Aging is a process of gradual functional decline leading to death. Reactive oxygen species (ROS) not only contribute to oxidative stress and cell damage that lead to aging but also serve as signaling molecules. Sestrins are evolutionarily conserved in all multicellular organisms and are required for regenerating hyperoxidized forms of peroxiredoxins and ROS clearance. However, whether sestrins regulate longevity in metazoans is still unclear. Here, we demonstrated that SESN-1, the only sestrin ortholog in Caenorhabditis elegans, is a positive regulator of lifespan. sesn-1 gene mutant worms had significantly shorter lifespans compared to wild-type animals, and overexpression of sesn-1 prolonged lifespan. Moreover, sesn-1 was found to play a key role in defense against several life stressors, including heat, hydrogen peroxide and the heavy metal copper; and sesn-1 mutants expressed higher levels of ROS and showed a decline in body muscle function. Surprisingly, loss of sesn-1 did not weaken the innate immune function of the worms. Together, these results suggest that SESN-1 is required for normal lifespan and its function in muscle cells prevents muscle degeneration over a lifetime.
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