[extropy-chat] AGING: New Theory
jpnitya at sapo.pt
Fri Apr 16 11:56:55 UTC 2004
My response time is a bit slower than usual but I thought I have a go at
At 18:49 03-04-2004, you wrote:
>First, lets assume the Free Radical theory of Aging which involves
>various aspects of Mitochondrial damage and aging are correct.
>[This explains why caloric restriction works.]
### Actually, I have a paragraph in a manuscript I'm working on that may
"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."
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.
>Second, lets assume you can't do too much about them because
>radicals and/or other pro-oxidants (e.g. nitric oxide) are being
>used as signal molecules (this may be somewhat controversial).
### 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.
>Third, lets assume that the free radicals lead to DNA mutations
>(which is one way cancer develops) or worse leads to DNA double
>strand breaks. (Radiation and perhaps toxic substances in
>food or the environment might contribute to this as well).
### There isn't any direct evidence that free radical damage to the DNA
causes ageing in mammals. Again, a paragraph from the same manuscript:
"One possibility is that ROS damage DNA and some evidence exists showing an
increase in oxidative damage to DNA with age (Hamilton et al., 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."
BTW, 8-oxo-dGTPase repairs 8-oxo-7,8-dihydroguanine, an abundant and
mutagenic form of oxidative DNA damage.
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.
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.
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.
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.
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?
All the best,
-------------- next part --------------
An HTML attachment was scrubbed...
More information about the extropy-chat