New drugs fostering high hopes

New drugs are looming on the horizon that could, if they live up to their promise, avert heart disease, diabetes, cancer and neurodegenerative disorders. By suppressing the common killers associated with aging, the drugs — sirtuin activators — could significantly prolong both health and life span.

But is the promise a mirage or a serious possibility?

The drugs are designed to mimic the effects of caloric restriction, a low calorie but healthful diet known to make laboratory mice live longer and more healthily but is too hard for all but the most ascetic of humans to keep to. One such drug, resveratrol, also a very minor ingredient of red wine, hit the headlines last week with a report by David Sinclair of Harvard Medical School and colleagues that it negates the bad effects of a high-fat diet in mice.

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 female rhesus monkeys that have been eating a reduced-calorie diet since 1987, scientists at the National Institute on Aging reported recently. If there's no trade-off between longevity and fertility, the theory of the evolution of caloric restriction could be wrong or incomplete.