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Published online before print June 11, 2008, 10.1101/gad.1650608
GENES & DEVELOPMENT 22:1753-1757, 2008
©2008 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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RESEARCH COMMUNICATION

Tissue-specific regulation of SIRT1 by calorie restriction

Danica Chen1, Joanne Bruno1, Erin Easlon2, Su-Ju Lin2, Hwei-Ling Cheng3, Frederick W. Alt3, and Leonard Guarente1,4

1 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 2 Section of Microbiology, University of California at Davis, Davis, California 95616, USA; 3 Howard Hughes Medical Institute, The Children’s Hospital, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this study, we challenge the paradigm that CR induces SIRT1 activity in all tissues by showing that activity of this sirtuin in the liver is, in fact, reduced by CR and activated by a high-caloric diet. We demonstrate this change both by assaying levels of SIRT1 and its small molecule regulators, NAD and NADH, as well as assessing phenotypes of a liver-specific SIRT1 knockout mouse on various diets. Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined.

[Keywords: Aging; calorie restriction; SIRT1]

Received January 11, 2008; revised version accepted April 29, 2008.

4 Corresponding author.

E-MAIL leng{at}mit.edu; FAX (617) 253-8699.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1650608.


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