The free radical theory of aging proposes that the impairment in physiological performance associated with aging is caused by the detrimental effects of oxygen free radicals. This is interesting because it provides us with a theoretical framework to understand aging and because it suggests a rationale for intervention, i.e., antioxidant administration. Thus, the study of antioxidant systems of the cell may be very important in gerontological studies. Glutathione is one of the main nonprotein antioxidants in the cell which, together with its related enzymes, constitute the “glutathione system.” The involvement of glutathione in aging has been known since the early seventies. Several studies have reported that reduced glutathione is decreased in cells from old animals, whereas oxidized glutathione tends to be increased. Recent experiments from our laboratory have underscored the importance of cellular compartmentation of glutathione. Mitochondrial glutathione plays a key role in the protection against free radical damage associated with aging. Oxidative damage to mitochondrial DNA is directly related to an oxidation of mitochondrial glutathione. In fact, aging is associated with oxidative damage to proteins, nucleic acids, and lipids. These molecular lesions may be responsible for the low physiological performance of aged cells. Thus, antioxidant supplementation may be a rational way to partially protect against age-associated impairment in performance. Apoptosis, a programmed cell death, is an area of research which has seen an explosive growth. Glutathione is involved in apoptosis: apoptotic cells have lower levels of reduced glutathione, and administration of glutathione precursors prevent, or at least delay, apoptosis. Age-associated diseases constitute a major concern for researchers involved in aging. Free radicals are involved in many such diseases; for instance, cancer, diabetes or atherosclerosis. The key role of glutathione and other antioxidants in the pathophysiology of aging and age-associated diseases is discussed in this review.
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Allen, R.G., Sohal, R.S.: Role ofglutathione in the aging and development of insects. In Insect aging. Collatz, K.G. and Sohal, R.S., Eds. Springer Verlag. Berlin Heidelberg. 1986 pp.168–181.
Al-Turk, W., Stohs, S.J., El-Rashidy F.H., Othman, S.: Changes in glutathione and its metabolizing enzymes in human erythrocytes and lymphocytes with age J. Pharm. Pharmacol, 39: 13–16, 1987.
Ames, B.N., Shigenaga, M., Hagen, T.M.: Oxidants, antioxidants and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA, 90: 7915–7922, 1993.
Barja, G., Pérez-Campo, R., López-Torres, L., Cadenas, S., Rojas, C.: Low mitochondrial free radical production as a longevity determinant in species following or not the rate of living theory. Mech. Aging Dev., 1996 (in press).
Beal, M.F., Hyman, B.T., Koroshetz, W.: Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? TINS, 16: 125–131, 1993.
Benzi, G., Marzatico, F., Pastoris, O., Villa, R.F.: Relationship between aging, drug treatment and the cerebral enzymatic antioxidant system. Exp. Gerontol., 24: 137–148, 1989.
Buja, L.M., Eigenbrodt, M.L., Eigenbrodt, E.H.: Apoptosis and Necrosis. Basic Types and Mechanisms of Cell Death. Arch. Pathol. Lab. Med. 117, 1208–1214, 1993.
Buttke, T.M., Sandstrom, P.A.: Oxidative stress as a mediator of apoptosis. Immunol. Today, 15: 7–10, 1994.
Cand, F. and Verdetti, J.: Superoxide dismutase, glutathione peroxidase, catalase, and lipid peroxidation in the major organs of the aging rats. Free Radical Biol. Med., 7:59–63, 1989.
Calleja, M., Peña, P., Ugalde, C., Ferreiro, C., Marco, R., Garesse, R.: Mitochondrial DNA remains intact during Drosophila aging, but the levels of mitochondrial transcripts are significantly reduced. J. Biol. Chem., 268:18891–18897, 1993.
Cannon, J.G., Orencole, S.F., Fielding, R.A., Meydani, M., Meydani, S.N., Fiatarone, M.A., Blumberg, J.B., Evans, W.J.: Acute phase response in exercise-interaction of age and vitamin-E on neutrophils and muscle enzyme release. Am. J. Physiol., 259:1990.
Carney, J.M., Starke-Reed, P.E., Oliver, C.N., Landum, R.W., Cheng, M.S., Wu, J.F. and Floyd, R.A.: Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-a-phenylnitrone. Proc. Natl. Acad. Sci. USA, 88:3633–3636, 1991.
Chance, B., Sies, H., Boveris, A.: Hydroperoxide metabolism in mammalian organs. Physiological Rev., 59: 527–604, 1979.
Corbisier, P., Remacle, J.: Involvement of mitochondria in cell degeneration. Eur. J. Cell Biol., 51: 173–182, 1990.
Coyle, J., Puttfaarcken, P.: Oxidative stress, glutamate and neurodegenerative disorders. Science, 262: 689–694, 1993.
Cutler, R.G.: Antioxidants and aging. Am. J. Clin. Nutr., 53: S373–S379, 1991.
De la Cruz, J., Burón, I., Roncero, I.: Morphological and functional studies during aging at mitochondrial level. Action of drugs. Int. J. Biochem., 22:729–735, 1990.
Deckwerth, T.L., Johnson, E.M.: Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J. Cell Biol., 123: 1207–1222, 1993.
Devasagayam, T.P.: Senescence-associated decrease of NADPH-induced lipid peroxidation in rat liver microsomes. FEBS Lett. 205, 246–50, 1986.
Devasagayam, T.P. and Tarachand, U.: Decreased lipid peroxidation in the rat kidney during gestation. Biochem. Biophys. Res. Commun. 145, 134–8, 1987.
Estrela, J.M., Obrador, E., Navarro, J., Lasso-de-la-Vega, M.C., Pellicer, J.: Elimination of Ehrlich tumors by ATP-induced growth inhibition, glutathione depletion and X-rays. Nature Med. 1, 84–88, 1995.
Ferrer, J.V., Gascó, E., Sastre, J., Pallardó, F.V., Asensi, M., Vifia, J.: Age-related changes in glutathione synthesis in the eye lens. Biochem. J., 269: 531–534, 1990.
Fucci, L., Oliver, C.N., Coon, M.J. and Stadtman, E.R.: Inactivation of key metabolic enzymes by mixed-function oxidation reactions: Possible implication in protein turnover and aging. Proc. Natl. Acad. Sci. USA, 80: 1521–1525, 1983.
Furukawa, T., Meydani, S.N., Blumberg, J.B.: Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech. Aging Dev., 38: 107–117, 1987.
Gadaleta, M.N., Petruzzella, V., Renis, M., Fracasso, F., Cantatore, P.: Reduced transcription of mitochondrial DNA in the senescent rat. Tissue dependence and effect of L-carnitine. Eur. J. Biochem. 187: 501–506, 1990.
Garcia de la Asuncion, J., Millán, A., Pill, R., Bruseghini, L., Esteras, A., Pallardó, F.V., Sastre, J., Viña, J.: Mitochondrial glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA. FASEB J., 10: 333–338, 1996.
Garland, D., Russell, P., Zigler, J.S. Jr.: The oxidative modification of lens proteins. Basic Life Sci. 49, 347–52. 1988.
Goldschmidt, L.: Seasonal variations in red cell glutathione levels with aging in mental patients and normal controls. Proc. Soc. Exp. Biol. Med., 133: 555–559, 1970.
Gordillo, E., Ayala, A., Lobato, M., Bautista, J., Machado, A.: Possible involvement of histidine residues in the loss of enzymatic activity of rat liver malic enzyme during aging. J. Biol. Chem., 263, 8053–8056, 1988.
Gotz, M.E., Freyberger, A., Riederer, P.: Oxidative Stress — A Role in the Pathogenesis of Parkinsons Disease. J. Neur. Transmission, 29: 241–249, 1990.
Gutteridge, J.M.C.: Copper-phenanthroline induced site specific oxygen radical damage to DNA. Detection of loosely bound trace copper in biological fluids. Biochem. J., 218: 983–985, 1984.
Gutteridge, J.M.C., Westermarck, T., and Halliwell, B.: Oxygen radical damage in biological systems. In: Free Radicals, Aging and Degenerative Diseases, pp: 99–139. eds J.E. Johson Jr., R. Walford, D. Harman, J. Miquel. Alan R. Liss, 1986.
Halliwell, B., Gutteridge, J.M.C.: Free Radicals in Biology and Medicine. Claredon, Oxford. 1989.
Hansford, R.G.: Lipid oxidation by heart mitochondria from young adult and senescent rats. Biochem J;170: 285–295, 1978.
Harman, D.: Aging: a theory based on free radical and radiation chemistry J. Gerontol, 11: 298–300, 1956.
Harman, D.: The aging process-Major risk factor for disease and death. Proc. Nat. Acad. Sci. USA, 88: 5360–5363, 1991.
Hazelton, G.A., Lang, C.A.: Glutathione contents of tissues in the aging mouse. Biochem. J;188: 25–30, 1980.
Hockenbery, D.M., Oltvai, Z.N., Yin, X.M., Milliman, C.L., Korsmeyer, S.J.: Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241–251, 1993.
Ikebe, S., Tanaka, M., Ohno, K., Sato, W., Hattori, K., Kondo, T., Mizuno, Y., Ozawa, T.: Increase of deleted mitochondrial DNA in the striatum in Parkinsons Disease and senescence. Biochem. Biophys. Res. Commun; 170: 1044–1048, 1990.
Jankovic, B.D.: Neuromodulation. From phenomenology to molecular evidence. Ann. N.Y. Acad. Sci. 741, 1–38, 1994.
Johns, D.R.: Mitochondrial DNA and disease. New Engl. J. Med; 333:638–644, 1995.
Kalra, J., Rajput, A.H., Mantha, S.V., Chaudhary, A.K., Prasad, K.: Oxygen free radical producing activity of polymorphonuclear leukocytes in patients with Parkinson’s disease. Moll. Cell. Biochem. 112, 181–6, 1992.
Knekt, P., Heliovaara, M., Rissanen, A., Aromaa, A., Aaran, R.-K.: Serum antioxidant vitamins and risk of cataract. Br. Med. J. 305: 1392–1394, 1992.
Kroemer, G., Petit, P., Zamzami, N., Vaysiere, J.L. and Mignotte, B.: The biochemistry of programmed cell death. FASEB J; 9:1277–1287, 1995.
Ku, H., Brunk, U.T., Sohal, R.S.: Relationship between mitochondrial superoxide and hydroperoxide production and longevity of mammalian species. Free Radical Biol. Med; 15: 621–627, 1993.
Leske, M.C., Chylack, L.T. Jr., Wu, S.Y.: The lens opacities case-control study. Risk factors for cataract. Arch. Ophthalmol. 109: 244–251, 1991.
Levine, R.L.: Oxidative modification of glutamine synthetase II. Characterization of the ascorbate model system. J. Biol. Chem; 258:11828–11833, 1983.
Linnane, A., Marzuki, S., Ozawa, T., Tanaka, M.: Mitochondrial DNA mutations as an important contributor to aging and degenerative diseases. Lancet, 642–645, 1989.
Lippman, R.D.: Rapid “in vivo” quantification and comparison of hydroperoxides and oxidized collagen in aging mice, rabbits and man. Exp. Gerontol, 20: 1–5, 1985.
Lippman, R.D.: Free radical-induced lipoperoxidation and aging. In: Handbook of Free Radicals and Antioxidants in Biomedicine Vol. I eds J. Miquel, A.T. Quintanilha, and H. Weber, CRC press, Boca Ratón Cal. USA. 1989.
López-Torres, M., Pérez-Campo, R., Rojas, C., Cadenas, S., Barja, G.: Maximum life span in vertebrates: correlation with liver antioxidant enzymes, glutathione system, ascorbate, urate sensitivity to peroxidation, true malondialdehyde, in vivo H2O2 and basal and, maximum aerobic capacity. Mech. Aging and Dev., 70: 177–99, 1993.
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.
Medvedev, Z.: An Attempt at a Rational Classification of Theories of Aging. Biological Reviews of the Cambridge Philosophical Society, 65: 375–398, 1990.
Meydani, M., Evans, W.J., Handelman, G., Biddle, L., Fielding, R.A., Meydani, S.N., Burrill, J., Fiatarone, M.A., Blumberg, J.B., Cannon, J.G.: Protective effect of vitamin E on exercise-induced oxidative damage in young and older adults. Am. J. Physiol., 33: R992–R998, 1993.
Miquel, J., Economos, A.C., Fleming, J., Johnson, J.E. Jr.: Mitochondrial role in cell aging. Exp. Gerontol., 15: 579–91, 1980.
Miquel, J., Lundgren, P.R., Johnson, J.E.: Spectrophotofluorimetric and electron microscopic study of lipofuscin accumulation in the testis of aging mice, J Gerontol., 33: 5–19, 1978.
Miquel, J., Fleming, J.E.: Theoretical and experimental support for an “oxygen radical-mitochondrial injury” hypothesis of cell aging. In: Free Radicals, Aging and Degenerative Diseases. Johnson, J.E. Jr., Walford, R., Harman, D., Miquel, J. eds. FF. New York: Alan R. Liss 1986, pp: 51–74.
Mizuno, Y., Ohta, K.: Regional distribution of thiobarbituric acid-reactive products, activities of enzymes regulating the metabolism of free radicals and some of the related enzymes. J. Neurochem, 46: 1344–1352, 1986.
Monti, D., Troiano, L., Tropea, F., Grassilli, E., Cossarizza, A., Barozzi, D., Pelloni, M.C., Tamassia, M.G., Bellomo, G., Franceschi, C.: Apoptosis — programmed cell death: a role in the aging process? Am. J. Clin. Nutr. 55: 1208S–14S, 1992.
Muskhelishvili, L., Hart, R.W., Turturro, A., James, S.J.: Age-related changes in the intrinsic rate of apoptosis in livers of diet-restricted and ad tibitum-fed B6C3F1 mice. Am. J. Pathol., 147: 20–24, 1995.
Nohl and Hegner, Do mitochondria produce oxygen radicals in vivo? Eur. J. Biochem. 82, 563–7, 1978.
Oliver, C.N., Ahn, B.W., Moerman, E.J., Goldstein, S., Stadtman, E.R.: Age-related changes in oxidized proteins. J. Biol. Chem. 262, 5488–5491, 1987.
Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A.: Effect of a combination of b carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150–5, 1996
Orr, W.C., Sohal, R.S.: The effects of catalase gene overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Arch. Biochem. Biophys. 297: 35–41, 1992.
Orr, W.C., Sohal, R.S.: Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science, 263: 1128–30, 1994.
Pallardó, F.V., Mompó, J., Esteve, J.M., Sastre, J., Asensi, M.A., Viña, J.: Glutathione oxidation increases in apoptotic fibroblasts. Role of apoptosis in aging. VIII Biennial Meeting. International Society for Free Radical Research Barcelona 1–5 October 1996.
Paradies, G., Ruggiero, F.M.: Effect of aging on the activity of the phosphate carrier and on the lipid composition in rat liver mitochondria. Arch. Biochem. Biophys., 284: 332–337, 1978.
Pinto, R.E., Bartley, WA.: Negative correlation between oxygen uptake and glutathione oxidation in rat liver homogenates. Biochem. J. 114, 5–9, 1969
Pryor, W.: Oxy-radicals and related species: their formation, lifetimes and reactions. Ann. Rev. Physiol. 48: 657–667, 1986.
Ratan, RR., Murphy, T.H, Baraban, J.M.: Oxidative stress induces apoptosis in embryonic cortical neurons. J. Neurochem., 62: 376–379, 1994.
Richter, C., Park, J.W., Ames, B.: Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci. USA, 85: 6465–6467, 1988.
Ritchie, J.P., Leutzinger, Y., Partharsarathy, S., Malloy, V., Orentreich, N., Zimmerman, J.A.: Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J., 8: 1302–1307, 1994.
Rikans, L.E., Moore, D.R.: Effect of aging on aqueous-sphase antioxidants in tissues of male Fischer rats. Biochem. Biophys. Acta, 966: 269–275, 1988.
Saez, G., Thornalley, P.J., Hill, H.A.O., Hems, R., Bannister, JV.: The production of free radicals during the autoxidation of cysteine and their effect on isolated rat hepatocytes. Biochim. Biophys. Acta, 719, 24–31, 1982
Santa Maria, C., Machado, A.: Effects of development and aging on pulmonary NADP-cytochrome c reductase, glutathione peroxidase, glutathione reductase and thioredoxin reductase activities in male and female rats. Mech. Aging Dev., 37: 183–195, 1987.
Sastre, J., Pallardó, F.V., Pá, R., Pellin, A., Juan, G., O’Connor, E., Estrela, J.M., Miquel, J., Viña, J.: Aging of the liver: Age-associated mitochondrial damage in intact hepatocytes. Hepatology 1996 (In press).
Scalettar, B.A., Abney, J.R., Hackenbrock, C.R.: Dynamics, structure and function are coupled in the mitochondrial matrix. Proc. Natl. Acad. Sci. USA., 88: 8057–8061, 1991.
Schwartzman, R.A. and Cidlowski, J.A.: Apoptosis: The biochemistry and Molecular Biology of Programmed Cell Death. Endocrine Rev. 14, 133–151, 1993.
Sawada, C.M., Carlson, J.C.: Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech. Aging Dev. 41:125–137, 1987.
Seto, N.O.L., Hayashi, S., Tener, G.M.: Overexpression of Cu-Zn superoxide dismutase in Drosophila does affect life-span. Proc. Natl. Acad. Sci. USA, 87: 4270–74, 1990.
Sevanian, A., Hochstein, P.: Mechanisms and consequences of lipid peroxidation in biological systems. Ann. Rev. Nutr, 5: 365–390, 1985.
Shigenaga, M.K., Hagen, T.M., Ames, B.N.: Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA, 91: 10771–8, 1994.
Sies, H., Bartoli, G.M., Burk, R.F., Waydhas, C.: Glutathione efflux from perfused rat liver after phenobarbital treatment, during drug oxidations, and in selenium deficiency. Eur. J. Biochem., 89: 113–118, 1978.
Sies, H.: Biochemistry of oxidative stress. Angewandte Chemie, 25: 1058–1071, 1986.
Sohal, R.S.: Hydrogen peroxide production by mitochondria may be a biomarker of aging. Mech. Age Dev., 60: 189–198, 1991.
Sohal, R.S., Arnold, L.A., Sohal, B,H.: Age-related changes in antioxidant enzymes and prooxidant generation in tissues of the rat with special reference to parameters in two insect species. Free Rad. Biol. Med., 9: 495–500, 1990.
Sohal, R.S., Dubey, A.: Mitochondrial oxidative damage, hydrogen peroxide release, and aging. Free Radical. Biol. Med., 16: 621–626, 1994.
Stadtman, E.R.: Protein oxidation and aging. Science, 257: 1220–1224, 1992.
Starke-Reed, P.E., Oliver, C.N.: Protein oxidation and proteolysis during aging and oxidative stress. Arch. Biochem. Biophys., 275: 559–567, 1989.
Smith, C.D., Carney, J.M., Starke-Reed, P.E., Oliver, C.N., Stadtman, E.R., Floyd, R.A., Markesbery, W.R.: Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc. Natl. Acad. Sci. USA, 88: 10540–10543, 1991.
Takeyama, N., Matsuo, N., Tanaka, T.: Oxidative damage to mitochondria is mediated by the Ca2+ inner membrane permeability transition. Biochem. J., 294: 719–25, 1993.
Trounce, I., Byrne, E., Marzuki, S.: Decline in skeletal muscle mitochondrial chain function: possible factor in aging. Lancet, 25 March: 637–639, 1989.
Tummino, P.J., Gafni, A.: A comparative study of succinate-supported respiration and ATP/ADP translocation in liver mitochondrial from adult and old rats. Mech Age. Dev., 59: 177–188, 1991.
Vaux, D.L.: Toward an understanding of the molecular mechanisms of physiological cell death. Proc. Natl. Acad. Sci. USA 90, 786–789, 1993.
Viña, J. (Editor). Glutathione: Metabolism and Physiological Functions. CRC Press, Boston, 1990
Viña, J., Hems, R., Krebs, H.A.: Maintenance of glutathione content in isolated hepatocytes. Biochem. J. 170, 627–630, 1978
Viña, J., Sastre, J., Anton, V., Bruseghini, L., Esteras, A., Asensi, M.: Effect of aging on glutathione metabolism. Protection by antioxidants. In Free Radicals and Aging. Emerit, I. and Chance, B. eds. Birkhauser Verlag. Basel. Switzerland 1992, pp. 136–144.
Vladimirov, Y.A., Archakov, A.I.: Lipid peroxidation in biomembranes (in Russian) Moscow: Nauka 1972.
Vladimirov, Y.A.: Free radical lipid peroxidation in biomembranes: Mechanism, regulation, and biological consequences. In: Free Radicals, Aging and Degenerative Diseases, eds.: J.E. Johnson Jr., R. Walford, D. Harman, J. Miquel. Alan R. Liss, pp: 141–195, 1986.
Wallace, D.C.: Mitochondrial DNA sequence variation in human evolution and disease. Proc. Natl. Acad. Sci. USA, 91: 8739–8746, 1994.
Wolman, M.: Oxidation of lipids and membranes I: in vivo formation of peroxidative lipid polymers. J. Supramol. struct. 3, 80–9, 1975.
Yen, T.C., Chen, Y.S., King, K.L., Yeh, S.H., Wei, Y.H.: Liver mitochondrial respiratory functions decline with age. Biochem. Biophys. Res. Commun., 165: 994–1003, 1989.
Zamzami, N., Marchetti, P., Castedo, M., Hirsch, T., Susin, S.A., Masse, B., Kroemer, G.: Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS lett. 384: 53–57, 1996a.
Zamzami, N.P., Susin, S.A., Marchetti, P., Hirsch, T., Castedo, M., Kroemer, G.: Mitochondrial control of nuclear apoptosis. J. Exp. Med., 183: 1533–1544, 1996b.
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Sastre, J., Pallardó, F.V. & Viña, J. Glutathione, oxidative stress and aging. AGE 19, 129–139 (1996). https://doi.org/10.1007/BF02434082
- oxidative stress