Maternal and genetic factors determine early life telomere length

In a broad range of species—including humans—it has been demonstrated that telomere length declines throughout life and that it may be involved in cell and organismal senescence. This potential link to ageing and thus to fitness has triggered recent interest in understanding how variation in telomere length is inherited and maintained. However, previous studies suffer from two main drawbacks that limit the possibility of understanding the relative importance of genetic, parental and environmental influences on telomere length variation. These studies have been based on (i) telomere lengths measured at different time points in different individuals, despite the fact that telomere length changes over life, and (ii) parent–offspring regression techniques, which do not enable differentiation between genetic and parental components of inheritance. To overcome these drawbacks, in our study of a songbird, the great reed warbler, we have analysed telomere length measured early in life in both parents and offspring and applied statistical models (so-called ‘animal models'') that are based on long-term pedigree data. Our results showed a significant heritability of telomere length on the maternal but not on the paternal side, and that the mother''s age was positively correlated with their offspring''s telomere length. Furthermore, the pedigree-based analyses revealed a significant heritability and an equally large maternal effect. Our study demonstrates strong maternal influence on telomere length and future studies now need to elucidate possible underlying factors, including which types of maternal effects are involved.     

Links between parental life histories of wild salmon and the telomere lengths of their offspring

The importance of parental contributions to offspring development and subsequent performance is self‐evident at a genomic level; however, parents can also affect offspring fitness by indirect genetic and environmental routes. The life history strategy that an individual adopts will be influenced by both genes and environment; and this may have important consequences for offspring. Recent research has linked telomere dynamics (i.e., telomere length and loss) in early life to future viability and longevity. Moreover, a number of studies have reported a heritable component to telomere length across a range of vertebrates, although the effects of other parental contribution pathways have been far less studied. Using wild Atlantic salmon with different parental life histories in an experimental split‐brood in vitro fertilization mating design and rearing the resulting families under standardized conditions, we show that there can be significant links between parental life history and offspring telomere length (studied at the embryo and fry stage). Maternal life history traits, in particular egg size, were most strongly related to offspring telomere length at the embryonic stage, but then became weaker through development. In contrast, paternal life history traits, such as the father's growth rate in early life, had a greater association in the later stages of offspring development. However, offspring telomere length was not significantly related to either maternal or paternal age at reproduction, nor to paternal sperm telomere length. This study demonstrates both the complexity and the importance of parental factors that can influence telomere length in early life.     

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.     

Paternal age and telomere length in twins: the germ stem cell selection paradigm

Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an ‘epigenetic’ mechanism through which paternal age plays a role in telomere length regulation in humans. Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers, which is not seen in monozygotic twins. This phenomenon might result from a paternal age‐dependent germ stem cell selection process, whereby the selected stem cells have longer telomeres, are more homogenous with respect to telomere length, and share resistance to aging.     

Nestling telomere shortening,but not telomere length,reflects developmental stress and predicts survival in wild birds

Developmental stressors often have long-term fitness consequences, but linking offspring traits to fitness prospects has remained a challenge. Telomere length predicts mortality in adult birds, and may provide a link between developmental conditions and fitness prospects. Here, we examine the effects of manipulated brood size on growth, telomere dynamics and post-fledging survival in free-living jackdaws. Nestlings in enlarged broods achieved lower mass and lost 21% more telomere repeats relative to nestlings in reduced broods, showing that developmental stress accelerates telomere shortening. Adult telomere length was positively correlated with their telomere length as nestling (r = 0.83). Thus, an advantage of long telomeres in nestlings is carried through to adulthood. Nestling telomere shortening predicted post-fledging survival and recruitment independent of manipulation and fledgling mass. This effect was strong, with a threefold difference in recruitment probability over the telomere shortening range. By contrast, absolute telomere length was neither affected by brood size manipulation nor related to survival. We conclude that telomere loss, but not absolute telomere length, links developmental conditions to subsequent survival and suggest that telomere shortening may provide a key to unravelling the physiological causes of developmental effects on fitness.     

Maternal telomere length inheritance in the king penguin

Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks'' age.     

Influences of inbreeding and genetics on telomere length in mice

We measured telomere lengths of blood leukocytes in several inbred and outbred mammalian species, using a telomere-specific fluorescent probe and flow cytometry. Humans, non-human primates, and three outbred populations of Peromyscus mice (Peromyscus leucopus, Peromyscus maniculatus, and Peromyscus polionotus) have short telomeres. Two common strains of laboratory mice, C57BL/6J and DBA/2J, have telomeres several times longer than most other mammals surveyed. Moreover, the two inbred laboratory mouse strains display significantly different telomere lengths, suggesting the existence of strain-specific genetic determinants. To further examine the effects of inbreeding, we studied three Peromyscus leucopus inbred lines (GS109, GS16A1, and GS16B), all derived from the outbred P. leucopus stock. Telomeres of all three inbred lines are significantly lengthened relative to outbred P. leucopus, and the three lines display strain-specific significantly different telomere lengths, much like the C57BL/6J and DBA/2J strains of M. musculus. To further characterize the genetic inheritance of telomere length, we carried out several crosses to obtain hybrid F₁ mice between parental strains displaying the phenotype of long and short telomeres. In all F₁ mice assayed, peripheral blood leukocyte telomere length was intermediate to that of the parents. Additionally, we generated F₂ mice from a cross of the (P. leucopus outbred × GS16B)F₁. Based on the distribution of telomere length in the F₂ population, we determined that more than five loci contribute to telomere length regulation in Peromyscus. We concluded that inbreeding, through unknown mechanisms, results in the elongation of telomeres, and that telomere length for a given species and/or sub-strain is genetically determined by multiple segregating loci.     

Paternal age is positively linked to telomere length of children

Telomere length is linked to age-associated diseases, with shorter telomeres in blood associated with an increased probability of mortality from infection or heart disease. Little is known about how human telomere length is regulated despite convincing data from twins that telomere length is largely heritable, uniform in various tissues during development until birth and variable between individuals. As sperm cells show increasing telomere length with age, we investigated whether age of fathers at conception correlated with telomere length of their offspring. Telomere length in blood from 125 random subjects was shown to be positively associated with paternal age (+22 bp yr -1, 95% confidence interval 5.2-38.3, P = 0.010), and paternal age was calculated to affect telomere length by up to 20% of average telomere length per generation. Males lose telomeric sequence faster than females (31 bp yr -1, 17.6-43.8, P < 0.0001 vs. 14 bp yr -1, 3.5-24.8, P < 0.01) and the rate of telomere loss slows throughout the human lifespan. These data indicate that paternal age plays a role in the vertical transmission of telomere length and may contribute significantly to the variability of telomere length seen in the human population, particularly if effects are cumulative through generations.     

Differences in telomere length between homologous chromosomes in humans

Telomeres are important structures for DNA replication and chromosome stability during cell growth. Telomere length has been correlated with the division potential of human cells and has been found to decrease with age in healthy individuals. Nevertheless, telomere lengths within the same cell are heterogeneous and certain chromosome arms typically have either short or long telomeres. Both the origin and the physiological consequences of this heterogeneity in telomere length remain unknown. In this study we used quantitative telomeric FISH combined with a method to identify the parental origin of chromosomes to show that significant differences in relative telomere intensities are frequently observed between chromosomal homologs in short-term stimulated cultures of peripheral blood lymphocytes. These differences appear to be stable for at least 4 months in vivo, but disappear after prolonged proliferation in vitro. The telomere length differences are also stable during in vitro growth of telomerase-negative fibroblast cells but can be abolished by exogenous telomerase expression in these cells. These findings suggest the existence of a mechanism maintaining differences in telomere length between chromosome homologs that is independent of telomere length itself.     

Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm

Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.     

Telomere length reveals cumulative individual and transgenerational inbreeding effects in a passerine bird

Inbreeding results in more homozygous offspring that should suffer reduced fitness, but it can be difficult to quantify these costs for several reasons. First, inbreeding depression may vary with ecological or physiological stress and only be detectable over long time periods. Second, parental homozygosity may indirectly affect offspring fitness, thus confounding analyses that consider offspring homozygosity alone. Finally, measurement of inbreeding coefficients, survival and reproductive success may often be too crude to detect inbreeding costs in wild populations. Telomere length provides a more precise measure of somatic costs, predicts survival in many species and should reflect differences in somatic condition that result from varying ability to cope with environmental stressors. We studied relative telomere length in a wild population of Seychelles warblers (Acrocephalus sechellensis) to assess the lifelong relationship between individual homozygosity, which reflects genome‐wide inbreeding in this species, and telomere length. In juveniles, individual homozygosity was negatively associated with telomere length in poor seasons. In adults, individual homozygosity was consistently negatively related to telomere length, suggesting the accumulation of inbreeding depression during life. Maternal homozygosity also negatively predicted offspring telomere length. Our results show that somatic inbreeding costs are environmentally dependent at certain life stages but may accumulate throughout life.     

Maternal predator‐exposure affects offspring size at birth but not telomere length in a live‐bearing fish

The perception of predation risk could affect prey phenotype both within and between generations (via parental effects). The response to predation risk could involve modifications in physiology, morphology, and behavior and can ultimately affect long‐term fitness. Among the possible modifications mediated by the exposure to predation risk, telomere length could be a proxy for investigating the response to predation risk both within and between generations, as telomeres can be significantly affected by environmental stress. Maternal exposure to the perception of predation risk can affect a variety of offspring traits but the effect on offspring telomere length has never been experimentally tested. Using a live‐bearing fish, the guppy (Poecilia reticulata), we tested if the perceived risk of predation could affect the telomere length of adult females directly and that of their offspring with a balanced experimental setup that allowed us to control for both maternal and paternal contribution. We exposed female guppies to the perception of predation risk during gestation using a combination of both visual and chemical cues and we then measured female telomere length after the exposure period. Maternal effects mediated by the exposure to predation risk were measured on offspring telomere length and body size at birth. Contrary to our predictions, we did not find a significant effect of predation‐exposure neither on female nor on offspring telomere length, but females exposed to predation risk produced smaller offspring at birth. We discuss the possible explanations for our findings and advocate for further research on telomere dynamics in ectotherms.     

Leukocyte telomere length in the Thoroughbred racehorse

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

The influence of phylogeny and life history on telomere lengths and telomere rate of change among bird species: A meta‐analysis

Longevity is highly variable among animal species and has coevolved with other life‐history traits, such as body size and rates of reproduction. Telomeres, through their erosion over time, are one of the cell mechanisms that produce senescence at the cell level and might even have an influence on the rate of aging in whole organisms. However, uneroded telomeres are also risk factors of cell immortalization. The associations of telomere lengths, their rate of change, and life‐history traits independent of body size are largely underexplored for birds. To test associations of life‐history traits and telomere dynamics, we conducted a phylogenetic meta‐analysis using studies of 53 species of birds. We restricted analyses to studies that applied the telomere restriction fragment length (TRF) method, and examined relationships between mean telomere length at the chick (Chick TL) and adult (Adult TL) stages, the mean rate of change in telomere length during life (TROC), and life‐history traits. We examined 3 principal components of 12 life‐history variables that represented: body size (PC1), the slow–fast continuum of pace of life (PC2), and postfledging parental care (PC3). Phylogeny had at best a small‐to‐medium influence on Adult and Chick TL (r ² = .190 and .138, respectively), but a substantial influence on TROC (r ² = .688). Phylogeny strongly influenced life histories: PC1 (r ² = .828), PC2 (.838), and PC3 (.613). Adult TL and Chick TL were poorly associated with the life‐history variables. TROC, however, was negatively and moderate‐to‐strongly associated with PC2 (unadjusted r = −.340; with phylogenetic correction, r = −.490). Independent of body size, long‐lived species with smaller clutches, and slower embryonic rate of growth may exhibit less change in telomere length over their lifetimes. We suggest that telomere lengths may have diverged, even among closely avian‐related species, yet telomere dynamics are strongly linked to the pace of life.     

Decreasing initial telomere length in humans intergenerationally understates age‐associated telomere shortening

Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age‐associated telomere shortening rate estimated by cross‐sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross‐sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross‐sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications.     

Comparing telomere length of sister chromatids in human lymphocytes using three-dimensional confocal microscopy

BACKGROUND: The length of the terminal sequences of linear chromosomes changes dynamically during cellular proliferation. A crucial element in the study of telomere-related regulation mechanisms is the ability to measure telomere lengths of individual chromosomes. Individual telomere lengths can be measured using digital imaging fluorescence microscopy-based techniques. We extended this method using confocal microscopy for the acquisition of three-dimensional (3D) images. Consequently, variations in measured signal intensities due to erroneous focusing are avoided. METHODS: We employed our 3D telomere sizing method to compare telomere lengths of sister chromatids within metaphase preparations from human lymphocytes. The samples were treated following a quantitative fluorescence in situ hybridization (Q-FISH) protocol using fluorescein isothiocyanate (FITC)-labeled telomeric peptidic nucleic acid (PNA) probes and propidium iodide (PI) counterstain. RESULTS: We demonstrated that the telomere lengths of two sister chromatids are not necessarily equal in human lymphocytes. Profound statistical analysis demonstrated significant differences in the distribution of the sister chromatid telomere lengths, but we were not able to prove a discrete distribution of telomere sister ratios. These telomere length differences were more apparent in older individuals. CONCLUSION: Whereas the majority of sister telomere pairs have equal lengths, surprisingly, a minority was significantly different in each individual studied. We are convinced that these observations are not linked to the methodology or the protocol applied. We suggest that a biological phenomenon might be involved.     

Stress, social rank and leukocyte telomere length

Blood leukocytes are a heterogeneous mixture of cell types whose telomere lengths differ greatly, reflecting variation in stem cell turnover and recruitment, expansion and replacement of more mature cell types as well as variable telomere loss and telomere repair. These differences in cell and telomere length dynamics, together with the evidence that telomere length is influenced strongly by genetic polymorphisms, greatly complicate the interpretation of claims that socio-economic status modulates the rate of telomere attrition.     

The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability

Loss of telomere function can induce cell cycle arrest and apoptosis. To investigate the processes that trigger cellular responses to telomere dysfunction, we crossed mTR-/- G6 mice that have short telomeres with mice heterozygous for telomerase (mTR+/-) that have long telomeres. The phenotype of the telomerase null offspring was similar to that of the late generation parent, although only half of the chromosomes were short. Strikingly, spectral karyotyping (SKY) analysis revealed that loss of telomere function occurred preferentially on chromosomes with critically short telomeres. Our data indicate that, while average telomere length is measured in most studies, it is not the average but rather the shortest telomeres that constitute telomere dysfunction and limit cellular survival in the absence of telomerase.     

Normal telomere lengths of spermatozoa in somatic cell-cloned bulls

Interesting questions have been raised regarding cloned animals, including whether cloning restores cellular senescence undergone by donor cells, and how long cloned animals will be able to live. In this study, focusing our attention on the fact that telomere lengths of spermatozoa are longer than those of any somatic cells and that telomere length is maintained throughout aging in humans, we compared the telomere lengths of spermatozoa in normal and two somatic cell-cloned cattle. The telomere lengths of the spermatozoa in the normal cattle (22.42+/-0.32 kb) were maintained throughout aging as in humans. In the cloned cattle, telomere lengths of the spermatozoa (25.8 and 20.9 kb) were the same as or longer than those found in normal cattle. Considering that telomere lengths of the donor cells, which had been derived from the muscle tissue of an old bull, were reported to be 20.1 kb, the results suggested that the telomere lengths of the germ cell line had extended from nucleus transfer to spermatogenesis. Moreover, we produced offspring (nine calves) from a somatic cell-cloned bull and measured the telomere lengths of their leukocytes. In all of the offspring, the telomere lengths of leukocytes were normal, too. These results indicate the possibility that somatic cloned bulls could be used as breeding sires.     

Egg colouration predicts brood size,telomere length and body condition of spotless starling fledglings

Understanding the impressive interspecific variation in avian eggshell colouration has attracted the attention of evolutionary ecologists for more than a century. Several functional explanations predict positive covariation between eggshell pigmentation and phenotypic quality of nestlings. We test this prediction in spotless starlings Sturnus unicolor by using biometric measurements and telomere length of hatchlings and fledglings as proxies of phenotypic quality. Female spotless starlings lay immaculate blue‐green eggs, a sexually selected signal directed to males. Pigmentation predicts positive associations with concentration of antioxidants and testosterone in the yolk and with paternal provisioning effort during nestling growth. Eggshell pigmentation (blue‐green chroma) is not associated with telomere length of hatchlings, which suggests weak maternal effects on this trait. However, we find negative associations of eggshell colouration with both body condition and telomere length of fledglings. Moreover, we find positive associations between eggshell colouration and clutch size, which suggests that sibling competition is higher in nests with more coloured eggshells. Previous works demonstrated that level of sibling competition is positively related to telomere erosion and, thus, the detected negative associations between eggshell colouration, body condition and telomere length of fledglings would reflect higher level of competition in nests with more coloured eggshells. We therefore speculate with the possibility that females that lay larger clutches also lay more coloured eggshells that elicit increased paternal provisioning effort and, thus, raise larger broods at the expense of telomere erosion of their offspring.