PMC

(A) The top line represents DNA containing two genes (arrows indicate transcription start sites; exons are shown in black); three CpG islands (CGI; green) located in a promoter, a 3′ end, and an intergenic area; two enhancers (red); a series of repeats (thin black lines); a non-CGI promoter (purple); and intergenic and intronic DNA (open boxes). The normal methylation state and aging changes are summarized in the light blue box. (B) Effector enzymes that switch DNA methylation on or off. DNMTs include DNMT1, DNMT3a, and DNMT3b; TETs include TET1, TET2, and TET3.

Young stem cells have relatively uniform epigenomes. During aging, stem cells replicate and stochastic errors in DNA methylation maintenance introduce epigenetic mosaicism. Exposures and/or chronic inflammation accelerate this process by promoting stem cell replication (e.g., for tissue repair) or by working directly on the epigenome. Continued epigenetic mosaicism results in restricted differentiation in some stem cells, leading to stem cell exhaustion and a selective growth advantage in other stem cells, which then leads to clonal expansion and local hyperproliferation. The combination of stem cell exhaustion and clonal expansion contributes to phenotypes and diseases of aging. In turn, these proliferative and restricted differentiation phenotypes promote epigenetic drift, creating a vicious cycle that exponentially increases the rate of some diseases such as cancer.