Abstract
BackgroundMammalian 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. These are CpG sites at which DNA methylation dynamics show significant correlations with age. We hypothesise that aDMPs are pan-mammalian and are a dynamic molecular readout of lifespan variation among different mammalian species.ResultsA large-scale integrated analysis of aDMPs in six different mammals reveals a strong negative relationship between rate of change of methylation levels at aDMPs and lifespan. This relationship also holds when comparing two different dog breeds with known differences in lifespans. In an ageing cohort of aneuploid mice carrying a complete copy of human chromosome 21, aDMPs accumulate far more rapidly than is seen 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.ConclusionsOverall, we define the first dynamic molecular readout of lifespan differences among 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.
Highlights
Mammalian species exhibit a wide range of lifespans
As mice have a considerably shorter lifespan than humans, the ability to detect associated differentially methylated positions (aDMPs) in mice suggests that the rate of DNA methylation change must be considerably faster
The mouse aDMP shows a methylation change of ~ 50% that occurs within just 35 weeks. To confirm this was a general feature of detected aDMPs, we calculated the rate of change of methylation per week for both human and mouse aDMPs and found that irrespective of whether we use conserved or non-conserved aDMP sites, mouse aDMPs showed a significantly (P value < 2.2 × 10–16) faster rate of change than human aDMPs (Fig. 1c, d), consistent with Stubbs et al [10]
Summary
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. These are CpG sites at which DNA methylation dynamics show significant correlations with age. We hypothesise that aDMPs are pan-mammalian and are a dynamic molecular readout of lifespan variation among different mammalian species. Body mass is positively correlated with lifespan across mammalian species, this relationship is not true within species such as dogs [2]. These factors are not dynamic molecular correlates of lifespan
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