A temporal hierarchy determines epigenetic aging

Aging involves processes spanning orders of magnitude in time, from fast events that occur at the molecular scale to the slow decrease of physiological function. Whether and how fast molecular events lead to the slow progression of aging, and what ultimately sets the timescale of aging, is not understood. Here, by focusing on dynamic changes in DNA methylation, we show how aging phenomena on long timescales emerge from the kinetics of fast molecular processes, providing a bridge between temporal scales. By combining DNA methylation sequencing data across a range of timescales with a statistical modeling-based approach, we show that DNA methylation aging is governed by a three-fold hierarchy of processes that dominate on distinct timescales: individual stochastic events in which enzymes interact with the DNA and with each other (milliseconds); the convergence of molecular concentrations to steady states (days to months); and stochastic transitions between these steady states (years to decades). Our findings provide a unified picture of how DNA methylation aging arises across temporal scales.