Skip to main navigation menu Skip to main content Skip to site footer

Narrative Review

Vol. 6 No. 1 (2001)

An Old Question Revisited: Current Understanding of Aging Theories

  • Tak Pan Wong, Ph.D.
November 8, 2020


“Why we age” is no longer a solely philosophical question. In parallel with the rising
awareness of the social ramifications of an aging population, basic research has expanded our understanding of the intricate nature of biological aging. The present paper aims at discussing our current understanding of the molecular and cellular alterations that accompany aging. To this end, the main theories on the mechanisms of aging, error theories and program theories, will be discussed. Special focus on neuronal aging is also presented to provide illustrative examples of these aging mechanisms.


  1. Statistics Canada. Population projections for 2001, 2006, 2011, 2016, 2021 and 2026. 2000.
  2. Day JC. Population projections of the United States by age, sex, race, and Hispanic origin: 1995 to 2000. Current Population Reports, 25. Washington, DC: Bureau of the Census, U.S. Printing Office; 1996.
  3. National Center for Health Statistics. Vital Statistics of the United States. 1995, II, Part A, section 6, 14. Hyattsville, MD: DHHS Publication; 1998.
  4. Crimmins EM, Saito Y, Reynolds SL. Further evidence on recent trends in the prevalence and incidence of disability among older Americans from two sources: the LSOA and the NHIS. Journal of Gerontology B Psychological Sciences and Social Sciences 1997; 52: S59-S71.
  5. Schneider EL. Aging in the third millennium. Science 1999; 283: 796-797.
  6. Comfort A. The Biology of Senescence. London: Churchill Livingstone; 1979.
  7. Harman D. The aging process: major risk factor for disease and death. Proceedings of the National Academy of Sciences USA 1991; 88: 5360-5363.
  8. Busse EW. Primary and secondary aging. In: Maddox GL, Roth G, Atchley R, eds. The Encyclopedia of Aging. New York: Springer; 1987: 534.
  9. Lim SY, Suzuki H. Intakes of dietary docosahexaenoic acid ethyl ester and egg phosphatidylcholine improve maze-learning ability in young and old mice. Journal of Nutrition 2000; 130: 1629-1632.
  10. Lopes LV, Cunha RA, Ribeiro JA. Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and cortex of young adult and old rats. Journal of Neurophysiology 1999; 82: 3196-3203.
  11. Swenson KL, Sands JM, Jacobs JD, Sladek CD. Effect of aging on vasopressin and aquaporin responses to dehydration in Fischer 344-brown-Norway F1 rats. American Journal of Physiology 1997; 273: R35-R40.
  12. Walford RL. Letter: When is a mouse “old”? Journal of Immunology 1976; 117: 352.
  13. Wexler BC. Co-existent arteriosclerosis, PAN, and premature aging. Journal of Gerontology 1970; 25: 373-380.
  14. Schlettwein-Gsell D. Survival curves of an old age rat colony. Gerontologia 1970; 16: 111-115.
  15. Sass B, Rabstein LS, Madison R, et al. Incidence of spontaneous neoplasms in F344 rats throughout the natural life-span. Journal of the National Cancer Institute 1975; 54: 1449-1456.
  16. Burek JD, Hollander CF. Incidence patterns of spontaneous tumors in BN/Bi rats. Journal of the National Cancer Institute 1977; 58: 99-105.
  17. Austad SN. Theories of aging: an overview. Aging (Milano) 1998; 10: 146-147.
  18. Olson CB. A review of why and how we age: a defense of multifactorial aging. Mechanisms of Ageing and Development 1987; 41: 1-28.
  19. Lithgow GJ, Kirkwood TB. Mechanisms and evolution of aging. Science 1996; 273: 80.
  20. Eichhorn GL. Aging, genetics, and the environment: potential of errors introduced into genetic information transfer by metal ions. Mechanisms of Ageing and Development 1979; 9: 291-301.
  21. Vijg J. Somatic mutations and aging: a re-evaluation. Mutation Research 2000; 447: 117-135.
  22. Henshaw PS, Riley EF, Stapleton GE. The biologic effects of pile radiations. Radiology 1947; 49: 349-364.
  23. Szilard L. On the nature of the aging process. Proceedings of the National Academy of Sciences USA 1959; 45: 30-35.
  24. Failla G. The aging process and carcinogenesis. Annals of the New York Academy of Science 1958; 71: 1124-1135.
  25. Curtis HJ. Cellular processes involved in aging. Federation Proceedings 1964; 23: 662-665.
  26. Dani SU. Mechanisms of aging: a survey. In: Dani SU, Hori A, Walter GF, eds. Principles of Neural Aging. Amsterdam: Elsevier; 1997: 5-17.
  27. Hall KY, Hart RW, Benirschke AK, Walford RL. Correlation between ultraviolet-induced DNA repair in primate lymphocytes and fibroblasts and species maximum achievable life span. Mechanisms of Ageing and Development 1984; 24: 163-173.
  28. Maslansky CJ, Williams GM. Ultraviolet light-induced DNA repair synthesis in hepatocytes from species of differing longevities. Mechanisms of Ageing and Development 1985; 29: 191-203.
  29. Hart RW, Setlow RB. Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proceedings of the National Academy of Sciences USA 1974; 71: 2169-2173.
  30. Rattan SI. DNA damage and repair during cellular aging. International Review of Cytology 1989; 116: 47-88.
  31. Curtis H, Crowley C. Chromosome aberrations in liver cells in relation to the somatic mutation theory of aging. Radiation Research 1963; 19: 337-344.
  32. Crowley K, Curtis HJ. The development of somatic mutations in mice with age. Proceedings of the National Academy of Sciences USA 1963; 49: 626-628.
  33. Hayflick L. Current theories of biological aging. Federation Proceedings 1975; 34: 9-13.
  34. Tucker JD, Spruill MD, Ramsey MJ, et al. Frequency of spontaneous chromosome aberrations in mice: effects of age. Mutation Research 1999; 425: 135-141.
  35. Ono T, Miyamura Y, Ikehata H, et al. Spontaneous mutant frequency of lacZ gene in spleen of transgenic mouse increases with age. Mutation Research 1995; 338: 183-188.36. Rose MR, Archer MA. Genetic analysis of mechanisms of aging.
  36. Rose MR, Archer MA. Genetic analysis of mechanisms of aging. Current Opinion in Genetics and Development 1996; 6: 366-370.
  37. Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 1992; 256: 628-632.
  38. Maynard Smith J. A theory of ageing. Nature 1959; 184: 956-957.
  39. Kirkwood TB. DNA, mutations and aging. Mutation Research 1989; 219: 1-7.
  40. Dempsey JL, Pfeiffer M, Morley AA. Effect of dietary restriction on in vivo somatic mutation in mice. Mutation Research 1993; 291: 141-145.
  41. Jones IM, Thomas CB, Tucker B, et al. Impact of age and environment on somatic mutation at the hprt gene of T lymphocytes in humans. Mutation Research 1995; 338: 129-139.
  42. Lee AT, DeSimone C, Cerami A, Bucala R. Comparative analysis of DNA mutations in lacI transgenic mice with age. FASEB Journal 1994; 8: 545-550.
  43. Martus HJ, Dolle ME, Gossen JA, et al. Use of transgenic mouse models for studying somatic mutations in aging. Mutation Research 1995; 338: 203-213.
  44. Ono T, Ikehata H, Nakamura S, et al. Age-associated increase of spontaneous mutant frequency and molecular nature of mutation in newborn and old lacZ-transgenic mouse. Mutation Resesarch 2000; 447: 165-177.
  45. Weindruch R. Caloric restriction and aging. Scientific American 1996; 274: 46-52.
  46. Nicolas AS, Lanzmann-Petithory D, Vellas B. Caloric restriction and aging. Journal of Nutrition, Health and Aging 1999; 3: 77-83.
  47. Aidoo A, Desai VG, Lyn-Cook LE, et al. Attenuation of bleomycin-induced Hprt mutant frequency in female and male rats by calorie restriction. Mutation Research 1999; 430: 155-163.
  48. Odagiri Y, Uchida H, Hosokawa M, et al. Accelerated accumulation of somatic mutations in the senescence- accelerated mouse. Nature Genetics 1998; 19: 116-117.
  49. Grist SA, McCarron M, Kutlaca A, et al. In vivo human somatic mutation: frequency and spectrum with age. Mutation Research 1992; 266: 189-196.
  50. Dubrova YE, Jeffreys AJ, Malashenko AM. Mouse minisatellite mutations induced by ionizing radiation. Nature Genetics 1993; 5: 92-94.
  51. Wong LJ, Ashizawa T, Monckton DG, et al. Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent. American Journal of Human Genetics 1995; 56: 114-122.
  52. McEachern MJ, Krauskopf A, Blackburn EH. Telomeres and their control. Annual Review of Genetics 2000; 34: 331-358.
  53. Olovnikov AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. Journal of Theoretical Biology 1973; 41: 181-190.
  54. Butler MG, Tilburt J, DeVries A, et al. Comparison of chromosome telomere integrity in multiple tissues from subjects at different ages. Cancer Genetics and Cytogenetics 1998; 105: 138-144.
  55. Bodnar AG, Ouellette M, Frolkis M, et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279: 349-352.56. Moustacchi E. DNA damage and repair: consequences on dose- responses. Mutation Research 2000; 464: 35-40.
  56. Heinrich H, Holz J. Myocardial apoptosis in the overloaded and the aging heart: a critical role of mitochondria? European Cytokine Network 1998; 9: 693-695.
  57. Singhal PC, Reddy K, Franki N, et al. Age and sex modulate renal expression of SGP-2 and transglutaminase and apoptosis of splenocytes, thymocytes, and macrophages. Journal of Investigative Medicine 1997; 45: 567-575.
  58. Ginaldi L, De Martinis M, D’Ostilio A, et al. Cell proliferation and apoptosis in the immune system in the elderly. Immunology Research 2000; 21: 31-38.
  59. Franceschi C. Cell proliferation, cell death and aging. Aging (Milano) 1989; 1: 3-15.
  60. Barr PJ, Tomei LD. Apoptosis and its role in human disease. Biotechnology (NY) 1994; 12: 487-493.
  61. Warner HR, Fernandes G, Wang E. A unifying hypothesis to explain the retardation of aging and tumorigenesis by caloric restriction. Journal of Gerontology A Biological Sciences and Medical Sciences 1995; 50: B107-B109.
  62. Wareham KA, Lyon MF, Glenister PH, Williams ED. Age related reactivation of an X-linked gene. Nature 1987; 327: 725-727.
  63. Singhal RP, Mays-Hoopes LL, Eichhorn GL. DNA methylation in aging of mice. Mechanisms of Ageing and Development 1987; 41: 199-210.
  64. Holliday R. Strong effects of 5-azacytidine on the in vitro lifespan of human diploid fibroblasts. Experimental Cell Research 1986; 166: 543-552.
  65. Fanestil DD, Barrows CH Jr. Aging in the rotifer. Journal of Gerontology 1965; 20: 462-469.
  66. Strehler BL. Further studies on the thermally induced aging of Drosophila melanogaster. Journal of Gerontology 1962; 17: 347-352.
  67. Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proceedings of the National Academy of Sciences USA 1995; 92: 11190-11194.
  68. Mehlhorn RJ. Oxidants and antioxidants in aging. In: Timiras PS, ed. Physiological Basis of Aging and Geriatrics. Florida: CRC Press, Inc.; 1994: 61-73.
  69. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiological Reviews 1979; 59: 527-605.
  70. Liu SS. Generating, partitioning, targeting and functioning of superoxide in mitochondria. Bioscience Reports 1997; 17: 259-272.
  71. Sohal RS, Sohal BH. Hydrogen peroxide release by mitochondria increases during aging. Mechanisms of Ageing and Development 1991; 57: 187-202.
  72. Rikans LE, Hornbrook KR. Lipid peroxidation, antioxidant protection and aging. Biochimica et Biophysica Acta 1997; 1362: 116-127.
  73. Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. Journal of Biologica Chemstry 1997; 272: 20313-20316.
  74. Gaczynska M, Bartosz G. Crosslinking of membrane proteins during erythrocyte ageing. International Journal of Biochemistry 1986; 18: 377-382.
  75. Izzotti A, Cartiglia C, Taningher M, et al. Age-related increases of 8-hydroxy-2’-deoxyguanosine and DNA-protein crosslinks in mouse organs. Mutation Research 1999; 446: 215-223.
  76. Zahn RK, Zahn-Daimler G, Ax S, et al. Assessment of DNA-protein crosslinks in the course of aging in two mouse strains by use of a modified alkaline filter elution applied to whole tissue samples. Mechanisms of Ageing and Development 1999; 108: 99-112.
  77. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. International Journal of Biochemistry and Cell Biology 1995; 27: 647-653.
  78. Herrero A, Barja G. H2O2 production of heart mitochondria and aging rate are slower in canaries and parakeets than in mice: sites of free radical generation and mechanisms involved. Mechanisms of Ageing and Development 1998; 103: 133-146.
  79. Mates JM, Sanchez-Jimenez F. Antioxidant enzymes and their implications in pathophysiologic processes. Frontiers in Bioscience 1999; 4: D339-D345.
  80. Jovanovic SV, Simic MG. Antioxidants in nutrition. Annals of the New York Academy of Science 2000; 899: 326-334.
  81. Yargicoglu P, Agar A, Gumuslu S, et al. Age-related alterations in antioxidant enzymes, lipid peroxide levels, and somatosensory-evoked potentials: effect of sulfur dioxide. Archives of Environmental Contamination and Toxicology 1999; 37: 554-560.
  82. Joseph JA, Shukitt-Hale B, Denisova NA, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. Journal of Neuroscience 1999; 19: 8114-8121.
  83. Ishii N, Fujii M, Hartman PS, et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 1998; 394: 694-697.
  84. Patnaik SK, Kanungo MS. Soluble alanine aminotransferase of the liver of rats of various ages: induction, characterization and changes in patterns. Indian Journal of Biochemistry and Biophysics 1976; 13: 117-124.
  85. Chatterjee B, Roy AK. Changes in hepatic androgen sensitivity and gene expression during aging. Journal of Steroid Biochemistry and Molecular Biology 1990; 37: 437-445.
  86. Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol- 3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 1996; 382: 536-539.
  87. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277: 942-946.
  88. Ewbank JJ, Barnes TM, Lakowski B, et al. Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science 1997; 275: 980-983.
  89. Lakowski B, Hekimi S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 1996; 272: 1010-1013.
  90. Aiello GL, Rita P. The cost of an action potential. Journal of Neuroscience Methods 2000; 103: 145-149.
  91. Filburn CR, Edris W, Tamatani M, et al. Mitochondrial electron transport chain activities and DNA deletions in regions of the rat brain. Mechanisms of Ageing and Development 1996; 87: 35-46.
  92. Sastre J, Pallardo FV, Garcia de la Asuncion J, Vina J. Mitochondria, oxidative stress and aging. Free Radical Research 2000; 32: 189-198.
  93. Kaneko T, Tahara S, Matsuo M. Non-linear accumulation of 8- hydroxy-2’-deoxyguanosine, a marker of oxidized DNA damage, during aging. Mutation Research 1996; 316: 277-285.
  94. Randerath K, Putman KL, Osterburg HH, et al. Age-dependent increases of DNA adducts (I-compounds) in human and rat brain DNA. Mutation Research 1993; 295: 11-18.
  95. Mandavilli BS, Rao KS. Neurons in the cerebral cortex are most susceptible to DNA-damage in aging rat brain. Biochemistry and Molecular Biology International 1996; 40: 507-514.
  96. Perry G, Nunomura A, Hirai K, et al. Oxidative damage in Alzheimer’s disease: the metabolic dimension. International Journal of Developmental Neuroscience 2000; 18: 417-421.
  97. Christen Y. Oxidative stress and Alzheimer disease. American Journal of Clinical Nutrition 2000; 71: 621S-629S.
  98. Offen D, Hochman A, Gorodin S, et al. Oxidative stress and neuroprotection in Parkinson’s disease: implications from studies on dopamine-induced apoptosis. Advances in Neurology 1999; 80: 265-269.
  99. Youdim MB, Riederer P. Understanding Parkinson’s disease. Scientific American 1997; 276: 52-59.
  100. Gerlach M, Desser H, Youdim MB, Riederer P. New horizons in molecular mechanisms underlying Parkinson’s disease and in our understanding of the neuroprotective effects of selegiline. Journal of Neural Transmission Suppl. 1996; 48: 7-21.
  101. Naoi M, Maruyama W. Cell death of dopamine neurons in aging and Parkinson’s disease. Mechanisms of Ageing and Development 1999; 111: 175-188.
  102. Sastry PS, Rao KS. Apoptosis and the nervous system. Journal of Neurochemistry 2000; 74: 1-20.
  103. Sohal RS, Brunk UT. Lipofuscin as an indicator of oxidative stress and aging. Advances in Experimental Medicine and Biology 1989; 266: 17-26.
  104. Oenzil F, Kishikawa M, Mizuno T, Nakano M. Age-related accumulation of lipofuscin in three different regions of rat brain. Mechanisms of Ageing and Development 1994; 76: 157-163.
  105. Monji A, Morimoto N, Okuyama I, et al. Effect of dietary vitamin E on lipofuscin accumulation with age in the rat brain. Brain Research 1994; 634: 62-68.
  106. Bertoni-Freddari C, Giuli C, Pieri C. Effect of chronic vitamin E deficiency on the synapses of cerebellar glomeruli in young rats. Mechanisms of Ageing and Development 1984; 24: 225-232.
  107. Sah R, Schwartz-Bloom RD. Optical imaging reveals elevated intracellular chloride in hippocampal pyramidal neurons after oxidative stress. Journal of Neuroscience 1999; 19: 9209-9217.
  108. Saransaari P, Oja SS. Enhanced GABA release in cell-damaging conditions in the adult and developing mouse hippocampus. International Journal of Developmental Neuroscience 1997; 15: 163-174.
  109. Green AR, Hainsworth AH, Jackson DM. GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke. Neuropharmacology 2000; 39: 1483-1494.
  110. Lyden PD. GABA and neuroprotection. International Review of Neurobiology 1997; 40: 233-258.
  111. Lippa AS, Critchett DJ, Ehlert F, et al. Age-related alterations in neurotransmitter receptors: an electrophysiological and biochemical analysis. Neurobiology of Aging 1981; 2: 3-8.
  112. Stern WC, Pugh WW, Morgane PJ. Single unit activity in frontal cortex and caudate nucleus of young and old rats. Neurobiology of Aging 1985; 6: 245-248.
  113. Grady CL, Craik FI. Changes in memory processing with age. Current Opinion in Neurobiology 2000; 10: 224-231.
  114. Barnes CA. Normal aging: regionally specific changes in hippocampal synaptic transmission. Trends in Neurosciences 1994; 17: 13-18.
  115. Wong TP, Marchese G, Casu MA, et al. Loss of presynaptic and postsynaptic structures is accompanied by compensatory increase in action potential-dependent synaptic input to layer V neocortical pyramidal neurons in aged rats. Journal of Neuroscience 2000; 20: 8596-8606.


Download data is not yet available.