The role of DNA methylation in epigenetics of aging
Recent research suggests that epigenetics, especially DNA methylation, plays a mechanistic role in aging. Epigenetic clocks, which measure changes in a few hundred specific CpG sites, can accurately predict chronological age in a variety of species,including humans. These clocks are currently the best biomarkers for predictingmortalityin humans.
Additionally, several studies have characterized the effects of aging across the methylome in a wide variety of tissues
from humans andmice. A small fraction (~2%) of the CpG sites show age-related changes, either hypermethylation or
hypomethylation with aging. Evaluation of non-CpG site methylation has only been examined in a few studies, with
about ~0.5% of these sites showing achangewith age. Therefore,while only a small fraction ofcytosinesin the genome
show changes in DNA methylation with age, this represents 2 to 3 million cytosines in the genome. Importantly, the
only study to compare the effect of aging on DNA methylation in male and female mice and humans found that N95%
of the age-related changes in DNAmethylation in the hippocampus were sexually divergent, i.e., themethylation did
not differ betweenmales and females at young age but age-related changes occurredin one sex but not the other. The
age-related changes in DNA methylation tend to be enriched and under-represented in specific genomic contexts,
with some commonalities between tissues and species that require further investigation. The strongest evidence
that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions
(e.g., caloric restriction, dwarfism, and rapamycin treatment) in mice. These anti-aging interventions deaccelerate the epigenetic clocks and reverse/prevent 20 to 40% of the age-related changes in DNA methylation. It will be imporant in the future to demonstrate that at least some of the age-related changes in DNA methylation directly lead to alterations in the transcriptome of cells/tissues that could potentially contribute to aging.