From the December 4, 2006
By David Sinclair, M.D. and Anthony L. Komaroff, M.D.
A compound found in red wine may extend the human life span.
A report from the front lines.
Nothing seems more inevitable than aging and death--not even taxes. Every plant, animal and person you have ever seen will eventually die, including the person in the mirror. But some recent research suggests that aging as we know it may not be inevitable. Indeed, as our understanding of it grows, aging can be seen not as an immutable reality from which there is no escape, but as the product of biological processes that we may be able to control someday.
We already know that some animals do not seem to age. Many cold-water ocean fish, some amphibians and the American lobster never reach a fixed size; they continue to grow bigger, to be able to reproduce and to live until something kills them. What these creatures seem to be telling us is that something in their genes--and possibly in ours--controls the pace of aging, and that aging is not the fate of every living thing.
Throughout the history of life on earth, one of the most common difficulties that animals (and their cells) have faced has been a lack of food. About 70 years ago, scientists discovered that when animals are forced to live on 30 to 40 percent fewer calories than they would normally eat, something unusual happens: they become resistant to most age-related diseases--cancer, heart disease, diabetes, Alzheimer's--and live 30 to 50 percent longer. Restricting calories slows aging.
But how? What are the underlying genes that preserve vitality and stave off disease? No one knows for sure why aging occurs, but one important reason is probably the accumulation of DNA damage--from radiation, mutation-causing chemicals or, particularly, oxidants. Inside every animal cell are many mitochondria--little "power packs" that use oxygen to generate energy. In doing their jobs, however, mitochondria produce chemical byproducts--oxidants --that damage DNA and other components inside cells. It may not seem fair, but it's a fact of life. Fortunately, our cells are not defenseless against such assaults. They have genes that spring into action to defend against DNA damage, including genes that repair damaged mitochondria.
About 15 years ago, armed with powerful new molecular-research techniques, a few scientists began to investigate these genetic phenomena. At MIT, Dr. Leonard Guarente (along with one of the authors of this piece, David Sinclair) discovered that adding an extra copy of a gene called Sir2 caused yeast cells to live 30 percent longer. Today many researchers suspect that Sir2 or other sirtuin genes--which are present in all animals, including humans--are responsible for the health benefits of calorie restriction, perhaps by repairing our DNA. But if, in order to kick the sirtuins into action, we had to restrict our calorie intake by 30 to 40 percent, would it be of any practical use? Few of us would be capable of restricting our diets so severely that we were constantly hungry: whether or not it made life longer, it would surely make life feel longer.
So some scientists began to look for ways to trigger the sirtuin system into action without restricting calories. In 2003, a handful of sirtuin-activating compounds (STACs) were discovered. Resveratrol--a molecule produced in plants (such as red-wine grapes)--was the most potent. Since then, resveratrol and other STACs have enhanced the vitality and extended the life span of every species they have been fed to: yeast, fruit flies, worms and fish. The maximum life span of the fish increased 59 percent, the equivalent of a human's living to 194 years. Remarkable results, no doubt, but does resveratrol work in warmblooded furry animals?
In early November, a research team (co-led by Sinclair) reported in the journal Nature the first study of resveratrol's effects on the life span of a mammal. The study compared three groups of middle-aged mice on three different diets: (1) a standard diet; (2) a high-calorie, high-fat diet, and (3) a high-calorie, high-fat diet spiked with resveratrol. As expected, compared with the mice on a standard diet, the mice on the high-calorie, high-fat diet gained weight and developed fatty livers, inflammation in their heart muscle and a diabetes-like condition. And they died at a younger age. However, the mice on the high-calorie, high-fat diet that were also given resveratrol developed none of these complications: their physiology was that of a lean mouse. They were also more physically active, outperforming the untreated and overfed mice on tests of physical performance. Most striking, resveratrol reduced the risk of death by 30 percent.
Then, in mid-November, another research team reported in the journal Cell that mice treated with resveratrol were leaner and developed a greatly enhanced aerobic capacity; their muscles were like Lance Armstrong's, consuming oxygen more efficiently and containing greater numbers of healthy mitochondria (and thus greater capacity to generate energy). Incredibly, the mice could run twice as far without getting tired, despite never having run on a treadmill before. At least for mice, resveratrol is an outstanding performance-enhancing drug.
Tantalizing evidence indicates that resveratrol may also protect against aging-related diseases. In labs around the world, resveratrol has protected mice against heart disease, cancer, diabetes and Alzheimer's—the very diseases that reduce most people's life span.
The obvious question: what does all this mean for humans? Like the mice in these recent studies, many of us are also middle-aged mammals on a high-calorie, high-fat diet. Things that are true in mice are often, but not always, true in humans. In 2007 there will be much more aging research conducted in animals, and in humans. Some of the first human studies of resveratrol will see whether it can help people with either type 2 diabetes or a rare condition called MELAS syndrome that causes brain and muscle destruction in children. More important, research is underway to find sirtuin activators that have the same effects as resveratrol but are more potent. Several have already been identified, and their health effects in animals are being studied.
Because resveratrol is found in red wine, some people ask whether they should drink more red wine, or drink red wine to the exclusion of other alcoholic beverages. There is not enough resveratrol in red wine to make that a good idea: it would take 1,000 glasses to equal the daily dose given to the mice. Resveratrol tablets and capsules are now sold over the counter, but they are of no proven value in humans, and their manufacture is not controlled by the Food and Drug Administration. It is hard to predict whether or when resveratrol, or one of the other STACs, would be approved for use as a pharmaceutical, but it seems unlikely in the next seven to 10 years.
Some people shudder at the thought of a treatment to extend human life, imagining that the added years would be ones of frailty and of failing intellect and strength. However, the animals that get added time from resveratrol treatment are, by all measures, remarkably vital until the end. It has been estimated that drugs that maintain health and vitality could save the U.S. economy tens of trillions of dollars. For example, a permanent 1 percent reduction in mortality from cancer would have a value to current and future generations of Americans of nearly $500 billion. Many scientists are encouraging Congress to increase funding for aging research, to launch the equivalent of the Apollo program. Only a few humans made it to the moon. In the future, millions may live a century or more, and remain vital and productive during those added years.
Dr. Sinclair is an associate professor of pathology, codirector of the Paul F. Glenn Laboratories at Harvard Medical School (HMS), and cofounder of Sirtris Pharmaceuticals, the company conducting trials of resveratrol.
Dr. Komaroff is the Simcox-Clifford-Higby Professor of Medicine at HMS and editor in chief of the Harvard Health Letter. For more health information from HMS, go to health.harvard.edu