Metabolism, like other aspects of life, involves tradeoffs. Oxidant by-products of normal metabolism cause extensive damage to DNA, protein, and lipid. We argue that this damage (the same as that produced by radiation) is a major contributor to aging and to degenerative diseases of aging such as cancer, cardiovascular disease, immune-system decline, brain dysfunction, and cataracts. Antioxidant defenses against this damage include ascorbate, tocopherol, and carotenoids. Dietary fruits and vegetables are the principal source of ascorbate and carotenoids and are one source of tocopherol. Low dietary intake offruits and vegetables doubles the risk of most types of cancer as compared to high intake and also markedly increases the risk of heart dise and cataracts. Since only 9% of Americans eat the recommended five servings of fruits and vegetables per day, the opportunity for improving health by improving diet is great.The degenerative diseases associated with aging include cancer, cardiovascular disease, immune-system decline, brain dysfunction, and cataracts. The functional degeneration of somatic cells during aging appears, in good part, to contribute to these diseases. The relationship between cancer and age in various mammalian species illustrates this point. Cancer increases with about the fifth power of age in both short-lived species, such as rats, and long-lived species, such as humans. Thus a marked decrease in age-specific cancer rates has accompanied the marked increase in lifespan that has occurred in 60 million years of mammalian evolution; i.e., cancer rates are high in a 2-year-old rat, but low in a 2-year-old human. One important factor in longevity appears to be basal metabolic rate, which is about 7 times higher in a rat than in a human and which could markedly affect the level of endogenous oxidants and other mutagens produced as by-products of metabolism. The level of oxidative DNA damage appears to be roughly related to metabolic rate in a number of mammalian species (1-3).

We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by nito dria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial fumctins decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane.

gamma-tocopherol is the major form of vitamin E in many plant seeds and in the US diet, but has drawn little attention compared with alpha-tocopherol, the predominant form of vitamin E in tissues and the primary form in supplements. However, recent studies indicate that gamma-tocopherol may be important to human health and that it possesses unique features that distinguish it from alpha-tocopherol. gamma-Tocopherol appears to be a more effective trap for lipophilic electrophiles than is alpha-tocopherol. gamma-Tocopherol is well absorbed and accumulates to a significant degree in some human tissues; it is metabolized, however, largely to 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which is mainly excreted in the urine. gamma-CEHC, but not the corresponding metabolite derived from alpha-tocopherol, has natriuretic activity that may be of physiologic importance. Both gamma-tocopherol and gamma-CEHC, but not alpha-tocopherol, inhibit cyclooxygenase activity and, thus, possess antiinflammatory properties. Some human and animal studies indicate that plasma concentrations of gamma-tocopherol are inversely associated with the incidence of cardiovascular disease and prostate cancer. These distinguishing features of gamma-tocopherol and its metabolite suggest that gamma-tocopherol may contribute significantly to human health in ways not recognized previously. This possibility should be further evaluated, especially considering that high doses of alpha-tocopherol deplete plasma and tissue gamma-tocopherol, in contrast with supplementation with gamma-tocopherol, which increases both. We review current information on the bioavailability, metabolism, chemistry, and nonantioxidant activities of gamma-tocopherol and epidemiologic data concerning the relation between gamma-tocopherol and cardiovascular disease and cancer.

Oxidative damage to DNA is shown to be extensive and could be a major cause of the physiological changes associated with aging and the degenerative diseases related to aging such as cancer. The oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (oh8dG), one of the -20 known oxidative DNA damage products, has been measured in DNA isolated from various organs of Fischer 344 rats of different ages. oh8dG was present in the DNA isolated from all the organs studied: liver, brain, kidney, intestine, and testes. Steady-state levels of oh8dG ranged from 8 to 73 residues per 10' deoxyguanosine residues or 0.2-2.0 x 105 residues per cell. Levels of oh8dG in DNA increased with age in liver, kidney, and intestine but remained unchanged in brain and testes. The urinary excretion of oh8dG, which presumably reflects its repair from DNA by nuclease activity, decreased with age from 481 to 165 pmol per kg of body weight per day for urine obtained from 2-month-and 25-month-old rats, respectively. 8-Hydroxyguanine, the proposed repair product of a glycosylase activity, was also assayed in the urine. We estimate -9 x 104 oxidative hits to DNA per cell per day in the rat. The results suggest that the age-dependent accumulation of oh8dG residues observed in DNA from liver, kidney, and intestine is principally due to the slow loss of DNA nuclease activity; however, an increase in the rate of oxidative DNA damage cannot be ruled out.The biochemical mechanisms of aging are under extensive investigation but remain poorly understood. Endogenous metabolic processes are implicated as important factors in aging by the impressive inverse correlation between life-span and species-specific metabolic rate (1).The damage produced by endogenously produced oxygen radicals has been proposed to be a major contributor to aging and the degenerative diseases associated with it, such as cancer and heart disease (2-7). In vivo, oxygen radicals are mainly produced as by-products of normal metabolism (8) from phagocytic cells (9) and from lipid peroxidation (10). Numerous defense systems protect cellular macromolecules against oxidation; nevertheless, there is a high rate of damage to DNA (11), proteins (12), and lipids (10, 13). The steadystate level of oxidatively modified nucleosides in genomic and mitochondrial DNA in rats (11) and the release of these damage products in human and rodent urine (14-16) have been determined. Oxidative damage to DNA has been estimated as 104 hits per cell per day in humans and 1 order of magnitude higher in rodents (7,14,15).Some evidence suggests that an increased production of reactive oxygen species and/or a decreased efficiency of antioxidant defense systems is associated with aging (17,18). Endogenous oxidative damage to lipids (19) and proteins (12) has been reported to increase with age. Damage to DNA has been reported to increase with age in rats fed diets deficient in vitamin E, but not in rats fed vitamin E-sufficient diets (20).The purpose of this study was to evaluate endogenous oxidative damage to DNA as...

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