Aging and Sex, DNA Repair in
67
flies), also transferred the ability to live
about 25% longer.
1.7
Other Work Indicating the Central Role
of DNA Damage and DNA Repair
in Aging
Numerous studies have been performed
in mammals on the correlation between
the ability of cells to repair DNA and
the life span of the species from which
the cells were taken. The life spans of
the species varied from 1.5 years for the
shrew to 95 years for man. Almost all of
the studies showed a positive correlation
between DNA repair capacity and life span.
Many experiments have been performed
on the effect of adding antioxidants to the
diets of organisms upon the organism’s
life span. Although the results of such
experiments are not entirely consistent,
certain antioxidants have been found to
generally increase life span. Vitamin E,
for example, has been found to increase
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nematodes, and paramecium.
More than 50 studies have been per-
formed to examine the possible experi-
mental acceleration of aging by externally
applied DNA-damaging agents. Overall,
it has been found that sublethal doses
of ionizing radiation or DNA-damaging
chemicals in the diet shorten life span,
but many speciFc aspects of normal ag-
ing are not accelerated. Several authors
have noted that the distribution (over time
and in different tissues) of DNA dam-
ages induced by external agents does not
closely mimic that of natural damages.
This difference could explain why the
life-shortening effects induced by external
agents do not closely conform to natural
aging. In particular, natural damages prob-
ably accumulate gradually, so they would
tend to build up in nondividing cells, while
they would be diluted out in dividing cells.
Exposure to an external agent over a brief
period, on the other hand, could cause
equally large numbers of damages to non-
dividing and rapidly dividing cells. The
effect on rapidly dividing cells could be
very large by interfering with DNA repli-
cation. In addition, if oxidative damages
are important in normal aging, then brain
cells, which have a high level of oxidative
metabolism should have more damages
than most other cell types. Externally ap-
plied damages would not be expected to
produce this particular type of bias. Thus,
the general Fnding that sublethal expo-
sure to DNA-damaging agents shortens
life span, while not uniformly accelerat-
ing the natural aging process, is consistent
with the DNA damage theory of aging.
1.8
Calorie Restriction and Aging
Numerous studies have shown that calorie
restriction in yeast, nematode worms,
fruit flies, and rodents can give life
span extension. The transcription of a
large number of genes is altered with
calorie restriction. In rat muscle, 34 of
800 genes tested were altered in their
transcription under calorie restriction,
with some of the largest changes being
upregulation of Cu/ZnSOD and MnSOD.
In fruit flies, where 14,028 genes were
assessed, 2,188 showed signiFcant up- or
downregulation after calorie restriction.
In particular, DNA repair genes were
downregulated (which may reflect reduced
DNA damage). Evaluation of upregulated
genes was problematic, however, because
expression measures are proportional to
the total mRNA pool, and there was
massive downregulation of a large number
of genes related to cell growth, and
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