The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

Prospects for Intervention
to do better than that would be to identify refinements that no species has yet found; that
would require an astronomical improvement in our understanding of the relationship
between a protein’s sequence and its function.
Option i is the next against the wall. OXPHOS appears to have evolved only once in
history; it is an astoundingly subtle process. Our chances of coming up with something
equivalent (which lacks OXPHOS’s side-effects) are vanishingly small. This is not least because
the laws of thermodynamics dictate that energy conversion can be done efficiently only by
extracting it in a series of small steps. It is no use getting energy out of chemical bonds
(in glucose, etc.) if it mostly goes into heat—it has to be channelled into phosphorylation—
and any such system must, in order to achieve the same energetic efficiency, be about as
complex as OXPHOS itself is. Biology we might hope to tinker with; physics is another
matter.
Now let us consider option g. I believe that it can be discarded even without extending
it to a specific proposal for implementing it (which, in the first place, is not by any means
easy to think of). If mitochondria with reduced ability to generate a proton gradient were
somehow selected against, it follows that mitochondria with an unusually large proton
gradient would be selected for. And, as noted in Section 8.5.4, this is exactly the predicted
property of mitochondria that have suffered a point mutation in an ATP synthase subunit.
Such mitochondria are clearly no more useful to the cell than those which SOS amplifies. In
fact, the reversal of SOS may be even worse than that: it may be rapidly lethal to all cells,
irrespective of their mitochondrial genotype(s). If it were implemented in the most direct
way, by reversing the preference of lysosomes to digest mitochondria that have become
dysfunctionally leaky to protons, then in one mitochondrial generation all cells would become
populated mainly with mitochondria that are burning oxygen for all they are worth and
making no ATP.
That leaves four lines of exploration: c, f, h and j. All have been touted as realistic ways
forward. However, I believe that c and f are likely to fail. The problem they both face is that
the restoration of normal mtDNA in the cell cannot be instantaneous: it can only act to
increase the number of functioning mitochondria, steadily, until the cell is restored to health.
But, as we have seen, a cell some of whose mitochondria are working and some not exerts a
huge selective pressure to amplify the mutant ones and to destroy the wild-type ones. I
therefore predict that either option c, reintroduction of wildtype mtDNA 2-4 or option f,
destruction of mutant mtDNA (either explicitly or by suppressing its ability to be replicated)
so as to promote amplification, by default, of the residual wildtype mtDNA 5-7 will be
overpowered by selective pressure the other way. Destruction of mutant mtDNA has an
additional risk: it may in fact accelerate the loss of OXPHOS. The fact that we can make
mtDNA-less (ρ 0 ) cells in vitro by inhibiting mtDNA replication tells us that mitochondria
can, if forced, divide even when they have failed to replicate their DNA. Genetic drift ensures
that nearly all mitochondria in a heteroplasmic cell are homozygous; thus, many cells may
harbour some mitochondria homozygous for a mild, hypomorphic mutation which reduces
OXPHOS but not so much as to give a selective advantage. (This is particularly the case in
the inherited diseases discussed in Section 6.6.5.) If this hypomorphic mtDNA were destroyed,
mitochondria would be formed which had no mtDNA and were thus completely
OXPHOS-less; these, unlike the hypomorphs, would be clonally amplified and take over
their host cell (see Fig. 13.1).
This leaves us with options h and j, which are the subject of the rest of this chapter and
the following two. Some may feel that the process of elimination I have conducted above is
unjustifiably cavalier. I certainly see nothing wrong with trying to influence the aging process
by any of the means I have rejected above. For example, option a might be attempted by
targeting a SOD to the intermembrane space, as has recently been done in yeast; 8 option k
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