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Jeff Sutherland

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Calorie restriction molecular mechanism found

Life Extension Update, 3 June 2004

Research in mouse tissue conducted by MIT professor of biology Leonard Guarente and colleagues, published in the online version of Nature ( on June 2 2004, found that calorie restriction effects a protein that controls whether fat is stored or released. Calorie restriction has been found to extend the lifespan of every species in which it has been tested, and many humans have adopted the diet in hope of extending their own lives. The protein is the product of the mammalian gene sirtuin 1 (Sirt1), similar to the SIR2 gene that has been found to mediate the effects of calorie restriction in yeast. When Sirt1 senses short-term famine, such as is mimicked by calorie restriction, it turns off the receptors that keep fat in fat cells, and fat is released or metabolized rather than stored. The authors explain that the “Sirt1 protein activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal the Sirt1 protein binds to and represses the genes that are controlled by PPAR-gamma, the fat regulator.”

Dr Guarante elaborated, “The ability of fat cells to sense famine and release the fat is regulated by this gene. We like to think this applies to people as well as mice, but we don’t know for sure. If we could make this happen in people, it wouldn’t just make them live longer; it might also help prevent diseases of aging, like cancer, diabetes and heart disease . . . If we could make a drug that would bind to Sirt1 and fool the body into thinking that it needed to release that fat, then maybe people could get the benefits of calorie restriction without the side effects.”

Because white adipose tissue makes hormones, including leptin which controls satiety, Guarente speculates that fat cells also tell the body how fast to age. He added, “Conversely, fewer fat cells tell the body that it’s time to hunker down for survival. This means that evolutionarily speaking, fat plays a very important role.

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