Epigenetic fidelity in complex biological systems and implications for ageing

Abstract

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 chrono- logical 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.

Accurate aging clocks based on accumulating stochastic variation

“…Reducing such random variation by tightening regulatory mechanisms such as methylation maintenance and gene expression would be predicted to slow the aging process and could provide targetable approaches. This is therefore consistent with the epigenetic maintenance system (EMS) theory 25 , or the recently proposed information fidelity theory of aging 92 .…”

A comprehensive map of the ageing blood methylome

“…We also show that the increase in entropy is driven by the differential shifts that trend from high and low methylation fractions in young, to intermediate methylation states at older ages; also referred to as the ‘smoothening of the epigenetic landscape,’ however, intermediately methylated CpGs that drift away from the mean towards fully methylated and unmethylated states decrease entropy, exhibiting ‘antientropic’ properties. It has been proposed that ‘anti-entropic’ CpGs could represent genes that become increasingly regulated 6 , a theory worth investigating further. Since the majority of DMPs are entropic, the net global effect is an increase in entropy with age.…”

“…Entropy can summarise all the age-related changes in DNAm using a single value, for a sample at a particular age, making it a highly useful in capturing the entirety of the age-related changes in the methylome. Previous literature has shown that DMPs shifting towards a methylation fraction of 50% drive entropy 4,5 , but there are also subsets of DMPs that trend away from the mean and may oppose or counteract the effect 6 .…”