The Mysteries of Aging:
Edward J. Masoro, Ph.D
Is Diet a Contributing Factor?
Professor and Director
Aging Research and Education Center
Univeristy of Texas Health Science Center
at San Antonio
Photo Courtesy National Library of Medicine,
Early RecollectionsOne of my earliest recollections is of observing how different my grandparents were from my parents. Watching the changes that occurred in our family dog also provided me with a clear picture of the progressive nature of aging. Aging is familiar to all of us. Small wonder that most people feel that we understand it. Only as a mature biologist did I come to realize that the biological mechanisms of aging were unknown and that why aging should occur at all was a mystery yet to be solved. The mysteries of aging are currently being explored intently by a sector of the scientific community, for both theoretical and increasingly practical purposes.
Old Age: A Definition
It is often difficult to know exactly what is meant by the term aging. Some think of aging as merely what happens to living organisms over time. This conceptualization is very broad, embracing as it does the stages of development prior to maturity, postmaturational processes that are stable or change in a beneficial manner, as well as postmaturational deterioration. However, as used by most laymen and scientists, aging refers solely to postmaturational deterioration.
Because of this ambiguity, it would be helpful if a specific term were used for the postmaturational deteriorative aspect of aging and the word senescence has been suggested. Unfortunately, there has been resistance to its use because some confuse senescence with the term senility which refers to the markedly deteriorated state of extreme old age. In this article, we will use senescence when referring to the progressive deterioration starting in young adulthood and ending in senility.
The Study of Senescence
Interest in the study of senescence has grown tremendously in the past twenty years. Gerontology is the name of the multidisciplinary branch of science which studies senescence and whose participating specialties include biology, medicine, psychology, and sociology.
Biologists have long been interested in gerontology because of the puzzle of why an organism that has developed from a fertilized egg into a complex structural and functional entity cannot indefinitely maintain its integrity. Why do we grow old at all? This is particularly perplexing because biological organisms draw upon external energy sources to grow and to repair damage. Moreover, it is hard to understand why a trait so harmful to the individual as senescence has not been eliminated by evolution.
Beyond these intriguing theoretical questions, serious practical considerations have arisen in recent years to spark interest in gerontology. During the twentieth century, there has be an explosion in the fraction of the population over 65 years of age in the United States and other developed nations, as a result of increased protection from premature death due to infectious disease and other environmental hazards. This increase in longevity, although welcomed by most of us, also has a negative side. Because of senescence the elderly consume much of societal resources. Economic, legal, and ethical challenges involved in balancing the needs of the old and of the young are of increasing concern. A goal of biological gerontology is the development of interventions that will retard senescence, thereby reducing the resources consumed by old people.
Nutrition and Senescence
Throughout history, claims have been made for dietary substances which purportedly influence aging. Unfortunately, the supporting evidence for many of these claims is less than compelling. Even in substantiated research, often what is being referred to is a specific age-associated disease and not global organismic senescence. For example, there is reasonably strong evidence that dietary fat promotes coronary heart disease; it has also been shown that increasing dietary calcium may help retard osteoporosis. However, the only nutritional manipulation that has clearly been shown to influence senescence in a global fashion is the reduction of food intake in laboratory rodents, called dietary restriction (DR).
Dietary Restriction: A Possible Clue to the Nature of Senescence
In 1915, Osborne and Mendel, distinguished Yale University nutritionists, reported suggestive evidence that reducing the food intake of rats increased their length of life. McCay and his nutritionist colleagues at Cornell University built upon the earlier research and in 1935 reported data which clearly established the life-extending action of reducing food intake of rats. They postulated that the extension of length of life was due to the slowing down of the stages of growth.
This remarkable finding was not vigorously pursued until the 1970's, for two probable reasons. First, between the 1930's and 1960's, the field of nutrition was discovering new vitamins and the need for trace elements and this activity resulted in a "the more the better" philosophy which was not conducive to exploring the virtues of less. Then, too, gerontology as a field of endeavor did not emerge fully until the 1970's, promoting an interest in old age research.
In the 1970's many investigators turned their attention to the DR phenomenon. In the following years, intense research activity ensued, of which I was a part. I believed that slowing senescence could serve as a powerful tool for uncovering the nature of the biological processes underlying senescence. Of course, I also recognized that such studies might uncover information leading to interventions which retard senescence in humans.
What Dietary Restriction Research Uncovered
The standard procedure for feeding rats in the laboratory has been to give the animals continuous access to food, a procedure called ad libitum feeding. In DR studies, food intake is restricted to 50 to 60% of that consumed by the ad libitum fed animals. The many studies carried out with mice and rats (including one with hamsters) have confirmed that DR markedly increases the mean, median, and maximum length of life. Findings on the mortality characteristics of rodent populations clearly establish that DR retards senescence.
In addition to effects on mortality, DR has also been found to maintain most physiological processes in a youthful state at ages at which ad libitum fed rats exhibit marked deterioration of these processes. Even more striking are the findings that most age associated diseases are delayed or prevented. Clearly, DR slows senescence in a global manner.
How Does Dietary Restriction Work?
Which dietary component or components are responsible for these remarkable findings? Studies revealed that the slowing of senescence was not due to reducing the intake of a specific dietary component. Other studies revealed DR is quite effective in retarding senescence when initiated after maturation rather than soon after weaning (which had been the usual procedure). These findings ruled out the postulate of McCay and colleagues that slowing of development was an important factor in the life span extension by DR. The alternative conclusion was that DR must retard senescence by reducing calorie (energy) intake.
These findings suggested that the effects of DR might be due to a reduction in body fat content. This suggestion was particularly attractive because it is known that excess body fat in humans promotes some diseases and decreases longevity. However, studies on mice and rats revealed that although DR reduces body fat content, the decrease in body fat does not play a causal role in the slowing of senescence.
Metabolic rate, which refers to the rate of fuel use per unit of body mass, had long been believed to play an major role in senescence; indeed, it was proposed early in this century that the greater the metabolic rate, the faster the rate of senescence. The fact that the reduction in energy intake was the responsible dietary factor pointed to the likelihood that reduction in metabolic rate underlies the antisenescence action of DR.
Careful analyses of the rats studied in our laboratory revealed that metabolic rate need not be decreased for DR to have its antisenescence action. This surprising finding relates to the fact that the body mass of rats is reduced by DR in proportion to the reduction in dietary energy intake with the result that the metabolic rates of dietary restricted and ad libitum fed rats are similar.
Although a decrease in the intensity of fuel use does not underlie the antisenescence action of DR, it is quite possible that other characteristics of fuel use may be involved. Indeed, we have found that at least two characteristics of fuel use are influenced by DR in a fashion that could slow senescence.
Glucose is the carbohydrate fuel which circulates in the blood. As its blood concentration increases, its rate of use as a fuel increases. In addition, increasing concentrations of blood insulin increases the rate of glucose fuel use. Unfortunately, above normal blood glucose and/or insulin levels are damaging. It is also possible, although not yet established, that over a life span normal concentrations of glucose and insulin may also be damaging and thereby be contributors to senescence. Thus, it is noteworthy that dietary-restricted rats are able to maintain lower blood levels of glucose and insulin than ad libitum fed rats, while still using glucose as effectively as fuel. This striking phenomenon may at least in part underlie the ability of DR to slow senescence.
The other characteristic of fuel use altered by DR relates to oxygen, a substance which plays a key role in the use of fuel by most organisms. The involvement of oxygen in fuel use generates damaging oxygen-containing compounds, called free radicals. DR has been found to decrease the rate of generation of these free radicals, as well as enhancing defense mechanisms which protect organisms from damage from such compounds. These altered characteristics of oxygen metabolism might well be part of the mechanism underlying the slowing of senescence by DR.
In addition to protection against damage due to a fuel utilization, recent studies indicate that DR increases the ability to cope with many other kinds of damage, such as surgical trauma, inflammatory agents, excessive heat, and toxic chemicals. Thus, it is reasonable to suggest that DR has a general protective action rather than specifically acting to slow senescence. Indeed, information is accumulating in regard to the nature of this protective action.
The adrenal cortex secretes a class of hormones called glucocorticoids which have long been known to assist animals in coping with many kinds of damage. DR has been found to increase the daily peak blood concentration of glucocorticoids in rats. This elevation of blood glucocorticoid levels might protect the animal from long-term damages inherent in fuel use, as well as damage due to inevitable environmental factors such as high summer temperatures, radiation, and toxic substances in food. Of course, this view of its antisenescence function is based on the reasonable but unproven assumption that aging is caused by long-term, low intensity damaging agents.
Of all the claims for nutrition as an influence on aging, only DR in laboratory rodents has been shown to globally slow senescence.
Whether DR retards senescence in other classes of mammals (including humans) is not known; the high cost in resources to execute such studies in long-lived animals has up to now precluded definitive answers. However, even if it turns out that DR does not slow senescence in humans, research of this phenomenon in rodents is likely to yield information of value for the development of interventions that will lessen the deterioration which commonly occurs with advancing age in humans. Aging is still a mystery, but its dynamics are unfolding.
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