How Going Hungry Might Save Cells

Slashing calories extends life in nearly every species tested in the lab. New research hints at how this happens in mammals, delineating the effects in rodents of a gene associated with aging and influenced by diet.

The discovery grows out of research by Leonard Guarente and colleagues at the Massachusetts Institute of Technology (MIT), who found a yeast gene, SIR2, that appeared to slow aging when calories were cut (ScienceNOW, 26 September 2000). The group then found a similar gene in mice--SIRT1--but it wasn't clear whether SIRT1 applies the same brakes to aging.

Recent research by both Guarente (ScienceNOW, 3 June) and his former postdoc David Sinclair, now at Harvard Medical School in Boston, suggest that it does. A paper by Sinclair's team, published online 17 June by Science, examines how cells survive when SIRT1 levels change. It's long been known that cells from calorically restricted animals resist apoptosis, or programmed cell death. Sinclair wondered if SIRT1 had a hand in this.

First, his lab and collaborators at the National Institute on Aging in Bethesda, Maryland, studied rats on low-calorie diets. Their brain, liver, kidney, and fat tissue all showed levels of SIRT1 protein at least 50% above normal. Next, Sinclair's team collected human cells and immersed them in serum from the calorically restricted rats. The serum forced an uptick in SIRT1 levels and protected the cells from apoptosis.

Sinclair then guessed that two key players were insulin and insulin growth factor-1, known to be lowered in calorie-restricted animals. Adding either to the mix blunted the serum's effects, making the human cells express less SIRT1. Furthermore, his group found, excess SIRT1 represses a critical initiator of apoptosis--a protein called Bax, which punches holes in a cell's mitochondria and induces cell death.

The paper is "truly beautiful," says Eric Verdin, a molecular biologist at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco. But it's just one piece of an intricate puzzle, Verdin adds. Most biologists assume that SIRT1 has other effects, and "it's become really hard to figure out [their] relative importance," says Matt Kaeberlein, a molecular biologist at the University of Washington, Seattle. Sinclair and others also note that SIRT1's activities in a petri dish may not mirror what it does in an animal.

Related sites
Sinclair and colleagues' Science Express paper
David Sinclair's lab
Leonard Guarente's lab

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