Chapter 6 - Genome-Wide DNA Methylation Changes During Aging

Abstract

Differences in DNA methylation patterns have been observed among individuals of disparate ages in both a tissue-dependent manner and tissue-independent manner. In general, high-density regions of cytosine–guanine dinucleotides (CpG)—typically in gene promoters—are unmethylated in healthy cells of younger individuals and may acquire methylation with aging, whereas CpGs in low-density regions are methylated and may lose methylation with aging. Population-based genome-wide DNA methylation studies have identified several common features of age-related DNA methylation across tissue types, including the preferential targeting of genes involved in stem cell function. Enrichment for age-related methylation alterations among these genes suggests that the observed decline in stem cell function with age may be, in part, linked to age-related DNA methylation shifts. Methylation differences across age groups are thought to arise from a gradual process known as “epigenetic drift,” increases or decreases of methylation at specific loci that can then spread to adjacent sites. Age-related methylation differences resulting from epigenetic drift have been observed to exhibit both tissue-specific and tissue-independent patterns. As a result, the importance of deconvoluting cell-type-specific methylation patterns when analyzing methylation in complex mixtures, such as blood DNA, has gained recognition, and statistical techniques have emerged to adjust for potential confounding by cell type. Future work is needed to elucidate the mechanisms of age-related DNA methylation and how these may affect both the aging phenotype and the risk of age-related disease. Where possible, these studies should include target tissue types, rather than surrogates, and address potential variation in cell-type proportions in order to understand the tissue-dependent and tissue-independent effects. A more comprehensive understanding of age-related DNA methylation may assist in both the prevention of age-related diseases and identifying interventions that promote healthy aging.