SRT1720 improves survival and healthspan of obese mice

Robin K. Minor; Joseph A. Baur; Ana P. Gomes; Theresa M. Ward; Anna Csiszar; Evi M. Mercken; Kotb Abdelmohsen; Yu Kyong Shin; Carles Canto; Morten Scheibye-Knudsen; Melissa Krawczyk; Pablo M. Irusta; Alejandro Martín-Montalvo; Basil P. Hubbard; Yongqing Zhang; Elin Lehrmann; Alexa A. White; Nathan L. Price; William R. Swindell; Kevin J. Pearson; Kevin G. Becker; Vilhelm A. Bohr; Myriam Gorospe; Josephine M. Egan; Mark I. Talan; Johan Auwerx; Christoph H. Westphal; James L. Ellis; Zoltan Ungvari; George P. Vlasuk; Peter J. Elliott; David A. Sinclair; Rafael De Cabo

doi:10.1038/srep00070

SRT1720 improves survival and healthspan of obese mice

Robin K. Minor, Joseph A. Baur, Ana P. Gomes, Theresa M. Ward, Anna Csiszar, Evi M. Mercken, Kotb Abdelmohsen, Yu Kyong Shin, Carles Canto, Morten Scheibye-Knudsen, Melissa Krawczyk, Pablo M. Irusta, Alejandro Martín-Montalvo, Basil P. Hubbard, Yongqing Zhang, Elin Lehrmann, Alexa A. White, Nathan L. Price, William R. Swindell, Kevin J. PearsonKevin G. Becker, Vilhelm A. Bohr, Myriam Gorospe, Josephine M. Egan, Mark I. Talan, Johan Auwerx, Christoph H. Westphal, James L. Ellis, Zoltan Ungvari, George P. Vlasuk, Peter J. Elliott, David A. Sinclair, Rafael De Cabo

Research output: Contribution to journal › Article › peer-review

258 Scopus citations

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.

Original language	English
Article number	70
Journal	Scientific Reports
Volume	1
DOIs	https://doi.org/10.1038/srep00070
State	Published - 2011

Bibliographical note

Funding Information:
This research was conducted under a Cooperative Research and Development Agreement (CRADA) between Sirtris, a GSK Company, and the National Institute on Aging, National Institutes of Health (NIA/NIH). Microarray data are archived under the accession number GSE19102. JAB is supported by NIH Pathway to Independence Award R00AG031182. We are grateful to Dawn Nines, Dawn Phillips and Justine Lucas for their excellent animal care. We also thank Larry Brant for help with data analyses and Olga Carlson for technical assistance. Funding was provided by the Intramural Research Program of the NIA/NIH, the Swiss National Science Foundation and the ERC Ideas program. Funding to DAS was provided by the NIH/NIA Extramural Research Program and the Glenn Foundation for Medical Research.

ASJC Scopus subject areas

General

Access to Document

10.1038/srep00070

Cite this

Minor, R. K., Baur, J. A., Gomes, A. P., Ward, T. M., Csiszar, A., Mercken, E. M., Abdelmohsen, K., Shin, Y. K., Canto, C., Scheibye-Knudsen, M., Krawczyk, M., Irusta, P. M., Martín-Montalvo, A., Hubbard, B. P., Zhang, Y., Lehrmann, E., White, A. A., Price, N. L., Swindell, W. R., ... De Cabo, R. (2011). SRT1720 improves survival and healthspan of obese mice. Scientific Reports, 1, Article 70. https://doi.org/10.1038/srep00070

@article{b92f896788ed4c30ac1aff1e1294280e,

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.",

author = "Minor, {Robin K.} and Baur, {Joseph A.} and Gomes, {Ana P.} and Ward, {Theresa M.} and Anna Csiszar and Mercken, {Evi M.} and Kotb Abdelmohsen and Shin, {Yu Kyong} and Carles Canto and Morten Scheibye-Knudsen and Melissa Krawczyk and Irusta, {Pablo M.} and Alejandro Mart{\'i}n-Montalvo and Hubbard, {Basil P.} and Yongqing Zhang and Elin Lehrmann and White, {Alexa A.} and Price, {Nathan L.} and Swindell, {William R.} and Pearson, {Kevin J.} and Becker, {Kevin G.} and Bohr, {Vilhelm A.} and Myriam Gorospe and Egan, {Josephine M.} and Talan, {Mark I.} and Johan Auwerx and Westphal, {Christoph H.} and Ellis, {James L.} and Zoltan Ungvari and Vlasuk, {George P.} and Elliott, {Peter J.} and Sinclair, {David A.} and {De Cabo}, Rafael",

note = "Funding Information: This research was conducted under a Cooperative Research and Development Agreement (CRADA) between Sirtris, a GSK Company, and the National Institute on Aging, National Institutes of Health (NIA/NIH). Microarray data are archived under the accession number GSE19102. JAB is supported by NIH Pathway to Independence Award R00AG031182. We are grateful to Dawn Nines, Dawn Phillips and Justine Lucas for their excellent animal care. We also thank Larry Brant for help with data analyses and Olga Carlson for technical assistance. Funding was provided by the Intramural Research Program of the NIA/NIH, the Swiss National Science Foundation and the ERC Ideas program. Funding to DAS was provided by the NIH/NIA Extramural Research Program and the Glenn Foundation for Medical Research.",

year = "2011",

doi = "10.1038/srep00070",

language = "English",

volume = "1",

}

Minor, RK, Baur, JA, Gomes, AP, Ward, TM, Csiszar, A, Mercken, EM, Abdelmohsen, K, Shin, YK, Canto, C, Scheibye-Knudsen, M, Krawczyk, M, Irusta, PM, Martín-Montalvo, A, Hubbard, BP, Zhang, Y, Lehrmann, E, White, AA, Price, NL, Swindell, WR, Pearson, KJ, Becker, KG, Bohr, VA, Gorospe, M, Egan, JM, Talan, MI, Auwerx, J, Westphal, CH, Ellis, JL, Ungvari, Z, Vlasuk, GP, Elliott, PJ, Sinclair, DA & De Cabo, R 2011, 'SRT1720 improves survival and healthspan of obese mice', Scientific Reports, vol. 1, 70. https://doi.org/10.1038/srep00070

TY - JOUR

T1 - SRT1720 improves survival and healthspan of obese mice

AU - Minor, Robin K.

AU - Baur, Joseph A.

AU - Gomes, Ana P.

AU - Ward, Theresa M.

AU - Csiszar, Anna

AU - Mercken, Evi M.

AU - Abdelmohsen, Kotb

AU - Shin, Yu Kyong

AU - Canto, Carles

AU - Scheibye-Knudsen, Morten

AU - Krawczyk, Melissa

AU - Irusta, Pablo M.

AU - Martín-Montalvo, Alejandro

AU - Hubbard, Basil P.

AU - Zhang, Yongqing

AU - Lehrmann, Elin

AU - White, Alexa A.

AU - Price, Nathan L.

AU - Swindell, William R.

AU - Pearson, Kevin J.

AU - Becker, Kevin G.

AU - Bohr, Vilhelm A.

AU - Gorospe, Myriam

AU - Egan, Josephine M.

AU - Talan, Mark I.

AU - Auwerx, Johan

AU - Westphal, Christoph H.

AU - Ellis, James L.

AU - Ungvari, Zoltan

AU - Vlasuk, George P.

AU - Elliott, Peter J.

AU - Sinclair, David A.

AU - De Cabo, Rafael

N1 - Funding Information: This research was conducted under a Cooperative Research and Development Agreement (CRADA) between Sirtris, a GSK Company, and the National Institute on Aging, National Institutes of Health (NIA/NIH). Microarray data are archived under the accession number GSE19102. JAB is supported by NIH Pathway to Independence Award R00AG031182. We are grateful to Dawn Nines, Dawn Phillips and Justine Lucas for their excellent animal care. We also thank Larry Brant for help with data analyses and Olga Carlson for technical assistance. Funding was provided by the Intramural Research Program of the NIA/NIH, the Swiss National Science Foundation and the ERC Ideas program. Funding to DAS was provided by the NIH/NIA Extramural Research Program and the Glenn Foundation for Medical Research.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84859909860&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859909860&partnerID=8YFLogxK

U2 - 10.1038/srep00070

DO - 10.1038/srep00070

M3 - Article

C2 - 22355589

AN - SCOPUS:84859909860

SN - 2045-2322

VL - 1

JO - Scientific Reports

JF - Scientific Reports

M1 - 70

ER -

SRT1720 improves survival and healthspan of obese mice

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this