NAD⁺ is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD⁺ levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD⁺ levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD⁺ prevents age-associated metabolic decline and promotes longevity in worms. These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPR^mt) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD⁺ levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.