The Molecular Genetics of Aging pp 45-66

Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 29)

Current Issues Concerning the Role of Oxidative Stress in Aging: A Perspective

  • Rajindar S. Sohal
  • Robin J. Mockett
  • William C. Orr


The main tenet of the oxidative stress hypothesis of aging is that accrual of molecular oxidative damage is the principal causal factor in the senescence-related loss of ability to maintain homeostasis. This hypothesis has garnered a considerable amount of supportive correlational evidence, which is now being extended experimentally in transgenic Drosophila overexpressing antioxidative defense enzymes. Some of these studies have reported extensions of life span, while others have not. Interpretation of life spans in poikilotherms is complicated by a number of factors, including the interrelationship between metabolic rate and longevity. The life spans of poikilotherms can be extended multifold by reducing the metabolic rate but without affecting the metabolic potential, i.e., the total amount of energy expended during life. A hypometabolic state in poikilotherms also enhances stress resistance and activities of antioxidative enzymes. It is emphasized that extension of life span without simultaneously increasing metabolic potential is of questionable biological significance.


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  1. Adelman R, Saul RL, Ames BN (1988) Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci USA 85: 2706–2708PubMedGoogle Scholar
  2. Agarwal S, Sohal RS (1994a) Aging and proteolysis of oxidized proteins. Arch Biochem Biophys 309: 24–28PubMedGoogle Scholar
  3. Agarwal S, Sohal RS (1994b) DNA oxidative damage and life expectancy in houseflies. Proc Natl Acad Sci USA 91: 12332–12335PubMedGoogle Scholar
  4. Agarwal S, Sohal RS (1994c) Aging and protein oxidative damage. Mech Ageing Dev 75: 11–19PubMedGoogle Scholar
  5. Allen RG, Sohal RS (1982) Life-lengthening effects of y-radiation on the adult housefly, Musca domestica. Mech Ageing Dev 20: 369–375PubMedGoogle Scholar
  6. Allen RG, Farmer KJ, Newton RK, Sohal RS (1984) Effects of paraquat administration on longevity, oxygen consumption, lipid peroxidation, superoxide dismutase, catalase, glutathione reductase, inorganic peroxides and glutathione in the adult housefly. Comp Biochem Physiol 78C: 283–288Google Scholar
  7. Anisimov VN, Mylnikov SV, Oparina TI, Khavinson VKh (1997) Effect of melatonin and pineal peptide preparation epithalamin on life span and free radical oxidation in Drosophila melanogaster. Mech Ageing Dev 97: 81–91PubMedGoogle Scholar
  8. Anisimov VN, Mylnikov SV, Khavinson VKh (1998) Pineal peptide preparation epithalamin increases the life span of fruit flies, mice and rats. Mech Ageing Dev 103: 123–132PubMedGoogle Scholar
  9. Bartosz G, Leyko W, Fried R (1979) Superoxide dismutase and lifespan of Drosophila melanogaster. Experientia 35: 1193PubMedGoogle Scholar
  10. Bieschke ET, Wheeler JC, Tower J (1998) Doxycycline-induced transgene expression during Drosophila development and aging. Mol Gen Genet 258: 571–579PubMedGoogle Scholar
  11. Bitterman N, Skapa E, Gutterman A (1997) Starvation and dehydration attenuate CNS oxygen toxicity in rats. Brain Res 761: 146–150PubMedGoogle Scholar
  12. Bohr VA, Anson RM (1995) DNA damage, mutation and fine structure DNA repair in aging. Mutat Res 338: 25–34PubMedGoogle Scholar
  13. Brack C, Bechter-Thüring, E, Labuhn M (1997) N-acetylcysteine slows down ageing and increases the life span of Drosophila melanogaster. Cell Mol Life Sci 53: 960–966PubMedGoogle Scholar
  14. Breimer LH (1983) Urea-DNA glycosylase in mammalian cells. Biochemistry 22: 4192–4197PubMedGoogle Scholar
  15. Campbell JA (1936) Body temperature and oxygen poisoning. J Physiol 89: 17P - 18 PGoogle Scholar
  16. Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59: 527–605PubMedGoogle Scholar
  17. Comfort A, Youhotsky-Gore I, Pathmanathan K (1971) Effect of ethoxyquin on the longevity of C3H mice. Nature 229: 254–255PubMedGoogle Scholar
  18. Farmer KJ, Sohal RS (1989) Relationship between superoxide anion radical generation and aging in the housefly, Musca domestica. Free Radical Biol Med 7: 23–29Google Scholar
  19. Fleming JE, Leon HA, Miguel J (1981) Effects of ethidium bromide on development and aging of Drosophila: implications for the free radical theory of aging. Exp Gerontol 16: 287–293PubMedGoogle Scholar
  20. Fleming JE, Shibuya RB, Bensch KG (1987) Lifespan, oxygen consumption and hydroxyl radical scavenging capacity of two strains of Drosophila melanogaster. Age 10: 86–89Google Scholar
  21. Gilbert DL, Gerschman R, Fenn WO (1955) Effects of fasting and X-irradiation on oxygen poisoning in mice. Am J Physiol 181: 272–274PubMedGoogle Scholar
  22. Grune T, Reinheckel T, Davies KJA (1997) Degradation of oxidized proteins in mammalian cells. FASEB J 11: 526–534PubMedGoogle Scholar
  23. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300PubMedGoogle Scholar
  24. Harman D (1978) Free radical theory of aging: nutritional implications. Age 1: 145–152Google Scholar
  25. Harman D (1981) The aging process. Proc Natl Acad Sci USA 78: 7124–7128PubMedGoogle Scholar
  26. Hart RW, Setlow RB (1974) Correlation between deoxyribonucleic acid excision-repair and lifespan in a number of mammalian species. Proc Natl Acad Sci USA 71: 2169–2173PubMedGoogle Scholar
  27. Herbert V (1994) The antioxidant supplement myth. Am J Clin Nutr 60: 157–158PubMedGoogle Scholar
  28. Hermes-Lima M, Storey JM, Storey KB (1998) Antioxidant defenses and metabolic depression.Google Scholar
  29. The hypothesis of preparation for oxidative stress in land snails. Comp Biochem Physiol B 120:437–448Google Scholar
  30. Hirano T, Yamaguchi R, Asami S, Iwamoto N, Kasai H (1996) 8–hydroxyguanine levels in nuclear DNA and its repair activity in rat organs associated with age. J Gerontol A Biol Sci Med Sci 51: B303–B307Google Scholar
  31. Hollstein MC, Brooks P, Linn S, Ames BN (1984) Hydroxymethyluracil DNA glycosylase in mammalian cells. Proc Natl Acad Sci USA 81: 4003–4007PubMedGoogle Scholar
  32. Hwang C, Sinskey AJ, Lodish HF (1992) Oxidized redox state of glutathione in the endoplasmic reticulum. Science 257: 1496–1502PubMedGoogle Scholar
  33. Ishikawa T, Sakurai J (1986) In vivo studies on age dependency of DNA repair with age in mouse skin. Cancer Res 46: 1344–1348PubMedGoogle Scholar
  34. Izmaylov DM, Obukhova LK (1996) Geroprotector efficiency depends on viability of control population: lifespan investigation in Drosophila melanogaster. Mech Ageing Dev 91: 155164Google Scholar
  35. Izmaylov DM, Obukhova LK (1999) Geroprotector effectiveness of melatonin: investigation of lifespan of Drosophila melanogaster. Mech Ageing Dev 106: 233–240PubMedGoogle Scholar
  36. Jazwinski SM (1996) Longevity, genes, and aging. Science 273: 54–59PubMedGoogle Scholar
  37. Johnson TE, Shook D, Murakami S, Cypser J (1999) Increased resistance to stress is a marker for gerontogenes leading to increased health and longevity in nematodes. In: Bohr VA, Clark BFC, Stevnsner T (eds) Molecular biology of aging. Munksgaard, Copenhagen, pp 25–34Google Scholar
  38. Koga T, Takumi K (1995) Nutrient starvation induces cross protection against heat, osmotic, or H202 challenge in Vibrio parahaemolyticus. Microbiol Immunol 39: 213–215PubMedGoogle Scholar
  39. Kohn RR (1971) Effect of antioxidants on life span of C57BL mice. J Gerontol 26: 378–380Google Scholar
  40. Ku H-H, Brunk UT, Sohal RS (1993) Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radical Biol Med 15: 621–627Google Scholar
  41. Lamb MJ, McDonald RP (1973) Heat tolerance changes with age in normal and irradiated Drosophila melanogaster. Exp Gerontol 8: 207–217PubMedGoogle Scholar
  42. Lee YJ, Ducoff HS (1984) Radiation-enhanced resistance to oxygen: a possible relationship to radiation-enhanced longevity. Mech Ageing Dev 27: 101–109PubMedGoogle Scholar
  43. Lin Y-J, Seroude L, Benzer S (1998) Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282: 943–946PubMedGoogle Scholar
  44. Loeb J, Northrop J (1917) On the influence of food and temperature upon the duration of life. J Biol Chem 32: 103–121Google Scholar
  45. Manton KG, Stallard E, Wing S (1991) Analyses of black and white differentials in the age trajectory of mortality in two closed cohort studies. Stat Med 10: 1043–1059PubMedGoogle Scholar
  46. Massie HR, Williams TR (1979) Increased longevity of Drosophila melanogaster with lactic and gluconic acids. Exp Gerontol 14: 109–115PubMedGoogle Scholar
  47. Massie HR, Baird MB, Piekielniak MJ (1976) Ascorbic acid and longevity in Drosophila. Exp Gerontol 11: 37–41PubMedGoogle Scholar
  48. Massie HR, Aiello VR, Williams TR, Baird MB, Hough JL (1993) Effect of vitamin A on longevity. Exp Gerontol 28: 601–610PubMedGoogle Scholar
  49. McArthur MC, Sohal RS (1982) Relationship between metabolic rate, aging, lipid peroxidation and fluorescent age pigment in milkweed bug, Oncopeltus fasciatus (hemiptera). J Gerontol 37: 268–274Google Scholar
  50. McCord JM (1995) Superoxide radical: controversies, contradictions, and paradoxes. Proc Natl Acad Sci USA 209: 112–117Google Scholar
  51. Miguel J, Economos AC (1979) Favorable effects of the antioxidants sodium and magnesium thiazolidine carboxylate on the vitality and life span of Drosophila and mice. Exp Gerontol 14: 279–285Google Scholar
  52. Miguel J, Lundren PR, Bensch KG, Atlan H (1976) Effects of temperature on the life span, vitality and fine structure of Drosophila melanogaster. Mech Ageing Dev 5: 347–370Google Scholar
  53. Miguel J, Fleming J, Economos AC (1982) Antioxidants, metabolic rate and aging in Drosophila.Arch Gerontol Geriatr 1: 159–165Google Scholar
  54. Miguel J, Binnard R, Fleming JE (1983) Role of metabolic rate and DNA-repair in Drosophila aging: implications for the mitochondrial mutation theory of aging. Exp Gerontol 18: 167–171Google Scholar
  55. Mockett RJ, Sohal RS, Orr WC (1999) Overexpression of glutathione reductase extends survival in transgenic Drosophila melanogaster under hyperoxia but not normoxia. FASEB J 13: 1733–1742PubMedGoogle Scholar
  56. Newton RK, Ducore JM, Sohal RS (1989) Relationship between life expectancy and endogenous DNA single-strand breakage, strand break induction and DNA repair capacity in the adult housefly, Musca domestica. Mech Ageing Dev 49: 259–270PubMedGoogle Scholar
  57. Nohl H, Hegner D (1978) Do mitochondria produce oxygen radicals in vivo? Eur J Biochem 82: 563–567PubMedGoogle Scholar
  58. Omar BA, Gad NM, Jordan MC, Striplin SP, Russell WJ, Downey JM, McCord JM (1990) Cardioprotection by Cu,Zn-superoxide dismutase is lost at high doses in the reoxygenated heart. Free Radical Biol Med 9: 465–471Google Scholar
  59. Orr WC, Sohal RS (1992) The effects of catalase gene overexpression on life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch Biochem Biophys 297: 35–41PubMedGoogle Scholar
  60. Orr WC, Sohal RS (1993) Effects of Cu-Zn superoxide dismutase overexpression on life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch Biochem Biophys 301: 34–40PubMedGoogle Scholar
  61. Orr WC, Sohal RS (1994) Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263: 1128–1130PubMedGoogle Scholar
  62. Orr WC, Arnold LA, Sohal RS (1992) Relationship between catalase activity, life span and some parameters associated with antioxidant defenses in Drosophila melanogaster. Mech Ageing Dev 63: 287–296PubMedGoogle Scholar
  63. Oudes AJ, Herr CM, Olsen Y, Fleming JE (1998) Age-dependent accumulation of advanced glycation end-products in adult Drosophila melanogaster. Mech Ageing Dev 100: 221–229PubMedGoogle Scholar
  64. Pacifici RE, Davies KJA (1991) Protein, lipid and DNA repair systems in oxidative stress: the free-radical theory of aging revisited. Gerontology 37: 166–180PubMedGoogle Scholar
  65. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL (1998) Extension of Drosophila lifespan by overexpression of human SODI in motorneurons. Nat Genet 19: 171–174PubMedGoogle Scholar
  66. Parmar MKB, Machin D (1995) Survival analysis: a practical approach. John Wiley and Sons, ChichesterGoogle Scholar
  67. Parsons PA (1996) Rapid development and a long life: an association expected under a stress theory of aging. Experientia 52: 643–646PubMedGoogle Scholar
  68. Pearl R (1928) The rate of living. Alfred A Knopf, New YorkGoogle Scholar
  69. Pennisi E (1998) Single gene controls fruit fly life-span. Science 282: 856PubMedGoogle Scholar
  70. Ragland SS, Sohal RS (1973) Mating behavior, physical activity, and aging in the housefly, Musca domestica. Exp Gerontol 8: 135–145PubMedGoogle Scholar
  71. Reveillaud I, Niedzwiecki A, Bensch KG, Fleming JE (1991) Expression of bovine superoxide dismutase in Drosophila melanogaster augments resistance to oxidative stress. Mol Cell Biol 11: 632–640PubMedGoogle Scholar
  72. Reveillaud I, Phillips J, Duyf B, Hilliker A, Kongpachith A, Fleming JE (1994) Phenotypic rescue by a bovine transgene in a Cu,Zn-superoxide dismutase-null mutant of Drosophila melanogaster. Mol Cell Biol 14: 1302–1307PubMedGoogle Scholar
  73. Rubner M (1908) Das Problem der Lebensdauer and seine Beziehungen zum Wachstum and Ernährung. Oldenburg, MünchenGoogle Scholar
  74. Ruddle DL, Yengoyan LS, Miguel J, Marcuson R, Fleming JE (1988) Propyl gallate delays senescence in Drosophila melanogaster. Age 11: 54–58Google Scholar
  75. Schmidt-Nielsen K (1984) Scaling: why is animal size so important? Cambridge University Press, CambridgeGoogle Scholar
  76. Seto NOL, Hayashi S, Tener GM (1990) Overexpression of Cu,Zn-superoxide dismutase in Drosophila does not affect life span. Proc Natl Acad Sci USA 87: 4270–4274PubMedGoogle Scholar
  77. Sohal RS (1982) Oxygen consumption and life span in the adult male housefly, Musca domestica. Age 5: 21–24Google Scholar
  78. Sohal RS (1986) The rate of living theory: a contemporary interpretation. In: Collatz KG, Sohal RS (eds) Insect aging. Springer, Berlin Heidelberg New York, pp 23–44Google Scholar
  79. Sohal RS (1988) Effect of hydrogen peroxide administration on life span, superoxide dismutase, catalase and glutathione in the adult housefly, Musca domestica. Exp Gerontol 23: 211–216PubMedGoogle Scholar
  80. Sohal RS, Allen RG (1986) Relationship between oxygen metabolism, aging and development. Adv Free Radical Biol Med 2: 117–160Google Scholar
  81. Sohal RS, Brunk UT (1990) Lipofuscin as an indicator of oxidative stress. In: Porta EA (ed) Lipofuscin and ceroid pigments. Plenum, New York, pp 17–29Google Scholar
  82. Sohal RS, Dubey A (1994) Mitochondrial oxidative damage, hydrogen peroxide release, and aging. Free Radical Biol Med 16: 621–626Google Scholar
  83. Sohal RS, Sohal BH (1991) Hydrogen peroxide release by mitochondria increases during aging. Mech Ageing Dev 57: 187–202PubMedGoogle Scholar
  84. Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273: 5963Google Scholar
  85. Sohal RS, Wolfe LS (1986) Lipofuscin: characteristics and significance. In: Swaab DF, Fliers E, Mirmiran M, Van Gool WD, Van Haaren F (eds) Progress in brain research, 70. Elsevier, Amsterdam, pp 171–183Google Scholar
  86. Sohal RS, Farmer KJ, Allen RG, Cohen NR (1984a) Effect of age on oxygen consumption, superoxide dismutase, catalase, glutathione, inorganic peroxides and chloroform-soluble antioxidants in the adult male housefly, Musca domestica. Mech Ageing Dev 24: 185–195PubMedGoogle Scholar
  87. Sohal RS, Farmer KJ, Allen RG, Ragland SS (1984b) Effect of diethyldithiocarbamate on life span, metabolic rate, superoxide dismutase, catalase, inorganic peroxides and glutathione in the adult housefly, Musca domestica. Mech Ageing Dev 24: 175–183PubMedGoogle Scholar
  88. Sohal RS, Allen RG, Farmer KJ, Newton RK, Toy PL (1985a) Effects of exogenous antioxidants on the levels of endogenous antioxidants, lipid-soluble fluorescent material and life-span in the housefly, Musca domestica. Mech Ageing Dev 31: 329–336PubMedGoogle Scholar
  89. Sohal RS, Muller A, Koletzko B, Sies H (1985b) Effect of age and ambient temperature on n-pentane production in adult housefly, Musca domestica. Mech Ageing Dev 29: 317–326PubMedGoogle Scholar
  90. Sohal RS, Svensson I, Sohal BH, Brunk UT (1989) Superoxide anion radical production in different animal species. Mech Ageing Dev 49: 129–135PubMedGoogle Scholar
  91. Sohal RS, Arnold L, Orr WC (1990a) Effect of age on superoxide dismutase, catalase, glutathione reductase, inorganic peroxides, TBA-reactive material, GSH/GSSG, NADPH/NADP+ and NADH/NAD+ in Drosophila melanogaster. Mech Ageing Dev 56: 223–235PubMedGoogle Scholar
  92. Sohal RS, Arnold LA, Sohal BH (1990b) Age-related changes in antioxidant enzymes and prooxidant generation in tissues of the rat with special reference to parameters in two insect species. Free Radical Biol Med 10: 495–500Google Scholar
  93. Sohal RS, Sohal BH, Brunk UT (1990c) Relationship between antioxidant defenses and longevity in different mammalian species. Mech Ageing Dev 53: 217–227PubMedGoogle Scholar
  94. Sohal RS, Svensson I, Brunk UT (1990d) Hydrogen peroxide production by liver mitochondria in different species. Mech Ageing Dev 53: 209–215PubMedGoogle Scholar
  95. Sohal RS, Agarwal S, Dubey A, Orr WC (1993) Protein oxidative damage is associated with life expectancy. Proc Natl Acad Sci USA 90: 7255–7259PubMedGoogle Scholar
  96. Sohal RS, Agarwal S, Candas M, Forster M, Lal H (1994a) Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev 76: 215–224PubMedGoogle Scholar
  97. Sohal RS, Ku H-H, Agarwal S, Forster MJ, Lal H (1994b) Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev 74: 121–133PubMedGoogle Scholar
  98. Sohal RS, Agarwal A, Agarwal S, Orr WC (1995a) Simultaneous overexpression of copper-and zinc-containing superoxide dismutase and catalase retards age-related oxidative damage and increases metabolic potential in Drosophila melanogaster. J Biol Chem 270: 15671–15674PubMedGoogle Scholar
  99. Sohal RS, Sohal BH, Orr WC (1995b) Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage, and longevity in different species of flies. Free Radical Biol Med 19: 499–504Google Scholar
  100. Starke-Reed PE, Oliver CN (1989) Protein oxidation and proteolysis during aging and oxidative stress. Arch Biochem Biophys 275: 559–567PubMedGoogle Scholar
  101. Sun J, Tower J (1999) FLP Recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the lifespan of adult Drosophila melanogaster flies. Mol Cell Biol 19: 216–228PubMedGoogle Scholar
  102. Tatar M, Khazaeli AA, Curtsinger JW (1997) Chaperoning extended life. Nature 390: 30PubMedGoogle Scholar
  103. Teixeira HD, Schumacher RI, Meneghini R (1998) Lower intracellular hydrogen peroxide levels in cells overexpressing CuZn-superoxide dismutase. Proc Natl Acad Sci USA 95: 7872–7875PubMedGoogle Scholar
  104. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330: 1029–1035Google Scholar
  105. Van Voorhies WA, Ward S (1999) Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc Natl Acad Sci USA 96: 11399–11403PubMedGoogle Scholar
  106. Wheeler JC, Bieschke ET, Tower J (1995) Muscle-specific expression of Drosophila hsp70 in response to aging and oxidative stress. Proc Natl Acad Sci USA 92: 10408–10412PubMedGoogle Scholar
  107. Yong-Xing M, Yue Z, Chuan-Fu W, Zan-Shun W, Su-Ying C, Mei-Hua S, Jie-Ming G, Jian-Gang Z, Qi G, Lin H (1997) The aging retarding effect of `Long-Life CiLi’. Mech Ageing Dev 96: 171–180Google Scholar
  108. Yu BP (1996) Aging and oxidative stress: modulation by dietary restriction. Free Radical Biol Med 21: 651–668Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • Rajindar S. Sohal
    • 1
  • Robin J. Mockett
    • 1
  • William C. Orr
    • 1
  1. 1.Department of Biological SciencesSouthern Methodist UniversityDallasUSA

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