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Published Online June 17, 2004
Science DOI: 10.1126/science.1099196

Reports

Submitted on April 15, 2004
Accepted on June 9, 2004

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. Sinclair 1*

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, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
4 Laboratory of Experimental Gerontology, 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.
David A. Sinclair , E-mail: david_sinclair{at}hms.harvard.edu

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 pro-apoptotic 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.


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Gene expression profiling reveals a signaling role of glutathione in redox regulation.
M. Fratelli, L. O. Goodwin, U. A. Orom, S. Lombardi, R. Tonelli, M. Mengozzi, and P. Ghezzi (2005)
PNAS 102, 13998-14003
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Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria.
L. Bevilacqua, J. J. Ramsey, K. Hagopian, R. Weindruch, and M.-E. Harper (2005)
Am J Physiol Endocrinol Metab 289, E429-E438
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2-Deoxyglucose as an Energy Restriction Mimetic Agent: Effects on Mammary Carcinogenesis and on Mammary Tumor Cell Growth In vitro.
Z. Zhu, W. Jiang, J. N. McGinley, and H. J. Thompson (2005)
Cancer Res. 65, 7023-7030
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Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging.
G. C. Kujoth, A. Hiona, T. D. Pugh, S. Someya, K. Panzer, S. E. Wohlgemuth, T. Hofer, A. Y. Seo, R. Sullivan, W. A. Jobling, et al. (2005)
Science 309, 481-484
   Abstract »    Full Text »    PDF »
Differential Regulation of Amino Acid Transporter SNAT3 by Insulin in Hepatocytes.
S. Gu, C. J. Villegas, and J. X. Jiang (2005)
J. Biol. Chem. 280, 26055-26062
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Pre-B-Cell Colony-Enhancing Factor Regulates NAD+-Dependent Protein Deacetylase Activity and Promotes Vascular Smooth Muscle Cell Maturation.
E. van der Veer, Z. Nong, C. O'Neil, B. Urquhart, D. Freeman, and J. G. Pickering (2005)
Circ. Res. 97, 25-34
   Abstract »    Full Text »    PDF »
SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1{alpha}.
S. Nemoto, M. M. Fergusson, and T. Finkel (2005)
J. Biol. Chem. 280, 16456-16460
   Abstract »    Full Text »    PDF »
SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes.
T. Shi, F. Wang, E. Stieren, and Q. Tong (2005)
J. Biol. Chem. 280, 13560-13567
   Abstract »    Full Text »    PDF »
Role of NAD-dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin-induced cell death in vertebrate cells.
N. Matsushita, Y. Takami, M. Kimura, S. Tachiiri, M. Ishiai, T. Nakayama, and M. Takata (2005)
Genes Cells 10, 321-332
   Abstract »    Full Text »    PDF »
Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors.
C. Subramanian, A. W. Opipari Jr., X. Bian, V. P. Castle, and R. P. S. Kwok (2005)
PNAS 102, 4842-4847
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SIRT1 Shows No Substrate Specificity in Vitro.
G. Blander, J. Olejnik, E. Krzymanska-Olejnik, T. McDonagh, M. Haigis, M. B. Yaffe, and L. Guarente (2005)
J. Biol. Chem. 280, 9780-9785
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Histone acetylation and deacetylation: importance in inflammatory lung diseases.
P. J. Barnes, I. M. Adcock, and K. Ito (2005)
Eur. Respir. J. 25, 552-563
   Abstract »    Full Text »    PDF »
New Treatments for Denervating Diseases.
D. Pleasure (2005)
J Child Neurol 20, 258-262
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Long-Lived Growth Hormone Receptor Knockout Mice: Interaction of Reduced Insulin-Like Growth Factor I/Insulin Signaling and Caloric Restriction.
K. A. Al-Regaiey, M. M. Masternak, M. Bonkowski, L. Sun, and A. Bartke (2005)
Endocrinology 146, 851-860
   Abstract »    Full Text »    PDF »


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