The Pace of Epigenetic Drift is Slower in Long-Lived Species

Epigenetic drift is a measure of age-related change in epigenetic marks that alter the structure of packaged DNA in the cell nucleus, and thus control gene expression by making regions accessible or inaccessible to the translation machinery that produces RNA from gene sequences. Regardless of whether epigenetic drift is a form of damage contributing to aging, or a reflection of stochastic molecular damage within cells and consequent disarray in signaling and environment, one would in either case expect it to scale with species life span. Longer-lived species must show a slower pace of change in measures of aging, it would be surprising to find a measure for which this was not the case.

Epigenetic drift or "disorder" increases across the mouse lifespan and is suggested to underlie epigenetic clock signals. While the role of epigenetic drift in determining maximum lifespan across species has been debated, robust tests of this hypothesis are lacking. Here, we test if epigenetic disorder at various levels of genomic resolution explains maximum lifespan across four mammal species. We show that epigenetic disorder increases with age in all species and at all levels of genomic resolution tested. The rate of disorder accumulation occurs faster in shorter lived species and corresponds to species adjusted maximum lifespan.

While the density of cytosine-phosphate-guanine dinucleotides ("CpGs") is negatively associated with the rate of age-associated disorder accumulation, it does not fully explain differences across species. Our findings support the hypothesis that the rate of epigenetic drift explains maximum lifespan and provide partial support for the hypothesis that CpG density buffers against epigenetic drift.