Living in an oxygenated environment has required the evolution of effective cellular strategies to detect and detoxify metabolites of molecular oxygen known as reactive oxygen species. Here we review evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span.
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Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 2, 298–300 (1957).
McCord, J. M. & Fridovich, I. Superoxide dismutase. An enzymatic function for erythrocuperin (hemocuperin). J. Biol. Chem. 244, 6049–6055 (1969).
Ku, H. H., Brunk, U. T. & Sohal, R. S. Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radical Biol. Med. 15, 621–627 (1993).
Finkel, T. Oxygen radicals and signaling. Curr. Opin. Cell Biol. 10, 248–253 (1998).
Nishikawa, T. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000).
Nemoto, S., Takeda, K., Yu, Z. X., Ferrans, V. J. & Finkel, T. A role for mitochondrial oxidants as regulators of cellular metabolism. Mol. Cell. Biol. 20, 7311– 7318 (2000).
Suh, Y. A. et al. Cell transformation by the superoxide-generating oxidase Mox1 . Nature 401, 79–82 (1999).
Geiszt, M., Kopp, J. B., Varnai, P., & Leto, T. L. Identification of Renox, an NAD(P)H oxidase in kidney. Proc. Natl Acad. Sci. USA 97, 8010–8014 ( 2000).
Turrens, J. F. Superoxide production by the mitochondrial respiratory chain. Biosci. Rep. 17, 3–8 ( 1997).
Golubev, A. G. The other side of metabolism: a review. Biochemistry 61, 1443–1460 (1996).
Boveris, A. & Chance, B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem. J. 134, 707–716 (1973).
Skulachev, V. P. Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q. Rev. Biophys. 29, 169–202 ( 1996).
Vidal-Puig, A. J. et al. Energy metabolism in uncoupling protein 3 gene knockout mice . J. Biol. Chem. 275, 16258– 16266 (2000).
Chae, H. Z., Kang, S. W. & Rhee, S. G. Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. Methods Enzymol. 300, 219–226 (1999).
Stadtman, E. R. Protein oxidation and aging. Science 257, 1220–1224 (1992).
Yan, L. J., Levine, R. L. & Sohal, R. S. Oxidative damage during aging targets mitochondrial aconitase. Proc. Natl Acad. Sci. USA 94, 11168–11172 (1997).
Goto, S. et al. Carbonylated proteins in aging and exercise: immunoblot approaches . Mech. Age.Dev. 107, 245– 253 (1999).
Dukan, S. et al. Protein oxidation in response to increased transcriptional or translational errors. Proc. Natl Acad. Sci. USA 97, 5746–5749 (2000).
Beckman, K. B. & Ames, B. N. The free radical theory of aging matures. Physiol. Rev. 78, 547–581 (1998).
Esposito, L. A., Melov, S., Panov, A., Cottrell, B. A. & Wallace, D. C. Mitochondrial disease in mouse results in increased oxidative stress. Proc. Natl Acad. Sci. USA 96, 4820–4825 (1999).
Melov, S. et al. Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc. Natl Acad. Sci. USA 96, 846– 851 (1999).
Packer, L. & Fuehr, K. Low oxygen concentration extends the lifespan of cultured human diploid cells. Nature 267 , 423–425 (1977).
von Zglinicki, T., Saretzki, G., Docke, W. & Lotze, C. Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp. Cell Res. 220, 186– 193 (1995).
Chen, Q. & Ames, B. N. Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc. Natl Acad. Sci. USA 91, 4130–4134 (1994).
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 ( 1997).
Lee, A. C. et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274 , 7936–7940 (1999).
Johnson, T. M., Yu, Z. X., Ferrans, V. J., Lowenstein, R. A. & Finkel, T. Reactive oxygen species are downstream mediators of p53-dependent apoptosis. Proc. Natl Acad. Sci. USA 93, 11848–11852 ( 1996).
Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W. & Vogelstein, B. A model for p53-induced apoptosis. Nature 389, 300–305 ( 1997).
Sachsenmaier, C. et al. Involvement of growth factor receptors in the mammalian UVC response. Cell 78, 963– 972 (1994).
Wang, X., McCullough, K. D., Franke, T. F. & Holbrook, N. J. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J. Biol. Chem. 275, 14624–14631 (2000).
Knebel, A., Rahmsdorf, H. J., Ullrich, A. & Herrlich, P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J. 15 , 5314–5325 (1996).
Lee, S. R., Kwon, K. S., Kim, S. R. & Rhee, S. G. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366 –15372 (1998).
Burdon, R. H. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation . Free Radical Biol. Med. 18, 775– 794 (1995).
Saitoh, M. et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17, 2596– 2606 (1998).
Adler, V. et al. Regulation of JNK signaling by GSTp. EMBO J. 18, 1321–1334 (1999).
Allen, R. G. & Tresini, M. Oxidative stress and gene regulation . Free Radical Biol. Med. 28, 463– 499 (2000).
Godon, C. et al. The H2O2 stimulon in Saccharomyces cerevisiae . J. Biol. Chem. 273, 22480– 22489 (1998).
Richardson, A. & Holbrook, N. J. in Cellular Aging and Cell Death (eds Holbrook, N. J., Martin, G. R. & Lockshin, R. A.) 67–89 (Wiley, New York, 1996).
Morimoto, R. I. & Santoro, M. G. Stress-inducible responses and heat shock proteins: new pharmacologic targets for cytoprotection . Nature Biotechnol. 16, 833– 838 (1998).
Lee, C. K., Klopp, R. G., Weindruch, R. & Prolla, T. A. Gene expression profile of aging and its retardation by caloric restriction . Science 285, 1390–1393 (1999).
Lee, C. K., Weindruch, R. & Prolla, T. A. Gene-expression profile of the ageing brain in mice . Nature Genet. 25, 294– 297 (2000).
Wheeler, J. C., Bieschke, E. T. & Tower, J. Muscle-specific expression of Drosophila hsp70 in response to aging and oxidative stress. Proc. Natl Acad. Sci. USA 92, 10408–10412 ( 1995).
Guyton, K. Z. et al. Age-related changes in activation of mitogen-activated protein kinase cascades by oxidative stress. J. Invest. Dermatol. Symp. Proc. 3, 23–27 ( 1998).
Guyton, K. Z. et al. Activation of mitogen-activated protein kinase by hydrogen peroxide: role in cell survival following oxidant injury. J. Biol. Chem. 271, 4138–4142 ( 1996).
Liu et. al. Age-related decline in MAP kinase activity in EGF-stimulated rat hepatocytes. J. Biol. Chem. 271, 3604–3607 (1996)
Poynter, M. E. & Daynes, R. A. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging . J. Biol. Chem. 273, 32833– 32841 (1998).
Supakar, P. C., Jung, M. H., Song, C. S., Chatterjee, B. & Roy, A. K. Nuclear factor kappa B functions as a negative regulator for the rat androgen receptor gene and NF-kappa B activity increases during the age-dependent desensitization of the liver. J. Biol. Chem. 270, 837–842 ( 1995).
Ponnappan, U. Regulation of transcription factor NFkappa B in immune senescence. Front. Biosci. 1, D152–D168 (1998).
Larsen, P. L. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 90, 8905– 8909 (1993).
Vanfleteren, J. R. Oxidative stress and ageing in Caenorhabditis elegans. Biochem. J. 292, 605–608 (1993).
Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997).
Murakami, S. & Johnson, T. E. A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143, 1207–1218 (1996).
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).
Branicky, R., Benard, C. & Hekimi, S. clk-1, mitochondria, and physiological rates. Bioessays 22, 48–56 ( 2000).
Ishii, N. et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394 , 694–697 (1998).
Taub, J. et al. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature 399, 162–166 (1999).
Melov, S. et al. Extension of lifespan with superoxide dismutase/catalase mimetics . Science 289, 1567–1569 (2000).
Dudas S. et al. A coordinate upregulation of antioxidant gene activities is associated with the delayed onset of senescence in a long-lived strain of Drosophila . J. Gerontol. A 50, B117– B127 (1995).
Harshman, L. G. & Haberer, B. A. Oxidative stress resistance: a robust correlated response to selection in extended longevity lines of Drosophila melanogaster. J. Gerontol. A 55, B415–B417 (2000).
Lin, Y. J., Seroude, L. & Benzer, S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282, 943–946 (1998).
Mockett, R. J., Sohal, R. S. & Orr, W. C. Overexpression of glutathione reductase extends survival in transgenic Drosophila melanogaster under hyperoxia but not normoxia . FASEB J. 13, 1733–1742 (1999).
Orr, W. C. & Sohal, R. S. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263, 1128–1130 ( 1994).
Sun, J. & Tower, J. FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol. Cell Biol. 19, 216–228 ( 1999).
Parkes, T. L. et al. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nature Genet. 19, 171–174 (1998).
Seto, N. O., Hayashi, S. & Tener, G. M. Overexpression of Cu-Zn superoxide dismutase in Drosophila does not affect life-span. Proc. Natl Acad. Sci. USA 87, 4270–4274 ( 1990).
Orr, W. C. & Sohal, R. S. 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).
Huang, T. et al. Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J. Gerontol. Biol. Sci. A 55, B5–B9 (2000).
Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402 , 309–313 (1999).
Kao, A. W. et al. Insulin stimulates the phosphorylation of the 66- and 52-kilodalton Shc isoforms by distinct pathways. Endocrinology 138 , 2474–2480 (1997).
Masoro, E. J. Caloric restriction and aging: an update. Exp. Gerontol. 35, 299–305 (2000).
Sohal, R. S. & Weindruch, R. Oxidative stress, caloric restriction, and aging. Science 273, 59– 63 (1996).
Heydari, A. R., Wu, B., Takahashi, R., Strong, R. & Richardson, A. Expression of heat shock protein 70 is altered by age and diet at the level of transcription. Mol. Cell Biol. 13, 2909–2918 (1993).
Hall, D. M. et al. Caloric restriction improves thermotolerance and reduces hyperthermia-induced cellular damage in old rats. FASEB J. 14, 78–86 (2000).
Roth, G. S., Ingram, D. K. & Lane, M. A. Calorie restriction in primates: will it work and how will we know? J. Am. Geriatr. Soc. 47, 896–903 (1999).
McCall, M. R. & Frei, B. Can antioxidant vitamins maternally reduce oxidative damage in humans? Free Radical Biol. Med. 26, 1034–1053 (1999).
Yu, B. P. Approaches to anti-aging intervention: the promises and the uncertainties . Mech. Ageing Dev. 111, 73– 87 (1999).
Podmore, I. D. et al. Vitamin C exhibits pro-oxidant properties. Nature 392, 559–559 ( 1998).
Melov, S. et al. A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nature Genet. 18, 159–163 (1998).
Rong, Y. et al. EUK-134, a synthetic superoxide dismutse and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology. Proc. Natl Acad. Sci. USA 96, 9897– 9902 (1999).
Lithgow, G. J. et al. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc. Natl Acad. Sci. USA 92, 7540–7544 ( 1995).
Johnson, T. E. & Hartman, P. S. Radiation effects on life span in Caenorhabditis elegans. J. Gerontol. Biol. Sci. 43, B137–B141 ( 1988).
Tatar, M., Khazaeli, A. A. & Curtsinger, J. W. Chaperoning extended life. Nature 390, 30 (1997).
Martin, G. M., Austad, S. N. & Johnson, T. E. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nature Genet. 13, 25–34 (1996).
Cypser, J. R. & Johnson, T. E. The spe-10 mutant has longer life and increased stress resistance. Neurobiol. Aging 20, 503–512 (1999).
Murakami, S. & Johnson, T. E. Life extension and stress resistance in Caenorhabditis elegans modulated by the tkr-1 gene. Curr. Biol. 8, 1091–1094 (1998).
Abe, J. & Berk, B. C. Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc. Med. 8, 59–64 ( 1998).
Wojcicki, J. et al. Effect of selenium and vitamin E on the development of experimental atherosclerosis in rabbits. Atherosclerosis 87, 9–16 (1991).
Lebovitz, R. M. et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc. Natl Acad. Sci. USA 93, 9782–9787 (1996).
Li, Y. B. et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide-dismutase. Nature Genet. 11, 376–381 (1995).
Wang, P. H. et al. Overexpression of human copper, zinc-superoxide dismutase (SOD1) prevents postischemic injury. Proc. Natl Acad. Sci. USA 95, 4556–4560 ( 1998).
Martensson, J., Steinherz, R., Jain, A. & Meister, A. Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage. Proc. Natl Acad. Sci. USA 86, 8727 –8731 (1989).
Rozanowska, M. et al. Blue light-induced reactivity of retinal age pigment. In vitro generation of oxygen-reactive species. J. Biol. Chem. 270, 18825–18830 (1995).
Hayes, K. C. Retinal degeneration in monkeys induced by deficiencies of vitamin E or A . Invest. Ophthalmol. 13, 499– 510 (1974).
Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).
Andreassen, O. A., Dedeoglu, A., Klivenyi, P., Beal, M. F., & Bush, A. I. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familiar amyotrophic lateral sclerosis. Neuroreport 11, 2491– 2493 (2000).
Nagano, S., Ogawa, Y., Yanagihara, T., & Sakoda, S. Benefit of a combined treatment with trientine and ascorbate in familiar amyotrophic lateral sclerosis model mice. Neurosci. Lett. 265, 159–162 (1999).
Lafon-Cazal, M., Pietri, S., Culcasi, M. & Bockaert, J. NMDA-dependent superoxide production and neurotoxicity. Nature 364 , 535–537 (1993).
Parker, W. D. Jr, B oyson, S. J. & Parks, J. K. Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann. Neurol. 26, 719–723 (1989).
Hennekens, C. H. et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N. Engl. J. Med. 334, 1145–1149 (1996).
Stephens, N. G. et al. Randomised controlled trial of vitamin E in patients with coronary disease. Cambridge Heart Antioxidant Study (CHAOS). Lancet 347, 781–786 ( 1996).
The Alpha-Tocopherol Beta Carotene 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. 330, 1029–1035 (1994).
Seddon, J. M. et al. The use of vitamin supplements and the risk of cataract among US male physicians. Am. J. Public Health 84, 788–792 (1994).
Hankinson, S. E. et al. Nutrient intake and cataract extraction in women: a prospective study. Br. Med. J 305, 335– 339 (1992).
The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease . N. Engl. J. Med. 328, 176– 183 (1993).
Sano, M. et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study . N. Engl. J. Med. 336, 1216– 1222 (1997).
Louwerse, E. S., Weverling, G. J., Bossuyt, P. M., Meyjes, F. E. & de Jong, J. M. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch. Neurol. 52, 559–564 ( 1995).
We thank I. Rovira and R. Wange for their help in the design of illustrations, and T. Johnson, D. Longo, B. Howard, R. Levine, M. Gorospe and N. Epstein for thoughtful comments and discussions.
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Finkel, T., Holbrook, N. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000). https://doi.org/10.1038/35041687
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