The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
A common belief is that experiments designed to accelerate aging are uninformative,
because shortening lifespan is easy. This logic is severely flawed: such studies are hugely
informative when they “fail”—when the organism exhibits normal lifespan despite the
challenge. Two recent examples are especially spectacular, but have received little attention
compared to related work that is less relevant to human aging.
The first concerns the possible role of telomere shortening in aging. I mentioned in
Section 7.4 that telomeres were shown in 1992 to shorten with age; 62 but in fact, the data
presented showed no shortening whatsoever after the age of about 20. This has recently
been confirmed in a much bigger study. 63 It makes sense, because the cell type studied was
dermal fibroblasts, the ones which replicative senescence studies have most often employed,
and these cells must divide during the years when we are growing (since, obviously, our skin
is growing in area), but thereafter their turnover is next to nil except when stimulated by
tissue damage nearby. But this does not, in itself, tell us whether telomere shortening matters
in aging: all it tells us is that telomere shortening of dermal fibroblasts doesn’t matter (since
it doesn’t happen). Therefore, a much more profound conclusion—in short, that telomere
shortening doesn’t matter in aging at all, at least not in mice—is available from experiments
with knockout mice that have no telomerase activity. Their mean and maximum lifespan
are absolutely undiminished, even if they are bred together for five generations so that their
germ line has progressively shorter telomeres. 64-66 After six generations there are various
deleterious effects due to impaired cell division, but that is of no relevance whatever to how
normal mice age. Yet, even the researchers who performed this study chose to give more
prominence to the phenotype of these sixth-generation mice than to the lack of phenotype
of the earlier-generation mice. The result is that much more media attention has been paid
to the successful abolition of replicative senesence in vitro by constitutive expression of
telomerase 67 —a result which, while hugely important for many biomedical purposes, tells
us nothing whatever about aging.
Knockout mice are also the vehicle for the other “failed acceleration of aging” that I
find so informative. Knockout mice have been made which lack each of the three isoforms
of superoxide dismutase, and only the mitochondrial one causes early (perinatal, in fact)
lethality. 68,69 The cytosolic and extracellular ones seem to be wholly dispensable. 70,71 Again,
however, the authors of the latter studies 70,71 focused attention not on this aspect of their
work but on the finding, much less relevant to aging, that the mice lacking the nonmitochondrial
isoforms were less resistant to acute oxidative stress. Partly as a result, much
more attention has been paid to the very different (and clearly, again, much less relevant to
human aging) results of the corresponding work on fruit flies, whose lifespan is reduced by
80% when they lack cytosolic SOD 72 and increased by 40% when they overexpress it. 73,74 It
has been widely overlooked that the survival of the knockout mice is easily the strongest
evidence yet for Harman’s contention 22 that oxidative damage is especially important in
mitochondria. In vitro work has shown a similar pattern for phospholipid glutathione peroxidase
(for which knockout mice are not yet available). 75
I feel that the recent findings that mtDNA mutation levels are actually very high 76-78
must be methodologically flawed, since the phenomenon of clonal amplification of mutant
mtDNA must necessarily make highly heteroplasmic cells too short-lived (see Section 9.1).
Therefore, if mitochondrial decline really does matter as much as is indicated by the above
results, we must either put the blame on lipofuscin (as Brunk has suggested, 56b,56c but which
is not yet supported by in vivo evidence) or else find a way in which a low level of mutant
mtDNA can matter. The “reductive hotspot” hypothesis is, as yet, the only way the field has
come up with whereby it can matter.