The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

88
The Mitochondrial Free Radical Theory of Aging
Some other prominent theories of aging have come under circumstantial challenge
because of our ability, by dietary supplementation or depletion, to influence the rate of
accumulation of the supposed causative agent, and the finding that this is not accompanied
by changes in the rate of aging in general. For example, vitamin E deficiency markedly
accelerates the accumulation of lipofuscin in lysosomes, 6 but does not accelerate aging;
conversely some chemicals are known (particularly centrophenoxine, also known as
meclophenoxate) which seem to dissolve lipofuscin 7,8 but do not seem to retard aging
(except perhaps by inducing voluntary calorie restriction 9a —see Section 10.4). This is not a
proof that lipofuscin is unimportant in aging, because the dietary modulation may not be
affecting the “important” lipofuscin in vivo, but it does constitute circumstantial evidence.
(However, both the vitamin E and the centrophenoxine findings have been contradicted in
more recent studies.) 9b-9d Similar interventions are being developed (in rodents) to retard
and reverse glycation of long-lived proteins; 10 likewise, as yet there are no reports of lifespan
effects. (On the other hand, the deleterious effects of these changes will surely increase to
life-threatening levels if given significantly more time. Thus, if we were to identify and thoroughly
subvert the major driving force(s) in aging, it would become correspondingly more
necessary also to subvert many currently peripheral phenomena. Such work is therefore an
unarguably vital contribution to life extension research.)
The theory that was perhaps the most similar to MiFRA in terms of its compatibility
with known facts and the size of the gaps that remained in it was the telomere theory. This
is based on the long-established finding 11 that vertebrate cells, with the exception of cancer
cells, cannot be grown indefinitely in culture: their rate of division gradually slows, until
eventually they stop dividing altogether, a phenomenon termed replicative senescence. The
telomere theory of aging is founded on a proposed mechanism for replicative senescence: it
suggests that the rate of aging is predominantly determined by the progressive loss of DNA
from the ends of chromosomes of dividing cells, a process that was first postulated by
Olovnikov in 1971 12,13 and independently by Watson. 14 This is proposed not as a challenge
to the evidently central role of oxidative stress, but rather as a process which—by an as yet
undetermined mechanism—brings oxidative stress about. The fact that oxidative stress
appears to affect non-dividing cells more than dividing ones is proposed to result from the
dependence of these non-dividing cells on material (maybe proteinaceous, maybe hormonal)
secreted by the dividing ones, and in particular from the inability of the non-dividing cells
to cope with changes in the level and/or nature of these secretions which result from the
shortening of the dividing cells’ telomeres.
The telomere theory also ranked well by the theoretical and experimental criteria
discussed earlier. On the theoretical side, telomere shortening can readily be fitted into a
positive feedback loop, which is necessary in order to explain why aging accelerates as it
progresses (see Section 5.6.3). In this case, then, we seek a mechanism whereby telomere
shortening might be accelerated by oxidative stress. A possible mechanism is that DNA
damage from oxidative stress is not repaired when it occurs in telomeric DNA, but instead is
allowed to develop into a full-blown chromosome break, following which the segment of
DNA beyond the break is lost. Turning to the experimental criteria: accelerated telomere
shortening in oxidative stress was confirmed experimentally. 15,16 It was in due course also
confirmed (but see Section 10.15) that human telomeres do shorten with age; 17 it was
moreover found—at least in cell culture—that cells with very short telomeres did indeed
undergo changes of gene expression, 18 and finally in 1998 that maintenance of telomerase
expression allowed normal (that is, non-cancerous) cells in culture to avoid replicative
senescence. 19-21 The main gap in this hypothesis, as of 1995, was the failure to identify any
relevant secreted substance whose changing levels might harm non-dividing cells (or to
identify the relevance of secreted substances that have been identified, such as collagenase