The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

History of the Mitochondrial Free Radical Theory of Aging, 1954-1995
6.5.3. Molecular Correlations with Longevity
In this book, however, the major topic of discussion is not why species have the lifespan
they do but how. In other words, we want to identify the molecules whose reaction rates
determine the rate of aging, and which therefore vary in detailed structure from one organism
to the next in a manner correlated with longevity. Two very strong molecular correlations
have indeed been discovered, and they both provide strong circumstantial evidence
for the controlling role of oxidative stress in aging.
6.5.3.1. Longevity and Membrane Oxidizability
It is difficult to measure directly the rate at which the membranes in a tissue undergo
oxidation, because this damage is constantly being put right by turnover of various sorts.*
Relatively easy, however, is to measure the composition of a tissue—or of a chemical category
extracted from it, such as its lipids. Better still, one can first fractionate the tissue into its
cellular components and then determine the lipid composition of a single fraction, such as
the mitochondria.
When this is done, a very great difference is found between the membranes of short-lived
and long-lived animals of similar specific metabolic rate. The same difference is found when
comparing rats to pigeons as when comparing horses to humans. 31,32 In both cases, the fatty
acid side chains of the phospholipids in the mitochondrial membranes are much less unsaturated
on average in the longer-lived animal. The degree of unsaturation of a fatty acid is
the number of carbon-carbon double bonds, C=C, in the chain; a fully saturated fatty acid
has no C=C bonds, only C-C bonds. This is thus very suggestive of the importance of oxidative
stress in aging, because only regions between two C=C bonds of fatty acids are susceptible
to oxidation by LECs (see Section 3.9). 33
6.5.3.2. Longevity and Superoxide Production
The second correlation, found in some of the same studies, also strongly supports the
idea that oxidative stress is central in setting the rate of aging. Longer-lived animals apparently
generate less superoxide. 31,34 Their respiratory chain enzymes seem, simply, to be more
fastidious about not fumbling electrons. The likelihood that an electron will become detached
from a respiratory chain component and annexed by oxygen is likely to be very dependent
upon the exact shape of the enzyme in question, which is of course determined by the
amino acid sequences of its various subunits.** These sequences are highly conserved in
evolution, but differences certainly exist, and they may well cause significant variations in
how often an electron can be fumbled.
6.5.4. Longevity and Calorie Restriction
During this time, it was also becoming increasingly accepted that calorie restriction
(CR—also, unfortunately, often termed DR, ER or FR, for diet, energy and food) could
reliably and significantly increase the lifespan of many species, notably laboratory mice: this
had in fact been discovered some decades previously. 35,36 Calorie restriction is achieved by
* However, there are measures of the rate of repair of some molecules. DNA is an easy one, because many DNA
repair processes involve removing a damaged nucleotide and discarding it into the blood stream, and thence
into the urine. 30 The quantity of nucleotide derivatives in urine is one of the best measures of the rate of
increase of DNA damage with age.
** The non-protein ubisemiquinone is the molecule believed to do most of the fumbling, but recall from
Section 2.3.3.3 that it exists only bound to Complexes I and III, so their exact shape is the relevant variable
under evolutionary control.
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