The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

A Descriptive Introduction to Human Aging
Our DNA is actually suffering spontaneous damage at a much greater rate than is
indicated by mutations, but the vast majority of this damage is repaired quickly and correctly.
Damage of this sort might fairly be called “proto-mutations.” The class of DNA damage
which happens more often than any other is the simple falling-off of a base: purines (adenine
and guanine: see Fig. 2.10) fall off much more often than pyrimidines, and their loss is
called depurination. This is easy to correct accurately, because the other strand of the DNA
has the complementary base. Another is the loss of an NH2 (amine) group in favour of a
hydroxyl group (OH): this is called deamination.* Again, the deamination of any nucleotide
of DNA always produces a molecule that is not a normal constituent of DNA, so it is
detectable and reversible.
There are two crucial determinants, therefore, of the rate at which mature, irreparable
mutations occur. They are the rate at which proto-mutations occur and the quality of those
proto-mutations’ repair—that is, the proportion of proto-mutations that are repaired
correctly. A major determinant of the quality of repair is the speed of repair. If a mutation
happens and nothing is done about it for a while, another one may happen close by. The
double mutation may be harder to repair correctly than two single ones each repaired at
once. A more frequent situation is when there is only one proto-mutation but it is replicated
before being repaired. For example: if a cytosine is deaminated, it becomes uracil, which is
not normally part of DNA (only RNA), but some cytosines in DNA are deliberately
methylated (a hydrogen atom is replaced by a CH3 group) as a regulatory mechanism, and
deamination of a methylated cytosine (methylcytosine) makes thymine. This therefore makes
a mispair—a thymine paired to a guanine. 13 There is a specific enzyme that detects thymines
paired to guanines and turns them back to cytosine, so in general there is no problem. But if
a cell replicates its DNA while there are deaminated methylcytosines in it, this mispairing
will be lost: the thymine will be seen as legitimate by the DNA polymerase and the new
strand will be constructed with an adenine. The mutation thus becomes permanent.
It is interesting to note that the rates of these two processes (damage and repair) are
likely to be sensitive to a factor that also regulates the rate of atherogenesis: namely, the
preponderance of LECs. In this case, the place where the LECs matter is in the nucleus.
LECs are mutagenic, since they react with nucleic acids just as readily as with lipids
(see Section 3.4), so their levels will influence the rate of occurrence of proto-mutations.
The rate of repair is also likely to suffer from increasing LEC levels, since the proteins which
perform that repair are themselves vulnerable to damage—and hence inactivation, or (worse)
erroneous function—by LECs.
We also appear to possess an anti-cancer mechanism which works in a different way,
and which may also be impaired by LECs. Cells that have suffered some, but not all, of the
mutations necessary to cause a tumor seem to be identified and induced to die. This process
is up-regulated in rodents undergoing caloric restriction, a regime which substantially
increases their lifespan (see Section 6.5.4), and has been proposed 14 to explain why caloric
restriction reduces the incidence of cancer.
5.3. Disorganization of Connective Tissue: Skin, Artery, Eye,
Cartilage
Another major feature of aging with which we are all familiar is the loss of elasticity in
the skin. This is much more pronounced in sun-exposed skin than elsewhere, indicating
that damage is probably caused mainly by ultraviolet light; but that does not explain why it
accumulates. The skin’s elasticity derives from the fibres of connective protein in the lower
* The replacement is in fact followed by a rearrangement that moves the hydrogen of the hydroxyl group onto
a nearby nitrogen.
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