The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

CHAPTER 12
Some Testable Predictions of MiFRA
It has often been observed that gerontology is heavy on data but light on theory. A
consequence of this is that, when a theory is propounded which fits the data already
available, it may be unusually difficult to identify experiments to test it: the problem is that
so many of the experiments have already been done in the attempt to inspire a theory in the
first place. Nonetheless, several tests of MiFRA are available. Before introducing them, it
may be worth stressing that each really only tests a component of MiFRA. In a sense this is
inevitable for a theory with so much structure and detail; furthermore, it inspires confidence
that, if MiFRA is broadly correct but some details are wrong, the falsification of those details
will lead more rapidly to a corrected hypothesis than is typical when an entire theory has to
be abandoned.
12.1. Some Predictions of SOS
The hypothesis that SOS is the mechanism of mtDNA decline with aging makes a specific
prediction with regard to which mutations will and will not accumulate in affected cells. As
noted earlier, SOS is proposed to occur when the mutation has the effect of reducing the
proton gradient at the inner membrane of its host mitochondrion. Any mutation that inhibits
the respiratory chain will have this effect, but a mutation that inhibits the ATP synthase,
without at the same time inhibiting the respiratory chain, will not. Therefore, point mutations
in the two ATPase subunits should not accumulate in postmitotic cells.
I noted in Section 8.5.4 that there is already preliminary evidence in support of this.
Müller-Höcker has reported seeing cells which lack ATPase activity, but that all such cells
had also lost cytochrome c oxidase activity. 1 However, this result must be considered
preliminary since the antibody used stains the wholly nuclear-coded F1-ATPase as well as
the Fº. Similarly, Schon has reported a failure of accumulation of point mutations in the
region 8991-8995 within ATPase 6, determined by an assay which did show slight
accumulation at a tRNA site 2 (see Section 6.6.4). Again, though, the fact that this study only
assayed for mutations at five of the 844 base pairs in the ATPase genes weakens the confidence
with which one can cite it in support of SOS. What is needed is a systematic survey of point
mutations throughout the mitochondrial genome, to establish which do and do not accumulate.
It must be stressed that such a survey should, if at all possible, look at mutations that
are known (or seem very likely) seriously or totally to disrupt the relevant gene’s function.
The preference of most studies to date has been to pursue point mutations which have been
shown to cause inherited diseases, but the fact that such mutations are inherited strongly
suggests that they have only a rather slight deleterious effect on gene function: if they were
more serious, they would cause embryonic lethality. This is clear from an examination of
the range of mutations so far identified as causing inherited diseases: all are missense
mutations, which change one amino acid into another, as opposed to nonsense mutations
which turn an amino acid codon into a stop codon and thereby truncate the protein 3
(see Section 6.6.5).
The Mitochondrial Free Radical Theory of Aging, by Aubrey D.N.J. de Grey.
©1999 R.G. Landes Company.