The road to the discovery of the first SIRT-type gene began in 1991 when two MIT graduate students asked Guarente if they could join his laboratory to study the process of aging. They were Brian Kennedy, now at the University of Washington, and Nicanor Austriaco, now a Dominican priest who teaches biology and theology at Providence College in Rhode Island.

Aging had long been a difficult and unpromising field for biologists, but Guarente said his students could have a year to search for genes that might affect aging in yeast. In reality, it took them four years just to find a strain of yeast that lived longer than others. A gene called sir-2, for silent information regulator-2, turned out to be responsible for this longevity effect.

The lab was then joined by Sinclair, a young postdoctoral student from the University of New South Wales in Australia, who figured out the unusual mechanism by which sir-2 repressed aging in yeast. Guarente then found that the gene is activated by a common chemical that reflects the level of metabolism in a cell. He proposed that sir-2 and its counterpart genes in animals were the mediators of caloric restriction: the genes sense when the body is running low on nutrients and direct a wide range of metabolic adjustments, from preserving tissues to burning off fat reserves.

Meanwhile, tension began developing between Guarente and Sinclair, who in 1999 started his own laboratory at Harvard Medical School. Sinclair published a report that caloric restriction worked through a quite different mechanism in yeast than the one Guarente had identified. The rivalry was not just scientific. Guarente, with Cynthia Kenyon of the University of California, San Francisco, had founded Elixir Pharmaceuticals to develop drugs for greater health and lifespan. Sinclair started a rival company, Sirtris, to pursue similar goals.

"This has run me through so many emotions, some of which I didn't know I had," Guarente told Science magazine in 2004 in an article about the falling out between him and his former student.

But continuing research has brought about a realignment of forces. Guarente and Sinclair have reconciled, saying their disagreements were technical and never personal. Each of their proposed mechanisms is correct, they say, and yeast uses both to respond to caloric restriction.

They have found a common cause in disputing a challenge raised by two other former students of Guarente, Kennedy of the University of Washington, and Matt Kaeberlein, who argue that yeast longevity via caloric restriction does not operate through sir-2 at all.