The Mitochondrial Free Radical Theory of Aging

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Tue Nov 9 10:16:10 EST 1999


Magnus Lynch wrote:

> How about engineering a virus which only replicates in mammalian
> mitochondria (as opposed to nucleus/cytoplasm) and which can only
> replicate when the free radical concentration in a given mitochondria
> is substantially less than normal. This virus would, thus only
> reproduce in the mitochondria implicated in your "reductive hotspot
> hypothesis". If a distinctive peptide was coded for in the viral genome
> it could be inferred that cells expressing this peptide on MHC I have
> defective mitochondria. Immunisation against this peptide would
> selectively kill the cells responsible for the "reductive hotspot
> hypothesis".

You'll go far :-)  Seriously, this is the sort of imaginative thinking
in which too few experts engage, and I applaud it.  The main problems
with this particular proposal are (a) that we don't know any viruses
that target the mitochondrion, so we don't have a starting point from
which to do the engineering, and (b) the difference in free radical
levels in the mitochondrial matrix (where DNA replication would occur)
is probably very slight, due to the presence of SOD etc; the place
where radical levels are likely to be different is the intermembrane
space.  However, there is a much more direct version of your proposal.
According to my model, cells in this anaerobic state up-regulate a
plasma membrane enzyme called the PMOR (plasma membrane oxidoreductase)
in order to get rid of the electrons that are not being donated to O2
by cytochrome c oxidase.  This enzyme could thus be a target for the
cell-killer (see Chapter 14).

Aubrey de Grey





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