The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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A Descriptive Introduction to Human Aging Our DNA is actually suffering spontaneous damage at a much greater rate than is indicated by mutations, but the vast majority of this damage is repaired quickly and correctly. Damage of this sort might fairly be called “proto-mutations.” The class of DNA damage which happens more often than any other is the simple falling-off of a base: purines (adenine and guanine: see Fig. 2.10) fall off much more often than pyrimidines, and their loss is called depurination. This is easy to correct accurately, because the other strand of the DNA has the complementary base. Another is the loss of an NH2 (amine) group in favour of a hydroxyl group (OH): this is called deamination.* Again, the deamination of any nucleotide of DNA always produces a molecule that is not a normal constituent of DNA, so it is detectable and reversible. There are two crucial determinants, therefore, of the rate at which mature, irreparable mutations occur. They are the rate at which proto-mutations occur and the quality of those proto-mutations’ repair—that is, the proportion of proto-mutations that are repaired correctly. A major determinant of the quality of repair is the speed of repair. If a mutation happens and nothing is done about it for a while, another one may happen close by. The double mutation may be harder to repair correctly than two single ones each repaired at once. A more frequent situation is when there is only one proto-mutation but it is replicated before being repaired. For example: if a cytosine is deaminated, it becomes uracil, which is not normally part of DNA (only RNA), but some cytosines in DNA are deliberately methylated (a hydrogen atom is replaced by a CH3 group) as a regulatory mechanism, and deamination of a methylated cytosine (methylcytosine) makes thymine. This therefore makes a mispair—a thymine paired to a guanine. 13 There is a specific enzyme that detects thymines paired to guanines and turns them back to cytosine, so in general there is no problem. But if a cell replicates its DNA while there are deaminated methylcytosines in it, this mispairing will be lost: the thymine will be seen as legitimate by the DNA polymerase and the new strand will be constructed with an adenine. The mutation thus becomes permanent. It is interesting to note that the rates of these two processes (damage and repair) are likely to be sensitive to a factor that also regulates the rate of atherogenesis: namely, the preponderance of LECs. In this case, the place where the LECs matter is in the nucleus. LECs are mutagenic, since they react with nucleic acids just as readily as with lipids (see Section 3.4), so their levels will influence the rate of occurrence of proto-mutations. The rate of repair is also likely to suffer from increasing LEC levels, since the proteins which perform that repair are themselves vulnerable to damage—and hence inactivation, or (worse) erroneous function—by LECs. We also appear to possess an anti-cancer mechanism which works in a different way, and which may also be impaired by LECs. Cells that have suffered some, but not all, of the mutations necessary to cause a tumor seem to be identified and induced to die. This process is up-regulated in rodents undergoing caloric restriction, a regime which substantially increases their lifespan (see Section 6.5.4), and has been proposed 14 to explain why caloric restriction reduces the incidence of cancer. 5.3. Disorganization of Connective Tissue: Skin, Artery, Eye, Cartilage Another major feature of aging with which we are all familiar is the loss of elasticity in the skin. This is much more pronounced in sun-exposed skin than elsewhere, indicating that damage is probably caused mainly by ultraviolet light; but that does not explain why it accumulates. The skin’s elasticity derives from the fibres of connective protein in the lower * The replacement is in fact followed by a rearrangement that moves the hydrogen of the hydroxyl group onto a nearby nitrogen. 55
56 The Mitochondrial Free Radical Theory of Aging layers of the skin, called the dermis. These fibres are made mainly from two proteins, collagen and elastin, which are secreted by specialised cells (fibroblasts) and linked into a network outside the cells. This network is not subject to the rapid turnover that intracellular proteins undergo. But, contrary to what is commonly stated, it is (in most tissues, anyway) amenable to some turnover—its half-life in rats is a few months. 15 Fibroblasts are able to secrete an enzyme called collagenase, which breaks collagen down and allows fibres to be replaced. This happens in response to ultraviolet damage, in fact. 16 Unfortunately the repair process is not very precise, so that the network of fibres becomes progressively less organised. This matters, because the regularity of the fibrous network is essential for its elasticity. Again, the point to focus on is not that this damage occurs but that it worsens as we get older. In this case, the worsening is because the ability of fibroblasts to perform the turnover process diminishes with age. This diminution seems to be due to three cellular changes. The first is that, as with DNA repair, the ability of all cells (fibroblasts included) to synthesise protein gradually declines with age. The second is that fibroblasts (along with other skin cell types) diminish in number throughout life. 17 The third, rather more curious, reason is that older tissues destroy a large proportion of newly-created, so undamaged, collagen: 18 this may be due to excessive collagenase production by a few cells that are approaching replicative senescence. 19a Elastin (sometimes—see below) and the other two classes of extracellular matrix protein, proteoglycans and structural glycoproteins, are also slowly recycled. 19b Osteoarthritis is another disease of this type. There, the material whose turnover is inadequate is again collagen, but this time it is the collagen in the cartilage of our joints. As in the skin, it seems that the main reason why collagen turnover diminishes with age is that the fibroblasts which produce and recycle it diminish in number and also in efficacy. 20 A very similar process happens in the lens of the eye, and also in the walls of our major arteries. Both of these are elastic, and need to remain so in order to do their job. They undergo the same sort of damage as UV causes in the skin—random, extra cross-linking of the elastic protein (elastin in the arteries, crystallin in the lens). In this case, though, the reason why the process accelerates with age is one step more indirect. These two materials are not just recycled very slowly, they aren’t recycled at all; thus there are no recycling-responsible cells to blame for the decline. Rather, the cross-linking accelerates because it is caused not by ultraviolet light but by a chemical, and that chemical is increasingly inefficiently removed from the blood. The chemical is simply glucose, and this damage done by too much circulating glucose is called glycation.* Levels of glucose in the blood are controlled by the extremely rapid release of insulin in response to glucose arriving in the blood from the gut. That response diminishes with age, because the uptake of glucose in response to elevated blood insulin becomes increasingly sluggish (especially in inactive or obese individuals); 21 this is probably, once again, a change brought about by (a) reduced function of the glucose uptake process and (b) a reduction in the number of relevant cells. The pathological manifestation of this effect is late-onset (Type II) diabetes. This group of symptoms of aging, therefore, seems to have two underlying driving causes: functional decline of cells, and decrease of cell number due to non-replacement of cells that die. The non-replacement is superficially somewhat curious, since fibroblasts are perfectly capable of cell division—and indeed perform it very rapidly in response to wounding. One very plausible theory is that the avoidance of division in response to the very slow loss of cells that occurs with aging is a defence against cancer: non-division is tolerable (albeit only for a lifetime), whereas each and every cell division carries a risk of DNA replication error that could, if it happened in the wrong gene, initiate a cancer that would kill us sooner. This is not a complete explanation of the phenomenon, however: we * Note that glycation is more wide-ranging than this; we will return to it in Sections 5.6.3 and 6.5.6.
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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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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 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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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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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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