The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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138 The Mitochondrial Free Radical Theory of Aging 65. Lee HW, Blasco MA, Gottlieb GJ et al. Essential role of mouse telomerase in highly proliferative organs. Nature 1998; 392:569-574. 66. Rudolph KL, Chang S, Lee HW et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999; 96:701-712. 67. 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. 68. Li Y, Huang TT, Carlson EJ et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 1995; 11:376-381. 69. Lebowitz RM, Zhang H, Vogel H et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutasedeficient mice. Proc Natl Acad Sci USA 1996; 93:9782-9787. 70. Reaume AG, Elliott JL, Hoffman EK et al. Motor neurons in Cu/Zn superoxide dismutasedeficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 1996; 13:43-47. 71. Carlsson LM, Jonsson J, Edlund T et al. Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci USA 1995; 92:6264-6268. 72. Phillips JP, Campbell SD, Michaud D et al. Null mutation of copper/zinc superoxide dismutase in Drosophila confers hypersensitivity to paraquat and reduced longevity. Proc Natl Acad Sci USA 1989; 86:2761-2765. 73. Orr WC, Sohal RS. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 1994; 263:1128-1130. 74. Parkes TL, Elia AJ, Dickinson D et al. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet 1998; 19:171-174. 75. Arai M, Imai H, Koumura T et al. Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells. J Biol Chem 1999; 274:4924-3493. 76. Kovalenko SA, Kopsidas G, Kelso JM et al. Deltoid human muscle mtDNA is extensively rearranged in old age subjects. Biochem Biophys Res Commun 1997; 232:147-152. 77. Hayakawa M, Katsumata K, Yoneda M et al. Age-related extensive fragmentation of mitochondrial DNA into minicircles. Biochem Biophys Res Commun 1996; 226:369-377. 78. Nagley P, Wei YH. Ageing and mammalian mitochondrial genetics. Trends Genet 1998; 14:513-517.
CHAPTER 11 A Challenge from Textbook Bioenergetics and Free Radical Chemistry This chapter might, logically, have been included as a section of the previous chapter, since it addresses a challenge to SOS. A thorough response to this particular challenge, however, is necessarily chapter-sized. The challenge is as follows: “SOS states that mitochondria which have lost respiratory chain function will do their membranes less LEC-mediated damage. Since such mitochondria increase in number with age, therefore, SOS predicts that the levels of LECs generated by the respiratory chain will fall with age. This is known to be incorrect—superoxide and hydrogen peroxide levels rise with age.” 1,2a There are two gaps in this challenge. The first is the assumption that the levels of LECs in mitochondrially non-mutant cells—which remain in the great majority throughout life —will stay the same with age. The second is the assumption that the LECs which damage mitochondrial membranes are among those whose levels rise with age. The fragility— indeed, inaccuracy—of these two assumptions is the subject of this chapter. 11.1. The Effect of Oxidative Stress on Non-Mutant Mitochondria We saw in Chapter 5 that oxidative stress probably impairs everything that cells do. It seems certain, therefore, that oxidative stress makes cells progressively more sluggish in disposing of LECs as they are generated. If so, then an unchanged rate of LEC production (which is what we would predict in mitochondrially healthy cells) will maintain a higher steady-state concentration of LECs. Thus, superoxide levels may rise with age simply because mitochondrially healthy cells are suffering increasing oxidative stress. Since mitochondrially wild-type cells always outnumber anaerobic ones by a factor of hundreds or more, this change can reasonably be expected to outweigh any reduction in superoxide production by the few mitochondrially mutant cells. The rise in superoxide production with age thus tells us nothing about the cause of the rising oxidative stress; in particular it does not eliminate SOS as that cause. 11.2. Perhydroxyl: The Forgotten Radical The above argument may have appeared to be a clear-cut rebuttal of the challenge with which this chapter began, but it is not. There are both theoretical and experimental reasons to think that, in fact, mutant mitochondria do generate more superoxide than healthy ones. This strikes at the heart of SOS, since without slower peroxidation a mutant mitochondrion will not be amplified. First I shall summarize this theoretical and experimental work, and then I shall explain why higher superoxide production is, after all, compatible with SOS. The Mitochondrial Free Radical Theory of Aging, by Aubrey D.N.J. de Grey. ©1999 R.G. Landes Company.
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COMPANY de Grey The Mitochondrial F
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ISBN: 1-57059-564-X MOLECULAR BIOLO
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7. The Status of Gerontological The
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17. Conclusion: The Role of the Ger
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I cannot overstate my profound grat
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CHAPTER 1 Introduction 1.1. What Is
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Introduction Some may feel that all
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6 The Mitochondrial Free Radical Th
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8 The Mitochondrial Free Radical Th
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10 The Mitochondrial Free Radical T
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18 Fig. 2.7. The respiratory chain.
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24 Fig. 2.9. Types of protein impor
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26 Fig. 2.10. Why the DNA bases pai
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CHAPTER 3 An Introduction to Free R
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An Introduction to Free Radicals Ta
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An Introduction to Free Radicals Fi
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CHAPTER 6 History of the Mitochondr
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History of the Mitochondrial Free R
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CHAPTER 7 The Status of Gerontologi
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Prospective Impact on the Healthy H
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Prospective Impact on the Healthy H
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196 The Mitochondrial Free Radical
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198 The Mitochondrial Free Radical
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Index Symbols “~”, 19 A Acetald
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Index Copper 35, 107 see also trans
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Index Heart comparison to man-made
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Index genetic code 23, 115-118, 177
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Index Perhydroxyl radical 41, 122,
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Index protonation see protonation (
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MOLECULAR BIOLOGY INTELLIGENCE UNIT
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