Rejuvenating the damaged and aged heart: lessons from development

Mammals have evolutionarily sacrificed their cardiac regenerative capacity in order to maintain high-output contractile function. This developmental trade-off involves integrated metabolic and epigenetic regulation, as well as microenvironmental maturation, all of which contribute to the withdrawal of cardiomyocytes from the cell-cycle. Reactivating juvenile regulatory networks-through the induction of transcription factors, metabolic reprogramming, and modulation of the cellular niche-may offer a strategy to restore proliferative potential in adult cardiomyocytes. Notably, cardiac aging appears to recapitulate the disruption of these regulatory mechanisms. Therefore, we propose that reprogramming strategies capable of reversing the developmental barriers to regeneration may represent a promising approach to counteract cardiac senescence.