Raphael ThysResearchers here demonstrate that, in mice, many biological markers of aging (in the epigenome, transcriptome, and metabolome) are made more youthful by a short in vivo exposure to the Yamanaka factors capable of reprogramming cells into induced pluripotent stem cells. That process also resets epigenetic marks on the genome to a youthful configuration, improving mitochondrial function, among other benefits. In this case, the goal of a short treatment is to minimize any possible cell conversion, keeping the reprogramming exposure short enough to only change epigenetic markers, gene expression, and cell behavior to be more youthful. The primary challenge in bringing this class of therapy to the clinic will be the long-term safety questions, how to assess (and then minimize) the risk of cancer via unwanted pluripotency of cells, when the consequences of that risk might take years to become visible in humans.
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 used the reprogrammable mice known as i4F-B which carries a ubiquitous doxycycline-inducible OSKM transgene, abbreviated as i4F. Mice of both sexes were used, and of different ages; young (females, 13 weeks), old (females, 55 weeks) and very old (males and females, 100 weeks). Doxycycline was administered in the drinking water for a period of 7 days. Mice were sacrificed two or four weeks after doxycycline removal. 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.