Tests Begin on Drugs That May Slow Aging

It may be the ultimate free lunch — how to reap all the advantages of a calorically restricted diet, including freedom from disease and an extended healthy life span, without eating one fewer calorie. Just take a drug that tricks the body into thinking it’s on such a diet.

It sounds too good to be true, and maybe it is. Yet such drugs are now in clinical trials. Even if they should fail, as most candidate drugs do, their development represents a new optimism among research biologists that aging is not immutable, that the body has resources that can be mobilized into resisting disease and averting the adversities of old age.

This optimism, however, is not fully shared. Evolutionary biologists, the experts on the theory of aging, have strong reasons to suppose that human life span cannot be altered in any quick and easy way. But they have been confounded by experiments with small laboratory animals, like roundworms, fruit flies and mice. In all these species, the change of single genes has brought noticeable increases in life span.

With theorists’ and their gloomy predictions cast in the shade, at least for the time being, experimental biologists are pushing confidently into the tangle of linkages that evolution has woven among food intake, fertility and life span. “My rule of thumb is to ignore the evolutionary biologists — they’re constantly telling you what you can’t think,” Gary Ruvkun of the Massachusetts General Hospital remarked this June after making an unusual discovery about longevity.

Excitement among researchers on aging has picked up in the last few years with the apparent convergence of two lines of inquiry: single gene changes and the diet known as caloric restriction.

In caloric restriction, mice are kept on a diet that is healthy but has 30 percent fewer calories than a normal diet. The mice live 30 or 40 percent longer than usual with the only evident penalty being that they are less fertile.

People find it almost impossible to maintain such a diet, so this recipe for longevity remained a scientific curiosity for many decades. Then came the discovery of the single gene changes, many of which are involved in the body’s regulation of growth, energy metabolism and reproduction. The single gene changes thus seem to be pointing to the same biochemical pathways through which caloric restriction extends life span.

If biologists could only identify these pathways, it might be possible to develop drugs that would trigger them. Such drugs could in principle have far-reaching effects. Mice on caloric restriction seem protected from degenerative disease, which may be why they live longer. A single drug that protected against some or all the degenerative diseases of aging would enable people to enjoy more healthy years, a great benefit in itself, even if it did not extend life span.

The leading candidates for such a role are drugs called sirtuin activators, which may well be mimicking caloric restriction, in whole or in part. The chief such drug is resveratrol, a minor ingredient of grapes and red wine. Sirtris Pharmaceuticals, of Cambridge, Mass., is now conducting clinical trials of resveratrol, in a special formulation, and of small-molecule drugs that also activate sirtuin but can be given in much lower doses. The resveratrol formulation and one of the small chemicals have passed safety tests and are now being tested against diabetes and other diseases. The Food and Drug Administration does not approve drugs to delay aging, because aging in its view is not a disease.

The sirtuin activators have a strong scientific pedigree. They emerged as the surprising outcome of a quest begun in 1991 by Leonard P. Guarente of M.I.T. to look for genes that might prolong life span in yeast, a single-cell organism. Working with David A. Sinclair, now at Harvard Medical School, he discovered such a gene, one called sir-2. People and mice turned out to have equivalent genes, called sirt genes, that produce proteins called sirtuins.

Dr. Guarente then found that the sirtuins can detect the energy reserves in a cell and are activated when reserves are low, just what would be needed for a protein that mediates the effects of caloric restriction. Dr. Sinclair and colleagues screened a number of chemicals for their ability to activate sirtuin, and resveratrol landed at the top of the list. The chemical was already known as the suspected cause of the French paradox, the fact that the French eat a high fat diet without penalty to their longevity.

The two researchers and their colleagues thus argued that caloric restriction works by activating sirtuins, and so drugs that activate sirtuins should offer the same health benefits.

In 2004 Dr. Sinclair co-founded Sirtris with Christoph Westphal, a scientific entrepreneur. Helped by growing interest in the sirtuin story, Dr. Westphal was able to sell the company last year to GlaxoSmithKline for $720 million.

Dr. Sinclair says that “the results from the Sirtris compounds are promising and will be submitted for publication in coming months.”

But despite the high promise and strong scientific foundation of the sirtuin approach, it has yet to be proved that Sirtris’s drugs will work. The first of many questions is that of whether caloric restriction applies at all to people.

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