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Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing.

The Journal of cell biology (2017-06-02)
Bernadette Carroll, Glyn Nelson, Yoana Rabanal-Ruiz, Olena Kucheryavenko, Natasha A Dunhill-Turner, Charlotte C Chesterman, Qabil Zahari, Tong Zhang, Sarah E Conduit, Christina A Mitchell, Oliver D K Maddocks, Penny Lovat, Thomas von Zglinicki, Viktor I Korolchuk
ABSTRACT

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.

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