Aging and Sex, DNA Repair in
59
of these genetic alterations are described
below.
1.
MGMT
. One frequent type of DNA
damage (see Table 1) is O
6
-methylguanine,
caused by low levels of alkylating agents
present in food, water, air, and tobacco
smoke, and formed by normal processes in
the body mediated by gastric bacteria and
macrophages. O
6
-methylguanine is specif-
ically repaired by a DNA repair enzyme
called
O
6
-
methylguanine-DNA methyltrans-
ferase
(MGMT). MGMT transfers the extra
methyl group from guanine in DNA to
a particular amino acid within itself and
becomes ‘‘used up’’ after the transfer oc-
curs. The
MGMT
gene codes for one of
the Fve DNA repair mechanisms listed
in Section 1.1. As indicated in Table 2,
when 100 copies of the
MGMT
gene were
inserted into the mouse genome, these
mice (under the usual conditions of mouse
maintenance) had their life span extended
and died at a considerably slower rate than
wild-type mice.
2.
SOD
.A
n
o
t
h
e
rim
p
o
r
t
a
n
tt
y
p
eo
f
metabolically caused DNA damage is ox-
idative damage, the most frequent damage
identiFed (Table 1). An apparently un-
avoidable by-product of normal respiratory
metabolism is the production of reac-
tive oxygen species (ROS) from molecular
oxygen, and ROS cause oxidative dam-
age. ROS include free radicals (where
the symbol
indicates an unpaired elec-
tron): the superoxide radical (O
2
)and
the hydroxyl radical (OH
). Another oxy-
gen respiration by-product is hydrogen
peroxide
(
H
2
O
2
)
.H
2
O
2
,i
fno
tremoved
,
it diffuses fairly easily through the cell,
and when it encounters ±e
2
+
(the ferrous
ion), it can undergo the ±enton reac-
tion and produce OH
and other ROS.
ROS produce a number of lesions in
DNA, including base lesions, sugar le-
sions (the deoxyribose sugar is in the
backbone of DNA), DNA–protein cross-
links, single-strand breaks, double-strand
breaks, and abasic sites.
The major ROS produced by the cell
is O
2
, formed in the mitochondria (the
energy-producing organelles of the cell).
Superoxide dismutase (SOD) occurs in
two forms, manganese SOD (MnSOD)
and copper/zinc SOD (Cu/ZnSOD). Both
forms of SOD convert O
2
to the less dam-
aging H
2
O
2
, and then another enzyme,
catalase, converts H
2
O
2
to molecular oxy-
gen and water. MnSOD occurs in the mi-
tochondria and Cu/ZnSOD occurs in the
cytoplasm.AsshowninTable2,anumber
of investigators have found that insert-
ing genes producing higher than normal
levels of superoxide dismutase into the
fruit fly (
Drosophila melanogaster
)genome
r
e
su
l
t
sinl
i
f
esp
ane
x
t
en
s
ion
.In
s
e
r
t
ion
of genes producing either MnSOD or
Cu/ZnSOD caused life span extension, al-
though the artiFcially inserted Cu/ZnSOD
only produced life span extension when
its expression was restricted to the motor
neurons, or solely to the adult phase of the
fruit fly life cycle.
Aging has been found to correlate with
increased levels of oxidative products, such
as protein carbonyls and 8-oxo-guanine in
DNA, and fruit flies lacking either catalase
or Cu/ZnSOD have a reduced life span.
±urther, selection of a population of fruit
flies for increased life span correlates
with strongly increased expression of
both MnSOD and Cu/ZnSOD. Reverse
selection of these long life span flies to
a shorter life span resulted in reduced
expression of Cu/ZnSOD.
3.
MsrA
. In addition to DNA damage,
free
radicals
damage
proteins,
lipids,
and carbohydrates. Most proteins have
a short half-life (averaging about three
days in mouse liver). Oxidatively damaged
proteins and lipids are subject to both
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