Leontieva Olga V, Blagosklonny Mikhail V
Department of Cell Stress Biology, Roswell Park Cancer Institute, Elms and Carlson Streets, Buffalo, NY 14263, USA.
Aging (Albany NY). 2016 Dec 30;8(12):3535-3551. doi: 10.18632/aging.101155.
Rapamycin slows organismal aging and delays age-related diseases, extending lifespan in numerous species. In cells, rapamycin and other rapalogs such as everolimus suppress geroconversion from quiescence to senescence. Rapamycin inhibits some, but not all, activities of mTOR. Recently we and others demonstrated that pan-mTOR inhibitors, known also as dual mTORC1/C2 inhibitors, suppress senescent phenotype. As a continuation of these studies, here we investigated in detail a panel of pan-mTOR inhibitors, to determine their optimal gerosuppressive concentrations. During geroconversion, cells become hypertrophic and flat, accumulate lysosomes (SA-beta-Gal staining) and lipids (Oil Red staining) and lose their re-proliferative potential (RPP). We determined optimal gerosuppressive concentrations: Torin1 (30 nM), Torin 2 (30 nM), AZD8055 (100 nM), PP242 (300 nM), both KU-006379 and GSK1059615 (1000 nM). These agents decreased senescence-associated hypertrophy with IC50s: 20, 18, 15, 200 and 400 nM, respectively. Preservation of RPP by pan-mTOR inhibitors was associated with inhibition of the pS6K/pS6 axis. Inhibition of rapamycin-insensitive functions of mTOR further contributed to anti-hypertrophic and cytostatic effects. Torin 1 and PP242 were more "rapamycin-like" than Torin 2 and AZD8055. Pan-mTOR inhibitors were superior to rapamycin in suppressing hypertrophy, senescent morphology, Oil Red O staining and in increasing so-called "chronological life span (CLS)". We suggest that, at doses lower than anti-cancer concentrations, pan-mTOR inhibitors can be developed as anti-aging drugs.
雷帕霉素可减缓机体衰老，延缓与年龄相关的疾病，延长多种物种的寿命。在细胞中，雷帕霉素和其他雷帕霉素类似物（如依维莫司）可抑制细胞从静止状态向衰老状态的转变。雷帕霉素可抑制mTOR的部分而非全部活性。最近，我们和其他研究人员证明，泛mTOR抑制剂（也称为双mTORC1/C2抑制剂）可抑制衰老表型。作为这些研究的延续，我们在此详细研究了一组泛mTOR抑制剂，以确定它们的最佳衰老抑制浓度。在细胞转变过程中，细胞会变得肥大且扁平，积累溶酶体（SA-β-Gal染色）和脂质（油红染色），并丧失其再增殖潜能（RPP）。我们确定了最佳衰老抑制浓度：托瑞米芬1（30 nM）、托瑞米芬2（30 nM）、AZD8055（100 nM）、PP242（300 nM）、KU-006379和GSK1059615（均为1000 nM）。这些药物可降低与衰老相关的肥大，其IC50分别为：20、18、15、200和400 nM。泛mTOR抑制剂对RPP的保留与对pS6K/pS6轴的抑制有关。对mTOR雷帕霉素不敏感功能的抑制进一步促进了抗肥大和细胞生长抑制作用。托瑞米芬1和PP242比托瑞米芬2和AZD8055更具“雷帕霉素样”特性。泛mTOR抑制剂在抑制肥大、衰老形态学、油红O染色以及延长所谓的“时序寿命（CLS）”方面优于雷帕霉素。我们建议，在低于抗癌浓度的剂量下，泛mTOR抑制剂可开发为抗衰老药物。
