Damage Accumulation Stochastic Theories

The 'damage' or 'error' theories emphasize intrinsic and environmental insults to our cellular components that accumulate throughout life and gradually cause alterations in biological function and the physiological decline associated with aging.

Somatic mutation and DNA repair Damage to DNA occurs throughout the lifetime of a cell. If this damage is not repaired or removed then mutations may result. Mutations may result in the synthesis of aberrant proteins with altered or absent biological function; alterations to the transcriptional and translational machinery of a cell; and deregulation of gene control. The accumulation of mutations on their own, or in combination with other age-related changes, may lead to alterations in cellular function and ultimately the onset of age-related disease.

Error catastrophe This theory suggests that damage to mechanisms that synthesize proteins results in faulty proteins, which accumulate to a level that causes catastrophic damage to cells, tissues, and organs. Altered protein structure has been clearly demonstrated to occur with age; however, most of these changes are posttranslational in nature, and hence do not support this theory of aging. Such changes to protein structure may result in progressive loss of 'self-recognition' by the cells of the immune system and thus increase the likelihood that the immune system would identify self-cells as foreign and launch an immune attack. Indeed, the incidence of autoimmune episodes is known to increase with age.

Cross-linking The cross-linking theory states that an accumulation of cross-linked biomolecules caused by a covalent or hydrogen bond damages cellular and tissue function through molecular aggregation and decreased mobility. The modified malfunctional biomolecules accumulate and become increasingly resistant to degradation processes and may represent a physical impairment to the functioning of organs. There is evidence in vitro for such cross-linking over time in collagen and in other proteins, and in DNA. Many agents exist within the body that have the potential to act as cross-linking agents, e.g., aldehydes, antibodies, free radicals, quinones, citric acid, and polyvalent metals, to name but a few.

Free radicals The most popular, widely tested and influential of the damage accumulation theories of aging is the 'free radical' theory, first proposed by Harman in 1956. Free radicals from intrinsic and extrinsic sources (Table 1) can lead to activation of cytoplasmic and/or nuclear signal transduction pathways, modulation of gene and protein expression, and also alterations to the structure and ultimately the function of biomolecules. Free radicals may thus induce alterations to normal cell, tissue, and organ functions, which may result in a breakdown of homeostatic mechanisms and lead to the onset of age-related disorders and ultimately death. It can

Table 1 Extrinsic and intrinsic sources of free radicals

Extrinsic sources

Intrinsic sources

Radiation: ionizing, ultraviolet

Drug oxidation: paracetamol, carbon tetrachloride, cocaine Oxidizing gases: oxygen, ozone, nitrogen dioxide

Xenobiotic elements: arsenic (As), lead (Pb), mercury (Hg), cadmium (Cd) Redox cycling substances: paraquat, diquat, alloxan, doxorubicin Heat shock

Cigarette smoke and combustion products

Plasma membrane: lipoxygenase, cycloxygenase, NADPH oxidase Mitochondria: electron transport, ubiquinone, NADH dehydrogenase Microsomes: electron transport, cytochrome p450, cytochrome b5 Peroxisomes: oxidases, flavoproteins

Phagocytic cells: neutrophils, macrophytes, eosinophils, endothelial cells Auto-oxidation reactions:

Metal catalyzed reactions Other: hemoglobin, flavins, xanthine oxidase, monoamine oxidase, galactose oxidase, indolamine dioxygenase, tryptophan dioxygenase Ischemia - reperfusion be predicted from this theory that the life span of an organism may be increased by slowing down the rate of initiation of random free radical reactions or by decreasing their chain length. Studies have demonstrated that it is possible to increase the life span of cells in vitro by culturing them with various antioxidants or free radical scavengers. Antioxidant supplementation with a spin-trapping agent has been demonstrated to increase the lifespan of the senescence accelerated mouse, although as yet there is little evidence for increasing the life span of a normal mammalian species by such strategies.

Mitochondrial DNA damage This hypothesis combines elements of several theories, covering both the stochastic and genetic classes of aging theories. It is proposed that free radical reactive oxygen species generated in the mitochondria contribute significantly to the somatic accumulation of mitochondrial DNA mutations. This leads to a downward spiral wherein mitochondrial DNA damage results in defective mitochondrial respiration that further enhances oxygen free radical production, mitochon-drial DNA damage, and mutation. This leads to the loss of vital bioenergetic capacity eventually resulting in aging and cell death.

The absence of evidence that exclusively supports any one theory leaves no doubt that aging is due to many processes, interactive and interdependent, that determine life span and death.

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