The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
of unsettlingly large gaps in the theoretical framework: something which, as previous chapters
have discussed, is broadly a thing of the past.
Consequently I shall devote this chapter to an examination of how, if the theory set out
in previous chapters is indeed correct, we may in principle be able to retard human aging.
The two approaches which I consider most promising will then be analysed in detail in the
following chapters.
13.1. Some Probably Futile Approaches
In principle, if there is indeed a single chain of events which dominates the rate at
which we age, the progress of aging could be greatly retarded by breaking any link in that
chain. Some such treatments might not be able to reverse aging that has already occurred,
but a clean break of any link in the causal chain should put a brake on further progress.
Similarly, a treatment that only weakens, rather than breaks, one of the links would still
retard aging, albeit to a lesser extent. The first question one should consider, therefore, is:
“Supposing (for sake of argument) that MiFRA is correct, which links in it are the most
amenable to disruption?”
Here are the possibilities which seem to be available. They each seek to subvert some
link in the chain of events leading from mtDNA mutations to systemic oxidative stress, and
are listed in causal order with respect to that chain. In theory one might extend the list to
include treatments of the effects of oxidative stress, but I have avoided this because, as
discussed in Section 6.5, the strong evidence from inter-species comparisons is that such
“late-acting” interventions (by which is meant causally late, as opposed to late in the lifespan)
are ineffective if the tide of early events is allowed to continue unabated.
a. Stop the spontaneous mutation of mtDNA
b. Repair spontaneous mutations of mtDNA
c. Introduce extra, wild-type mtDNA into mutant mitochondria
d. Stop OXPHOS from fumbling electrons and making LECs
e. Stop LECs from damaging mitochondrial membranes
f. Destroy mutant mtDNA before it takes over the cell
g. Reverse SOS—give mutant mtDNA a selective disadvantage
h. Abolish cells’ reliance on wild-type mtDNA for OXPHOS
i. Abolish cells’ reliance on OXPHOS for autonomous ATP synthesis
j. Kill cells that have lost OXPHOS function (have become anaerobic)
k. Prevent anaerobic cells from causing the peroxidation of plasma lipids
l. Prevent mitochondrially healthy cells from importing peroxidised lipids
A reasonable first step in deciding which of these is most realistically addressable is to
consider what the body already does. Options a, b, d, e, k and l can, I feel, be excluded from
further consideration on the grounds that the human body already works very hard to achieve
them, by means that have been described earlier in this book, and this work is done by
genetically determined machinery that has been developed by natural selection. Humans
are among the longest-lived species for our metabolic rate, so there is unlikely to be any
grossly suboptimal feature of this machinery. It is possible that, by studying species which
do even better than us (as has been eloquently urged by Austad) 1 we could identify some of
the slightly suboptimal ones, manifest as refinements that these species have achieved, but
mimicking those refinements might be impractically laborious even with the development
of reliable gene therapy (which is discussed in Section 13.4). Moreover, even the most
exceptional birds achieve mortality rate doubling times (see Section 17.1) only about 50%
greater than ours, 1 so this approach could only retard aging by that factor; the deleterious
effects of introducing such genetic changes into a genome that has evolved without them
are virtually certain to outweigh that and result in no net slowdown of aging. The only way