Today, the National Institute on Aging (NIA) supports CR research in both rodents and primates to the tune of $3 million per year. Much of the rodent work is directed at discovering the mechanism that underlies CR, while the primate studies are showing that CR lowers blood sugar, eliminates diabetes, lowers cholesterol, and reduces blood pressure in genetically susceptible animals. This confirms previous findings in rodent studies and is leading some researchers to believe that eventually CR will be a means of extending maximum life span and retarding chronic disease in humans.
DEFINED FOCUS: "As an institute, our underlying interest is to understand the mechanism, not to produce longer-lived individuals," says NIA's Richard Sprott
In 1985, Sprott managed to obtain 10 years of funding from NIA for investigators who wanted to do CR research. This support began at $1 million per year for research to establish biomarkers of aging in rodents. Sprott explains that biomarkers "are measures that would allow you to determine the rate at which an organism is aging in less than the full-life span of the animal"-ideally in six months or a year. Then any miracle antiaging substance or regimen could be tested against that biomarker or, more likely, a pair of biomarkers, to see if the biomarkers were slowed by the miracle intervention. (A group of biomarkers is expected to be published in 1998, according to Sprott.)
EVOLVING ROLE: NCTR’s Angelo Turturro explains how calorically restricted rats ended up being used as controls in the direct study of aging
In 1987, NIA began funding primate studies to replicate findings from the hundreds of rodent studies done in the 1960s and 1970s by scientists like Roy Walford at the Center for Health Sciences at the University of California, Los Angeles, Edward Masaro at the University of Texas Health Sciences Center at San Antonio, and Morris Ross, a nutritional oncologist at Fox Chase Cancer Center in Philadelphia. They looked at the fat, carbohydrate, and protein content as well as the vitamin and mineral content of the diets of calorically restricted rats, says Turturro. "They showed it was the total amount of energy that mattered and not where you got your calories from," he notes. If CR could extend maximum life span and retard chronic disease in monkeys, by implication, it could apply to humans (D. Ingram et al., Journal of Gerontology: Biological Sciences, 45:B148-63, 1990).
DISEASE DETERRENT?: Studies by Maryland's Barbara Hansen show that caloric restriction has delayed the onset of diabetes in genetically predisposed monkeys.
In ongoing, unpublished work on monkeys with early diabetes, Hansen has shown that a CR regimen can reverse the disease. The mechanism is unclear. "We do know that insulin action is impaired in the obese and in diabetics. so from that standpoint there is a linkage," she states, "but whether the one causes the other is hypothetical."
HEART BENEFITS: Data from Wisconsin’s Rick Weindruch's lab suggest calorically restricted monkeys have lower blood pressure and cholestoral levels than their heavy-eating peers.
Preliminary data from Weindruch's lab also suggest that lipoproteins from calorically restricted monkeys are less likely to adhere to artery walls than are lipoproteins in the blood of their heavy-eating peers. Blood pressure is lower, too.
This is in line with findings from the lab of George Roth, chief of the molecular physiology and genetics section at NIA. Roth is in the 10th year of a primate study. He has found lower blood triglycerides, lower blood pressure, and higher levels of HDL cholesterol in his calorically restricted monkeys than in their well-fed counterparts. "We think they are going to be less likely to develop cardiovascular problems," says Roth. He has also found lower body temperature (M. Lane et al., Proceedings of the National Academy of Sciences, 93:4159-64, 1996), reduced metabolism, and the retardation of puberty by about one year in males.
Roth recently reported on a possible biomarker of aging called pentosidine, a chemical compound found in skin collagen. Its increase with age is associated with the severity of complications in diabetes and end-stage renal disease (G. Roth et al., PNAS, 93:485-90, 1996). Preliminary data suggest that it accumulates more slowly in calorically restricted rodents and primates.
How CR works to increase life span and retard chronic disease in animals remains a mystery. Roth points to a number of contenders for the mechanism, such as altered characteristics of glucose utilization, decreased oxygen radical damage, reduced glycation of macromolecules, changes in gene expression, and alterations in stress hormones (G. Roth et al., Nature Medicine, 1:414-5, 1995). This means that the organism is moving into survival mode, expending less energy, lowering its metabolism, and exposing its body to less wear and tear, according to Roth.
DIFFERENT ASSESSMENT: "It's not that [caloric restriction] increases longevity," contends critic Leonard Hayflick, "it's that ad lib feeding reduces longevity."
Hayflick also questions the notion that people would be willing to eat 30 percent fewer calories to live longer. And even if CR were to work, he contends that the extended period of life, probably spent wasting away in a nursing home, isn't desirable.
But Weindruch counters that CR results do not depend on using ad lib-fed controls (R. Weindruch et al., J. of Nutrition, 116:641-54, 1986). "We found that a group that was 25 percent restricted relative to the average ad lib intake level is a better control," he maintains. Thus, CR findings are not contingent on the use of obese controls, he says.
Neither does Weindruch think that the animal data show an increased maximal life span leads to added years of decrepitude and, by implication, long periods of nursing home care. To the contrary, he points to an increased "health span"-the portion of an organism's life when it is disease-free-as one of the benefits of CR. "The CR animals show less signs of disease and also retarded rates of change of both physiological and biochemical outcomes that change with age," he says.
Another criticism comes from Reubin Andres, clinical director of NIA, who isn't convinced that lean humans have decreased mortality. He says that data show that when weight is plotted against mortality, a J-shaped curve results. In other words, very lean and very fat people have higher mortality rates, while people who gain a few pounds each decade after the age of 20 have the best survival rates.
However, Roth argues that the studies cited by Andres are observational, not controlled, trials. "If you took the people who did the best," he says, "and divided them into CR and ad lib groups, you might see the restricted group do even better." Others have also criticized this work because it includes smokers and people with subclinical diseases, such as cancer, both of which will lead to weight loss and premature death (J. Manson et al., New England Journal of Medicine, 333:677-85, 1995).
CR investigators differ in the extent to which they think CR will apply to humans. Some, like Roth and Walford, believe it will ultimately extend maximum life span. Others, such as Sprott, are primarily interested in what might be learned about age-dependent susceptibility to cancer and other diseases. In particular, Sprott wants to learn how CR might affect tumor- suppressing genes. "As an institute," he explains, "our underlying interest is to understand the mechanism, not to produce longer-lived individuals."
LESS IS MORE: Cancer Researcher David Kritchevsky notes that "all the things that should be good for you, work better" with caloric restriction.
INDUSTRY POTENTIAL: NIA's George Roth believes that once the mechanism that underlies caloric restriction is found, its effects could be mimicked pharmacologically.
They may have been encouraged by the work of Walford. Along with a crew of seven, Walford underwent a short trial of CR in Biosphere II, an enclosed, artificial habitat constructed near Tucson, Ariz., in the early 1990s (Opinion, The Scientist, Jan. 24, 1994, page 11). The researchers grew their own food and, owing to miscalculation, ended up producing only enough for an 1,800-calorie-per-day allotment for the six months of the study. Average weight fell 26 pounds in the men and 15 in the women. The average total cholesterol went from 193 to 123, blood glucose from 92 to 74, and blood pressure from 109/74 to 89/58. (R. Walford et al., PNAS, 89:11533-537, 1992).
And plans are already under way on the part of NCTR and the University of Tennessee to determine if intestinal bypass surgery in the morbidly obese, accompanied by a 1,500-calorie-per-day diet, will produce the same metabolic changes as seen in calorically restricted rats. This study will be headed by toxicologist Ron Hart at NCTR, surgeon George Cowan of the University of Tennessee Health Sciences Center, and nutritionist Cynthia Buffington, director of research at the Obesity and Wellness Center at the University of Tennessee.
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Of course, a prerequisite for a pill is a good understanding of the mechanism that underlies CR. That's something that Roth feels will take another three or four years. Then the CR effect could be mimicked pharmacologically, he says. "You could still enjoy your food, but trick your cells into thinking that they were on CR."
Paul McCarthy is a freelance health and science writer based in Littleton, Colo.