Ageing-associated DNA methylation dynamics are a molecular readout of lifespan variation among mammalian species.

Abstract

Mammalian species exhibit a wide range of lifespans. To date, a robust and dynamic molecular readout of these lifespan differences has not yet been identified. Recent studies have established the existence of ageing-associated differentially methylated positions (aDMPs) in human and mouse - CpG sites at which DNA methylation dynamics shows a significant correlation with age. We hypothesized that aDMPs are pan-mammalian, and a dynamic molecular readout of lifespan variation amongst different mammalian species. A large-scale integrated analysis of aDMPs in six different mammals revealed a strong negative relationship between rate of change of methylation levels at aDMPs and lifespan. This relationship also holds in an example of a within-species comparison - between two different dog breeds with known differences in lifespans. In an ageing cohort of aneuploid mice carrying a complete copy of human chromosome 21 (Tc1 mice), aDMPs accumulated far more rapidly than was found in human tissues, revealing that DNA methylation at aDMP sites is largely shaped by the nuclear trans-environment, and represents a robust molecular readout of the ageing cellular milieu. Overall, we define the first dynamic molecular readout of lifespan differences amongst mammalian species, and propose that aDMPs will be an invaluable molecular tool for future evolutionary and mechanistic studies aimed at understanding the biological factors that determine lifespan in mammals.