Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program)

摘要: In proliferating cells, mTOR is active and promotes cell growth. When the cycle arrested, then converts reversible arrest to senescence (geroconversion). Rapamycin other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 PP242), which inhibit both mTORC1 TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in cells), preserved re-proliferative potential (RP) in arrested cells. p21-arrested Torin 1 PP242 detectably geroconversion at concentrations as low 1-3 nM 10-30 nM, reaching maximal gerosuppression 30 300 respectively. Near-maximal coincided with p-S6K(T389) p-S6(S235/236). Dual prevented senescent morphology hypertrophy. Our study warrants investigation into whether doses dual will prolong animal life span delay age-related diseases. A new class anti-aging drugs can be envisioned.