Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum. ### Competing Interest Statement D.E.M.H is a founder and shareholder at Chronomics Limited. G.K. is founder of Samsara Therapeutics and advisor of The Longevity Labs. W.R. is consultant and shareholder of Cambridge Epigenetix. M.S. is founder, shareholder and advisor of Senolytic Therapeutics, Inc., Iduna Therapeutics, Inc, and RejuverSen, AG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.