The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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A Descriptive Introduction to Human Aging 31. Brunk UT, Wihlmark U, Wrigstad A et al. Accumulation of lipofuscin within retinal pigment epithelial cells results in enhanced sensitivity to photo-oxidation. Gerontology 1995; 41 Suppl 2:201-212. 32. Miyaji C, Watanabe H, Minagawa M et al. Numerical and functional characteristics of lymphocyte subsets in centenarians. J Clin Immunol 1997; 17:420-429. 33. Harman D. Free radical theory of aging: Effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice. J Gerontol 1968; 23:476-482. 34. Kohn RR. Effect of antioxidants on life-span of C57BL mice. J Gerontol 1971; 26:378-380.; 35. Hagen TM, Ingersoll RT, Wehr CM et al. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci 1998; 95:9562-9566. 36. Paniker NV, Srivastava SK, Beutler E. Glutathione metabolism of the red cells. Effect of glutathione reductase deficiency on the stimulation of hexose monophosphate shunt under oxidative stress. Biochim Biophys Acta 1970; 215:456-460. 37. Sies H. Oxidative stress: Introductory remarks. In: Sies H, ed. Oxidative stress. London: Academic Press, Inc., 1985:1-8. 38. Wendel A. Measurement of in vivo lipid peroxidation and toxicological significance. Free Radic Biol Med 1987; 3:355-358. 39. de Grey ADNJ. A mechanism proposed to explain the rise in oxidative stress during aging. J Anti-Aging Med 1998; 1:53-66. 40. Kristal BS, Yu BP. An emerging hypothesis: Synergistic induction of aging by free radicals and Maillard reactions. J Gerontol 1992; 47A:B107-B114. 41. Kawamura M, Heinecke JW, Chait A. Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway. J Clin Invest 1994; 94:771-778. 42. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40:405-412. 43. Iqbal M, Probert LL, Alhumadi NH et al. Protein glycosylation and advanced glycosylated endproducts (AGEs) accumulation: An avian solution? J Gerontol A 1999: 54:B171-B176. 63
CHAPTER 6 History of the Mitochondrial Free Radical Theory of Aging, 1954-1995 This chapter, unlike the rest of the book, is structured explicitly as a narrative. The theoretical and experimental advances which have given rise to the mitochondrial free radical theory of aging are many and varied, and their contributions to the overall theory are liable to be lost in a purely descriptive account. Here, then, is a roughly chronological summary of how the theory approached its current state. 6.1. Precursors of the Mitochondrial Free Radical Theory Gerontologists of the 19th and early 20th century performed many studies aimed at gaining an understanding of what biological properties underlie longevity. Biochemistry was insufficiently advanced to be of use, but by the 1920s it was possible to perform quite sophisticated experiments on live animals. The foremost example, which is often cited to this day, was the work of Raymond Pearl, culminating in his book “The Rate of Living.” 1 In this and prior work, he established detailed correlations between the longevity of fruit flies and certain genetic and environmental factors: in particular, he found that conditions which made the flies less active, due to either temperature or genetic inability to fly, increased their lifespan. He concluded from these studies that, “In general the duration of life varies inversely as the rate of energy expenditure during life.” He was not, however, in a position to hypothesise in any detail how this relationship might come about. 6.2. The First Mechanistic Idea The theory whose modern version will be described in the coming chapters was born in early November, 1954. The man who had the initial idea was then a 38-year-old research associate at the Donner Laboratory of Medical Physics in Berkeley, named Denham Harman. He had spent seven years at Shell Oil working on the chemical properties of free radicals, followed by a course in biology at Stanford. With the help of this cross-disciplinary background, he realised that the reactions which are initiated by free radicals could—in theory—be the driving force for the increasing macromolecular disorganisation that seemed to underlie the aging process. The most amazing thing, to me, about Harman’s idea was that he thought of this before it was known that toxic free radicals existed in the human body at all.* He based the idea only on the fact that oxygen exists in the human body, and on his knowledge that, at the temperature and in the chemical environment of the human body, it might be prone to initiate such reactions. * It had just been established 2 that one well-known and altogether unreactive component of the human body, melanin, is a free radical, and also that their formation was implicated in the toxic effects of hyperoxia and X rays, 3a but that cannot really be considered a hint that any highly reactive ones are constitutively present. 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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CHAPTER 10 Frequently-Asked Questio
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Frequently-Asked Questions The effe
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Frequently-Asked Questions Table 10
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Frequently-Asked Questions through
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Frequently-Asked Questions has been
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Frequently-Asked Questions SOS, sin
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Frequently-Asked Questions for almo
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Frequently-Asked Questions Fig. 10.
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Frequently-Asked Questions Fig. 10.
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Frequently-Asked Questions of elect
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Frequently-Asked Questions Referenc
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Frequently-Asked Questions 45. Clay
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CHAPTER 11 A Challenge from Textboo
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A Challenge from Textbook Bioenerge
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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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