The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
Statement 4 is essentially a one-sentence summary of Chapter 5. The major classes of
deleterious, late-onset macroscopic change in the human body, which were enumerated
and described there, are all maintenance failures. At first glance this is virtually a truism,
since maintenance is simply the avoidance of degradative changes; after maturity (or, in
women, menopause), all changes are degradative and are reasonably classified as aspects of
aging. In fact it is not quite so simple, because the abolition of a decline in the quality of
maintenance is not equivalent to abolition of damage, only to abolition of acceleration of
that damage. Thus, with permanently youthful maintenance processes we would still age,
but at a constant, rather than accelerating, rate. That is quite sufficient, however, to justify
statement 4, since the degree of acceleration of aging over a lifetime is very substantial.
Only statement 2 is somewhat less well supported, as yet. It seems highly likely that the
process described in Section 9.6 (haemin-driven oxidation of LDL components, which
promote further chain reactions after import) occurs to some extent, since all the component
steps are chemically favoured. But the only evidence that this process (together with parallel
ones also initiated by the PMOR of anaerobic cells) is the main source of oxidative stress is
negative: that there seems to be no other process to account for it. Inside a mitochondrially
healthy cell, the only macroscopic irreversible change (in the sense defined in Section 5.6)
that occurs with time is the accumulation in lysosomes of lipofuscin, a fluorescent concoction
of protein, lipids and iron atoms which is popularly known as “age pigment.” But it is unclear
how lipofuscin can be doing cells any harm at all (except in the extreme case of the aged
retina: see Section 5.4), since it is packaged up in lysosomes. It is thus very hard to blame
lipofuscin for oxidative stress (though not completely unreasonable: Brunk has suggested 14,15
that it causes problems passively, by attracting the futile attentions of hydrolytic enzymes,
which are thereby in shorter supply to digest newly-phagocytosed material). Similarly, no
other extracellular mediator of oxidative stress has been convincingly proposed. Some
antioxidant hormones decline in activity with age, but their supplementation seems to confer
no great benefit, suggesting that they are only peripherally involved. Finally, insofar as there
remains doubt that anaerobic cells are the main source of oxidative stress, one must recall
that there is no shortage of available tests, as was discussed in Section 12.2.
In summary, then, there appears to be a significant possibility that the theory presented
here is correct in the strong sense defined in Section 7.1, namely that complete abolition of
the effects of somatic mtDNA mutations would slow all other aspects of aging by at least a
factor of two.
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