Aspirin Inhibits Oxidant Stress, Reduces Age-Associated Functional Declines, and Extends Lifespan of Caenorhabditis elegans

Aims: Oxidative stress and inflammation are leading risk factors for age-associated functional declines. We assessed aspirin effects on endogenous oxidative-stress levels, lifespan, and age-related functional declines, in the nematode Caenorhabditis elegans. Results: Both aspirin and its salicylate moiety, at nontoxic concentrations (0.5-1 mM), attenuated endogenous levels of reactive oxygen species (p < 0.001), and upregulated antioxidant genes encoding superoxide dismutases (especially sod-3, p < 0.001), catalases (especially ctl-2, p < 0.0001), and two glutathione-S-transferases (gst-4 and gst-10; each p < 0.005). Aspirin, and to a lesser degree salicylate, improved survival of hydrogen peroxide, and in the absence of exogenous stress aspirin extended lifespan by 21%-23% (each p < 10(-9)), while salicylate added 14% (p < 10(-6)). Aspirin and salicylate delayed age-dependent declines in motility and pharyngeal pumping (each p < 0.005), and decreased intracellular protein aggregation (p < 0.0001)-all established markers of physiological aging-consistent with slowing of the aging process. Aspirin fails to improve stress resistance or lifespan in nematodes lacking DAF-16, implying that it acts through this FOXO transcription factor. Innovation: Studies in mice and humans suggest that aspirin may protect against multiple age-associated diseases by reducing all-cause mortality. We now demonstrate that aspirin markedly slows many measures of aging in the nematode. Conclusions: Aspirin treatment is associated with diminished endogenous oxidant stress and enhanced resistance to exogenous peroxide, both likely mediated by activation of antioxidant defenses. Our evidence indicates that aspirin attenuates insulin-like signaling, thus protecting against oxidative stress, postponing age-associated functional declines and extending C. elegans lifespan under benign conditions. Antioxid. Redox Signal. 18, 481-490.