The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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188 The Mitochondrial Free Radical Theory of Aging 20. Hiesel R, Combettes B, Brennicke A. Evidence for RNA editing in mitochondria of all major groups of land plants except the Bryophyta. Proc Natl Acad Sci USA 1994; 91:629-633. 21. Michaelis G, Vahrenholz C, Pratje E. Mitochondrial DNA of Chlamydomonas reinhardtii: the gene for apocytochrome b and the complete functional map of the 15.8 kb DNA. Molec Gen Genet 1990; 223:211-216. 22. Seo BB, Kitajima-Ihara T, Chan EKL et al. Molecular remedy of complex I defects: Rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cells. Proc Natl Acad Sci USA 1998; 95:9167-9171. 23. Robinson BH. Use of fibroblast and lymphoblast cultures for detection of respiratory chain defects. Meth Enzymol 1996; 264:454-464. 24. Kellems RE, Allison VF, Butow RA. Cytoplasmic type 80S ribosomes associated with yeast mitochondria. IV. Attachment of ribosomes to the outer membrane of isolated mitochondria. J Cell Biol 1975; 65:1-14. 25. Suissa M, Schatz G. Import of proteins into mitochondria. Translatable mRNAs for imported mitochondrial proteins are present in free as well as mitochondria-bound cytoplasmic polysomes. J Biol Chem 1982; 257:13048-13055. 26. a)Sorensen MA, Kurland CG, Pedersen S. Codon usage determines translation rate in Escherichia coli. J Mol Biol 1989; 207:365-377. 26. b)Corral-Debrinski M, Belgareh N, Blugeon C et al. Overexpression of yeast karyopherin Pse1p/Kap121p stimulates the mitochondrial import of hydrophobic proteins in vivo. Mol Microbiol 1999; 31:1499-1511. 27. Sirrenberg C, Bauer MF, Guiard B et al. Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22. Nature 1996; 384:582-585. 28. Koehler CM, Jarosch E, Tokatlidis K et al. Import of mitochondrial carriers mediated by essential proteins of the intermembrane space. Science 1998; 279:369-373. 29. Walz J, Erdmann A, Kania M et al. 26S proteasome structure revealed by three-dimensional electron microscopy. J Struct Biol 1998; 121:19-29. 30. Perler FB. InBase, the New England Biolabs Intein Database. Electronic database available at http://www.neb.com/neb/inteins.html 31. Wu H, Hu Z, Liu XQ. Protein trans-splicing by a split intein encoded in a split DnaE gene of Synechocystis sp. PCC6803. Proc Natl Acad Sci USA 1998; 95:9226-9231. 32. de Grey ADNJ. Mitochondrial gene therapy: a paradigm for the biomedical application of inteins. Trends Biotechnol 2000; in press.
CHAPTER 16 Prospective Impact on the Healthy Human Lifespan The message of the previous two chapters is that we have a realistic chance of achieving, in only a few decades, a degree of control over the rate of human aging which far exceeds anything that has hitherto seemed feasible. Since that conclusion is rather dramatic, I will use this penultimate chapter to stand back from the technical details and critique it on various other grounds, as well as briefly analysing some of its scientific predictions. The closing chapter then considers a few implications of these predictions, for society at large and (more especially) for the gerontologist; that discussion has the brevity and limited scope which is appropriate in a book principally focused on the scientific issues, but it cannot be omitted entirely. 16.1. Plausibility of Engineered Negligible Senescence A number of eloquent and senior gerontologists have dismissed the possibility of great extensions of healthy lifespan on purely biological grounds, by examining what would be necessary in order to achieve massively improved maintenance and repair of tissue. All such arguments of which I am aware are drastically flawed. Most of the examples I critique in this section come from a very clear and information-packed book published only four years ago by a very prominent gerontologist; 1 they are suitable for analysis not only for that reason but also because that book, like this, was written so as to be accessible to a wide audience. 16.1.1. Plausibility of Indefinite Maintenance One of the commonest arguments that indefinite maintenance is impossible appeals to an analogy between the human body and man-made machines. An example is that the heart is a pump, with many similarities to man-made pumps, albeit with somewhat better efficiency, durability and reliability than any which man has built so far. From this is inferred that, once it does finally begin to lose functionality, the heart can only be kept “on the road” by being overhauled in the same sort of way as a man-made pump. In particular, it would have to be stopped for the duration of that overhaul, and a backup pump substituted. In the specific case of the heart it is unclear how this can be considered a remotely conclusive argument against the feasibility of such maintenance, since exactly that substitution is already done during heart transplants. But there is a much more fundamental flaw in it, which applies equally to any organ, irrespective of our ability to overhaul it by invasive surgery: namely, that it is over-anthropomorphic with regard to scale. It is indeed clear that an engineer cannot overhaul a heart-sized, man-made pump, with a spanner and screwdriver, without first stopping it. But if the pump were the size of St. Paul’s Cathedral, while nevertheless built entirely from independently replaceable components that were all the size of bolts and screws, then the only problem that the engineer would have in performing the overhaul while the pump remained in operation would be with the G-forces. And that—in fact, a 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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CHAPTER 3 An Introduction to Free R
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CHAPTER 7 The Status of Gerontologi
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The Status of Gerontological Theory
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CHAPTER 8 The Search for How Mutant
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The Search for How Mutant mtDNA is
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CHAPTER 9 The Search for How So Few
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The Search for How So Few Anaerobic
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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 Fig. 10.
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Frequently-Asked Questions Fig. 10.
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Frequently-Asked Questions of elect
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