Aging and Sex, DNA Repair in
69
in mammals indicate that long-lived, non-
dividing, differentiated cells accumulate
DNA damage with time. This damage
may account for many of the progres-
sive declines in functions that deFne
aging.
3.
Cellular redundancy
.L
ikerepa
i
r
,ce
l
-
lular redundancy may be another strategy
for coping with DNA damage in nondivid-
ing cells. The brain has an unusually high
level of oxidative metabolism compared to
other organs. Brain neurons are nondivid-
ing and there is evidence for DNA damage
accumulation in the brain. There is a clear
loss of neurons with age. Compared to
young rats, old rats have about a 50%
loss of neurons in many regions of their
brains. Numerous studies in humans have
also shown a loss of neurons with age. The
brain appears to use a strategy of cellular
redundancy to compensate for the loss of
neurons with age. It has been estimated
that the brain is twofold larger than neces-
sary for short-term survival. Comparisons
of different mammalian species indicate
that the maximum life span in mammals
is directly proportional to brain size. Thus,
th
eb
r
a
inapp
e
a
r
st
ob
ep
r
o
t
e
c
t
edf
r
om
loss of neuronal function by cellular re-
dundancy, and this type of redundancy
may be signiFcant in determining life
span.
1.10
Potential Immortality of the Germ Line
C
e
l
l
so
ft
h
eg
e
rml
i
n
ea
r
ec
a
p
a
b
l
eo
f
avoiding aging. While multicellular organ-
isms ordinarily age and die, their germ
line is potentially immortal. The germ
line is distinguished from other cell lines
by periodic meiosis. HRR is especially
promoted during meiosis, when the ho-
mologous chromosomes are closely paired
along their length. Meiosis appears to be
an adaptation for removing DNA dam-
ages through HRR, and the potential
immortality of the germ line may be re-
lated to this special repair capability. This
idea has been tested, using single-celled
paramecia that can undergo either asexual
or sexual reproduction. When they grow
asexually, clones of
Paramecium tetraure-
lia
age (show reduced vigor) and then
die. These paramecia have a macronu-
cleus containing 800 to 1,500 copies of
the genome that expresses cellular func-
tions, and a micronucleus that contains
the germ line DNA.
If the macronuclei of clonally young
paramecia are injected into old paramecia,
the old paramecia have their life span pro-
longed. In contrast, cytoplasmic transfer
from young to old paramecia does not pro-
longthelifespanoftheoldparamecia.This
suggests that the macronucleus, rather
than the cytoplasm, determines clonal ag-
ing. Asexually growing clones of parame-
cia have been found to accumulate DNA
damage in the macronucleus over succes-
sive generations of clonal growth. Upon
sexual reproduction (conjugation) or self-
fertilization (automixis), a new macronu-
cleus develops from the micronucleus and
the old macronucleus disintegrates. Both
of these processes (conjugation and au-
tomixis) include meiosis, which involves
pairing of homologous chromosomes and
the opportunity for homologous recom-
binational repair (HRR) of DNA (see
Section 2.3). It was found that at a few
clonal generations after meiosis, the level
of DNA damage in macronuclear DNA is
low but then increases as the cells undergo
clonal aging. Thus, accumulation of DNA
damage in the macronucleus may account
for clonal aging and DNA repair during
meiosis (principally HRR) may account, in
large part, for the potential immortality of
the germ line.
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