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.
Pubmed ID: 23870130 RIS Download
Mesh terms: Aging | Animals | Caenorhabditis elegans | Caenorhabditis elegans Proteins | Forkhead Transcription Factors | Hepatocytes | Longevity | Mice | Mitochondria | NAD | Poly(ADP-ribose) Polymerase Inhibitors | Reactive Oxygen Species | Signal Transduction | Sirtuin 1 | Sirtuins | Transcription Factors | Unfolded Protein Response
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.