Arresting old age

Behind the proposed new drugs lies some 15 years of research, much of it by Leonard Guarente of MIT and a talented but fractious group of former students, several of whom have presumed to challenge aspects of his ideas. The research has now reached a point at which at least two companies, Elixir Pharmaceuticals and Sirtris, are trying to develop drugs based in whole or in part on its implications.

But success is by no means guaranteed, for several reasons. Caloric restriction has not been proved to improve health or prolong life in people; even if it does, the effect could be much smaller than the 30 percent of extra life and health enjoyed by laboratory mice.

Nor is it clear that the genetic mechanism that Guarente believes is responsible for the effects of caloric restriction, a group of genes known as the SIRT family, is the only one involved. Some biologists suspect that drugs like resveratrol may act not through the SIRT genes but in some other way, which would mean the results reported last week give no support to the idea that the SIRT genes mediate the response to caloric restriction.

Finally, the benefits of caloric restriction are assumed to have evolved as a strategy for switching resources between reproduction and tissue maintenance. Such a mechanism would greatly help an organism ride out successive waves of feast and famine. That would explain why mice on caloric restriction generally become infertile.

So it is somewhat puzzling that the fat mice fed resveratrol by Sinclair showed no decline in fertility. Nor have a group of female rhesus monkeys who have been eating a reduced-calorie diet since 1987, scientists at the National Institute on Aging reported recently. If there8217;s no trade-off between longevity and fertility, the theory of the evolution of caloric restriction could be wrong or incomplete.

The road to the discovery of the first SIRT-type gene began in 1991 when two graduate students at MIT asked Guarente if they could join his laboratory to study ageing. 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.

Guarente said his students could have a year to search for genes that might affect aging in yeast. In the event, they took 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, who figured out the unusual mechanism by which sir-2 repressed aging in yeast. Guarente then found the gene is activated by a common chemical that reflects the level of metabolism in a cell. He proposed 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.

To figure out the role of the seven SIRT genes, both Guarente and Sinclair engineered two sets of genetically altered mice. For each SIRT gene, one strain lacks the gene entirely and another makes extra amounts of the gene8217;s product. The knockout mice, by their deficiencies, should show what the lost gene does; its effects will be larger in the overexpressor mice.

The SIRTs intervene in the body8217;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, Dr. Guarente said in a recent talk at the Mount Sinai School of Medicine.

NICHOLAS WADE