Progress Towards Decoupling Epigenetic Rejuvenation from Cell Identity Change in Partial Reprogramming

Reprogramming cells using the Yamanaka factors produces both a reset of epigenetic patterns to a more youthful configuration and a change in cell identify. One of the primary challenges inherent in reprogramming to achieve rejuvenation is avoidance of this altered cell identity. Reprogramming isn't an immediate switch, it is a slow process over hours to days, but a fraction of reprogrammed cells do change into induced pluripotent stem cells after some period of exposure to reprogramming factors. This is an undesirable outcome when delivering a reprogramming therapy; if new approaches can be found that do not alter cell identity, that would make reprogramming a much more viable basis for rejuvenation treatments.

Partial somatic cell reprogramming has been touted as a promising rejuvenation strategy. However, its association with mechanisms of aging and longevity at the molecular level remains unclear. We identified a robust transcriptomic signature of reprogramming in mouse and human cells that revealed co-regulation of genes associated with reprogramming and response to lifespan-extending interventions, including those related to DNA repair and inflammation. We found that age-related gene expression changes were reversed during reprogramming, as confirmed by transcriptomic aging clocks.

The longevity and rejuvenation effects induced by reprogramming in the transcriptome were mainly independent of pluripotency gain. Decoupling of these processes allowed predicting interventions mimicking reprogramming-induced rejuvenation (RIR) without affecting somatic cell identity, including an anti-inflammatory compound osthol, ATG5 overexpression, and C6ORF223 knockout. Overall, we revealed specific molecular mechanisms associated with RIR at the gene expression level and developed tools for discovering interventions that support the rejuvenation effect of reprogramming without posing the risk of neoplasia.