Universal DNA methylation age across mammalian tissues

Abstract

Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of 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, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations 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 and compelling evidence.

Hibernation slows epigenetic aging in yellow-bellied marmots

“…Most CpGs in promoter regions were hypermethylated with age (supplementary material). DNAm aging in marmots was proximal to polycomb repressor complex targets (PRC2, EED) with H3K27ME3 marks (supplementary material), which is a consistent observed pattern in all mammals 70 . The enriched pathways were largely associated with development, cell differentiation and homeostasis.…”

Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging

“…Even though iPSCs correspond to an embryonic state and the transition to these cells involves major molecular changes, including changes in the epigenome, this rejuvenation event can be assessed by epigenetic clocks. Most recently, universal mammalian clocks have been developed based on conserved cytosines, whose methylation levels change with age across mammalian species ( 40 ).…”

DNA methylation aging and transcriptomic studies in horses

“…EED, SUZ12) targets that are marked with H3K27ME3 modification ( Figure S3; Table S5 ). This is a general and conserved DNAm aging pattern in all mammalian species 38 .…”