The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Status of Gerontological Theory in 1995
7.3. The Two Big Mechanistic Gaps in MiFRA’95
The first mechanistic gap was that no one had identified a plausible mechanism to
account for the preferential amplification of mutant mtDNA at the expense of wild-type
DNA, nor for the fact that this amplification occurred to a far greater extent in non-dividing
cells than in rapidly dividing ones. We knew that this happened, but without a simple and
free-standing model for how it happened one was haunted by the lingering doubt that it
was not an autonomous process at all. Perhaps, instead, it was merely a subtle and relatively
harmless downstream effect of oxidative stress, and the dominant source of that oxidative
stress was unrelated to it.
The other gap was that, however one counted them, very few cells ever actually suffered
this OXPHOS collapse at all. Estimates based on quantitative PCR varied widely, and it
was tempting to dismiss them as methodologically flawed; but histochemical analysis left
no real doubt that the proportion of cells affected was under 1% even at death, and in
most tissues much less than that. It was therefore necessary, if mtDNA decline really were
the main driving force, to identify a mechanism whereby this tiny proportion of sick cells
engendered stress to mitochondrially healthy cells. On the face of it, such transmission
seemed highly implausible, because the ATP synthesis capacity of the huge majority, the
mitochondrially healthy cells, would only need to increase by that 1% or less in order to
supply the energetic needs of the anaerobic few.
Both these gaps in the mitochondrial free radical theory of aging may now be bridged.
They will be dealt with in turn in the next two chapters. But first, in order to see why—despite
these problems—many workers remained convinced that mtDNA decline had a major role, we
must also briefly consider the alternatives.
7.4. Some Other Theories and Their Difficulties
I finished Chapter 6 at (roughly) 1995 mainly for a personal reason: it was in that year
that I became involved in theoretical gerontology. The next two chapters will resume the
story, with emphasis on my contributions; thus it is appropriate to conclude this chapter
with a brief review of my impressions of the subject at that time. The question that, necessarily,
confronted me first was where to begin—which of the many lines of thought that
gerontologists had promulgated hitherto was, by my intuition, the most promising and hence
the most attractive to try to extend.
Just as some variants of the mitochondrial free radical theory had fallen by the wayside
due to experimental refutation, so some of the other mechanisms that had previously been
proposed to underlie aging became increasingly unsustainable. One prominent example
was Orgel’s error catastrophe theory. 4 This theory was based on the knowledge that there
was a non-zero error rate in both transcription and translation, so that some proportion
of protein in all cells will have the wrong amino acid sequence even though the gene coding
for it is correct. Orgel realised that, while a small proportion of incorrect protein would do
no harm in most contexts, there was one potential exception—the proteins that actually
perform transcription and translation. An erroneous protein involved in either of those
processes might very well increase the chance that more errors would be introduced into
subsequently constructed proteins. In particular, it could cause errors in the construction
of new copies of itself. Above a certain threshold level, this would become a vicious cycle—a
catastrophe—whereby eventually the cell would cease to be able to construct any correct
protein and would thus die. This theory received widespread acclaim at first, on account of
its undeniable elegance and simplicity. Now, however, essentially no one believes it, simply
because it has become possible to determine whether there is in fact a significant buildup
of incorrect proteins (that is, ones with incorrect amino acid sequence rather than with
oxidative damage) with age, and there is not. 5
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