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The Aging Process Proc. Nati Acad. Sci. USA Vol. 78, No. 11, pp. 7124-7128, November 1981 Medical Sciences The aging process (free radicals/evolution/antioxidants/degenerative diseases/longevity) DENHAM HARMAN University ofNebraska College of Medicine, Departments of Medicine and Biochemistry, Omaha, Nebraska 68105 Communicated by Melvin Calvin, July 13, 1981 ABSTRACT Aging is the progressive accumulation ofchanges level. Similarly, aging at the multicellular level may be consid- with time that are associated with or responsible for the ever-in- ered the result ofthe aging processes proceeding in all the cells, creasing susceptibility to disease and death which accompanies with environmental influences now including the effects ofthe advancing age. These time-related changes are attributed to the aging cells on each other and the changes with time ofthe con- agingprocess. The nature ofthe aging process has been the subject nective tissues. Death of multicellular life occurs because of ofconsiderable speculation. Accumulating evidence now indicates death or dysfunction, or both, ofcells involved in functions vital that the sum ofthe deleterious free radical reactions going on con- to the cells as awhole (e.g., functions in mammals such as those tinuously throughout the cells and tissues constitutes the aging of the center process or is a major contributor to it. In mammalian systems the respiratory or of the myocardium). free radical reactions are largely those involving oxygen. The nature ofthe aging process has been the subject ofcon- Dietary manipulations expected to lower the rate ofproduction siderable speculation (1). Suggested possibilities include (i) en- of free radical reaction damage have been shown (i) to increase codement ofaging in DNA (made manifest in a manner similar the life span of mice, rats, fruit flies, nematodes, and rotifers, as to development), (ii) progressive breakdown in accuracy in pro- well as the "life span" of neurospora; (#-) to inhibit development tein synthesis, (iii) crosslinkage of macromolecules, (iv) in ofsome forms ofcancer; (ii) toenhance humoral andcell-mediated higher organisms, "attack" of the immune system on self-anti- immune responses; and (iv) to slow development of amyloidosis gens, and (v) free radical reaction damage. This paper is mainly and the autoimmune disorders of NZB and NZB/NZW mice. In limited to a discussion of the last-named possibility not only addition, studies strongly suggest that free radical reactions play because accumulating evidence indicates that aging is largely a significant role in the deterioration of the cardiovascular and due to free radical reaction damage but also because it shows central nervous systems with age. promise of serving as a useful guide in the search for practical The free radical theory of aging provides reasonable explana- means of further increasing the healthy human life span. tions for age-associated phenomena, including (i) the relationship The free radical theory (2-6) of aging assumes that there is ofthe average life spans ofmammalian species to their basal met- a single basic cause of aging, modified by genetic and environ- abolic rates, (ii) the clustering of degenerative diseases in the ter- mental factors, and postulates that free radical reactions are in- minal part of the life span, (iii) the beneficial effect of food re- volved in aging and age-related disorders. These reactions arise striction on life span, (iv) the greater longevity of females, and (v) upon exposure to ionizing radiation, from nonenzymatic reac- the increase in autoimmune manifestations with age. tions, and from enzymatic reactions, particularly those of the It is not unreasonable to expect on the basis ofpresent data that two major energy-gaining processes employed by living the healthy life span can be increased by 5-10 or more years by things-photosynthesis (7) and the reduction of 02 to water keeping body weight down, at a level compatible with a sense of (8-10). They probably also arise as well in the reduction ofsome well-being, while ingesting diets adequate in essential nutrients terminal electron acceptors employed by anaerobes: probably but designed to minimize random free radical reactions in the with NO3 (11, 12), possibly with CO2 (11), and maybe with body. SO- (11). Although this theory is applicable to all life, the fol- lowing comments are directed largely to mammalian aging, in Aging is the progressive accumulation ofchanges with time as- which 02 is the main source ofdamaging free radical reactions, sociated with or responsible for the ever-increasing suscepti- because ofthe importance attached to slowing the aging process bility to disease and death which accompanies advancing age. in man. These time-related changes are attributed to the aging process. The ubiquitous free radical reactions are initiated continu- This process may be common to all living things, for the phe- ously throughout cells and tissues from both enzymatic and nomenon of aging and death is universal. If so, both aging and nonenzymatic reactions; examples include enzymatic reactions the rate of the aging process are under genetic control to some involved in the respiratory chain (8, 9, 13, 14), in phagocytosis extent for the manifestations of aging, and life span differs be- (10), and in the cytochrome P-450 system (15); nonenzymatic tween species and individual members of a species. Further, reactions of oxygen (16, 17) with organic compounds; and non- like all chemicals and chemical reactions, the manifestations of enzymatic reactions initiated by ionizing radiation (18). Because aging-which reflect chemical composition-and the rate ofthe of the high chemical reactivity of the intermediates, free radi- aging process should be subject to environmental influences. cals, itwould be expected that all components ofthe body would Aging and death of single cells then can be viewed as being be in a due to the aging process, the changes with time and their rates constantly subject to some degree of chemical change ofproduction being under genetic control but subject to mod- more-or-less random manner, somewhat like the effects pro- ification by the environment, with death ensuing when one or duced by the free radicals formed by ionizing radiation (18). more activities vital to the cell are depressed below some critical These expected changes include: (i) accumulative oxidative al- terations in the long-lived molecules collagen (19), elastin (20), The publication costs ofthis article were defrayed in part by page charge and chromosomal material (21, 22); (ii) breakdown ofmucopoly- payment. This article must therefore be hereby marked "advertise- saccharides through oxidative degradation (23); (iii) accumula- ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. tion of metabolically inert material such as ceroid and age pig- 7124 Downloaded by guest on September 23, 2021 Medical Sciences: Harman Proc. NatL Acad. Sci. USA 78 (1981) 7125 ment through oxidative polymerization reactions involving hibit prostacyclin synthetase (60, 61); prostacyclin is a potent lipids, particularly polyunsaturated lipids, and proteins (24, 25); inhibitor ofplatelet aggregation (61)-believed to be one ofthe (iv) changes in membrane characteristics of such elements as events contributing to the development of atherosclerosis mitochondria and lysosomes because of lipid peroxidation (26, (62)-and a strong vasodilator (61, 63). Further, studies of se- 27); and (v) arteriolocapillary fibrosis secondary to vessel injury lenium deficiency in man (64) and pigs (65, 66)-the deficiency by products resulting from peroxidation of serum and vessel- is associated with myocardial and vascular damage-and a study wall components (28). Defenses have evolved that help to limit ofthe effect ofselenium and vitamin E on myocardial necrosis the production offree radical damage to "tolerable" levels. They induced by isoprenaline treatment or coronary artery ligation include antioxidants, such as the tocopherols (29) and carotenes (67) indicate that free radical reactions are continuously present (10) (like tocopherols, good quenchers ofsinglet oxygen); heme- in the cardiovascular system and that the rate ofaccumulation containing peroxidases (30) (catalase is an important member of damage produced by them is limited to tolerable values ofthis group); selenium-containing glutathione peroxidase (30); largely by glutathione peroxidase. Likewise, the incidence of superoxide dismutases (31); and DNA repair mechanisms (32, the common forms of cardiovascular disease is low in areas 33). where the dietary intake ofselenium is high and vice versa (49, Dietary manipulations expected to further lower the rate of 68, 69). The ability of glutathione peroxidase to "buffer" free production offree radical reaction damage, briefly summarized radicalreaction damage may largely accountforthe inconclusive recently (6), give results in accord with the free radical theory results (70) obtained in studies designed to alter atherogenesis of aging. rates in minipigs by diets formulated to change the level offree For example, dietary antioxidants increase the life span of radical reactions in the serum; the diets contained varying mice (34-38), rats (39), fruit flies (37, 38), nematodes (40), and amounts ofpolyunsaturated fats and ofcopper. rotifers (41), as well as the "life span" ofneurospora (42). In the Lipofuscin (age pigment) accumulates with age (71) in the case of mice, addition of 1.0% (wt/wt) 2-mercaptoethylamine various areas
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