Aging through an epitranscriptomic lens

The mechanistic causes of aging, the time-related decline in function and good health that leads to increased mortality, remain poorly understood. Here we propose that age-dependent alteration of the epitranscriptome, encompassing more than 150 chemically distinct post-transcriptional modifications or editing events, warrants exploration as an important modulator of aging. The epitranscriptome is a potent regulator of RNA function, diverse cellular processes and tissue regenerative capacity. To date, only a few studies link alterations in the epitranscriptome to molecular and physiological changes during aging; however, epitranscriptome dysfunction is associated with and underlies several age-associated pathologies, including cancer and neurodegenerative, cardiovascular and autoimmune diseases. For example, changes in RNA modifications (such as N6-methyladenosine and inosine) impact cardiac physiology and are linked to cardiac fibrosis. Although an uncharted research focus, mapping epitranscriptome alterations in the context of aging may elucidate novel predictors of both health and lifespan, and may identify therapeutic targets for attenuating aging and abrogating age-related diseases. In this Perspective, McMahon et al. examine the emerging roles and implications of post-transcriptional RNA modifications, or the epitranscriptome, in aging and age-related diseases, highlighting potential epitranscriptomic mechanisms and/or their dysfunction that may regulate the aging process.