Age at maturation has sex- and temperature-specific effects on telomere length in a fish

Telomeres are highly conserved nucleoprotein structures which protect genome integrity. The length of telomeres is influenced by both genetic and environmental factors, but relatively little is known about how different hereditary and environmental factors interact in determining telomere length. We manipulated growth rates and timing of maturation by exposing full-sib nine-spined sticklebacks (Pungitius pungitius) to two different temperature treatments and quantified the effects of temperature treatments, sex, timing of maturation, growth rate and family (genetic influences) on telomere length. We did not find the overall effect of temperature treatment on the relative telomere length. However, we found that variation in telomere length was related to timing of maturation in a sex- and temperature-dependent manner. Telomere length was negatively related to age at maturation in elevated temperature and early maturing males and females differed in telomere length. Variation in growth rate did not explain any variation in telomere length. The broad sense heritability (h ²) of telomere length was estimated at h ² = 0.31 ? 0.47, suggesting predominance of environmental over genetic determinants of telomere length variability. This study provides the first evidence that age at maturation together with factors associated with it are influencing telomere length in an ectotherm. Future studies are encouraged to identify the extent to which these results can be replicated in other ectotherms.     

Shared environmental factors associated with telomere length maintenance in elderly male twins

During aging, chromosome ends, or telomeres, gradually erode or shorten with each somatic cell division. Loss of telomere length homeostasis has been linked to age-related disease. Remarkably, specific environmental assaults, both physical and psychological, have been shown to correlate with shortened telomeres. However, the extent that genetic and/or environmental factors may influence telomere length during later stages of lifespan is not known. Telomere length was measured in 686 male US World War II and Korean War veteran monozygotic (MZ) and dizygotic (DZ) twins (including 181 MZ and 125 DZ complete pairs) with a mean age of 77.5 years (range 73-85 years). During the entire process of telomere length measurement, participant age and twin status were completely blinded. White blood cell mean telomere length shortened in this elderly population by 71 base pairs per year (P < 0.0001). We observed no evidence of heritable effects in this elderly population on telomere length maintenance, but rather find that telomere length was largely associated with shared environmental factors (P < 0.0001). Additionally, we found that individuals with hypertension and cardiovascular disease had significantly shorter telomeres (P = 0.0025 and 0.002, respectively). Our results emphasize that shared environmental factors can have a primary impact on telomere length maintenance in elderly humans.     

Telomere length analysis in residents of a community exposed to arsenic

Differentiated cells telomere length is an indicator of senescence or lifespan; however, in peripheral blood leukocytes the relative shortening of the telomere has been considered as a biological marker of aging, and lengthening telomere as an associated risk to cancer. Individual’s age, type of tissue, lifestyle, and environmental factors make telomere length variable. The presence of environmental carcinogens such as arsenic (As) influence as causal agents of these alterations, the main modes of action for As described are oxidative stress, reduction in DNA repair capacity, overexpression of genes, alteration of telomerase activity, and damage to telomeres. The telomeres of leukocytes resulting a finite capacity of replication due to the low or no activity of the telomerase enzyme, therefore, elongation telomere in this kind of cells is a potential biological marker associated with the development of chronic diseases and carcinogenesis.     

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

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

Telomere length predicts survival independent of genetic influences

Telomeres prevent the loss of coding genetic material during chromosomal replication. Previous research suggests that shorter telomere length may be associated with lower survival. Because genetic factors are important for individual differences in both telomere length and mortality, this association could reflect genetic or environmental pleiotropy rather than a direct biological effect of telomeres. We demonstrate through within-pair analyses of Swedish twins that telomere length at advanced age is a biomarker that predicts survival beyond the impact of early familial environment and genetic factors in common with telomere length and mortality. Twins with the shortest telomeres had a three times greater risk of death during the follow-up period than their co-twins with the longest telomere measurements [hazard ratio (RR) = 2.8, 95% confidence interval 1.1–7.3, P  = 0.03].     

Increased telomere size in sperm cells of mammals with long terminal (TTAGGG)n arrays

An increase in the length of telomeres in human sperm compared to somatic cells has long been noted and considered within a popular hypothesis involving telomere shortening and cell aging. In the present study we determined telomere length in two species with long terminal TTAGGG arrays—bovine and porcine. Using several independent methods we demonstrate that the telomeres in the sperm of human, porcine and bovine are elongated by 69%, 24%, and 14%, respectively, in comparison with somatic tissues. Therefore, increased sperm telomere length is a feature preserved throughout mammalian evolution. The biological role of this phenomenon is discussed in the context of telomere functions in meiosis and fertilization. Mol. Reprod. Dev. 51:98–104, 1998.© 1998 Wiley-Liss, Inc.     

Telomere Length Profiles in Humans: All Ends are Not Equal

Telomere length is an important parameter of telomere function since it determines number of aspects controlling chromosome stability and cell division. Since telomeres shorten with age in humans and premature aging syndromes are often associated with the presence of short telomeres, it has been proposed that telomere length is also an important parameter for organismal aging. How mean telomere lengths are determined in humans remains puzzling, but it is clear that genetic and epigenetic factors appear to be of great importance. Experimental evidence obtained from many different organisms has provided the basis for a widely accepted counting mechanism based on a negative feedback loop for telomerase activity at the level of individual telomeres. In addition, recent studies in both normal and pathological contexts point to the existence of chromosome-specific mechanisms of telomere length regulation determining a telomere length profile, which is inherited and maintained throughout life. In this review, we recapitulate the available data, propose a synthetic view of telomere length control mechanisms in humans and suggest new approaches to test current hypotheses.     

Sex‐specific telomere length and dynamics in relation to age and reproductive success in Cory’s shearwaters

Individuals in free‐living animal populations generally differ substantially in reproductive success, lifespan and other fitness‐related traits, but the molecular mechanisms underlying this variation are poorly understood. Telomere length and dynamics are candidate traits explaining this variation, as long telomeres predict a higher survival probability and telomere loss has been shown to reflect experienced “life stress.” However, telomere dynamics among very long‐lived species are unresolved. Additionally, it is generally not well understood how telomeres relate to reproductive success or sex. We measured telomere length and dynamics in erythrocytes to assess their relationship to age, sex and reproduction in Cory's shearwaters (Calonectris borealis), a long‐lived seabird, in the context of a long‐term study. Adult males had on average 231 bp longer telomeres than females, independent of age. In females, telomere length changed relatively little with age, whereas male telomere length declined significantly. Telomere shortening within males from one year to the next was three times higher than the interannual shortening rate based on cross‐sectional data of males. Past long‐term reproductive success was sex‐specifically reflected in age‐corrected telomere length: males with on average high fledgling production were characterized by shorter telomeres, whereas successful females had longer telomeres, and we discuss hypotheses that may explain this contrast. In conclusion, telomere length and dynamics in relation to age and reproduction are sex‐dependent in Cory's shearwaters and these findings contribute to our understanding of what characterises individual variation in fitness.     

Work-related exhaustion and telomere length: a population-based study

Background

Psychological stress is suggested to accelerate the rate of biological aging. We investigated whether work-related exhaustion, an indicator of prolonged work stress, is associated with accelerated biological aging, as indicated by shorter leukocyte telomeres, that is, the DNA-protein complexes that cap chromosomal ends in cells.

Methods

We used data from a representative sample of the Finnish working-age population, the Health 2000 Study. Our sample consisted of 2911 men and women aged 30–64. Work-related exhaustion was assessed using the Maslach Burnout Inventory - General Survey. We determined relative leukocyte telomere length using a quantitative real-time polymerase chain reaction (PCR) -based method.

Results

After adjustment for age and sex, individuals with severe exhaustion had leukocyte telomeres on average 0.043 relative units shorter (standard error of the mean 0.016) than those with no exhaustion (p = 0.009). The association between exhaustion and relative telomere length remained significant after additional adjustment for marital and socioeconomic status, smoking, body mass index, and morbidities (adjusted difference 0.044 relative units, standard error of the mean 0.017, p = 0.008).

Conclusions

These data suggest that work-related exhaustion is related to the acceleration of the rate of biological aging. This hypothesis awaits confirmation in a prospective study measuring changes in relative telomere length over time.     

Telomere length is independently associated with age,oxidative biomarkers,and sport training in skeletal muscle of healthy adult males

In skeletal muscle, which mainly contains postmitotic myonuclei, it has been suggested that telomere length remains roughly constant throughout adult life, or shortens in response to physiopathological conditions in muscle diseases or in the elderly. However, telomere length results from both the replicative history of a specific tissue and the exposure to environmental, DNA damage-related factors, therefore the predictive biological significance of telomere measures should combine the analysis of the various interactive factors. In the present study, we analysed any relationship between telomere length [mean and minimum terminal restriction fragment (TRF) length] chronological age, oxidative damage (4-HNE, protein carbonyls), catalase activity, and heat shock proteins expression (αB-crystallin, Hsp27, Hsp90) in semitendinous muscle biopsies of 26 healthy adult males between 20 and 50 years of age, also exploring the influence of regular exercise participation. The multiple linear regression analysis identified age, 4-HNE, catalase, and training status as significant independent variables associated with telomere length and jointly accounting for ～30–36% of interindividual variation in mean and/or minimum TRF length. No association has been identified between telomere length and protein carbonyl, αB-crystallin, Hsp27, and Hsp90, as well as between age and the variables related to stress response. Our results showed that skeletal muscle from healthy adults displays an age-dependent telomere attrition and that oxidised environment plays an age-independent contribution, partially influenced by exercise training.     

Sex-specific telomere length profiles and age-dependent erosion dynamics of individual chromosome arms in humans

During aging, telomeres are gradually shortened, eventually leading to cellular senescence. By T/C-FISH (telomere/centromere-FISH), we investigated human telomere length differences on single chromosome arms of 205 individuals in different age groups and sexes. For all chromosome arms, we found a linear correlation between telomere length and donor age. Generally, males had shorter telomeres and higher attrition rates. Every chromosome arm had its individual age-specific telomere length and erosion pattern, resulting in an unexpected heterogeneity in chromosome-specific regression lines. This differential erosion pattern, however, does not seem to be accidental, since we found a correlation between average telomere length of single chromosome arms in newborns and their annual attrition rate. Apart from the above-mentioned sex-specific discrepancies, chromosome arm-specific telomere lengths were strikingly similar in men and women. This implies a mechanism that arm specifically regulates the telomere length independent of gender, thus leading to interchromosomal telomere variations.     

Telomere regulation: lessons learnt from mice and men,potential opportunities in horses

Telomeres are genetically conserved nucleoprotein complexes located at the ends of chromosomes that preserve genomic stability. In large mammals, somatic cell telomeres shorten with age, owing to the end replication problem and lack of telomere-lengthening events (e.g. telomerase and ALT activity). Therefore, telomere length reflects cellular replicative reserve and mitotic potential. Environmental insults can accelerate telomere attrition in response to cell division and DNA damage. As such, telomere shortening is considered one of the major hallmarks of ageing. Much effort has been dedicated to understanding the environmental perturbations that accelerate telomere attrition and therapeutic strategies to preserve or extend telomeres. As telomere dynamics seem to reflect cumulative cellular stress, telomere length could serve as a biomarker of animal welfare. The assessment of telomere dynamics (i.e. rate of shortening) in conjunction with telomere-regulating genes and telomerase activity in racehorses could monitor long-term animal health, yet it could also provide some unique opportunities to address particular limitations with the use of other animal models in telomere research. Considering the ongoing efforts to optimise the health and welfare of equine athletes, the purpose of this review is to discuss the potential utility of assessing telomere length in Thoroughbred racehorses. A brief review of telomere biology in large and small mammals will be provided, followed by discussion on the biological implications of telomere length and environmental (e.g. lifestyle) factors that accelerate or attenuate telomere attrition. Finally, the utility of quantifying telomere dynamics in horses will be offered with directions for future research.     

Social Isolation Shortens Telomeres in African Grey Parrots (Psittacus erithacus erithacus)

Telomeres, the caps of eukaryotic chromosomes, control chromosome stability and cellular senescence, but aging and exposure to chronic stress are suspected to cause attrition of telomere length. We investigated the effect of social isolation on telomere length in the highly social and intelligent African Grey parrot (Psittacus erithacus erithacus). Our study population consisted of single-housed (n = 26) and pair-housed (n = 19) captive individuals between 0.75 to 45 years of age. Relative telomere length of erythrocyte DNA was measured by quantitative real-time PCR. We found that telomere length declined with age (p<0.001), and socially isolated parrots had significantly shorter telomeres compared to pair-housed birds (p<0.001) – even among birds of similar ages. Our findings provide the first evidence that social isolation affects telomere length, which supports the hypothesis that telomeres provide a biomarker indicating exposure to chronic stress.     

Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings

Background

Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.

Methodology

Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.

Principal Findings

The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years'' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).

Conclusions

These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.     

Interactions between parental traits,environmental harshness and growth rate in determining telomere length in wild juvenile salmon

A larger body size confers many benefits, such as increased reproductive success, ability to evade predators and increased competitive ability and social status. However, individuals rarely maximize their growth rates, suggesting that this carries costs. One such cost could be faster attrition of the telomeres that cap the ends of eukaryotic chromosomes and play an important role in chromosome protection. A relatively short telomere length is indicative of poor biological state, including poorer tissue and organ performance, reduced potential longevity and increased disease susceptibility. Telomere loss during growth may also be accelerated by environmental factors, but these have rarely been subjected to experimental manipulation in the natural environment. Using a wild system involving experimental manipulations of juvenile Atlantic salmon Salmo salar in Scottish streams, we found that telomere length in juvenile fish was influenced by parental traits and by direct environmental effects. We found that faster‐growing fish had shorter telomeres and there was a greater cost (in terms of reduced telomere length) if the growth occurred in a harsher environment. We also found a positive association between offspring telomere length and the growth history of their fathers (but not mothers), represented by the number of years fathers had spent at sea. This suggests that there may be long‐term consequences of growth conditions and parental life history for individual longevity.     

Chinese hamster telomeres are comparable in size to mouse telomeres.

We report here the results of a telomere length analysis in four male Chinese hamsters by quantitative fluorescence in situ hybridization (Q-FISH). We were able to measure telomere length of 64 (73%) of 88 Chinese hamster telomeres. We could not measure telomere length in chromosome 10 or in the short arms of chromosomes 5, 6, 7 and 8 because of the overlaps between the interstitial and terminal telomeric signals. Our analysis in the 73% of Chinese hamster telomeres indicate that their average length is approximately 38 kb. Therefore, Chinese hamster telomeres are comparable in length to mouse telomeres, but are much longer than human telomeres. Similar to previous Q-FISH studies on human and mouse chromosomes, our results indicate that individual Chinese hamster chromosomes may have specific telomere lengths, suggesting that chromosome-specific factors may be involved in telomere length regulation.     

Inheritance of telomere length in a bird

Telomere dynamics are intensively studied in human ageing research and epidemiology, with many correlations reported between telomere length and age-related diseases, cancer and death. While telomere length is influenced by environmental factors there is also good evidence for a strong heritable component. In human, the mode of telomere length inheritance appears to be paternal and telomere length differs between sexes, with females having longer telomeres than males. Genetic factors, e.g. sex chromosomal inactivation, and non-genetic factors, e.g. antioxidant properties of oestrogen, have been suggested as possible explanations for these sex-specific telomere inheritance and telomere length differences. To test the influence of sex chromosomes on telomere length, we investigated inheritance and sex-specificity of telomere length in a bird species, the kakapo (Strigops habroptilus), in which females are the heterogametic sex (ZW) and males are the homogametic (ZZ) sex. We found that, contrary to findings in humans, telomere length was maternally inherited and also longer in males. These results argue against an effect of sex hormones on telomere length and suggest that factors associated with heterogamy may play a role in telomere inheritance and sex-specific differences in telomere length.     

Short Telomeres are Sufficient to Cause the Degenerative Defects Associated with Aging

Telomerase function is critical for telomere maintenance. Mutations in telomerase components lead to telomere shortening and progressive bone marrow failure in the premature aging syndrome dyskeratosis congenita. Short telomeres are also acquired with aging, yet the role that they play in mediating age-related disease is not fully known. We generated wild-type mice that have short telomeres. In these mice, we identified hematopoietic and immune defects that resembled those present in dyskeratosis congenita patients. When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wild-type mice with short telomeres still displayed degenerative defects. Our findings implicate telomere length as a unique heritable trait that, when short, is sufficient to mediate the degenerative defects of aging, even when telomerase is wild-type.     

Biological clocks as age estimation markers in animals: a systematic review and meta-analysis

Various biological attributes associated with individual fitness in animals change predictably over the lifespan of an organism. Therefore, the study of animal ecology and the work of conservationists frequently relies upon the ability to assign animals to functionally relevant age classes to model population fitness. Several approaches have been applied to determining individual age and, while these methods have proved useful, they are not without limitations and often lack standardisation or are only applicable to specific species. For these reasons, scientists have explored the potential use of biological clocks towards creating a universal age-determination method. Two biological clocks, tooth layer annulation and otolith layering have found universal appeal. Both methods are highly invasive and most appropriate for post-mortem age-at-death estimation. More recently, attributes of cellular ageing previously explored in humans have been adapted to studying ageing in animals for the use of less-invasive molecular methods for determining age. Here, we review two such methods, assessment of methylation and telomere length, describing (i) what they are, (ii) how they change with age, and providing (iii) a summary and meta-analysis of studies that have explored their utility in animal age determination. We found that both attributes have been studied across multiple vertebrate classes, however, telomere studies were used before methylation studies and telomere length has been modelled in nearly twice as many studies. Telomere length studies included in the review often related changes to stress responses and illustrated that telomere length is sensitive to environmental and social stressors and, in the absence of repair mechanisms such as telomerase or alternative lengthening modes, lacks the ability to recover. Methylation studies, however, while also detecting sensitivity to stressors and toxins, illustrated the ability to recover from such stresses after a period of accelerated ageing, likely due to constitutive expression or reactivation of repair enzymes such as DNA methyl transferases. We also found that both studied attributes have parentally heritable features, but the mode of inheritance differs among taxa and may relate to heterogamy. Our meta-analysis included more than 40 species in common for methylation and telomere length, although both analyses included at least 60 age-estimation models. We found that methylation outperforms telomere length in terms of predictive power evidenced from effect sizes (more than double that observed for telomeres) and smaller prediction intervals. Both methods produced age correlation models using similar sample sizes and were able to classify individuals into young, middle, or old age classes with high accuracy. Our review and meta-analysis illustrate that both methods are well suited to studying age in animals and do not suffer significantly from variation due to differences in the lifespan of the species, genome size, karyotype, or tissue type but rather that quantitative method, patterns of inheritance, and environmental factors should be the main considerations. Thus, provided that complex factors affecting the measured trait can be accounted for, both methylation and telomere length are promising targets to develop as biomarkers for age determination in animals.     

Investigating how telomere dynamics,growth and life history covary along an elevation gradient in two passerine species

Telomeres are specialized non‐coding DNA sequences that cap the end of chromosomes and protect genome integrity. Because telomeres shorten during development and their length at maturity is often associated with survival, one hypothesis is that telomere erosion during early growth is closely associated with life history trajectories of individuals and species. Elevation gradients lead to systematic changes in environmental factors, and thus they provide unique opportunities to explore how life history trajectories and telomere dynamics can covary under various environmental conditions. Here, we address this question in chicks of two tit species distributed foremost at low elevation (the great tit Parus major) or at high elevation (the coal tit Periparus ater). With increasing elevation, great tits showed delayed breeding, and their chicks a slower development, higher telomere erosion and shorter telomere length at day 16. Although coal tit parents delayed also their breeding with increasing elevation, their chicks had a faster development, higher telomere erosion but no reduced telomere length at day 16. This last result is explained by coal tit chicks having longer telomeres at day 7 at high than low elevation, thus mitigating effects of fast telomere erosion before fledging. Our findings on life histories support the idea that great tits and coal tits are best adapted to low and high elevation, respectively. Our data on telomere provide however no support for a direct link between early growth rate and telomere dynamics, but underline complex interplays between telomere dynamics and environmental conditions experienced early in life, thereby urging for studies identifying how early life conditions actually determine fledgling's telomere length.