Glutathione intake promotes longevity through the activation of SIR-2.1 and DAF-16 (FoxO) pathway in C. elegans

Oxidative stress has a prominent role in lifespan regulation of the living organisms. One of the endogenous free radical scavenger systems is associated with GSH, the most abundant nonprotein thiol in mammalian cells, acting as a major reducing agent and antioxidant defence. We have recently designed a series of novel S-acyl-GSH derivatives capable to prevent amyloid oxidative stress and cholinergic dysfunction in Alzheimer disease models, upon the increase of GSH intake. In this study we show that the longevity of wild-type N2 Caenorhabditis elegans strain was significantly enhanced by dietary supplementation with linolenoyl-SG (lin-SG) thioester with respect to ethyl ester of GSH, linolenic acid or vitamin E. RNA interference analysis and activity inhibition assay indicate that lifespan extension was mediated by the upregulation of SIR-2.1, a NAD-dependent histone deacetylase ortholog of mammalian SIRT1. In particular, lin-SG-mediated overexpression of sir-2.1 appears to be related to the DAF-16 (FoxO) pathway. Moreover, lin-SG derivative protects N2 worms from the paralysis and oxidative stress induced by Ab/H2O2 exposure. Overall, our findings put forward lin-SG thioester as an antioxidant supplement triggering sirtuin upregulation, thus opening new future perspectives for healthy aging or delayed onset of oxidative-related diseases.