Towards a Universal Epigenetic Clock for Mammals

Epigenetic marks are constantly added to and removed from CpG sites on the genome, controlling gene expression and thus cell behavior. The pattern of epigenetic marks in any given cell shifts in response to environment and circumstances, and some of those changes are characteristic of the presence of the underlying molecular damage of aging. Epigenetic clocks can thus be constructed from weighted combinations of epigenetic mark status at various CpG sites in order to measure biological age. Existing epigenetic clocks are specific to a given species, but here researchers process an enormous amount of data from many species to produce epigenetic clocks that are universal to all placental mammals. If this result holds up well in further testing, then such universal clocks could help to speed up the development of therapies that target the mechanisms of aging.

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 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.



Given the universality of the clock accros mammalian species and the conserved genes involved, it seems a lot more likely that aging is programmed and methylation is an effector (and even a cause) of a programmed aging process. This is of course not incopatible with damage accumulating at a faster rate once this process is launched and acts long enough with a bigger role at later stages. Aging and death have a defined ecological role and seems to be another "developmental" stage.

Posted by: Guillermo Fernandez Alvarez at February 3rd, 2021 5:30 AM

A wild (and naive?) hypothesis (I guess it was already discussed somewhere (along with evidence against it), but I couldn't find it online):
The process common to all mammals that the clock tracks is the accumulation of methylation patterns that (activate/silence genes to) promote growth and/or inhibit cell death. As chronological time passes, such "selfish" methylation patterns become more prevalent in the body - simply by natural selection. These epimutations probably often favor growth/death-resistance at the expense of pathways that maintain organismal homeostasis. Thus, the more such methylation patterns accumulate, the closer the organism is to death.

I would love to hear about any evidence that contradict this hypothesis, as it stubbornly refuses to leave my head.

Posted by: Oren Milman at August 23rd, 2021 4:43 PM
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