From: Aubrey de Grey (ag24@gen.cam.ac.uk)
Date: Wed Apr 30 2003 - 14:35:59 MDT
Rafal Smigrodzki wrote:
> ### We seem to agree that code disparity was the main problem in
> transferring mt genes to the nucleus, although other factors like
> hydrophobicity could play a role as well.
Right -- just that I would go further: the code disparity has been
absolutely insurmountable wherever it has existed, and hydrophobicity
has been insurmountable for a few genes and very difficult for a few
others.
> ### See: Desurmont C. Caillaud JM. Emmanuel F. Benoit P. Fruchart JC.
> Castro G. Branellec D. Heard JM. Duverger N. Complete atherosclerosis
> regression after human ApoE gene transfer in ApoE-deficient/nude mice.
> [Journal Article] Arteriosclerosis, Thrombosis & Vascular Biology.
> 20(2):435-42, 2000 Feb.
Ah, I wondered whether you were thinking of something like this. That
sort of experiment "doesn't count", in my view. These animals are so
high in cholesterol that the recycling system of compounds that are
normally no problem, such as unmodified cholesterol, is overwhelmed.
If you make an animal accumulate stuff at a hugely accelerated rate,
then sure, a lot of what they accumulate will be stuff that a normal
animal wouldn't have accumulated in the first place because they could
break it down, so if you then relieve the handicap they will go ahead
and break it down. What this paper doesn't tell us (I've just read the
full text) is the key question: do the apoE-/- mice with transfected
human apoE have less lesion at 199 days old than age-matched apoE+/+
mice? I bet they have more -- "complete" in the title is misleading,
since the text says there was a reduction from 220 to 28 mm^2 lesion
area, only a factor of eight.
> ### Genetically determined obesity (e.g leptin deficiency) manifests
> early in life, and yet we know that maintenance of body weight is a
> dynamic balancing process, and can be tilted early or late in either
> direction. You can have fatty streaks appearing early and developing
> very fast, if your LDL is very high, in hereditary
> hypercholesterolemia, or they can develop slower, if you have only the
> Western diet going against you. The balance can be out of kilter
> because of hereditary, or acquired changes in your genome, or due to
> non-genetic changes (like formation of insoluble aggregates). So far we
> have insufficient data to answer the question of the specific
> contribution of such factors in PD, AD, and, AFAIK, in most other
> aging-related conditions.
I don't see the relevance of this. My point about fatty streaks in
childhood is that they appear in the context of a normal diet: we all
get them in our aortas by the age of ten. I agree fully that changes
to how much you push a homeostatic system will cause changes in its
equilibrium state (just like Desurmont's mice), but we're not talking
about any such changes here.
> ### My boss, Davis Parker, likes the idea of clonal expansion, too. Why
> do you think COX negativity must precede hyperproliferation if this
> hypothesis is true?
It doesn't need to do so in ALL mechanisms of clonal expansion, by any
means -- but in Patrick's model, hyperproliferation must precede COX
negativity, no question. I claim that my model for the mechanism of
clonal expansion (BioEssays 19:161) is the most consistent with all
available data ... but then I would, wouldn't I :-)
> ### If the effective number of mtDNA genomes undergoing replication is
> smaller than the total number of mitos, then drift can occur pretty
> fast.
True -- "stem mitochondria" is how Bruce Ames has described this. But
it really only works if the effective number is 1, because there seem
to be very few cells with anywhere near a 50/50 ratio of wild-type to
mutant genomes -- indicating that cells pass through that middle phase
a lot faster than drift should allow. Evidence for stem mitochondria
is conspicuous by its absence, so far.
Aubrey de Grey
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