Reversal of Aging via in Vivo Epigenetic Reprogramming

Abstract

Aging is a degenerative process leading to tissue dysfunction and death. A proposed cause of aging is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage. Changes to DNA methylation patterns over time form the basis of 'aging clocks', but whether old individuals retain information to reset the clocks and, if so, whether it would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal aged mice. This process, which we call the reversal of information loss via epigenetic reprogramming or REVIVER, requires non-global, active DNA demethylation by TET enzymes and the downstream enzyme TDG, indicating that alterations in DNA methylation patterns may not simply indicate age, but participate in aging. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.