title: Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program).
abstract: In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 and PP242), which inhibit both mTORC1 and TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in proliferating cells), mTOR inhibitors preserved re-proliferative potential (RP) in arrested cells. In p21-arrested cells, Torin 1 and PP242 detectably suppressed geroconversion at concentrations as low as 1-3 nM and 10-30 nM, reaching maximal gerosuppression at 30 nM and 300 nM, respectively. Near-maximal gerosuppression coincided with inhibition of p-S6K(T389) and p-S6(S235/236). Dual mTOR inhibitors prevented senescent morphology and hypertrophy. Our study warrants investigation into whether low doses of dual mTOR inhibitors will prolong animal life span and delay age-related diseases. A new class of potential anti-aging drugs can be envisioned.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Leontieva
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Zoya N
authors.initials: ZN
authors.lastname: Demidenko
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000737:chemistry*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D011687:Purines / Q000737:chemistry*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001798:Blood Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D046912:Multiprotein Complexes; D011687:Purines; C031024:torin; C515074:ridaforolimus; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus
keywords: Gerotarget; Pathology Section; aging; pan-mTOR inhibitors; rapalogs; rapamycin; senescence