Theories Of Biological Aging

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As witnessed by the search for the "fountain of youth" and the time-honored popularity of tales and treatments concerned with the aging process, prolongevity has been a continuing quest since the dawn of human history. Although the commercial and health literature abounds with suggestions for staying healthy, looking good, and living as long as one can, the inevitability of corporeal existence is universally recognized. Acceptance of personal mortality does not mean, however, that the human life span cannot be prolonged. But in order to achieve prolongevity, if not immortality, we first need to know what makes us age.

Hippocrates was the first medical researcher to study the aging process, which he attributed to a loss of body heat. Erasmus Darwin, a nineteenth-century British physician, considered aging to be due to a loss of irritability in the neural and muscular tissue, whereas Eli Metchnikoff viewed it as being caused by a state of autointoxication, or poisoning by a toxic substance produced by the body. More recent explanations for the aging process may be classified, for convenience, into breakdown theories, substance theories, and genetic theories. These proposed explanations, which are more appropriately designated as "hypotheses" rather than theories, are not mutually exclusive. In fact, a combination of several theories will probably be necessary to obtain a reasonable explanation of why we age.

Breakdown, or wear-and-tear theories, propose that aging is the result of wear and tear, stress, or exhaustion of organs and cells. Body organs certainly seem to wear out with usage and exposure to certain environmental stimuli, but the fact that active exercise enhances the functioning of many organs—at least up to a point-would seem to contradict a simple wear-and-tear explanation. Another "breakdown" explanation is based on the observation that readjusting after physical exertion or exercise becomes progressively more difficult with aging. For this reason, Comfort (1964) considered aging to be the consequence of accumulating homeostatic faults or errors and the resulting failure to maintain a steady internal balance.

Two additional examples of breakdown theories are immunological theory and autoimmune theory. The former views aging as a result of the gradual deterioration of the immune system, leading to a decline in the ability of the body to defend itself against disease, injury, and foreign or abnormal cells. Disorders such as adult-onset diabetes, senile dementia, and certain vascular diseases are consistent with this explanation. So is the diminished production with aging of hormones secreted by the thymus gland that regulate the production of T cells (Zatz & Goldstein, 1985). However, the fact that animals without immune systems still age would suggest that, rather than being a cause of aging, the observed decline in the functioning of the immune system may merely be the result of changes in the endocrine system.

The autoimmunity theory is based on the notion that the aging body becomes progressively less adept at differentiating between normal and abnormal cells, and consequently produces antibodies to attach both kinds of cells. This rejection of the body's own tissues is seen, for example, in rheumatoid arthritis, a disease found more often in older than younger adults. Like changes in the immune system, however, autoimmunity is probably a correlate or consequence of aging rather than a cause of the process.

Substance theories view aging as resulting from changes in collagen and the proliferation of mutant cells, cross-linkage of molecules, the accumulation of free radicals at the cellular level, or the secretion of certain hormones. At the tissue level, strands of collagen, a protein material found in connective tissue, increase with aging, causing reduced elasticity of the visceral organs, slower healing, and other changes in the body. Abnormal and mutant cells also proliferate with aging, increasing the chances of developing cancer. In fact, one theory of aging —error accumulation theory— holds that the accumulation of random errors in the mechanism by which new proteins are synthesized causes dysfunctioning and ultimately the death of cells.

Cross-linkage, the inadvertent coupling of large intracellular and extracellular molecules that cause connective tissue to stiffen, also increases with aging. When such cross-linkages occur between strands of DNA molecules, the cells may be unable to read genetic information properly and thereby fail to produce enzymes that maintain body functions. Like changes in the immune system, however, cross-linkage is thought to be a result rather than a cause of aging.

Also directed toward the cellular levels is the theory that aging is due to the accumulation of free radicals and other chemical garbage within cells. Free radicals are highly reactive molecules or parts of molecules produced by adverse reactions of body cells to radiation, air pollution, and oxygen. The popularity of antioxidants such as vitamins A, C, and E is based to some extent on the finding that the production of new free radicals is inhibited by them. Although free radicals are important to the functioning of the im mune and digestive systems, they contribute to many degenerative conditions (e.g., sagging skin, cancer, heart disease) and may damage other cells or their DNA (Harman, 1987). The damage, however, is usually repaired too promptly to be a primary cause of biological aging.

Other kinds of "garbage" or waste products that can affect cell functioning do increase with aging. For example, mitochondria, the small "energy machines" within the cytoplasm that are composed of highly unsaturated fats, sugar, and protein molecules, have been suggested as a possible factor. This theory holds that aging is caused by oxidation of the fat molecules in the mitochondria, a process that interferes with their energy-releasing function. Another cellular-garbage theory points to the accumulation of inert substances such as the lipofuscins, pigmented granules containing lipids, carbohydrates, and protein, as interfering with the functioning of cells.

Hormonal theories have been stimulated by observations of the massive amounts of hormones released by Pacific red salmon before they die. Denckla (1974) proposed that aging is due to "blocking hormones" such as antithyroid hormones released by the hypothalamus or DECO (decreased oxygen consumption) hormones secreted by the pituitary that keep cells from using thyroid hormones. It has also been suggested that an "aging clock" in the hypothalamus alters the level of hormones and brain chemicals in older adults, thereby deregulating body functioning and hastening death.

As indicated previously, the existence of an "aging clock," or a prewired, genetically based aging program in the hypothalamus or elsewhere in the body has been proposed by a number of researchers. Supporting this notion is the finding that the cells of a particular species can subdivide only a certain number of times before they die (approximately 50 in humans), a limit that is lower for older than younger members of a species (Hayflick, 1977,1980). This Hayflick limit has been determined only in vitro, however, and, in any case, is not reached during the course of a normal human life span.

As mentioned at the beginning of this section, no single theory is adequate by itself to explain the aging process. Heredity certainly affects the rate of aging, but so does the way in which you live—what you eat and drink, whether you smoke, what kinds of physical, chemical, and social environments you live in, whether you exercise and rest properly, how much psychological stress you experience.2 Thus, the rate of aging varies not only from species to species but also from individual to individual within the same species, and within the same tribe or primary group. Furthermore, the evidence points to multiple sites of aging—tissue, cellular, and nuclear—and at least two kinds of aging processes—accidental damage to molecules, membranes, or body parts, and aging due to a genetic program. Particularly fas-

2The longest-living person in recent years was Jeanne Calment, a Frenchwoman who died in 1997 at the ripe old age of 122. Madame Calment, who recalled meeting Vincent Van Gogh in 1888, attributed her long life to an occasional glass of port and a diet rich in olive oil (Los Angeles Times, August 5, 1997, p. A18).

cinating is research, stimulated by the genetic program or "aging-clock" hypothesis, on the DNA and RNA molecules that are responsible for cell replication and what turns them on and off. The possible locus of such a clock in the hypothalamus, pituitary gland, and thymus gland and its functioning are also under continuing investigation.

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