SRT1720 Improves Survival and Healthspan of Obese Mice

Authors

• Robin K. Minor, National Institutes of Health
• Joseph A. Baur, University of Pennsylvania
• Ana P. Gomes, Harvard Medical School
• Theresa M. Ward, National Institutes of Health
• Anna Csiszar, University of Oklahoma Health Sciences Center
• Evi M. Mercken, National Institutes of Health
• Kotb Abdelmohsen, National Institutes of Health
• Yu-Kyong Shin, National Institutes of Health
• Carles Canto, Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland
• Morten Scheibye-Knudsen, National Institutes of Health
• Melissa Krawczyk, National Institutes of Health
• Pablo M. Irusta, National Institutes of Health
• Alejandro Martín-Montalvo, National Institutes of Health
• Basil P. Hubbard, Harvard Medical School
• Yongqing Zhang, National Institutes of Health
• Elin Lehrmann, National Institutes of Health
• Alexa A. White, National Institutes of Health
• Nathan L. Price, Harvard Medical School
• William R. Swindell, Harvard Medical School
• Kevin J. Pearson, University of KentuckyFollow
• Kevin G. Becker, National Institutes of Health
• Vilhelm A. Bohr, National Institutes of Health
• Myriam Gorospe, National Institutes of Health
• Josephine M. Egan, National Institutes of Health
• Mark I. Talan, National Institutes of Health
• Johan Auwerx, Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland
• Christoph H. Westphal, Sirtris
• James L. Ellis, Sirtris
• Zoltan Ungvari, University of Oklahoma Health Sciences Center
• George P. Vlasuk, Sirtris
• Peter J. Elliott, Sirtris
• David A. Sinclair, Harvard Medical School
• Rafael de Cabo, National Institutes of Health

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.

Document Type

Article

Publication Date

8-18-2011

Notes/Citation Information

Published in Scientific Reports, v. 1, 70.

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visithttp://creativecommons.org/licenses/by-nc-nd/3.0/

Digital Object Identifier (DOI)

http://dx.doi.org/10.1038/srep00070

Repository Citation

Minor, Robin K.; Baur, Joseph A.; Gomes, Ana P.; Ward, Theresa M.; Csiszar, Anna; Mercken, Evi M.; Abdelmohsen, Kotb; Shin, Yu-Kyong; Canto, Carles; Scheibye-Knudsen, Morten; Krawczyk, Melissa; Irusta, Pablo M.; Martín-Montalvo, Alejandro; Hubbard, Basil P.; Zhang, Yongqing; Lehrmann, Elin; White, Alexa A.; Price, Nathan L.; Swindell, William R.; Pearson, Kevin J.; Becker, Kevin G.; Bohr, Vilhelm A.; Gorospe, Myriam; Egan, Josephine M.; Talan, Mark I.; Auwerx, Johan; Westphal, Christoph H.; Ellis, James L.; Ungvari, Zoltan; Vlasuk, George P.; Elliott, Peter J.; Sinclair, David A.; and de Cabo, Rafael, "SRT1720 Improves Survival and Healthspan of Obese Mice" (2011). Graduate Center for Nutritional Sciences Faculty Publications. 5.
https://uknowledge.uky.edu/nutrisci_facpub/5