The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
mitochondria is the major source of oxidative stress. It used to be considered satisfactory to
invoke the “vicious cycle” as an answer to this—we start off with a little bit of oxidative
stress, which has a slight impact on mitochondrial function, which increases oxidative stress,
etcetera—but, as discussed in Section 6.6, that logic is very hard to reconcile with the fact
that mitochondria in all cells (even non-dividing cells) are constantly recycled. This recycling
involves the division of the mitochondrion, which entails the incorporation into it of
newly-synthesised, pristine proteins and lipids. That dilutes out the oxidative damage that
had accumulated, so there should be an asymptotic, stable level of damage, i.e. no vicious
cycle. The only component of mitochondria to which this logic does not apply is its DNA,
since the new DNA is synthesised by copying the old DNA so will be as damaged (mutant)
as the old copy. So, in summary, if mtDNA damage is not the driving force in aging then nor
are mitochondria in general—they can only amplify that force.*
Answer 3, which is the most robust, is that there is no bias because the mtDNA sequence
does not significantly affect its somatic mutability. MiFRA is ultimately based on the
observation that somatic cells accumulate spontaneously mutant mtDNA. Thus, it says that
the rate of aging is determined by the rate at which spontaneous mutations occur. That rate
is dependent on, at least:
a. the fidelity of mtDNA replication;
b. the efficacy of repair of mtDNA damage before it becomes stable;
c. the rate at which mutagens (such as free radicals) are generated near the mtDNA; and
d. the rate at which those mutagens are destroyed by antioxidants.
Of these four, only (c) is affected by the mtDNA sequence itself (since free radicals
mainly come from accidental loss of electrons from the partly mt-coded respiratory chain).
All enzymes responsible for mtDNA replication, mitochondrial biosynthesis in general, repair
of mtDNA damage, destruction of free radicals, etc., are nuclear-coded. There is also evidence
(from transition/transversion ratio and from the high mutability of the tRNA genes: see
Section 2.4.5) that the bulk of spontaneous mtDNA mutation is from replication error rather
than from oxidative damage, so (c) may be secondary anyway.
One other way in which the mtDNA sequence can potentially affect its mutability, which
has nothing to do with what it encodes, is mentioned in Section 12.1 as a possible test of
SOS, because it may be relatively easy to detect.
10.13. Why Don’t Plasma Antioxidants Totally Prevent LDL
Oxidation?
The problem is as follows: It has long been known that all the cell types present in the
arterial wall—endothelial cells, smooth muscle cells, macrophages—can induce LDL
oxidation in vitro, but the same studies also found that addition of antioxidants to the culture
medium completely prevented LDL oxidation. 57,58 The concentrations of antioxidants
which were required for this were well below what exists in plasma.
Far from being a challenge to MiFRA, however, this can be considered as a point in its
favour. We cannot doubt that LDL does get oxidized in vivo: this is the conclusion of dozens
of studies over the past decade that have explored the etiology of atherosclerosis and LDL’s
involvement therein. This is therefore a serious paradox, and one that has resisted elucidation
for many years. But MiFRA provides a very straightforward explanation. It predicts that the
interstitium contains a small—but steadily rising with age—number of anaerobic cells, and
that these cells are fairly bristling with lonely electrons all the time. Now, if that same quantity
*A weakness in this logic is that not all the damaged mitochondrial protein and lipid is recycled: a tiny
fraction of it accumulates as lipofuscin. Lipofuscin is generally thought to be harmless, but may not be. 56b,56c