Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing.
Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing.
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DOI：
10.1083/jcb.201610113
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发表时间：
2017-07-03
期刊：
影响因子：
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通讯作者：
Korolchuk VI
中科院分区：
文献类型：
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作者：
Carroll B;Nelson G;Rabanal-Ruiz Y;Kucheryavenko O;Dunhill-Turner NA;Chesterman CC;Zahari Q;Zhang T;Conduit SE;Mitchell CA;Maddocks ODK;Lovat P;von Zglinicki T;Korolchuk VI
目前还不清楚mTORC1信号在衰老和年轻细胞中的差异。卡罗尔等人表明，衰老导致组成型mTORC 1活化以及对血清和氨基酸饥饿的抗性。这与自噬增加、细胞质膜去极化和初级纤毛缺陷有关。哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）和细胞衰老相互密切相关，并与生物体衰老密切相关。抑制mTORC1是延长寿命的最佳干预措施，最近的证据表明，清除衰老细胞也可以改善健康和寿命。增强mTORC1活性驱动衰老的特征表型，尽管负责增加活性的潜在机制还没有很好地理解。我们已经确定，在人成纤维细胞呈现衰老的压力，复制枯竭，或癌基因激活，mTORC 1是组成性的活性和抵抗血清和氨基酸饥饿。这部分是由衰老细胞质膜的去极化驱动的，这导致初级纤毛缺陷和抑制生长因子信号传导的结果失败。此外，增加的自噬和高水平的细胞内氨基酸可以起到支持饥饿条件下mTORC 1活性的作用。纠正这些表型的干预措施恢复了对mTORC 1信号通路的敏感性并导致死亡，表明持续的信号传导支持衰老细胞存活。
It is unclear how mTORC1 signaling differs in senescent and young cells. Carroll et al. show that senescence leads to constitutive mTORC1 activation and resistance to serum and amino acid starvation. This is associated with elevated autophagy, depolarization of cell plasma membrane, and primary cilia defects. Mammalian target of rapamycin complex 1 (mTORC1) and cell senescence are intimately linked to each other and to organismal aging. Inhibition of mTORC1 is the best-known intervention to extend lifespan, and recent evidence suggests that clearance of senescent cells can also improve health and lifespan. Enhanced mTORC1 activity drives characteristic phenotypes of senescence, although the underlying mechanisms responsible for increased activity are not well understood. We have identified that in human fibroblasts rendered senescent by stress, replicative exhaustion, or oncogene activation, mTORC1 is constitutively active and resistant to serum and amino acid starvation. This is driven in part by depolarization of senescent cell plasma membrane, which leads to primary cilia defects and a resultant failure to inhibit growth factor signaling. Further, increased autophagy and high levels of intracellular amino acids may act to support mTORC1 activity in starvation conditions. Interventions to correct these phenotypes restore sensitivity to the mTORC1 signaling pathway and cause death, indicating that persistent signaling supports senescent cell survival.