The Aging Process

Aging is commonly defined as the accumulation of diverse harmfull changes occurring in cells and tissues with advancing age that are responsible for the increased risk of disease and death (Harman 2003). The observation that most of the animals living in a natural environment rarely show that accumulation of diverse harmful changes occurring in cells and tissues simply because they die earlier for predation, disease, starvation, or drought indicates that aging is a phenomenon unique to humans.

“In other words, the advancing knowledge of hygiene and biomedicine has led us to discover the aging process, something that was teleologically not intended for us to be experienced (Hayflick 2000)”

Life expectancy is defined as the average total number of years that a human expects to live. Differently, life span is the maximum number of years that a human can live. While the human life span has substantially remained unchanged for the past 100,000 years at ~125 years, life expectancy has sensibly increased (~27 years during the last century), especially in Western Countries. The lengthening of life expectancy is mainly due to the elimination of most infectious diseases occurring in youth, better hygiene, and the adoption of antibiotics and vaccines. What is needed to increase lifespan is a topic of intensifying research.

The major theories of aging (the free radical theory, the immunologic theory, the inflammation theory and the mitochondrial theory) are all specific of a particular cause of aging. They provide useful and important insights for the understanding of physiological changes occurring with aging. But the search for a single cause of aging (such as a single gene or the decline of a body system) has recently been replaced by the view of aging as an extremely complex, multifactorial process. It seems that several processes simultaneously interact and operate at different levels of functions in the body. Therefore, different theories of aging should be considered as complementary in order to explain some or all the features of the normal aging process.

The most influential of current theories, the free radical/oxidation theory of aging is supported by a large and growing body of evidence. Free radicals are atoms or molecules that contain at least one unpaired electron. This makes the molecules chemically unstable and allows them to react easily with other compounds in the body. In so doing, free radicals and other reactive oxidants can cause extensive damage to cells and tissues, impairing the immune system and leading to infections and various degenerative disorders, such as cardiovascular disease. Perhaps worst of all, they can damage the DNA in our cells and put us at risk for cancer. Many researchers believe that the havoc that free radicals and other reactive oxidants wreak on our bodies is the basis for the aging process.

Lately however new areas of focus have started to gain traction. In particular around cell metabolism. For example the findings around Nicotinamide Adenine Dinucleotide (NAD+) which is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and polymerases. These cellular NAD+ concentrations reduce during aging. Supplementation is shown to improve health span in mouse models of muscle aging and cognitive decline. The mechanism of action is not fully clear, but it may involve activation of sirtuin NAD-dependent protein deacetylases, along with enhanced mitochondrial function. Other sirtuin activators also improve health span and slightly extend life span in mice. It would appear science is coming closer to influencing the aging process and related illnesses.

In the side bar of this page you can find a description of the leading aging theories.

References

1.Ahmed A, Tollefsbol T. Telomeres and telomerase: basic science implications for aging. J Am Geriatr Soc. 2001;49:1105–9. [PubMed]
2.Alexeyev MF, LeDoux SP, Wilson GL. Mitochondrial DNA and aging. Clin Sci (Lond) 2004;107:355–64. [PubMed]
3.Allen JA, Coombs MM. Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA. Nature. 1980;287:244–5. [PubMed]
4.Ames BN. Endogenous oxidative DNA damage, aging, and cancer. Free Radic Res Commun. 1989;7:121–8. [PubMed]
5.Anisimov VN. Life span extension and cancer risk: myths and reality. Exp Gerontol. 2001;36:1101–36. [PubMed]
6.Arking R, Burde V, Graves K, et al. Forward and reverse selection for longevity in Drosophila is characterized by alteration of antioxidant gene expression and oxidative damage patterns. Exp Gerontol. 2000;35:167–85. [PubMed]
7.Artandi SE. Telomeres, telomerase, and human disease. N Engl J Med. 2006;355:1195–7. [PubMed]
8.Austad SN. Retarded senescence in an insular population of opossums. J Zool. 1993;229:695–708.
9.Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Res. 1998;78:547–81. [PubMed]
10.Besedovsky H, Del Rey A. Immune-neuro-endocrine interactions: facts and hypotheses. Endocrinol Rev. 1996;17:64–102. [PubMed]
11.Blackburn EH. Telomere states and cell fates. Nature. 2000;408:53–6. [PubMed]
12.Bodnar AG, Ouellette M, Frolkis M, et al. Extension of lifespan by introduction of telomerase into human cells. Science. 1998;279:349–52. [PubMed]
13.Bowles D, Torgan C, Ebner S, et al. Effects of acute, submaximal exercise on skeletal muscle vitamin E. Free Radic Res Commun. 1991;14:139–43. [PubMed]
14.Brand FN, Kiely DK, Kannel WB, et al. Family patterns of coronary heart disease mortality: the Framingham Longevity Study. J Clin Epidemiol. 1992;45:169–74. [PubMed]
15.Bryan TM, Englezou A, Dalla-Pozza L, et al. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med. 1997;3:1271–4. [PubMed]
16.Bryan TM, Englezou A, Gupta J, et al. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J. 1995;14:4240–8. [PMC free article] [PubMed]
17.Butler RN, Fossel M, Harman SM, et al. Is there an anti-aging medicine? J Gerontol A Biol Sci Med Sci. 2002;57A:B333–8. [PubMed]
18.Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000;29:222–30. [PubMed]
19.Campisi J. The biology of replicative senescence. Eur J Cancer. 1997;33:703–9. [PubMed]
20.Campisi J. Cellular senescence and cell death. In: Timiras PS, editor. Physiological basis of aging and geriatrics. 3rd edn. CRC; Boca Raton, FL: 2003. pp. 47–59.
21.Carmeli E, Coleman R, Reznick AZ. The biochemistry of aging muscle. Exp Gerontol. 2002;37:477–89. [PubMed]
22.Cesari M, Kritchevsky SB, Leeuwenburgh C, et al. Oxidative damage and platelet activation as new predictors of mobility disability and mortality in elders. Antioxid Redox Signal. 2005 in press. [PubMed]
23.Chung HY, Kim HJ, Kim JW, et al. The inflammation hypothesis of aging – Molecular modulation by calorie restriction. Ann N Y Acad Sci. 2001;928:327–35. [PubMed]
24.Cong YS, Wen J, Bacchetti S. The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet. 1999;8:137–42. [PubMed]
25.Davies KJ, Quintanilha A, Brooks GA, et al. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Comm. 1982;107:1292–9. [PubMed]
26.Daynes RA, Araneo BA. Prevention and reversal of some age-associated changes in immunologic responses by supplemental dehydroepiandrosterone sulfate therapy. Aging: Immunology, and Infectious Disease. 1992;3:135–53.
27.De Benedictis G, Rose G, Carrieri G, et al. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J. 1999;13:1532–6. [PubMed]
28.De La Fuente M. Effects of antioxidants on immune system ageing. Eur J Clin Nutr. 2002;56:S5–S8. [PubMed]
29.de Lange T. Human telomeres are attached to the nuclear matrix. EMBO J. 1992;11:717–24. [PMC free article] [PubMed]
30.Dirks AJ, Leeuwenburgh C. Caloric restriction in humans: potential pitfalls and health concerns. Mech Age Dev. 2006;127:1–7. [PubMed]
31.Fabris N. Neuroendocrine-immune interactions: a theoretical approach to ageing. Arch Gerontol Geriatr. 1991;12:219–30. [PubMed]
32.Finkel CE. The regulation of physiological changes during mammalian aging. Q Rev Biol. 1976;51:49–83. [PubMed]
33.Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–47. [PubMed]
34.Fontana L, Meyer TE, Klein S, et al. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci. 2004;101:6659–63. [PMC free article] [PubMed]
35.Fossel M. Telomerase and the aging cell: implications for human health. JAMA. 1998;279:1732–5. [PubMed]
36.Franceschi C. Cell proliferation and cell death in the aging process. Aging Clin Exp Res. 1989;1:3–13.
37.Franceschi C, Bonafe M, Valensin S, et al. Inflamm-aging–An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000a;908:244–54. [PubMed]
38.Franceschi C, Valensin S, Bonafe M, et al. The network and remodeling theories of aging: historical background and new perspectives. Exp Gerontol. 2000b;35:879–96. [PubMed]
39.Funk WD, Wang CK, Shelton DN, et al. Telomerase expression restores dermal integrity to in vitro-aged fibroblasts in a reconstituted skin model. Exp Cell Res. 2000;258:270–8. [PubMed]
40.Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature. 1989;337:331–7. [PubMed]
41.Haldane JBS. New paths in genetics. Allen & Unwin; London: 1941.
42.Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60. [PubMed]
43.Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol. 1957;2:298–300. [PubMed]
44.Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972;20:145–7. [PubMed]
45.Harman D. The free radical theory of aging. Antioxid Redox Signal. 2003;5:557–61. [PubMed]
46.Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36. [PubMed]
47.Hayflick L. How and why we age. Exp Gerontol. 1998;33:639–53. [PubMed]
48.Hayflick L. New approaches to old age. Nature. 2000a;403:365. [PubMed]
49.Hayflick L. The future of ageing. Nature. 2000b;408:267–9. [PubMed]
50.Hayflick L. “Anti-Aging” is an oxymoron” J Gerontol A Biol Sci Med Sci. 2004;59A:573–8. [PubMed]
51.Holliday R. Aging is no longer an unsolved problem in biology. Ann N Y Acad Sci. 2006;1067:1–9. [PubMed]
52.Huerre MR, Gounon P. Inflammation: patterns and new concepts. Res Immunol. 1996;147:417–34. [PubMed]
53.Ivanova R, Lepage V, Charron D, et al. Mitochondrial genotype associated with French Caucasian centenarians. Gerontology. 1998;44:349. [PubMed]
54.Kanungo MS. A model for aging. J Theor Biol. 1975;53:253–61. [PubMed]
55.Knight JA. Review: Free radicals, antioxidants and immune system. Ann Clin Lab Sci. 2000;30:145–58. [PubMed]
56.Kowald A, Kirkwood TB. A network theory of ageing: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the ageing process. Mutat Res. 1996;316:209–36. [PubMed]
57.Larsen PL. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc Natl Acad Sci. 1993;90:8905–9. [PMC free article] [PubMed]
58.Lingner J, Hughes TR, Shevchenko A, et al. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science. 1997;276:561–7. [PubMed]
59.Liu K, Schoonmaker MM, Levine BL, et al. Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc Natl Acad Sci. 1999;96:5147–52. [PMC free article] [PubMed]
60.Loison A, Festa-Bianchet M, Gaillard JM, et al. Age-specific survival in five populations of ungulates: evidence of senescence. Ecology. 1999;80:2539–54.
61.Mandavilli BS, Santos JH, Van Houten B. Mitochondrial DNA repair and aging. Mutat Res. 2002;509:127–51. [PubMed]
62.McCall MR, Frei B. Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radic Biol Med. 1999;26:1034–53. [PubMed]
63.McGeer EG, McGeer PL. Brain inflammation in Alzheimer disease and the therapeutic implications. Curr Pharm Des. 1999;5:821–36. [PubMed]
64.Medvedev ZA. An attempt at a rational classification of theories of aging. Biol Rev. 1990;65:375–98. [PubMed]
65.Melov S, Ravenscroft J, Malik S, et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science. 2000;289:1567–9. [PubMed]
66.Meydani M, Evans WJ, Handelman G, et al. Protective effect of vitamin E on exercise-induced oxidative damage in young and older adults. Am J Physiol. 1993;264:R992–8. [PubMed]
67.Meyerson M, Counter CM, Eaton EN, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–95. [PubMed]
68.Miquel J, Economos AC, Fleming J, et al. Mitochondrial role in cell aging. Exp Gerontol. 1980;15:575–91. [PubMed]
69.Mobbs CV, Bray GA, Atkinson RL, et al. Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span. J Gerontol A Biol Sci Med Sci. 2001;56:34–44. [PubMed]
70.Niranjan BG, Bhat NK, Avadhani NG. Preferential attack of mitochondrial DNA by aflatoxin B1 during hepatocarcinogenesis. Science. 1982;215:73–5. [PubMed]
71.Pawelek G, Effros C, Caruso C, et al. T cells and aging. Front Biosci. 1999;4:216–69. [PubMed]
72.Puca AA, Dalay MJ, Brewster SJ, et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc Natl Acad Sci. 2001;98:10505–8. [PMC free article] [PubMed]
73.Rhyu MS. Telomeres, telomerase, and immortality. J Natl Cancer Inst. 1995;87:884–94. [PubMed]
74.Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci. 1988;85:6465–7. [PMC free article] [PubMed]
75.Ross OA, McCormack R, Curran MD, et al. Mitochondrial DNA polymorphism: its role in longevity of the Irish population. Exp Gerontol. 2001;36:1161–78. [PubMed]
76.Rossi SC, Gorman N, Wetterhahn KE. Mitochondrial reduction of the carcinogen chromate: formation of chromium(V) Chem Res Toxicol. 1988;1:101–7. [PubMed]
77.Rowe JW, Kahn RL. Human aging: usual and successful. Science. 1987;237:143–9. [PubMed]
78.Rowe JW, Kahn RL. Successful aging. Aging (Milano) 1998;10:142–4. [PubMed]
79.Sapolsky RM. Rudman Stress, the aging brain, and the mechanisms of neuron death. MIT Press; Cambridge, MA: 1992.
80.Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev. 1986;7:284–301. [PubMed]
81.Sastre J, Pallardo FV, Garcia de la Asuncion J, et al. Mitocondria, oxidative stress and aging. Free Rad Res. 2000;32:189–98. [PubMed]
82.Selye H. The stress of life. McGraw-Hill; New York: 1976.
83.Shay JW, Gazdar AF. Telomerase in the early detection of cancer. J Clin Pathol. 1997;50:106–9. [PMC free article] [PubMed]
84.Shay JW, Wright WE. Telomerase activity in human cancer. Curr Opin Oncol. 1996;8:66–71. [PubMed]
85.Shringarpure R, Davies KJ. Protein turnover by the proteasome in aging and disease. Free Radic Biol Med. 2002;32:1084–9. [PubMed]
86.Tanaka M, Gong JS, Zhang J, et al. Mitochondrial genotype associated with longevity. Lancet. 1998;351:185–6. [PubMed]
87.Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science. 2003;299:1346–51. [PubMed]
88.Timiras PS. Biological perspectives on aging. Am Sci. 1978;66:605–13. [PubMed]
89.Tower J. Transgenic methods for increasing Drosophila life span. Mech Age Dev. 2000;118:1–14. [PubMed]
90.Ulaner GA, Giudice LC. Developmental regulation of telomerase activity in human fetal tissues during gestation. Mol Hum Reprod. 1997;3:769–73. [PubMed]
91.Vaziri H, Benchimol S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol. 1998;8:279–82. [PubMed]
92.Walford RL, Mock D, MacCallum T, et al. Physiologic changes in humans subjected to severe, selective calorie restriction for two years in biosphere 2: health, aging, and toxicological perspectives. Toxicol Sci. 1999;52:61–5. [PubMed]
93.Wayne SJ, Rhyne RL, Garry PJ, et al. Cell-mediated immunity as predictor of morbidity and mortality in subjects over 60. J Gerontol. 1990;45:M45–8. [PubMed]
94.Weindruch R, Walford RL, Fligiel S, et al. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986;116:641–54. [PubMed]
95.Weinert BT, Timiras PS. Theories of aging. J Appl Physiol. 2003;95:1706–16. [PubMed]
96.Weyer C, Walford RL, Harper IT, et al. Energy metabolism after 2 y of energy restriction: the biosphere 2 experiment. Am J Clin Nutr. 2000;72:946–53. [PubMed]
97.Wick M, Zubov D, Hagen G. Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT) Gene. 1999;232:97–106. [PubMed]
98.Wunderlich V, Schutt M, Bottger M, et al. Preferential alkylation of mitochondrial deoxyribonucleic acid by N-methyl-N-nitrosourea. Biochem J. 1970;118:99–109. [PMC free article] [PubMed]