The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

Ablation of Anaerobic Cells: Techniques and Hurdles
14.5. Segmental Cell Death
The last obstacle to this treatment may well be the most severe. We saw in Section 9.6
that muscle, though not being the tissue type most affected by mitochondrial decline in
terms of performance, is probably the most important in terms of its toxicity because we
have so much of it. Thus, unless we can apply this treatment to muscle it is probably not
going to do us much good. This means that we must address a feature of SOS in muscle that
was discussed in Section 6.6.1: its segmentality.
Recall that the proportion of muscle fibers that have lost OXPHOS activity by old age,
as observed in transverse sections (where the muscle is cut perpendicular to the fibers, so
that each fiber appears as a disc) is under 1%, but the length of an anaerobic segment as
revealed in longitudinal staining (where a single fiber is separated from the sample and
stained along its length) is almost always under 1 mm. Since fibers can be many inches long,
this means that a hefty proportion of fibers are anaerobic somewhere or other. Apoptosis is
inducible in muscle fibers, but is unlikely to stop at the same boundaries that mitochondria
do: if it kills anything then it will probably kill the whole fiber. Thus, the damage done to
tissue by this treatment may, after all, outweigh its benefits.
The main reason not to regard this as a complete show-stopper for the whole idea is
that we still do not understand apoptosis all that well, especially not in tissues (such as
muscle) where it plays a very minor role—if any—in normal tissue development and
turnover. I consider it quite possible that, as our understanding increases—and it is increasing
extremely quickly as I write, with the elucidation of the roles of caspases, cytochrome c,
Bcl-2 and several other proteins—we will learn how the apoptotic program can be modulated
to restrict itself only to a small segment of a muscle fiber. That would not be the end of the
story, since the complete absence of this segment might have effects on the rest of the fiber,
such as the failure to transmit the action potential when a motor neuron fires. Again, however,
such problems seem to me to be potentially remediable if satellite cells can be recruited to
replace the deleted segments; the new fibers formed after a wound fuse with the surviving
portion of existing fibers, so this is not particularly unrealistic.
Another plausible way out of this difficulty would be to stimulate necrosis, rather than
apoptosis, in the affected cells. Necrosis can be induced in small regions of muscle tissue by
bupivacaine hydrochloride, and if the concentration is appropriate the fibers are killed but
the neighbouring satellite cells survive and regenerate the tissue. 7,8 This has been used recently
as a way of reducing the levels of mutant mtDNA in muscle of a sufferer from an inherited
mtDNA mutation. 9 The difficulty with necrosis is that, unlike apoptosis, we do not yet
understand how to trigger it selectively in individual cells: it is therefore a treatment which,
at present, is potentially useful only for reducing the extremely high tissue-wide levels of
mutant mtDNA seen in these strange inherited diseases.
References
1. Corral-Debrinski M, Horton T, Lott MT et al. Mitochondrial DNA deletions in human
brain: Regional variability and increase with advanced age. Nature Genet 1992; 2:324-329.
2. Cortopassi GA, Shibata D, Soong NW et al. A pattern of accumulation of a somatic deletion
of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 1992; 89:7370-7374.
3. Mays PK, McAnulty RJ, Campa JS et al. Age-related changes in collagen synthesis and
degradation in rat tissues. Importance of degradation of newly synthesized collagen in
regulating collagen production. Biochem J 1991; 276:307-313.
4. Mitrovic D, Quintero M, Stankovic A et al. Cell density of adult human femoral condylar
articular cartilage. Joints with normal and fibrillated surfaces. Lab Invest 1983; 49:309-316.
5. Miyaji C, Watanabe H, Minagawa M et al. Numerical and functional characteristics of
lymphocyte subsets in centenarians. J Clin Immunol 1997; 17:420-429.
6. Lowenstein DH, Parent JM. Brain, heal thyself. Science 1999; 283:1126-1127.
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