Fundamental equations linking methylation dynamics to maximum lifespan in mammals

Many studies have investigated the connection between the rate of change in diverse molecular markers and maximum lifespan across species. We describe a framework to address doubts that the rate of change in any biomarker displays a trivial inverse relation to lifespan. We leverage this framework on two comprehensive methylation datasets. The first connects the rate of change in blood methylation to the lifespan of 93 dog breeds. The second associates the rate of change in distinct chromatin states with the maximum lifespan of 125 mammalian species. We show how methylation levels in selected chromatin states shift with age across the lifespan. Our research reveals three significant outcomes: First, a reciprocal relationship exists between the rate of methylation change in bivalent promoter regions and maximum lifespan. Second, the association between age and average methylation within these bivalent promoter regions bears no relation to maximum lifespan. Third, the rate of methylation change in young animals is related to that in old animals. Our mathematical derivations draw connections between these findings. A substantial part of our mathematical framework for analyzing maximum lifespan can be applied to other molecular assessments as well. Overall, our study demonstrates that epigenetic aging rates in specific chromatin states exhibit an inverse relationship with maximum lifespan. ### Competing Interest Statement Steve Horvath is a founder of the non-profit Epigenetic Clock Development Foundation which licenses several patents from his former employer UC Regents. The other authors declare no conflicts of interest.