Erin E. Ehmke

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

ABSTRACT Aging is often perceived as a degenerative process resulting from random accrual of cellular damage over time. Despite this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, we hypothesized that one can build pan-mammalian clocks that measure age in all mammalian species. To address this, we generated data using 11,754 methylation arrays, each profiling up to 36 thousand cytosines in highly-conserved stretches of DNA, from 59 tissue-types derived from 185 mammalian species. From these methylation profiles, we constructed three age predictors, each with a single mathematical formula, termed universal pan-mammalian clocks that are accurate in estimating the age (r>0.96) of any mammalian tissue. Deviations between epigenetic age and chronological age relate to mortality risk in humans, mutations that affect the somatotropic axis in mice, and caloric restriction. We characterized specific cytosines, whose methylation levels change with age across most mammalian species. These cytosines are greatly enriched in polycomb repressive complex 2-binding sites, are located in regions that gradually lose chromatin accessibility with age and are proximal to genes that play a role in mammalian development, cancer, human obesity, and human longevity. Collectively, these results support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new compelling evidence. SUMMARY This study identifies and characterizes evolutionarily conserved cytosines implicated in the aging process across mammals and establishes pan mammalian epigenetic clocks.

Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

"Are Vigilance, Risk From Avian Predators and Group Size Consequences of Habitat Structure? A Comparison of Three Species of Squirrel Monkey (Saimiri oerstedii, S. boliviensis, and S. sciureus)" published on 01 Jan 2003 by Brill.

Abstract Current theory frames animal dispersal as an outcome of potentially complex, multi-factorial interactions and tradeoffs that may vary across individual, sex, rank, age, social group, species, habitat and time. Empirical data relevant to a broad range of the potential costs and benefits incurred by dispersal are, not surprisingly, limited for many mammals and other vertebrates. Here we present the first report on dispersal in a wild population of the Neotropical primate Saimiri sciureus (Primates: Cebidae). Long-term observations (1998-2001) of this squirrel monkey represent part of a broader study of the forest community at Raleighvallen in the Central Suriname Nature Reserve. These new dispersal records for S. sciureus are combined with comparable information from congeners, S. boliviensis in Peru and S. oerstedii in Costa Rica. The resulting three-way compilation includes the ecological, social and mating context for each congener. Further enhancing the inherent phylogenetic control of a within-genus comparison, these data were collected with the explicit intent of joint analyses, and the study sites for these small, arboreal social mammals are three of the least disturbed extant Neotropical forests in the historical record.Saimiri appears to merit description as the genus with the most diverse set of species dispersal patterns yet documented among mammals. (1) S. sciureus of both sexes undertake dispersal on several to many occasions during their lifetime. Females and immatures commonly transfer between troops. The large portion of male S. sciureus spend their adult years as solitary or peripheral males. Few males attain secure residence in a mixed-sex troop, a prerequisite for mating success. (2) On attainment of sexual maturity, male S. boliviensis emigrate with their same-age cohort, first joining all-male bands, and eventually entering mixed-sex troops with this same natal male birth cohort. Natal female S. boliviensis are philopatric and form cohesive matrilines. Within-troop competition determines each matriline's priority of access to fruit resources. (3) In contrast to both S. sciureus and S. boliviensis, S. oerstedii males are philopatric and maintain tight affiliation with same age-cohort males. Natal female S. oerstedii emigrate as juveniles prior to their first mating season, and may undertake secondary dispersals in subsequent years.Squirrel monkeys represent a genus with realistic prospects of discriminating the costs and benefits germane to species-typical dispersal strategies. To this end, we collate 30 different causal parameters commonly invoked as influencing mammalian dispersal patterns. Each of these factors is assessed separately for possible influence on the empirically determined sex and species differences. We predict the possible consequences of direct and inclusive fitness interactions on dispersal outcomes for future testing with genetic data. Components of Saimiri selective regimes particularly salient to female dispersal strategies include food competition, foraging benefits provided by kin and inbreeding avoidance. Dispersal patterns among male Saimiri are constrained by mate competition and the consequent reproductive skew, in addition to enhanced predation risk during dispersal forays. Little evidence, however, suggests that relative to familiar landscapes, exploitation of novel ranging areas substantially increases foraging costs or predation risk for dispersing squirrel monkeys of either sex. We then compare the species-specific dispersal regimes initially identified with the univariate array of proposed costs and benefits to the tradeoffs predicted by a selection of contemporary multivariate dispersal models. The multivariate models did not, however, improve substantially upon the collective insights on cost-benefit regimes achieved with the univariate hypotheses. Conclusions regarding the selective regimes structuring dispersal among squirrel monkeys are best considered provisional until genetic data become available allowing tests of our inferences concerning kin relationships and population structure of the study populations.