The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
absolutely astounding that our antioxidant systems are able to keep us alive at all. They are
just incredibly good already. One reason why it may be very little use to add more antioxidant
is that the longer-lived among us are already balancing optimally the levels of the various
components of our highly complex and subtle natural system, so that adding more of one
of them can only destabilise it. In more concrete biochemical terms, this could derive in
large part from the ability of “antioxidants” to become pro-oxidant—that is, to promote
rather than inhibit deleterious free radical reactions—if present at high concentrations.
Vitamin E has been especially well studied in this regard. 25b,25c
One can also hypothesize a detailed mechanistic explanation, based on the reactions
described in Section 3.7. Superoxide cannot initiate lipid peroxidation directly, but in the
presence of iron (including iron bound to proteins, most relevantly cytochrome c) it can
cause “branching” of peroxidation chain reactions, which is equivalent to initiation since it
turns one chain reaction into two. Furthermore, it was recently established 26 that the
initiation-competent superoxide derivative which does nearly all initiation in the
mitochondrial inner membrane is almost certainly the perhydroxyl radical, HO2•, and not
the hydroxyl radical (HO•) which most people have usually blamed. (The reason for this,
and its rather extensive bioenergetic ramifications, are explored in detail in Chapter 11.)
HO2• is formed directly from superoxide by the addition of a proton, with no involvement
of other molecules (even as catalysts), whereas HO• and all the other LECs discussed in
Chapter 3 are formed by subsequent reactions, such as the splitting of hydrogen peroxide.
We saw in Section 6.5.6 that greater longevity seems to require lowered superoxide
production—more assiduous destruction of superoxide seems not to work—so we can infer
that more assiduous destruction of downstream products of superoxide will also not work.
The relevance of this to the efficacy of dietary antioxidants is that they do not destroy
superoxide or HO2•, only their pro-oxidant derivatives (such as lipid radicals), which,
according to the research described above, are of only minor importance in aging.
10.5. Why Hasn’t SOS Been Tested in Flies or Worms?
Drosophila (a fruit fly) and Caenorhabditis (a nematode worm) might initially appear
to be very promising model organisms for testing SOS: not only are they long-standing
objects of experimental research, with very extensive genetics, but also their cells are virtually
all non-dividing in adulthood. Unfortunately, however, this optimism is misplaced, because
SOS almost certainly doesn’t happen to them. SOS requires cells to exist for enough
mitochondrial generations that a spontaneous mutation can take over the cell. Minimally,
this is the logarithm to base 2 of the number of mitochondrial genomes per cell. Since both
Drosophila and Caenorhabditis live only a few weeks, their mitochondria would have to be
recycled every day or two at least for SOS to happen. We do not know how fast they do turn
over, but a rate of that order seems very unlikely. Indeed, it has been reported that mtDNA
in Drosophila remains intact during aging: 27 such deletions as are found in adult flies
accumulate during development rather than in the adult. 28
In that case, why do they die so young? A plausible answer is simply that their antioxidant
defenses are a great deal less good than ours. For example, flies do not have a gene for glutathione
peroxidase, 29 which is one of the central pillars of our antioxidant system (though
they do have glutathione reductase). 30 Thus, they die of the basal level of oxidative stress,
without needing their mitochondria to amplify it.
10.6. How Can Mutant Mitochondria Survive, Let Alone
Out-Compete Working Ones?
The problem implied in this question is that mitochondrial replication requires
(as noted earlier) the import of hundreds of nuclear-coded proteins, and the import process