Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Nov 8;91(23):10771–10778. doi: 10.1073/pnas.91.23.10771

Oxidative damage and mitochondrial decay in aging.

M K Shigenaga 1, T M Hagen 1, B N Ames 1
PMCID: PMC45108  PMID: 7971961

Abstract

We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.

Full text

PDF
10771

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adachi K., Fujiura Y., Mayumi F., Nozuhara A., Sugiu Y., Sakanashi T., Hidaka T., Toshima H. A deletion of mitochondrial DNA in murine doxorubicin-induced cardiotoxicity. Biochem Biophys Res Commun. 1993 Sep 15;195(2):945–951. doi: 10.1006/bbrc.1993.2135. [DOI] [PubMed] [Google Scholar]
  2. Amenta F., Ferrante F., Lucreziotti R., Ricci A., Ramacci M. T. Reduced lipofuscin accumulation in senescent rat brain by long-term acetyl-L-carnitine treatment. Arch Gerontol Geriatr. 1989 Sep-Oct;9(2):147–153. doi: 10.1016/0167-4943(89)90035-6. [DOI] [PubMed] [Google Scholar]
  3. Ames B. N., Shigenaga M. K., Hagen T. M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7915–7922. doi: 10.1073/pnas.90.17.7915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arnheim N., Cortopassi G. Deleterious mitochondrial DNA mutations accumulate in aging human tissues. Mutat Res. 1992 Sep;275(3-6):157–167. doi: 10.1016/0921-8734(92)90020-p. [DOI] [PubMed] [Google Scholar]
  5. Asano K., Amagase S., Matsuura E. T., Yamagishi H. Changes in the rat liver mitochondrial DNA upon aging. Mech Ageing Dev. 1991 Nov 1;60(3):275–284. doi: 10.1016/0047-6374(91)90040-7. [DOI] [PubMed] [Google Scholar]
  6. Aureli T., Miccheli A., Ricciolini R., Di Cocco M. E., Ramacci M. T., Angelucci L., Ghirardi O., Conti F. Aging brain: effect of acetyl-L-carnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR spectroscopy. Brain Res. 1990 Aug 27;526(1):108–112. doi: 10.1016/0006-8993(90)90255-a. [DOI] [PubMed] [Google Scholar]
  7. Bandy B., Davison A. J. Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med. 1990;8(6):523–539. doi: 10.1016/0891-5849(90)90152-9. [DOI] [PubMed] [Google Scholar]
  8. Bartness T. J., Elliott J. A., Goldman B. D. Control of torpor and body weight patterns by a seasonal timer in Siberian hamsters. Am J Physiol. 1989 Jul;257(1 Pt 2):R142–R149. doi: 10.1152/ajpregu.1989.257.1.R142. [DOI] [PubMed] [Google Scholar]
  9. Beal M. F. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol. 1992 Feb;31(2):119–130. doi: 10.1002/ana.410310202. [DOI] [PubMed] [Google Scholar]
  10. Beal M. F., Hyman B. T., Koroshetz W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci. 1993 Apr;16(4):125–131. doi: 10.1016/0166-2236(93)90117-5. [DOI] [PubMed] [Google Scholar]
  11. Boffoli D., Scacco S. C., Vergari R., Solarino G., Santacroce G., Papa S. Decline with age of the respiratory chain activity in human skeletal muscle. Biochim Biophys Acta. 1994 Apr 12;1226(1):73–82. doi: 10.1016/0925-4439(94)90061-2. [DOI] [PubMed] [Google Scholar]
  12. Bondy S. C. Reactive oxygen species: relation to aging and neurotoxic damage. Neurotoxicology. 1992 Spring;13(1):87–100. [PubMed] [Google Scholar]
  13. Bowling A. C., Mutisya E. M., Walker L. C., Price D. L., Cork L. C., Beal M. F. Age-dependent impairment of mitochondrial function in primate brain. J Neurochem. 1993 May;60(5):1964–1967. doi: 10.1111/j.1471-4159.1993.tb13430.x. [DOI] [PubMed] [Google Scholar]
  14. Brand M. D., Couture P., Else P. L., Withers K. W., Hulbert A. J. Evolution of energy metabolism. Proton permeability of the inner membrane of liver mitochondria is greater in a mammal than in a reptile. Biochem J. 1991 Apr 1;275(Pt 1):81–86. doi: 10.1042/bj2750081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Brand M. D. The proton leak across the mitochondrial inner membrane. Biochim Biophys Acta. 1990 Jul 25;1018(2-3):128–133. doi: 10.1016/0005-2728(90)90232-s. [DOI] [PubMed] [Google Scholar]
  16. Brustovetsky N. N., Amerkhanov Z. G., Popova EYu, Konstantinov A. A. Reversible inhibition of electron transfer in the ubiquinol. Cytochrome c reductase segment of the mitochondrial respiratory chain in hibernating ground squirrels. FEBS Lett. 1990 Apr 9;263(1):73–76. doi: 10.1016/0014-5793(90)80708-q. [DOI] [PubMed] [Google Scholar]
  17. Brustovetsky N. N., Mayevsky E. I., Grishina E. V., Gogvadze V. G., Amerkhanov Z. G. Regulation of the rate of respiration and oxidative phosphorylation in liver mitochondria from hibernating ground squirrels, Citellus undulatus. Comp Biochem Physiol B. 1989;94(3):537–541. doi: 10.1016/0305-0491(89)90193-4. [DOI] [PubMed] [Google Scholar]
  18. Bulpitt K. J., Pikó L. Variation in the frequency of complex forms of mitochondrial DNA in different brain regions of senescent mice. Brain Res. 1984 May 21;300(1):41–48. doi: 10.1016/0006-8993(84)91339-8. [DOI] [PubMed] [Google Scholar]
  19. Byrne E., Dennett X. Respiratory chain failure in adult muscle fibres: relationship with ageing and possible implications for the neuronal pool. Mutat Res. 1992 Sep;275(3-6):125–131. doi: 10.1016/0921-8734(92)90017-j. [DOI] [PubMed] [Google Scholar]
  20. Choi D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988 Oct;1(8):623–634. doi: 10.1016/0896-6273(88)90162-6. [DOI] [PubMed] [Google Scholar]
  21. Corral-Debrinski M., Horton T., Lott M. T., Shoffner J. M., Beal M. F., Wallace D. C. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet. 1992 Dec;2(4):324–329. doi: 10.1038/ng1292-324. [DOI] [PubMed] [Google Scholar]
  22. Corral-Debrinski M., Shoffner J. M., Lott M. T., Wallace D. C. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res. 1992 Sep;275(3-6):169–180. doi: 10.1016/0921-8734(92)90021-g. [DOI] [PubMed] [Google Scholar]
  23. Cortopassi G. A., Arnheim N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 1990 Dec 11;18(23):6927–6933. doi: 10.1093/nar/18.23.6927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Coyle J. T., Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993 Oct 29;262(5134):689–695. doi: 10.1126/science.7901908. [DOI] [PubMed] [Google Scholar]
  25. Dawson V. L., Dawson T. M., London E. D., Bredt D. S., Snyder S. H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6368–6371. doi: 10.1073/pnas.88.14.6368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Dowson J. H., Wilton-Cox H., Cairns M. R., Ramacci M. T. The morphology of lipopigment in rat Purkinje neurons after chronic acetyl-L-carnitine administration: a reduction in aging-related changes. Biol Psychiatry. 1992 Jul 15;32(2):179–187. doi: 10.1016/0006-3223(92)90021-q. [DOI] [PubMed] [Google Scholar]
  27. Duffy P. H., Feuers R. J., Leakey J. A., Nakamura K., Turturro A., Hart R. W. Effect of chronic caloric restriction on physiological variables related to energy metabolism in the male Fischer 344 rat. Mech Ageing Dev. 1989 May;48(2):117–133. doi: 10.1016/0047-6374(89)90044-4. [DOI] [PubMed] [Google Scholar]
  28. Duffy P. H., Feuers R., Nakamura K. D., Leakey J., Hart R. W. Effect of chronic caloric restriction on the synchronization of various physiological measures in old female Fischer 344 rats. Chronobiol Int. 1990;7(2):113–124. doi: 10.3109/07420529009056963. [DOI] [PubMed] [Google Scholar]
  29. Eilers M., Endo T., Schatz G. Adriamycin, a drug interacting with acidic phospholipids, blocks import of precursor proteins by isolated yeast mitochondria. J Biol Chem. 1989 Feb 15;264(5):2945–2950. [PubMed] [Google Scholar]
  30. Favit A., Nicoletti F., Scapagnini U., Canonico P. L. Ubiquinone protects cultured neurons against spontaneous and excitotoxin-induced degeneration. J Cereb Blood Flow Metab. 1992 Jul;12(4):638–645. doi: 10.1038/jcbfm.1992.88. [DOI] [PubMed] [Google Scholar]
  31. Fernandez-Silva P., Petruzzella V., Fracasso F., Gadaleta M. N., Cantatore P. Reduced synthesis of mtRNA in isolated mitochondria of senescent rat brain. Biochem Biophys Res Commun. 1991 Apr 30;176(2):645–653. doi: 10.1016/s0006-291x(05)80233-5. [DOI] [PubMed] [Google Scholar]
  32. Fiore L., Rampello L. L-acetylcarnitine attenuates the age-dependent decrease of NMDA-sensitive glutamate receptors in rat hippocampus. Acta Neurol (Napoli) 1989 Oct;11(5):346–350. [PubMed] [Google Scholar]
  33. Folkers K., Morita M., McRee J., Jr The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun. 1993 May 28;193(1):88–92. doi: 10.1006/bbrc.1993.1593. [DOI] [PubMed] [Google Scholar]
  34. Fraga C. G., Shigenaga M. K., Park J. W., Degan P., Ames B. N. Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4533–4537. doi: 10.1073/pnas.87.12.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Franceschi C., Cossarizza A., Troiano L., Salati R., Monti D. Immunological parameters in aging: studies on natural immunomodulatory and immunoprotective substances. Int J Clin Pharmacol Res. 1990;10(1-2):53–57. [PubMed] [Google Scholar]
  36. Frei B., Kim M. C., Ames B. N. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4879–4883. doi: 10.1073/pnas.87.12.4879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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. 1990 Feb 14;187(3):501–506. doi: 10.1111/j.1432-1033.1990.tb15331.x. [DOI] [PubMed] [Google Scholar]
  38. Gadaleta M. N., Rainaldi G., Lezza A. M., Milella F., Fracasso F., Cantatore P. Mitochondrial DNA copy number and mitochondrial DNA deletion in adult and senescent rats. Mutat Res. 1992 Sep;275(3-6):181–193. doi: 10.1016/0921-8734(92)90022-h. [DOI] [PubMed] [Google Scholar]
  39. Ghirardi O., Caprioli A., Milano S., Giuliani A., Ramacci M. T., Angelucci L. Active avoidance learning in old rats chronically treated with levocarnitine acetyl. Physiol Behav. 1992 Jul;52(1):185–187. doi: 10.1016/0031-9384(92)90451-7. [DOI] [PubMed] [Google Scholar]
  40. Gille J. J., Joenje H. Cell culture models for oxidative stress: superoxide and hydrogen peroxide versus normobaric hyperoxia. Mutat Res. 1992 Sep;275(3-6):405–414. doi: 10.1016/0921-8734(92)90043-o. [DOI] [PubMed] [Google Scholar]
  41. Gupta S. Membrane signal transduction in T cells in aging humans. Ann N Y Acad Sci. 1989;568:277–282. doi: 10.1111/j.1749-6632.1989.tb12517.x. [DOI] [PubMed] [Google Scholar]
  42. Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem. 1992 Nov;59(5):1609–1623. doi: 10.1111/j.1471-4159.1992.tb10990.x. [DOI] [PubMed] [Google Scholar]
  43. Hansford R. G. Bioenergetics in aging. Biochim Biophys Acta. 1983 Apr 15;726(1):41–80. doi: 10.1016/0304-4173(83)90010-1. [DOI] [PubMed] [Google Scholar]
  44. Hansford R. G. Lipid oxidation by heart mitochondria from young adult and senescent rats. Biochem J. 1978 Feb 15;170(2):285–295. doi: 10.1042/bj1700285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Hatch G. M., Vance D. E., Wilton D. C. Rat liver mitochondrial phospholipase A2 is an endotoxin-stimulated membrane-associated enzyme of Kupffer cells which is released during liver perfusion. Biochem J. 1993 Jul 1;293(Pt 1):143–150. doi: 10.1042/bj2930143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Hayakawa M., Torii K., Sugiyama S., Tanaka M., Ozawa T. Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA of human diaphragm. Biochem Biophys Res Commun. 1991 Sep 16;179(2):1023–1029. doi: 10.1016/0006-291x(91)91921-x. [DOI] [PubMed] [Google Scholar]
  47. Henneberry R. C., Novelli A., Cox J. A., Lysko P. G. Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised neurons. An hypothesis for cell death in aging and disease. Ann N Y Acad Sci. 1989;568:225–233. doi: 10.1111/j.1749-6632.1989.tb12512.x. [DOI] [PubMed] [Google Scholar]
  48. Hoch F. L. Cardiolipins and biomembrane function. Biochim Biophys Acta. 1992 Mar 26;1113(1):71–133. doi: 10.1016/0304-4157(92)90035-9. [DOI] [PubMed] [Google Scholar]
  49. Hoch F. L. Lipids and thyroid hormones. Prog Lipid Res. 1988;27(3):199–270. doi: 10.1016/0163-7827(88)90013-6. [DOI] [PubMed] [Google Scholar]
  50. Holehan A. M., Merry B. J. Lifetime breeding studies in fully fed and dietary restricted female CFY Sprague-Dawley rats. 1. Effect of age, housing conditions and diet on fecundity. Mech Ageing Dev. 1985 Dec;33(1):19–28. doi: 10.1016/0047-6374(85)90106-x. [DOI] [PubMed] [Google Scholar]
  51. Holliday R. Food, reproduction and longevity: is the extended lifespan of calorie-restricted animals an evolutionary adaptation? Bioessays. 1989 Apr;10(4):125–127. doi: 10.1002/bies.950100408. [DOI] [PubMed] [Google Scholar]
  52. Huber L. A., Xu Q. B., Jürgens G., Böck G., Bühler E., Gey K. F., Schönitzer D., Traill K. N., Wick G. Correlation of lymphocyte lipid composition membrane microviscosity and mitogen response in the aged. Eur J Immunol. 1991 Nov;21(11):2761–2765. doi: 10.1002/eji.1830211117. [DOI] [PubMed] [Google Scholar]
  53. JANSKY L. Total cytochrome oxidase activity and its relation to basal and maximal metabolism. Nature. 1961 Mar 18;189:921–922. doi: 10.1038/189921a0. [DOI] [PubMed] [Google Scholar]
  54. Jakovcic S., Swift H. H., Gross N. J., Rabinowitz M. Biochemical and stereological analysis of rat liver mitochondria in different thyroid states. J Cell Biol. 1978 Jun;77(3):887–901. doi: 10.1083/jcb.77.3.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Joseph J. A., Roth G. S. Cholinergic systems in aging: the role of oxidative stress. Clin Neuropharmacol. 1992;15 (Suppl 1 Pt A):508A–509A. doi: 10.1097/00002826-199201001-00264. [DOI] [PubMed] [Google Scholar]
  56. KUNKEL H. O., CAMPBELL J. E., Jr Tissue cytochrome oxidase activity and body weight. J Biol Chem. 1952 Sep;198(1):229–236. [PubMed] [Google Scholar]
  57. Kirkwood T. B. DNA, mutations and aging. Mutat Res. 1989 Jan;219(1):1–7. doi: 10.1016/0921-8734(89)90035-0. [DOI] [PubMed] [Google Scholar]
  58. Ku H. H., Brunk U. T., Sohal R. S. Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic Biol Med. 1993 Dec;15(6):621–627. doi: 10.1016/0891-5849(93)90165-q. [DOI] [PubMed] [Google Scholar]
  59. Laganiere S., Yu B. P. Modulation of membrane phospholipid fatty acid composition by age and food restriction. Gerontology. 1993;39(1):7–18. doi: 10.1159/000213509. [DOI] [PubMed] [Google Scholar]
  60. Leprat P., Ratinaud M. H., Julien R. A new method for testing cell ageing using two mitochondria specific fluorescent probes. Mech Ageing Dev. 1990 Mar 15;52(2-3):149–167. doi: 10.1016/0047-6374(90)90121-u. [DOI] [PubMed] [Google Scholar]
  61. Linnane A. W., Baumer A., Maxwell R. J., Preston H., Zhang C. F., Marzuki S. Mitochondrial gene mutation: the ageing process and degenerative diseases. Biochem Int. 1990 Dec;22(6):1067–1076. [PubMed] [Google Scholar]
  62. Linnane A. W., Zhang C., Baumer A., Nagley P. Mitochondrial DNA mutation and the ageing process: bioenergy and pharmacological intervention. Mutat Res. 1992 Sep;275(3-6):195–208. doi: 10.1016/0921-8734(92)90023-i. [DOI] [PubMed] [Google Scholar]
  63. Lipton S. A., Choi Y. B., Pan Z. H., Lei S. Z., Chen H. S., Sucher N. J., Loscalzo J., Singel D. J., Stamler J. S. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature. 1993 Aug 12;364(6438):626–632. doi: 10.1038/364626a0. [DOI] [PubMed] [Google Scholar]
  64. Lipton S. A. Models of neuronal injury in AIDS: another role for the NMDA receptor? Trends Neurosci. 1992 Mar;15(3):75–79. doi: 10.1016/0166-2236(92)90013-x. [DOI] [PubMed] [Google Scholar]
  65. Liu Y., Rosenthal R. E., Starke-Reed P., Fiskum G. Inhibition of postcardiac arrest brain protein oxidation by acetyl-L-carnitine. Free Radic Biol Med. 1993 Dec;15(6):667–670. doi: 10.1016/0891-5849(93)90171-p. [DOI] [PubMed] [Google Scholar]
  66. Malis C. D., Weber P. C., Leaf A., Bonventre J. V. Incorporation of marine lipids into mitochondrial membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8845–8849. doi: 10.1073/pnas.87.22.8845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Manfridi A., Forloni G. L., Arrigoni-Martelli E., Mancia M. Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-L-carnitine and NGF. Int J Dev Neurosci. 1992 Aug;10(4):321–329. doi: 10.1016/0736-5748(92)90021-q. [DOI] [PubMed] [Google Scholar]
  68. Marnett L. J., Hurd H. K., Hollstein M. C., Levin D. E., Esterbauer H., Ames B. N. Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104. Mutat Res. 1985 Jan-Feb;148(1-2):25–34. doi: 10.1016/0027-5107(85)90204-0. [DOI] [PubMed] [Google Scholar]
  69. McCarter R., Masoro E. J., Yu B. P. Does food restriction retard aging by reducing the metabolic rate? Am J Physiol. 1985 Apr;248(4 Pt 1):E488–E490. doi: 10.1152/ajpendo.1985.248.4.E488. [DOI] [PubMed] [Google Scholar]
  70. Mecocci P., MacGarvey U., Kaufman A. E., Koontz D., Shoffner J. M., Wallace D. C., Beal M. F. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol. 1993 Oct;34(4):609–616. doi: 10.1002/ana.410340416. [DOI] [PubMed] [Google Scholar]
  71. Meldrum B., Garthwaite J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990 Sep;11(9):379–387. doi: 10.1016/0165-6147(90)90184-a. [DOI] [PubMed] [Google Scholar]
  72. Miquel J., Fleming J. E. A two-step hypothesis on the mechanisms of in vitro cell aging: cell differentiation followed by intrinsic mitochondrial mutagenesis. Exp Gerontol. 1984;19(1):31–36. doi: 10.1016/0531-5565(84)90029-9. [DOI] [PubMed] [Google Scholar]
  73. Miranda A. F., Ishii S., DiMauro S., Shay J. W. Cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence for a nuclear DNA-encoded mutation. Neurology. 1989 May;39(5):697–702. doi: 10.1212/wnl.39.5.697. [DOI] [PubMed] [Google Scholar]
  74. Monyer H., Hartley D. M., Choi D. W. 21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures. Neuron. 1990 Aug;5(2):121–126. doi: 10.1016/0896-6273(90)90302-v. [DOI] [PubMed] [Google Scholar]
  75. Müller-Höcker J. Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: an age-related alteration. J Neurol Sci. 1990 Dec;100(1-2):14–21. doi: 10.1016/0022-510x(90)90006-9. [DOI] [PubMed] [Google Scholar]
  76. Müller-Höcker J., Schneiderbanger K., Stefani F. H., Kadenbach B. Progressive loss of cytochrome c oxidase in the human extraocular muscles in ageing--a cytochemical-immunohistochemical study. Mutat Res. 1992 Sep;275(3-6):115–124. doi: 10.1016/0921-8734(92)90016-i. [DOI] [PubMed] [Google Scholar]
  77. Münscher C., Müller-Höcker J., Kadenbach B. Human aging is associated with various point mutations in tRNA genes of mitochondrial DNA. Biol Chem Hoppe Seyler. 1993 Dec;374(12):1099–1104. doi: 10.1515/bchm3.1993.374.7-12.1099. [DOI] [PubMed] [Google Scholar]
  78. Münscher C., Rieger T., Müller-Höcker J., Kadenbach B. The point mutation of mitochondrial DNA characteristic for MERRF disease is found also in healthy people of different ages. FEBS Lett. 1993 Feb 8;317(1-2):27–30. doi: 10.1016/0014-5793(93)81484-h. [DOI] [PubMed] [Google Scholar]
  79. Nakahara I., Kikuchi H., Taki W., Nishi S., Kito M., Yonekawa Y., Goto Y., Ogata N. Changes in major phospholipids of mitochondria during postischemic reperfusion in rat brain. J Neurosurg. 1992 Feb;76(2):244–250. doi: 10.3171/jns.1992.76.2.0244. [DOI] [PubMed] [Google Scholar]
  80. Nohl H., Hegner D. Do mitochondria produce oxygen radicals in vivo? Eur J Biochem. 1978 Jan 16;82(2):563–567. doi: 10.1111/j.1432-1033.1978.tb12051.x. [DOI] [PubMed] [Google Scholar]
  81. Novelli A., Reilly J. A., Lysko P. G., Henneberry R. C. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res. 1988 Jun 7;451(1-2):205–212. doi: 10.1016/0006-8993(88)90765-2. [DOI] [PubMed] [Google Scholar]
  82. Okayasu T., Curtis M. T., Farber J. L. Structural alterations of the inner mitochondrial membrane in ischemic liver cell injury. Arch Biochem Biophys. 1985 Feb 1;236(2):638–645. doi: 10.1016/0003-9861(85)90668-x. [DOI] [PubMed] [Google Scholar]
  83. Pande S. V., Parvin R. Characterization of carnitine acylcarnitine translocase system of heart mitochondria. J Biol Chem. 1976 Nov 10;251(21):6683–6691. [PubMed] [Google Scholar]
  84. Pappu A. S., Fatterpaker P., Sreenivasan A. Phospholipase A2 of rat liver mitochondria in vitamin E deficiency. Biochem J. 1978 May 15;172(2):349–352. doi: 10.1042/bj1720349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Paradies G., Ruggiero F. M. Age-related changes in the activity of the pyruvate carrier and in the lipid composition in rat-heart mitochondria. Biochim Biophys Acta. 1990 Apr 5;1016(2):207–212. doi: 10.1016/0005-2728(90)90060-h. [DOI] [PubMed] [Google Scholar]
  86. Paradies G., Ruggiero F. M., Dinoi P. Decreased activity of the phosphate carrier and modification of lipids in cardiac mitochondria from senescent rats. Int J Biochem. 1992 May;24(5):783–787. doi: 10.1016/0020-711x(92)90012-p. [DOI] [PubMed] [Google Scholar]
  87. 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. 1991 Feb 1;284(2):332–337. doi: 10.1016/0003-9861(91)90304-2. [DOI] [PubMed] [Google Scholar]
  88. Paradies G., Ruggiero F. M., Gadaleta M. N., Quagliariello E. The effect of aging and acetyl-L-carnitine on the activity of the phosphate carrier and on the phospholipid composition in rat heart mitochondria. Biochim Biophys Acta. 1992 Jan 31;1103(2):324–326. doi: 10.1016/0005-2736(92)90103-s. [DOI] [PubMed] [Google Scholar]
  89. Pikó L., Bulpitt K. J., Meyer R. Structural and replicative forms of mitochondrial DNA in tissues from adult and senescent BALB/c mice and Fischer 344 rats. Mech Ageing Dev. 1984 Jul;26(1):113–131. doi: 10.1016/0047-6374(84)90170-2. [DOI] [PubMed] [Google Scholar]
  90. Pikó L., Hougham A. J., Bulpitt K. J. Studies of sequence heterogeneity of mitochondrial DNA from rat and mouse tissues: evidence for an increased frequency of deletions/additions with aging. Mech Ageing Dev. 1988 Jun;43(3):279–293. doi: 10.1016/0047-6374(88)90037-1. [DOI] [PubMed] [Google Scholar]
  91. Porter R. K., Brand M. D. Body mass dependence of H+ leak in mitochondria and its relevance to metabolic rate. Nature. 1993 Apr 15;362(6421):628–630. doi: 10.1038/362628a0. [DOI] [PubMed] [Google Scholar]
  92. Richter C., Park J. W., Ames B. N. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6465–6467. doi: 10.1073/pnas.85.17.6465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Ruggiero F. M., Cafagna F., Petruzzella V., Gadaleta M. N., Quagliariello E. Lipid composition in synaptic and nonsynaptic mitochondria from rat brains and effect of aging. J Neurochem. 1992 Aug;59(2):487–491. doi: 10.1111/j.1471-4159.1992.tb09396.x. [DOI] [PubMed] [Google Scholar]
  94. Rugolo M., Lenaz G. Monitoring of the mitochondrial and plasma membrane potentials in human fibroblasts by tetraphenylphosphonium ion distribution. J Bioenerg Biomembr. 1987 Dec;19(6):705–718. doi: 10.1007/BF00762304. [DOI] [PubMed] [Google Scholar]
  95. Sacher G. A., Hart R. W. Longevity, aging and comparative cellular and molecular biology of the house mouse, Mus musculus, and the white-footed mouse, Peromyscus leucopus. Birth Defects Orig Artic Ser. 1978;14(1):71–96. [PubMed] [Google Scholar]
  96. Sato T., Tauchi H. Age changes of mitochondria of rat kidney. Mech Ageing Dev. 1982 Oct;20(2):111–126. doi: 10.1016/0047-6374(82)90063-x. [DOI] [PubMed] [Google Scholar]
  97. Schoonen W. G., Wanamarta A. H., van der Klei-van Moorsel J. M., Jakobs C., Joenje H. Hyperoxia-induced clonogenic killing of HeLa cells associated with respiratory failure and selective inactivation of Krebs cycle enzymes. Mutat Res. 1990 May-Jul;237(3-4):173–181. doi: 10.1016/0921-8734(90)90023-k. [DOI] [PubMed] [Google Scholar]
  98. Sershen H., Harsing L. G., Jr, Banay-Schwartz M., Hashim A., Ramacci M. T., Lajtha A. Effect of acetyl-L-carnitine on the dopaminergic system in aging brain. J Neurosci Res. 1991 Nov;30(3):555–559. doi: 10.1002/jnr.490300313. [DOI] [PubMed] [Google Scholar]
  99. Simpson J. R., Isacson O. Mitochondrial impairment reduces the threshold for in vivo NMDA-mediated neuronal death in the striatum. Exp Neurol. 1993 May;121(1):57–64. doi: 10.1006/exnr.1993.1071. [DOI] [PubMed] [Google Scholar]
  100. Smith M. W., Collan Y., Kahng M. W., Trump B. F. Changes in mitochondrial lipids of rat kidney during ischemia. Biochim Biophys Acta. 1980 May 28;618(2):192–201. doi: 10.1016/0005-2760(80)90025-9. [DOI] [PubMed] [Google Scholar]
  101. Sohal R. S., Brunk U. T. Mitochondrial production of pro-oxidants and cellular senescence. Mutat Res. 1992 Sep;275(3-6):295–304. doi: 10.1016/0921-8734(92)90033-l. [DOI] [PubMed] [Google Scholar]
  102. Sohal R. S., Dubey A. Mitochondrial oxidative damage, hydrogen peroxide release, and aging. Free Radic Biol Med. 1994 May;16(5):621–626. doi: 10.1016/0891-5849(94)90062-0. [DOI] [PubMed] [Google Scholar]
  103. Sohal R. S., Sohal B. H. Hydrogen peroxide release by mitochondria increases during aging. Mech Ageing Dev. 1991 Feb;57(2):187–202. doi: 10.1016/0047-6374(91)90034-w. [DOI] [PubMed] [Google Scholar]
  104. Sohal R. S., Svensson I., Brunk U. T. Hydrogen peroxide production by liver mitochondria in different species. Mech Ageing Dev. 1990 Apr 30;53(3):209–215. doi: 10.1016/0047-6374(90)90039-i. [DOI] [PubMed] [Google Scholar]
  105. Sohal R. S., Svensson I., Sohal B. H., Brunk U. T. Superoxide anion radical production in different animal species. Mech Ageing Dev. 1989 Aug;49(2):129–135. doi: 10.1016/0047-6374(89)90096-1. [DOI] [PubMed] [Google Scholar]
  106. Soong N. W., Hinton D. R., Cortopassi G., Arnheim N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet. 1992 Dec;2(4):318–323. doi: 10.1038/ng1292-318. [DOI] [PubMed] [Google Scholar]
  107. Spoerri P. E. Mitochondrial alterations in ageing mouse neuroblastoma cells in culture. Monogr Dev Biol. 1984;17:210–220. [PubMed] [Google Scholar]
  108. Stadtman E. R. Protein oxidation and aging. Science. 1992 Aug 28;257(5074):1220–1224. doi: 10.1126/science.1355616. [DOI] [PubMed] [Google Scholar]
  109. Sucher N. J., Lipton S. A. Redox modulatory site of the NMDA receptor-channel complex: regulation by oxidized glutathione. J Neurosci Res. 1991 Nov;30(3):582–591. doi: 10.1002/jnr.490300316. [DOI] [PubMed] [Google Scholar]
  110. Taglialatela G., Angelucci L., Ramacci M. T., Werrbach-Perez K., Jackson G. R., Perez-Polo J. R. Stimulation of nerve growth factor receptors in PC12 by acetyl-L-carnitine. Biochem Pharmacol. 1992 Aug 4;44(3):577–585. doi: 10.1016/0006-2952(92)90452-o. [DOI] [PubMed] [Google Scholar]
  111. Takamura T., Sugiyama S., Ozawa T. The effects of ubidecarenone derivatives on the action of phospholipase. Arzneimittelforschung. 1987 Feb;37(2):153–156. [PubMed] [Google Scholar]
  112. Tauchi H., Sato T. Changes in hepatic cell mitochondria during parabiosis between old and young rats. Mech Ageing Dev. 1980 Jan;12(1):7–14. doi: 10.1016/0047-6374(80)90023-8. [DOI] [PubMed] [Google Scholar]
  113. Torii K., Sugiyama S., Takagi K., Satake T., Ozawa T. Age-related decrease in respiratory muscle mitochondrial function in rats. Am J Respir Cell Mol Biol. 1992 Jan;6(1):88–92. doi: 10.1165/ajrcmb/6.1.88. [DOI] [PubMed] [Google Scholar]
  114. Trounce I., Byrne E., Marzuki S. Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet. 1989 Mar 25;1(8639):637–639. doi: 10.1016/s0140-6736(89)92143-0. [DOI] [PubMed] [Google Scholar]
  115. Vorbeck M. L., Martin A. P., Park J. K., Townsend J. F. Aging-related decrease in hepatic cytochrome oxidase of the Fischer 344 rat. Arch Biochem Biophys. 1982 Mar;214(1):67–79. doi: 10.1016/0003-9861(82)90009-1. [DOI] [PubMed] [Google Scholar]
  116. WEINBACH E. C., GARBUS J. Oxidative phosphorylation in mitochondria from aged rats. J Biol Chem. 1959 Feb;234(2):412–417. [PubMed] [Google Scholar]
  117. Wallace D. C. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628–632. doi: 10.1126/science.1533953. [DOI] [PubMed] [Google Scholar]
  118. Wallace D. C., Ye J. H., Neckelmann S. N., Singh G., Webster K. A., Greenberg B. D. Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: mitochondrial DNA genes sustain seventeen times more mutations. Curr Genet. 1987;12(2):81–90. doi: 10.1007/BF00434661. [DOI] [PubMed] [Google Scholar]
  119. Wilson P. D., Franks L. M. The effect of age on mitochondrial ultrastructure and enzymes. Adv Exp Med Biol. 1975;53:171–183. doi: 10.1007/978-1-4757-0731-1_13. [DOI] [PubMed] [Google Scholar]
  120. 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. 1989 Dec 29;165(3):944–1003. doi: 10.1016/0006-291x(89)92701-0. [DOI] [PubMed] [Google Scholar]
  121. Yu B. P., Suescun E. A., Yang S. Y. Effect of age-related lipid peroxidation on membrane fluidity and phospholipase A2: modulation by dietary restriction. Mech Ageing Dev. 1992 Aug;65(1):17–33. doi: 10.1016/0047-6374(92)90123-u. [DOI] [PubMed] [Google Scholar]
  122. van den Berg J. J., Op den Kamp J. A., Lubin B. H., Kuypers F. A. Conformational changes in oxidized phospholipids and their preferential hydrolysis by phospholipase A2: a monolayer study. Biochemistry. 1993 May 11;32(18):4962–4967. doi: 10.1021/bi00069a035. [DOI] [PubMed] [Google Scholar]
  123. von Zglinicki T., Marzabadi M. R., Roomans G. M. Water and ion distributions in myocytes cultured under oxidative stress mimic changes found in the process of aging. Mech Ageing Dev. 1991 Apr 1;58(1):49–60. doi: 10.1016/0047-6374(91)90119-k. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES