Source: New York Times
Date: 7 November 2006

Aging Drugs: Hardest Test Is Still Ahead


three long-lived mice

A new class of drugs is 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 of age, the drugs, sirtuin activators, could significantly prolong both health and lifespan.

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 M.I.T. 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 Dr. 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 Dr. 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 there’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 M.I.T. asked Dr. 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 Dr. 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 David 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. Dr. 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 a certain amount of tension was developing between Dr. Guarente and Dr. Sinclair, who in 1999 started his own laboratory at Harvard Medical School. Dr. Sinclair published a report that caloric restriction worked through a quite different mechanism in yeast than the one Dr. Guarente had identified. The rivalry was not just scientific. Dr. Guarente, with Dr. Cynthia Kenyon of the University of California, San Francisco, had founded Elixir Pharmaceuticals to develop drugs for greater health and lifespan. Dr. 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,” Dr. 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. Dr. Guarente and Dr. 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 Dr. Guarente, Brian Kennedy and Matt Kaeberlein, who argue that yeast longevity via caloric restriction does not operate through sir-2 at all.

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 Dr. Guarente and Dr. 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.

Dr. 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 Dr. Guarente’s view.

Rather, the seven SIRTs take specific actions to protect the body against insult, including against common diseases of 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, Dr. 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, Dr. 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,” Dr. 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 Dr. Sinclair, who has been taking resveratrol for three years.

One day last month, he and a reporter spent five minutes searching a Harvard Medical School parking lot for a grimy green Honda Accord. Dr. Sinclair had forgotten where he had parked his car. “So much for resveratrol improving memory,” he grumbled.

The car retrieved, he drove to Sirtris’s headquarters in Cambridge, where he shares an office with Christoph Westphal, the company’s chief executive. Dr. Westphal disagrees with his colleague that taking resveratrol is a good idea, saying a therapeutic dose cannot be maintained in the bloodstream. He politely conceded Dr. Sinclair’s position that a lower dose might be effective over the long term.

Sirtris has developed a modified form of resveratrol, called SRT501, that reaches high levels in the bloodstream. It is now being tested in people for safety and its ability to control glucose levels. Dr. Westphal plans to gauge the drug’s use in treating diabetes and a rare form of dementia caused by defective mitochondria. Sirtris has also developed several other chemicals that activate sirtuins at doses one-thousandth that of resveratrol. The F.D.A. will approve them, if safe and effective, only to treat specific diseases, but it could be inferred that the drugs might thereby extend lifespan. “We believe this is a new therapeutic modality,” Dr. Westphal said. “We think it can change medical care.”

Sirtris has raised $82 million so far. It has a heavyweight group of biotech entrepreneurs on its board and well-known M.I.T. researchers, like Philip Sharp and Robert Langer, on its scientific advisory board. Still, these luminaries could be backing the wrong horse. Across town, that is the view at Sirtris’s rival, Elixir Pharmaceuticals.

Elixir has chosen to emphasize leads developed from Dr. Kenyon’s work on a different set of genes that affect aging, rather than on the sirtuin work of Dr. Guarente. “We think the sirtuins are extraordinarily interesting but just don’t yet have the proof that these enzymes will be useful in metabolic disease,” said William Heiden, Elixir’s chief executive.

“It’s a proven artifact that resveratrol activates sirtuins,” said Peter DiStefano, Elixir’s chief scientific officer, referring to Dr. Sinclair’s 2003 search for such chemicals.

Both Elixir executives argue that the biology of the seven SIRT genes needs to be better worked out before it is worth trying to develop drugs based on them. In their view, it is not even clear if the sirtuins should be activated or inhibited for best effect. Indeed, Elixir has developed several chemicals that inhibit SIRT1’s sirtuin.

This has brought about the odd circumstance that Sirtris is trying to activate SIRT1 and Elixir to inhibit it. Can both companies possibly be right? Dr. Guarente’s consulting agreement with Elixir has expired, and he welcomes the interest that Sirtris is now taking in his work. Both activation and inhibition of SIRT1 could be useful, he says judiciously, if during caloric restriction the gene’s activity goes up in some tissues and down in others.

The body’s metabolism is governed by such a complex array of genetic circuits that it will be years before the role of the seven SIRTs is fully understood. But if they really embody an ancient mechanism for fortifying the body against disease, then all that is needed is a safe drug that tricks the SIRT genes into thinking feast is famine. The theory is enticing, even if sirtuins and certainty still lie far apart.
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