Aging as a Failure of Epigenetic Repair Fidelity

Aging is a complex phenomenon, and deciphering the underlying causes and effects has posed significant challenges. In this presentation we highlight informatic traits of the epigenetic system that make it a singular candidate for the root cause of aging. We demonstrate that the epigenetic system has inherent limitations, leading to a distinct class of DNA methylation loci that exhibit increased variance tightly correlated with chronological age. By exploring the concept of epigenetic “activation functions” and their topological features, we show the patterns of epigenetic deregulation and argue that these patterns are a consequence of the logical necessities of the epigenetic system. We discuss our results showing that epigenetic fidelity serves as a powerful predictor of age across species and introduce a deep-learning model that exclusively relies on variance information for age estimation. We identify the classes of epigenetic loci associated with age-correlated variation, uncovering their role in regulating gene transcription. Our discoveries suggest that this interplay initiates a feedback cycle of system-wide deregulation, contributing to the progressive collapse into the aging phenotype. Overall, we propose a novel theory of biological systemic aging, and discuss why, how, and when epigenetic aging becomes inevitable.