The phenomenon of growth, decline and death-aging-has been the source of considerable speculation (1,8,10) . This cycle seems to be a more or less direct function of the metabolic rate and this in turn depends on the species (animal or plant) on which are superimposed the factors of heredity and the effects of the stresses and strains of life-which alter the metabolic activity.The universality of this phenomenon suggests that the reactions which cause it are basically the same in all living things . Viewing this process in the light of present day free radical and radiation chemistry and of radiobiology, it seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents. ' Irradiation of living things induces mutation, cancer, and aging (9). Inasmuch as these also arise spontaneously in nature, it is natural to inquire if the processes might not be similar. It is believed that one mechanism of irradiation effect is through liberation of OH and HO, radicals (12) . There is evidence, although indirect, that these two highly active free radicals are produced normally in living systems. In the first place, free radicals are present in living cells; this was recently demonstrated in vivo by a paramagnetic resonance absorption method (3) . Further, it was shown that the concentration of free radicals increased with increasing metabolic activity in conformity with the postulates set forth some years ago that free radicals were involved in biologic oxidation-reduction reactions (11,13) . Are some of these free radicals OH and/or HO or radicals of a similar high order of reactivity, and where might they arise in the cell?The most likely source of OH and HO, radicals, at least in the animal cell, would be the interaction of the respiratory enzymes involved Submitted. forpobiintion Much 2 3, 1956.7ûie research was performed under the auspices of the Atomic Fmeru Commtnlon.Published on a gttnt from the Forest Park Foundation to the journal of Gerontology .in the direct utilization of molecular oxygen, particularly those containing iron, and by the action of catalane on hydrogen peroxide. This follows from the fact that it has been known for many years that iron salts catalyze the air oxidation of organic compounds (5, 6, 14, 15); OH radicals are believed to be involved in these reactions (13) . Iron salts also catalyze the decomposition of hydrogen peroxide to water and oxygen-a reaction that involves OH and HO, radicals (16) . Further, recent studies in this laboratory on the inactivation of rat liver catalase suggest that the OH radical is involved . The catalane activity of the homogenates both in the presence and absence of hydrogen donors such as sodium bisulfite, sodium hypophosphite, pyrogallol, and mercaptans remains relatively constant under an atmosphere of nitrogen. However, in the presence of air, catalane activity rapidly decreases and the rate of decrease is accelerated in the presence ...

The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization. The latter determines the rate of accumulation of mitochondria1 damage produced by free radical reactions, the rate increasing with the rate of oxygen consumption, which ultimately causes death.

Aging is the progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age. These time-related changes are attributed to the aging process. The nature ofthe aging process has been the subject ofconsiderable speculation. Accumulating evidence now indicates that the sum ofthe deleterious free radical reactions going on continuously throughout the cells and tissues constitutes the aging process or is a major contributor to it. In mammalian systems the free radical reactions are largely those involving oxygen.Dietary manipulations expected to lower the rate of production of free radical reaction damage have been shown (i) to increase the life span of mice, rats, fruit flies, nematodes, and rotifers, as well as the "life span" of neurospora; (#-) to inhibit development ofsome forms ofcancer; (ii) to enhance humoral and cell-mediated immune responses; and (iv) to slow development of amyloidosis and the autoimmune disorders of NZB and NZB/NZW mice. In addition, studies strongly suggest that free radical reactions play a significant role in the deterioration of the cardiovascular and central nervous systems with age.The free radical theory of aging provides reasonable explanations for age-associated phenomena, including (i) the relationship of the average life spans of mammalian species to their basal metabolic rates, (ii) the clustering of degenerative diseases in the terminal part of the life span, (iii) the beneficial effect of food restriction on life span, (iv) the greater longevity of females, and (v) the increase in autoimmune manifestations with age.

Toxic oxygen free radicals have been implicated as important pathologic mediators in many clinical disorders. We discuss the chemistry of oxygen radical production and the roles of iron and of various antioxidants as well as the diseases that have received active attention in oxy-radical research. Particular attention is focused on cigarette smoke oxidants, ischemia-reperfusion-induced radical production, carcinogenesis, and aging. Such research may well provide a firm foundation for therapeutic breakthroughs.

Aging is the accumulation of changes that increase the risk of death. Aging changes can be attributed to development, genetic defects, the environment, disease, and an inborn process: the aging process. The latter is the major risk factor for disease and death after age 28 in the developed countries. In these countries, average life expectancies at birth (ALE-B) now range from 76 to 79 years, 6-9 years less than the limit of approximately 85 years imposed by aging. Aging changes may be caused by free radical reactions. The extensive studies based on this possibility hold promise that the ALE-B can be extended to >85 years and the maximum life span increased.