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hTERT gene therapies hold significant promise for treating age-related diseases. However, further research is required to address the challenges of delivery and ethical considerations. We hypothesized that exosomes derived from hTERT-immortalized cells could function similarly to hTERT gene therapies by maintaining telomere length and attenuating cellular senescence biomarkers. In this study, we overexpressed the hTERT gene in Human Foreskin Fibroblast-1 cells (HFF cells) to produce hTERT-immortalized HFF cells (hT-HFF cells). We then used exosomes derived from these hT-HFF cells to treat human fibroblasts, HFF cells. Our results demonstrated that these exosomes effectively attenuated biomarkers of cellular senescence in HFF cells. Furthermore, analysis revealed that hTERT mRNA was indeed packaged into the exosomes from hT-HFF cells. This mRNA was capable of elongating telomeres and delaying cellular senescence in HFF cells. Therefore, exosomes from hT-HFF cells show potential as a treatment for age-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The timing of organisms' senescence is developmentally programmed but also shaped by the interaction between environmental inputs and life-history traits. In ectotherms, ageing dynamics are still poorly understood even though their body temperature, metabolism, or growth trajectory are very sensitive to environmental changes. Here, we investigated the role of life-history traits such as age, sex, body size, body condition, and tail autotomy (i.e self-amputation) in shaping telomere length in six populations of the Algerian sand lizard (Psammodromus algirus) distributed along an elevational gradient from 300 to 2500 m above the sea level. Additionally, we compiled the available information on reptiles' telomere length in a review table. Our cross-sectional study shows that older lizards have longer telomeres, which might be mostly linked to the selective disappearance of individuals with shorter telomeres or, alternatively, mediated by a higher expression of telomerase across their life. In fact, variation in telomere length across elevation was explained by age structure of lizards; thus, in contrast to our predictions, altitude had no effect on telomere length in this study system. Telomere length was unaffected by tail regeneration and was sex-independent, but positively correlated with body condition, which might be linked to high somatic investment. Hence, our results suggest that life-history traits such as age or body condition can be major drivers of telomere dynamics for this species, whereas environmental conditions apparently had scarce or no effects on lizard telomeres. Our findings emphasize the relevance of understanding species' life histories for fully disentangling the causes and consequences of differences in ageing in ectotherms., Competing Interests: Declaration of competing interest No conflict of interest declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The present study aimed to examine associations of the testosterone/estradiol ratio, human leukocyte telomerase reverse transcriptase (hTERT) expression and telomerase activity of peripheral blood mononuclear cells (PBMCs) with aging and the presence of coronary artery disease (CAD). Telomeres in leukocytes are shorter in individuals with CAD than in healthy individuals of the same age. Levels of sex hormones are related to aging, and the ratio of testosterone to estradiol has been linked to CAD in men. Here we compared younger men (22 ± 2 yr, n = 26), middle-aged men (31 ± 5 yr, n = 35), older men without CAD (60 ± 10 yr, n = 30) and older men with CAD (63 ± 8 yr, n = 30) in terms of testosterone/estradiol ratio, leukocyte telomerase reverse transcriptase (hTERT) expression, activity of telomerase in peripheral blood mononuclear cells (PBMCs), and length of PBMC telomeres. Levels of hTERT mRNA of leukocyte and PBMC telomerase activity were significantly lower in older men than in younger or middle-aged men (p < 0.05). These two parameters, as well as testosterone/estradiol ratio, were significantly lower in older men with CAD than in all the other groups (p < 0.05). The sex hormone ratio correlated significantly with age, hTERT mRNA levels, PBMC telomerase activity and telomere length (p < 0.05). These results support the hypothesis that sex hormone balance is a biomarker of telomerase function, and that both of these parameters change as men age or develop CAD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Leukocyte telomere length (LTL), a biological marker of aging that is associated with age-related diseases, is longer in master endurance runners (ER) than age-matched controls, but the underlying mechanisms are poorly investigated. The LTL, nitric oxide (NO), and redox balance of ER master runners were analyzed and compared to untrained middle-aged and young adults. We hypothesized that NO and redox balance at baseline would be related to longer LTL in ER athletes. Participants (n = 38) were long-term ER runners (n = 10; 51.6 ± 5.2 yrs.; 28.4 ± 9.4 yrs. of experience) and untrained age-matched (n = 17; 46.6 ± 7.1 yrs) and young controls (n = 11; 21.8 ± 4.0 yrs). Volunteers were assessed for anamnesis, anthropometrics, and blood sampling. Measurements of pro-and anti-oxidant status and DNA extraction were performed using commercial kits. Relative LTL was determined with qPCR analyses (T/S). While the middle-aged controls had shorter LTL than the young group, no difference was observed between ER athletes and young participants. A large effect size between the LTL of ER athletes and middle-aged controls (d = 0.85) was also observed. The ER athletes and untrained young group had better redox balance according to antioxidant/pro-oxidant ratios compared to middle-aged untrained participants, which also had lower values for redox parameters (TEAC/TBARS, SOD/TBARS, and CAT/TBARS; all p < 0.05). Furthermore, the NO level of ER athletes (175.2 ± 31.9 μM) was higher (p < 0.05) than middle-aged controls (67.2 ± 23.3 μM) and young participants (129.2 ± 17.3 μM), with a significant correlation with LTL (r = 0.766; p = 0.02). In conclusion, ER runners have longer LTL than age-matched controls, which in turn may be related to better NO bioavailability and redox balance status., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Telomeres, the terminal nucleoprotein structures of eukaryotic chromosomes, play pleiotropic functions in cellular and organismal aging. Telomere length (TL) varies throughout life due to the influence of genetic factors and to a complex balancing between "shortening" and "elongation" signals. Telomerase, the only enzyme that can elongate a telomeric DNA chain, and telomeric repeat-containing RNA (TERRA), a long non-coding RNA involved in looping maintenance, play key roles in TL during life. Despite recent advances in the knowledge of TL, TERRA and telomerase activity (TA) biology and their measurement techniques, the experimental and theoretical issues involved raise a number of problems that should carefully be considered by researchers approaching the "telomere world". The increasing use of such parameters - hailed as promising clinically relevant biomarkers - has failed to be paralleled by the development of automated and standardized measurement technology. Consequently, associating given TL values to specific pathological conditions involves on the one hand technological issues and on the other clinical-biological issues related to the planning of clinically relevant association studies. Addressing these issues would help avoid major biases in association studies involving TL and a number of outcomes, especially those focusing on psychological and bio-behavioral variables. The main challenge in telomere research is the development of accurate and reliable measurement methods to achieve simple and sensitive TL, TERRA, and TA detection. The discovery of the localization of telomeres and TERRA in cellular and extracellular compartments had added an additional layer of complexity to the measurement of these age-related biomarkers. Since combined analysis of TL, TERRA and TA may well provide more exhaustive clinical information than a single parameter, we feel it is important for researchers in the various fields to become familiar with their most common measurement techniques and to be aware of the respective merits and drawbacks of these approaches., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Telomere attrition is associated with increased morbidity and mortality of various age-related diseases. Reports of association between telomere length (TL) and all-cause mortality remain inconsistent. In the present study, a meta-analysis was performed using published cohort studies and un-published data from the Swedish Twin Registry (STR). Twenty-five studies were included: four STR cohorts (12,083 individuals with 2517 deaths) and 21 published studies. In the STR studies, one standard deviation (SD) decrement of leukocyte TL corresponded to 13% increased all-cause mortality risk (95% confidence interval [CI]: 7%-19%); individuals in the shortest TL quarter had 44% higher hazard (95% CI: 27%-63%) than those in the longest quarter. Meta-analysis of all eligible studies (121,749 individuals with 21,763 deaths) revealed one SD TL decrement-associated hazard ratio of 1.09 (95% CI: 1.06-1.13); those in the shortest TL quarter had 26% higher hazard (95% CI: 15%-38%) compared to the longest quarter, although between-study heterogeneity was observed. Analyses stratified by age indicated that the hazard ratio was smaller in individuals over 80 years old. In summary, short telomeres are associated with increased all-cause mortality risk in the general population. However, TL measurement techniques and age at measurement contribute to the heterogeneity of effect estimation., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To examine the association between telomere length and neurodevelopment in children., Methods: We examined the relationship between relative telomere length (rTL) and neurodevelopmental outcomes at 9 and 30 months, and 5 years of age in children enrolled in the Seychelles Child Development Study Nutrition Cohort 1 (NC1). Relative telomere length was measured in cord blood and in child blood at age five. Multivariable linear regression examined associations between neurodevelopmental outcomes and rTL adjusting for relevant covariates., Results: Mean rTL was 1.18 at birth and 0.71 at age five. Increased cord blood rTL was associated with better scores on two neurodevelopmental tests, the psychomotor developmental index (β = 4.01; 95% confidence interval (CI) = 0.17, 7.85) at age 30 months, and the Woodcock Johnson test of achievement letter-word score (β = 2.88; CI = 1.21-4.56) at age five. The Woodcock Johnson test of achievement letter-word score remained statistically significant after two outliers were excluded (β = 2.83; CI = 0.69, 4.97); the psychomotor developmental index did not (β = 3.62; CI = -1.28, 8.52). None of the neurodevelopmental outcomes at age five were associated with five-year rTL., Conclusion: Although increased cord blood rTL was associated with better test scores for a few neurodevelopmental outcomes, this study found little consistent evidence of an association between rTL and neurodevelopment. Future studies with a larger sample size, longer follow-up, and other relevant biological markers (e.g. oxidative stress) are needed to clarify the role of rTL in neurodevelopment and its relevance as a potential surrogate measure for oxidative stress in the field of developmental neurotoxicity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sirtuin 6 (SIRT6) is a member of the sirtuin family NAD + -dependent deacetylases with multiple roles in controlling organism homeostasis, lifespan, and diseases. Due to its complex and opposite functional roles, this sirtuin is considered a two-edged sword in health and disease. Indeed, SIRT6 improves longevity, similarly to the founding yeast member, silent information regulator-2 (Sir2), and modulates genome stability, telomere integrity, transcription, and DNA repair. Its deficiency is associated with chronic inflammation, diabetes, cardiac hypertrophy, obesity, liver dysfunction, muscle/adipocyte disorders, and cancer. Besides, pieces of evidence showed that SIRT6 is a promoter of specific oncogenic pathways, thus disclosing its dual role regarding cancer development. Collectively, these findings suggest that multiple mechanisms, to date not entirely known, underlie the intriguing roles of SIRT6. Here we provide an overview of the current molecular mechanisms through which SIRT6 controls cancer and heart diseases, and describe its recent implications in the atherosclerotic plaque development., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Several monogenic inherited diseases that display features of human premature aging correlate with shortened telomeres, and are referred to collectively as telomeropathies. These disorders have overlapping symptoms and a common underlying mechanism of telomere dysfunction, but also exhibit variable symptoms and age of onset, suggesting they fall along a spectrum of disorders. Primary telomeropathies are caused by defects in the telomere maintenance machinery, whereas secondary telomeropathies have some overlapping symptoms with primary telomeropathies, but are generally caused by mutations in DNA repair proteins that contribute to telomere preservation. Here we review both the primary and secondary telomeropathies, discuss potential mechanisms for tissue specificity and age of onset, and highlight outstanding questions in the field and future directions toward elucidating disease etiology and developing therapeutic strategies., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Previous studies linking telomere length (TL) and health have been largely associational. We apply genetic instrumental variables (IV) analysis, also known as Mendelian randomization, to test the hypothesis that shorter TL leads to poorer health. This method reduces bias from reverse causation or confounding., Methods: We used two approaches in this study that rely on two separate data sources: (1) individual-level data from the Health and Retirement Study (HRS) (N=3734), and (2) coefficients from genome-wide association studies (GWAS). We employed two-sample genetic IV analyses, constructing a polygenic risk score (PRS) of TL-associated single nucleotide polymorphisms. The first approach examined the association of the PRS with nine individual health outcomes in HRS. The second approach took advantage of estimates available in GWAS databases to estimate the impact of TL on five health outcomes using an inverse variance-weighted meta-analytic technique., Results: Using individual-level data, shorter TL was marginally statistically significantly associated with decreased risk of stroke and increased risk of heart disease. Using the meta-analytic approach, shorter TL was associated with increased risk of coronary artery disease (OR 1.02 per 100 base pairs, 95%CI: 1.00, 1.03)., Discussion: With the exception of a small contribution to heart disease, our findings suggest that TL may be a marker of disease rather than a cause. They also demonstrate the utility of the inverse variance-weighted meta-analytic approach when examining small effect sizes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Our aim was to examine whether chronic social stress is associated with telomere length throughout the life course, following our protocol published in 2014. Structured searches were conducted in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and grey from their start date onwards. Reference lists of retrieved citations were hand searched for relevant studies. Eighteen studies published until May 1, 2015 investigating the association between chronic social stress (as defined by poverty, exposure to violence, or family caregiving) and telomere length in healthy or diseased adults and children were independently selected by 2 reviewers. Sixteen of those studies were cross-sectional and two had a longitudinal design. Studies differed in type of stress exposure, method to measure telomere length and cell type. As meta-analysis could not be conducted, the data were synthesized as a narrative review. Based on this comprehensive review, chronic social stress accompanies telomere shortening in both early and adult exposures, with most eligible studies showing a significant relationship. We discuss the significance of chronic stress of social origin and the potential for social interventions through public policies and we recommend methodological improvements that would allow for future meta-analysis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aging is the universal, intrinsic, genetically-controlled, evolutionarily-conserved and time-dependent intricate biological process characterised by the cumulative decline in the physiological functions and their coordination in an organism after the attainment of adulthood resulting in the imbalance of neurological, immunological and metabolic functions of the body. Various biological processes and mechanisms along with altered levels of mRNAs and proteins have been reported to be involved in the progression of aging. It is one of the major risk factors in the patho-physiology of various diseases and disorders. Recently, the discovery of pervasive transcription of a vast pool of heterogeneous regulatory noncoding RNAs (ncRNAs), including small ncRNAs (sncRNAs) and long ncRNAs (lncRNAs), in the mammalian genome have provided an alternative way to study and explore the missing links in the aging process, its mechanism(s) and related diseases in a whole new dimension. The involvement of small noncoding RNAs in aging and age-related diseases have been extensively studied and recently reviewed. However, lncRNAs, whose function is far less explored in relation to aging, have emerged as a class of major regulators of genomic functions. Here, we have described some examples of known as well as novel lncRNAs that have been implicated in the progression of the aging process and age-related diseases. This may further stimulate research on noncoding RNAs and the aging process., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Multiple studies have demonstrated that telomere length predicts mortality and that telomeres shorten with age. Although rarely acknowledged these associations do not dictate causality. I review telomerase knockout and overexpression studies and find little support that telomeres cause aging. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress., (Copyright © 2015 The Author. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Leukocyte telomere length (LTL) shortens with age and short LTL has been associated with increased mortality and increased risk for some age-related outcomes. This study aims to analyse the associations of smoking habits with LTL and rate of LTL change per year in older adults., Methods: LTL was measured by quantitative PCR at baseline in 3600 older adults, who were enrolled in a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Terminal Restriction Fragment analysis was additionally performed in a sub-sample to obtain absolute LTL in base pairs. Multivariate linear regression models were used to estimate associations of smoking habits with baseline LTL and changes in LTL over time., Results: LTL was inversely associated with age (r=-0.090, p<0.0001). Women had longer LTL than men (p<0.0001). Smoking was inversely associated with LTL. On average, current smokers had 73 base pairs (BP) shorter LTL compared to never smokers. Smoking intensity and pack-years of smoking were also inversely associated with LTL, and a positive association was observed with years since smoking cessation. Slower LTL attrition rates were observed in ever smokers over 8years of follow-up., Conclusions: Our cross-sectional analysis supports suggestions that smoking might contribute to shortening of LTL but this relationship could not be shown longitudinally. The overall rather small effect sizes observed for smoking-related variables suggest that LTL reflects smoking-related health hazards only to a very limited extent., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of this systematic review is to assess the effects of exercise on telomeres length. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Scopus, LILACS, SPORTDiscus and Web of Science from inception to August 2014. All articles that assessed the effects of exercise in telomere length were included in this review. The search strategy used the following combinations of terms: telomere AND "motor activity" OR exercise OR "physical activity". Two reviewers, working independently, screened all titles and abstracts to identify studies that could meet inclusion criteria. Whenever possible, and if appropriate, we performed a random-effect meta-analysis of study outcomes. Thirty-seven original studies were included in this systematic review, including 41,230 participants. Twenty articles did not find statistically significant association, whereas 15 described a positive association. Two papers found an inverted "U" correlation. There is a tendency toward demonstrating an effect of exercise on telomere length. Few prospective studies were found, many studies did not reach statistical significance and there was an important methodological diversity. For this reason, a possible significant association between physical activity and telomere length remains an open question., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The shortening of telomeres as a causative factor in ageing is a widely discussed hypothesis in ageing research. The study of telomere length and its regenerating enzyme telomerase in the longest-lived non-colonial animal on earth, Arctica islandica, should inform whether the maintenance of telomere length plays a role in reaching the extreme maximum lifespan (MLSP) of >500years in this species. Since longitudinal measurements on living animals cannot be achieved, a cross-sectional analysis of a short-lived (MLSP 40years from the Baltic Sea) and a long-lived population (MLSP 226years Northeast of Iceland) and in different tissues of young and old animals from the Irish Sea was performed. A high heterogeneity of telomere length was observed in investigated A. islandica over a wide age range (10-36years for the Baltic Sea, 11-194years for Irish Sea, 6-226years for Iceland). Constant telomerase activity and telomere lengths were detected at any age and in different tissues; neither correlated with age or population habitat. Stable telomere maintenance might contribute to the long lifespan of A. islandica. Telomere dynamics are no explanation for the distinct MLSPs of the examined populations and thus the cause of it remains to be investigated., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The specific processes that cause aging of the cardiac tissue remain elusive. C57BL/6 (B6) mice are commonly used for investigating age-related diseases in mammals. We thus sought to evaluate the cardiac aging process in B6 mice. Cardiac tissues from the newborn (B6 NB), 2month-old (B6 2M) and 21-27month-old B6 mice (B6 aged) were used for the investigation. Several age-related cellular processes were evaluated, including telomere shortening, changes in p53 and p16 expression, changes in mitochondria DNA expression and DNA deletion, and alteration of mitochondria. We found that the aging of the B6 mice cardiac tissue is associated with the maintenance of telomere length, increased expression of p53 and p16, mild changes in mitochondrial DNA expression but widespread DNA deletion, and significant alterations of the mitochondrial ultrastructure within the cardiac tissue. The results of our studies suggest that mitochondrial DNA deletions, which affect the mitochondrial ultrastructure, cytochrome C oxidase activity, and p53 expression, are significantly associated with cardiac aging and may be a source of age-related heart failure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To provide a systematic review of the relationship between age and leukocyte telomere length (LTL) in adults., Methods: Relevant studies were identified by a systematic search of Medline, EMBASE and ISI Web of Knowledge databases. Key data, such as age and LTL, were extracted from the studies along with correlation coefficients and yearly attrition rates where available. Obtained data were used to calculate weighted means and correlation coefficients., Results: Overall, 124 cross-sectional studies and 5 longitudinal studies were identified. A statistically significant inverse correlation between mean age and mean LTL across cross-sectional studies was observed for both absolute (r=-0.338, p<0.0001) and relative LTL (r=-0.295, p=0.0088). From mean LTL and ages, a yearly telomere loss of 24.7 base pairs (BP)/year was estimated by weighted linear regression. Weighted means of within study correlation of age and TL and yearly telomere loss rate estimates from cross-sectional studies were also in a similar order of magnitude (-0.380 and 21.91 BP/year). The few longitudinal studies reported somewhat higher mean telomere loss rates (between 32.2 and 45.5 BP/year)., Conclusion: While a decrease of LTL with age is out of question, data on variation of the decrease according to sex, age and other potential determinants especially from longitudinal data are still sparse., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Physical activity has been associated with alterations in telomere length, a potential indicator of biological aging, but several inconsistencies exist. Our aim was to investigate the associations between physical activity in midlife and leukocyte telomere length (LTL) measured in old age in the Helsinki Businessmen Study, Finland. At entry, in 1974, 782 men (mean age 47) completed a questionnaire about their physical activity and this was collapsed into 3 categories: low (n=148), moderate (n=398) and high physical activity (n=236, 7 of whom had a competitive activity level). After 29-year follow-up in 2003, mean LTL and the proportion of short (<5 kB) telomeres were measured from DNA samples of a random subcohort of survivors (n=204, mean age 76) using the Southern blot technique. Adjusted for age, body mass index (BMI), cholesterol and smoking in 1974, the moderate physical activity group had longer mean LTL (8.27 kB, SE 0.05) than the low (8.10 kB, SE 0.07), or high (8.10 kB, SE 0.05) physical activity groups (P=0.03 between groups). Conversely, the proportion of short telomeres was lowest in the moderate physical activity group (11.35%, SE 0.25), and higher in the high (12.39%, SE 0.29), and the low physical activity (12.21%, SE 0.39) groups (P=0.02 between groups). We conclude that the results of this observational cohort study give support to the idea that both low and high physical activity is in the long-term associated with factors shortening LTL., (Copyright © 2012 Elsevier Inc. All rights reserved.)