SRT1720 improves survival and healthspan of obese mice

被引：224

作者：

Minor, Robin K. ^{[1
]}

Baur, Joseph A. ^{[2
]}

Gomes, Ana P. ^{[3
]}

Ward, Theresa M. ^{[1
]}

Csiszar, Anna ^{[4
]}

Mercken, Evi M. ^{[1
]}

Abdelmohsen, Kotb ^{[5
]}

Shin, Yu-Kyong ^{[6
]}

Canto, Carles ^{[7
]}

Scheibye-Knudsen, Morten ^{[8
]}

Krawczyk, Melissa ^{[9
]}

Irusta, Pablo M. ^{[1
,11
]}

Martin-Montalvo, Alejandro ^{[1
]}

Hubbard, Basil P. ^{[3
]}

Zhang, Yongqing ^{[10
]}

Lehrmann, Elin ^{[10
]}

White, Alexa A. ^{[6
]}

Price, Nathan L. ^{[3
]}

Swindell, William R. ^{[12
]}

Pearson, Kevin J. ^{[1
,13
]}

Becker, Kevin G. ^{[10
]}

Bohr, Vilhelm A. ^{[8
]}

Gorospe, Myriam ^{[5
]}

Egan, Josephine M. ^{[6
]}

Talan, Mark I. ^{[9
]}

Auwerx, Johan ^{[7
]}

Westphal, Christoph H. ^{[14
]}

Ellis, James L. ^{[14
]}

Ungvari, Zoltan ^{[4
]}

Vlasuk, George P. ^{[14
]}

Elliott, Peter J. ^{[14
]}

Sinclair, David A. ^{[3
]}

de Cabo, Rafael ^{[1
]}

机构：

[1] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA

[2] Univ Penn, Sch Med, Dept Physiol, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA

[3] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA

[4] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK 73104 USA

[5] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA

[6] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA

[7] Ecole Polytech Fed Lausanne, LISP, CH-1015 Lausanne, Switzerland

[8] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA

[9] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA

[10] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA

[11] Georgetown Univ, Med Ctr, Dept Human Sci, Washington, DC 20007 USA

[12] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[13] Univ Kentucky, Grad Ctr Nutr Sci, Lexington, KY 40536 USA

[14] Sirtris, Cambridge, MA 02139 USA

来源：

SCIENTIFIC REPORTS | 2011年 / 1卷

基金：

瑞士国家科学基金会;

关键词：

SMALL-MOLECULE ACTIVATORS; SIRT1; ACTIVATION; MITOCHONDRIAL BIOGENESIS; CALORIC RESTRICTION; RESVERATROL; PROTECTS; SIRTUINS; INFLAMMATION; PGC-1-ALPHA; INHIBITION;

D O I：

10.1038/srep00070

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Sirt1 is an NAD1-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-1a-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.

引用

页数：10

共 48 条

[1] Dynamic regulation of PGC-1α localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response [J].

Anderson, Rozalyn M. ;

Barger, Jamie L. ;

Edwards, Michael G. ;

Braun, Kristina H. ;

O'Connor, Clare E. ;

Prolla, Tomas A. ;

Weindruch, Richard .

AGING CELL, 2008, 7 (01) :101-111

[2] SirT1 Gain of Function Increases Energy Efficiency and Prevents Diabetes in Mice [J].

Banks, Alexander S. ;

Kon, Ning ;

Knight, Colette ;

Matsumoto, Michihiro ;

Gutierrez-Juarez, Roger ;

Rossetti, Luciano ;

Gu, Wei ;

Accili, Domenico .

CELL METABOLISM, 2008, 8 (04) :333-341

[3] Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart [J].

Barger, J. L. ;

Kayo, T. ;

Pugh, T. D. ;

Prolla, T. A. ;

Weindruch, R. .

EXPERIMENTAL GERONTOLOGY, 2008, 43 (09) :859-866

[4] A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice [J].

Barger, Jamie L. ;

Kayo, Tsuyoshi ;

Vann, James M. ;

Arias, Edward B. ;

Wang, Jelai ;

Hacker, Timothy A. ;

Wang, Ying ;

Raederstorff, Daniel ;

Morrow, Jason D. ;

Leeuwenburgh, Christiaan ;

Allison, David B. ;

Saupe, Kurt W. ;

Cartee, Gregory D. ;

Weindruch, Richard ;

Prolla, Tomas A. .

PLOS ONE, 2008, 3 (06)

[5] Resveratrol improves health and survival of mice on a high-calorie diet [J].

Baur, Joseph A. ;

Pearson, Kevin J. ;

Price, Nathan L. ;

Jamieson, Hamish A. ;

Lerin, Carles ;

Kalra, Avash ;

Prabhu, Vinayakumar V. ;

Allard, Joanne S. ;

Lopez-Lluch, Guillermo ;

Lewis, Kaitlyn ;

Pistell, Paul J. ;

Poosala, Suresh ;

Becker, Kevin G. ;

Boss, Olivier ;

Gwinn, Dana ;

Wang, Mingyi ;

Ramaswamy, Sharan ;

Fishbein, Kenneth W. ;

Spencer, Richard G. ;

Lakatta, Edward G. ;

Le Couteur, David ;

Shaw, Reuben J. ;

Navas, Placido ;

Puigserver, Pere ;

Ingram, Donald K. ;

de Cabo, Rafael ;

Sinclair, David A. .

NATURE, 2006, 444 (7117) :337-342

[6] Therapeutic potential of resveratrol:: the in vivo evidence [J].

Baur, Joseph A. ;

Sinclair, David A. .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (06) :493-506

[7] A high-throughput respirometric assay for mitochondrial biogenesis and toxicity [J].

Beeson, Craig C. ;

Beeson, Gyda C. ;

Schnellmann, Rick G. .

ANALYTICAL BIOCHEMISTRY, 2010, 404 (01) :75-81

[8] Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity [J].

Beher, Dirk ;

Wu, John ;

Cumine, Suzanne ;

Kim, Ki Won ;

Lu, Shu-Chen ;

Atangan, Larissa ;

Wang, Minghan .

CHEMICAL BIOLOGY & DRUG DESIGN, 2009, 74 (06) :619-624

[9] Mechanism of human SIRT1 activation by resveratrol [J].

Borra, MT ;

Smith, BC ;

Denu, JM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (17) :17187-17195

[10] Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase [J].

Brunet, A ;

Sweeney, LB ;

Sturgill, JF ;

Chua, KF ;

Greer, PL ;

Lin, YX ;

Tran, H ;

Ross, SE ;

Mostoslavsky, R ;

Cohen, HY ;

Hu, LS ;

Cheng, HL ;

Jedrychowski, MP ;

Gygi, SP ;

Sinclair, DA ;

Alt, FW ;

Greenberg, ME .

SCIENCE, 2004, 303 (5666) :2011-2015

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