The Mitochondrial Free Radical Theory of Aging

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Wed Nov 17 10:45:03 EST 1999


Randall Parker wrote:

> Another way to do it would be to inject a piece of DNA that codes for 
> death of the mitochondrion only if there are no protein synthesis 
> enzymes present. 
> 
> However, I see a couple of problems with such a scheme: 
> 
> A) the injected protein could get mutated by free radical damage and 
> get accidentally turned on.

Yes.  This is, however, a generic difficulty of gene therapy and as
such is being addresed in many other contexts, so it may be solved.

> B) If one is going to go to all the trouble to inject DNA into 
> mitochondria then why not inject DNA that restore the mitochondria to 
> their original functional state? 
> ie why not fix the bad stuff rather than kill the bad stuff?

Again correct.  I have reasons for believing that all methods based on
introducing new DNA into the mitochondrion may be unsuccessful, in fact
-- see section 13.1 -- but if I'm wrong, then indeed the obvious thing
to introcude is new copies of the mtDNA itself.

There is a trickier problem, though: some mtDNA mutations are in the
protein-coding or tRNA genes, not in the rRNA genes which are the only
mtDNA-encoded components of the protein synthesis machines (ribosomes).
Those mutations would not be eliminated in your scheme.

> Would the concentration of tRNA be higher in a mitochondrion if other 
> aspects of protein synthesis in the mitochondrion were knocked out? ie 
> wouldn't there be yet other indicators within a mitochondrion that it 
> was no longer functioning? 

Plenty.  However, as you say, it is not necessarily obvious whether the
non-function is transient or permanent.  This is a very general problem.
It constitutes a strong argument in favour of therapies that can be
administered very frequently (perhaps orally), because such therapies
can err strongly on the side of caution, affecting perhaps only a small
subset of the intended cells each time while being very good at avoiding
healthy cells.  Alternatively it argues for therapies which (in principle)
do no harm when turned on in healthy cells, such as the mitochondrial gene
therapy ("allotopic expression") approach I have advocated.

Aubrey de Grey





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