David Sinclair, Ph.D.

David Sinclair, Ph.D.David Sinclair, Ph.D. is Co-Director of the Paul F. Glenn Laboratories for the Molecular Biology of Aging, a Professor of Genetics at Harvard Medical School, Associate Member of the Broad Institute for Systems Biology, and co-founder of Sirtris Pharmaceuticals, Waltham, MA. Dr. Sinclair’s research aims to identify conserved longevity control pathways and devise small molecules that activate them, with a view to preventing and treating diseases caused by aging. His lab was the first to identify small molecules called STACs that can activate the SIRT pathway and extend lifespan of a diverse species. They also discovered key components of the aging regulatory pathway in yeast and is now focused on finding genes and STACs that extend the healthy lifespan of mice.

Dr. Sinclair obtained a BS with first-class honors at the University of New South Wales, Sydney, and received the Commonwealth Prize for his research. In 1995, he received a Ph.D. in Molecular Genetics and was awarded the Thompson Prize for best thesis work. He worked as a postdoctoral researcher with Dr. Leonard Guarente at M.I.T. being recruited to Harvard Medical School at the age of 29. Dr. Sinclair has received several additional awards including a Helen Hay Whitney Postdoctoral Award, and a Special Fellowship from the Leukemia Society, a Ludwig Scholarship, a Harvard-Armenise Fellowship, an American Association for Aging Research Fellowship, and is currently a New Scholar of the Ellison Medical Foundation. He’s also won the Genzyme Outstanding Achievement in Biomedical Science Award for 2004.

Direct Contact

Harvard Medical School
Department of Genetics
77 Avenue Louis Pasteur
Boston MA 02115 USA
Telephone: (617) 432-3931
Fax: (617) 432-6225
Email:
Lab Website: http://genetics.med.harvard.edu/sinclair/

Selected Publications

Howitz, KT., Bitterman, KJ., Cohen, HY., Lamming, DW., Lavu, S., Wood, JG., Zipkin, RE., Chung P., Kisielewski, A., Zhang, L., Scherer, B., Sinclair DA. (2003) Small molecule sirtuin activators that extend S. cerevisiae lifespan. Nature, 425:191-196 PMID: 12939617

Cohen, HY, Miller, C, Bitterman, KJ, Wall, NR, Hekking, B, Kessler, B, Gorospe, M, de Cabo, R.,Sinclair, DA. (2004) Calorie restriction promotes cell survival by inducing SIRT1. Science, 305:390-2. PMID:15205477

Wood, J, Rogina, B, Lavu, S, Howitz, KT, Helfand, SL, Tatar, M, Sinclair, DA. (2004). Sirtuin activators mimic calorie restriction and delay aging in metazoans. Nature, 430:686-9. PMID:15254550

Lamming, D, Latorre-Esteves, M, Medvedik, O, Wong, S.N., Tsang, F.A, Wang, C, Lin, S-J, Sinclair, DA (2005) HST2 mediates SIR2-independent lifespan extension by calorie restriction. Science, 309(5742):1861-4. PMID:16051752

Baur, J, Pearson, K., 25 authors, deCabo, R, Sinclair, DA. (2006) Resveratrol increases health and survival of mice on a high calorie diet. Nature 444(16): 337-342. PMID:17086191

Yang, HY, Baur, J and Sinclair DA. (2007) Design and synthesis of SIRT1 activators that extend yeast lifespan. Aging Cell, 6(1):35-43. PMID:17156081

Milne, J., Sinclair, D., Olefsky, J., Jirousek, M, Westphal, C. (2007) Novel Small Molecule Activators of SIRT1 as Therapeutics for Treatment of Type 2 Diabetes. Nature, 450(7170):712-6. PMCID: PMC2753457

Yang, HY, Yang, T, Baur, JA, Perez, E, Matsui, T, Carmona, JJ, Lamming, DW, Souza-Pinto, NC, Bohr, VA, Rosenzweig, A, de Cabo, R, Sauve, AA, Sinclair, DA. (2007) Nutrient-regulated NAD+ levels in mitochondria dictate cell survival. Cell, 130(6):1095-107. PMC336668

Firestein, RA, Blander, G. and Michan, S., Bhimavarapu, A, Luikenhuis, S., de Cabo, R., Hahn, WC, Guarente, LP, and Sinclair, DA. (2008) SIRT1 is a tumor suppressor in a model of colon cancer. 2008; PLoS One, 3(4):2020

Pearson, K*, Baur, J*, Lewis, KN, Peshkin, L, Price, NL. Navas, P., Ingram, D., Wolf, N., Ungvari, Z, Sinclair, DA*, de Cabo, RA* (2008). Resveratrol delays age-related deterioration and mimics aspects of dietary restriction in mice on a standard diet. Cell Metabolism, 8(2):157-68. PMC2538685

Oberdoerffer, P., Michan, S. McVay, M. - 8 authors - Mills, K., Bonni, A., Yankner, B., Scully, R., Prolla, TA., Alt, FW. and David A. Sinclair, D. (2008). DNA damage-induced alterations in chromatin contribute to genomic integrity and age-related changes in gene expression. Cell,135(5):907-18. PMCID: PMC2853975

Minor, R., Baur, J, Gomes, A., Price, N., Hubbard, B., Westphal, C., Ellis, J., Vlasuk, G., Sinclair, D.A. deCabo, R. (2011) SRT1720 improves survival and healthspan of obese mice. Nature Reports 1, 70. PMC3216557

Ramadori, G., Fujikawa, T., Anderson, J., Berglund, E.J., Frazao, R., Michan, S., Vianna, C., Sinclair,D.A., Elias, C. and Coppari. R. (2011) SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metabolism, 14(3):301-12 PMC3172583

Price, N.L., Gomes, A.P., Ling, A.J., Martin-Montalvo, A, North, B.J., Hubbard, B.P., Agarwal,B. Davis,J., Varamini, B. Hafner, A., Rolo,A., Palmeira,C.M., de Cabo,R., Baur,J., and Sinclair, D.A. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metabolism, 15(5): 675-0 PMC2538685

Escande, C., Nin, V., Price, N., Capellini, V., Gomes, A., Barbosa, M.T., O’Neil, L., White, T.A, Sinclair, D.A., Chini, E.N. (2012) The flavonoid apigenin is an inhibitor of the NAD+ase CD38. Diabetes, 62(4):1084-93. PMID: 23172919

Han, J., Hubbard, BP., Lee, J., Montagna, C., Lee, HW., Sinclair, DA., and Suh, Y. (2013) Analysis of 41 cancer cell lines reveals excessive allelic loss and novel mutations in the SIRT1 gene. Cell Cycle, epub. Jan 15. PMID: 23255128

Armour, SM., Bennett, EJ., Braun, CR., Zhang, XY., McMahon, SB., Gygi, SP., Harper, JW., and Sinclair, DA. (2013). A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Molecular Cell Biology, 33(8):1487-502. PMID: 23382074.

Hubbard, BP., Gomes, AP., Dai, H., Li, J., Case, AW., Considine, T., Riera, TV., Lee, JE. E, Sy., Lamming, DW., Pentelute, BL., Schuman, ER., Stevens, LA., Ling, AJ., Armour, SM., Michan, S., Zhao, H., et al., Hamuro, Y., Moss, J., Perni, RB., Ellis, JL., Vlasuk, GP., and Sinclair, DA. (2013). Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science, Vol. 339: 1216-1219. PMID: 23471411

Biason-Lauber, A., Boni-Schnetzler, M., Hubbard, BP., Bouzakri, K., Brunner, A., Cavelti-Weder, C., Keller, C., Meyer-Boni, M., Meier, DT., Brorsson, C., et al., Sinclair, DA., and Donath, MY. (2013) Identification of a SIRT1 mutation in a family with type 1 diabetes. Cell Metabolism, PMID: 23473037

Lai, L., Yan, L., Gao, S., Hu, CL., Ge, H., Davidow, A., Park, M., Bravo, C., Iwatsubo, K., Ishikawa, Y., Auwerx, J., Sinclair, DA, Vatner, SF., and Vatner, DE. (2013) Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway. Circulation, PMID: 23526361

Sinclair, DA. (2013) Studying the Replicative Life Span of Yeast Cells in Biological Aging. Ed. Trygve Tollesbol. Springer, NY, USA.Hubbard BP, Loh C, Gomes AP, Li J, Lu Q, Doyle TL, Disch JS, Armour SM, Ellis JL, Vlasuk GP, Sinclair DA. (2013) Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism. Cell Cycle. 20;12(14). PMID: 23797592

Tilly, JL. and Sinclair, DA. (2013) Germline energetics, aging, and female fertility. Cell Metabolism, 17(6):838-50. NIHMS 482422

Martin-Montalvo, A., 23 authors, Sinclair, D.A., Wolf, N.A., Spindler, S., Bernier, M. and de Cabo, R. (2013) Metformin improves healthspan and lifespan in mice. Nature Communications, in press

Chen, J., Michan, S., Juan, A., Hurst, CG, Hatton CJ, Pei, DT, Joyal, J, Evans, LP, Cui, Z, Stahl, A., Sapieha, P, Sinclair, DA, Smith, LEH. (2013) Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy. Angiogenesis, in press.

Hua, J., Guerin, K., Chen J., Michan, S., Stahl, A., Krah, N., Seaward, M., Dennison, R., Juan, A., Hatton, C., Sapieha, P., Sinclair, D.A., Smith, L. (2013) Resveratrol inhibits pathological retinal neovascularization in vldlr-/-mice. Angiogenesis, in press.

Schmeisser, K., Mansfeld, J., Kuhlow, D., Weimert, S., Zarse, K., Prieve, S., Heiland, I. Birringer, M., Groth, M., Segref, A., Werner, C., Schmeisser, S., Schuster, S., Pfeiffer, A., Guthke, R., Platzer, M., Hoppe, T., Cohen, C., Sinclair, D.A., Ristow, M. (2013) Theniacin metabolite 1-mthylnicotinamide extends lifespan in a PARP/sirtuin-dependent manner by including a transient redox signal. Nature Chemical Biolog in press.

Santos Franco S, De Falco L, Ghaffari S, Brugnara C, Sinclair DA, Mattè A, Iolascon A, Mohandas N, Bertoldi M, An X, Siciliano A, Rimmelé P, Cappellini MD, Michan S, Zoratti E, Janin A, De Franceschi L. Resveratrol accelerates erythroid maturation by activation of FOXO3 and ameliorates anemia in beta-thalassemic mice. 2013. Haematologica. Aug 23

Hubbard BP and Sinclair DA. Measurement of sirtuin enzyme activity using a substrate-agnostic fluorometric nicotinamide assay. Methods Mol Biol. 2013;1077:167-77

Sinclair DA. Studying the replicative life span of yeast cells. Methods Mol Biol. 2013;1048:49-63.

Chen J, Michan S, Juan AM, Hurst CG, Hatton CJ, Pei DT, Joyal JS, Evans LP, Cui Z, Stahl A, Sapieha P, Sinclair DA, Smith LE. Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy. Angiogenesis. 2013;16(4):985-92

Sinclair D.A. and Guarente, L. Small molecule activators of sirtuins for the treatment of age-related diseases. Annual Revews Phramacol. Sci. 2013. 54:363-80.

Hubbard and Sinclair, D.A. Small molecule sirtuin activators. J. Experimental Medicine (2013) In press.

Hubbard BP, Sinclair DA. Measurement of sirtuin enzyme activity using a substrate-agnostic fluorometric nicotinamide assay. Methods Mol Biol. 2013, 1077:167-77.

Sinclair D.A. and Guarente, L. Small molecule activators of sirtuins for the treatment of age-related diseases. Annual Revews Pharmacol. Sci. (2013) 54:363-80.

Hubbard and Sinclair, D.A. Small molecule modulators of sirtuins. Trends in Pharmacol Sci (2014), in press.

Michan, S., Juan, A.M., Hurst, C.G., Cui, Z., Evans, L.P., Hatton, C.J., Pei, D.T., Ju, M., Sinclair, D.A., Smith, L.E.H., Chen, J. Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy. PLoS One 2013, 9(1):e85031.

Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL,

Harrison DE. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J

Gerontol A Biol Sci Med Sci. 2013 68(1):6-16. PMID: 22451473

Gomes, A.P., Price N.L., Lin A.Y, Moslehi, J., Montgomery, M., Rajman, L., White, J.P., Teodoro, J.S., Wran, C.D., Hubbard, B.P., Mercken, E.M., Palmeira, C., de Cabo, R., Rolo, A.P., Turner, N., Bell, E. and Sinclair, D.A. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 2013 155(7):1624-38.

Wu, E.W., Gomes, A.P. and Sinclair, D.A. Geroncogenesis: Metabolic changes during aging as a driver of tumorigenesis. 2014. Cancer Cell, 25:12-19

Yoon, C., Ling, A.Y., Isik, M., Lee, D.D., Steinbaugh, M.J., Sack, L., Boduch. A.N., Blackwell, T.B., Sinclair, D.A*, Elledge, S.J.* GLTSCR2/PICT1 links mitochondrial stress and Myc signaling. Proc. Natl. Acad. Sci., 2014, in press