Aging and Sex, DNA Repair in
65
increased carcinogenesis. Such fairly good
compensation for DNA repair enzyme
defects may be the basis for normal aging,
but increased carcinogenesis, shown by
mice with the DNA repair mutations listed
in Table 4. As shown in Fig. 1, XPA and
XPC proteins each occur as one member
of a pair of complexed proteins whose
function is recognition of DNA damage
to be repaired by an NER pathway. It is
possible that the other complexes that can
recognize DNA damage can compensate,
at some level, when one of the recognition
complexes is absent.
Further, in some instances, genetic
alterations caused increased SOD produc-
tion in fruit flies but did not affect aging.
However, the inserted
SOD
gene may have
been turned on under the control of pro-
moters expressing in tissues where it may
not have been useful, or at rather low levels.
1.6
Negative Correlation between Mito-
chondrial ROS Production and Life Span
If DNA damage is the major cause of aging,
ROS are a major source of DNA damage,
and mitochondria are a major source of
ROS, then animals with mitochondria
producing higher levels of ROS may
have a shorter life span, other factors
being equal. Comparisons were made
between long-lived birds and short-lived
mammals. Pigeons, with a maximum life
span of 35 years were compared with rats
(of similar body size) with a maximum
life span of 4 years, and parakeets and
canaries (maximum life spans of 21 and
24 years, respectively) were compared with
mice (maximum life span of 3.5 years).
Mitochondrial ROS production was lower
in the longer-lived avian species. However,
in addition, pigeons were shown to have
higher levels of SOD in brain, heart,
and kidney than the levels shown by
rats, so there was also higher antioxidant
enzymatic protection in the longer-lived
pigeon. This indicates that antioxidant
enzymes, which confer resistance to an
externally added source of ROS may be
of comparable importance to longevity as
endogenous rates of ROS production. The
values of one measured DNA-damaged
base, 8-oxodeoxyguanine, were lower in
canary brain and parakeet heart nuclear
DNA than in the comparison tissues of the
mouse, while in the other comparisons,
the level of this one damaged base was
not signi±cantly different in nuclear DNA.
In another experiment quoted by Herrero
and Barja, other workers showed that
nuclei of starlings (another long-lived bird,
maximum life span of 20 years) have less
DNA breaks and abasic sites after exposure
to H
2
O
2
than those of mice.
Mice heterozygous for a MnSOD defect
(MnSOD
+
/
mice) have higher levels
of oxidative damage to DNA, protein,
and lipids in their mitochondria, but
no increased damage to nuclear DNA
or cytoplasmic proteins. The MnSOD
+
/
mice live as long as wild-type mice,
showing that mitochondrial DNA damage
(as distinct from nuclear DNA damage)
may not be central to longevity. This may
be because there are on the order of 1,000
mitochondria per cell, and mitochondria
with excess damage may be replaced by
replication of less damaged mitochondria.
In Section 1.3.2, we mentioned that the
long-lived strains of fruit flies have higher
levels of antioxidant defense enzymes. The
long-lived flies also had mitochondria that
had lower levels of ROS leakage. These
less leaky mitochondria, when transferred
to short-lived flies through maternal in-
heritance (only maternal mitochondria are
passed on to and maintained in progeny
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