Molecular and Biologic Factors in Aging: The Origins, Causes, and Prevention of Senescence

  • George T. BakerIII
  • George R. Martin


Chronologic and biologic aging begin at conception, although senescent changes, defined here as functional declines, are usually apparent only after sexual maturation.1 With time, physiologic decrements become increasingly more common and increasingly compromise health and survival. Particularly notable is a reduced capacity with age to adjust to a variety of everyday stresses, probably due to defects in basic homeostatic mechanisms.2 The rates of aging and the life span for any species are governed by two general features: a genetic component that imparts a species-specific capability to carry out basic biologic processes necessary for life and reproduction and environmental, and lifestyle components that are superimposed on the intrinsic genetic design and can influence the overall rates of aging and susceptibility to disease processes.3


Life Span Caloric Restriction Heat Shock Response Heat Shock Factor Heat Shock Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Finch CE. Longevity, Senescence, and the Genome. Chicago: University of Chicago Press; 1990.Google Scholar
  2. 2.
    Shock NW. Physiological aspects of aging in man. Annu Rev Physiol. 1961; 23: 97–122.CrossRefGoogle Scholar
  3. 3.
    Baker GT III, Shock NW. Theoretical concepts governing gerontological research. In: Ingram DK, Baker GT III, Shock NW, eds. The Potential for Nutritional Modulation of Aging Processes. Trumbull, CT: Food and Nutrition Press; 1991; 3–15.Google Scholar
  4. 4.
    Gompertz B. On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies. Philo Trans R Soc Lond. 1825; 115: 513–585.CrossRefGoogle Scholar
  5. 5.
    Baker GT III, Sprott RL. Biomarkers of aging. Exp Gerontol. 1988; 23: 223–239.PubMedCrossRefGoogle Scholar
  6. 6.
    Hochschild R. Can an index of aging be constructed for evaluating treatments to retard aging rates? A 2,462-person study. J Gerontol. 1990; 45 (6): B187 - B214.PubMedCrossRefGoogle Scholar
  7. 7.
    Balin AK, ed. Practical Handbook of Human Biologic Age Determination. Boca Raton, FL: CRC Press; 1994.Google Scholar
  8. 8.
    Ingram DK, Stoll S, Baker GT III. Is attempting to assess biological age worth the effort? Gerontologist. 1995; 35: 707–710.CrossRefGoogle Scholar
  9. 9.
    Shock NW, Greulich RC, Andres R, et al. Normal Human Aging: The Baltimore Longitudinal Study of Aging. Publ. No. 84–2450. Washington, DC: U.S. Dept. HHS, Public Health Service, National Institutes of Health, National Institute on Aging; 1984.Google Scholar
  10. 10.
    Fozard JL, Metter EJ, Brant LJ, et al. Physiology of aging. In: Grafman J, ed. Gerontechnology. Eindhoven University Press; 1993: 141–167.Google Scholar
  11. 11.
    Miller RA. Aging and immune function: cellular and biochemical analysis. Exp Gerontol. 1994;29:21–36.Google Scholar
  12. 12.
    Hearts and Arteries. NIH publication no. 94–3738. Washington, DC: U.S. Dept. HHS, PHS National Institute on Aging, National Institutes of Health; 1994.Google Scholar
  13. 13.
    Rodeheffer RJ, Gerstenblith G, Becker LC, et al. Exercise cardiac output is maintained with advancing age in healthy subjects: cardiac dilation and increased volume compensate for a diminished heart rate. Circulation. 1994; 69: 203–213.CrossRefGoogle Scholar
  14. 14.
    Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol. 1976; 31: 155–163.PubMedCrossRefGoogle Scholar
  15. 15.
    Bergeman CS, Chipuer HM, Plomin R, et al. Genetic and environmental effects on openness to experience, agreeableness, and conscientiousness: an adoption/twin study. J Personality. 1993; 61: 159–179.PubMedCrossRefGoogle Scholar
  16. 16.
    Pearson JD, Morrell CH, Gordan-Salant S, et al. Gender differences in a longitudinal study of age associated hearing loss. J Acoust Soc Am. 1995; 97: 1196–1205.PubMedCrossRefGoogle Scholar
  17. 17.
    Ship JA, Weiffenbach JM. Age, gender, medical treatment, and medication effects on smell identification. J Gerontol. 1993; 48: M26–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Ship JA, Pearson JD, Cruise LJ, et al. Longitudinal changes in smell identification. J Gerontol. 1996.Google Scholar
  19. 19.
    Weiffenbach JM. Chemical sense in aging. In: Getchell, TC, et al., eds. Smell and Taste in Health and Disease. New York: Raven Press; 1991: 369–379.Google Scholar
  20. 20.
    West S, Vitale S, Halfrisch J, et al. Are antioxidant supplements protective of age related macular degeneration? Arch Ophthamol. 1994; 112: 227–237.Google Scholar
  21. 21.
    Brandt LJ, Gordon-Salant S, Pearson JD, et al. Risk factors related to age-associated hearing loss. J Am Acad Audio. 1996.Google Scholar
  22. 22.
    Ross R. Polypeptide growth factors and atherosclerosis. Trends Cardiovasc Med. 1991; 1: 277–282.PubMedCrossRefGoogle Scholar
  23. 23.
    Olshansky SJ, Carnes BA, Cassel C. In search of Methuselah: estimating the upper limits to human longevity. Science. 1990; 250: 634.PubMedCrossRefGoogle Scholar
  24. 24.
    Abbot MH, Murphy EA, Bolling DR, et al. The familial component in longevity. A study of offspring of nonagenarians. II. Preliminary analysis of the completed study. Johns Hopkins Med J. 1974; 134: 1–16.Google Scholar
  25. 25.
    Jalavisto E. Inheritance of longevity according to Finnish and Swedish genealogies. Ann Med Internae Fenniae. 1951; 40: 263–274.Google Scholar
  26. 26.
    Kallman FJ. Twin data on the genetics of aging. In: Wolstenholme GE, O’Connor CM, eds. Methodology of the Study of Aging. Boston: Little, Brown; 1957: 131–143.Google Scholar
  27. 27.
    Sacher GA. Relation of lifespan to brain weight and body weight in mammals. Ciba Found Colloq Aging. 1959; 5: 115–133.Google Scholar
  28. 28.
    Rubner M. Das Problem der Lebensdauer and seine Beziehungen zum Wachstum and Ernahrung. Munich: Oldenbourg; 1908.Google Scholar
  29. 29.
    Pearl R. The Rate of Living. New York and London: Knopf; 1928.Google Scholar
  30. 30.
    Hart RW, Setlow RB. Correlation between deoxyribonucleic acid excision repair and lifespan in a number of mammalian species. Proc Natl Acad Sci USA. 1974; 71: 2169–2173.PubMedCrossRefGoogle Scholar
  31. 31.
    Harman D. Role of free radicals in mutation, cancer, aging, and maintenance of life. Radiat Res. 1962; 16: 752–763.CrossRefGoogle Scholar
  32. 32.
    Munkres KD. Genetic coregulation of longevity and antioxienzymes in Neurospora carssa. Free Radical Biol Med. 1990; 8: 355–361.CrossRefGoogle Scholar
  33. 33.
    Johnson TE. Age-1 mutants of Caenorhabditis elegans prolong life by modifying the Gompertz rate of aging. Science. 1990; 249: 908–912.Google Scholar
  34. 34.
    Arking R, Dukas SP, Baker GT III. Genetic and environmental factors regulating the expression of an extended longevity phenotype in a long lived strain of Drosophila. Genetics. 1993; 91: 127–142.Google Scholar
  35. 35.
    Orr WC, Sohal RS. Extension of life-span by over expression of super oxide dismutase and catalase in Drosophila melanogaster. Science. 1994; 263: 1128–1130.Google Scholar
  36. 36.
    Ames BN, Shigenaga MK. Oxidants are a major contributor to aging. Ann NY Acad Sci. 1992; 663: 85–96.PubMedCrossRefGoogle Scholar
  37. 37.
    Cortopassi G, Liu Y. Genotypic selection of mitochondrial and oncogenic mutations in human tissue suggests mechanisms of age-related pathophysiology. Mutat Res. 1995; 338 (1–6): 151–159.PubMedGoogle Scholar
  38. 38.
    Cortopassi GA, Shibata D, Soong N-W, et al. A pattern of accumulation of a somatic deletion of mitochondria[DNA in aging tissues. Proc Natl Acad Sci USA. 1992; 89: 73707374.Google Scholar
  39. 39.
    Effros RB, Boucher N, Porter V, et al. Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol. 1994; 29 (6): 601–609.PubMedCrossRefGoogle Scholar
  40. 40.
    Schächter F, Faure-Delanef L, Guénot R, et al. Genetic associations with human longevity at the APO-E and ACE loci. Nature Genet. 1994; 6: 29–32.PubMedCrossRefGoogle Scholar
  41. 41.
    Schächter F, Cohen D, Kirkwood T. Prospects for the genetics of human longevity. Hum Genet. 1993; 91: 519526.Google Scholar
  42. 42.
    Turner TR, Weiss ML. The genetics of longevity in humans. In: Crews DE, Garruto RM, eds. Biological Anthropology and Aging. New York: Oxford University Press; 1994: 76–100.Google Scholar
  43. 43.
    McKusick VA. Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Automosomal Recessive, and X-Linked Phenotypes. 7th ed. Baltimore: Johns Hopkins University Press; 1986.Google Scholar
  44. 44.
    Martin GM, Ogburn CE, Sprague CA. Effects of age on cell division capacity. In: Danon D, Shock NW, Marois M, eds. Aging: A Challenge to Science and Society. New York: Oxford University Press; 1981: 124–135.Google Scholar
  45. 45.
    Robbins JH, Kraemer KH, Lutzner MA, et al. Xeroderma pigmentosum. An inherited disease with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Ann Intern Med. 1974; 80: 211–248.Google Scholar
  46. 46.
    Brown WT, Zebrower M, Kieras FJ. Progeria, a model disease for the study of accelerated aging. In: Woodhead AV, Blackett AD, Hollaender A, eds. Basic Life Sciences. 1984; 35: 375–396.Google Scholar
  47. Strittmeyer WJ, Roses AD. Apolipoprotein E and Alzheimer disease. Proc Natl Acad Sci USA. 1995; 92:4725–4727.Google Scholar
  48. 48.
    Brousseau T, Legrain S, Berr C, et al. Confirmation of the E4 allele of the apolipoprotein E gene as a risk factor for late-onset Alzheimer’s disease. Neurology. 1994; 44: 342–344.Google Scholar
  49. 49.
    Schellenberg GD. Genetic dissection of Alzheimer disease, a heterogeneous disorder. Proc Natl Acad Sci USA. 1995; 92: 8852–8859.CrossRefGoogle Scholar
  50. 50.
    Morrison NA, Qi JC, Takita A, et al. Prediction of bone density from vitamin D receptor alleles. Nature. 1994; 367: 284–289.PubMedCrossRefGoogle Scholar
  51. 51.
    Eisman JA, Morrison NA, Kelly PJ, et al. Genetics of osteoporosis and vitamin D receptor alleles. Calcif Tissue Int. 1995;56(1)S48–49.Google Scholar
  52. 52.
    Howard G, Nguyen T, Morrison N, et al. Genetic influences on bone density: physiological correlates of vitamin D receptor gene alleles in premenopausal women. J Clin Endocrinol Metab. 1995; 80 (9): 2800–2805.PubMedCrossRefGoogle Scholar
  53. 53.
    Hustmyer FG, Peacock M, Huis S, et al. Bone mineral density in relation to polymorphism at the vitamin D receptor gene locus. J Clin Invest. 1994; 94: 2130–2134.PubMedCrossRefGoogle Scholar
  54. 54.
    Medawar PB. Old age and natural death. Mod Q. 1946; 1: 30–56.Google Scholar
  55. 55.
    Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Evolution. 1957; 11: 398–411.CrossRefGoogle Scholar
  56. 56.
    Hamilton WD. The molding of senescence by natural selection. J Theoret Biol. 1966; 12: 12–45.CrossRefGoogle Scholar
  57. 57.
    Rose MR. The Evolutionary Biology of Aging. Oxford: Oxford University Press; 1991.Google Scholar
  58. 58.
    Brooks A, Lithgow GJ, Johnson TE. Mortality rate in a genetically heterogeneous population of Caenorhabditis elegans. Science. 1994; 263: 668–671.Google Scholar
  59. 59.
    Buck S, Nicholoson M, Dudas S, et al. Larval regulation of adult longevity in a genetically-selected long-lived strain of Drosophila. Heredity. 1993; 71: 23–32.CrossRefGoogle Scholar
  60. 60.
    Diamond TB. Why do disused proteins become genetically lost or repressed? Nature. 1986; 321: 565–567.PubMedCrossRefGoogle Scholar
  61. 61.
    Kirkwood TB. Comparative evolutionary aspects of longevity. In: Finch CE, Schneider EL, eds. Handbook of the Biology of Aging. 2nd ed. New York: Van Nostrand; 1985: 27–45.Google Scholar
  62. 62.
    Austad SH, Fisher KE. Mammalian aging, metabolism and ecology: evidence from the bats and marsupials. J Gerontol. 1991; 46: B47 - B53.PubMedCrossRefGoogle Scholar
  63. 63.
    Olshansky SJ, Carnes BA, Cassel CK. The aging of the human species. Sci Am. 1993; 268: 46–52.Google Scholar
  64. 64.
    Lee AK, Cockburn A. Evolutionary Ecology of Marsupials. New York: Cambridge University Press; 1985.CrossRefGoogle Scholar
  65. 65.
    Robertson OH. Prolongation of the lifespan of kokanee salmon (O. nerka kennerlyi) by castration before beginning development. Proc Natl Acad Sci USA. 1961; 47: 609–621.PubMedCrossRefGoogle Scholar
  66. 66.
    Moore GH. Aetiology of the Die-Off of Male Antechinus stuartii. Canberra: Australian National University, Thesis 1974.Google Scholar
  67. 67.
    Diamond JM. Big-bang reproduction and aging in male marsupial mice. Nature. 1982;298:115–116.Google Scholar
  68. 68.
    Wodinsky J. Hormonal inhibition of feeding of death in octopus. Control by optic gland secretion. Science. 1977; 198: 948–951.PubMedCrossRefGoogle Scholar
  69. 69.
    Rowe JW, Kahn RL. Human aging: usual and successful. Science. 1987; 237: 143–149.PubMedCrossRefGoogle Scholar
  70. 70.
    McGinnis JM, Foege WH. Actual causes of death in the United States. JA MA. 1993; 270: 2207–2211.Google Scholar
  71. 71.
    Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607.Google Scholar
  72. 72.
    Broughton DL, Taylor R. Deterioration of glucose tolerance with age: the role of insulin resistance. Age Ageing. 1991; 20: 221–225.PubMedCrossRefGoogle Scholar
  73. 73.
    Shimokata H, Muller DC, Fleg JL, et al. Age: an independent determinant of glucose tolerance. Diabetes. 1991; 40: 44–51.PubMedCrossRefGoogle Scholar
  74. 74.
    Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995; 75: 473–486.PubMedGoogle Scholar
  75. 75.
    Muller DC, Elahi D, Tobin JD, et al. Insulin response during the oral glucose tolerance test: the role of age, sex, body fat, and the pattern of fat distribution. 1996; Aging-Clin Exp. 8: 13–21.Google Scholar
  76. 76.
    Lakatta EG. Myocardial adaptations in advanced age. Basic Res Cardiol. 1993; 88 (2): 125–133.PubMedGoogle Scholar
  77. 77.
    Vaitkevicius PV, Fleg JL, Engel JH, et al. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation. 1993; 88: 1456–1462.PubMedCrossRefGoogle Scholar
  78. 78.
    Pauly RR, Passaniti A, Crow M, et al. Experimental models that mimic the differentiation and dedifferentiation of vascular cells. Circulation. 1992; 86 (suppl III): 68–73.Google Scholar
  79. 79.
    Smith DWE. Human Longevity. New York: Oxford University Press; 1993.Google Scholar
  80. 80.
    Samaan SA, Crawford MH. Estrogen and cardiovascular function after menopause. J Am Coll Cardiol. 1995; 26 (6): 1403–1410.PubMedCrossRefGoogle Scholar
  81. 81.
    Baker GT III, Jacobson M, Mokrynski G. Aging in Drosophila. In: Cristofalo VJ, ed. Handbook of Cell Biology of Aging. Boca Raton, FL: CRC Press; 1985: 511–578.Google Scholar
  82. 82.
    Carey JR, Leido P, Orozco D, et al. Slowing of mortality rates at older ages in large medfly cohorts. Science. 1992; 258: 457–461.PubMedCrossRefGoogle Scholar
  83. 83.
    Carey JR, Liedo P. Sex mortality differentials and selective survival in large medfly cohorts: implications for human sex mortality differentials. Gerontologist. 1995; 35 (5): 588–596.PubMedCrossRefGoogle Scholar
  84. 84.
    Adelman RC, Roth GS, eds. Testing the Theories of Aging. Boca Raton, FL: CRC Press; 1982.Google Scholar
  85. 85.
    Medvedev ZA. An attempt at a rational classification of theories of aging. Biol Rev. 1990; 65: 375–398.PubMedCrossRefGoogle Scholar
  86. 86.
    Ames BN. Endogenous DNA damage as related to nutrition and aging. In: Ingram DK, Baker GT III, Shock NW, eds. The Potential for Nutritional Modulation of Aging Processes. Trumbull, CT: Food and Nutrition Press; 1991: 251–261.Google Scholar
  87. 87.
    Stadtman ER. Protein oxidation and aging. Science. 1992; 257: 1220–1224.PubMedCrossRefGoogle Scholar
  88. 88.
    Cerami A. Hypothesis: glucose as a mediator of aging. J Am Geriatr Soc. 1985; 33: 626–634.PubMedGoogle Scholar
  89. 89.
    Martin GR, Danner DB, Holbrook NJ. Aging-causes and defense. Annu Rev Med. 1993; 44: 419–429.PubMedCrossRefGoogle Scholar
  90. 90.
    Szilard L. On the nature of the aging process. Proc Natl Acad Sci USA. 1959; 45: 43–54.CrossRefGoogle Scholar
  91. 91.
    National Center for Health Statistics. Advance Report of Final Mortality Statistics-1990. Hyattsville, MD: HHS, Monthly Vital Statistics Report; 1993:41(7).Google Scholar
  92. 92.
    Liu Y, Hernandez AM, Shibata D, et al. BCL-2 translocation frequency rises with age in humans. Proc Natl Acad Sci USA. 1994; 91: 8910–8914.PubMedCrossRefGoogle Scholar
  93. 93.
    Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative disease of aging. Proc Natl Acad Sci USA. 1993; 90: 7951–7922.CrossRefGoogle Scholar
  94. 94.
    Tice RR, Setlow RB. DNA repair and replication in aging organisms and cells. In: Finch CE, Schneider EL, eds. Handbook of the Biology of Aging. New York: Von Nostrand Reinhold; 1985: 173.Google Scholar
  95. 95.
    Bohr VA, Anson RM. DNA damage, mutation and fine structure DNA repair in aging. Mutat Res. 1995; 338: 25–34.PubMedCrossRefGoogle Scholar
  96. 96.
    Liebermann DA, Hoffman B, Steinman RA. Molecular controls of growth arrest and apoptosis: 53-dependent and independent pathways. Oncogene. 1995;11(1):199–210.Google Scholar
  97. 97.
    Canman CE, Chen CY, Lee MH, et al. DNA damage responses: p53 induction, cell cycle perturbations, and apoptosis. Cold Spring Harb Symp Quant Biol. 1994; 59: 277–286.PubMedCrossRefGoogle Scholar
  98. 98.
    Wei Q, Matanoske GM, Farmer MA, et al. DNA repair and aging in basal cell carcinoma: a molecular epidemiology study. Proc Natl Acad Sci USA. 1993; 90: 1614–1618.PubMedCrossRefGoogle Scholar
  99. 99.
    Yu BP. Oxidative damage by free radicals and lipid peroxidation in aging. In: Yu BP, ed. Free Radicals and Aging. Boca Raton, FL: CRC Press; 1993: 57–88.Google Scholar
  100. 100.
    Richter C, Park JW, Ames BN. Normal oxidative damages to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA. 1998; 85: 6465.CrossRefGoogle Scholar
  101. 101.
    Linnane A, Marzuki S, Ozawa T, et al. Mitochondrial DNA mutation as an important contribution to aging and degenerative diseases. Lancet. 1989; 1: 642–645.PubMedCrossRefGoogle Scholar
  102. 102.
    Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative disease? Science. 1992; 256: 628632.Google Scholar
  103. 103.
    Wallace DC. Mitochondrial diseases: genotype versus phenotype. Trends Genet. 1993; 9 (4): 128–133.PubMedCrossRefGoogle Scholar
  104. 104.
    Schoffner JM, Wallace DC. Oxidative phosphorylation and mitrochondrial DNA mutations: diagnosis and treatment. Annu Rev Nutr. 1994; 14: 535–568.CrossRefGoogle Scholar
  105. 105.
    Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol. 1995; 38 (3): 357–366.PubMedCrossRefGoogle Scholar
  106. 106.
    Morase CT, Ricci E, Petruzzella V, et al. Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nature Genet. 1992; 1: 359–367.CrossRefGoogle Scholar
  107. 107.
    LeDoux SP, Wilson GL, Beecham EJ, et al. Repair of mitrochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis. 1992; 13: 1967–1973.PubMedCrossRefGoogle Scholar
  108. 108.
    Mecocci P, MacGarvey U, Kaufman AF, et al. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol. 1993; 34: 609–616.PubMedCrossRefGoogle Scholar
  109. 109.
    Hayakawa M, Hattori H, Sygiyama S, et al. Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts. Biochem Biophys Res Commun. 1992; 189: 979–985.PubMedCrossRefGoogle Scholar
  110. 110.
    Agarwal S, Sohal RJ. DNA oxidative damage and life expectancy in houseflies. Proc Natl Acad Sci USA. 1994; 91: 12332–12335.PubMedCrossRefGoogle Scholar
  111. 111.
    Lee CM, Chung SS, Kaczkowski JM, et al. Multiple mitochondrial DNA deletions associated with age in skeletal muscle of rhesus monkeys. J Gerontol. 1993; 48 (6): B201–205.PubMedCrossRefGoogle Scholar
  112. 112.
    Gadaleta MN, Rinaldi G, Lezza AMS, et al. Mitochondrial DNA copy number and mitrochondrial DNA deletion in adult and senescent rats. Mutat Res. 1992; 275: 181–193.PubMedCrossRefGoogle Scholar
  113. 113.
    Chen X, Simonetti S, DiMauro S, et al. Accumulation of mitrochondrial DNA deletions in organisms with various lifespans. Bull Mol Biol Med. 1993; 18: 57–66.Google Scholar
  114. 114.
    Brossas JY, Barreau E, Courtois Y, et al. Multiple deletions in mitrochondrial DNA are present in senescent mouse brain. Biochem Biophys Res Commun. 1994; 202: 654–669.PubMedCrossRefGoogle Scholar
  115. 115.
    Melov S, Lithgow GJ, Fischer DR, et al. Increased frequency of deletions in the mitochondrial genome with age of Caenorhabditis elegans. Nucleic Acids Res. 1995; 23 (8): 1419–1425.PubMedCrossRefGoogle Scholar
  116. 116.
    Takasawa M, Hayakawa M, Sugiyama S, et al. Age-associated damage in mitochondrial function in rat hearts. Exp Gerontol. 1993; 28: 269–280.PubMedCrossRefGoogle Scholar
  117. 117.
    Hattori K, Tanaka M, Sugiyama S, et al. Age-dependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. Am Heart J. 1991; 121: 1735–1742.PubMedCrossRefGoogle Scholar
  118. 118.
    Corral-Debrinski M, Horton T, Lott MT, et al. Mitochondrial deletions in human brain: regional variability and increase with advancing age. Nature Genet. 1992; 2 (4): 324–329.PubMedCrossRefGoogle Scholar
  119. 119.
    Randerath K, Randerath E, Filburn C. Genomic and mitochondrial DNA alterations with aging. In: Schneider EL, Rowe JW, eds. Handbook of the Biology of Aging, 4th ed. New York: Academic Press; 1996.Google Scholar
  120. 120.
    Yen T-C, King K-L, Lee HC, et al. Age-dependent increase of mitochondrial DNA deletions together with lipid peroxides and superoxide dismutase in human liver mitochondria. Free Radic Biol Med. 1994; 16: 207–214.PubMedCrossRefGoogle Scholar
  121. 121.
    Higami Y, Shimokawa I, Okimoto T, et al. Vulnerability to oxygen radicals is more important than impaired repair in hepatocytic deoxyribonucleic acid damage in aging. Lab Invest. 1994; 71: 650–656.PubMedGoogle Scholar
  122. 122.
    Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med. 1995; 48: 223–234.CrossRefGoogle Scholar
  123. 123.
    Masoro EJ, Katz MS, McMahan CA. Evidence for the glycation theory of aging from the food restricted rodent model. J Gerontol Biol Sci. 1989; 44: B20 - B22.CrossRefGoogle Scholar
  124. 124.
    Miyata S, Monnier V. Immunohistochemical detection of advanced glycosylation end products in diabetic tissues using monoclonal antibody to pyrroline. J Clin Invest. 1992; 89 (4): 1102–1112.PubMedCrossRefGoogle Scholar
  125. 125.
    Monnier VM, Vishwanath V, Frank KE, et al. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci USA. 1984; 81: 583–587.PubMedCrossRefGoogle Scholar
  126. 126.
    Hasaegawa G, Hunter AJ, Charonis AS. Matrix nonenzymatic glycosylation leads to altered cellular phenotype and intracellular tyrosine phosphorylation. J Biol Chem. 1995; 270 (7): 3278–3283.CrossRefGoogle Scholar
  127. 127.
    Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycoylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest. 1994; 70 (2): 138–151.PubMedGoogle Scholar
  128. 128.
    Schmidt AM, Hori O, Brett J, et al. Cellular receptors for advanced glycation end product. Implication for induction of oxidant stress and cellular dysfunctions in the pathogenesis of vascular lesion. Arterio Thromb. 1994;14(10):15211528.Google Scholar
  129. 129.
    Sell RS, Lane MA, Johnson WA, et al. Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proc Natl Acad Sci USA. 1996; 93: 485–490.PubMedCrossRefGoogle Scholar
  130. 130.
    Baker GT III. Effects of various antioxidants on aging in Drosophila. Toxicol Industrial Health. 1993; 9 (1/2): 163–186.Google Scholar
  131. 131.
    Camhi SL, Lee P, Choi AM. The oxidative stress response. New Horiz. 1995; 3 (2): 170–182.PubMedGoogle Scholar
  132. 132.
    Schenk H, Klein M, Erdbrugger W, et al. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kB and AP-1. Proc Natl Acad Sci USA. 1994; 91: 1672–1676.PubMedCrossRefGoogle Scholar
  133. 133.
    Pacifici RE, Davies KJA. Protein, lipid, and DNA repair systems in oxidative stress: the free-radical theory of aging revisited. Gerontology. 1991; 37: 166–180.PubMedCrossRefGoogle Scholar
  134. 134.
    Azhar S, Cao L, Reaven E. Alteration of the adrenal antioxidant defense system during aging in rats. J Clin Invest. 1995; 96: 1414–1424.PubMedCrossRefGoogle Scholar
  135. 135.
    Holbrook NJ, Liu Y, Fornace AJ. Signaling events controlling the molecular response to genotoxic stress. In: Feigen Y, Morimoto RI, Yahara I, Poila BS, eds. Stress Induced Cellular Responses. New York: Springer; 1996.Google Scholar
  136. 136.
    Sarge KD, Murphy SP, Morimoto RI. Activation of heat shock gene transcription by heat shock factor 1 involves oligomerization, acquisition of DNA-binding activity, and nuclear localization and can occur in the absence of stress. Mol Cell Biol. 1993; 13 (5): 3122–3133.Google Scholar
  137. 137.
    Fawcett TW, Sylvester SL, Sarge KD, et al. Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1. J Biol Chem. 1994; 269 (51): 32272–32278.PubMedGoogle Scholar
  138. 138.
    Blake MJ, Udelsman R, Feulner GJ, et al. Stress-induced HSP70 expression in adrenal cortex: a glucocorticoid sensitive, age-dependent response. Proc Natl Acad Sci USA. 1991; 88: 9873–9877.PubMedCrossRefGoogle Scholar
  139. 139.
    Udelsman R, Blake MJ, Stagg CA, et al. Vascular heat shock protein expression in response to stress: endrocrine and autonomic regulation of this age-dependent response. J Clin Invest. 1993; 91: 465–473.PubMedCrossRefGoogle Scholar
  140. 140.
    Liu AC, Lin Z, Choi HS, et al. Attenuated induction of heat shock gene expression in aging diploid fibroblast. J Biol Chem. 1989; 264: 12037–12045.PubMedGoogle Scholar
  141. 141.
    Liu Y, Gorospe M, Yang C, Holbrook NJ. Role of mitogen-activated protein kinase phosphatase during the cellular response to genotoxic stress. Inhibition of c-jun N-terminal activity and AP-1-dependent gene activation. J Biol Chem. 1995; 270 (15): 8377–8380.PubMedCrossRefGoogle Scholar
  142. 142.
    Mivechi NF, Giaccia AJ. Mitogen-activated protein kinase acts as a negative regulator of the heat shock response in NIH3T3 cells. Cancer Res. 1995;55(23):5512–5519.Google Scholar
  143. 143.
    Stein GH, Dulic V. Origins of G1 arrest in senescent human fibroblasts. Bioessays. 1995; 17 (6): 537–543.PubMedCrossRefGoogle Scholar
  144. 144.
    Waldman T, Kinzler KW, Vogelstein B. P21 is necessary for the p53 mediated G1 arrest in human cancer cells. Cancer Res. 1995; 55: 5187–5190.PubMedGoogle Scholar
  145. 145.
    Ling CC, Guo M, Chen CH, et al. Radiation-induced apoptosis: effects of cell age and dose fractionation. Cancer Res. 1995;55(22):5207–5212.Google Scholar
  146. 146.
    Hayflick L, Moorehead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961; 25: 585–621.PubMedCrossRefGoogle Scholar
  147. 147.
    Hayflick L. Aging, longevity, and immortality in vitro. Exp Gerontol. 1992; 27: 363–374.PubMedCrossRefGoogle Scholar
  148. 148.
    Cristofalo VJ. The destiny of cells: mechanisms and implications of senescence. Gerontologist. 1985; 25: 577–583.PubMedCrossRefGoogle Scholar
  149. 149.
    Cristofalo VJ, Pingolo RJ. Replicative senescence of human fibroblast-like cells in culture. Physiol Rev. 1993; 72: 617–638.Google Scholar
  150. 150.
    Martin GM. Genetic and environmental modulations of chromosomal stability: their roles in aging and oncogenesis. Ann NY Acad Sci. 1991; 621: 401–417.PubMedCrossRefGoogle Scholar
  151. 151.
    McCormick A, Campisi J. Cellular aging and senescence. Curr Opinion Cell Biol. 1991; 3: 230–234.PubMedCrossRefGoogle Scholar
  152. 152.
    Ning Y, Pereira-Smith OM. Molecular genetic approaches to the study of cellular senescence. Mutat Res. 1991; 256: 303–310.PubMedCrossRefGoogle Scholar
  153. 153.
    Harley CB, Futcher AB, Greider CW. Telomeres shorten during aging of human fibroblasts. Nature. 1990; 345: 458–460.PubMedCrossRefGoogle Scholar
  154. 154.
    Greider CW. Mammalian telomere dynamics: healing, fragmentation shortening and stabilization. Curr Opinion Genet Dev. 1994; 4 (2): 203–211.CrossRefGoogle Scholar
  155. 155.
    Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991; 256: 1271–1282.Google Scholar
  156. 156.
    Allsopp RC, Harley CB. Evidence for a critical telomere length in senescent human fibroblast. Exp Cell Res. 1995;219(4130–139.Google Scholar
  157. 157.
    Noda A, Ning Y, Venable SF, et al. Cloning of senescent cell-derived inhibitors of DNA synthesis. Exp Cell Res. 1994; 211 (1): 90–98.PubMedCrossRefGoogle Scholar
  158. 158.
    el-Delry WS, Tokino T, Velculescu VE, et al. WAP1, a potential mediator of p53 tumor suppression. Cell. 1993; 75 (4): 816–825.Google Scholar
  159. 159.
    Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Clpl is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993; 75 (4): 805–816.PubMedCrossRefGoogle Scholar
  160. 160.
    Orrenius S. Apoptosis: molecular mechanisms and implications for human disease. J Intern Med. 1995; 237: 529–536.PubMedCrossRefGoogle Scholar
  161. 161.
    Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995; 267: 1456–1462.PubMedCrossRefGoogle Scholar
  162. 162.
    Slater AF, Nobel CS, Orrenius S. The role of intracellular oxidants in apoptosis. Biochim Biophys Acta. 1995; 271 (1): 59–62.Google Scholar
  163. 163.
    Martin DP, Schmidt RE, DeStefano PS, et al. Inhibitors of protein and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J Cell Biol. 1991; 106: 829–844.CrossRefGoogle Scholar
  164. 164.
    English HF, Kyprianou N, Isaacs JT. Relationship between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration. Prostrate. 1989; 15: 233–250.CrossRefGoogle Scholar
  165. 165.
    Eastman A. Assays for DNA fragmentation, endonucleases, and intracellular pH and Cap’ associated with apoptosis. Methods Cell Biol. 1995; 48: 41–55.CrossRefGoogle Scholar
  166. 166.
    Nicholson DW, Ambereen A, Thornberry NA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995; 376: 37–43.PubMedCrossRefGoogle Scholar
  167. 167.
    Xia Z, Dickens M, Raingeaud J, Davis RJ, et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995; 270 (5240): 1326–1331.PubMedCrossRefGoogle Scholar
  168. 168.
    Williams GT, Smith CA. Molecular regulation of apoptosis: genetic controls on cell death. Cell. 1993; 4: 777–779.CrossRefGoogle Scholar
  169. 169.
    Miyashita T, and Reed JC. Bel-2 gene transfer increases relative resistance of S49.1 and WEH17.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoid and multiple chemotherapeutic drugs. Cancer Res. 1992;52:5407–5411.Google Scholar
  170. 170.
    Xin XM, Oltvai ZN, Korsmeyer SJ. BH1 and BH2 domains of Bd-2 are required for inhibition of apoptosis and heterodimerization with BAX. Nature. 1994; 369: 321–323.CrossRefGoogle Scholar
  171. 171.
    Monti D, Troiano L, Tropea R, et al. Autoimmunity, apoptosis defects and retroviruses. Adv Exp Med Biol. 1995; 374: 183–201.CrossRefGoogle Scholar
  172. 172.
    Warner HR, Fernandes G, Wang E. A unifying hypothesis to explain the retardation of aging and tumorigenesis by caloric restriction. J Gerontol. 1995; 50 (3): B107–109.Google Scholar
  173. 173.
    Cotman CW, Anderson AJ. A potential role for apoptosis in neurodegeneration and Alzheimer’s disease. Mol Neurobiol. 1995; 10 (1): 19–45.PubMedCrossRefGoogle Scholar
  174. 174.
    Lo AC, Houenou LJ, Oppenhein RW. Apoptosis in the nervous system: morphological features, methods, pathology, and prevention. Arch Hist Cytol. 1995;58(2):139149.Google Scholar
  175. 175.
    Wood KA, Dipasquale B, Youle RJ. In situ labeling of granule cells for apoptosis-associated DNA fragmentation reveals different mechanisms of cell loss in developing cerebellum. Neuron. 1993; 11 (4): 621–632.PubMedCrossRefGoogle Scholar
  176. 176.
    Patal T, Gores GJ. Apoptosis and hepatobililary disease. Hepatology. 1995; 21 (6): 1725–1741.Google Scholar
  177. 177.
    James SJ, Muskhelishvili L. Rates of apoptosis and proliferation vary with caloric intake and may influence the incidence of spontaneous hepatoma in C57BL/6 x c3H. Cancer Res. 1994; 54 (21): 5508–5510.PubMedGoogle Scholar
  178. 178.
    Grasi-Karupp B, Bursch W, Ruttkay-Nedecky B, et al. Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carciogenesis in rat liver. Proc Natl Acad Sci USA. 1994; 91 (21): 9995–9999.CrossRefGoogle Scholar
  179. 179.
    Baker GT III, Martin GR. Biological aging and longevity: underlying mechanisms and potential interventions. J Aging Physical Activity. 1994; 2: 304–328.Google Scholar
  180. 180.
    Powell HE, Caspersen CJ, Hoplan JP, Ford ES. Physical activity and chronic diseases. Am J Clin Nutr. 1989; 49: 999–1006.PubMedGoogle Scholar
  181. 181.
    Goodrick CL, Ingram DK, Reynolds MA, et al. Effects of intermittent feeding upon growth, activity and longevity in rats allowed voluntary exercise. Exp Aging Res. 1983; 9: 203–209.PubMedCrossRefGoogle Scholar
  182. 182.
    Holloszy JO. Exercise increased average longevity of female rats despite increased food intake and no growth retardation. J Gerontol. 1993; 48: B97 - B100.PubMedCrossRefGoogle Scholar
  183. 183.
    Holloszy JO, Smith EK, Vining M, Adams SA. Effect of voluntary exercise on longevity of rats. J Appl Physiol. 1985; 59: 826–831.PubMedGoogle Scholar
  184. 184.
    Lee I, Paffenbarger RS. Physical activity and the risk of developing colorectal cancer among college alumni. J Natl Cancer Inst. 1991; 83: 1324–1329.PubMedCrossRefGoogle Scholar
  185. 185.
    Holloszy JO, ed. Sarcopenia: muscle atrophy in old age. J Gerontol Biol Med Sci. 1995; 50A.Google Scholar
  186. 186.
    Ingram DK, Reynolds MA. The relationship of body weight to longevity within laboratory rodent species. In: Woodhead AD, Thompson KH, eds. Evolution of Longevity in Animals. New York: Plenum Press; 1987: 247–282.CrossRefGoogle Scholar
  187. 187.
    Milgram NW, Racine RJ, Nellis P, et al. Maintenance on L-deprenyl prolongs life in aged male rats. Life Sci. 1990; 47: 415–420.PubMedCrossRefGoogle Scholar
  188. 188.
    Thyagarajan S, Meites J, Quadri SK. Deprenyl reinitiates estrous cycles, reduces serum prolactin, and decreases the incidence of mammary and pituitary tumors in old acyclic rats. Endrocrinology. 1995; 136 (3): 1103–1110.CrossRefGoogle Scholar
  189. 189.
    Daynes RA, Araneo BA. Prevention and reversal of some age associated changes in immunological response by supplemental dihydroepiandosterone sulfate therapy. Aging Immunol Infect Dis. 1992; 13: 5–154.Google Scholar
  190. 190.
    Carney JM, Starke-Reed PE, Oliver CN, 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-buty-phenylnitrone. Proc Natl Acad Sci USA. 1991; 88: 3633–3636.PubMedCrossRefGoogle Scholar
  191. 191.
    Floyd RA, Carney JM. The role of metal ions in oxidative processes and aging. Toxicol Industrial Health. 1993; 9 (1/2): 197–214.Google Scholar
  192. 192.
    Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev. 1994; 74 (1): 139–162.PubMedGoogle Scholar
  193. 193.
    Mortel KF, Meyer JS. Lack of postmenopausal estrogen replacement therapy and the risk of dementia. J Neuropsychiatry Clin Neurosci. 1995;7(3):334–337.Google Scholar
  194. 194.
    Evans WJ, Campbell WW. Sarcopenia and age-related changes in body composition and functional capacity. J Nutr. 1993; 123: 465–468.PubMedGoogle Scholar
  195. 195.
    Fiatarone MA, Evans WJ. The etiology and reversibility of muscle dysfunction in the aged. J Gerontol. 1993; 48: 7783.CrossRefGoogle Scholar
  196. 196.
    Fiatarone MA, Marks EC, Ryan ND, et al. High intensity strength training in nonagenarians: effects on skeletal muscle. JAMA. 1990; 263: 3029–3034.PubMedCrossRefGoogle Scholar
  197. 197.
    Harris SS, Caspersen CJ, Defriese GH, Estes EH. Physical activity counseling for healthy adults as a primary preventive intervention in the clinical setting. JAMA. 1989; 261: 3590–3598.Google Scholar
  198. 198.
    Mittleman MA, MacClure M, Tofler GH, et al. Triggering of acute myocardial infarction by heavy physical exertion-protection against triggering by regular exertion. N Engl J Med. 1993; 329: 1684–1690.CrossRefGoogle Scholar
  199. 199.
    Weindruch R, Walford RL. The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: Charles C. Thomas, 1988.Google Scholar
  200. 200.
    Weindruch R, Warner HR, Starke-Reed PE. Future directions of free radical research in aging. In: Yu BP, ed. Free Radicals in Aging. Boca Raton, FL: CRC Press; 1993:269295.Google Scholar
  201. 201.
    Lane MA, Ball SS, Ingram DK, Cutler RG, Engel J, Read V, Roth GS. Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory end points. Am J Physiol. 1995; 268 (Endrocrinol Metab 31): E941 - E948.PubMedGoogle Scholar
  202. 202.
    Lane MA, Baer DJ, Rumpler WV, et al. Caloric restriction lower body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents. Proc Natl Acad Sci USA. 1996; 93: 4519–4564.CrossRefGoogle Scholar
  203. 203.
    Masoro EJ. Food restriction in rodents. An evaluation of its role in the study of aging. J Gerontol. 1988; 43: B59 - B56.PubMedCrossRefGoogle Scholar
  204. 204.
    Feuers RJ, Weindruch R, Hart RW. Caloric restriction, aging, and antioxidant enzymes. Mutat Res. 1993; 295 (4–6): 191–200.PubMedGoogle Scholar
  205. 205.
    Hursting SD, Perkins SN, Phang JM. Caloric restriction delays spontaneous tumorigenesis in p53-knockout transgenic mice. Proc Natl Acad Sci USA. 1994; 91: 70367040.Google Scholar
  206. 206.
    Stampfer MJ, Hennekens CH, Manson J, et al. Vitamin E consumption and the risk of coronary heart disease in women. N Engl J Med. 1993; 328: 1444–1450.Google Scholar
  207. 207.
    Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993; 328: 1450–1456.Google Scholar
  208. 208.
    Fraga CG, Motchnik PA, Shiginaga MK, et al. Ascorbic acid protects against endogenous oxidative damage in human sperm. Proc Natl Acad Sci USA. 1991; 88: 110031 1006.Google Scholar
  209. 209.
    Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994; 15: 1029–1035.Google Scholar
  210. 210.
    Meites J. Anti-aging interventions and their neuroendocrine aspects in mammals. J Reprod Fertility. 1993; 49: 1–9.Google Scholar
  211. 211.
    Blackman MR, Elahi D, Harman SM. Endrocrinology and aging. In: DeGroot LJ, eds. Endocrinology. Philadelphia: WB Saunders; 1994: 2702–2730.Google Scholar
  212. 212.
    Rudman D, Feller AG, Cohn L, et al. The effects of human growth hormone on body composition in elderly men. J Hormone Res. 1991; 36: 73–81.CrossRefGoogle Scholar
  213. 213.
    Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993; 14 (1): 20–39.PubMedGoogle Scholar
  214. 214.
    Ikari H, Zhang L, Mastrangeli A, et al. Adenovirus-mediated gene transfer of dopamine DZ receptor cDNA into rat striatum. Mol Brain Res. 1995; 34: 315–320.PubMedCrossRefGoogle Scholar
  215. 215.
    Crystal RG. Transfer of genes to humans: early lessons and obstacles to success. Science. 1995; 270: 404–410.PubMedCrossRefGoogle Scholar
  216. 216.
    Gittings NE, Fozard JL. Age changes in visual acuity. Exp Gerontol. 1986; 21: 423–434.PubMedCrossRefGoogle Scholar
  217. 217.
    Shock NW, Norris AH. Neuromuscular coordination as a factor in age changes in muscular exercise. In: Brunner D, Jokl E, eds. Medicine and Sport, Vol. 4, Physical Activity and Aging. Basel/New York: S. Karger; 1970.Google Scholar
  218. 218.
    Freeman JT. Aging: Its History and Literature. New York: Humana Science Press; 1979.Google Scholar
  219. 219.
    Zeman FD. Life’s later years: studies in the medical history of old age. Parts 1 to 10. J Mt Sinai Hosp. 1945;11:45–51; 12:833–846.Google Scholar
  220. 220.
    Cowdry EV, ed. Problems of Ageing: Biological and Medical Aspects. Baltimore: Williams Wilkins; 1939.Google Scholar
  221. 221.
    Cowdry EV, ed. Problems of Ageing: Biological and Medical Aspects. 2nd ed. Baltimore: Williams Wilkins; 1942.Google Scholar
  222. 222.
    Lansing AI, ed. Cowdry’s Problems of Ageing. 3rd ed. Baltimore: Williams Wilkins; 1952.Google Scholar
  223. 223.
    Shock NW, Baker GT III. The International Association of Gerontology: A Chronicle-1950 to 1986. New York: Springer; 1988.Google Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • George T. BakerIII
  • George R. Martin

There are no affiliations available

Personalised recommendations