Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Cell Cycle. 2012 Nov 1;11(21):3926-31. doi: 10.4161/cc.21908. Epub 2012 Sep 17.
Growth-promoting and nutrient/mitogen-sensing pathways such as mTOR convert p21- and p16-induced arrest into senescence (geroconversion). We have recently demonstrated that hypoxia, especially near-anoxia, suppresses geroconversion. This gerosuppressive effect of hypoxia correlated with inhibition of the mTOR/S6K pathway but not with modulation of the LKB1/AMPK/eEF2 pathway. Here we further show that mTOR inhibition is required for gerosuppression by hypoxia, at least in some cellular models, because depletion of TSC2 abolished mTOR inhibition and gerosupression by hypoxia. Also, in two cancer cell lines resistant to inhibition of mTOR by both p53 and hypoxia, hypoxia did not suppress geroconversion. Therefore, the effects of hypoxia on the oxygen-sensing mTOR pathway and geroconversion are cell type-specific. We also briefly discuss replicative senescence, organismal aging and free radical theory.
促进生长和营养/有丝分裂原感应途径，如 mTOR，将 p21 和 p16 诱导的阻滞转化为衰老（衰老转化）。我们最近证明，缺氧，特别是近缺氧，抑制衰老转化。这种缺氧的衰老抑制作用与 mTOR/S6K 途径的抑制相关，但与 LKB1/AMPK/eEF2 途径的调节无关。在这里，我们进一步表明，mTOR 抑制是缺氧引起衰老抑制所必需的，至少在某些细胞模型中是这样，因为 TSC2 的耗竭消除了缺氧引起的 mTOR 抑制和衰老抑制。此外，在两种对 p53 和缺氧抑制 mTOR 均有抗性的癌细胞系中，缺氧并未抑制衰老转化。因此，缺氧对氧感应 mTOR 途径和衰老转化的影响是细胞类型特异性的。我们还简要讨论了复制性衰老、生物体衰老和自由基理论。
