Questioning causal involvement of telomeres in ageing

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

Stabilising survival selection on pre-senescent expression of a sexual ornament followed by a terminal decline

Senescence is a decrease in functional capacity, increasing mortality rate with age. Sexual signals indicate functional capacity, because costs of ornamentation ensure signal honesty, and are therefore expected to senesce, tracking physiological deterioration and mortality. For sexual traits, mixed associations with age and positive associations with life expectancy have been reported. However, whether these associations are caused by selective disappearance and/or within-individual senescence of sexual signals, respectively, is not known. We previously reported that zebra finches with redder bills had greater life expectancy, based on a single bill colour measurement per individual. We here extend this analysis using longitudinal data and show that this finding is attributable to terminal declines in bill redness in the year before death, with no detectable change in presenescent redness. Additionally, there was a quadratic relationship between presenescent bill colouration and survival: individuals with intermediate bill redness have maximum survival prospects. This may reflect that redder individuals overinvest in colouration and/or associated physiological changes, while below-average bill redness probably reflects poorer phenotypic quality. Together, this pattern suggests that bill colouration is defended against physiological deterioration, because of mate attraction benefits, or that physiological deterioration is not a gradual process, but accelerates sharply prior to death. We discuss these possibilities in the context of the reliability theory of ageing and sexual selection

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

Dietary restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR, and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n = 1223 from 23 studies comprising 46 effect sizes involving DR (n = 17) and rapamycin treatment (n = 29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR =  − 0.72; CI =  − 1.17, -0.28; p = 0.0015). In contrast, DR reduced post-infection survival (lnHR = 0.80; CI = 0.08, 1.52; p = 0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (p < 0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR, our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans

Dietary restriction extends lifespan across different temperatures in the fly

1. Dietary restriction (DR) has been consistently shown to extend lifespan across a range of taxa. However, it has recently been reported that DR does not extend lifespan at certain, namely lower, temperatures in flies (Drosophila melanogaster). Similar to the interpretation of other findings that appear to question DR's universality, this finding has been interpreted as suggesting that lifespan extension in response to DR is an artefact of benign laboratory conditions. 2. We re-test this hypothesis, now using a strain that shows robust lifespan extension at 25°C (across three prior experiments), and using a range of five diets across two temperatures, 18°C and 21°C. 3. We found the DR longevity response to be robust, extending lifespan irrespective of temperature. We measured fecundity as a positive control for the DR phenotype, and found, as predicted, that DR reduces egg laying. 4. We suggest differences in experimental setup, genetic lines used and variation in the diet-lifespan reaction norm are responsible for this discrepancy. In addition, starting with a strain and conditions that show a lifespan extension by DR, as we do here, and then changing environment and/or genotype promises a more robust test of DR modulating factors. 5. In conclusion, it will be important for results that question DR as a phenotype to not be overinterpreted readily, as with a substantially larger sample size and a larger range of diets we were unable to replicate this prior work

How to catch a Smurf? - Ageing and beyond... In vivo assessment of intestinal permeability in multiple model organisms

The Smurf Assay (SA) was initially developed in the model organism Drosophila melanogaster where a dramatic increase of intestinal permeability has been shown to occur during ageing. We have since validated the protocol in multiple other model organisms and have utilised the assay to further our understanding of ageing. The SA has now also been used by other labs to assess intestinal barrier permeability. The SA in itself is simple, however numerous small details can have considerable impact on its experimental validity and subsequent interpretation. Here, we provide detailed update on the SA technique and explain how to catch a Smurf while avoiding the most common experimental fallacie

The hidden costs of dietary restriction: Implications for its evolutionary and mechanistic origins

Dietary restriction (DR) extends life span across taxa. Despite considerable research, universal mechanisms of DR have not been identified, limiting its translational potential. Guided by the conviction that DR evolved as an adaptive, pro-longevity physiological response to food scarcity, biomedical science has interpreted DR as an activator of pro-longevity molecular pathways. Current evolutionary theory predicts that organisms invest in their soma during DR, and thus when resource availability improves, should outcompete rich-fed controls in survival and/or reproduction. Testing this prediction in Drosophila melanogaster (N > 66,000 across 11 genotypes), our experiments revealed substantial, unexpected mortality costs when flies returned to a rich diet following DR. The physiological effects of DR should therefore not be interpreted as intrinsically pro-longevity, acting via somatic maintenance. We suggest DR could alternatively be considered an escape from costs incurred under nutrient-rich conditions, in addition to costs associated with DR

Early-life environment and differences in costs of reproduction in a preindustrial human population

Reproduction is predicted to trade-off with long-term maternal survival, but the survival costs often vary between individuals, cohorts and populations, limiting our understanding of this trade-off, which is central to life-history theory. One potential factor generating variation in reproductive costs is variation in developmental conditions, but the role of early-life environment in modifying the reproduction-survival trade-off has rarely been investigated. We quantified the effect of early-life environment on the trade-off between female reproduction and survival in pre-industrial humans by analysing individual-based life-history data for >80 birth cohorts collected from Finnish church records, and between-year variation in local crop yields, annual spring temperature, and infant mortality as proxies of early-life environment. We predicted that women born during poor environmental conditions would show higher costs of reproduction in terms of survival compared to women born in better conditions. We found profound variation between the studied cohorts in the correlation between reproduction and longevity and in the early-life environment these cohorts were exposed to, but no evidence that differences in early-life environment or access to wealth affected the trade-off between reproduction and survival. Our results therefore do not support the hypothesis that differences in developmental conditions underlie the observed heterogeneity in reproduction-survival trade-off between individuals

Androgen elevation accelerates reproductive senescence in three-spined stickleback

Costs of reproduction shape the life-history evolution of investment in current and future reproduction and thereby aging. Androgens have been proposed to regulate the physiology governing these investments. Furthermore, androgens are hypothesized to play a central role in carotenoid-dependent sexual signaling, regulating how much carotenoids are diverted to ornamentation and away from somatic maintenance, increasing oxidative stress, and accelerating aging. We investigated these relationships in male three-spined stickleback in which we elevated 11-ketotestosterone and supplied vitamin E, an antioxidant, in a 2 × 2 design. Androgen elevation shortened the time stickleback maintained reproductive activities. We suspect that this effect is caused by 11-ketotestosterone stimulating investment in current reproduction, but we detected no evidence for this in our measurements of reproductive effort: nest building, body composition, and breeding coloration. Carotenoid-dependent coloration was even slightly decreased by 11-ketotestosterone elevation and was left unaffected by vitamin E. Red coloration correlated with life expectancy and reproductive capacity in a quadratic manner, suggesting overinvestment of the individuals exhibiting the reddest bellies. In contrast, blue iris color showed a negative relationship with survival, suggesting physiological costs of producing this aspect of nuptial coloration. In conclusion, our results support the hypothesis that androgens regulate investment in current versus future reproduction, yet the precise mechanisms remain elusive. The quadratic relationships between sexual signal expression and aspects of quality have wider consequences for how we view sexual selection on ornamentation and its relationship with aging

Early‐life telomere length predicts life‐history strategy and reproductive senescence in a threatened wild songbird

Telomeres are well known for their associations with lifespan and ageing across diverse taxa. Early-life telomere length can be influenced by developmental conditions and has been shown positively affect lifetime reproductive success in a limited number of studies. Whether these effects are caused by a change in lifespan, reproductive rate or perhaps most importantly reproductive senescence is unclear. Using long-term data on female breeding success from a threatened songbird (the hihi, Notiomystis cincta), we show that the early-life telomere length of individuals predicts the presence and rate of future senescence of key reproductive traits: clutch size and hatching success. In contrast, senescence of fledging success is not associated with early-life telomere length, which may be due to the added influence of biparental care at this stage. Early-life telomere length does not predict lifespan or lifetime reproductive success in this species. Females may therefore change their reproductive allocation strategy depending on their early developmental conditions, which we hypothesise are reflected in their early-life telomere length. Our results offer new insights on the role that telomeres play in reproductive senescence and individual fitness and suggest telomere length can be used as a predictor for future life history in threatened species

Adult telomere length is positively correlated with survival and lifetime reproductive success in a wild passerine

Explaining variation in individual fitness is a key goal in evolutionary biology. Recently, telomeres, repeating DNA sequences capping chromosome ends, have gained attention as a biomarker for body state, physiological costs, and senescence. Existing research has provided mixed evidence for whether telomere length correlates with fitness, including survival and reproductive output. Moreover, few studies have examined how the rate of change in telomere length correlates with fitness in wild populations. Here, we intensively monitored an insular population of house sparrows, and collected longitudinal telomere and life history data (16 years, 1225 individuals). We tested whether telomere length and its rate of change predict fitness measures, namely survival, lifespan and annual and lifetime reproductive effort and success. Telomere length positively predicted short-term survival, independent of age, but did not predict lifespan, suggesting either a diminishing telomere length—survival correlation with age or other extrinsic factors of mortality. The positive association of telomere length with survival translated into reproductive benefits, as birds with longer telomeres produced more genetic recruits, hatchlings and reared more fledglings over their lifetime. In contrast, there was no association between telomere dynamics and annual reproductive output, suggesting telomere dynamics might not reflect the costs of reproduction in this population, potentially masked by variation in individual quality. The rate of change of telomere length did not correlate with neither lifespan nor lifetime reproductive success. Our results provide further evidence that telomere length correlates with fitness, and contribute to our understanding of the selection on, and evolution of, telomere dynamics