Caloric restriction slows brain aging
Aubrey de Grey
ag24 at mole.bio.cam.ac.uk
Mon Jul 10 14:38:05 EST 2000
Paul Brookes wrote:
> > What is your preferred interpretation of how CR decreases
> > mitochondrial ROS production?
> Right now I don't have a specific interpretation, although one could
> invoke a number of things such as fatty acid compositional changes in
> mitochondrial membranes bought about by selective loss of a particular
> species during CR. I don't think it would be unreasonable to say that
> reducing overall food intake would result in loss (or retention) of
> some things more than others.
Agreed; however, that really only works for things we don't synthesise.
For fatty acids that we make, gene-expression changes to desaturases etc
would seem to be the more likely adaptation.
> > Intervention: Allotopic expression of mtDNA-encoded proteins
> There's a very good reason its been discussed for 15 years and not much
> done so far - mitochondria have been in existance for millions of years,
> and therefore there must be a very good reason that they haven't lost all
> their genes to the nucleus yet.
On the contrary, this is an absolutely rotten reason. Evolution has to
rely on mutations, whereas we can make arbitrary alterations to sequences
rather easily. This is a perfectly sufficient explanation for why there
has been no gene transfer since animals diverged from plants and fungi,
because at about that time the mitochondrial genetic code began to treat
UGA as tryptophan rather than STOP, with the result that our mitochondrial
genes rapidly became littered with TGA's that were previously TGG's, which
caused any later gene transfer to the nucleus to encode brutally truncated
proteins. This could only be overcome by the astronomically unlikely
back-mutation of the TGA's prior to any other mutations elsewhere in the
gene. A prediction of this interpretation is that in plants, where the
mitochondrial genetic code has stayed standard, there should be plenty of
variability of gene complement between taxa, including nuclear versions of
our "dirty baker's dozen", and that is indeed what's found (Chlamydomonas
being the current record-holder). No one has even got around to cloning
most of these genes, let alone working out how the proteins get into the
mitochondrion despite their hydrophobicity, but that may change soon.
The sad situation is that Bill Martin (author of the TIG piece) and the
other people who have explored this topic are almost all evolutionists,
not biotechnologists. The TIG article, in particular, is very heavily
focused on chloroplasts, in which for all we know there are indeed other
forces retaining genes in the organelle.
The cytosolic toxicity idea is of course also rendered dead on arrival by
(among other arguments) the very example you give, cytochrome c, which is
nuclear-coded in all species yet examined: the problem is entirely solved
by making the heme in the mitochondrion and attaching it after import.
> A better way to go around this might be to try and get "simpler" versions
> of the respiratory proteins in, for example bacterial or yeast complexes
> with less sub-units, which might be easier to transport/import.
This is rendered problematic by the fact that the mt-coded subunits are
(with only one exception, ATP8, the one which was most easily expressed
allotopically as long ago as 1986) all still present in the corresponding
bacterial enzymes, with comparable hydrophobicity. Yeast doesn't have
Complex I at all -- it uses a non-proton-pumping NADH dehydrogenase that
has only one, nuclear-coded, polypeptide -- and Yagi's group are looking
at rescuing Complex I mutations with that enzyme, with astonishingly
promising initial results (see Seo et al., 1998 PNAS and 1999 BBA), so
that may be a solution to half the problem.
> Alternatively, some mechanism for preventing mtDNA mutation in the
> first place, or expediting its repair, such as mito' targetted plasmids
> containing DNA repair enzymes, or coding for antioxidant enzymes
These are fine ideas for retarding the rate of accumulation of damage,
but I'm focusing on reversing it.
> or maybe just whole "replacement mtDNA" plasmids to correct the damage
This is being pursued by Seibel's group; I thnk it's unlikely to work
because of the selective advantage of dysfunctional mitochondria.
> The nuclear replacement route seems a long way off currently.
Let's see what you say when you've seen my Tibtech paper :-)
Aubrey de Grey
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