Epigenetic predictors of maximum lifespan and other life history traits in mammals

Abstract

Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species and for identifying interventions that extend lifespan.

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

“…We used the universal maximum lifespan predictor 17 to estimate the potential maximum lifespan (predicted-maxLS) of mice. Predicted-maxLS was uncorrelated with chronological age ( Table 1 ), and this is expected since the chronological age represents the time when the biospecimens were collected; not the time of natural demise.…”

“…We note that the predicted-maxLS overestimated the strain max-LS by 0.7 to 3 years (median error of +1.6 years). Nonetheless, the correlation between individual-level predicted-, and strain-level observed maxLS is remarkable considering that both the universal clock and max-LS predictor are pan-mammalian, and species- and tissue-agnostic 17,38 . Our results suggest that these universal epigenetic predictors of biological aging, and lifespan are informative of the subtle and normative lifespan variation in a family of inbred mice.…”

“…The development of the universal pan-tissue epigenetic clocks of age, and the universal maximum lifespan predictor are described in Lu et al 38 , and Li et al 17 , respectively. For the present work, we utilized the universal clock that predicts relative age, defined as individual age relative to the maximum lifespan of its species, followed by inverse transformation to estimate DNAmAge 38 .…”

“…This pan-mammalian DNAm array (HorvathMammalMethylChip40) provides a common platform to measure DNAm, and has been used to build universal epigenetic clocks that can estimate age across a variety of tissues and mammalian species 15,16 . Another remarkable development with this array is the novel lifespan predictor that can estimate the maximum lifespan of over 190 mammals at high accuracy 17 .…”

“…15,16 Another remarkable development with this array is the novel lifespan predictor that can estimate the maximum lifespan of over 190 mammals at high accuracy. 17 Here, we test the performance and applicability of these novel DNAm clocks and lifespan predictor in a genetically diverse cohort of mice belonging to the BXD family. 18,19 The BXDs are a well-established mouse genetic reference panel that were first created as a family of recombinant inbred (RI) strains by crossing two inbred progenitors: C57BL/6J (B6) and DBA/2J (D2).…”