Seminars

All eukaryotes experience an increase in epigenetic entropy over time, but how it occurs and whether it is a cause of aging are not known. Using a mouse model, we find that epigenetic alterations, following faithful DNA repair, cause aging at molecular, physiological, and cognitive levels. Short-term induction of Oct4, Sox2, and Klf4 in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity. We further identify chemical cocktails that, in less than a week, restore a youthful gene expression profile and reverse cellular aging. These findings suggest that the pace and direction of mammalian aging can be epigenetically reprogrammed.