The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

Frequently-Asked Questions
for almost as long as mtDNA’s circularity. 45 Conditions that select for fusion will necessarily
also select for recombination, as a way of stabilising the hybrid genotype of the mitochondrion
and thereby protecting it from genetic drift, as shown in Figure 10.2. And indeed, a more
recent study 46 which essentially repeated the above work 44 but using genotypes in which
recombination products could be easily detected, found them in large quantity.
In conclusion, therefore, the evidence that incomplete and/or rare fusion of
mitochondria occurs is very strong, but the evidence that it occurs fully and frequently
enough to obliterate the forces of intermitochondrial Darwinian selection is not at all
strong. The evidence does not, therefore, constitute a challenge to the admissibility of SOS
as the mechanism of mitochondrial decline during aging.
10.9. Why Doesn’t the Body Just Let (or Make) Affected Cells Die?
This question has a simple, short answer: we don’t know. In fact, it is not all that easy to
establish incontrovertibly that such cells do not indeed die and get replaced. This would
give a simple explanation for why we see so few: they struggle on for a little while but then
succumb, so the ones we see are those which have gone anaerobic only very recently.
This sounds splendid in principle, but—at least in muscle—it seems to be wrong,
probably because of the segmental distribution of anaerobic regions in fibers. The body can
repair grossly damaged muscle by proliferation of satellite cells to make new fibers, and this
includes fusion of new fibers with the surviving parts of old ones, but the gradual reduction
of fiber number during aging 47 suggests that the body may be unable to replace a small
segment of one fiber in the middle of a bundle of healthy ones. If so, the only option would
be to replace the whole fiber—or, possibly, many fibers—when a segment fails; this scale of
fiber turnover would be highly inefficient.
The theory that muscle turnover occurs in response to mitochondrial decline is also
challenged by the observed steady accumulation of damaged fiber segments. As noted in
Section 5.6, any turnover at all should (if anaerobic cells are indeed the main sources of
systemic oxidative stress) lead to an eventual equilibrium situation, where cells are dying
and being replaced as rapidly as they are suffering OXPHOS collapse, and not to the steady
accumulation of anaerobic cells that is in fact seen.
There is the possibility, however, that whole fibers are destroyed without replacement.
This may occur, and would contribute to loss of muscle mass with aging. Moreover, the loss
of muscle mass with aging is known to impair many homeostatic mechanisms, 48,49 so can
cause increased oxidative stress and accelerate mtDNA damage. This possibility needs further
detailed investigation—perhaps also in negligibly senescing species (see Section 12.3).
Cells of some other tissues (such as the liver), however, which can divide on demand
but actually do so rather rarely, probably are destroyed fairly quickly when they become
anaerobic. If they did not, we would expect to see nearly the same level of anaerobic cells
there as in muscle—in fact, probably even more, since the energy utilisation in the liver is
very high—but we in fact see only a smaller proportion. (Cells in the liver certainly die for
many other reasons, though, so we cannot be sure of this logic.)
A neater—though unmechanistic—explanation is the same as that discussed in
Section 6.5.2: we live long enough for our evolutionary niche, so evolution doesn’t care.
This is certainly not the only example of an “obvious” imperfection (in longevity terms)
that evolution has failed to correct: the nonspecificity of macrophages for oxidized LDL,
mentioned in Section 5.1, is another. A third is cancer. Malignant tumours can progress
beyond a very small size only by the generous co-operation of the body in providing an
adequate blood supply, something which one might think it could easily deny. Indeed, some
highly promising experimental cancer treatments involve inducing the body not to provide
blood supply to tumours. 50a However, very recent work has shown that older animals have
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