Theories of Aging

There are many theories of aging, but few are widely accepted. Aging proceeds at different rates in different species. Even within a species, aging proceeds at different rates among individuals. A reasonable conclusion is that aging must be genetically controlled, at least to some extent. Both within and between species, lifestyle and exposures may alter the aging process.

Some theories of aging focus on what controls the degenerative and entropic processes that occur with aging and why the controls exist as they do. Other theories focus on the evolutionary origins of senescence. All of these theories generally agree that senescence does not offer a genetic advantage and developed mainly because it is not selected against.

Loose cannon theory: This theory posits that an entropy-producing agent--free radicals or glucose--slowly disrupts cellular macromolecular constituents. Theoretically, free radicals, generated during oxidative phosphorylation, can modify macromolecules, primarily through oxidation. Considerable evidence suggests that oxidative damage increases with aging. For example, in older organisms, specific amino acids in specific proteins tend to be oxidized residues, decreasing the specific activity of these proteins. Additionally, production of specific oxidized derivatives of nucleotides from DNA increases.

Glucose is thought to promote senescence through nonenzymatic attachment to proteins and nucleic acids, via the same process that produces glycated Hb. There is little direct evidence that glycation has a major role in senescence, except that glycated protein levels increase with aging. However, recent studies suggest that glucose metabolism promotes oxidative damage; also, dietary restriction reduces plasma glucose (minimizing oxidative damage) and increases maximum life span. Thus, interest in the role of glucose metabolism in promoting senescence continues.

Rate of living theory: This theory posits that smaller mammals tend to have high metabolic rates and thus tend to die at an earlier age than larger mammals. Thus, the rate of living theory is related to the idea that free radicals and other metabolic by-products play a role in senescence. However, studies of metabolic rates have shown wide variation in the correlation between size and longevity, undermining the credibility of this theory.

Weak link theory: This theory posits that a specific physiologic system--usually the neuroendocrine or immune system--is particularly vulnerable (presumably to entropic processes) during senescence. Failure of the weak system accelerates dysfunction of the whole organism. Failure of the neuroendocrine system would be expected to produce severe impairments in homeostatic systems, including loss of reproductive function and metabolic regulation, which occur with aging. Failure of the immune system would be expected to produce an increased susceptibility to infection and a decreased ability to reject tumor cells. However, there is little evidence that failure of either system directly contributes to age-related diseases or to mortality. In fact, recent studies indicate that neuroendocrine overactivity (eg, of the sympathetic nervous system or the insulin-like pathway), rather than failure, may drive certain aspects of the aging process.

Error catastrophe theory: This theory posits that errors in DNA transcription or RNA translation eventually lead to genetic errors promoting senescence. Although data suggest that older organisms have altered proteins reflecting such genetic changes, this theory does little to explain most observed age-related changes.

Master clock theory: This theory is one of the oldest theories of aging and no longer has much credibility; it states that aging is under direct genetic control. Teleologically, it suggests that the rate of aging within each species has developed for the good of each species. Individual variation develops because of maladaptation, exposure, and lifestyle. In the wild, such maladapted individuals tend to die out, and the well-adapted ones persist, altering longevity in the best interest of the species.

Exactly what controls the rate of aging is unknown. It could be a gene that controls telomere shortening or some other process of cell division, or it could be genetic control of another cellular process not involved in division, such as DNA repair, resulting in apoptosis.

This topic was last updated June 2006.