Molecular medicine-Consequences of Unrepaired DNA Damage

If accumulated DNA damages are the
cause of aging, then repair processes
would be less than 100% efficient; some
types of unrepaired damages left each day
would gradually build up in nondividing or
slowly dividing cells.Most investigators examining
the presence of DNA damages in
tissues of young versus old mammals (usually
rodents) have found an accumulation
of damaged bases or single- or doublestrand
breaks with age. The tissues where
accumulation of DNA damage has been
shown include liver, kidney, heart,muscle,
and brain.
A number of different types of DNA
damage have been tested for their effects
on transcription and DNA replication. It
was found that transcription is blocked
by UV-induced damages (mainly pyrimidine
dimers) by adducts produced by
derivatives of benzo[a]pyrene, N-acetoxy-
2-fluorenylacetamide, or aflatoxin B1 and
also by the oxidized base, thymine glycol.
UV-induced DNA damages and thymine
glycol have also been shown to block DNA
replication. These findings suggest that
many types of DNA damage inhibit transcription
and replication.
A reduction in the ability to transcribe
mRNA should lead to a decline in the
function of the cells. In fact, in mammalian
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)
O6-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)
aThese numbers were calculated from the values in the references
by methods indicated in the literature.
brain, it has been shown that as singlestrandDNAdamages
accumulate with age,
mRNA synthesis and protein synthesis decline,
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 synthesis
decline, cellular structures deteriorate,
cells die, and this is accompanied by a reduction
in muscle strength and speed of
contraction. Thus, for brain and muscle,
accumulation ofDNAdamage 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 cellular
function has also been observed. In
general, it appears that tissues composed
of nondividing or slowly dividing cells accumulate
DNA damage and experience
functional declines with age.