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

Carroll, B. et al. (2017) Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing. Journal of Cell Biology, 216(7), pp. 1949-1957. (doi: 10.1083/jcb.201610113) (PMID:28566325) (PMCID:PMC5496614)

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.

• Item Type: Articles
• Additional Information: This project was carried out with funding support from the Biotechnology and Biological Sciences Research Council (V.I. Korolchuk [BB/M023389/1] and T. von Zglinicki) and British Skin Foundation (V.I. Korolchuk and B. Carroll; BSF4775), as well as the National Health and Medical Research Council, Australia (C.A. Mitchell and S.E. Conduit).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Maddocks, Professor Oliver and Zhang, Mr Tong
• Authors: Carroll, B., Nelson, G., Rabanal-Ruiz, Y., Kucheryavenko, O., Dunhill-Turner, N. A., Chesterman, C. C., Zahari, Q., Zhang, T., Conduit, S. E., Mitchell, C. A., Maddocks, O. D.K., Lovat, P., von Zglinicki, T., and Korolchuk, V. I.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Cell Biology
• Publisher: Rockfeller University Press
• ISSN: 0021-9525
• ISSN (Online): 1540-8140
• Published Online: 31 May 2017
• Copyright Holders: Copyright © 2017 Carroll et al.
• First Published: First published in Journal of Cell Biology 216(7): 1949-1957
• Publisher Policy: Reproduced under a Creative Commons license