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).

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The free radical theory of aging, conceived in 1956, has turned 40 and is rapidly attracting the interest of the mainstream of biological research. From its origins in radiation biology, through a decade or so of dormancy and two decades of steady phenomenological research, it has attracted an increasing number of scientists from an expanding circle of fields. During the past decade, several lines of evidence have convinced a number of scientists that oxidants play an important role in aging. (For the sake of simplicity, we use the term oxidant to refer to all "reactive oxygen species," including O2-., H2O2, and .OH, even though the former often acts as a reductant and produces oxidants indirectly.) The pace and scope of research in the last few years have been particularly impressive and diverse. The only disadvantage of the current intellectual ferment is the difficulty in digesting the literature. Therefore, we have systematically reviewed the status of the free radical theory, by categorizing the literature in terms of the various types of experiments that have been performed. These include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, the manipulation of metabolic activity and oxygen tension, treatment with dietary and pharmacological antioxidants, in vitro senescence, classical and population genetics, molecular genetics, transgenic organisms, the study of human diseases of aging, epidemiological studies, and the ongoing elucidation of the role of active oxygen in biology.

Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.

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