Dual mTORC1/C2 inhibitors: gerosuppressors with potential anti-aging effect

Abstract

Over the past decade, our understanding of the molecular and cellular mechanisms presiding over cellular and tissue decline with aging has greatly advanced. Classical hallmarks of aging cell include increasing levels of reactive oxygen species, DNA damage and senescence entry, which disrupt tissue architecture and function. Tissue dysfunction with aging has been shown to correlate with a cellular switch from a G0 reversible quiescence state into a G0 irreversible senescence state (geroconversion), causing a permanent proliferative block. The TOR (target of rapamycin) kinase has been shown to promote geroconversion. Rapamycin and other rapalogs specifically suppress activity of the mammalian TOR (mTOR) complex 1 (mTORC1) -but not mTOR complex 2 (mTORC2)- and decrease senescence entry, thus preserving proliferative potential. In this perspective, we briefly comment recent progress of Leontieva and colleagues showing a new class of non-rapalog drugs that target simultaneously mTORC1 and mTORC2 and prevent geroconversion in a more efficient way than rapamycin. Its potential future use as rejuvenating, anti-aging therapeutics is therefore proposed.