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

TLDR

OSKM factors can reprogram differentiated cells into pluripotent stem cells, yet the mechanisms underlying partial, reversible reprogramming that preserves cell identity remain poorly understood. We examined DNA methylation, transcriptomic, and metabolomic changes in naturally aged mice after a single transient OSKM expression period. This transient reprogramming reverses aging‑associated DNA methylation, transcriptional, and metabolomic signatures in multiple tissues and serum, enhances tissue repair, and extends longevity in progeroid mice.

Abstract

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, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, 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 and biomarkers 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 toward a younger configuration in multiple tissues and in the serum.