DNA methylation in genes associated with the evolution of ageing and disease: A critical review

Ageing is characterised by a physical decline in biological functioning which results in a progressive risk of mortality with time. As a biological phenomenon, it is underpinned by the dysregulation of a myriad of complex processes. Recently, however, ever-increasing evidence has associated epigenetic mechanisms, such as DNA methylation (DNAm) with age-onset pathologies, including cancer, cardiovascular disease, and Alzheimer's disease. These diseases compromise healthspan. Consequently, there is a medical imperative to understand the link between epigenetic ageing, and healthspan. Evolutionary theory provides a unique way to gain new insights into epigenetic ageing and health. This review will: (1) provide a brief overview of the main evolutionary theories of ageing; (2) discuss recent genetic evidence which has revealed alleles that have pleiotropic effects on fitness at different ages in humans; (3) consider the effects of DNAm on pleiotropic alleles, which are associated with age related disease; (4) discuss how age related DNAm changes resonate with the mutation accumulation, disposable soma and programmed theories of ageing; (5) discuss how DNAm changes associated with caloric restriction intersect with the evolution of ageing; and (6) conclude by discussing how evolutionary theory can be used to inform investigations which quantify age-related DNAm changes which are linked to age onset pathology.