68
Aging and Sex, DNA Repair in
other targeted areas. Thus, genes whose
absolute transcription abundance remains
unchanged will appear to be upregulated.
Overall, calorie restriction results in
slower accrual of oxidative damage. The
steady state oxidative damage measured
represents the equilibrium between oxi-
dant generation, oxidant scavenging, re-
pair, and protein and lipid turnover (DNA
does not turn over, although it is re-
paired, with damaged bases and nearby
bases being replaced). The consensus is
that the primary reason for lower ox-
idative damage observed after calorie re-
s
t
r
ic
t
ionisareduc
t
ioninthegenera
t
ion
of ROS.
1.9
General Strategies for Coping with DNA
Damage and Some Consequences
Different organisms, or even different
tissues within the same organism, appear
to use different strategies for dealing with
DNA damage. The three major strategies
are described below.
1.
Cell replacement strategy
.B
on
em
a
r
-
row and hemopoietic cells of man, guinea
pig, and mouse seem to maintain their
population numbers by a cell-replacement
strategy. For instance, mouse bone mar-
row cells have a turnover time of about
1 to 2 days, and there appear to be no
signi±cant differences in the erythrocyte
production from marrow stem cell lines
in old and young adult mice, suggest-
ing that DNA damages do not accumulate
in this cell population. However, rapidly
dividing cells are vulnerable to accumula-
tion of mutations, which arise by errors of
replication. Hematopoietic stem cells accu-
mulate mutations (not damages) as people
age from birth to 96 years. The accumu-
lation of mutations in replicating somatic
cells is widely regarded as the cause of
cancer.
2.
DNA repair in nondividing somatic cell
populations
. The organs including brain,
muscle, and liver consist, largely, of non-
dividing cells, and these cells carry out
DNA repair as a strategy of coping with
DNA damages. However, DNA repair is
less than 100% ef±cient, and DNA dam-
ages accumulate with time. Brain, muscle,
and liver are subject to some of the
more conspicuous progressive declines
in function characteristic of human ag-
ing. Investigations were reviewed in 1992
on the accumulation of DNA damage
in mammalian muscle, brain, and liver.
In that review, 4 studies on muscle, 9
on brain, and 14 on liver reported ac-
cumulation of DNA damage with age.
In most of these investigations, the type
of damage measured was single-strand
breaks. In 1996, an increase in DNA
single- and double-strand breaks in neu-
rons of the rat cerebral cortex with age
was found. Neurons in young 4-day-old
rats had about 3,000 single-strand breaks,
which increased to 7,400 in neurons of
old rats more than 2 years of age. Double-
strand breaks increased from about 156
in young rats to about 600 in old rats.
It was suggested that gradual accumula-
tion of DNA damage with age could be a
primary reason for the breakdown of the
metabolic machinery leading to the even-
tual senescence and death of the neuron.
I
twasfoundinthesameyeartha
tDNA
adducts, a type of DNA damage, increase
in rat brain with age. Some of these were
identi±ed as malondialdehyde adducts of
dGMP. It was suggested that this accu-
mulation of DNA damages may contribute
to cerebral aging. A signi±cant increase
in single-strand breaks/alkali-labile sites
with age in rat liver hepatocytes were re-
ported in 1994. Thus, numerous studies
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