<html>
<body>
Hi!<br><br>
My response time is a bit slower than usual but I thought I have a go at
this nonetheless.<br><br>
At 18:49 03-04-2004, you wrote:<br>
<blockquote type=cite class=cite cite>First, lets assume the Free Radical
theory of Aging which involves<br>
various aspects of Mitochondrial damage and aging are correct.<br>
[This explains why caloric restriction works.]</blockquote><br>
### Actually, I have a paragraph in a manuscript I'm working on that may
interest you:<br><br>
"Given the large number of age-related changes, it is crucial to
evaluate the predictions of each theory and follow a system-level
approach of which genetic manipulations in animal models are a crucial
tool. The mechanisms of CR are a perfect example for the open-minded
scepticism that should be implemented in ageing research. As mentioned
earlier, both the GH/IGF-1 axis and ROS production appear to change in
CR. Hypothesis aiming to explain CR based on either mechanism are
theoretically sound. Yet while a clear cause-effect phenotype is
witnessed when manipulating the components of the GH/IGF-1 axis, such is
not the case for ROS. Therefore, the GH/IGF-1 axis, not oxidative damage,
is the main candidate for explaining CR."<br><br>
By manipulating the components I mean genetic manipulations in animal
models, such as mice. If you genetically manipulate a number of
components of the GH/IGF-1 axis you get a phenotype very similar to CR.
If you manipulate ROS production or damage, you don't. So a clear
cause-effect phenotype is witnessed suggesting the GH/IGF-1 axis is, at
least partly, the mechanism involved in CR. No direct evidence exists
that ROS are a cause of CR.<br><br>
<blockquote type=cite class=cite cite>Second, lets assume you can't do
too much about them because<br>
radicals and/or other pro-oxidants (e.g. nitric oxide) are being<br>
used as signal molecules (this may be somewhat
controversial).</blockquote><br>
### I agree with the view that ROS are signalling molecules and there is
good evidence supporting this view and supporting the idea that ROS are
important in development.<br><br>
<blockquote type=cite class=cite cite>Third, lets assume that the free
radicals lead to DNA mutations<br>
(which is one way cancer develops) or worse leads to DNA double<br>
strand breaks. (Radiation and perhaps toxic substances in<br>
food or the environment might contribute to this as
well).</blockquote><br>
### There isn't any direct evidence that free radical damage to the DNA
causes ageing in mammals. Again, a paragraph from the same
manuscript:<br><br>
"One possibility is that ROS damage DNA and some evidence exists
showing an increase in oxidative damage to DNA with age (Hamilton <i>et
al.</i>, 2001). Yet overexpression of catalase in the nucleus did not
prevent oxidative damage to DNA (Schriner et al., 2000) and knocking out
the gene responsible for 8-oxo-dGTPase failed to accelerate ageing
(Tsuzuki et al., 2001). These results hint that the free radical and the
DNA damage theories of ageing are not complementary."<br><br>
BTW, 8-oxo-dGTPase repairs 8-oxo-7,8-dihydroguanine, an abundant and
mutagenic form of oxidative DNA damage.<br><br>
What I'm saying is that although oxidative damage to the DNA accumulates
with age in some tissues, it is not proven this is a cause rather an
effect of ageing. And the cited experiments suggest this is an effect of
ageing.<br><br>
Refs:<br><br>
Hamilton, M.L., Van Remmen, H., Drake, J.A., Yang, H., Guo, Z.M., Kewitt,
K., Walter, C.A., Richardson, A., 2001. Does oxidative damage to DNA
increase with age? Proc Natl Acad Sci U S A 98, 10469-10474.<br><br>
Schriner, S.E., Ogburn, C.E., Smith, A.C., Newcomb, T.G., Ladiges, W.C.,
Dolle, M.E., Vijg, J., Fukuchi, K., Martin, G.M., 2000. Levels of dna
damage are unaltered in mice overexpressing human catalase in nuclei.
Free Radic Biol Med 29, 664-673.<br><br>
Tsuzuki, T., Egashira, A., Igarashi, H., Iwakuma, T., Nakatsuru, Y.,
Tominaga, Y., Kawate, H., Nakao, K., Nakamura, K., Ide, F., Kura, S.,
Nakabeppu, Y., Katsuki, M., Ishikawa, T., Sekiguchi, M., 2001.
Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding
8-oxo-dGTPase. Proc Natl Acad Sci U S A 98, 11456-11461.<br><br>
As for the rest of your theory, Robert, I agree with the view that
changes in DNA over time play a role in ageing. This could even be the
case in stem cell stocks, as suggested by Van Zant's work. Yet I have
some reservations on the idea that only one type of DNA damage causes
ageing. At a first glance, it just doesn't seem right. Like I wrote
previously on the mechanisms of CR, your idea is theoretically sound but
there is no direct evidence in support of it. Can you think of one or two
experiments that can prove or disprove your theory?<br><br>
All the best,<br><br>
Joao</body>
</html>