The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

174
The Mitochondrial Free Radical Theory of Aging
This begins to look like a serious problem once one considers the course that aging
takes. The rate at which cells enter SOS evidently accelerates rather rapidly during life. 1,2
Thus, a 10% false negative rate (that is, a removal of only 90% of the anaerobic cells) seems
inadequate; we would want to aim for at most 1% in order to restore the number of such
cells to levels obtaining many years previously.
However, this should be easier to achieve if we can live with erring considerably the
other way, and we probably can. Since so few cells are affected by SOS, it seems likely that
even a 100% false positive rate (that is, a removal of as many healthy cells as anaerobic ones)
would have no detectable deleterious effect. A further encouraging point with respect to
frequency of treatment is that it should not need to become progressively more frequent as
an individual gets older (presuming we solve the other problems).
Another reason for optimism is based on the observation that gene therapy may not
need to be involved (see Section 13.3). It is not particularly fanciful to imagine a chemical
capable of selectively triggering apoptosis in cells with a hyperactive PMOR, which could be
administered without medical supervision—perhaps even orally. Such an option would of
course allow the possibility of very frequent, even daily, treatment; this would in turn allow
a very high false negative rate for each individual treatment.
14.3. Disposal of Dead Cells
This is very unlikely to be a problem. The apoptotic program is just that: a program.
Once the initiating events are in progress, there is a very precise and well-controlled series
of changes of expression of various proteins, many of them already well characterised, which
control not only the cell’s cessation of function but also its destruction by macrophages. It is
reasonable to suppose that induction of apoptosis of anaerobic cells will involve the
stimulation of an early event in normal apoptosis; thus, the strong likelihood is that all the
usual downstream events will follow without further intervention. That includes disposal
of the “carcass.”
14.4. Replacement of Dead Cells
This is much more likely to be a major obstacle. Many cell types in mammals certainly
become depleted during life, as noted in Sections 5.3 and 5.5. 3-5 This has been proposed to
be a trade-off mechanism, since the organism would benefit from the replacement of the
dead cell only if that replacement is accurate, and there is always the risk of DNA replication
error possibly leading to cancer. Thus, if a cell of a particular type becomes inviable quite
frequently, such as in the liver, then it must be replaced regularly in order that the tissue will
last a lifetime. But if the tissue in question is less severely exposed to toxins, its cells may die
only very rarely; in that case, enough cells may remain by old age even if no replacement
whatsoever is done. In practice, many cell types appear to adopt this latter strategy most of
the time, though they can be stimulated to proliferate in exceptional circumstances such as
wounding.
What, then, is likely to be the consequence of removing anaerobic cells, in terms of
their replacement? My hunch, and it is only that, is that the affected tissues will respond very
much as now, by not replacing them, and that this will have minimal impact on the tissue
because so few cells are involved. Moreover, as noted elsewhere we must clearly address the
general issue of replacement of dead cells (irrespective of why they died) in tissues that are
not usually inclined to replace them; it is reasonable to hope that such treatment, once it is
developed for seriously affected cell types such as thymocytes and fibroblasts, will be adaptable
to muscles and possibly even nerves too. 6