The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
Furthermore, the involvement of LDL (or other material transported in the blood)
gives us a preliminary explanation for why the cells whose function is most affected by
aging are not exactly the same ones as those whose mtDNA mutation load is highest. In
particular, it is found that muscle fibers accumulate more mutant mtDNA than most other
tissues, 38 but old muscle fibers can work just as well as young ones—the loss of strength
associated with old age is almost entirely due to reduced exercise. 39 Similarly, the failure of
young muscle to thrive when transplanted into old mice, and the converse success of old
muscle transplanted into young mice, has been shown to derive from the old mice’s reduced
ability to re-enervate the transplanted tissue, rather than from any reduced capability of the
muscle fibers themselves. 40 A reasonable conclusion is that nervous tissue is the main victim
of mtDNA-mediated oxidative damage, but muscle is the main toxin.
9.7. Alternative Pathways
The pathway proposed in the previous section is quite complex, and is unlikely to be
unique. It is therefore worthwhile to examine some possible variations.
It is possible that some electron efflux from anaerobic cells is effected by a lactate/
pyruvate couple, rather than via the PMOR. However, there is evidence against an age-related
increase of either lactate or pyruvate in plasma, 10 so this seems likely to play at most a minor
role. On the other hand, it could be argued that the rise in lactate or pyruvate levels would
be very slight and might be outweighed by secondary factors; therefore, a much better test
would be to double-stain muscle tissue asking whether cytochrome c oxidase inactivity
colocalises with hyperactivity of lactate dehydrogenase (LDH), the enzyme that converts
pyruvate to lactate. Histochemical quantification of LDH activity is routine, 41 so this is a
relatively straightforward experiment.
The next step is the transfer of electrons from the PMOR to oxygen, forming superoxide.
It is possible that electrons might move directly from the PMOR to haemin, with no
intermediate, or alternatively via some other intermediate. The involvement of some
intermediate seems likely, because it serves as a reservoir which can be filled and tapped
asynchronously; it thereby allows haemin-bound iron to receive electrons when at some
distance from the anaerobic cell. This permits a greater throughput of electrons than if
physical adjacency of the two were necessary. Oxygen was identified above as the likely major
intermediate, since it is present in much greater amounts in plasma than any other plausible
electron acceptor/donor; it has also been implicated in LDL oxidation, 42,43 though this is
not certain. 44 There have been suggestions that ascorbate itself can act as a pro-oxidant
electron donor, but this has been clearly shown not to be the case in physiological conditions. 45
The role of haemin as the supplier of iron is also probably not unique. I presented
arguments above for why transferrin and ferritin are less prone to be involved, but this
should not be construed as proof that they are not involved at all. Free iron and copper are
hardly present in plasma, due to the activity of ceruloplasmin, 46 but may also play a minor
part.
Finally, LDL is not the only oxidisable substance imported by cells; they also import
free* fatty acids from the plasma. This indeed constitutes the most important pathway of
fatty acid import, since the amounts of phospholipid or cholesteryl ester imported in LDL
are regulated only by the cell’s need for cholesterol. 47a But plasma contains a powerful
enzymatic defense against the oxidation of free fatty acids: a selenium-dependent
phospholipid hydroperoxide glutathione peroxidase, which reduces lipid hydroperoxides to
alcohols, which cannot participate in chain reactions. 47b This means that the levels of free
lipid hydroperoxides in plasma are extremely low, thus protecting cells from importing
* Strictly, not free but bound to albumin until import. 46