[extropy-chat] AGING: New Theory

[Joao Magalhaes]

Hi!

My response time is a bit slower than usual but I thought I have a go at 
this nonetheless.

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 
interest you:

"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.

Refs:

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,

Joao 
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