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Free Radical Theory of AgingThe theory was discovered by Denham Harman, who suggested that free radicals produced during aerobic respiration cause cumulative oxidative damage, resulting in aging and death. The theory gained credibility with the identification in 1969 of the enzyme superoxide dismutase (SOD). The use of SOD as a tool to locate subcellular sites of O2· generation led to a realization that mitochondria are a principal source of endogenous oxidants. There are numerous sites of oxidant generation. Of these, four have attracted much attention in research:
In addition to these sources of oxidants, there exist numerous other enzymes capable of generating oxidants under normal or pathological conditions, often in a tissue-specific manner. However, despite the great number of intracellular sources of oxidant that have been identified, in terms of ranking their relative importance, the field is still very much in its infancy. To fight the free radicals, cells are equipped with an impressive repertoire of antioxidant enzymes, as well as small antioxidant molecules. These antioxidant defences vary between species, and the differences in antioxidant defenses between species have been suggested to explain differences in life span. In terms of measuring the oxidative damage caused by free radicals, the benchmarks have been described as "accumulation, modification, and depletion", meaning: accumulation of end products of oxidative damage (such as lipofuscin), modification of existing structures (such as oxidative adducts in DNA), and depletion (such as the loss of enzymatic activity or reduced thiols). In studies researchers have been asking a very important question: what is the cause of age-related oxidative damage? For one, some suggest it could result from less active antioxidant defenses and repair, but studies that have measured age-related changes in antioxidant defenses have generated conflicting results. Research has also looked into the repair of oxidative damage and if its activity decrease with age. The majority of evidence suggests that there is probably not an overall age-associated change in the intrinsic ability of cells to degrade damaged proteins. 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