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Genetic analysis of ageing: role of oxidative damage and environmental stresses

Abstract

Evolutionary theory predicts substantial interspecific and intraspecific differences in the proximal mechanisms of ageing. Our goal here is to seek evidence for common (‘public’) mechanisms among diverse organisms amenable to genetic analysis. Oxidative damage is a candidate for such a public mechanism of ageing. Long-lived strains are relatively resistant to different environmental stresses. The extent to which these stresses produce oxidative damage remains to be established.

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References

  1. Medawar, P.B. Old age and natural death. Modern Quarterly. 1, 30–56 (1946).

    Google Scholar 

  2. Medawar, P.B. An Unsolved Problem of Biology (H.K. Lewis, London, 1952).

    Google Scholar 

  3. Hamilton, W.D. The moulding of senescence by natural selection. J. Theor. Biol. 12, 12–45 (1966).

    Article  CAS  PubMed  Google Scholar 

  4. Charlesworth, B. Evolution in Age-Structured Populations, 2nd Edn. (Cambridge University Press, Cambridge, 1994).

  5. Williams, G.C., Pleiotropy, natural selection, and the evolution of senescence. Evolution. 11, 398–411 (1957).

    Article  Google Scholar 

  6. Rose, M.R. & Charlesworth, B. A test of evolutionary theories of senescence. Nature. 287, 141–142 (1980).

    Article  CAS  PubMed  Google Scholar 

  7. Hughes, K.A. & Charlesworth, B. A genetic analysis of senescence in Drosophila. Nature 367, 64–66 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Wilson, P.W.F. et al. Apolipoprotein E alleles, dyslipidemia, and coronary heart diseasa. JAMA. 272, 1666–1671 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Saunders, A.M. et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1467–1472 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Rose, M.R. Laboratory evolution of postponed senescence in Drosophila melanogaster. Evolution 38, 1004–1010 (1984).

    Article  PubMed  Google Scholar 

  11. Luckinbill, L.S., Arking, R., Clare, M.J., Cirocco, W.C. & Buck, S.A. Selection for delayed senescence in Drosophila melanogaster. Evolution 38, 996–1003 (1984).

    Article  PubMed  Google Scholar 

  12. Zwaan, B., Bijlmsa, R. & Hoekstra, R.F. Direct selection on life span in Drosophila melanogaster. Evolution 49, 649–659 (1995a).

    Article  PubMed  Google Scholar 

  13. Partridge, L. & Fowler, K. Direct and correlated responses to selection on age at reproduction in Drosophila melanogaster. Evolution 46, 76–91 (1992).

    Article  PubMed  Google Scholar 

  14. Shook, D.R., Brooks, A. & Johnson, T.E. Mapping quantitative trait specifying hermaphrodite survival or self fertility in the nematode Caenorhabditis elegans. Genetics 142, 801–17 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Albin, R.L. Antagonistic pleiotropy, mutation accumulation, and human genetic disease. in Genetics and Evolution of Aging.(Eds Rose, M.R. & Finch, C.E.) 307–314 (Kluwer Academic Publishers, Amsterdam, 1994).

    Chapter  Google Scholar 

  16. Finch, C.E. & Rose, M.R. Hormones and the physiological architecture of life history evolution. Q. Rev. Biol. 70, 1–52 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Kirkwood, T.B.L. The disposable soma theory of aging. in Genetic Effects on Aging II(ed.Harrison, D.E.) 9–19 (Telford Press, Caldwell, NJ, 1990).

    Google Scholar 

  18. Wilding, G. Endocrine control of prostate cancer. Cancer Surv. 23, 43–62 (1995).

    CAS  PubMed  Google Scholar 

  19. Adams, M.R., Williams, J.K. & Kaplan, J.R. Effects of androgens on coronary artery aterosclerosis and atherosclerosis-related impairment of vascular responsiveness. Arterioscl. Thromb. Vasc. Biol. 15, 562–570 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Grossman, C.J. Interactions between the gonadal steroids and the immune system. Science 227, 257–261 (1985).

    Article  CAS  PubMed  Google Scholar 

  21. Cerami, A. Hypothesis: glucose as a mediator of aging. J. Am. Geriatr. Soc. 33, 626–634 (1985).

    Article  CAS  PubMed  Google Scholar 

  22. Monnier, V.M., Sell, D.R., Ramanakoppa, J. & S. Miyata, Mechanisms of protection against damage mediated by the Maillard reaction in aging. Gerontol. 37, 152–165 (1991).

    Article  CAS  Google Scholar 

  23. Dickman, C.R. & Braithwaite, R.W. Postmating mortality of males in the dasyurid marsupials, Dasyurus and Parantechinus. J. Mamm. 73, 143–147 (1992).

    Article  Google Scholar 

  24. Austad, S.N. Retarded senescence in an insular population of Virginia (Didelphis virginiana) opossums. J. Zool. Lond. 229, 695–708 (1993).

    Article  Google Scholar 

  25. Kenyon, C. Ponce d-elegans: genetic quest for the fountain of youth. Cell. 84, 501–504 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Kirkwood, T.B.L. & Cremer, T. Cytogerontology since 1881: a reappraisal of August Weismann and a review of modern progress. Hum. Genet. 60, 101–121 (1982).

    Article  CAS  PubMed  Google Scholar 

  27. Rothstein, M. Biochemical Approaches to Aging. (Academic Press, New York, 1982).

    Google Scholar 

  28. Van Remmen, H., Ward, W.F., Sabia, R.V. & Richardson, A. Gene expression and protein degradation. in Handbook of Physiology (ed Masoro, E.J.) 171–234 (Oxford University Press, New York, 1995).

  29. Swisshelm, K., Disteche, C.M., Thorvaldsen, J., Nelson, A. & Salk, D. Age-related increase in methylation of ribosomal genes and inactivation of chromosome-specific rRNA gene clusters in mouse. Mutat. Res. 237, 131–146 (1990).

    Article  CAS  PubMed  Google Scholar 

  30. Sell, D.R. & Monnier, V.M. Aging of long-lived proteins: extracellular matrix (collagens, elastins, proteoglycans) and lens crystallins. in Aging (ed. Masoro, E.J.) (Oxford University Press, New York, 1995).

  31. Harman, D. Free-radical theory of aging: increasing the functional life span. Ann. NY Acad. Sci. 717, 1–15 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Swartz, H.M. & Mäder, K. Free radicals in aging: theories, facts, and artifacts. in Molecular Aspects of Aging (eds Esser, K. & Martin, G.M.) (John Wiley & Sons Ltd., Chichester, England, 1995).

    Google Scholar 

  33. Stadtman, E.R. Protein oxidation and aging. Science 267, 1220–1224 (1992).

    Article  Google Scholar 

  34. Newcomb, T.G. & Loeb, L.A. Oxidative DNA damage and mutagenesis. in DNA Damage and Repair (eds Nickoloff, J. & Hoekstra, M.) (Human Press, Totowa, New Jersey, 1996).

    Google Scholar 

  35. Shigenaga, M.K., Hagen, T.M. & Ames, B.N. Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA 91, 10771–10778 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Griffiths, A.J.F. Fungal senescence. Annu. Rev. Genet. 26, 351–372 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Osiewacz, H.D. Aging and genetic instabilities. in Molecular Aspects of Aging (eds Esser, K & Martin, G. M.) 29–44 (John Wiley and Sons, Chichester, 1995).

    Google Scholar 

  38. Jazwinski, S.M., Handbook of the Biology of Aging, 4th edn. (eds Rowe,J. W. & Schneider, E. L.) 39–54 (Academic Press, New York, 1996).

    Google Scholar 

  39. Munkres, K.D., Genetic coregulation of longevity and antioxienzymes in Neurospora crassa. Free Rad. Biol. Med. 8, 355–361 (1990).

    Article  CAS  PubMed  Google Scholar 

  40. Kennedy, B.K., Austriaco, N.R.,Jr, Zhang, J. & Guarente, L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell. 80, 485–496 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. D'Mello, N.P. et al. Cloning and characterization of LAG1, a longevity-assurance gene in yeast. J. Biol. Chem. 269, 15451–15459 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Jazwinski, S.M. The genetics of aging in the yeast Saccharomyces cerevisiae. Genetica. 91, 35–51 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Sun, J., Kale, S.P., Childress, A.M., Pinswasdi, C. & Jazwinski, S.M. Divergent roles of RAS1 and RAS2 in yeast longevity. J. Biol. Chem. 269, 18638–18645 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Kale, S.P. & Jazwinski, S.M. Differential response to UV stress and DNA damage during the yeast replicative life span. Dev. Genet. (in the press).

  45. Bertrand, H. Senescence is coupled to induction of an oxidative phosphorylation stress response by mitochondrial MA mutations in Neurospora. Can. J. Bot. 73, S198–S204 (1995).

    Article  CAS  Google Scholar 

  46. Munkres, K.D. & Furtek, C. A. Selection of conidial longevity mutants of Neurospora crassa.Mech. Ageing Dev. 25, 47–62 (1984).

    Article  CAS  PubMed  Google Scholar 

  47. Munkres, K.D. Selection and analysis of superoxide dismutase mutants of Neurospora. Free Rad. Biol. Med. 13, 305–318 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Longo, V.D., Gralla, E.B. & Valentine, J.S. Superoxide dismutase activity is essential for respiratory growth and stationary phase survival in Saccharomyces cerevisiae: in vivo mitochondrial production of toxic oxygen species under normal aeration. J. Biol. Chem. (in the press).

  49. Wood, W.B. The Biology of Caenorhabditis elegans (Cold Spring Harbor Press, Cold Spring Harbor, New York, 1988).

  50. Lithgow, G.J. in Handbook of the Biology of Aging, 4th Edn. (eds Rowe, J. W. & Schneider, E. L.) 55–73 (Academic Press, New York, 1996).

    Google Scholar 

  51. Johnson, T.E. & Hutchinson, E.W. Absence of strong heterosis for life span and other life history traits in Caenorhabditis elegans. Genetics 134, 465–474 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Friedman, D.B. & Johnson, T.E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Friedman, D.B. & Johnson, T.E. Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J. Gerontol. Bio. Sci. 43, B102–B109 (1988).

    Article  CAS  Google Scholar 

  54. Lithgow, G.J., White, T.M., Melov, S. & Johnson, T.E. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc. Natl. Acad. Sci. USA 92, 7540–7544 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Larsen, P.L. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 90, 8905–8909 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vanfleteren, J.R. Oxidative stress and ageing in Caenorhabditis elegans. Biochem J. 292, 605–608 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Murakami, S. & Johnson, T.E. A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics (in the press).

  58. Jurkiewicz, B.A. & Buettner, G.R. Ultraviolet light-induced free radical formation in skin: An electron paramagnetic resonance study. Photochem. PhotoBiol. 59, 1–4 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Godar, D.E., Thomas, D.P., Miller, S.A. & Lee, W. Long-wave length UVA radiation induced oxidative stress, cytoskeletal damage and hemolysis. Photochem. PhotoBiol. 57, 1018–1026 (1993).

    Article  CAS  PubMed  Google Scholar 

  60. Johnson, T.E. The increased life span of age-1 mutants in Caenorhabditis elegans results from lowering the Gompertz rate of aging. Science 249, 908–12 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. Duhon, S.A. & Johnson, T.E. Movement as an index of vitality: comparing wild type and the age-1 mutant of Caenorhabditis elegans. J. Gerontol. Biol. Sci. 50, B254–B261 (1995).

    Article  CAS  Google Scholar 

  62. Vanfleteren, J.F. & DeVreese, A. The gerontogenes age-1 and daf-2 determine metabolic rate potential in aging Caenorhabditis elegans. FASEB. J. 9, 1355–1361 (1996).

    Article  Google Scholar 

  63. Melov, S., Lithgow, G.J., Fischer, D.R., Tedesco, P.M. & Johnson, T.E. Increased frequency of deletions in the mitochondrial genome with age of Caenorhabditis elegans. Nucl. Acids Res. 23, 1419–1425 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Riddle, D. The dauer larva, in The Nematode Caenorhabditis elegans. (ed. Wood, W. B.) 393–412 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1988).

  65. Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C.elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

    Article  CAS  PubMed  Google Scholar 

  66. Larsen, P.L., Albert, P.S. & Riddle, D.L. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139, 1567–1583 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wong, A., Boutis, P. & Hekimi, S. Mutations in the clk-1 gene of Caenorhabditis elegans_affect developmental and behavioral timing. Genetics 139, 1247–1259 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Van Voorhies, W.A. Production of sperm reduces nematode lifespan. Nature 360, 456–458 (1992).

    Article  CAS  PubMed  Google Scholar 

  69. Gems, D. & Riddle, D.R. Longevity in Caenorhabditis elegans reduced by mating but not gamete production. Nature 379, 723–25 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Ebert, R.H. et al. Longevity-determining genes in Caenorhabditis elegans: chromosomal mapping of multiple noninteractive loci. Genetics 135, 1003–1010 (1993).

    Article  CAS  PubMed  Google Scholar 

  71. Wattiaux, J.M. Cumulative parental effects in Drosophila subobscura. Evolution 22, 406–421 (1968).

    Article  CAS  PubMed  Google Scholar 

  72. Wattiaux, J.M. Parental age effects in Drosophila pseudoobscura. Exp. Gerontol. 3, 55–61 (1968b).

    Article  CAS  PubMed  Google Scholar 

  73. Service, P.M., Hutchinson, E.W., MacKinley, M.D. & Rose, M.R. Resistance to environmental stress in Drosophila melanogaster selected for postponed senescence. Physiol. Zool. 58, 380–389 (1985).

    Article  Google Scholar 

  74. Service, P.M. Physiological mechanisms of increased stress resistance in Drosophila melanogaster. Physiol. Zool. 60, 321–326 (1987).

    Article  Google Scholar 

  75. Arking, R., Buck, S., Berrios, A., Dwyer, S. & Baker, G.T. Elevated paraquat resistance can be used as a bioassay for longevity in a genetically based long-lived strain of Drosophila. Dev. Genet. 12, 362–370 (1991).

    Article  CAS  PubMed  Google Scholar 

  76. Rose, M.R., Vu, L.N., Park, S.U. & Graves, J.L. Jr., Selection on stress resistance increases longevity in Drosophila melanogaster. Exp. Gerontol. 27, 241–250 (1992).

    Article  CAS  PubMed  Google Scholar 

  77. Hillesheim, E. & Stearns, S.C. Correlated responses in life-history traits to artificial selection for body weight in Drosophila melanogaster. Evolution 46, 745–752 (1992).

    Article  PubMed  Google Scholar 

  78. Zwaan, B., Bujlsma, R. & Hoekstra, R.F. Artificial selection for developmental time in Drosophila melanogaster in relation to the evolution of aging: direct and correlated responses. Evolution 49, 635–648 (1995).

    Article  PubMed  Google Scholar 

  79. Buck, S., Wells, R.A., Dudas, S.R., Baker, G.T. & Arking, R. Chromosomal localization and regulation of the longevity determinant genes in a selected strain of Drosophila melanogaster. Heredity 71, 11–22 (1993).

    Article  PubMed  Google Scholar 

  80. Dudas, S.P. & Arking, R. A coordinate upregulation of antioxidant gene activities is associated with the delayed onset of senescence in a long-lived strain of Drosophila. J. Gerontol. Biol. Sci. 50A, B117–B127 (1995).

    Article  CAS  Google Scholar 

  81. Johnson, T.E., Lithgow, G.J., Murakami, S., Duhon, S.A. & Shook, D.R. Genetics of aging and longevity in lower organisms. in Cellular Aging and Cell Death (eds Holbrook, N. & Martin, G. R.) 1–17 (John Wiley and Sons, NY, 1996).

    Google Scholar 

  82. Hutchinson, E.W. & Rose, M.R. Quantitative genetic analysis of postponed aging in Drosophila melanogaster. in Genetic Effects of Aging II. (ed. Harrison, D.L.) 65–85 felford Press, Caldwell, NJ, 1990).

  83. Fleming, J.E., Spicer, G.S., Garrison, R.C. & Rose, M.R. Two-dimensional protein electrophoretic analysis of postponed aging in Drosophila. Genetica 91, 183–198 (1993).

    Article  CAS  PubMed  Google Scholar 

  84. Clare, M.J. & Luckinbill, L.S. The effects of gene-environment interaction on the expression of longevity. Heredity 55, 19–26 (1985).

    Article  PubMed  Google Scholar 

  85. Service, P.M., Hutchinson, E.W. & Rose, M.R. Multiple genetic mechanisms for the evolution of senescence in Drosophila melanogaster. Evolution 42, 708–716 (1988).

    Article  CAS  PubMed  Google Scholar 

  86. Buck, S. et al. Larval regulation of adult longevity in a genetically-selected long-lived strain of Drosophila. Heredity 71, 23–32 (1993).

    Article  PubMed  Google Scholar 

  87. Hilliker, A.J., Dufy, B., Evans, D. & Phillips, J.P. Urate-null rosy mutants of Drosophila melanogaster are hypersensitive to oxygen stress. Proc. Natl. Acad. Sci. USA 89, 4343–4347 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Griswold, C.M., Matthews, A.L., Bewley, K.E. & Mahaffey, J.W. Molecular characterization and rescue of acatalasemic mutants of Drosophila melanogaster. Genetics 134, 781–788 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Orr, W.C. & Sohal, R.C. Extension of life span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263, 1128–1130 (1994).

    Article  CAS  PubMed  Google Scholar 

  90. Orr, W.C. & Sohal, R.C. The effects of catalase gene overexpression on life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch. Biochem. Biophys. 297, 35–41 (1992).

    Article  CAS  PubMed  Google Scholar 

  91. Orr, W.C. & Sohal, R.C. Effects of Cu-Zn superoxide dismutase overexpression on life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch. Biochem. Biophys. 301, 34–40 (1993).

    Article  CAS  PubMed  Google Scholar 

  92. Masoro, E.J. FRAR course on laboratory approaches to aging. Nutrition, including diet restriction, in mammals. Aging. 5, 269–275 (1993).

    CAS  PubMed  Google Scholar 

  93. Gelman, R., Watson, A., Bronson, R. & Yunis, E. Murine chromosomal regions correlated with longevity. Genetics 118, 693–704 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Covelli, V. et al. Inheritance of immune responsiveness, life span, and disease incidence in interline crosses of mice selected for high or low multispecific antibody production. J. Immunol. 142, 1224–1234 (1989).

    CAS  PubMed  Google Scholar 

  95. Puel, A., Groot, P.C., Lathrop, M.G., Demant, P. & Mouton, D. Mapping of genes controlling quantitative antibody production in Biozzi mice. J. Immunol. 154, 5799–5805 (1995).

    CAS  PubMed  Google Scholar 

  96. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. Mote, P.L., Grizzle, J.M., Walford, R.L. & Spindler, S.R. Aging alters hepatic expression of insulin receptor and c-jun mRNA in the mouse. Mutat. Res. 256, 7–12 (1991).

    Article  CAS  PubMed  Google Scholar 

  98. Yu, B.P. Antioxidant action of dietary restriction in the aging process. J. Nutr. Sci. Vitaminol. Tokyo. 39, S75–S83 (1993).

    Article  CAS  PubMed  Google Scholar 

  99. Sohal, R.S., Ku, H.H., Agarwal, S., Forster, M.J. & Lal, H. Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech. Ageing Dev. 74, 121–133 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Sohal, R.S., Agarwal, S., Candas, M., Forster, M.J. & Lal, H. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech. Ageing Dev. 76, 215–224 (1994).

    Article  CAS  PubMed  Google Scholar 

  101. Hass, B.S., Hart, R.W., Lu, M.H. & Lyn-Cook, B.D. Effects of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vitro. Mutat. Res. 295, 281–289 (1993).

    Article  CAS  PubMed  Google Scholar 

  102. Wolf, N.S., Penn, P.E., Jiang, D., Fei, R.G. Pendergrass, W.R. Caloric restriction: conservation of in vivo cellular replicative capacity accompanies life-span extension in mice. Exp. Cell Res. 217, 317–323 (1995).

    Article  CAS  PubMed  Google Scholar 

  103. Chen, Q., Fischer, A., Reagan, J.D., Yan, L.J. & Ames, B.N. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc. Natl. Acad. Sci. USA 92, 4337–4341 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sundaresan, M., Zu-Xi, Y., Ferrans, V.J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    Article  CAS  PubMed  Google Scholar 

  105. Korsmeyer, S.J., Yin, X.M., Oltvai, Z.N., Veis-Novack, D.J. & Linette, G.P. Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family. Biochem. Biophys. Acta 1271, 63–66 (1995).

    PubMed  Google Scholar 

  106. Farlie, P.G., Dringen, R., Rees, S.M., Kannourakis, G. & .bcl-2 transgene expression can protect neurons against developmental and induced cell death. Proc. Natl. Acad. Sci. USA 92, 4397–4401 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Czech, C., Masters, C. & Beyreuther, K. Alzheimer's disease and transgenic mice. J. Neural Transm. Suppl. 44, 219–230 (1994).

    CAS  PubMed  Google Scholar 

  108. Hsiao, K.K., Loh, J., Nilsen, S. & Johannsdottir, R. Strain dependence of longevity and behavior in transgenic mice expressing mutant Alzheimer amyloid precursor protein. Soc. Neurosci. 21, 257 (1995).

    Google Scholar 

  109. Games, D. et. al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373, 523–527 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. LaFerla, F.M., Tinkle, B.T., Bieberich, C.J., Haudenschild, C.C. & Jay, G., Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nature Genet. 9, 21–30 (1995).

    Article  CAS  PubMed  Google Scholar 

  111. Hensley, K. et al. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc. Nail. Acad. Sci. USA 91, 3270–3274 (1994).

    Article  CAS  Google Scholar 

  112. Butterfield, D.A., Hensley, K., Harris, M., Mattson, M. & Carney, J. . β-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem. Biophys. Res. Comm. 200, 710–715 (1994).

    Article  CAS  PubMed  Google Scholar 

  113. The SAM Model of Senescence, in Proceedings of the First International Conference on Senescence (ed. Takeda, T.) (Excerpta Medica, Amsterdam, 1994).

  114. Kitado, H., Higuchi, K. & Takeda, T. Molecular genetic characterization of the senescence-accelerated mouse (SAM) strains. J. Gerontol. 49, B247–254 (1994).

    Article  CAS  PubMed  Google Scholar 

  115. Teramoto, S., Fukuchi, Y., Uejima, Y., Ito, H. & Orimo, H. Age-related changes in GSH content of eyes in mice — a comparison of senescence-accelerated mouse (SAM) and C57BL/J mice. Comp. Biochem. Physiol. 102, 693–696 (1992).

    Article  CAS  Google Scholar 

  116. Uejima, Y., Fukuchi, Y, Teramoto, S., Tabata, R. & Orimo, H. Age changes in visceral content of glutathione in the senescence accelerated mouse (SAM). Mech. Ageing Dev. 67, 129–139 (1993).

    Article  CAS  PubMed  Google Scholar 

  117. Liu, J. & Mori, A. Age-associated changes in superoxide dismutase activity, thiobarbituric acid reactivity and reduced glutathione level in the brain and liver in senescence accelerated mice (SAM): a comparison with ddY mice. Mech. Ageing Devel. 71, 23–30 (1993).

    Article  CAS  Google Scholar 

  118. Teramoto, S., Fukuchi, Y., Uejima, Y., Teramoto, K Orimo, H. Biochemical characteristics of lungs in senescence-accelerated mouse (SAM). Eur. Respir. J. 8, 450–456 (1995).

    Article  CAS  PubMed  Google Scholar 

  119. Martin, G.M. Genetic modulation of the senescent phenotype of Homo sapiens. Exp. Gerontol. 31, 49–59 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Martin, G.M. Genetic syndromes in man with potential relevance to the pathobiology of aging. Birth Defects. 14, 5–39 (1978).

    CAS  PubMed  Google Scholar 

  121. Martin, G.M. Syndromes of accelerated aging. Natl. Cane. Inst. Monogr. 60, 241–247 (1982).

    CAS  Google Scholar 

  122. Rose, M.R. in Evolutionary Biology of Aging. (Oxford University Press, New York, 1991).

  123. Schachter, F. et al. Genetic associations with human longevity at the APOE and ACE loci. Nature Genet. 6, 29–32 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Strittmatter, W.J. & Roses, A.D. Apolipoprotein E and Alzheimer disease. Proc. Natl. Acad. Sci. USA 92, 4725–4727 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Oliver, C.N., Ahn, B.W., Moerman, E.J., Goldstein, S. & Stadtman, E.R. Age-related changes in oxidized proteins. J. Biol. Chem. 262, 5488–5491 (1987).

    Article  CAS  PubMed  Google Scholar 

  126. Cristofalo, V.J. & Pignolo, R.J. Cell culture as a model. in Handbook of Physiology, (ed Masoro, E.J.) 53–82 (Oxford University Press, New York, 1995).

    Google Scholar 

  127. Martin, G.M. Clonal attenuation: causes and consequences. J. Gerontol. 48, 6171–172 (1993).

    Article  Google Scholar 

  128. Oshima, J., Campisi, J., Tannock, T.C.A. & Martin, G.M. Regulation of c-fos expression in senescing Werner syndrome fibroblasts differs from that observed in senescing fibroblasts from normal donors. J. Cell. Physio. 162, 277–283 (1995).

    Article  CAS  Google Scholar 

  129. Schulz, V.P. et al. Accelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells. Hum. Genet, (in the press).

  130. Fukuchi, K., Martin, G.M. & Monnat, R.J.,Jr., Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natl. Acad. Sci. USA 86, 5893–5897 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yu, C.E. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996).

    Article  CAS  PubMed  Google Scholar 

  132. Carney, J.M. et al. Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. Proc. Natl. Acad. Sci. USA 88, 3633–3636 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Schapira, A.H. Oxidative stress in Parkinson's disease. Neuropathol. Appl. 21, 3–9 (1995).

    Article  CAS  Google Scholar 

  134. Beal, M.F., Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol. 38, 357–566 (1995).

    Article  CAS  PubMed  Google Scholar 

  135. Benzi, G. & Moretti, A. Are reactive oxygen species involved in Alzheimer's disease?. Neurobiol. Aging. 16, 661–674 (1995).

    CAS  Google Scholar 

  136. Sagara, Y., Dargusch, R., Klier, F.G., Schubert, D. & Behl, C. Increased antioxidant enzyme activity in amyloid beta protein-resistant cells. J. Neurosci. 16, 497–505 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Thomas, T., Thomas, G., McLendon, C, Sutton, T & Mullan, M. β-amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168–171 (1996).

    Article  CAS  PubMed  Google Scholar 

  138. Wallace, D.C., Shoffner, J.M., Trounce, I. & Brown, M.D. Mitochondrial DNA mutations in human degenerative diseases and aging. Biochem. Biophys. Acta. 1271, 141–151 (1995).

    PubMed  Google Scholar 

  139. Schindler, D. & Hoehn, H. Fanconi anemia mutation causes cellular susceptibility to ambient oxygen. Am. J. Hum. Genet. 43, 429–435 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Degan, P. et al. In vivo accumulation of 8-hydroxy-2′-deoxyguanosine in DNA correlates with release of reactive oxygen species in Fanconi's anaemia families. Carcinogenesis 16, 735–741 (1995).

    Article  CAS  PubMed  Google Scholar 

  141. Bondy, S.C. & Guo, S.X. Effect of ethanol treatment on indices of cumulative oxidative stress. Euro. J. Pharmacol. 270, 349–55 (1994).

    CAS  Google Scholar 

  142. Volm, M., Koomagi, R., Mattern, J. & Stammler, G. Heat shock (hsp70) and resistance proteins in non-small cell lung carcinomas. Cancer Lett. 96, 195–200 (1995).

    Article  Google Scholar 

  143. Carey, J.R., Liedo, P., Orozco, D. Vaupel, J.W. Slowing of mortality rates at older ages in large medfly cohorts. Science 258, 457–461 (1992).

    Article  CAS  PubMed  Google Scholar 

  144. Curtsinger, J.W., Fukui, H.H., Townsend, D.R. & Vaupel, J.W. Demography of genotypes: failure of the limited life-span paradigm in Drosophila melanogaster. Science 268, 461–463 (1992).

    Article  Google Scholar 

  145. Martin, G.M. Genetic and environmental modulations of chromosomal stability: their roles in aging and oncogenesis. Ann. NY Acad. Sci. 621, 401–17 (1991).

    Article  CAS  PubMed  Google Scholar 

  146. Johnson, T.E. & Wood, W.B. Genetic analysis of life-span in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 79, 6603–6607 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Duhon, S.A., Murakami, S. & Johnson, T.E. Direct isolation of longevity mutants in the nematode, Caenorhabditis elegans. Dev. Genet.(in the press).

  148. Graves, J.L., Luckinbill, L.S. & Nichols, A. Flight duration and wing beat frequency in long- and short-lived Drosophila melanogaster. J. Insect Physiol. 34, 1021–1026 (1988).

    Article  Google Scholar 

  149. Graves, J.L., Toolson, E.C., Jeong, C., Vu, L.N. & Rose, M.R. Desiccation, flight, glycogen and postponed senescence in Drosophila melanogaster. Physiol. Zool. 65, 268–286 (1992).

    Article  CAS  Google Scholar 

  150. Ingram, D.K., Weindruch, R., Spangler, E.L., Freeman, J.R. & Walford, R.L. Dietary restriction benefits learning and motor performance of aged mice. J. Gerontol. 42, 78–81 (1987).

    Article  CAS  PubMed  Google Scholar 

  151. Johnson, T.E. Aging can be genetically dissected into component processes using long-lived lines of Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 84, 3777–3781 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Martin, G., Austad, S. & Johnson, T. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 13, 25–34 (1996). https://doi.org/10.1038/ng0596-25

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