisms that may mediate the connection between early stress and poor physical and mental health. Critical to interrupting the health sequelae of ACEs such as abuse, neglect, and neighborhood disorder, is the discovery of biomarkers of risk and resilience. The molecular markers of chronic stress exposure, telomere length and mtDNAcn, represent critical biological links between ACEs and poor health outcomes. We examine how telomeres and mtDNAcn may exacerbate health disparities and contribute to the intergenerational transmission of trauma. Finally, we explore how these molecular markers of early stress exposure may help define the role of resilience and develop effective interventions to moderate ACE health risk impact.

RevDate: 2018-08-01

Molina-Molina M, R Borie (2018)

Clinical implications of telomere dysfunction in lung fibrosis.

Current opinion in pulmonary medicine, 24(5):440-444.

PURPOSE OF REVIEW: Telomere attrition has been proposed as one of the aging hallmarks in pulmonary fibrosis. Telomere shortening and telomerase gene mutations have been widely evaluated in recent years. Reduced telomere length may be identified in a quarter of patients with sporadic idiopathic pulmonary fibrosis (IPF) and half of those cases with family aggregation. However, telomere studies have not transferred from the research field to the clinic. This review is focused on our current understanding of the pathogenic implication of telomere dysfunction in lung fibrosis and its relevance in the clinical setting.

RECENT FINDINGS: The most prevalent clinical expression of telomere dysfunction is IPF. Disease onset is usually seen at a younger age and family aggregation is frequently present. Short telomere syndrome is associated in a minority of cases and includes premature hair greying, bone marrow failure and liver cirrhosis. However, patients often present with some extrapulmonary associated telomeric features and related comorbidities that may help to suspect telomere defects. Telomere shortening confers a poor prognosis and reduced lung-transplant free survival time in IPF and other nonidiopathic pulmonary fibrotic entities.

SUMMARY: Telomere dysfunction associates some common clinical features that could modify patient management in pulmonary fibrosis.

RevDate: 2018-08-01

Mersaoui SY, RJ Wellinger (2018)

Fine tuning the level of the Cdc13 telomere-capping protein for maximal chromosome stability performance.

Current genetics pii:10.1007/s00294-018-0871-3 [Epub ahead of print].

Chromosome stability relies on an adequate length and complete replication of telomeres, the physical ends of chromosomes. Telomeres are composed of short direct repeat DNA and the associated nucleoprotein complex is essential for providing end-stability. In addition, the so-called end-replication problem of the conventional replication requires that telomeres be elongated by a special mechanism which, in virtually all organisms, is based by a reverse transcriptase, called telomerase. Although, at the conceptual level, telomere functions are highly similar in most organisms, the telomeric nucleoprotein composition appears to diverge significantly, in particular if it is compared between mammalian and budding yeast cells. However, over the last years, the CST complex has emerged as a central hub for telomere replication in most systems. Composed of three proteins, it is related to the highly conserved replication protein A complex, and in all systems studied, it coordinates telomerase-based telomere elongation with lagging-strand DNA synthesis. In budding yeast, the Cdc13 protein of this complex also is essential for telomerase recruitment and this specialisation is accompanied by additional regulatory adaptations. Based on recent results obtained in yeast, here, we review these issues and present an updated telomere replication hypothesis. We speculate that the similarities between systems far outweigh the differences, once we detach ourselves from the historic descriptions of the mechanisms in the various organisms.

RevDate: 2018-08-01

Tummala H, Collopy LC, Walne AJ, et al (2018)

Homozygous OB-fold variants in telomere protein TPP1 are associated with dyskeratosis congenita like phenotypes.

Blood pii:blood-2018-03-837799 [Epub ahead of print].

RevDate: 2018-07-31

Sanft T, Usiskin I, Harrigan M, et al (2018)

Randomized controlled trial of weight loss versus usual care on telomere length in women with breast cancer: the lifestyle, exercise, and nutrition (LEAN) study.

Breast cancer research and treatment pii:10.1007/s10549-018-4895-7 [Epub ahead of print].

PURPOSE: Some studies suggest that telomere shortening may be associated with increased breast cancer risk and mortality. Obesity is also associated with increased breast cancer risk and mortality. Few studies have examined changes in telomere length in overweight or obese breast cancer survivors. The purpose of our study was to examine the effect of a 6-month diet- and exercise-induced weight loss intervention versus usual care on telomere length in breast cancer survivors.

METHODS: 151 breast cancer survivors with body mass index (BMI) ≥ 25 kg/m2 were randomly assigned to a 6-month weight loss intervention (n = 93) or to usual care (n = 58). Fasting blood samples, height, weight, physical activity, and diet were measured at baseline and 6-months. Relative telomere length (RTL) was measured by quantitative-polymerase chain reaction (qPCR) done on buffy coat-extracted genomic DNA. Mean baseline to 6-month changes were compared between groups (intention-to-treat) using generalized estimating equations.

RESULTS: Complete telomere data were available in 125 participants. Women were 58 ± 8 years, with BMI 33.0 ± 6.2 kg/m2 and were 2.9 ± 2.5 years from diagnosis; 90% were non-Hispanic white, and 76% had stage 0/I breast cancer. After 6 months, women randomized to weight loss had 3% telomere lengthening compared to 5% shortening in the usual care group (p = 0.12). Among women with stage 0/I, the intervention group experienced 7% telomere lengthening compared to 8% shortening in the usual care group (p = 0.01). No intervention effect was observed in women with stage II/III breast cancer.

CONCLUSION: Our findings suggest a weight loss intervention in stage 0 and 1 breast cancer survivors may lead to telomere lengthening, compared to a shortening in their usual care counterparts.

RevDate: 2018-07-31

Hiraishi N, Terai M, Fujiwara M, et al (2018)

Quantitative fluorescence in situ hybridization for investigation of telomere length dynamics in the pituitary gland using samples from 128 autopsied patients.

Tissue & cell, 53:1-7.

In order to investigate the population dynamics of telomere status, we measured the telomere lengths of glandular cells in the adenohypophysis (AH) and pituicytes, a type of glial cell, in the neurohypophysis (NH) of 128 autopsied humans (65 men, 63 women, 0 and 102 years) using our original quantitative fluorescence in situ hybridization (Q-FISH) method. Telomeres in the AH shortened with aging in both men and women, but those of pituicytes did not. Pituicyte telomeres were significantly longer in women than in men. The data suggest that telomeres shorten with age in the AH, whereas those in pituicytes maintain a constant length throughout life. Comparison of pituicyte telomere lengths among 5 generations, <18, 18-69, 70-79, 80-89, and >90 years, revealed a tendency for telomeres to be longer in individuals in their 80 s and 90 s than in those in their 70 s. These findings lend support to the widely held notion that humans with longer telomeres may have a longer life span, and shed light on the biology of pituitary gland in terms of telomere length dynamics, as well contributing to the development of bioengineered hormone-producing cell replacement strategies and regenerative therapies.

RevDate: 2018-07-30

Kachuri L, Saarela O, Bojesen SE, et al (2018)

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

International journal of epidemiology pii:5061128 [Epub ahead of print].

Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.

Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.

Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.

Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

RevDate: 2018-07-30

Lucas T, Woerner J, Pierce J, et al (2018)

Justice for all? Beliefs about justice for self and others and telomere length in African Americans.

Cultural diversity & ethnic minority psychology pii:2018-36930-001 [Epub ahead of print].

OBJECTIVE: Believing in justice can protect health. Among marginalized racial minorities however, both endorsing and rejecting beliefs about justice might be critical. The current research examined links between African Americans' beliefs about justice for self and for others and telomere length (TL)-an indicator of biological aging that is increasingly implicated in racial health disparities, with shorter telomeres indicating poorer health.

METHOD: Healthy African Americans (N = 118; 30% male; M age = 31.63 years) completed individual differences measures of justice beliefs for self and others and then provided dried blood spot samples that were assayed for TL.

RESULTS: We expected that a belief in justice for self would be positively associated with TL, whereas a belief in justice for others would be negatively associated. A significant 3-way interaction with chronological age confirmed this hypothesis-among older African Americans, TL was positively associated with believing in justice for self, but only when this belief was accompanied by a weak endorsement of the belief in justice for others.

CONCLUSION: Findings underscore that for racial minorities, health might be best protected when justice beliefs are both endorsed and rebuffed. (PsycINFO Database Record

RevDate: 2018-07-30

Sorochynska K, Sych N, Duda A, et al (2018)

Dynamics of Telomere Length and Telomerase Activity in the Human Fetal Liver at 5-12 Weeks of Gestation.

Stem cells international, 2018:1385903.

Fetal stem cell- (FSC-) based therapy is a promising treatment option for many diseases. The differentiation potential of FSCs is greater than that in adult stem cells, and they are more tissue-specific and have lower immunogenicity and better intrinsic homing than embryonic ones. Embryonic stem cells have higher proliferative potential than FSCs but can cause teratomas. Therefore, an evaluation of this potential represents an important biomedical challenge. Since regulation of telomere length (TL) is one mechanism governing cellular proliferation, TL is a useful surrogate marker for cell replicative potential. The prenatal dynamics of TL, however, has never been comprehensively studied. In the present study, dynamics of TL and telomerase activity in the human fetal liver during 5-12 weeks of gestation is examined. Both TL and telomerase activity were positively correlated with week of gestation. For both parameters studied, the trend to increase was evident up to 10th week of gestation. After that, they reached a plateau and remained stable. These findings indicate that telomerase activity remains high during the fetal stage, suggesting high replicative capacity of FSCs and their considerable potential for transplantation therapies. These findings, however, are preliminary only due to small sample size and require further evaluation.

RevDate: 2018-07-30

Zhang N, Tse G, T Liu (2018)

Telomere length and contrast-induced nephropathy.

RevDate: 2018-07-30

Haapanen MJ, Perälä MM, Salonen MK, et al (2018)

Telomere Length and Frailty: The Helsinki Birth Cohort Study.

Journal of the American Medical Directors Association, 19(8):658-662.

OBJECTIVES: Telomere length is associated with aging-related pathologies. Although the association between telomere length and frailty has been studied previously, only a few studies assessing longitudinal changes in telomere length and frailty exist.

DESIGN: Longitudinal cohort study.

SETTING AND PARTICIPANTS: A subpopulation of the Helsinki Birth Cohort Study consisting of 1078 older adults aged 67 to 79 years born in Helsinki, Finland, between 1934 and 1944.

MEASURES: Relative leukocyte telomere length (LTL) was measured using quantitative real-time polymerase chain reaction at the average ages of 61 and 71 years, and at the latter the participants were assessed for frailty according to Fried criteria.

RESULTS: The mean ± SD relative LTLs were 1.40 ± 0.29 (average age 61 years) and 0.86 ± 0.30 (average age 71 years) for the cohort. A trend of shorter mean relative LTL across frailty groups was observed at 61 years (P = .016) and at 71 years (P = .057). Relative LTL at age 61 years was significantly associated with frailty: per 1-unit increase in relative LTL, the corresponding relative risk ratio (RRR) of frailty was 0.28 (95% confidence interval [CI] 0.08-0.97), adjusting for several confounders. Also, LTL at age 71 years was associated with frailty (RRR 0.18, 95% CI 0.04-0.81) after adjustment for sex, age, and adult socioeconomic status, but further adjustment attenuated the association. No associations between telomere shortening and frailty were observed during the 10-year follow-up.

CONCLUSIONS: Shorter relative LTL was associated with frailty in cross-sectional and longitudinal analyses, but telomere shortening was not, suggesting that short LTL may be a biomarker of frailty.

RevDate: 2018-07-29

Luke B (2018)

Telomere regulation.

RevDate: 2018-07-27

Gokarn R, Solon-Biet S, Youngson NA, et al (2018)

The Relationship Between Dietary Macronutrients and Hepatic Telomere Length in Aging Mice.

The journals of gerontology. Series A, Biological sciences and medical sciences, 73(4):446-449.

Macronutrients and dietary energy influence aging, age-related health, and life span. Reduction in telomere length has been proposed as one mechanism for aging. Therefore, this study investigated the effects of varying ratios of dietary macronutrients and energy on telomere length in older adult mice. C57Bl/6 mice were fed ad libitum their entire life on one of 25 diets varying in protein, carbohydrates, fat, and energy. Average telomere length ratio (ATLR) was measured by polymerase chain reaction in livers of a subset of 161 mice aged 15 months. There was a significant positive relationship between ATLR and carbohydrate intake and a negative relationship with protein intake, but no relationships with fat or energy intake. Analysis using the Geometric Framework and Generalized Additive Models confirmed that carbohydrate intake was positively associated with ATLR, while the longest ATLR was achieved by mice restricted to low protein, high carbohydrate diets. ATLR distribution across the diets was parallel to median life-span results previously published. ATLR was associated with blood levels of some amino acids (asparagine, glutamate, taurine) but not with blood levels of fatty acids, hepatic mitochondrial function, or nutrient sensing pathways. In conclusion, mice on low protein, high carbohydrate diets have the longest hepatic telomeres and longest life span.

RevDate: 2018-07-27

Denham J, MM Denham (2018)

Leukocyte telomere length in the Thoroughbred racehorse.

Animal genetics [Epub ahead of print].

Thoroughbred racehorses possess superior cardiorespiratory fitness levels and are at the pinnacle of athletic performance compared to other breeds of horses. Although equine athletes have undergone years of artificial selection for racing performance, musculoskeletal injuries and illnesses are common and concerns relating to animal welfare have been proposed. Leukocyte telomere length is indicative of biological age, and accelerated telomere shortening occurs with excess physical and psychological stress. This study was designed to explore the association between leukocyte telomere length, biological factors (age, sex and coat colour), training status, winnings and race history parameters. Blood was collected from 146 Thoroughbred racehorses from around Geelong, Victoria, Australia. DNA was extracted from leukocytes; telomere length was measured using qPCR and analysed in context with traits obtained from the Racing Australia website. Age was inversely correlated with telomere length (r = -0.194, P = 0.019). The oldest horses (≥11 years) in the highest age quartile possessed shorter telomeres compared to younger horses in the first, second and third quartiles (≤2, 3-5 and 6-10 years respectively; P < 0.05). No statistically significant associations were observed between telomere length and biological factors, training status, winnings or race history parameters in age-adjusted analyses. The study findings suggest that Thoroughbred horses may undergo age-related telomere shortening similar to other mixed breeds and humans. Despite concerns from some quarters regarding the welfare of racehorses, there was a lack of accelerated biological ageing observed in the present study, as indicated by leukocyte telomere length.

RevDate: 2018-07-26

Willis M, Reid SN, Calvo E, et al (2018)

A Scoping Systematic Review of Social Stressors and Various Measures of Telomere Length Across the Life Course.

Ageing research reviews pii:S1568-1637(18)30133-8 [Epub ahead of print].

Numerous studies examine the relationship between social stressors and telomere length (TL). Beyond considering methods and major findings, this scoping systematic review takes a novel approach as it groups studies according to the types of social stressor considered and by age groups. Following PRISMA guidelines, we searched PubMed, Web of Science, Embase, and Scopus. We included all English-language human subject research articles that modeled any measure of TL as a dependent variable and exposure to a social stressor as an independent variable. For the sample of 105 articles, we summarized methods and findings by type of social stressor (socioeconomic stressors, stressful life events, work-related stressors, and neighborhood stressors) and by age of the study population (infants/children, middle-aged adults, older adults, and mixed samples of middle-aged and older adults). We found more variation in TL measurement methodology in studies of infants/children and older adults than in studies focusing on middle-aged adults. The most consistent finding was a relationship between early-life stressors and shorter TL. Work and neighborhood stressors, and older populations, are currently understudied. Across all stressors, limited evidence suggests that the stress-TL relationship may be moderated by characteristics such as age, sex, and race/ethnicity. We conclude with specific suggestions for future research.

RevDate: 2018-07-26

Zhang Y, Wang C, Jin Y, et al (2018)

Activating the PGC-1α/TERT Pathway by Catalpol Ameliorates Atherosclerosis via Modulating ROS Production, DNA Damage, and Telomere Function: Implications on Mitochondria and Telomere Link.

Oxidative medicine and cellular longevity, 2018:2876350.

Catalpol, an iridoid glucoside, has been found present in large quantities in the root of Rehmannia glutinosa L. and showed a strong antioxidant capacity in the previous study. In the present work, the protective effect of catalpol against AS via inhibiting oxidative stress, DNA damage, and telomere shortening was found in LDLr-/- mice. This study also shows that activation of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/telomerase reverse transcriptase (TERT) pathway, which is the new link between mitochondria and telomere, was involved in the protective effects of catalpol. Further, by using PGC-1α or TERT siRNA in oxLDL-treated macrophages, it is proved that catalpol reduced oxidative stress, telomere function, and related DNA damage at least partly through activating the PGC-1α/TERT pathway. Moreover, dual luciferase activity assay-validated catalpol directly enhanced PGC-1α promoter activity. In conclusion, our study revealed that the PGC-1α/TERT pathway might be a possible therapeutic target in AS and catalpol has highly favorable characteristics for the treatment of AS via modulating this pathway.

RevDate: 2018-07-26

Chatterjee S, de Gonzalo-Calvo D, Derda AA, et al (2018)

Leukocyte telomere length correlates with hypertrophic cardiomyopathy severity.

Scientific reports, 8(1):11227 pii:10.1038/s41598-018-29072-8.

Telomere length is a marker of biological aging. Short leukocyte telomere length has been associated with various conditions including cardiovascular disorders. Here, we evaluated if patients with hypertrophic cardiomyopathy have altered leukocyte telomere length and whether this is associated with disease severity. A quantitative polymerase chain reaction-based method was used to measure peripheral blood leukocyte telomere length in 59 healthy control subjects and a well-characterized cohort of 88 patients diagnosed with hypertrophic cardiomyopathy: 32 patients with non-obstructive cardiomyopathy (HNCM) and 56 patients with obstructive cardiomyopathy (HOCM). We observed shorter leukocyte telomeres in both HNCM and HOCM patients compared to healthy controls. Furthermore, leukocyte telomere length was inversely associated with HCM even after adjusting for age and sex. Telomere length of HOCM patients was also inversely correlated with left ventricular outflow tract obstruction. Therefore, HOCM patients were categorized by tertiles of telomere length. Patients in the first tertile (shortest telomeres) had a significantly increased left ventricular posterior wall thickness at end-diastole and higher left ventricular outflow tract gradients, whereas the left ventricular end-diastolic diameter was lower compared with patients in the second and third tertile. In summary, telomere length is associated with the severity of the disease in the HOCM subtype.

RevDate: 2018-07-26

Yang SF, Sun AA, Shi Y, et al (2018)

Structural and functional characterization of the RBBP4-ZNF827 interaction and its role in NuRD recruitment to telomeres.

The Biochemical journal pii:BCJ20180310 [Epub ahead of print].

The nucleosome remodeling and histone deacetylase (NuRD) complex is an essential multi-subunit protein complex that regulates higher-order chromatin structure. Cancers that use the Alternative Lengthening of Telomeres (ALT) pathway of telomere maintenance recruit NuRD to their telomeres. This interaction is mediated by the N-terminal domain of the zinc finger protein ZNF827. NuRD-ZNF827 plays a vital role in the ALT pathway by creating a molecular platform for recombination-mediated repair. Disruption of NuRD binding results in loss of ALT cell viability. Here, we present the crystal structure of the NuRD subunit RBBP4 bound to the N-terminal 14 amino acids of ZNF827. RBBP4 forms a negatively charged channel that binds to ZNF827 through a network of electrostatic interactions. We identify the precise amino acids in RBBP4 required for this interaction, and demonstrate that disruption of these residues prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity. These data provide insight into the structural and functional determinants of NuRD activity at ALT telomeres.

RevDate: 2018-07-25

Li Y, DM Dorfman (2018)

Highly atypical myeloblasts in acute myeloid leukaemia with myelodysplasia-related changes in a patient with short telomere syndrome.

British journal of haematology [Epub ahead of print].

RevDate: 2018-07-24

Ryan CP, Hayes MG, Lee NR, et al (2018)

Reproduction predicts shorter telomeres and epigenetic age acceleration among young adult women.

Scientific reports, 8(1):11100 pii:10.1038/s41598-018-29486-4.

Evolutionary theory predicts that reproduction entails costs that detract from somatic maintenance, accelerating biological aging. Despite support from studies in human and non-human animals, mechanisms linking 'costs of reproduction' (CoR) to aging are poorly understood. Human pregnancy is characterized by major alterations in metabolic regulation, oxidative stress, and immune cell proliferation. We hypothesized that these adaptations could accelerate blood-derived cellular aging. To test this hypothesis, we examined gravidity in relation to telomere length (TL, n = 821) and DNA-methylation age (DNAmAge, n = 397) in a cohort of young (20-22 year-old) Filipino women. Age-corrected TL and accelerated DNAmAge both predict age-related morbidity and mortality, and provide markers of mitotic and non-mitotic cellular aging, respectively. Consistent with theoretical predictions, TL decreased (p = 0.031) and DNAmAge increased (p = 0.007) with gravidity, a relationship that was not contingent upon resource availability. Neither biomarker was associated with subsequent fertility (both p > 0.3), broadly consistent with a causal effect of gravidity on cellular aging. Our findings provide evidence that reproduction in women carries costs in the form of accelerated aging through two independent cellular pathways.

RevDate: 2018-07-23

Van Ly D, Low RRJ, Frölich S, et al (2018)

Telomere Loop Dynamics in Chromosome End Protection.

Molecular cell pii:S1097-2765(18)30500-8 [Epub ahead of print].

Telomeres regulate DNA damage response (DDR) and DNA repair activity at chromosome ends. How telomere macromolecular structure contributes to ATM regulation and its potential dissociation from control over non-homologous end joining (NHEJ)-dependent telomere fusion is of central importance to telomere-dependent cell aging and tumor suppression. Using super-resolution microscopy, we identify that ATM activation at mammalian telomeres with reduced TRF2 or at human telomeres during mitotic arrest occurs specifically with a structural change from telomere loops (t-loops) to linearized telomeres. Additionally, we find the TRFH domain of TRF2 regulates t-loop formation while suppressing ATM activity. Notably, we demonstrate that ATM activation and telomere linearity occur separately from telomere fusion via NHEJ and that linear DDR-positive telomeres can remain resistant to fusion, even during an extended G1 arrest, when NHEJ is most active. Collectively, these results suggest t-loops act as conformational switches that specifically regulate ATM activation independent of telomere mechanisms to inhibit NHEJ.

RevDate: 2018-07-21

Lin CC, Wang HY, Liaw SF, et al (2018)

Effect of oral appliance on circulating leukocyte telomere length and SIRT1 in obstructive sleep apnea.

Clinical oral investigations pii:10.1007/s00784-018-2560-5 [Epub ahead of print].

OBJECTIVES: The increased cardiovascular risk seen in patients with obstructive sleep apnea (OSA) may be due to combination of oxidative stress, systemic inflammation and damage to leukocyte telomere length (LTL) seen with aging. Another molecule, Sirtuin 1 (SIRT1), a histone/protein deacetylase, regulates endothelial nitric oxide synthase and is involved in different aspects of cardiovascular disease, aging and stress resistance. The aim of this study was to evaluate the effects of mandibular advancement device (MAD) on the circulating LTL and SIRT1 protein level in peripheral blood mononuclear cells (PBMCs) in patients with OSA.

MATERIALS AND METHODS: Forty patients with moderately severe to severe OSA who desired MAD and 20 healthy controls were prospectively enrolled. The LTL was measured by quantitative polymerase chain reaction while SIRT1 protein levels in PBMC was assessed using a Sirtuin 1 ELISA Kit. All study subjects underwent baseline sleep study, with OSA patients having repeat testing at 3 months after MAD.

RESULTS: Compared to healthy subjects, patients with OSA at baseline had lower LTL and SIRT1 protein levels in PBMC. After 3 months of MAD, 24 OSA patients, designated as MAD responders, median (range) LTL increased from (0.556 [0.393-0.748]) to (0.708 [0.533-0.893]) and SIRT1 protein levels in PBMC increased from 0.58 ± 0.23 pg/μg of total protein to 0.95 ± 0.26 pg/μg of total protein. For the 16 MAD unresponsive patients, LTL and SIRT1 protein levels remained low.

CONCLUSIONS: Successful treatment of OSA with MAD can restore LTL and SIRT1 protein levels in PBMC.

CLINICAL RELEVANCE: LTL and SIRT1 protein levels in PBMC can be improved following effective treatment of OSA using MAD.

RevDate: 2018-07-21

Mazidi M, Kengne AP, Cheskin LJ, et al (2018)

Serum lipophilic antioxidants levels are associated with leucocyte telomere length among US adults.

Lipids in health and disease, 17(1):164 pii:10.1186/s12944-018-0781-x.

BACKGROUND: To examine the association between serum concentrations of antioxidant and telomere length (TL) in U.S adults.

METHODS: Participants of the National Health and Nutrition Examination Survey (NHANES) with data available on TL measures from 2001 to 2002 were included. Serum lipophilic antioxidants level was measured using high performance liquid chromatography with photodiode array detection. We used analysis of co-variance and multivariable-adjusted linear regression models, accounting for the survey design and sample weights.

RESULTS: Of the 5992 eligible participants, 47.5% (n = 2844) were men. The mean age was 46.9 years overall, 47.2 years in men and 46.6 in women (p = 0.071). In age, sex, race, education, marital status, adiposity, smoking, C-reactive protein adjusted linear regressions, antioxidant, serum α-carotene, trans-β-carotene, cis- β-carotene, β-cryptoxanthin and combined Lutein/zeaxanthin were positively and significantly associated with TL (all p < 0.001).

CONCLUSIONS: Our findings support a possible positive association between serum concentrations of lipophylic antioxidant and TL. The implications of this association deserve further investigation.

RevDate: 2018-07-20

Rachakonda S, Srinivas N, Mahmoudpour SH, et al (2018)

Telomere length and survival in primary cutaneous melanoma patients.

Scientific reports, 8(1):10947 pii:10.1038/s41598-018-29322-9.

Telomere repeats at chromosomal ends, critical to genomic integrity, undergo age-dependent attrition. Telomere length, a polygenic trait, has been associated with risk of several disorders including cancers. In contrast to association of long telomeres with increased risk of several cancers, including melanoma, emerging reports suggest that short telomeres predict poor survival in patients with different cancers. In this study based on 1019 stage I and II cutaneous melanoma patients, we show an association between the patients with short telomeres and poor melanoma-specific survival (HR 2.05, 95% CI 1.33-3.16) compared to patients with long telomeres. Due to inverse correlation between age and telomere length (r -0.19, P < 0.0001), we stratified the patients into quantiles based on age at diagnosis and also carried out age-matched analysis. The effect of short telomeres on survival was determined by using multivariate Cox regression that included composite genetic risk score computed from genotyping of the patients for telomere-length associated polymorphisms. The effect of decreased telomere length on poor melanoma-specific survival was particularly strong in patients within the age quantile below 30 years (HR 3.82, 95% CI 1.10-13.30) and between 30-40 years (HR 2.69, 95% CI 1.03-7.03). Our study shows that in contrast to increased melanoma risk associated with increased telomere length, decreased telomere length predicts poor survival in melanoma subgroups.

RevDate: 2018-07-20

Feng X, Hsu SJ, Bhattacharjee A, et al (2018)

CTC1-STN1 terminates telomerase while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells.

Nature communications, 9(1):2827 pii:10.1038/s41467-018-05154-z.

Telomerase elongates the telomeric G-strand to prevent telomere shortening through conventional DNA replication. However, synthesis of the complementary C-strand by DNA polymerase α is also required to maintain telomere length. Polymerase α cannot perform this role without the ssDNA binding complex CST (CTC1-STN1-TEN1). Here we describe the roles of individual CST subunits in telomerase regulation and G-overhang maturation in human colon cancer cells. We show that CTC1-STN1 limits telomerase action to prevent G-overhang overextension. CTC1-/- cells exhibit telomeric DNA damage and growth arrest due to overhang elongation whereas TEN1-/- cells do not. However, TEN1 is essential for C-strand synthesis and TEN1-/- cells exhibit progressive telomere shortening. DNA binding analysis indicates that CTC1-STN1 retains affinity for ssDNA but TEN1 stabilizes binding. We propose CTC1-STN1 binding is sufficient to terminate telomerase action but altered DNA binding dynamics renders CTC1-STN1 unable to properly engage polymerase α on the overhang for C-strand synthesis.

RevDate: 2018-07-19

Zhdanov DD, Gladilina YA, Grishin DV, et al (2018)

Contact-independent suppressive activity of regulatory T cells is associated with telomerase inhibition, telomere shortening and target lymphocyte apoptosis.

Molecular immunology, 101:229-244 pii:S0161-5890(18)30566-2 [Epub ahead of print].

Regulatory T cells (Tregs) play a fundamental role in the maintenance of immunological tolerance by suppressing effector target T, B and NK lymphocytes. Contact-dependent suppression mechanisms have been well-studied, though contact-independent Treg activity is not fully understood. In the present study, we showed that human native Tregs, as well as induced ex vivo Tregs, can cause in vitro telomere-dependent senescence in target T, B and NK cells in a contact-independent manner. The co-cultivation of target cells with Tregs separated through porous membranes induced alternative splicing of the telomerase catalytic subunit hTERT (human Telomerase Reverse Transcriptase), which suppressed telomerase activity. Induction of the hTERT splicing variant was associated with increased expression of the apoptotic endonuclease EndoG, a splicing regulator. Inhibited telomerase in target cells co-cultivated with Tregs for a long period of time led to a decrease in their telomere lengths, cell cycle arrest, conversion of the target cells to replicative senescence and apoptotic death. Induced Tregs showed the ability to up-regulate EndoG expression, TERT alternative splicing and telomerase inhibition in mouse T, B and NK cells after in vivo administration. The results of the present study describe a novel mechanism of contact-independent Treg cell suppression that induces telomerase inhibition through the EndoG-provoked alternative splicing of hTERT and converts cells to senescence and apoptosis phenotypes.

RevDate: 2018-07-20

Massey DS, Wagner B, Donnelly L, et al (2018)

Neighborhood Disadvantage and Telomere Length: Results from the Fragile Families Study.

The Russell Sage Foundation journal of the social sciences : RSF, 4(4):28-42.

Telomeres are repetitive nucleotide sequences located at the ends of chromosomes that protect genetic material. We use data from the Fragile Families and Child Wellbeing Study to analyze the relationship between exposure to spatially concentrated disadvantage and telomere length for white and black mothers. We find that neighborhood disadvantage is associated with shorter telomere length for mothers of both races. This finding highlights a potential mechanism through which the unique spatially concentrated disadvantage faced by African Americans contributes to racial health disparities. We conclude that equalizing the health and socioeconomic status of black and white Americans will be very difficult without reducing levels of residential segregation in the United States.

RevDate: 2018-07-18

Bernal A, Zafon E, Domínguez D, et al (2018)

Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs.

International journal of molecular sciences, 19(7): pii:ijms19072078.

Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre-malignant immortalised cells, we ectopically expressed telomerase in telomere-compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period-aggravated by p53 deficiency-and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy.

RevDate: 2018-07-18

Jin M, Lee EC, Ra SW, et al (2018)

Relationship of Absolute Telomere Length With Quality of Life, Exacerbations, and Mortality in COPD.

Chest pii:S0012-3692(18)30803-1 [Epub ahead of print].

BACKGROUND: COPD is an age-related disease. The role of cellular senescence in COPD has not been fully elucidated. This study examined the relationship between telomere length of peripheral blood leukocytes and clinical outcomes, including health status, rate of exacerbations, and risk of mortality in individuals with COPD.

METHODS: Using quantitative polymerase chain reaction, we measured the absolute telomere length (aTL) of DNA extracted from blood samples of 576 participants with moderate-to-severe COPD treated with either azithromycin or placebo for 12 months in the Macrolide Azithromycin for Prevention of Exacerbations of COPD (MACRO) study. All participants were followed for approximately 13 months, during which time health status and exacerbations were carefully ascertained, and an additional 29 months for mortality. The rates of exacerbation and mortality were determined by dividing the aTL into two groups using the median value as the cutoff.

RESULTS: Participants with shorter telomere length had worse health status defined by higher St. George's Respiratory Questionnaire scores (β = -0.09, P = .034). In the placebo arm of the study, the rate of exacerbation (rate ratio, 1.50; 95% CI, 1.16-1.95; P = .002) and the risk of mortality (hazard ratio, 9.45; 95% CI, 2.85-31.36; P = .015) were significantly higher in the shorter telomere group than in the longer telomere group; these differences were not observed in the azithromycin arm (interaction P = .008 for exacerbation and interaction P = .017 for mortality) CONCLUSIONS: These data suggest that replicative senescence may help to predict poor outcomes in COPD. Shorter leukocyte telomere lengths may represent a clinically translatable biomarker for identifying individuals at increased risk of poor clinical outcomes in COPD.

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ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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Good Beginner's Books

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

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Papers in Classical Genetics

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

Digital Books

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

Timelines

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

Biographies

Biographical information about many key scientists.

Selected Bibliographies

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

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