56
Aging and Sex, DNA Repair in
Thus, aging and sex appear to be two sides of the same coin. Aging reflects the
accumulation of DNA damage and sex reflects the removal of DNA damage, and in
diploid organisms, the masking of mutations by complementation.
1
The DNA Damage Theory of Aging
1.1
Occurrence of DNA Damage and Pathways
of DNA Repair
Except for certain viruses with an RNA
genome, the genomes of most organisms
are composed of DNA. If DNA damage is
the cause of aging, then DNA damage is ex-
pected to occur frequently in multicellular
organisms. Table 1 lists some important
types of DNA damage caused by normal
metabolic processes in mammals. These
data suggest, for instance, that in the rat at
least 95,000 DNA damages of various types
occur, averaged over all cell types, per cell
per day. The majority of these damages
alter the structure of only a single DNA
strand, so the redundant information in
the complementary strand can usually be
used to repair the damage. The damages
shown in Table 1 are the newly occurring
damages, most being rapidly repaired.
Five major DNA repair pathways known
to be utilized by cells to repair the damages
indicated in Table 1 are as follows:
Nucleotide excision repair (NER) [with
two subpathways, largely using the
same enzymes: transcription coupled
repair (TCR) and global genomic repair
(GGR)]
Base excision repair (BER)
Nonhomologous end joining (NHEJ)
Homologous
recombinational
repair
(HRR)
O
6
-methylguanine-DNA methyltrans-
ferase (MGMT)
1.2
Consequences of Unrepaired DNA Damage
If accumulated DNA damages are the
cause of aging, then repair processes
would be less than 100% ef±cient; some
types of unrepaired damages left each day
would gradually build up in nondividing or
slowly dividing cells. Most investigators ex-
amining the presence of DNA damages in
tissues of young versus old mammals (usu-
ally rodents) have found an accumulation
of damaged bases or single- or double-
strand breaks with age. The tissues where
accumulation of DNA damage has been
shown include liver, kidney, heart, muscle,
and brain.
Anumb
e
ro
fd
i
f
f
e
r
en
tt
yp
e
so
fDNA
damage have been tested for their effects
on transcription and DNA replication. It
was found that transcription is blocked
by UV-induced damages (mainly pyrim-
idine dimers) by adducts produced by
derivatives of benzo[a]pyrene,
N
-acetoxy-
2-fluorenylacetamide, or aflatoxin B
1
and
also by the oxidized base, thymine glycol.
UV-induced DNA damages and thymine
glycol have also been shown to block DNA
replication. These ±ndings suggest that
many types of DNA damage inhibit tran-
scription 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
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