title: The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling.
abstract: 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.
authors.affiliation: Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.forename: Elena
authors.initials: E
authors.lastname: Katsyuba
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.forename: Carles
authors.initials: C
authors.lastname: Cantó
authors.forename: Adrienne
authors.initials: A
authors.lastname: Mottis
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Jo
authors.forename: Mohan
authors.initials: M
authors.lastname: Viswanathan
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D008136:Longevity; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D009243:NAD; C507014:SIR-2.1 protein, C elegans; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins