According to the Free Radical Theory of Aging free radicals may even underlie the aging process itself, accounting for why mice age so much more rapidly than humans. Most of the free radicals are produced by mitochondria, and most of the free radical damage is to mitochondrial membranes and mitochondrial DNA [EXPERIMENTAL BIOLOGY AND MEDICINE; Wei, YH; 227:671-682 (2002)]. Between one and five percent of the oxygen used by mitochondria to generate energy results in the formation of superoxide radicals. Nonetheless, the most long-lived species have the lowest levels of antioxidant enzymes — having low rates of free radical production and high efficiency of DNA repair [JOURNAL OF COMPARATIVE PHYSIOLOGY B; Perez-Campo,R; 168(3):149-158 (1998)].
Primates have lost the capacity to synthesize ascorbate, and therefore have a requirement for the substance as a vitamin (Vitamin C) in the diet. But primates compensate for this loss by having very high serum levels of the water-soluble anti-oxidant urate (uric acid). An analysis of mammalian species has shown a significant positive correlation between urate per specific metabolic rate (calories per gram per day) and maximum lifespan [ARCHIVES OF GERONTOLOGY AND GERIATRICS; Cutler,RG; 3:321-348 (1984)]. Uric acid is not only a water-soluble antioxidant and singlet oxygen quencher, but is an iron chelator that can protect ascorbate from iron-catalyzed generation of reduced iron [AMERICAN JOURNAL OF CLINICAL NUTRITION; Sevanaian,A; 54:1129S-1134S (1991)].
The tocopherol radical (Toc.) is at best useless for further lipid peroxidation termination, and at worst a pro-oxidant. It must be regenerated (recycled) to the reduced form by other antioxidants. Smokers given a high polyunsaturated diet (safflower oil) suffer oxidative damage that is considerably worsened by the addition of alpha-tocopherol [ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY; Weinberg,RB; 21(6):1029-1033 (2001)
CoEnzyme Q (ubiquinol) or Vitamin C regenerates Vitamin E — and Vitamin C is in turn regenerated by glutathione or lipoic acid. Glutathione is effective against hydrogen peroxide and hydroxyl radicals in the aqueous phase of cells. Lipoic acid is more effective than glutathione in regenerating Vitamin C and can additionally chelate free-radical-generating metal ions. NADH or NADPH (energy-containing molecules resulting from glycolysis or oxidative phosphorylation) can regenerate glutathione or lipoic acid, thus completing the antioxidant network for membrane lipid peroxidation
Free radical production has been shown to increase with age in studies of insects and mammals, and the rate of increase is in inverse proportion to the lifespan of the species [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES; Sohal, RS; 663:74-84 (1992)]. CRAN (Caloric Restriction with Adequate Nutrition) reduces free radical production and extends maximum lifespan. But only a few animal experiments have indicated extension of maximum lifespan by antioxidant substances. Even if these experiments were valid, the results may have been due to effects other than antioxidant action. Many more studies and many larger studies on this subject would be greatly beneficial. "An ounce of prevention is worth a ton of cure" — reducing free radical production in the first place is far more efficient than trying to neutralize free radicals after they have been produced.
Primates have lost the capacity to synthesize ascorbate, and therefore have a requirement for the substance as a vitamin (Vitamin C) in the diet. But primates compensate for this loss by having very high serum levels of the water-soluble anti-oxidant urate (uric acid). An analysis of mammalian species has shown a significant positive correlation between urate per specific metabolic rate (calories per gram per day) and maximum lifespan [ARCHIVES OF GERONTOLOGY AND GERIATRICS; Cutler,RG; 3:321-348 (1984)]. Uric acid is not only a water-soluble antioxidant and singlet oxygen quencher, but is an iron chelator that can protect ascorbate from iron-catalyzed generation of reduced iron [AMERICAN JOURNAL OF CLINICAL NUTRITION; Sevanaian,A; 54:1129S-1134S (1991)].
The tocopherol radical (Toc.) is at best useless for further lipid peroxidation termination, and at worst a pro-oxidant. It must be regenerated (recycled) to the reduced form by other antioxidants. Smokers given a high polyunsaturated diet (safflower oil) suffer oxidative damage that is considerably worsened by the addition of alpha-tocopherol [ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY; Weinberg,RB; 21(6):1029-1033 (2001)
CoEnzyme Q (ubiquinol) or Vitamin C regenerates Vitamin E — and Vitamin C is in turn regenerated by glutathione or lipoic acid. Glutathione is effective against hydrogen peroxide and hydroxyl radicals in the aqueous phase of cells. Lipoic acid is more effective than glutathione in regenerating Vitamin C and can additionally chelate free-radical-generating metal ions. NADH or NADPH (energy-containing molecules resulting from glycolysis or oxidative phosphorylation) can regenerate glutathione or lipoic acid, thus completing the antioxidant network for membrane lipid peroxidation
Free radical production has been shown to increase with age in studies of insects and mammals, and the rate of increase is in inverse proportion to the lifespan of the species [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES; Sohal, RS; 663:74-84 (1992)]. CRAN (Caloric Restriction with Adequate Nutrition) reduces free radical production and extends maximum lifespan. But only a few animal experiments have indicated extension of maximum lifespan by antioxidant substances. Even if these experiments were valid, the results may have been due to effects other than antioxidant action. Many more studies and many larger studies on this subject would be greatly beneficial. "An ounce of prevention is worth a ton of cure" — reducing free radical production in the first place is far more efficient than trying to neutralize free radicals after they have been produced.
