Other Free Encyclopedias » Medicine Encyclopedia » Aging Healthy - Part 3 » Caloric Restriction Nutrition - Studies On Rats And Mice, Studies On Humans And Nonhuman Primates, Future Research Directions

Caloric Restriction Nutrition - Studies On Rats And Mice

age aging physiological genetic body life action aging

Most research on the life-extending effects of long-term dietary restriction has been done on rats and mice. These studies have shown that the effects on longevity do not relate to a decrease in the intake of a specific nutrient, such as vitamins, minerals, and protein, or a dietary contaminant, but rather result from a decrease in intake of calories. It is for this reason that this phenomenon is referred to as caloric restriction.

Caloric restriction has been found to markedly increase the length of life when initiated in the young adult. It also does so when started as late as early middle age, but less markedly than in younger animals.

With increasing age, there is an increase in mortality. Analysis of age-specific mortality (the fraction of the population that dies during a specific age interval) reveals that caloric restriction reduces the age-associated increase in age-specific mortality of adult rats and mice. This finding strongly suggests that caloric restriction extends the length of life by slowing the rate of aging, a conclusion supported by the fact that it retards the age-associated deterioration of physiological functions. These functions range from fundamental cellular processes, such as DNA repair, apoptosis, proteolysis, signal transduction, gene expression, and many others, to integrated organismic functions, such as negotiating a maze. Caloric restriction also delays the occurrence or slows the progression of most age-associated diseases in rodents, including many different cancers, as well as degenerative diseases, such as nephropathy, cardiomyopathy, cataracts, and autoimmune diseases.

Many studies have aimed at discovering the mechanisms underlying the antiaging action of caloric restriction. Such knowledge would provide insights in the quest to understand the basic nature of aging and to develop interventions in aging. In their 1935 publication, McCay and his colleagues proposed that food restriction extended length of life in rats by retarding development and growth. However, the finding that life extension occurs when food restriction is started in adult life invalidates this hypothesis.

Caloric restriction is known to decrease the content of body fat, and excess body fat is associated with premature death in humans. Thus, some have hypothesized that caloric restriction increases the length of life by decreasing body fat. However, studies on rats by Helen Bertrand and her associates in Texas, and on mice by David Harrison and his associates in Maine, found that caloric restriction's action on body fat is not related to the antiaging effect.

Caloric restriction also decreases the body temperature of rats and mice. It is known that reducing the body temperature of poikilotherms (species in which body temperature varies with the environmental temperature) increases their life span. It was hypothesized that caloric restriction increases the length of life of rodents by decreasing body temperature, but several lines of evidence indicate this is not a valid hypothesis. For example, caloric restriction causes the body temperature in mice to decrease much more than in rats, but the increase in length of life is similar in both species. Also, restricting food intake in fish increases length of life without lowering body temperature. Finally, while the body temperature of mice maintained in a warm environment is not decreased by caloric restriction, these mice continue to exhibit most antiaging effects.

It is known that biological molecules, such as DNA, proteins, and lipids, are damaged by reactive oxygen molecules such as hydroxyl and superoxide radicals. Reactive oxygen molecules are generated by intrinsic living processes as well as environmental factors. In 1996, Rajindar Sohal and Richard Weindruch suggested that caloric restriction retards aging by decreasing oxidative damage. Caloric restriction does, indeed, retard the age-associated accumulation of oxidatively damaged molecules. It is often stated that this protective action results from a lowered specific metabolic rate (metabolic rate per unit of body mass); however, studies on both rats and mice have shown that caloric restriction can have life-extending and antiaging actions without decreasing the specific metabolic rate. Of course, a decreased production of reactive oxygen molecules is not dependent on a reduction in metabolic rate. Furthermore, enhancement of antioxidant defenses would also protect against damage from reactive oxygen molecules even if their rate of production did not change. Caloric restriction may well decrease the rate of production of reactive oxygen molecules, and/or increase the level of protection against their damaging effect, but there are not yet sufficient data to judge the importance of either. Indeed, the fact that caloric restriction increases the repair or removal and replacement of damaged molecules may play the major role in its ability to reduce the accumulation of oxidatively damaged molecules. However, the question of whether this ability of caloric restriction protects against the accumulation of oxidative damage is the reason for its antiaging action cannot be answered until the importance of oxidative damage in aging is clearly established.

Food restriction has been found to result in sustained reductions in blood levels of glucose and insulin without decreasing the ability to use glucose as a fuel. It does so, at least in part, by increasing insulin sensitivity. It has long been known that elevated blood levels of glucose and/ or insulin cause damage similar to aging, and it has been suggested that maintenance of low levels of these substances underlies the antiaging action. Although much has been learned about the mechanisms responsible for the decreased levels of glucose and insulin, the hypothesis of their playing a major role in the antiaging action remains to be tested.

In 1998, this author proposed the hormesis hypothesis. Hormesis is defined as the beneficial action resulting from the response to a low-intensity stressor. Caloric restriction in rats and mice meets the criteria of hormesis. It causes a daily moderate elevation of blood glucocorticoid level, a characteristic action of a low-intensity stressor, and, in regard to beneficial action, it increases the ability of rats and mice to cope with the damaging actions of acute, intense stressors such as surgery, toxic chemicals, and high environmental temperature. Since aging appears to be the result of the accumulation of unrepaired damage due to intrinsic processes, as well as environmental agents and their interactions, this increased ability to cope with stressors may well be the basis for the retardation of aging by caloric restriction. Indeed, genetic manipulations that retard aging in fruit flies, nematodes, and yeast have also been shown to increase the ability of these organisms to cope with acute, intense stressors. Moreover, the increased daily levels of blood glucocorticoids may well play a major role in the increased resistance to acute, intense stressors and in the antiaging action. Caloric restriction also enhances expression of stress response genes, thereby increasing the production of proteins that protect cells against damaging agents, possibly including agents that promote aging. Although many actions of caloric restriction fall within the realm of hormesis, this hypothesis has yet to be rigorously tested.

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