title: SRT1720 improves survival and healthspan of obese mice.
abstract: Sirt1 is an NAD(+)-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals.
authors.affiliation: Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Robin K
authors.initials: RK
authors.lastname: Minor
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.forename: Ana P
authors.initials: AP
authors.lastname: Gomes
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ward
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.forename: Evi M
authors.initials: EM
authors.lastname: Mercken
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.forename: Yu-Kyong
authors.initials: YK
authors.lastname: Shin
authors.forename: Carles
authors.initials: C
authors.lastname: Canto
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.forename: Melissa
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Irusta
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martín-Montalvo
authors.forename: Basil P
authors.initials: BP
authors.lastname: Hubbard
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: Alexa A
authors.initials: AA
authors.lastname: White
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Price
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pearson
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
authors.forename: Mark I
authors.initials: MI
authors.lastname: Talan
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Westphal
authors.forename: James L
authors.initials: JL
authors.lastname: Ellis
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Elliott
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000503:physiopathology*; D010179:Pancreas / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; D005947:Glucose