IN searching for ways to extend the human life span and to ward off the diseases of old age, some scientists find themselves focusing not on enhancing diet but rather on limiting it.
Their approach grows out of increasingly convincing evidence that longevity can be significantly increased by "undernutrition" - a diet that contains all the required nutrients but about a third fewer calories than are needed to maintain "normal" body weight.
Eating less, their animal studies indicate, can add the human equivalent of 40 years to a mammal's life. It can also delay agerelated declines in immune responses and diminish the risk of developing diseases associated with aging such as heart ailments, cancer, kidney disease and arthritis. Instead of becoming ill, many of the animals on restricted diets eventually simply die of old age.
Although all the research has been in laboratory mammals, the scientists involved are confident that their findings would also apply to people.
According to recent studies, merely reducing the protein content of the diet without lowering calories may be an effective technique to delay aging. Dr. Edward J. Masoro, chairman of the department of physiology at the University of Texas Health Sciences Center at San Antonio, showed that cutting protein intake in half significantly lengthened the lives of laboratory rats, though not as much as when their calorie intake was reduced to 60 percent of normal.
Furthermore, Dr. Masoro and Dr. Roy Walford have recently shown that the benefits of "undernutrition without malnutrition" apparently can be reaped even if food restriction does not begin until middle age. Dr. Walford, a pathologist and expert on aging at the School of Medicine at the University of California at Los Angeles, reported earlier this year that reduction of food intake starting in "middle age" in two long-lived species of mice resulted in a 10 to 20 percent increase in the animal's life span.
Dr. Walford's earlier studies showed that feeding mice from birth a diet containing 60 percent of the usual calories delayed the agerelated decline in the animals' ability to ward off infections and reject foreign tissues. The restricted diet also delayed the appearance of immunological "errors" - autoimmune disorders in which the body attacks itself.
Studies in mice conducted at Memorial Sloan-Kettering Cancer Center in New York by Dr. Gabriel Fernandes, an immunologist who has just moved to the University of Texas, where he will collaborate with Dr. Masoro, showed that lowering the fat composition of the diet had reduced the animals' risk of developing immunological deficiency diseases and cancer. When the same strain of mice was placed on a low-protein diet, age-related declines in immune responses were inhibited.
In another strain, reduction in both dietary fat and calories protected the animals against cardiovascular disease. Dr. Fernandes and his colleagues also found that severe calorie restrictions could inhibit and sometimes completely prevent the development of mammary (breast) cancer in a strain of mice prone to that disease.
Dr. Robert A. Good, an immunologist at the Oklahoma Medical Research Foundation in Oklahoma City who is a former co-worker of Dr. Fernandes, says there is "now abundant evidence that even genetically determined diseases may be modified or even entirely prevented by limiting the protein, calories or fat content of the diet." He foresees the use of scientifically modified diets to combat immunodeficiency diseases, cancer, blood vessel disorders, kidney disease and various autoimmune diseases, including arthritis.
"Long-term undernutrition is thus far the only method we know of that retards aging and extends the maximum life span of warm-blooded animals," Dr. Walford said in a telephone interview. "The finding is undoubtedly applicable to humans because it works in every animal species thus far studied."
According to Dr. Masoro, "If we can manipulate aging in the rat by nutrition, we probably can do it in any mammal." On the restricted diet, animals lose a quarter to a third of their body weight and stabilize there. Though the ability of food restriction to prolong life was first shown in animal studies at Cornell University nearly half a century ago, and repeated in occasional experiments since then, these earlier observations were largely viewed as "curiosities" that had no real bearing on the human aging process.
Comparable research has never been done on people. Human studies of the effects of calorie restriction have involved malnourished people who consumed inadequate amounts of most essential nutrients. In many of the studies, the malnourished individuals lived in environments that fostered the spread of infectious diseases and provided poor medical care.
Dramatic increases in average survival, or life expectancy, have occurred since the evolution of Homo sapiens. In Ancient Rome, for example, only half the population lived to the age of 22, whereas in the United States today, half survive to about 76. If the major diseases of advanced life were cured, the average person would live to about 90.
But, Dr. Masoro and Dr. Walford point out, none of these actual and theoretical changes in life expectancy have any effect on the maximum human life span, which since the dawn of recorded history has ended at around 100 years.
However, they said if the response of people to food restriction was found to be similar to laboratory animals, the maximum life span would be extended to 140 years, and average length of life would increase to more than 120. At the same time, a smaller proportion of the aged population would be afflicted with chronic, debilitating diseases.
In addition to unveiling a possible route to increased longevity, the studies of food restriction are providing important clues to the fundamental nature of the aging process. Thus far, for example, the studies by Dr. Masoro and others have shown that aging is not simply an accumulation of diseases or changes in body composition. Nor does immunological deterioration represent the essence of aging, though Dr. Walford considers the immune system the "pacemaker" of the aging process.
As the human body ages, marked changes take place in most physiological functions, although the age at which various functions begin to deteriorate and the rate of their decline varies markedly. Thus, the immune system reaches its physiological peak at puberty and slowly declines thereafter until old age, when it functions at only 10 to 20 percent of its peak, Dr. Walford reports. The body's ability to use oxygen during exercise declines steadily between the ages of 7 and 80. The speed at which nerve messages travel diminishes only slowly with increasing age, whereas maximum breathing capacity and blood flow through the kidneys drop more precipitously, especially after age 30.
The net result of these and other losses in body functions is "a reduced capacity to carry on physiological activities and a compromised ability to respond to challenges," Dr. Masoro said. For example, the decline in kidney function with age leads to a "markedly reduced ability of old people to meet the challenge of a high-salt diet," the Texas researcher explained.
Thus, a variety of chronic, debilitating diseases can afflict the age-compromised body. And, of course, the overall risk of death increases with age, with the probability of dying doubling every eight years after the age of 35.
The body also undergoes a major change in composition as it ages. The proportion of muscle tissue declines after 30 and the proportion of the body that is fat increases until at least 55, though body weight may remain stable. Bone loss begins in the fourth decade and proceeds much more rapidly in women than in men.
"All these characteristics of aging are in all likelihood secondary events," said Dr. Masoro, whose studies of food restriction have indicated that these factors are the result, not the cause, of aging. "The primary aging process is more likely to be a progressive change in some fundamental aspect of the physiology of all cells or possibily certain key cells."
Dr. Walford's evidence suggests that a small group of genes called the major histocompatibility complex, or MHC, is the ultimate regulator of aging. The MHC makes up only one-fourth of 1 percent of an animal's total genetic material. Yet throughout the body it influences functions that are considered critical to the aging process: immune responses, repairs of damage to DNA (the master chemical of the genes) and removal of "free radicals," highly reactive substances that can damage cells and genes.
"The ability to repair DNA is directly related to longevity," Dr. Walford noted. "If you look at the level of DNA repair in various species, you get a direct relationship between the rate of repair and the life span," he said. "Even among different species of primates, we've shown this to be true." He added that future studies at his laboratory would explore the influence of diet on DNA repair and other MHC-directed functions. He and Dr. Masoro also plan to study specific dietary manipulations to define more precisely which factors are critical to increasing longevity and diminishing illness.
Dr. Masoro emphasized that he was not advocating malnutrition as a means of extending life. "Our animals are not malnourished - their diets are not below the recommended limits for any food substance. Our studies do not mean that cuts should be made in Government feeding programs."
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