Telomere Length Maintenance Research Articles

Mediterranean Diet and Telomere Length: A Systematic Review and Meta-Analysis

Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

PurposeThe maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined.MethodsWe investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR.ResultsMutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length.ConclusionOur results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

TRNA ADENOSINE DEAMINASE 3 is required for telomere maintenance in Arabidopsis thaliana.

KEY MESSAGE: tRNA Adenosine Deaminase 3 helps to sustain telomere tracts in a telomerase-independent fashion, likely through regulating cellular metabolism. Telomere length maintenance is influenced by a complex web of chromatin and metabolism-related factors. We previously reported that a lncRNA termed AtTER2 regulates telomerase activity in Arabidopsis thaliana in response to DNA damage. AtTER2 was initially shown to partially overlap with the 5' UTR of the tRNA ADENOSINE DEAMINASE 3 (TAD3) gene. However, updated genome annotation showed that AtTER2 was completely embedded in TAD3, raising the possibility that phenotypes ascribed to AtTER2 could be derived from TAD3. Here we show through strand-specific RNA-Seq, strand-specific qRT-PCR and bioinformatic analyses that AtTER2 does not encode a stable lncRNA. Further examination of the original tad3 (ter2-1/tad3-1) mutant revealed expression of an antisense transcript driven by a cryptic promoter in the T-DNA. Hence, a new hypomorphic allele of TAD3 (tad3-2) was examined. tad3-2 mutants showed hypersensitivity to DNA damage, but no deregulation of telomerase, suggesting that the telomerase phenotype of tad3-1 mutants reflects an off-target effect. Unexpectedly, however, tad3-2 plants displayed progressive loss of telomeric DNA over successive generations that was not accompanied by alteration of terminal architecture or end protection. The phenotype was exacerbated in plants lacking the telomerase processivity factor POT1a, indicating that TAD3 promotes telomere maintenance througha non-canonical, telomerase-independent pathway. The transcriptome of tad3-2 mutants revealed significant dysregulation of genes involved in auxin signaling and glucosinolate biosynthesis, pathways that intersect the stress response, cell cycle regulation and DNA metabolism. These findings indicate that the TAD3 locus indirectly contributes to telomere length homeostasis by altering the metabolic profile in Arabidopsis.

The effect of long-term ultra-endurance exercise and SOD2 genotype on telomere shortening with age.

Telomere shortening, a well-known biomarker of aging, is a complex process influenced by several intrinsic and lifestyle factors. Although habitual exercise may promote telomere length maintenance, extreme endurance exercise has been also associated with increased oxidative stress-presumed to be the major cause of telomere shortening. Therefore, the pace of telomere shortening with age may also depend on antioxidant system efficiency, which is, in part, genetically determined. In this study, we aimed to evaluate the impact of ultra-endurance exercise and oxidative stress susceptibility (determined by the rs4880 polymorphism in the superoxide dismutase 2 (SOD2) gene) on telomere length. Genomic DNA was obtained from 53 sedentary individuals (34 females, 19-67 yr) and 96 ultra-trail runners (31 females, 23-58 yr). Indeed, blood samples before and after finishing a 107-km-trail race were collected from 69 runners to measure c-reactive protein (CRP) levels and, thus, analyze whether acute inflammation response is modulated by the SOD2 rs4880 polymorphism. Our results revealed that telomere length was better preserved in ultra-trail runners compared with controls, especially in elderly runners who have been regularly training for many years. Carrying the SOD2 rs4880*A allele was significantly associated with having shorter telomeres, as well as with having increased CRP levels after the ultra-trail race. In conclusion, habitual ultra-endurance exercise had a beneficial effect on telomere length maintenance, especially at older ages. This study also suggested that the SOD2 rs4880 polymorphism may also have an impact on acute and chronic oxidative-related damage (inflammatory response and telomere length) after an ultra-trail race.NEW & NOTEWORTHY Habitual ultra-endurance exercise seems to promote telomere length maintenance, especially at older ages. In addition, the beneficial effect of ultra-endurance training on biological aging is higher in ultra-trail runners who have been engaged to ultra-endurance training during many years. Finally, and for the first time, this study shows that the SOD2 rs4880 polymorphism has a significant impact on telomere length, as well as on acute inflammatory response to a 107-km trail race.

Noncanonical role for Ku70/80 in the prevention of allergic airway inflammation via maintenance of airway epithelial cell organelle homeostasis.

Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.

Association between favourable changes in objectively measured physical activity and telomere length after a lifestyle intervention in pediatric patients with abdominal obesity.

The purpose of this study was to assess the effect of physical activity (PA) changes, measured by accelerometry, on telomere length (TL) in pediatric patients with abdominal obesity after a lifestyle intervention. One hundred and twenty-one children (7-16 years old) with abdominal obesity were randomized to the intervention (a moderately hypocaloric Mediterranean diet) or the usual care group (standard pediatric recommendations) for 22 months (a 2 month intensive phase and a subsequent 20 month follow-up). Both groups were encouraged to accumulate an extra 200 min/week of PA. TL was measured by MMqPCR. Data were analyzed in 102 subjects after 2 months and 64 subjects at the first 10 months of follow-up. Light PA level decreased in both groups after 12 months of intervention. At month 2, moderate to vigorous PA (MVPA) increased in the intervention group (+5.4 min/day, p = 0.035) and so did sedentary time in the usual care group (+49.7 min/day, p = 0.010). TL changes were positively associated (p < 0.050) with metabolic equivalents (METs), MVPA level, and number of steps, and were inversely associated with sedentary and light PA levels in the intervention group after the intensive phase. In conclusion, favourable changes in PA levels in the intensive phase of a lifestyle intervention could contribute to TL maintenance in a pediatric population with abdominal obesity. Novelty Changes in physical activity levels had a direct effect on telomere length, a biomarker of cellular aging and oxidative stress. PA advice based on The American College of Sports Medicine included in this intervention is easy to implement in primary care.

Functional Diversification of Replication Protein A Paralogs and Telomere Length Maintenance in Arabidopsis.

Replication protein A (RPA) is essential for many facets of DNA metabolism. The RPA gene family expanded in Arabidopsis thaliana with five phylogenetically distinct RPA1 subunits (RPA1A-E), two RPA2 (RPA2A and B), and two RPA3 (RPA3A and B). RPA1 paralogs exhibit partial redundancy and functional specialization in DNA replication (RPA1B and RPA1D), repair (RPA1C and RPA1E), and meiotic recombination (RPA1A and RPA1C). Here, we show that RPA subunits also differentially impact telomere length set point. Loss of RPA1 resets bulk telomeres at a shorter length, with a functional hierarchy for replication group over repair and meiosis group RPA1 subunits. Plants lacking RPA2A, but not RPA2B, harbor short telomeres similar to the replication group. Telomere shortening does not correlate with decreased telomerase activity or deprotection of chromosome ends in rpa mutants. However, in vitro assays show that RPA1B2A3B unfolds telomeric G-quadruplexes known to inhibit replications fork progression. We also found that ATR deficiency can partially rescue short telomeres in rpa2a mutants, although plants exhibit defects in growth and development. Unexpectedly, the telomere shortening phenotype of rpa2a mutants is completely abolished in plants lacking the RTEL1 helicase. RTEL1 has been implicated in a variety of nucleic acid transactions, including suppression of homologous recombination. Thus, the lack of telomere shortening in rpa2a mutants upon RTEL1 deletion suggests that telomere replication defects incurred by loss of RPA may be bypassed by homologous recombination. Taken together, these findings provide new insight into how RPA cooperates with replication and recombination machinery to sustain telomeric DNA.

Telomere Attrition in Neurodegenerative Disorders.

Telomere attrition is increased in various disorders and is therefore a potential biomarker for diagnosis and/or prognosis of these disorders. The contribution of telomere attrition in the pathogenesis of neurodegenerative disorders is yet to be fully elucidated. We are reviewing the current knowledge regarding the telomere biology in two common neurodegenerative disorders, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Furthermore, we are discussing future prospective of telomere research in these disorders. The majority of studies reported consistent evidence of the accelerated telomere attrition in AD patients, possibly in association with elevated oxidative stress levels. On the other hand in PD, various studies reported contradictory evidence regarding telomere attrition. Consequently, due to the low specificity and sensitivity, the clinical benefit of telomere length as a biomarker of neurodegenerative disease development and progression is not yet recognized. Nevertheless, longitudinal studies in large carefully selected cohorts might provide further elucidation of the complex involvement of the telomeres in the pathogenesis of neurodegenerative diseases. Telomere length maintenance is a complex process characterized by environmental, genetic, and epigenetic determinants. Thus, in addition to the selection of the study cohort, also the selection of analytical methods and types of biological samples for evaluation of the telomere attrition is of utmost importance.

Human Telomerase RNA: Telomerase Component or More?

Telomerase is a ribonucleoprotein complex that maintains the lengths of telomeres. Most studies of telomerase function have focused on the involvement of telomerase activation in the immortalization of cancer cells and cellular rejuvenation. However, some studies demonstrated that the results do not meet expectations for telomerase action in telomere maintenance. Recent results give reason to think that major telomerase components—the reverse transcriptase protein subunit and telomerase RNA—may participate in many cellular processes, including the regulation of apoptosis and autophagy, cell survival, pro-proliferative effects, regulation of gene expression, and protection against oxidative stress. However, the difficulties faced by scientist when researching telomerase component functions often reduce confidence in the minor effects observed in experiments. In this review, we focus on the analysis of the functions of telomerase components (paying more attention to the telomerase RNA component), both as a complex and as independent components, providing effects that are not associated with telomerase activity and telomere length maintenance. Despite the fact that the data on alternative roles of telomerase components look illusory, it would be wrong to completely reject the possibility of their involvement in other biological processes excluded from research/discussion. Investigations to improve the understanding of every aspect of the functioning of telomerase components will provide the basis for a more precise development of approaches to regulate cellular homeostasis, which is important for carcinogenesis and aging.

Essential factors involved in the precise targeting and insertion of telomere-specific non-LTR retrotransposon, SART1Bm

Telomere length maintenance is essential for most eukaryotes to ensure genome stability and integrity. A non-long terminal repeat (LTR) retrotransposon, SART1Bm, targets telomeric repeats (TTAGG)n of the silkworm Bombyx mori and is presumably involved in telomere length maintenance. However, how many telomeric repeats are required for its retrotransposition and how reverse transcription is initiated at the target site are not well understood. Here, using an ex vivo and trans-in vivo recombinant baculovirus retrotransposition system, we demonstrated that SART1Bm requires at least three (TTAGG) telomeric repeats and a longer poly(A) tail for its accurate retrotransposition. We found that SART1Bm retrotransposed only in the third (TTAGG) tract of three repeats and that the A residue of the (TTAGG) unit was essential for its retrotransposition. Interestingly, SART1Bm also retrotransposed into telomeric repeats of other species, such as human (TTAGGG)n repeats, albeit with low retrotransposition efficiency. We further showed that the reverse transcription of SART1Bm occurred inaccurately at the internal site of the 3′ untranslated region (UTR) when using a short poly(A) tail but at the accurate site when using a longer poly(A) tail. These findings promote our understanding of the general mechanisms of site-specific retrotransposition and aid the development of a site-specific gene knock-in tool.

Anti-CD3 and anti-CD28 antibodies conjugated with lipid microbubbles (MB-TAC) provide a superior expansion of human naive CD4+ and CD8+ T cells in long term culture

Abstract Anti-CD3 and anti-CD28 antibodies are a method of choice for general and physiological activation of human primary T cells in vitro. Here we report a comparison of the growth, cell death, and cytokine production of anti-CD3 and anti-CD28 antibodies conjugated with lipid microbubbles (MB-TCA) and the standard Dynal beads (D-TCA). In 56-day cultures with three repeated stimulation cycles (14 days per stimulation), we found that MB-TCA induced a significantly better expansion (~20-fold increase) of naïve CD4 and CD8 T cells than did D-TCA. We found the main difference between MB-TCA and D-TCA was not the speed of activation-induced initial T cell proliferation but rather the survival of activated T cells. Furthermore, we found that MB-TCA activated T cells had a better telomere length maintenance and produced less TNFα and other cytokines than did D-TCA. Finally, blocking TNFα action via antibody against TNFRSF1A significantly improved expansion of T cells activated by D-TCA in vitro. Together, we demonstrated that MB-TCA offers a better expansion of primary human T cells in vitro and will be a useful method for long term culture of primary human T cells for both basic and clinical applications.

Correlation of TCF4, GSK, TERT and TERC Expressions with Proliferation Potential of Early and Late Culture of Human Peripheral Blood Mesenchymal Stem Cells.

Objective In the recent years, mesenchymal stem cells (MSCs) were considered as the suitable source of cells for transplantation into the damaged tissues in regenerative medicine. There was low number of these cells in different organs and this characteristic was the main drawback to use them in treatment of diseases. Cellular senescence of the stem cells has been demonstrated to be dependent to the telomerase activity. The aim of present experimental study was to evaluate correlation of the expression of telomerase components and WNT signaling pathway in MSCs derived from human peripheral blood (PB-MSCs). Materials and Methods In this experimental study, following the isolation of MSCs from peripheral blood mononuclear cells, RNA was extracted from these cells in the early culture (8-9th days) and late culture (14-17th days). Then, expression of TERT, TERC, TCF4, GSK and CTNNB1 was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) based on SYBR Green. Results Our data indicated that there was a significantly reduced expression of TERT in the late culture of human MSCs derived from peripheral blood (P<0.05). Although a negative correlation was observed between GSK and TERC expression levels in the early culture of MSCs, spearman analysis showed that there was no significant correlation between the expression of telomerase components (TERC and TERT) and WNT signaling pathway (P>0.05). ConclusionThe obtained results suggested that WNT signaling pathway likely plays a minor role in the maintenance of telomere length and proliferation potential of MSCs.

Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance.

Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expressed at higher levels than necessary for maintaining functional telomere length, suggesting other possible adaptive functions. Emerging non-canonical roles of TERT include regulation of non-telomeric DNA damage responses, promotion of cell growth and proliferation, acceleration of cell cycle kinetics, and control of mitochondrial integrity following oxidative stress. Non-canonical activities of TERT primarily show cellular protective effects, and nuclear TERT has been shown to protect against cell death following double-stranded DNA damage, independent of its role in telomere length maintenance. TERT has been suggested to act as a chromatin modulator and participate in the transcriptional regulation of gene expression. TERT has also been reported to regulate transcript levels through an RNA-dependent RNA Polymerase (RdRP) activity and produce siRNAs in a Dicer-dependent manner. At the mitochondria, TERT is suggested to protect against oxidative stress-induced mtDNA damage and promote mitochondrial integrity. These extra-telomeric functions of TERT may be advantageous in the context of increased proliferation and metabolic stress often found in rapidly-dividing cancer cells. Understanding the spectrum of non-canonical functions of telomerase may have important implications for the rational design of anti-cancer chemotherapeutic drugs.

Loss of Repressor Activator Protein 1 Precipitates Cardiac Aging in Mice via p53/PPARα Signaling

BackgroundTelomere dysfunction has been linked to many aspects of the aging process. Increasing evidence indicates that telomere dysfunction leads to cardiac mitochondrial defects. Mammalian repressor activator protein 1 (Rap1) is one of the components of shelterin complex and essential for the maintenance of telomere length and structural integrity. Our preliminary work showed that aged Rap1 knockout (Rap1−/−) mice exhibited more pronounced aging‐associated phenotypes (including earlier hair graying, hair loss, reduced body weight). However, the effects of Rap1 on mitochondrial function and its contribution to cardiac aging are largely unknown. Thus, the present study investigated whether or not loss of Rap1 in mice precipitates cardiac aging and explored the underlying mechanisms.Methods and ResultsMice cardiac function was assessed with transthoracic echocardiography performed noninvasively using a Vevo 2100 high‐resolution imaging system. Deletion of Rap1 in mice aggravated aging‐related cardiac structural changes and dysfunction, as evidenced by increased left ventricular (LV) posterior wall end‐diastole and LV mass, reductions in ejection fraction and fractional shortening, as well as significantly reduced myocardial performance index (all p &lt; 0.05, Rap1−/− vs. age‐matched counterparts). These changes were associated with greater cardiac senescence (enhanced SA‐β‐gal staining), cardiac hypertrophy (enhanced wheat germ agglutinin staining and increased the ratio of heart weight with body weight), abnormalities in the mitochondrial ultrastructure (cristae fragmentation, vacuolization). Mechanistically, Rap1 deficiency led to shorter telomere (T/S ratio), enhanced DNA damage (γH2AX) and increased nuclear p53 level in vivo in the myocardium and in primary cardiomyocytes when compared to age‐matched counterparts (one year old). Chromatin immunoprecipitation revealed that p53 directly binded to the promote site of PPARα [a central regulator of cardiac fatty acid metabolism (FAM)] and repressed its expression. Rap1 deficiency impaired FAM (reduced CD36, CPT1α, ACADL level and palmitate‐induced oxygen consumption), while PFTα (a p53 inhibitor, i.p. 1.1 mg/kg/day) treatment in Rap1−/− mice significantly alleviated cardiac aging and enhanced FAM by restoration of PPARα.ConclusionsWith aging, Rap1 deficiency may lead to shorter telomere length, increase DNA damage and thereby activate p53, which in turn suppresses PPARα, leading to impaired FAM and mitochondrial defects with abnormal cardiac structure and dysfunction. These findings may identify a new cardiac dimension in the physiological role played by telomere‐Rap1.Support or Funding InformationThe authors’ work was supported by the General Research Fund (17123718M, Research Grants Council of Hong Kong).

Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling.

Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFβ) signalling pathway where inhibiting TGFβ signalling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes. Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGFβ signalling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFβ signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes. Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.

Therapeutic Targets in Telomerase and Telomere Biology of Cancers.

Telomeres play an important role to conserve genomic integrity by protecting the ends of chromosomes in normal cells. Since, their progressive shortening during successive cell division which lead to chromosomal instability. Notably, telomere length is perpetuated by telomerase in large majority of cancers, thereby ensure indefinite cell proliferation-a hallmark of cancer-and this unique feature has provided telomerase as the preferred target for drug development in cancer therapeutics. Cancer cells have acquired the potential to have telomere length maintenance by telomerase activation- up-regulation of hTERT gene expression in tumor cells is synchronized by multiple genetic and epigenetic modification mechanisms viz hTERT structural variants, hTERT promoter mutation and epigenetic modifications through hTERT promoter methylation which have been implicated in various cancers initiation and progression. In view of these facts, strategies have been made to target the underlining molecular mechanisms involved in telomerase reactivation as well as of telomere structure with special reference to distortion of sheltrin proteins. This review is focussed on extensive understanding of telomere and telomerase biology. which will provide indispensable informations for enhancing the efficiency of rational anticancer drug design. However, there is also an urgent need for better understanding of cell signalling pathways for alternative lengthening of telomere which is present in telomerase negative cancer for therapeutic targets.

Yeast Genome Maintenance by the Multifunctional PIF1 DNA Helicase Family.

The two PIF1 family helicases in Saccharomyces cerevisiae, Rrm3, and ScPif1, associate with thousands of sites throughout the genome where they perform overlapping and distinct roles in telomere length maintenance, replication through non-histone proteins and G4 structures, lagging strand replication, replication fork convergence, the repair of DNA double-strand break ends, and transposable element mobility. ScPif1 and its fission yeast homolog Pfh1 also localize to mitochondria where they protect mitochondrial genome integrity. In addition to yeast serving as a model system for the rapid functional evaluation of human Pif1 variants, yeast cells lacking Rrm3 have proven useful for elucidating the cellular response to replication fork pausing at endogenous sites. Here, we review the increasingly important cellular functions of the yeast PIF1 helicases in maintaining genome integrity, and highlight recent advances in our understanding of their roles in facilitating fork progression through replisome barriers, their functional interactions with DNA repair, and replication stress response pathways.

Association of dietary selenium intake with telomere length in middle-aged and older adults.

Growing evidence suggested that lifestyle factors including dietary habits may influence the telomere length which is a reliable marker of biological aging and predictor for chronic diseases. However, the role of dietary selenium intake in telomere length maintenance is rarely examined. We aimed to test the relationship between dietary selenium intake and telomere length among middle-aged and older adults in America. A total of 3194 United States adults older than 45 years old were extracted from the National Health and Nutrition Examination Survey (NHANES) in 1999-2000 and 2001-2002. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction (qPCR). Dietary selenium intake was assessed by a trained interviewer using 24-h dietary recall method. Generalized linear models were performed to evaluate the association of dietary selenium intake with telomere length. The restricted cubic spline analysis was used to further explore the nonlinear dose-response relationship between dietary selenium intake and telomere length. After adjusting potential confounders, every 20μg increase in dietary selenium intake was associated with 0.42% (95% CI: 0.02%, 0.82%) longer telomere length in all participants. In the subgroup analyses, dietary selenium intake was related to longer telomere length in females (Percentage change: 0.87%; 95% CI: 0.26%, 1.49%) and non-obese participants (Percentage change: 0.53%; 95% CI: 0.04%, 1.02%), but not in males (Percentage change: 0.04%; 95% CI:-0.49%, 0.57%) and obese participants (Percentage change: 0.21%; 95% CI:-0.47%, 0.91%). The restricted cubic spline analysis showed a linear association between dietary selenium intake and telomere length. This study indicated that the increased dietary selenium intake was associated with longer telomere length among middle-aged and older adults in America. These findings require further corroboration from future prospective studies.

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

BackgroundPrevious evidence suggests that plasma phospholipid fatty acids (PPFAs) and HOMA insulin resistance (HOMA-IR) are independently related to leukocyte telomere length (LTL). However, there is limited evidence of regarding the effect of their interaction on relative LTL (RLTL). Therefore, here, we aimed to determine the effect of the interaction between PPFAs and HOMA-IR on RLTL.MethodsWe conducted a cross-sectional study, involving a total of 1246 subjects aged 25–74 years. PPFAs and RLTL were measured, and HOMA-IR was calculated. The effect of the interaction between PPFAs and HOMA-IR on RLTL was assessed by univariate analysis, adjusting for potential confounders.ResultsIn age-adjusted analyses, multivariate linear regression revealed a significant association of the levels of elaidic acid, HOMA-IR, monounsaturated fatty acids (MUFA) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) with RLTL. After adjustment of age and gender, race, smoking, drinking, tea, and exercise, elaidic acid, and omega-3 (n-3) PUFA were negatively associated with RLTL, and HOMA-IR and n-6 PUFA were positively associated with RLTL. These associations were not significantly altered upon further adjustment for anthropometric and biochemical indicators. Meanwhile, the effect of the interaction of elaidic acid and HOMA-IR on RLTL was significant, and remained unchanged even after adjusting for the aforementioned potential confounders. Interestingly, individuals who had the lowest HOMA-IR and the highest elaidic acid levels presented the shortest RLTL.ConclusionsOur findings indicated that shorter RLTL was associated with lower HOMA-IR and higher elaidic acid level. These findings might open a new avenue for exploring the potential role of the interaction between elaidic acid and HOMA-IR in maintaining RLTL.

Telomere Length and Telomerase Activity in Immature Oocytes and Cumulus Cells of Women with Polycystic Ovary Syndrome.

Metaphase II oocytes (MII) from polycystic ovary syndrome (PCOS) frequently have impaired oocyte competence. Since telomere maintenance is important for folliculogenesis, oocyte maturation, and early embryonic development, we sought to verify the implications of PCOS on telomere length and telomerase activity in immature oocytes and cumulus cells. 43 PCOS and 67 control women were included, and anthropometric, biochemical, and hormonal characteristics were evaluated. The telomere length in germinal vesicle stage (GV) and in metaphase I (MI) oocytes, as well as in the cumulus cells of immature (CCI) and mature oocytes (CCM), and in leukocytes was measured by qPCR. The telomerase activity in reproductive cells was evaluated by the TRAPeze® XL Kit. The body mass index (p = 0.001), LH (p = 0.015), estradiol (p = 0.004), insulin (p = 0.002), testosterone (p < 0.0001), androstenedione (p = 0.001), free androgen index (p < 0.0001), and c-reactive protein (p = 0.003) were greater, while the FSH (p = 0.0002) was lower in the PCOS group. The telomere length in the CCI (p = 0.649) and CCM (p = 0.378) did not differ between the PCOS and the control groups. On the other hand, telomerase activity in the CCI (p = 0.003) and CCM (p = 0.022) was higher in the PCOS group. In the leukocyte's cells, the telomere length was reduced in the PCOS group (p = 0.025). In the GV and MI oocytes, no differences were observed in telomere length and telomerase activity between the groups. We showed that telomere length is not altered in reproductive cells from PCOS. However, higher telomerase activity in the CCI and CCM may be required for telomere length maintenance.