The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
giving mice a diet which is sufficient in protein, vitamins and minerals of all types, but is
perhaps 40% lower than normal in fats and carbohydrates. Crucially, it increases mice’s
maximum lifespan as well as the average, in contrast to antioxidants which appear only to
“rectangularise” the distribution of mortality by raising the average lifespan but not the
maximum (see Section 6.4). This phenomenon was largely ignored for nearly 40 years after
its discovery, but once real interest in it began (in the 1970s) people rapidly observed that
the association of calorie restriction with longer life might be at least broadly explained by
MiFRA, since the rate of turnover of nutrients determines the rate of transfer of electrons
along the respiratory chain, and would thus be expected to dictate the rate of production of
superoxide. 37 Initial calculations of specific metabolic rate based on caloric intake 37,38 showed
that, indeed, the calorie-restricted mice had lower metabolic rate proportional to their
increase in lifespan, in line with the rate-of-living theory. This was actually found to be in
error when metabolic rate was measured explicitly, 39 but more recent work has shown that
the detailed biochemical predictions of MiFRA (such as that repair enzymes will be
upregulated by CR) are indeed seen, in line with the inter-species molecular differences
noted in the previous section. Moreover, these same biochemical changes have been identified
in the ongoing studies of primate CR. 40-42
6.5.5. Longevity and Indeterminate Growth
In recent years, some interest—though still far less than seems motivated—has arisen
in the apparently very great longevity of several species of cold-blooded animal who continue
growing throughout their lives. Extreme examples include lobsters and certain fish; there
are also amphibian and reptile examples. A thorough discussion of these species was provided
by Finch. 43 These animals seem to live much longer than would be predicted by the
inter-species metrics discussed in the preceding sections.
Not only that: statistical measurements of the rate at which they age indicate, within
the accuracy available from the sample size, that they may not be aging at all—a phenomenon
termed negligible senescence. This is so dramatic a result that it is worth going into the
details of exactly what is being measured. There is only one basic requirement here: a way to
identify accurately how old an organism is. It turns out that some of the bones and other
hard tissues in these species are ideal for this, because they exhibit annual oscillations of
chemical composition, which build up from the outside like tree rings. 44 This means that
one can simply catch* a large number of a given species and plot their ages. A species that
does not age at all will show a curve in which the number of individuals of age N is always
the same fraction (95%, say) of the number that are age N-1, for any N above the age of
maturity; a species exhibits negligible senescence if its age distribution is statistically
indistinguishable from that. A species that is detectably aging shows a different curve, in
which this fraction is progressively smaller for larger N. The larger the study, the more
accurately one can distinguish between gradual and non-existent senescence, but all studies
are of finite size; the existence of non-senescing species, as opposed to a continuum of rates
of senescence, is therefore very hard to prove. The studies performed so far are not really
large or numerous enough to establish that any animal senesces (that is, the fraction defined
above increases) more than about twice as slowly as humans. I will discuss some options for
further work in this area in Section 12.3.
One must also choose the species of study with some care, because some species grow
throughout their life but die at a fairly young age anyway. Salmon are an example. 43
* "Catch" is not really the right word, in fact, because in the wild the rate of extrinsic mortality (death not
caused by old age) is so high that most organisms cannot be observed to age. Thus, such studies must usually
be done in captivity.