Insulin-Like Growth Factor I Prevents Cellular Aging via Activation of Mitophagy

الملخص EN

Mitochondrial dysfunction is a hallmark of cellular aging.

Mitophagy is a critical mitochondrial quality control mechanism that removes dysfunctional mitochondria and contributes to cell survival.

Insulin-like growth factor 1 (IGF-1) promotes survival of smooth muscle cells (SMCs), but its potential effect on cellular aging is unknown yet.

We found that IGF-1 decreased cell senescence, prevented DNA telomere shortening, increased mitochondrial membrane potential, activated cytochrome C oxidase, and reduced mitochondrial DNA damage in long-term cultured (aged) aortic SMC, suggesting an antiaging effect.

IGF-1 increased mitophagy in aged cells, and this was associated with decreased expression of cyclin-dependent kinase inhibitors p16 and p21 and elevated levels of Nrf2 and Sirt3, regulators of mitophagy and mitochondrial biogenesis.

SiRNA-induced inhibition of either Nrf2 or Sirt3 blocked IGF-1-induced upregulation of mitophagy, suggesting that the Nrf2/Sirt3 pathway was required for IGF-1’s effect on mitophagy.

PINK1 is a master regulator of mitophagy.

PINK1 silencing suppressed mitophagy and inhibited IGF-1-induced antiaging effects in aged SMC, consistent with an essential role of mitophagy in IGF-1’s effect on cellular aging.

Thus, IGF-1 inhibited cellular aging via Nrf2/Sirt3-dependent activation of mitophagy.

Our data suggest that activation of IGF-1 signaling is a novel potential strategy to activate mitophagy and slow cellular aging.