Associate Professor of Pathology, Co-director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging
Harvard Medical School
NRB-931
77 Avenue Louis Pasteur
Boston, MA 02115
PH: 617-432-3931
FAX: 617-432-6225
david_sinclair@hms.harvard.edu
Lab Website
Research Interests
In the past 10 years there has been a paradigm shift in our understanding of aging. Until the 1990’s, almost all researchers believed that the aging process was too complex to find single genes or drugs that could slow the process. Then geneticists began to uncover mutations that could dramatically extend the lifespan of laboratory organisms such as yeast, worms, flies, and mice. How could this be? We now know that the rate of aging is not predetermined. It is naturally regulated by a few critical genes. One of the key regulators of aging that we study is a gene called SIR2. Extra copies of the SIR2 gene extend lifespan of diverse organisms, from yeast to flies. The gene family, known as the "sirtuins" seems to have evolved about one billion years ago to increase an organism's defenses during times when food was scarce. We use a variety of models and methods to understand sirtuin function and how to extend lifespan, including yeast, nematode worms, mammalian cell culture, biochemistry, and transgenic/knockout mice. We have identified small molecules that extend lifespan by activating sirtuins and are testing their ability to treat diseases including cancer, heart disease, diabetes, and neurodegeneration.
Our goals are:
(i) To have a comprehensive understanding of sirtuin regulation and function in mammals
(ii) To have tested whether it is possible to extend the lifespan of a mouse by modulating the sirtuins or a sirtuin regulator
(iii) To more fully understand which tissues are important for the regulation of mammalian lifespan.
(iv) To discover whether it is possible to create a molecule that can activate longevity pathways and thereby treat age-related diseases such as cancer, cardiovascular disease, neurodegeneration, and diabetes.
Select Publications:
Cohen, H.Y., Miller, C., Bitterman, K.J., Wall, N.R., Hekking, B., Kessler, B., Howitz, KT., Gorospe, M., de Cabo, R, Sinclair, DA. Calorie restriction promotes cell survival by inducing SIRT1. Science 2004; 305(5682):390-2
Wood, J., Rogina, B., Lavu, S., Howitz, K.T., Helfand, S.L., Tatar, M., Sinclair, DA. Sirtuin activators mimic calorie restriction and delay aging in metazoans. Nature, 2004; 430:686-9
Lamming, D, Latorre-Esteves, M, Medvedik, O, Wong, S.N., Tsang, F.A, Wang, C, Lin, S-J, Sinclair, DA. HST2 mediates SIR2-independent lifespan extension by calorie restriction. Science 2005; 309(5742):1861-4.
Baur, J, Pearson, K, et al. Resveratrol increases health and survival of mice on a high calorie diet. Nature 2006; 444(16): 337-342
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