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Science 305 (5682): 390-392

Copyright © 2004 by the American Association for the Advancement of Science

Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase

Haim Y. Cohen,1 Christine Miller,1 Kevin J. Bitterman,1 Nathan R. Wall,1 Brian Hekking,1 Benedikt Kessler,1 Konrad T. Howitz,2 Myriam Gorospe,3 Rafael de Cabo,4 David A. Sinclair1*

Abstract: A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells.

1 Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
2 BIOMOL Research Laboratories, 5120 Butler Pike, Plymouth Meeting, PA 19462, USA.
3 Laboratory of Cellular and Molecular Biology, Post Office Box 12, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
4 Laboratory of Experimental Gerontology, Post Office Box 12, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.

* To whom correspondence should be addressed. E-mail: david_sinclair{at}hms.harvard.edu

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R. Zhang, H.-Z. Chen, J.-J. Liu, Y.-Y. Jia, Z.-Q. Zhang, R.-F. Yang, Y. Zhang, J. Xu, Y.-S. Wei, D.-P. Liu, et al. (2010)
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SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity.
T. Yoshizaki, S. Schenk, T. Imamura, J. L. Babendure, N. Sonoda, E. J. Bae, D. Y. Oh, M. Lu, J. C. Milne, C. Westphal, et al. (2010)
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Circadian Rhythms and Metabolic Syndrome: From Experimental Genetics to Human Disease.
E. Maury, K. M. Ramsey, and J. Bass (2010)
Circ. Res. 106, 447-462
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The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance.
I. Pagel-Langenickel, J. Bao, L. Pang, and M. N. Sack (2010)
Endocr. Rev. 31, 25-51
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Gene expression profiling of the short-term adaptive response to acute caloric restriction in liver and adipose tissues of pigs differing in feed efficiency.
S. Lkhagvadorj, L. Qu, W. Cai, O. P. Couture, C. R. Barb, G. J. Hausman, D. Nettleton, L. L. Anderson, J. C. M. Dekkers, and C. K. Tuggle (2010)
Am J Physiol Regulatory Integrative Comp Physiol 298, R494-R507
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Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase.
E.-H. Hong, S.-J. Lee, J.-S. Kim, K.-H. Lee, H.-D. Um, J.-H. Kim, S.-J. Kim, J.-I. Kim, and S.-G. Hwang (2010)
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