October 31, 2006 NYTIMES
One for the Ages: A Prescription That May Extend Life
How depressing, how utterly unjust, to be the one in your social circle who is aging least gracefully.
In a laboratory at the Wisconsin National Primate Research Center, Matthias is learning about time’s caprice the hard way. At 28, getting on for a rhesus monkey, Matthias is losing his hair, lugging a paunch and getting a face full of wrinkles.
Yet in the cage next to his, gleefully hooting at strangers, one of Matthias’s lab mates, Rudy, is the picture of monkey vitality, although he is slightly older. Thin and feisty, Rudy stops grooming his smooth coat just long enough to pirouette toward a proffered piece of fruit.
Tempted with the same treat, Matthias rises wearily and extends a frail hand. “You can really see the difference,” said Dr. Ricki Colman, an associate scientist at the center who cares for the animals.
What a visitor cannot see may be even more interesting. As a result of a simple lifestyle intervention, Rudy and primates like him seem poised to live very long, very vital lives.
This approach, called calorie restriction, involves eating about 30 percent fewer calories than normal while still getting adequate amounts of vitamins, minerals and other nutrients. Aside from direct genetic manipulation, calorie restriction is the only strategy known to extend life consistently in a variety of animal species.
How this drastic diet affects the body has been the subject of intense research. Recently, the effort has begun to bear fruit, producing a steady stream of studies indicating that the rate of aging is plastic, not fixed, and that it can be manipulated.
In the last year, calorie-restricted diets have been shown in various animals to affect molecular pathways likely to be involved in the progression of Alzheimer’s disease, diabetes, heart disease, Parkinson’s disease and cancer. Earlier this year, researchers studying dietary effects on humans went so far as to claim that calorie restriction may be more effective than exercise at preventing age-related diseases.
Monkeys like Rudy seem to be proving the thesis. Recent tests show that the animals on restricted diets, including Canto and Eeyore, two other rhesus monkeys at the primate research center, are in indisputably better health as they near old age than Matthias and other normally fed lab mates like Owen and Johann. The average lifespan for laboratory monkeys is 27.
The findings cast doubt on long-held scientific and cultural beliefs regarding the inevitability of the body’s decline. They also suggest that other interventions, which include new drugs, may retard aging even if the diet itself should prove ineffective in humans. One leading candidate, a newly synthesized form of resveratrol — an antioxidant present in large amounts in red wine — is already being tested in patients. It may eventually be the first of a new class of anti-aging drugs. Extrapolating from recent animal findings, Dr. Richard A. Miller, a pathologist at the University of Michigan, estimated that a pill mimicking the effects of calorie restriction might increase human life span to about 112 healthy years, with the occasional senior living until 140, though some experts view that projection as overly optimistic.
According to a report by the Rand Corporation, such a drug would be among the most cost-effective breakthroughs possible in medicine, providing Americans more healthy years at less expense (an estimated $8,800 a year) than new cancer vaccines or stroke treatments.
“The effects are global, so calorie restriction has the potential to help us identify anti-aging mechanisms throughout the body,” said Richard Weindruch, a gerontologist at the University of Wisconsin who directs research on the monkeys.
Many scientists regard the study of life extension, once just a reliable plotline in science fiction, as a national priority. The number of Americans 65 and older will double in the next 25 years to about 72 million, according to government census data. By then, seniors will account for nearly 20 percent of the population, up from just 12 percent in 2003.
Earlier this year, four prominent gerontologists, among them Dr. Miller, published a paper calling for the government to spend $3 billion annually in pursuit of a modest goal: delaying the onset of age-related diseases by seven years.
Doing so, the authors asserted, would lay the foundation for a healthier and wealthier country, a so-called longevity dividend.
“The demographic wave entering their 60s is enormous, and that is likely to greatly increase the prevalence of diseases like diabetes and heart disease,” said Dr. S. Jay Olshansky, an epidemiologist at the University of Illinois at Chicago, and one of the paper’s authors. “The simplest way to positively affect them all is to slow down aging.”
Science, of course, is still a long way from doing anything of the sort. Aging is a complicated phenomenon, the intersection of an array of biological processes set in motion by genetics, lifestyle, even evolution itself.
Still, in laboratories around the world, scientists are becoming adept at breeding animal Methuselahs, extraordinarily long lived and healthy worms, fish, mice and flies.
In 1935, Dr. Clive McCay, a nutritionist at Cornell University, discovered that mice that were fed 30 percent fewer calories lived about 40 percent longer than their free-grazing laboratory mates. The dieting mice were also more physically active and far less prone to the diseases of advanced age.
Dr. McCay’s experiment has been successfully duplicated in a variety of species. In almost every instance, the subjects on low-calorie diets have proven to be not just longer lived, but also more resistant to age-related ailments.
“In mice, calorie restriction doesn’t just extend life span,” said Leonard P. Guarente, professor of biology at the Massachusetts Institute of Technology. “It mitigates many diseases of aging: cancer, cardiovascular disease, neurodegenerative disease. The gain is just enormous.”
For years, scientists financed by the National Institute on Aging have closely monitored rhesus monkeys on restricted and normal-calorie diets. At the University of Wisconsin, where 50 animals survive from the original group of 76, the differences are just now becoming apparent in the older animals.
Those on normal diets, like Matthias, are beginning to show signs of advancing age similar to those seen in humans. Three of them, for instance, have developed diabetes, and a fourth has died of the disease. Five have died of cancer.
But Rudy and his colleagues on low-calorie meal plans are faring better. None have diabetes, and only three have died of cancer. It is too early to know if they will outlive their lab mates, but the dieters here and at the other labs also have lower blood pressure and lower blood levels of certain dangerous fats, glucose and insulin.
“The preliminary indicators are that we’re looking at a robust life extension in the restricted animals,” Dr. Weindruch said.
Despite widespread scientific enthusiasm, the evidence that calorie restriction works in humans is indirect at best. The practice was popularized in diet books by Dr. Roy Walford, a legendary pathologist at the University of California, Los Angeles, who spent much of the last 30 years of his life following a calorie-restricted regimen. He died of Lou Gehrig’s disease in 2004 at 79.
Largely as a result of his advocacy, several thousand people are now on calorie-restricted diets in the United States, says Brian M. Delaney, president of the Calorie Restriction Society.
Mike Linksvayer, a 36-year-old chief technology officer at a San Francisco nonprofit group, embarked on just such a diet six years ago. On an average day, he eats an apple or some cereal for breakfast, followed by a small vegan dish at lunch. Dinner is whatever his wife has cooked, excluding bread, rice, sugar and whatever else Mr. Linksvayer deems unhealthy (this often includes the entrée). On weekends, he occasionally fasts.
Mr. Linksvayer, 6 feet tall and 135 pounds, estimated that he gets by on about 2,000 to 2,100 calories a day, a low number for men of his age and activity level, and his blood pressure is a remarkably low 112 over 63. He said he has never been in better health.
“I don’t really get sick,” he said. “Mostly I do the diet to be healthier, but if it helps me live longer, hey, I’ll take that, too.”
Researchers at Washington University in St. Louis have been tracking the health of small groups of calorie-restricted dieters. Earlier this year, they reported that the dieters had better-functioning hearts and fewer signs of inflammation, which is a precursor to clogged arteries, than similar subjects on regular diets.
In previous studies, people in calorie-restricted groups were shown to have lower levels of LDL, the so-called bad cholesterol, and triglycerides. They also showed higher levels of HDL, the so-called good cholesterol, virtually no arterial blockage and, like Mr. Linksvayer, remarkably low blood pressure.
“Calorie restriction has a powerful, protective effect against diseases associated with aging,” said Dr. John O. Holloszy, a Washington University professor of medicine. “We don’t know how long each individual will end up living, but they certainly have a longer life expectancy than average.”
Researchers at Louisiana State University reported in April in The Journal of the American Medical Association that patients on an experimental low-calorie diet had lower insulin levels and body temperatures, both possible markers of longevity, and fewer signs of the chromosomal damage typically associated with aging.
These studies and others have led many scientists to believe they have stumbled onto a central determinant of natural life span. Animals on restricted diets seem particularly resistant to environmental stresses like oxidation and heat, perhaps even radiation. “It is a very deep, very important function,” Dr. Miller said. Experts theorize that limited access to energy alarms the body, so to speak, activating a cascade of biochemical signals that tell each cell to direct energy away from reproductive functions, toward repair and maintenance. The calorie-restricted organism is stronger, according to this hypothesis, because individual cells are more efficiently repairing mutations, using energy, defending themselves and mopping up harmful byproducts like free radicals.
“The stressed cell is really pulling out all the stops” to preserve itself, said Dr. Cynthia Kenyon, a molecular biologist at the University of California, San Francisco. “This system could have evolved as a way of letting animals take a timeout from reproduction when times are harsh.”
But many experts are unsettled by the prospect, however unlikely, of Americans adopting a draconian diet in hopes of living longer. Even the current epidemiological data, they note, do not consistently show that those who are thinnest live longest. After analyzing decades of national mortality statistics, federal researchers reported last year that exceptional thinness, a logical consequence of calorie restriction, was associated with an increased risk of death. This controversial study did not attempt to assess the number of calories the subjects had been consuming, or the quality of their diets, which may have had an effect on mortality rates.
Despite the initially promising results from studies of primates, some scientists doubt that calorie restriction can ever work effectively in humans. A mathematical model published last year by researchers at University of California, Los Angeles, and University of California, Irvine, predicted that the maximum life span gain from calorie restriction for humans would be just 7 percent. A more likely figure, the authors said, was 2 percent.
“Calorie restriction is doomed to fail, and will make people miserable in the process of attempting it,” said Dr. Jay Phelan, an evolutionary biologist at the University of California, Los Angeles, and a co-author of the paper. “We do see benefits, but not an increase in life span.”
Mice who must scratch for food for a couple of years would be analogous, in terms of natural selection, to humans who must survive 20-year famines, Dr. Phelan said. But nature seldom demands that humans endure such conditions.
Besides, he added, there is virtually no chance Americans will adopt such a severe menu plan in great numbers.
“Have you ever tried to go without food for a day?” Dr. Phelan asked. “I did it once, because I was curious about what the mice in my lab experienced, and I couldn’t even function at the end of the day.”
Even researchers who believe calorie restriction can extend life in humans concede that few Americans are likely to stick to such a restrained diet over a long period. The aging of the body is the aging of its cells, researchers like to say. While cell death is hardwired into every organism’s DNA, much of the infirmity that comes with advancing years is from an accumulation of molecular insults that, experts contend, may to some degree be prevented, even reversed.
“The goal is not just to make people live longer,” said Dr. David A. Sinclair, a molecular biologist at Harvard. “It’s to see eventually that an 80-year-old feels like a 50-year-old does today.”
In a series of studies, Dr. Kenyon, of the University of California, San Francisco, has created mutant roundworms that live six times longer than normal, largely because of a mutation in a single gene called daf-2. The gene encodes a receptor on the surface of cells similar to a receptor in humans that responds to two important hormones, insulin and the insulin-like growth factor 1 or IGF-1.
Insulin is necessary for the body to transport glucose into cells to fuel their operations. Dr. Kenyon and other researchers suggest that worm cells with mutated receptors may be “tricked” into sensing that nutrients are not available, even when they are. With its maintenance machinery thereby turned on high, each worm cell lives far longer — and so does the worm.
Many experts are now convinced that the energy-signaling pathways that employ insulin and IGF-1 are very involved in fixing an organism’s life span. Some researchers have even described Type 2 diabetes, which is marked by insensitivity to the hormone insulin, as simply an accelerated form of aging.
In yeast, scientists have discovered a gene similar to daf-2 called SIR2, that also helps to coordinate the cell’s defensive response once activated by calorie restriction or another external stressor. The genes encode proteins called sirtuins, which are found in both plants and animals.
A mammalian version of the SIR2 gene, called SIRT1, has been shown to regulate a number of processes necessary for long-term survival in calorie-restricted mice.
Scientists are now trying to develop synthetic compounds that affect the genes daf-2 and SIRT1.
Several candidate drugs designed to prevent age-related diseases, particularly diabetes, are on the drawing boards at biotech companies. Sirtris Pharmaceuticals, in Boston, already has begun testing a new drug in patients with Type 2 diabetes that acts on SIRT1 to improve the functioning of mitochondria, the cell’s energy factories.
While an anti-aging pill may be the next big blockbuster, some ethicists believe that the all-out determination to extend life span is veined with arrogance. As appointments with death are postponed, says Dr. Leon R. Kass, former chairman of the President’s Council on Bioethics, human lives may become less engaging, less meaningful, even less beautiful.
“Mortality makes life matter,” Dr. Kass recently wrote. “Immortality is a kind of oblivion — like death itself.”
That man’s time on this planet is limited, and rightfully so, is a cultural belief deeply held by many. But whether an increasing life span affords greater opportunity to find meaning or distracts from the pursuit, the prospect has become too great a temptation to ignore — least of all, for scientists.
“It’s a just big waste of talent and wisdom to have people die in their 60s and 70s,” said Dr. Sinclair of Harvard.
Published: November 7, 2006 NYTIMES
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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