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Research Paper|Volume 17, Issue 7|pp 1834—1851

Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy

Andrei O. Zheltukhin1, Peter M. Chumakov1, Andrei V. Budanov1,2,3
  • 1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
  • 2School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
  • 3Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
Received: November 20, 2024Accepted: June 30, 2025Published: July 28, 2025
https://doi.org/10.18632/aging.206290

Copyright: © 2025 Zheltukhin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Sestrins, evolutionarily conserved stress-responsive proteins, are increasingly recognized for their potential role in lifespan regulation. This study aimed to elucidate the influence of the sesn-1 gene on lifespan modulation during caloric deprivation (CD) in the model organism C. elegans. Our findings reveal that sesn-1 mediates lifespan extension under CD, primarily through the repression of mTORC1 kinase and activation of autophagy. Moreover, we identified an essential role for sesn-1 in enhancing stress resilience in nematodes, particularly in the context of nutrient sensing. Further investigations demonstrated sesn-1’s interaction with the GATOR2 protein complex, its role in maintaining muscle integrity and a potential synergy between sesn-1 and the FOXO pathway. Overall, our research underscores the profound implications of Sestrins in aging and stress resistance, shedding light on possible therapeutic avenues for prevention and treatment of age-associated disorders.