Genome-Wide DNA Methylation Ageing Trends

While the link between DNA methylation and ageing has been studied over a long period of time, recent findings and advances have sharpened the focus on the role of DNA methylation in the ageing process. Early studies began assessing the relationship of age and DNA methylation patterns over 40 years ago, using techniques such as liquid chromatography to assess bulk mean methylation levels in salmon, rodent, cattle, and chicken [66,67]. A pioneering study showed a significant loss of total DNA meth- ylation over the rodent life course across a number of tissues, a finding that was later validated in blood from a cross sectional human cohort consisting of both newborns and centenarians [68, 69l . These explorations laid the foundation for human DNA methylation ageing studies, and as technology continues to advance, allowing easier access to the entire methylome, we enter an exciting era of epigenetic ageing research.

It is estimated that one-third of the epigenome’s DNA methylation content changes in association with the ageing process, and recent advances have helped further elucidate the context and potential function of these changes. For example, the previously mentioned finding that DNA exhibits a gradual loss of mean methyla- tion over time has recently been shown to occur in a genomic context-specific manner. Loss of methylation preferentially occurs at regions of low CpG density, often located within a gene body [69] . Despite the fact that mean DNA methylation decreases with age, there are specific age-related methylation changes that involve a gain in methylation as well. These tend to be found within CpG islands, or areas of high CpG density [70, 71]. Together, these changes demonstrate a regression to the mean pattern—low CpG density regions, which are normally highly methylated lose DNA methylation with age, while high density regions which tend to have low levels of DNA methylation gain DNA methylation with age. Since most CpGs in the genome are methylated, this translates to a global loss of DNA methylation. An interesting exception to this pattern is repetitive elements, which tend to be highly methylated and lose DNA methylation with age, despite their high CpG density [72].

Clearly, the relationship between DNA methylation and age is highly complex, with specific patterns occurring at unique genetic regions. A host of research explorations including animal models, human longitudinal twin studies and age-variable

Fig. 3.3 Epigenetic drift results in divergent DNA methylation patterns with increasing age. In early life (left), identical twins have highly similar epigenetic patterns (individuals A and B), while individual C is distinct. Later in life (right), all individuals are more discordant, as epigenetic drift has altered lowly-methylated CpGs (lighter) to be more methylated, and higher-methylated CpGs (darker) to be less methylated

cohorts, have all contributed to identifying DNA methylation patterns with age. From the combination of these research findings, it is evident that two common trends of epigenetic aging have emerged: (1) random changes to DNA methylation that are inconsistent across individuals, and (2) predictable, site-specific DNA methylation changes occurring in a similar way across individuals with age [73, 74] (Fig. 3.3).