These disagreements about the mechanism of caloric restriction are confined to yeast, but may portend future disputes in the far more complex systems of mice and men. Both species possess a gene called SIRT1, which is the counterpart to the sir-2 gene. But they have also evolved six extra SIRT genes, known as SIRTs 2 to 7, which seem to perform related tasks. The protein enzymes made by the genes are known as sirtuins, a word biologists have derived, with a simplicity likely to make etymologists wince, from sir-2.

To figure out the role of the seven SIRT genes, both Guarente and Sinclair have engineered two sets of genetically altered mice. For each SIRT gene, one strain lacks the gene entirely and another makes extra amounts of the gene's product. The knockout mice, by their deficiencies, should show what the lost gene does. And its effects will be larger in the overexpressor mice.

Guarente believes that the full suite of seven genes is deployed in response to the stress of caloric restriction. Researchers used to think that the response to caloric restriction was a passive affair, with the organism living longer because it created fewer damaging byproducts of metabolism. This is incorrect in Guarente's view.

Rather, the seven SIRTs take specific actions to protect the body against insult, including against common diseases associated with aging. This prompts the hope that approvable drugs could be developed to trigger one or more SIRTs into the actions that ward off specific diseases. The SIRTs intervene in the body's metabolism in intricate ways that are only beginning to be understood. Mice that overexpress SIRT1 show eight properties of caloric restriction, including low cholesterol and low glucose and insulin blood levels, Guarente said in a recent talk at the Mount Sinai School of Medicine.

As for the other SIRT genes, SIRT2 is mostly expressed in the brain, Guarente said in an interview last month. Its role there is unknown because the SIRT2 knockout mouse appears normal. SIRT genes 3, 4 and 5 are active in the mitochondria, the energy-producing organelles that are part of every cell. They may "vindicate the school of thought that mitochondria are important in aging," Guarente said. SIRT6 is active in the nucleus of the cell and SIRT7 in the nucleolus, a compartment of the nucleus reserved for the assembly of ribosomes, the cell's protein-making machines.

A special property of the SIRT1 gene is to increase the number of mitochondria produced by neurons, Jill Milne of Sirtris reported at a recent meeting on the molecular genetics of aging. With extra energy, brain cells may be better able to ward off neurodegenerative diseases like Alzheimer's. The sirtuins could also improve memory, a fact often on the mind of Sinclair, who has been taking resveratrol for three years.