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

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 <i>sesn-1</i> gene on lifespan modulation during caloric deprivation (CD) in the model organism <i>C. elegans</i>. Our findings reveal that <i>sesn-1</i> mediates lifespan extension under CD, primarily through the repression of mTORC1 kinase and activation of autophagy(definition). Moreover, we identified an essential role for <i>sesn-1</i> in enhancing stress resilience in nematodes, particularly in the context of nutrient sensing. Further investigations demonstrated <i>sesn-1</i>'s interaction with the GATOR2 protein complex, its role in maintaining muscle integrity and a potential synergy between <i>sesn-1</i> 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.