Defining Mammalian Lifespan through Epigenetic Aging Timescales

Abstract

The lifespans of mammalian species vary across orders of magnitude, with the shortest on the order of a year and the longest more than one hundred years. These lifespans are influenced by both genetic and environmental factors. Here we asked whether we can define a molecular process that can be used to define the intrinsic molecular lifespan of a species that is largely independent of environmental factors. To address this question, we have focused on ‘epigenetic clocks’ - highly accurate age-predicting biomarkers based on DNA methylation. Our previous research has demonstrated that the alterations in DNA methylation related to age are non-linear, changing rapidly early in life and slowing down with advancing age. We have proposed the use of saturating exponential functions to represent these changes, which tend to stabilize at terminal methylation levels towards the end of an organism's lifespan. Our current study expands upon this by examining the exponential aging timescales across various mammalian species. We show that the DNA methylation trajectories of a broad range of species, ranging from mice to humans, adhere to a saturating exponential function. Furthermore, we find the timescale of this exponential decay to be about one third of a species’ lifespan. This striking and novel observation implies that we can define an intrinsic molecular lifespan of a species that is largely unaffected by environmental factors. Although the exact mechanisms behind the variation in species-specific rates remain unclear, we hypothesize that they may be linked to the distinct metabolic rates found in each species.