The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

CHAPTER 9
The Search for How So Few Anaerobic
Cells Cause So Much Oxidative Stress
The apparently low level of mutant mtDNA even in very elderly individuals was perhaps
the most powerful argument, in 1995, against the idea that mtDNA decline is central to
aging. This was stressed in a number of articles at the time; a representative study from
1992 1 drew particular attention to the fact that mitochondria undergo a functional decline
far in excess of the level of mutation, and inferred that mtDNA damage could therefore not
be the cause of this decline. Looking at it another way: we knew2 that cells can survive quite
well with only a fairly small proportion of functioning mitochondria. Therefore, the natural
inference was that a similar level of overcapacity would exist on a larger scale: that a tissue
would be able to function perfectly well even if a significant proportion of its cells had
undergone OXPHOS collapse. The overcapacity would not be expected to be so great as at
the intracellular level, because ATP does not diffuse freely between cells as it does within
cells; thus any mechanism whereby aerobic cells supported their anaerobic neighbours would
presumably have to involve some kind of active exchange of metabolites. But it certainly
seemed unreasonable to suppose that the body should encounter much difficulty if, say,
only 1% of its cells are anaerobic, unless there is some other source of oxidative stress. Thus,
the question of just how few cells were anaerobic in elderly people seemed to be an acid test
of MiFRA—as it stood then.
9.1. How Few?
There has been a great deal of dispute with regard to what proportion of the cells in a
given tissue actually suffer OXPHOS collapse by the time we die. By and large, the disagreement
has been about the absolute, rather than relative, levels of mutant mtDNA: that is, there is
broad consensus about which tissues accumulate more and which less. Moreover, so long as
one only considers postmitotic cell types, there is a reasonably good correlation between the
levels of mutant mtDNA and the energetic load of the tissue: the tissues that make a lot of
LECs, like the substantia nigra of the brain and the extraocular muscles in the eye, are more
heavily affected than the cerebellum or the average skeletal muscle. 3,4
The first obfuscating factor in assessing the absolute levels of a given mutation is
technological. Variants of PCR have been developed which identify point mutations
(see Section 6.6.4), but most such methods are of controversial sensitivity. It is therefore
still extremely difficult to measure, with the degree of accuracy that we would like, the relative
levels of two DNA sequences that differ in only one base pair when they are present in a
ratio exceeding 1:100. Unfortunately, this is exactly what is required in order to test for the
accumulation of mutant mtDNA with aging, because there are so many possible mutations
that (unless a few were far more common than the rest) each one would necessarily occur
only in a small minority of cells. This would be less of a problem if it were proven that point
The Mitochondrial Free Radical Theory of Aging, by Aubrey D.N.J. de Grey.
©1999 R.G. Landes Company.