Loss of epigenetic information as a cause of mammalian aging

Highlights

• Cellular responses to double-stranded DNA breaks erode the epigenetic landscape

• This loss of epigenetic information accelerates the hallmarks of aging

• These changes are reversible by epigenetic reprogramming

• By manipulating the epigenome, aging can be driven forward and backward

Summary

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called “ICE” (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.