Tissue-specific regulation of SIRT1 by calorie restriction.
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.
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Danica
D
Chen
Joanne
J
Bruno
Erin
E
Easlon
Su-Ju
SJ
Lin
Hwei-Ling
HL
Cheng
Frederick W
FW
Alt
Leonard
L
Guarente
D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009928:Organ Specificity; D056564:Sirtuin 1; D037761:Sirtuins / Q000096:biosynthesis* / Q000235:genetics
D009243:NAD; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins