Epigenetic fidelity in complex biological systems and implications for ageing

The study of age is plagued by a lack of delineation between the causes and effects within the ageing phenotype. This has made it difficult to fully explain the biological ageing process from first principles with a single definition. Lacking a clear description of the underlying root cause of biological age confounds clarity in this critical field. In this paper, we demonstrate that the epigenetic system has a built-in, unavoidable fidelity limitation and consequently demonstrate that there is a distinct class of DNA methylation loci that increases in variance in a manner tightly correlated with chronological age. We demonstrate the existence of epigenetic ‘activation functions’ and that topological features beyond these activation functions represent deregulation. We show that the measurement of epigenetic fidelity is an accurate predictor of cross-species age and present a deep-learning model that predicts exclusively from knowledge of variance. We find that the classes of epigenetic loci in which variation correlates with chronological age control genes that regulate transcription and suggest that the inevitable consequence of this is a feedback cycle of system-wide deregulation causing a progressive collapse into the phenotype of age. This paper represents a novel theory of biological systemic ageing with arguments as to why, how and when epigenetic ageing is inevitable. ### Competing Interest Statement JPM is CSO of YouthBio Therapeutics, an advisor/consultant for the Longevity Vision Fund and NOVOS, and the founder of Magellan Science Ltd, a company providing consulting services in longevity science.