Aging and epigenetic drift: a vicious cycle

Abstract

The term epigenetics refers to stable patterns of gene expression that are seen during differentiation or X chromosome inactivation and are not dependent on dynamic changes in coding DNA. These gene expression states are encoded in the epigenome - a collection of marks on DNA or on histone tails that are established during embryogenesis. Genome-wide studies in aging cells and tissues have uncovered stochastic DNA methylation drift (gradual increases or decreases at specific loci) that reflects imperfect maintenance of epigenetic marks. Drift creates epigenetic mosaicism in aging stem cells that could potentially restrict their plasticity and worsen phenotypes such as stem cell exhaustion and focal proliferative defects that can lead to cancer.

Figure 1. Dynamics of DNA methylation in genomic compartments.

(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.

Figure 2. A model of the effects of the aging epigenome on stem cell function.

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.