The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
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The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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Prospects for Intervention Fig. 13.1. See opposite page. 13.2. A Way to Obviate mtDNA The proteins encoded in the mtDNA are vital, integral components of the OXPHOS machinery. In rejecting option i, I have thus already accepted that these genes are indispensable. What is not so clear, however, is that they need to be carried in mitochondria. Could we not make copies of those genes and incorporate them into cells’ nuclear DNA? 169

170 The Mitochondrial Free Radical Theory of Aging These copies would be vastly less prone to spontaneous mutation than their mitochondrially-located counterparts, since they would be 1. far from mitochondria and the LECs they produce, 2. safe from replication error, since the nuclear DNA of non-dividing cells (which are the ones that matter) does not replicate, and 3. safe from the huge selective pressure for mutations that affects mitochondrially-located DNA. When a mtDNA mutation occurs, it will then not matter whether or not it is amplified, because the protein products of the mutant gene will not be necessary to the host mitochondrion. (And anyway, SOS predicts that it will actually not be amplified, because the host mitochondrion will be generating a normal proton gradient using the nuclear-coded protein.) In genetic terminology, the nuclear copy will complement the mutant mitochondrial one. This technique is termed allotopic expression of the mtDNA genes. There are numerous difficulties with this treatment. In focusing on it, I am in no way belittling these difficulties; all I claim is that none of them is so great as those which confront the alternative approaches rejected above. They will be discussed in detail in Chapter 15. 13.3. A Way to Destroy Anaerobic Cells Next, consider option j. Its logic is that OXPHOS collapse of only 1% of cells would be perfectly tolerable if it did not affect all the rest of our cells so badly. If those cells were removed, therefore, we would not suffer noticeably from their absence and we would benefit greatly from the loss of their toxic electrons. Accordingly, I think their removal is a plausible avenue for intervention, and I will examine it in detail in Chapter 14. This option for retarding aging has one clear advantage relative to complementation of mtDNA and one clear disadvantage. The disadvantage is that, unless and until ways are found to stimulate replacement of the ablated cells, there would be a steady—albeit slow—decline in the functionality of non-dividing tissues. This will be addressed further in Section 14.4. The advantage is that such a treatment may be developable—to a degree of reliability that makes it useful—more quickly than the complementation of mtDNA. This is because complementation of mtDNA by nuclear genes will definitely not be possible without gene therapy, whereas ablation of anaerobic cells may well be achievable by simpler technology. A discussion of what gene therapy is (and aims to become) is therefore appropriate. 13.4. Gene Therapy Gene therapy is the treatment of a medical condition by adding DNA to a patient’s cells. The DNA that one would add depends, naturally, on the condition which is being treated; in principle one can add whatever DNA one wants. In general one would want to add new, intact copies of genes whose existing copies were mutant, thus relieving the symptoms of the mutant genes. Development of treatments involving gene therapy really breaks into two parts: design and delivery. That is: 1. figure out what DNA to insert into the nucleus in order to achieve the effect; 2. figure out how to actually get that DNA into the nucleus of our cells. 13.4.1. How Close Is It? Delivery of DNA to cells is very complex. Luckily, however, it is the same for any DNA, and there are plenty of ailments other than aging which are caused by mutations and which could be treated by inserting new DNA. Thus, there is already a huge research effort worldwide seeking ways to do this. As with any technological advance, no one really knows how long it

Prospects for Intervention<br />

Fig. 13.1. See opposite page.<br />

13.2. A Way to Obviate mtDNA<br />

<strong>The</strong> proteins encoded in the mtDNA are vital, integral components <strong>of</strong> the OXPHOS<br />

machinery. In rejecting option i, I have thus already accepted that these genes are indispensable.<br />

What is not so clear, however, is that they need to be carried in mitochondria.<br />

Could we not make copies <strong>of</strong> those genes and incorporate them into cells’ nuclear DNA?<br />

169

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