Boulder, Colo. -- In a laboratory at the edge of the University of Colorado campus here, Thomas E. Johnson and his colleagues are creating the Methuselahs of the animal world. Like the biblical patriarch who supposedly lived for 969 years, the maggot-sized roundworms in Dr. Johnson's lab far exceed their normal life span. But unlike Methuselah, these nematodes have actually lived to their incredible old age. Dr. Johnson an his colleagues have genetically manipulated the transparent worms, known as Caenorhabditis elegans, to produce strains that live twice as long as normal.
In Montreal, researchers in the laboratory of Siegfried Hekimi at McGill University have produced roundworms that live even longer. Last spring they announced the discovery of two genes that, in combination, allow the nematodes to live five times their normal life span -- an achievement equivalent to producing a race of people capable of living nearly 400 years.
Those accomplishments and the recent successes of other scientists who have managed to extend substantially the life spans of a variety of other creatures, from fruit flies to mice, have sparked a flurry of activity in this new field, giving biologists confidence that the mysteries of aging may finally be within reach. A variety of fundamental questions remain: What causes living things to age? What happens physiologically in those creatures that are able to live two to five times as long as their counterparts? And, ultimately, can any of the means of extending the lives of fruit flies and worms be applied to humans?
Excitement over the recent developments brought a group of leading experts on aging together last month in Seattle to review the state of their field at the annual meeting of the American Association for the Advancement of Science. According to the scientists, three lines of research appear particularly fruitful in understanding the underlying biological mechanisms involved in aging. The first involves the manipulation of genes that increase an organism's resistance to environmental stresses, particularly the biologically harmful "free radicals" of oxygen -- molecules containing unpaired electrons that cause irreparable damage to cells. By genetically manipulating fruit flies to produce two enzymes, superoxide dismutase and catalase, that work together to break down free radicals, scientists at the University of California at Irvine and Southern Methodist University have been able to produce strains of flies that live the equivalent of 150 human years. Not only do the insects live longer with these extra anti-oxidants, said William C. Orr, an associate professor of biology at S.M.U.; they are also unexpectedly active in their old age. "We seem to be enhancing the vitality of the organisms, so they're more robust," he said.
Another promising avenue for understanding the physiology of human aging is a rare genetic disorder, Werner's syndrome, that causes an acceleration of the aging process in people. People with the disease typically begin developing age-related ailments in their 20s and die by their late 40s. George M. Martin, a professor of pathology at the University of Washington who has been studying the molecular process by which the Werner's gene destroys DNA, said he and collaborators at the University of Osaka discovered a variant of the gene that protects a segment of the Japanese population from diabetes, coronary-artery disease, and other age-related ailments.
A third promising line of research that scientists are pursuing involves the maintenance of animals on calorie-restricted diets. Since 1935, the scientists have known that laboratory rats and mice maintained on a calorically restricted diet live up to 50 per cent longer than normal. "Not only do they live longer, but they live better," said George S. Roth, a scientist at the Gerontology Research Center of the National Institute on Aging, in Baltimore. "They're healthier. They get the diseases of aging to a lesser extent and later in life." Similar experiments performed on snakes, worms, and flies have since produced similar results, leading scientists to suspect that they had found a physiological mechanism that controls aging. However, two important questions remained: "What was the mechanism by which caloric restriction exerted these anti-aging effects?" asked Dr. Roth. "And secondly, of course, will it work in people?"
In 1987, he and his colleagues began an experiment to try to answer those questions in a population of captive rhesus and squirrel monkeys. "It's obviously very difficult to do this kind of experiment in people," Dr. Roth explained. "So we opted to do it in the next best thing." Over the past decade, the experiment has grown to include more than 200 monkeys, one-half of which are allowed to eat as much as they want in two daily meals and one-half of which are fed 30 percent less of the same nutritionally balanced monkey chow. "The animals aren't short-changed on nutrients," said Dr. Roth. "We like to call this undernutrition without malnutrition."
He and his colleagues found that all of the health effects from calorie-restriction diets in rodents appear to occur in monkeys as well. When compared to the control group, for example, the calorically restricted monkeys are shorter, are about 20 to 25 per cent thinner, and reach sexual maturity about a year later. Because the monkeys normally live for 30 to 40 years, the researchers have not determined whether the calorically restricted primates, like mice and rats, actually live longer. But Dr. Roth said that by every health-related measure, the calorically restricted monkeys appear healthier and less likely to develop age-related diseases than their well-fed cousins. For example, the blood pressures of the calorically restricted animals are lower than those of the well-fed monkeys, and their levels of high-density lipoprotein, or "good cholesterol," are twice as high. "We think they'll be less likely to develop cardiovascular diseases as they get older," said Dr. Roth.
In addition, the calorically restricted monkeys have a better sensitivity to insulin and tolerance to glucose, suggesting that they are less likely to develop diabetes. They also have body temperatures that are about one degree centigrade lower than their well-fed cousins -- presumably because of their lowered metabolism -- and are more active than the other group as they age. But their appearance has suffered. Their pelts are less lustrous and their fur is missing in many places on their bodies. That isn't surprising, Dr. Roth said, given that fur is unimportant to the monkeys' survival in the laboratory. "What happens in a calorically restricted animal," he explained, "is that the metabolism is reset from a growth and reproductive strategy to a survival strategy."
Dr. Johnson of Colorado said this same principle could be seen in roundworms that face harsh environmental conditions. He and his colleagues have isolated a handful of genes that not only double the life spans of C. elegans, but also provide increased resistance to the damaging effects of high temperature, ultraviolet radiation, and oxygen metabolism. Several of the genes appear to accomplish this by lowering the worm's metabolism to the point where it can survive in suspended animation in environmentally resistant spores called dauers until the presence of food, water, and other favorable conditions allow it once again to grow and reproduce. A separate gene that the McGill researchers found produced a 50-per-cent increase in life span in nematodes was shown also to slow down the worms' metabolism. Their findings appeared in the February 14 issue of Science.
Scientists don't know how a lowered metabolism can reduce aging in animals. But many, like Dr. Johnson, suspect it could be linked to reductions in cellular damage from oxygen metabolism. In fact, Dr. Johnson and a colleague at the University of Idaho, Steven N. Austad, believe extension of life could be a general by-product of an organism's response to environmental stress. According to their idea, worms and other organisms possess a complement of genes capable of being switched on by harsh environmental conditions that allow them to survive and live long enough to reproduce. "I think there could absolutely be a parallel between dietary restriction and stress resistance," said Dr. Johnson. With an increased resistance to toxins, for example, starving animals searching for new sources of food would be better able to resist poisons. The need to find food may also explain why the calorie-restricted animals are more active than their well-fed counterparts. "A dietarily restricted rat will run five miles a day in a cage with a wheel, while a well-fed lab rat will run 100 yards a day, because it doesn't need to go looking for anything," Dr. Johnson explained. In addition, many of the same genes that produce this behavior in rats and help roundworms and rats resist environmental stresses and extend life are present in higher organisms. In other words, the same complement of genes that extend life and help resist stresses in roundworms probably does the same in monkeys and humans who are physiologically stressed by an extremely low-calorie diet.
That doesn't mean people should starve themselves to activate their internal fountains of youth. "I don't think I would give anybody a diet message at this point, based on our study," said Dr. Roth of the institute on aging. "Although I think the hypothesis that we're testing is going to turn out to be true -- that caloric restriction could benefit humans as well -- without some sort of clinical trial, without weighing side effects and tailoring diets to individuals, I think it would be premature." Nevertheless, the prospect has led two experts on aging to calculate that the average life span of humans could be boosted from 76 years to 120 years if people adopted extremely low-calorie diets. According to Caleb E. Finch and Malcolm C. Pike of the University of Southern California, who published their speculations in a paper in last May's Journal of Gerontology, 120 years is now the theoretical maximum age a human can expect to live. Only one person has ever exceeded that age. The oldest-known person who has ever lived -- Jeanne Calment of Arles, France -- celebrated her 122nd birthday on February 21. Dr. Roth and Dr. Johnson believe it won't be necessary for the rest of us to diet excessively to reach that age. Once the physiological mechanism of diet restriction is understood, they said, drugs could be developed to turn on the age-retarding genes. "We could trick the cells of the body into thinking that they are calorically restricted, but still allow individuals to eat all the food they want," said Dr. Roth. "That would be the ultimate goal of this research."
Copyright (c) 1997 by The Chronicle of Higher Education, Inc.
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