The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

History of the Mitochondrial Free Radical Theory of Aging, 1954-1995
Harman suggested 9 that this might be because some crucial component of cells, whose
rate of decline dictated the overall rate of aging, was not benefiting from the antioxidant
therapy. Since mitochondria were very likely to be the primary source of LECs in cells, and
since LECs (being so reactive) are likely to be very short-lived—in other words, to react with
something very nearby their site of creation—he reasoned that mitochondria were also very
likely to be the principal victims of LEC-mediated damage. He proposed, on this basis, that
aging was driven by the decline of mitochondria, caused by self-inflicted damage. This was,
therefore, the first statement of the mitochondrial free radical theory of aging, i.e., MiFRA.
This idea had little impact for several years, but was carried forward with great effect
during the 1980s. The human mitochondrial genome was sequenced in 1981, 13 facilitating
the isolation of mutant mitochondrial DNA and eventually its quantification. These
experiments strongly confirmed that mtDNA becomes increasingly damaged with age. 14
Further support came from the finding 15 that, broadly, the tissues which exhibited the most
mtDNA damage were the ones that consumed the most energy per unit volume and/or
generated the most reactive molecules: there was more in the substantia nigra (which makes
a lot of hydrogen peroxide) than in the cerebellum, for example, 16 and more in the extraocular
muscles (which are almost constantly active) than in the limbs. 17 (The correlation was not
perfect—in fact, an even better correlation was with regard to the rate of cell division of the
various tissues, a fact which became comprehensible only some time later: see Section 8.5.3.)
This correlation brought MiFRA strongly into line with the “rate of living” theory that high
metabolic rate shortens lifespan.
Moreover, many early hypotheses attempting to link the rise of oxidative stress with
the self-inflicted damage to mitochondria became testable and thereby fell by the wayside.
One such idea 18,19 was that mitochondria suffer damage to their DNA that inhibits their
ability to replicate it; thus a cell’s ability to synthesise ATP will progressively diminish with
age, because it cannot make enough of the mitochondrially encoded proteins. It was some
time before experimental techniques became able to test this idea—and to establish, as it
turned out, that it was wrong: mitochondrial numbers and mtDNA levels do not significantly
decline with age. 20 In fact, cells that carry a large quantity of mutant mtDNA appear to
over-replicate their mitochondria in a (futile) attempt to compensate for low OXPHOS
function. 21,22
6.4.1. The “Vicious Cycle” Theory
Another proposal which arose during this period survived for much longer. As will be
discussed in Chapter 11, it is generally found that production of superoxide rises with age,
and is also unusually high in the affected tissues of sufferers from genetic defects of the
respiratory chain. Since LECs are able to damage all classes of macromolecule, including
nucleic acids, it seemed clear that the rate at which mtDNA mutations occurred would rise
as the production of superoxide rose. (Oxidative damage to DNA does not directly cause
mutations, but it is known to cause inaccurate replication by the mitochondrial DNA
polymerase.) 23 But, as we have seen, the free radical theory (by this time) already implicated
mtDNA mutations as the cause of the rise in superoxide production with age. If they were
both its cause and its consequence, one had a vicious cycle which would cause exponential
increase in both (see Fig. 6.1)—which was exactly what was seen.
This theory was persuasive for all the right reasons: clear-cut, simple, and in absolute
accordance with the data. But, beginning in 1989, new and more detailed studies have
conclusively refuted it. In an effort to adhere at least vaguely to a chronological account, I
shall delay the description of that work until Section 6.6.
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