Near-starvation diets extend the life spans of a variety of organisms, but the mechanism remains murky. Now a study provides important clues about how caloric restriction might prolong life in mammals. The work may also lead to new treatments for diseases such as diabetes.
Starving yeast and flatworms live longer when they express a gene called Sir2 (ScienceNOW, 8 May, 2003). The gene appears to allow both organisms to sense when food is in short supply and take compensatory measures. Molecular physiologist Pere Puigserver of Johns Hopkins School of Medicine in Baltimore, Maryland, and his colleagues wondered if the mammalian equivalent of the gene, called SIRT1 (ScienceNOW, 17 June, 2004), also enables mammals to respond when calories are scarce.
The team's experiments suggest that it does. Hungry mice produce more of the protein encoded by the SIRT1 gene, the team reports in the 3 March Nature. And when the researchers simulated starvation in cultured mouse liver cells, the cells also ramped up SIRT1 production; when they added glucose, cells ramped it down.
Additional experiments suggest that in fasting mice, SIRT1 also helps liver cells respond to starvation signals by increasing sugar production. When the researchers turned off SIRT1 genes in cultured cells, the cells secreted less than half as much glucose as unaltered cells. The researchers think this effect might have to do with PGC-1a, a known regulator of sugar metabolism that was ramped up along with SIRT1 in their experiments with starved mice. Drugs that tweak these nutritional signaling pathways could one day keep diabetics from overloading their blood with sugar, Puigserver says. In addition, he believes that understanding this metabolic pathway can lead to new therapeutic approaches to aging.
"It's a nice piece of work," says molecular biologist Leonard Guarente of Massachusetts Institute of Technology in Cambridge, who first identified Sir2's role in aging. By showing that SIRT1 helps liver cells respond to calorie restriction, he says, the study helps "build a case" that low-calorie diets can extend life.