The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

History of the Mitochondrial Free Radical Theory of Aging, 1954-1995
(The mechanisms underlying this are programmed: this can be inferred from the very rapid
senescence that occurs at the end of a salmon’s life, in contrast to only gradual aging before
that, and in fact the neuroendocrine mechanisms that trigger it, shortly after spawning, are
now somewhat understood.) 45 Also, many fish—including some that grow throughout their
lives—exhibit an intermediate behaviour, senescing gradually just like mammals. 43 The same
range of types of aging is seen in amphibians and reptiles; there are even a few cases of
programmed senescence in mammals, 43 though no negligibly senescing mammals or birds
are known. Thus, indeterminate growth definitely does not confer negligible senescence, 46
as was originally 47 proposed. A much more difficult question to answer, with current data, is
whether negligible senescence requires indeterminate growth; some very longevous fishes
such as rockfish appear to grow extremely slowly if at all, so this may also not be the case.
A principal reason why species with indeterminate growth may be of great relevance to
MiFRA is that, in order to continue growing, they may continue cell division of all tissues,
including muscles and nerves, and they may thereby be escaping the mitochondrial decline
that overtakes other animals’ postmitotic cells (see Sections 6.4 and 8.5.3). It is possible,
alternatively, that the indeterminate growth is achieved purely by making the existing muscle
fibers and nerves longer, but this seems not to be what happens: certain amphibian species
have been shown to perpetuate neurogenesis and myogenesis throughout their lives. 48 Also,
lizards and snakes appear not to accumulate lipofuscin with age in spinal neurons, 49
suggesting that there may be neuronal turnover. We will return to these topics, too, in
Section 12.3.
6.5.6. Some Instructively Unexpected Non-Correlations
Most species of bird are much longer-lived for their metabolic rate than the average
mammal; this was the main motivation for the studies mentioned in Sections 6.5.3. The
natural prediction would be that every contributor to age-related degeneration will be
down-regulated in birds relative to mammals: not only will superoxide production be lower
and lipids less oxidizable, but also (for example) antioxidant enzymes will be present at
higher levels, and there will be less glucose in the blood so as to retard glycation. Curiously,
however, in both cases the reverse is seen. One early study reported a positive correlation of
superoxide dismutase with longevity, 50 but this was done using flightless mammals only
and was derived by factoring out specific metabolic rate—that is, the correlation was between
longevity and (SOD levels divided by oxygen consumption per unit mass). Such a
“correction” may seem well-motivated, but it is arbitrary: equally justifiable would be, for
example, to divide by the square of the metabolic rate. More recent studies compared birds
and mammals of similar metabolic rates, so no such correction was needed; these studies
showed an unambiguous negative correlation between most antioxidant enzyme levels and
longevity. 51,52 Similarly, birds have at least twice the blood glucose levels of mammals. 53a
This tells us that, in some way, antioxidants and low blood glucose are not important
for longevity. How can that be so? My answer brings us back to Harman’s 1972 insight that
the central determinants of the rate of longevity might be in some way inaccessible to dietary
antioxidants. They might also be inaccessible to enzymatic antioxidants, in which case no
positive correlation would be expected. We can go further and explain the negative correlation
by noting that, as explained in Section 5.7.2, no maintenance or defense system is likely to
be unnecessarily good. Thus, if an organism achieves longevity by low LEC production
(and thus low LEC-mediated damage to material inaccessible to antioxidant enzymes), there
will be the side-effect of low LEC-mediated damage to material that is accessible to them.
This allows the organism to lower its investment in the production of those enzymes
(see Fig. 6.2). A plausible compartment that lacks antioxidant enzymes is the mitochondrial
intermembrane space (see Section 11.2.3). 53b,53c
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