Fundamental equations linking methylation dynamics to maximum lifespan in mammals

We describe a framework that addresses concern that the rate of change in any aging biomarker displays a trivial inverse relation with maximum lifespan. We apply this framework to methylation data from the Mammalian Methylation Consortium. We study the relationship of lifespan with the average rate of change in methylation (AROCM) from two datasets: one with 90 dog breeds and the other with 125 mammalian species. After examining 54 chromatin states, we conclude three key findings: First, a reciprocal relationship exists between the AROCM in bivalent promoter regions and maximum mammalian lifespan: AROCM <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>∝</mml:mo></mml:math> 1/MaxLifespan. Second, the correlation between average methylation and age bears no relation to maximum lifespan, Cor(Methyl,Age) ⊥ MaxLifespan. Third, the rate of methylation change in young animals is related to that in old animals: Young animals' AROCM <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>∝</mml:mo></mml:math> Old AROCM. These findings critically hinge on the chromatin context, as different results emerge in other chromatin contexts.