Differential Responses of Dynamic and Entropic Aging Factors to Longevity Interventions

Aging across most species, including mice and humans, is characterized by an exponential acceleration of mortality rates. In search for the molecular basis of this phenomenon, we analyzed DNA methylation (DNAm) changes in aging mice. Utilizing principal component analysis (PCA) on DNAm profiles, we identified a primary aging signature with an exponential age dependency, closely reflecting the Gompertz law’s description of mortality acceleration. This signature is the manifestation of the dynamic instability in the organism’s state that drives the aging process in mice. It aligns closely with regression-based aging clocks and responds to interventions such as caloric restriction and parabiosis. Additionally, we identified a linear DNAm signature, indicative of a global demethylation level. Through single-cell DNAm (scDNAm) data from aging animals, we demonstrate that this signature captures the exponential expansion of the state space volume spanned by individual cells within an aging organism, and thus quantifying linearly increasing configuration entropy, likely an irreversible process. Consistent with this interpretation, we found that neither caloric restriction (CR) nor parabiosis significantly impacts the entropic feature, reinforcing its link to irreversible damage.