The Caloric Restriction and Life Longevity Connection
Public release date: 20-Sep-2007
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Contact: Davic Cameron
public_affairs@hms.harvard.edu
617-432-0442
Harvard Medical School
Researchers find connection between caloric restriction and longevity
BOSTON, Mass. (September 20, 2007)–For nearly 70 years scientists have known that caloric restriction prolongs life. In everything from yeast to primates, a significant decrease in calories can extend lifespan by as much as one-third. But getting under the hood of the molecular machinery that drives this longevity has remained elusive.
Now, reporting in the September 21 issue of the journal Cell, researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health, have discovered two genes in mammalian cells that act as gatekeepers for cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up and help protect cells from diseases of aging.
“We’ve reason to believe now that these two genes may be potential drug targets for diseases associated with aging,” says David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.
The new genes that Sinclair’s group have discovered, in collaboration with Anthony Sauve of Cornell Medical School and Rafael de Cabo of NIH, are called SIRT3 and SIRT4. They are members of a larger class of genes called sirtuins. (Another gene belonging to this family, SIRT1, was shown last year to also have a powerful impact on longevity when stimulated by the red-wine molecule resveratrol.)
In this paper, the newly discovered role of SIRT3 and SIRT4 drives home something scientists have suspected for a long time: mitochondria are vital for sustaining the health and longevity of a cell.
Mitochondria, a kind of cellular organ that lives in the cytoplasm, are often considered to be the cell’s battery packs. When mitochondria stability starts to wane, energy is drained out of the cell, and its days are numbered. In this paper, Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a longevity network that maintains the vitality of mitochondria and keeps cells healthy when they would otherwise die.
When cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT. As levels of NAMPT ramp up, a small molecule called NAD begins to amass in the mitochondria. This, in turn, causes the activity of enzymes created by the SIRT3 and SIRT4 genes–enzymes that live in the mitochondria–to increase as well. As a result, the mitochondria grow stronger, energy-output increases, and the cell’s aging process slows down significantly. (Interestingly, this same process is also activated by exercise.)
“We’re not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result SIRT3 and SIRT4,” says Sinclair, “but we do see that normal cell-suicide programs are noticeably attenuated. This is the first time ever that SIRT3 and SIRT4 have been linked to cell survival.”
In fact, the mitochondria appear to be so essential to the cell’s life that when all other energy sources inside the cell–including the nucleus–are wiped out, yet the mitochondria are kept intact and functional, the cell remains alive.
“Mitochondria are the guardians of cell survival,” says Sinclair. “If we can keep boosting levels of NAD in the mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4, then for a period of time the cell really needs nothing else.”
Sinclair and his colleagues have coined a phrase for this observation: the Mitochondrial Oasis Hypothesis.
SIRT3 and SIRT4 may now also be potential drug targets for diseases associated with aging. For example, in recent years scientists have become increasingly aware of the importance of mitochondrial function in treating diseases such as cancer, diabetes, and neurodegeneration.
“Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria,” says Sinclair. “Such a molecule could be used for many age-related diseases.”
According to Suave of Cornell, “This study also highlights how advanced technological methods can help resolve fundamental biological questions in ways that were hard to achieve as recently as a few years ago.”
This study is supported by the National Institutes of Health and the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. Sinclair and Suave are consultants to Sirtris Pharmaceuticals, a company aiming to treat diseases by modulating sirtuins. Sinclair is also a cofounder of Sirtris Pharmaceuticals and sits on their advisory board and board of directors.
For a copy of the paper, please contact public_affairs@hms.harvard.edu
Full Citation:
Cell, Volume 130, Issue 5, September 21, 2007
“Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival”
Hongying Yang(1,6), Tianle Yang(2), Joseph A. Baur(1), Evelyn Perez(3), Takashi Matsui(5), Juan J. Carmona(1), Dudley W. Lamming(1), Nadja C. Souza-Pinto(4), Vilhelm A. Bohr(4), Anthony Rosenzweig(5), Rafael de Cabo(3), Anthony A. Sauve(2), and David A. Sinclair(1)
1-Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical School, Boston, MA
2-Department of Pharmacology, Weill Medical College of Cornell University, New York, NY
3-Laboratory of Experimental Gerontology
4-Laboratory of Molecular Gerontology, National Institute on Aging, Institutes of Health, Baltimore, MD
5-Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA
6-Present address: Sirtris Pharmaceuticals, Cambridge, MA
Harvard Medical School (www.hms.harvard.edu) has more than 7,000 full-time faculty working in eight academic departments based at the School’s Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children’s Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
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Yes, Red Wine Holds Answer. Check Dosage.
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By NICHOLAS WADE
(Mice from Harvard Study of Resveratrol)
Published: November 2, 2006
Can you have your cake and eat it? Is there a free lunch after all, red wine included? Researchers at the Harvard Medical School and the National Institute on Aging report that a natural substance found in red wine, known as resveratrol, offsets the bad effects of a high-calorie diet in mice and significantly extends their lifespan.
Their report, published electronically yesterday in Nature, implies that very large daily doses of resveratrol could offset the unhealthy, high-calorie diet thought to underlie the rising toll of obesity in the United States and elsewhere, if people respond to the drug as mice do.
Resveratrol is found in the skin of grapes and in red wine and is conjectured to be a partial explanation for the French paradox, the puzzling fact that people in France enjoy a high-fat diet yet suffer less heart disease than Americans.
The researchers fed one group of mice a diet in which 60 percent of calories came from fat. The diet started when the mice, all males, were a year old, which is middle-aged in mouse terms. As expected, the mice soon developed signs of impending diabetes, with grossly enlarged livers, and started to die much sooner than mice fed a standard diet.
Another group of mice was fed the identical high-fat diet but with a large daily dose of resveratrol (far larger than a human could get from drinking wine). The resveratrol did not stop them from putting on weight and growing as tubby as the other fat-eating mice. But it averted the high levels of glucose and insulin in the bloodstream, which are warning signs of diabetes, and it kept the mice’s livers at normal size.
Even more striking, the substance sharply extended the mice’s lifetimes. Those fed resveratrol along with the high- fat diet died many months later than the mice on high fat alone, and at the same rate as mice on a standard healthy diet. They had all the pleasures of gluttony but paid none of the price.
Scientists have long known that a moderate intake of alcohol, and red wine in particular, is associated with a lowered risk of heart disease and other benefits. More recently, scientists began to suspect resveratrol had particularly powerful effects and began investigating its role in lifespan.
The researchers, led by David Sinclair and Joseph Baur at the Harvard Medical School and by Rafael de Cabo at the National Institute on Aging, also tried to estimate the effect of resveratrol on the mice’s physical quality of life. They gauged how well the mice could walk along a rotating rod before falling off, a test of their motor skills. The mice on resveratrol did better as they grew older, ending up with much the same staying power on the rod as mice fed a normal diet.
The researchers hope their findings will have relevance to people too. Their study shows, they conclude, that orally taken drugs “at doses achievable in humans can safely reduce many of the negative consequences of excess caloric intake, with an overall improvement in health and survival.”
Several experts said that people wondering if they should take resveratrol should wait until more results were in, particularly from safety tests in humans. Another caution is that the theory about why resveratrol works is still unproved.
“It’s a pretty exciting area, but these are early days,” said Dr. Ronald Kahn, president of the Joslin Diabetes Center in Boston.
Information about resveratrol’s effects on human metabolism should be available a year or so, Dr. Kahn said, adding, “Have another glass of pinot noir — that’s as far as I’d take it right now.”
The mice were fed a hefty dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol per liter, so a 150-lb person would need to drink 750 to 1,500 bottles of red wine a day to get such a dose.
Dr. Richard Hodes, director of the National Institute on Aging, which helped support the study, also said that people should wait for the results of safety testing. Substances that are safe and beneficial in small doses, like vitamins, sometimes prove to be harmful when taken in high doses, Dr. Hodes said.
One person who is not following this prudent advice, however, is Dr. Sinclair, the chief author of the study. He has long been taking resveratrol, though at a dose of only five milligrams per kilogram. Mice given that amount in a second feeding trial have shown similar, but less pronounced, results as those on the 24-milligram-a-day dose, he said.
Dr. Sinclair has had a physician check his metabolism, because many resveratrol preparations contain possibly hazardous impurities, but so far no ill effects have come to light. His wife, his parents, and “half my lab” are also taking resveratrol, he said.
Dr. Sinclair declined to name his source of resveratrol. Many companies sell the substance, along with claims that rivals’ preparations are inactive. One such company, Longevinex, sells an extract of red wine and knotweed that contains an unspecified amount of resveratrol. But each capsule is equivalent to “5 to 15 5-ounce glasses of the best red wine,” the company’s Web site asserts.
Dr. Sinclair is the founder of a company, Sirtris Pharmaceuticals, that has developed several chemicals intended to mimic the role of resveratrol but at much lower doses. Sirtris has begun clinical trials of one of these compounds, an improved version of resveratrol, with the aim of seeing if it helps control glucose levels in people with diabetes.
“We believe you cannot reach therapeutic levels in man with ordinary resveratrol,” said Dr. Christoph Westphal, the company’s chief executive.
Behind the resveratrol test is a considerable degree of scientific theory, some of it well established and some yet to be proved. Dr. Sinclair’s initial interest in resveratrol had nothing to do with red wine. It derived from work by Leonard Guarente of the Massachusetts Institute of Technology, who in 1995 found a gene that controlled the longevity of yeast, a single-celled fungus.
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Resveratrol - New York Times Article
Originally published by the New York Times: http://www.nytimes.com/2007/07/08/business/yourmoney/08stream.html
An Age-Defying Quest (Red Wine Included)
Imagine a pill, derived from a compound found in something as benign as red wine, that treated the most feared and debilitating diseases of aging: illnesses like diabetes, neurodegenerative conditions like Alzheimer’s and Parkinson’s, and many forms of cancer. Imagine, furthermore, that this pill had no injurious side effects. Imagine, finally, that the pill’s only side effect conferred what human beings have always wanted: an increase in life span. That’s what Sirtris wants to create.
Christoph Westphal, the chief executive of Sirtris, who has an M.D. and a Ph.D. in biology from Harvard Medical School, was previously a venture capitalist at Polaris Ventures and was a founder of Acceleron Pharma, Alnylam Pharmaceuticals and Momenta Pharmaceuticals, among other companies. The last two companies, which are publicly traded, have a combined market value of more $1.4 billion.
Sirtris was founded in the spring of 2004 by Dr. Westphal to commercialize the research of David Sinclair, a professor of pathology at Harvard Medical School and the director of the Glenn Laboratories for the Biological Mechanisms of Aging. Mr. Sinclair, who at the relatively youthful age of 37 is already renowned for his investigations into how we grow old, discovered in 2003 that a molecular compound called resveratrol, found in red wine and other plant products, extends the life span of mice by as much as 24 percent and the life span of other animals, such as flies and fish, by as much as 59 percent.
Dr. Westphal, a self-described “geek” who relaxes by reading papers in academic journals like Nature and Science, was stunned by Mr. Sinclair’s discovery, and visited him in his lab to discuss the implications for drug development. The two soon decided to start a company.
“I figured if there’s going to be one chance that I’d take an 80 percent pay cut to be the C.E.O. of a company rather than general partner in a venture firm, then this was it,” Dr. Westphal, 39, told me when I visited Sirtris’s offices in Cambridge, Mass. “If we’re right on this one, everyone’s going to want to take these drugs and they’re going to treat many of the major diseases of Western society.”
Since founding the company, Dr. Westphal and Mr. Sinclair have raised more than $103 million in venture funding, from various investors like Polaris Venture Partners, the Novartis Bioventures Fund and the Genzyme Corporation. In May, Sirtris completed a successful initial public offering, raising an additional $62 million in capital.
Thus, Sirtris now has $140 million in cash and annual expenses of only $37 million, according to Dr. Westphal.
“We can control our destiny,” he says. “We can actually go for this crazy idea that you can target genes that control the aging process.”
Mr. Sinclair believes that resveratrol works by activating a gene called SIRT-1, which many biologists think plays a fundamental, if still obscure, role in regulating life span in mammals. Scientists have shown that increasing the activity of SIRT-1 in animals slows down aging and postpones or eliminates diseases of old age.
No one really knows why SIRT-1 has the effect it does. One theory, proposed by Leonard Guarente, Mr. Sinclair’s mentor, who discovered the sirtuin genes (as they are collectively known) and is a biology professor at the Massachusetts Institute of Technology, is that SIRT-1 is activated by caloric restriction.
Biologists have known for 70 years that mice will live much longer when they are fed a nutritious diet with 30 to 40 percent fewer calories than they would normally eat. (Mr. Guarente and Mr. Sinclair think that this could be an ancient evolutionary adaptation to scarcity and starvation.) Resveratrol may therefore be mimicking caloric restriction without an arduous diet that few people can maintain for very long.
“Nobody knows why we age,” Mr. Sinclair explained to me. “We’re working on genes that increase fitness and defenses against diseases. The body mounts those defenses when it’s under adversity. Caloric restriction is one of those triggers and the molecules we’re developing are also one of those triggers.”
Dr. Westphal and Mr. Sinclair stress that they are not working to “cure” aging, a condition that, so far at least, is common to all humanity and that most physicians do not consider a disease. “Curing aging is not an endpoint the federal drug agency would recognize,” Dr. Westphal says dryly. Instead, both men say, they are working to ameliorate the diseases of aging.
While Mr. Sinclair has bragged that resveratrol is as “close to a miraculous molecule as you get,” much uncertainty surrounds his research and the commercialization of his discovery faces many challenges.
Quite apart from any scientific debate about why resveratrol works and whether it will have the same beneficial effect in humans that has been demonstrated in animals with short life spans, no one knows if resveratrol will be toxic when taken in therapeutic doses. Mr. Sinclair argues that the compound is unlikely to be toxic because it is modulating enzymes “that naturally go up and down according to diet.”
In any case, he says, mice have consumed as much as 400 milligrams of resveratrol per kilogram of body weight without ill effect. On the contrary, the rodents became sleek, slim and powerfully athletic. (A human would have to drink 10,000 bottles of wine a day to consume the same quantity of resveratrol.)
But Phillip A. Sharp, a 1993 Nobel laureate in medicine and physiology who has advised Sirtris, strongly disagrees: “Mice are not men, and even if you treat a mouse he can’t tell you if there’s something wrong with his paw,” said Mr. Sharp, who is also the director of the McGovern Institute for Brain Research at M.I.T. “Until you go into long-term human studies, there will always be unknown risks.”
SIRTRIS has begun such studies. The company has one compound, called SRT501, an improved formulation of resveratrol that is in early clinical trials for the treatment of diabetes. Later this year, Dr. Westphal says, the company will also begin clinical trials with SRT501 to treat Melas syndrome, a disorder of the cell’s mitochondria, in which sufferers age with unnatural haste.
The company is also developing other “sirtuin activators” that are unrelated to resveratrol, and which Dr. Westphal describes as “one thousand times” as powerful as SRT501. In theory, drugs derived from such compounds would be more effective at lower doses. Sirtris hopes to have its first drugs in commercial production by 2012 or 2013. While that may seem far off, it’s wonderfully fast for the biopharmaceutical industry, where development is onerously slow, difficult and uncertain.
This speed of research and development owes much to Dr. Westphal’s energy and Mr. Sinclair’s ambition.
“For as long as I can remember, I’ve wanted to develop drugs that combat diseases of aging,” Mr. Sinclair says. “As soon as I realized I was mortal, I started to worry. I set a goal to see if we could make drugs that would target the diseases of aging in my lifetime. I didn’t know it would be possible at all — and I didn’t know it would happen so quickly.”
Jason Pontin is the editor in chief and publisher of Technology Review, a magazine and Web site owned by M.I.T. E-mail:
pontin@nytimes.com
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