Cellular mechanisms by which age may impact reprogramming of somatic cells into iPSCs. Studies in mice indicate that aging hampers reprogramming efficiency [-]. This decrease may partly be due to the fact that old tissues contain a more heterogeneous pool of cells, including normal, pre-senescent, senescent and dysfunctional cells that may not reprogram. Senescence pathways including the p19ARF/p53/p21CIP1 and the p16INK4a/Rb pathways have been shown to constitute barriers to the reprogramming process [, , , -]. The reprogramming process per se induces a stress similar to senescence [] that may push pre-senescent cells into a fully senescent state, which may further hamper reprogramming. Although, initial studies suggest that iPSCs derived from old donors are as potent as their young counterparts in terms of pluripotency and re-differentiation potential, further studies are required to fully understand the impact of age on the iPSCs, including their tumorigenic potential.

Compounds that modulate well-known aging and metabolism pathways affect somatic cell reprogramming [, ]. Green boxes depict compounds that enhance reprogramming, and red boxes depict compounds that inhibit the process. The pro-reprogramming compounds have been shown to act in the early phase of reprogramming, potentially by preventing hyper activation of insulin/IGF-1 and mTOR pathways that may in turn induce cellular senescence and/or facilitate mesenchymal-to-epithelial transition []. It is not clear yet whether treatment with metformin hampers reprogramming or enhances it [, ].

Aspects of aging that can be ‘rejuvenated’ or not by reprogramming.