The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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100 The Mitochondrial Free Radical Theory of Aging 22. Ivanov AS, Putvinskii AV, Antonov VF et al. Magnitude of the protein permeability of liposomes following photoperoxidation of lipids. Biophysics 1977; 22:644-648. 23. Brookes PS, Rolfe DFS, Brand MD. The proton permeability of liposomes made from mitochondrial inner membrane phospholipids: Comparison with isolated mitochondria. J Membr Biol 1997; 155:167-174. 24. Mason RP, Walter MF, Mason PE. Effect of oxidative stress on membrane structure: Small-angle X-ray diffraction analysis. Free Radic Biol Med 1997; 23:419-425. 25. de Grey ADNJ. A proposed refinement of the mitochondrial free radical theory of aging. BioEssays 1997; 19:161-166. 26. a)Pallotti F, Chen X, Bonilla E et al. Evidence that specific mtDNA point mutations may not accumulate in skeletal muscle during normal human aging. Am J Hum Genet 1996; 59:591-602. 26. b) Gershon D. More on mitochondria and senescence. BioEssays 1997; 19:533-534. 26. c) de Grey ADNJ. More on mitochondria and senescence—Reply. BioEssays 1997; 19:534. 26. d) Kowald A. Do damaged mitochondria accumulate by delayed degradation? Exp Gerontol 1999; 34: 605-612. 26. e) Gershon D. The mitochondrial theory fo aging: Is the culprit a faulty disposal system rather than indigenous mitochonrial alteration? Exp Gerontol 1999; 34: 613-619. 27. Gosalvez M, Diaz-Gil J, Coloma J et al. Spectral and metabolic characteristics of mitochondrial fractions from rotenone-induced tumours. Br J Cancer 1977; 36:243-253. 28. Fawcett DW, Bloom W. A textbook of histology. 12th ed. New York: Chapman and Hall, 1994. 29. de Grey ADNJ. Incorporation of transmembrane hydroxide transport into the chemiosmotic theory. Bioelectrochem Bioenerg, submitted.
CHAPTER 9 The Search for How So Few Anaerobic Cells Cause So Much Oxidative Stress The apparently low level of mutant mtDNA even in very elderly individuals was perhaps the most powerful argument, in 1995, against the idea that mtDNA decline is central to aging. This was stressed in a number of articles at the time; a representative study from 1992 1 drew particular attention to the fact that mitochondria undergo a functional decline far in excess of the level of mutation, and inferred that mtDNA damage could therefore not be the cause of this decline. Looking at it another way: we knew2 that cells can survive quite well with only a fairly small proportion of functioning mitochondria. Therefore, the natural inference was that a similar level of overcapacity would exist on a larger scale: that a tissue would be able to function perfectly well even if a significant proportion of its cells had undergone OXPHOS collapse. The overcapacity would not be expected to be so great as at the intracellular level, because ATP does not diffuse freely between cells as it does within cells; thus any mechanism whereby aerobic cells supported their anaerobic neighbours would presumably have to involve some kind of active exchange of metabolites. But it certainly seemed unreasonable to suppose that the body should encounter much difficulty if, say, only 1% of its cells are anaerobic, unless there is some other source of oxidative stress. Thus, the question of just how few cells were anaerobic in elderly people seemed to be an acid test of MiFRA—as it stood then. 9.1. How Few? There has been a great deal of dispute with regard to what proportion of the cells in a given tissue actually suffer OXPHOS collapse by the time we die. By and large, the disagreement has been about the absolute, rather than relative, levels of mutant mtDNA: that is, there is broad consensus about which tissues accumulate more and which less. Moreover, so long as one only considers postmitotic cell types, there is a reasonably good correlation between the levels of mutant mtDNA and the energetic load of the tissue: the tissues that make a lot of LECs, like the substantia nigra of the brain and the extraocular muscles in the eye, are more heavily affected than the cerebellum or the average skeletal muscle. 3,4 The first obfuscating factor in assessing the absolute levels of a given mutation is technological. Variants of PCR have been developed which identify point mutations (see Section 6.6.4), but most such methods are of controversial sensitivity. It is therefore still extremely difficult to measure, with the degree of accuracy that we would like, the relative levels of two DNA sequences that differ in only one base pair when they are present in a ratio exceeding 1:100. Unfortunately, this is exactly what is required in order to test for the accumulation of mutant mtDNA with aging, because there are so many possible mutations that (unless a few were far more common than the rest) each one would necessarily occur only in a small minority of cells. This would be less of a problem if it were proven that point 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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An Introduction to Free Radicals Re
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A Challenge from Textbook Bioenerge
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160 The Mitochondrial Free Radical
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CHAPTER 14 Ablation of Anaerobic Ce
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Ablation of Anaerobic Cells: Techni
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CHAPTER 15 Transgenic Copies of mtD
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Transgenic Copies of mtDNA: Techniq
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CHAPTER 16 Prospective Impact on th
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Prospective Impact on the Healthy H
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Prospective Impact on the Healthy H
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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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