Rejuvenation by Partial Reprogramming of the Epigenome.

ABSTRACT

Epigenetic variation with age is one of the most important hallmarks of aging. Resetting or repairing the epigenome of aging cells in intact animals may rejuvenate the cells and perhaps the entire organism. In fact, differentiated adult cells, which by definition have undergone some epigenetic changes, are capable of being rejuvenated and reprogrammed to create pluripotent stem cells and viable cloned animals. Apparently, such reprogramming is capable of completely resetting the epigenome. However, attempts to fully reprogram differentiated cells in adult animals have failed in part because reprogramming leads to the formation of teratomas. A preliminary method to partially reprogram adult cells in mature Hutchinson-Gilford Progeria Syndrome (HGPS) mice by transient induction of the Yamanaka factors OSKM (Oct4/Sox2/Klf4/c-Myc) appears to ameliorate aging-like phenotypes in HGPS mice, and promote youthful regenerative capability in middle-aged wild-type individuals exposed to beta cell and muscle cell-specific toxins. However, whatever epigenetic repair is induced by transient reprogramming does not endure and may be due to the induction of key homeostatic regulators instead. Some of the effect of transient reprogramming may result from increased proliferation and enhanced function of adult stem cells. Partial reprogramming may point the way to new antiaging and proregenerative therapeutics. Redifferentiation of cells into their preexisting phenotype with simultaneous epigenomic rejuvenation is an interesting variation that also should be pursued. However, discovery of methods to more precisely repair the epigenome is the most likely avenue to the development of powerful new antiaging agents.