From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Tue Apr 22 2003 - 14:30:16 MDT
On Tue, 22 Apr 2003, Aubrey de Grey wrote:
> > I said:
> > First you have to get genetic engineering *cheap* and *fast) (that I'm
> > reasonably sure I know how to do) -- *then* everyone can easily tinker
> > with various genomes to get it to "work".
>
> No need here, really -- the hydrophobicity problem can be studied in
> vitro quite efficiently enough with existing technology.
Not so fast Aubrey -- if cost were not a problem then we would be
much further along by now (indeed as you point out the ideas may
be a decade or more old). You have to keep in mind that I've
spent $ millions of my own and others funds simply trying to
do the analysis part of the problem -- the engineering solutions
part can be much more expensive. Its slowly getting cheaper
but it could become *much* cheaper if funding sources would
make the right investments.
> No, no point -- elephants and whales have so vastly lower a specific
> metabolic rate that they don't need better maintenance machinery than
> us in order to live longer. (This is not to say that oxidative damage
> is the only thing that matters in aging, of course, only that it affects
> everything.)
Has there been any work to determine whether the lower metabolic
rate directly correlates with a lower cancer rate for their mass
(or # of cells)? I.e. do they have better cancer defenses than we
do or is it indeed due precisely to lower free radical production?
I've gone through the literature and both whales and elephants
do get cancer -- but in whales the cases seem to be associated
with pollution and in elephants it seems to be quite rare.
The sequencing would still make sense from the perspective of
looking at protein susceptibility to nitrosylation or deamidation.
> Give me the $50m, I could spend it much better than that...
I'm sure we both could... :-)
> Also, a genetic code disparity (UGA encoding STOP in the nucleus but
> tryptophan in the mitochondria) has been present since animals diverged
> from fungi (~1 billion years) and has totally prevented any gene transfer
> in that time -- all animals encode exactly the same 13 protein in their
> mtDNA.
Have you actually verified this? I was under the impression that
there was a significant variance in mtDNA sizes but of course you
have looked at this more than I.
I also disagree that evolution could not pull a rabbit out of the
hat. It would depend entirely on how many UGAs there would be
in a specific mtGene. I consider the prospect of adding a mt Signal
Sequence to be much more difficult than fixing the UGA problem.
After all one cannot know how frequently mutated mtDNA might substitute
all of the UGA codes with UGG codons (allowing an alternate Trp
coding) and subsequently transfer the genes to the nucleus.
There are other problems, see:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Codons.html
under "Mitochondrial Genes" -- but I'm not completely buying the
argument that gene migration in higher level organisms is "impossible".
> > An alternate
> > process might be more robust mtDNA repair -- right now its pretty
> > minimal compared to the nucleus (something like 120+ nuclear DNA
> > repair proteins).
>
> No - reversal or obviation of damage is what we need, not retardation.
One probably needs both -- there isn't a lot of conclusive evidence
that you can reduce the gene hydrophobicity enough to get all of the
genes into the nucleus so one may always be left with some mtDNA.
If so then one needs to increase the mt DNA damage prevention
and/or DNA repair capacities. I believe that some of the few
lifespan extending techniques via genetic engineering that have
been demonstrated to date involve targeting anti-oxidant proteins
into the mitochondria.
> Progress is being made here -- we now know roughly where in Complex
> I and precisely where in Complex III the superoxide is made. But
> making a modified enzyme that makes less (a) is probably very hard
> and (b) only retards aging, doesn't reverse it, so we might as well
> focus on a proper solution (nuclearising the genes).
For the reasons cited above we may need to try to do both.
Another question is whether the SO is being made by "perfect"
proteins or damaged proteins? If the proteins are becoming
damaged and increasing SO production then we are back to the
protein recycling issue all over again.
Robert
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