Aging and Sex, DNA Repair in
57
Tab. 1
Endogenous DNA damages in mammalian cells.
Type of damage
Approximate average incidence
(DNA damages/cell/day)
Oxidative
500,000 (young mouse brain)
2,000,000 (old mouse brain)
86,000 (rats, all tissues)
10,000 (humans, all tissues)
Depurinations
9,000 (humans and rats)
Single-strand break
7,200 (
in vitro
)
O
6
-methylguanine
2,000 (
in vitro
)
Double-strand break
>
40 (rats)
a
>
3(humans)
a
DNA cross-link
>
37 (rats)
a
>
3(humans)
a
Glucose 6-phosphate adduct
3 (humans)
a
These numbers were calculated from the values in the references
by methods indicated in the literature.
brain, it has been shown that as single-
strand DNA damages accumulate with age,
mRNA synthesis and protein synthesis de-
cline, neuron loss occurs, tissue function
is reduced, and functional impairments
directly related to the central processes
of aging (e.g. cognitive dysfunction and
decline in homeostatic regulation) occur.
Similarly, it has been shown in muscle
cells that as single-strand DNA damages
accumulate, mRNA and protein synthe-
sis decline, cellular structures deteriorate,
cells die, and this is accompanied by a re-
duction in muscle strength and speed of
contraction. Thus, for brain and muscle,
accumulation of DNA damage is paralleled
by declines in function, suggesting a direct
cause-and-effect relationship between the
accumulation of DNA damage and major
features of aging. In other cells, including
those of liver and lymphocytes, evidence
for an increase in DNA damage paralleled
by a decline in gene expression and cel-
lular function has also been observed. In
general, it appears that tissues composed
of nondividing or slowly dividing cells ac-
cumulate DNA damage and experience
functional declines with age.
1.3
Life Span Extension by Genetic Alterations
that Increase DNA Repair, Reduce
Oxidative Damage, or Reduce Cell Suicide
(Apoptosis) due to DNA Damage
Table 2 lists alterations in genes con-
trolling DNA repair, oxidant status, or
apoptosis that result in increased life span.
The increases in life span found with
the genetic alterations in Table 2 are usu-
ally an increase in the maximum life
span (not just the mean life span) by
about 30 to 40%. Mean life span can
be extended by reductions in tumorige-
nesis or acute and sporadic diseases, not
generally regarded as a cause of aging.
The organisms with increased maximum
life span reported here showed longer
spans of normal vigorous activity (not
merely slowed metabolism, which can
also extend life span). The cellular roles
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