The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
Harman published this idea as a paper entitled “Aging: a theory based on free radical
and radiation chemistry”, which came out first as an internal University of California
Radiation Laboratory report, in July 1955, and the following year as an article in the Journal
of Gerontology. 3b
6.3. Suppressiveness
A phenomenon which would, much later, be revealed as another clue to MiFRA was
discovered in the laboratory of Boris Ephrussi in the early 1950s, and first discussed in print
in 1955. 4 For some time it had been realised that baker’s yeast, whose full scientific name is
Saccharomyces cerevisiae, was an excellent organism for the study of really elementary
biological processes. It is unicellular, easy and cheap to culture, and there was even money in
it on account of its commercial relevance. It also has the feature of existing in either a haploid
or diploid state; sexual reproduction occurs by the fusing of two haploid cells to form a
diploid one, but both haploid and diploid cells also undergo asexual division. In 1996 it
became the first eukaryote whose genome was completely sequenced. 5
Ephrussi and his colleagues had reported previously 6,7 that colonies would constantly
arise in yeast cultures which grew more slowly than the rest of the culture, and were therefore
named “petite colonie”, usually shortened to petites. This property was shown to result from
loss of aerobic respiration, and in particular from “the lack of several enzymes (including
cytochrome oxidase) bound, in normal yeast, to particles sedimentable by centrifugation.”
(These particles were, of course, mitochondria.) But in their 1955 paper, they reported
something much stranger and more exciting. They found that many of the mutants which
arose in this way exerted a dominant effect when they underwent sexual reproduction. That
is: when a haploid petite cell was mated to a haploid wild-type cell, forming a diploid cell
with a hybrid (heteroplasmic) mitochondrial genotype, the culture that that diploid cell
gave rise to (by subsequent asexual reproduction) was more prone than average to contain
petite colonies, even though that original diploid cell exhibited no phenotype itself. This
was shown to be a characteristic carried in the cytoplasm of the petite cells, and was named
suppressiveness. It is now known to be caused by spontaneous deletions or point mutations
of the mitochondrial genome.
6.4. Mitochondria as Free Radical Victims
Gradually, over the next 15 years, more and more evidence came to light—much of it
due to Harman’s experimental work—indicating that his basic precept was absolutely right.
Reactive free radicals—LECs—were indeed discovered in living cells, and in 1969 an enzyme
was isolated which destroyed one. 8 The LEC was superoxide, which was already thought to
be likely to mediate oxidative damage, and the enzyme was SOD, superoxide dismutase.
In 1972, Harman made a further great theoretical contribution 9 to the hypothesis he
had originated. He had established, through many experiments over the previous 15 years,
that the most obvious choice (if his theory was correct) for a type of chemical that might
extend lifespan was only partly successful. 10-12 Such chemicals—antioxidants—act to soak
up LECs, so intake of (otherwise non-toxic!) antioxidants should lower the levels of LECs in
the body. If the free radical theory was correct, that should retard aging. Harman found that
he could indeed raise, quite considerably, the average lifespan of mice by feeding them various
antioxidants. What he could not do, however, was raise the maximum lifespan. All that
happened was that the distribution of mortality became more “rectangular”: most mice
lived nearly as long as the longest-lived. It seemed that there were some degenerative processes
which were non-universal, i.e., which predisposed some mice to die younger than others;
the exogenous antioxidants were successfully retarding these non-universal degenerative
processes, but not retarding the universal processes that were central to aging.