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.

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Establishing the age of a bloodstain provides forensic investigators with critical information on the time that a crime occurred. Our work presents a time since deposition (TSD) analysis that integrates visible absorbance spectroscopy and high-resolution automated electrophoresis data to quantify light absorbance and DNA degradation of whole blood over time. Passive bloodstains were created and treated on either FTA cards without anticoagulant or in microcentrifuge tubes with anticoagulant and tested over 11 different timepoints across 15 days at controlled temperature and relative humidity. A total of 41 variables were analyzed using linear regression, with six variables showing statistical independence and a relationship to time. A general negative trend was noticeable for the visible absorbance of a and b bands and concentration of high molecular weight DNA of the samples over time. We then conducted a principle component analysis (PCA) of all variables; the principal components integrated both DNA and absorbance data and generally improved the model fit (i.e. increased R 2 ). Importantly, our PCA findings demonstrated that the experimental effect of treatment and donor was largely accounted for in PC1, with PC2 reflecting the true relationship of the integrated metrics to time. Our data set and models are publicly available in an effort to build upon this study by incorporating environmental variables.

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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.