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Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes


Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes1,2. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity3,4,5,6,7,8,9. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival10,11,12,13,14. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

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Figure 1: Identification of potent SIRT1 activators unrelated to resveratrol.
Figure 2: In vitro characterization of activators of human SIRT1.
Figure 3: SIRT1 activators in mouse models of type 2 diabetes.
Figure 4: SIRT1 activator SRT1720 in the Zucker fa/fa rat model.


  1. Facchini, F. S., Hua, N., Abbasi, F. & Reaven, G. M. Insulin resistance as a predictor of age-related diseases. J. Clin. Endocrinol. Metab. 86, 3574–3578 (2001)

    Article  CAS  Google Scholar 

  2. Barzilai, N., Banerjee, S., Hawkins, M., Chen, W. & Rossetti, L. Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J. Clin. Invest. 101, 1353–1361 (1998)

    Article  CAS  Google Scholar 

  3. Bordone, L. & Guarente, L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nature Rev. Mol. Cell Biol. 6, 298–305 (2005)

    Article  CAS  Google Scholar 

  4. Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004)

    Article  ADS  CAS  Google Scholar 

  5. Heilbronn, L. K. et al. Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting. Obes. Res. 13, 574–581 (2005)

    Article  ADS  CAS  Google Scholar 

  6. Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005)

    Article  ADS  CAS  Google Scholar 

  7. Frye, R. A. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 260, 273–279 (1999)

    Article  CAS  Google Scholar 

  8. Frye, R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793–798 (2000)

    Article  CAS  Google Scholar 

  9. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)

    Article  ADS  CAS  Google Scholar 

  10. Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006)

    Article  ADS  CAS  Google Scholar 

  11. Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003)

    Article  ADS  CAS  Google Scholar 

  12. Jarolim, S. et al. A novel assay for replicative lifespan in Saccharomyces cerevisiae . FEMS Yeast Res. 5, 169–177 (2004).

    Article  CAS  Google Scholar 

  13. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006)

    Article  CAS  Google Scholar 

  14. Wood, J. G. et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686–689 (2004)

    Article  ADS  CAS  Google Scholar 

  15. Brink, C. B., Harvey, B. H., Bodenstein, J., Venter, D. P. & Oliver, D. W. Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology. Br. J. Clin. Pharmacol. 57, 373–387 (2004)

    Article  CAS  Google Scholar 

  16. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001)

    Article  CAS  Google Scholar 

  17. Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001)

    Article  CAS  Google Scholar 

  18. Napper, A. D. et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J. Med. Chem. 48, 8045–8054 (2005)

    Article  CAS  Google Scholar 

  19. Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999)

    Article  CAS  Google Scholar 

  20. Rogina, B. & Helfand, S. L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl Acad. Sci. USA 101, 15998–16003 (2004)

    Article  ADS  CAS  Google Scholar 

  21. Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae . Nature 423, 181–185 (2003)

    Article  ADS  CAS  Google Scholar 

  22. Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae . Science 289, 2126–2128 (2000)

    Article  ADS  CAS  Google Scholar 

  23. Sarabu, R. & Grimsby, J. Targeting glucokinase activation for the treatment of type 2 diabetes–a status review. Curr. Opin. Drug Discov. Dev. 8, 631–637 (2005)

    CAS  Google Scholar 

  24. Borra, M. T., Langer, M. R., Slama, J. T. & Denu, J. M. Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases. Biochemistry 43, 9877–9887 (2004)

    Article  CAS  Google Scholar 

  25. Heilbronn, L. K. et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. J. Am. Med. Assoc. 295, 1539–1548 (2006)

    Article  CAS  Google Scholar 

  26. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005)

    Article  ADS  CAS  Google Scholar 

  27. Rodgers, J. T. & Puigserver, P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl Acad. Sci. USA 104, 12861–12866 (2007)

    Article  ADS  CAS  Google Scholar 

  28. Banks, A. et al. Overexpression of the Sirtuin SIRT1 increases insulin sensitivity in aging mice. Diabetes 56 (S1), 0234-OR (2007).

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We thank C. Ozbal and W. LaMarr from BioTrove, Inc. for running the mass spectrometry samples; S. Schaertl, D. Winkler, N. Fay and T. Hesterkamp for work on the SIRT1 fluorescence polarization assay development; M. Saberi, P. P. Li , M. Lu, and A. Hevener for assistance and advice with the Zucker fa/fa studies; P. Romero, K. Normington, and M. Dipp for experimental advice and comments on the manuscript; M. Inghilterra for help in data analysis and data mining. D.A.S. is supported by an Ellison Medical Foundation Senior Scholarship, and grants from NIH/NIA and the Paul F. Glenn Medical Foundation. J.M.O. is supported by a University of California Discovery Biostar grant and NIH. S.S. is supported by a Mentor-Based Postdoctoral Fellowship from the American Diabetes Association awarded to J.M.O.

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Correspondence to Christoph H. Westphal.

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All authors declare competing financial interests except for S.S. All authors except for S.S., J.M.O. and D.S. are employees of Sirtris Pharmaceuticals. D.S. is a co-founder, Board member and consultant to Sirtris Pharmaceuticals. J.M.O. is a consultant to Sirtris Pharmaceuticals. Sirtris is a company whose goal is to develop drugs to treat age-related diseases.

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Milne, J., Lambert, P., Schenk, S. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007).

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