AGE

, Volume 6, Issue 3, pp 86–94 | Cite as

Free radical theory of aging: Consequences of mitochondrial aging

  • Denham Harman
Article

Abstract

Mitochondria may serve as biologic clocks. This paper provides plausible explanations, based on mitochondrial aging, of some aging phenomenon: a) the inverse relationship between basal metabolic rate and life span; b) the antioxidants studies thus far which increase the average life span of mice, depress body weight and fail to lengthen maximum life span; c) the association of degenerative diseases with the terminal part of the life span; d) the exponential nature of the mortality curve, and e) the beneficial effect of caloric restriction on degenerative diseases and life span. A short discussion is also presented of the effect of exercise on life span and aging of muscle mitochondria.

Keywords

Life Span Metabolic Rate Inverse Relationship Radical Theory Caloric Restriction 
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References

  1. 1.
    Harman, D.: The aging process. Proc. Natl. Acad. Sci. USA, 78: 7124–7128, 1981.PubMedGoogle Scholar
  2. 2.
    Harman, D.: Aging: a theory based on free radical and radiation chemistry. J. Gerontol., 11: 298–300, 1956.PubMedGoogle Scholar
  3. 3.
    Harman, D.: Role of free radicals in mutation, cancer, aging, and the maintenance of life. Radiation Res., 16: 753–763, 1962.PubMedGoogle Scholar
  4. 4.
    Harman, D.: Prolongation of life: rote of free radical reactions in aging. J. Amer. Geriatrics Soc., 17: 721–735, 1969.Google Scholar
  5. 5.
    Harman, D.: The biologic clock: the mitochondria? J. Amer. Geriatrics Soc., 20: 145–147, 1972.Google Scholar
  6. 6.
    Tocopherol, Oxygen, and Biomembranes, edited by de Duve, C., and Hayaishi, O., New York, Elsevier North-Holland, 1978.Google Scholar
  7. 7.
    Klebanoff, S. J.: Oxygen metabolism and the toxic properties of phagocytes. Ann. Intern. Med., 93: 480–489, 1980.PubMedGoogle Scholar
  8. 8.
    Flohé, L., Günzies, W. A., and Ladenstein, R.: Glutathione peroxidase, in Glutathione: Metabolism and Function, edited by Arias, I.M., and Jakoby, W. B., New York, Raven Press, 1976, pp. 115–138.Google Scholar
  9. 9.
    Fridovich, I.: Oxygen radicals, hydrogen peroxide, and oxygen toxicity, in: Free Radicals in Biology, Vol. 2, edited by Pryor, W. A., New York, Academic Press, 1977, pp. 239–277.Google Scholar
  10. 10.
    Superoxide and Superoxide Dismutases, edited by Michelson, A. M., McCord, J. M., and Fridovich, I., New York, Academic Press, 1977.Google Scholar
  11. 11.
    Ames, B. N., Cathcart, R., Schiviers, E., and Hochstein, P.: Uric acid provides an antioxidant defense in humans against oxidant-and radical-caused aging and cancer: a hypothesis. Proc. Natl. Acad. Sci. USA, 78: 6858–6852, 1981.PubMedGoogle Scholar
  12. 12.
    Hart, R. W., D’Ambrosio, S. M., Ng, K. J., and Modak, S. P.: Longevity, stability and DNA repair. Mech. Ageing Dev., 9: 203–223, 1979.PubMedCrossRefGoogle Scholar
  13. 13.
    DNA Repair Processes, edited by Nichols, W. W., and Murphy, D. G., Miami, Miami Symposium Specialists, 1977.Google Scholar
  14. 14.
    Harman, D.: Free radical theory of aging: effect of free radical inhibitors on the mortality rate of male LAF, mice. J. Gerontol., 23: 476–482, 1968.PubMedGoogle Scholar
  15. 15.
    Comfort, A.: Effect of ethoxyquin on the longevity of C3H mice. Nature, 229: 254–255, 1971.PubMedCrossRefGoogle Scholar
  16. 16.
    Emanuel, N. M.: Free radicals and the action of inhibitors of radical processes under pathological states and aging in living organisms and in man. Quart. Rev. Biophysics, 9: 283–308, 1976.CrossRefGoogle Scholar
  17. 17.
    Clapp, N. K., Satterfield, L. C., and Bowles, N. D.: Effects of the antioxidant butylated hydroxytoluene (BHT) on mortality in BALC/C mice. J. Gerontol., 34: 497–501, 1979.PubMedGoogle Scholar
  18. 18.
    Miquel, J., Economos, A. C.: Favorable effects of the antioxidants sodium and magnesium thiazolidine carboxylate on the vitality and life span of Drosophila and mice. Exper. Gerontol., 14: 279–285, 1979.CrossRefGoogle Scholar
  19. 19.
    Miquel, J., Johnson, Jr., J. E.: Effects of various antioxidants and radiation protectants on the life span and lipofuscin of Drosophila and C57BL/6J mice. The Gerontologist, 15, II: 25, 1975 (abstr.).Google Scholar
  20. 20.
    Bun-Hoi, N. P., Ratsunamanga, A. R.: Age retardation in the rat by nordihydroguaiaretic acid. C. R. Seances Soc. Biol., Paris, 153: 1180–1182, 1959.Google Scholar
  21. 21.
    Epstein, J., Gershon, D.: Studies on aging in nematodes, IV. The effect of antioxidants on cellular damage and life span. Mech. Ageing Dev. 1: 257–264, 1972.Google Scholar
  22. 22.
    Enesco, H. E., Verdone-Smith, C.: α-Tocopherol increases lifespan in the rotifer Philodina. Exper. Gerontol., 15: 335–338, 1980.CrossRefGoogle Scholar
  23. 23.
    Munkres, K. D., Minssen, M.: Aging of Neurospora Crassa. 1. Evidence for the free radical theory of aging from studies of a natural death mutant. Mech. Ageing Dev., 5: 79–98, 1976.PubMedCrossRefGoogle Scholar
  24. 72.
    Tachi, H., and Sato, T.: Age changes in size and number of mitochondria of human hepatic cells. J. Gerontol., 23: 454–461, 1968.Google Scholar
  25. 73.
    Weinbach, E. C., and Garbus, J.: Oxidative phosphorylation in mitochondria from aged rats. J. Biol. Chem., 234: 412–417, 1959.PubMedGoogle Scholar
  26. 74.
    Miquet, J., Oro, J., Bensch, K. G., and Johnson, Jr., J. E.: Lipofuscin: fine-structural and biochemical studies, in Free Radicals in Biology, Vol. 3, edited by Pryor, W. A., New York, Academic Press, 1977, pp. 133–182.Google Scholar
  27. 75.
    Miquel, J., Lundgren, D. R., and Johnson, Jr., J. E.: Spectrophotofluorometric and electron microscopic study of lipofuscin accumulation in the testes of aging mice. J. Gerontol., 33: 5–19, 1978.Google Scholar
  28. 76.
    Koobs, D. H., Schultz, R. L., and Jutzy, R. V.: The origin of lipofuscin and possible consequences to the myocardium. Arch. Pathol. Lab. Med., 102: 66–68, 1978.PubMedGoogle Scholar
  29. 77.
    Lambert, J. R., Shing, C. L., and Pritzker, K.P.H.: Brown bowel syndrome in Chron’s disease. Arch. Pathol. Lab. Med., 104: 201–205, 1980.PubMedGoogle Scholar
  30. 78.
    Kohn, R. R.: Intrinsic aging of postmitotic cells, in Aging Gametes, edited by Blandau, R. J., New York, S. Karger, 1975, pp. 1–18.Google Scholar
  31. 79.
    Miquel, J., Economos, A. C., Bensch, K. G., Atlan, H., and Johnson, Jr., J. E.: Review of cell aging in Drosophila and mouse. Age, 2: 78–88, 1979.CrossRefGoogle Scholar
  32. 80.
    Comfort A.: The Biology of Senescence, 3rd edition. New York, Elsevier, 1979, pp. 81–86.Google Scholar
  33. 81.
    Schmidt-Nielsen, K.: Energy metabolism, body size, and problems of scaling. Fed. Proc., 29: 1524–1532, 1970.PubMedGoogle Scholar
  34. 82.
    Leliévre, P., and Liébecq, C.: Metabolic effects of sulfur-containing radioprotective agents, in International Encyclopedia of Pharmacology and Therapeutics. Section 79. Sulfur-Containing Radioprotective Agents, edited by Bacq, Z. M., New York, Pergamon Press, 1975, pp. 239–259.Google Scholar
  35. 83.
    Pardini, R. S., Heidker, J. C., and Fletcher, D. C.: Inhibition of mitochondrial electron transport by nor-dihydroguaiaretic acid (NDGA). Biochem. Pharmacol., 19: 2695–2699, 1970.PubMedCrossRefGoogle Scholar
  36. 84.
    Pardini, R. S., Cotlin, J. C., Heidker, J. C., and Folkers, K.: Specificity of inhibition of Coenzyme Q — enzyme systems by lipoidal benzoquinone derivatives. J. Med. Chem., 15: 195–197, 1972.PubMedCrossRefGoogle Scholar
  37. 85.
    Miquel, J., Fleming, J., and Economos, A. C.: Antioxidants, metabolic rate and aging in Drosophila. Arch. Gerontol. Geriatrics, 1: 159–165, 1982.CrossRefGoogle Scholar
  38. 86.
    Cadenas, E., Boveris, A., Ragan, C. I., and Stoppani, A. O.M.: Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch. Biochem. Biophys., 180: 248–257, 1977.PubMedCrossRefGoogle Scholar
  39. 87.
    Boveris, A., Cadenas, E., and Stoppani, A. O.: Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. Biochem. J., 156: 435–344, 1976.PubMedGoogle Scholar
  40. 88.
    Ingledew, W. J., Salerno, J. C., and Ohnishi, T.: Studies on electron paramagnetic resonance spectra manifested by a respiratory chain hydrogen carrier. Arch. Biochem. Biophys. 177: 176–184, 1976.PubMedCrossRefGoogle Scholar
  41. 89.
    Emanuel, N. M., Duburs, G., Obukhov, L. K., and Uldrikis, J.: Drug for prophylaxis of aging and prolongation of lifetime. Chem. Abst., 94: 9632a, 1981.Google Scholar
  42. 90.
    Dublin, L. L., Lotka, A. J., and Spiegelman, M.: Length of Life. New York, The Ronald Press, 1949, p. 16.Google Scholar
  43. 91.
    Upton, A. C.: Pathobiology, in Handbook of the Biology of Aging, edited by Finch, C. E., and Hayflick, L., New York, Van Nostrand Reinhold, 1977, pp. 513–535.Google Scholar
  44. 92.
    Lundberg, W. O.: Mechanisms, in Lipids and Their Oxidation, edited by Schultz, H. W., Day, E. A., and Sinnhuber, R. O., Westport, The Avi Publ. Co., 1962, pp. 31–50.Google Scholar
  45. 93.
    Augustin, M. A., and Berry, S. K.: Effectiveness of antioxidants in refined, bleached and deodorized palm olein. J. Amer. Oil Chem. Soc., 60: 105–108, 1983.Google Scholar
  46. 94.
    Barrows, Jr., C. H., and Kokkonen, G. C.: Diet and life extension in animal model systems. Age, 1: 130–142, 1978.CrossRefGoogle Scholar
  47. 95.
    Masoro, E. J., Yu, B. P., and Bertrand, H. A.: Action of food restriction in delaying the aging process. Proc. Natl. Acad. Sci., USA, 79: 4239–4241, 1982.PubMedGoogle Scholar
  48. 96.
    Yu, B., Masoro, E. J., Murata, I., Bertrand, H. A., and Lynd, F. T.: Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: longevity, growth, lean body mass and disease. J. Gerontol., 37: 130–141, 1982.PubMedGoogle Scholar
  49. 97.
    Berg, B. N., and Simms, H. S.: Nutrition and longevity in the rat. III. Food restriction beyond 800 days. J. Nutr., 74: 23–32, 1961.Google Scholar
  50. 98.
    Ross, M. H.: Aging, nutrition and hepatic enzyme activity patterns in the rat. J. Nutr., 97:Suppl. 1, Part II, 563–602, 1969.Google Scholar
  51. 99.
    Barrows, Jr., C. H., and Kokkonen, G.: The effect of various dietary restricted regimes on biochemical variables in the mouse, Growth, 42: 71–85, 1978.PubMedGoogle Scholar
  52. 100.
    Goodrick, C. L.: Effects of long-term voluntary wheel exercise on male and female Wistar rats. Gerontology, 26: 22–33, 1980.PubMedCrossRefGoogle Scholar
  53. 101.
    Shephard, R. J.: Physical Activity and Aging. Chicago, Year Book Publ. Co., 1978, p. 273.Google Scholar
  54. 102.
    Leon, A. S., and Blackburn, H.: The relationship of physical activity to coronary heart disease and life expectancy. Ann. N. Y. Acad. Sci., 301: 561–578, 1977.PubMedGoogle Scholar
  55. 103.
    Brown, K. S., and Milvy, P.: A critique of several epidemiological studies of physical activity and its relationship to aging, health, and mortality. Ann. N. Y. Acad. Sci., 301: 703–719, 1977.PubMedGoogle Scholar
  56. 104.
    Davies, K. J. A., Quintanilha, A. T., Brooks, G. A., and Packer, L.: Free radicals and tissue damage produced by exercise. Biochem. Biophys. Res. Comm., 107: 1198–1205, 1982.PubMedCrossRefGoogle Scholar
  57. 105.
    Dillard, C. J., Litov, R. E., Savin, W. M., Dumelin, E. E., and Tappel, A. L.: Effects of exercise, vitamin E, and ozone on pulmonary function and lipid peroxidation. J. Appl. Physiol., 45: 927–932, 1978.PubMedGoogle Scholar
  58. 106.
    Cantu, R. C., Means, R. H., Micheli, L. J., Siegel, A. J., and Vinger, P.: Sports Medicine in Primary Care. Toronto, Collamore Press, 1982, p. 14.Google Scholar
  59. 107.
    Bassler, T. J.: Marathon running and immunity to atherosclerosis. Ann. N. Y. Acad. Sci., 301: 579–592, 1977.PubMedGoogle Scholar
  60. 108.
    Hartung, G. H., Foreyt, J. P., Mitchell, R. E., Vlasek, I., and Gotto, Jr., A. M.: Relation of diet to high-density-lipoprotein cholesterol in middle-aged marathon runners, joggers, and inactive men. New Engl. J. Med., 302: 357–361, 1980.PubMedCrossRefGoogle Scholar
  61. 109.
    Davies, K. J. A., Packer, L., and Brooks, G. A.: Biochemical adaptation of mitochondria, muscle, and whole-animal respiration to endurance training. Arch. Biochem. Biophysics, 209: 539–554, 1981.CrossRefGoogle Scholar
  62. 110.
    Patch, L. D., and Brooks, G. A.: Effects of training on VO2 max and VO2 during two running intensities in rats. Pflugers Arch., 386: 215–219, 1980.PubMedCrossRefGoogle Scholar
  63. 111.
    Tzagoloff, T.: Mitochondria. New York, Plenum Press, 1982, p. 237.Google Scholar
  64. 112.
    Schneider, E. L., Sternberg, H., Tice, R. R., Senula, G. C., Kram, D., Smith, J. R., and Bynum, G.: Cellular replication and aging. Mech. Ageing Dev., 9: 313–324, 1979.PubMedCrossRefGoogle Scholar
  65. 113.
    Medvedev, Z. A.: On the immortality of the germ line: genetic and biochemical mechanisms. A Review. Mech. Ageing Dev., 17: 331–359, 1981.CrossRefGoogle Scholar
  66. 114.
    Bernstein, H.: Recombinational repair may be an important function of sexual reproduction. Biosci., 33: 326–331, 1983.CrossRefGoogle Scholar
  67. 115.
    Tzagoloff, T.: Mitochondria. New York, Plenum Press, 1982, p. 268.Google Scholar

Copyright information

© American Aging Association, Inc. 1983

Authors and Affiliations

  • Denham Harman
    • 1
  1. 1.Departments of Medicine and BiochemistryUniversity of Nebraska College of MedicineOmaha

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