The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

A Descriptive Introduction to Human Aging
If everything that is oxidized were recycled, aging due to pro-oxidant damage simply could
not proceed indefinitely: it would asymptotically approach a maximum level but never exceed
it.*
Therefore, in seeking the root cause of the observed, inexorably rising pro-oxidant
levels, we can restrict ourselves to material that is not recycled at all. They are hearteningly
few in number:
1. some connective proteins (elastin, crystallin, maybe some others)
2. tissues that lose (and fail to replace) cells
3. nuclear DNA
4. mitochondrial DNA, maybe
5. lipofuscin
All of these except mitochondrial DNA are known, as described in the preceding sections,
to be intimately involved in one or other aspect of aging. Mitochondrial DNA is not
immediately implicated, but, as will be explained, it is also a prime suspect.
5.6.2. Oxidative and Reductive Stress
In 1985, Helmut Sies defined** the term "oxidative stress" as “a disturbance in the
prooxidant-antioxidant balance in favor of the former.” 37 His use of the word “balance” was,
I think, both insightful and unhelpful. It was insightful because it emphasises the fact that
pro-oxidants and antioxidants participate in a complex network of reactions, which are
broadly maintained in a stable equilibrium. If this equilibrium is disturbed, such as in disease,
it is restored once the disease has been overcome. But conversely, this emphasis on the stability
of the system gives a misleading impression of the possible role of oxidative stress in aging,
in which there is no such equilibrium; rather, there is an inexorable rise in the levels of
pro-oxidants, which is not balanced by a corresponding rise in antioxidants and which in
fact progressively diminishes those antioxidants’ efficacy.
There is another problem with the term “oxidative stress” which relates to the chemical
reactions involved. I stressed in Chapter 3 that LECs are generally more reactive than
non-LECs; they can be thought of as taking the initiative to undergo reactions of classes a
and b in Table 3.3. “Oxidation” is a term usually reserved for reactions in which the more
reactive molecule is the electron acceptor, but, as Table 3.3 shows, there are many important
reactions related to free radical chemistry in vivo in which the more reactive molecule is the
electron donor. Reactions of this sort are normally termed “reduction”; thus, a situation in
which there is an excess of LECs that are inclined to donate electrons would much better be
called “reductive stress”—a term which, though introduced as long ago as 1987, 38 has not
found widespread use. This is the situation at the earliest stage of LEC production by
mitochondria, where the ubisemiquinone in the respiratory chain donates electrons to
molecular oxygen to form superoxide. It is also the situation that I have proposed 39 to exist
at the cell membrane of respiration-deficient cells, as will be discussed in Chapter 9.
* This logic has clear implications for interventions that might retard aging. Many groups have investigated
the ability of certain antioxidant dietary supplements to reduce the steady-state levels of oxidative damage
to material that is recycled; for example, a recent investigation35 of the effects of combined supplementation
with acetyl-L-carnitine and R-lipoic acid was particularly impressive in restoring youthful metabolic performance
in rat liver. But we do not yet have lifespan data on these rats; I predict that their maximum lifespan
will not be much greater than controls.
** The term had, however, been in use in broadly this sense since at least 1970. 36
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