Aging clocks, entropy, and the limits of age-reversal

We analyze aging signatures of DNA methylation and longitudinal electronic medical records from the UK Biobank datasets and observe that aging is driven by a large number of independent and infrequent transitions between metastable states in a vast configuration space. The compound effect of configuration changes can be captured by a single stochastic variable, thermodynamic biological age (tBA), tracking entropy produced, and hence information lost during aging. We show that tBA increases with age, causes the linear and irreversible drift of physiological state variables, reduces resilience, and drives the exponential acceleration of chronic disease incidence and death risks. The entropic character of aging drift sets severe constraints on the possibilities of age reversal. However, we highlight the universal features of configuration transitions, suggest practical ways of suppressing the rate of aging in humans, and speculate on the possibility of achieving negligible senescence. ### Competing Interest Statement P.O.F. is a shareholder of Gero PTE. A.E.T., K.A.D., and P.O.F. were employed by Gero PTE during the work on the manuscript. The study was funded by Gero PTE.