UC San Diego

Aging is accompanied by widespread molecular changes, yet the relationships among these changes – and their ultimate causes – remain incompletely understood. This dissertation ix investigates the epigenetic and genomic alterations that accumulate during mammalian aging, their mechanistic origins, and potential strategies for intervention.First, I characterize the landscape of epigenetic aging across multiple layers of the epigenome. Through comprehensive analysis of six histone modifications and DNA methylation in >1,000 humans and mice, I demonstrate that age-related epigenetic changes are not isolated phenomena but rather reflect a coordinated remodeling process. Epigenetic changes across all layers converge upon a common set of genes, enabling the construction of a "pan-epigenetic" clock capable of predicting age from any epigenetic layer across species.Second, I establish that somatic mutations and epigenetic change are intimately coupled: mutations coincide with extensive remodeling of the surrounding methylome, and mutation-based age predictions mirror those derived from DNA methylation. These findings suggest that the progressive accumulation of somatic mutations may drive the epigenetic drift observed during aging.Third, I identify the DREAM complex (Dp, Rb-like-1, E2f, And MuvB) as a key regulator of somatic mutation and aging. DREAM transcriptionally represses DNA repair pathways, and I show that DREAM activity predicts somatic mutation rates, lifespan across 92 mammalian species, and Alzheimer's disease risk. Notably, genetic disruption of DREAM in mice reduces mutation accumulation in vivo.Together, these studies connect epigenetic aging, somatic mutation, and the transcriptional regulation of DNA repair – offering new perspectives on both the mechanisms of aging and opportunities for intervention.