Aubrey de Grey
ag24 at mole.bio.cam.ac.uk
Thu Feb 24 10:22:57 EST 2000
Magnus Lynch wrote:
> It has been demonstrated that telomeric sequences preferentially
> accumulate oxidative damage [Exp Cell Res, 1998 Feb, 239:1, 152-60]. I
> propose that telomeric sequences be incorporated in a mitochondrial
> genome and that this might slow the accumulation of mutations in coding
> regions of the genome. Although this intervention would not be as useful
> as the one discussed above, it has the advantage of being simple to
> implement in the immediate future.
> Does anybody think that this intervention would have any effect? Am I
> correct in thinking that it would be simple to implement?
My first impression is that this is a non-starter for a number of
reasons. First, as rjk3 noted, getting any DNA into mitochondria is
something we don't yet know how to do reliably. Second, adding stuff
that is easily oxidised only works if there is enough of it to work as
a "sacrificial" antioxidant, i.e. to soak up the free radicals so that
they don't attack the DNA that matters, but there are already other
highly oxidisable things in the mitochondrion (such as its membranes),
so adding a practical amount of DNA would not substantially change the
steady-state levels of free radicals. Third, the paper you mention
(and others from von Zglinicki's lab) finds that telomeres accumulate
oxidative damage very fast, but not why: my best guess of the reason is
that telomeres are very carefully protected (by various proteins -- see
de Lange's papers, mainly) from being joined end-to-end by enzymes that
repair double-strand breaks, and that this has the side-effect of also
restricting access to the DNA by enzymes involved in other types of
repair such as of single-strand breaks. But fourth and perhaps worst,
introducing repeated DNA of any sort would be predicted to increase the
chance of spontaneous deletions caused by recombination, because most
of the deletions seen in vivo are between direct repeats.
> Any further work with the P66 gene knockout mice that reduced apoptosis
> and extend life in rodents?
Not that I've heard. The head of that lab was invited to speak at the
recent Gordon Conference on Aging but he didn't turn up.
> One might try to find some way to diminish the number of non-respiring
> mitochondria, assumedly the good ones would then replicate.
Fine in principle. As yet, though, no practical approach to selective
destruction of non-respiring mitochondria has been proposed, and not
for want of trying. I'm very open to suggestions. A related strategy
is being pursued by Doug Turnbull's group in Newcastle, namely to
inhibit the replication of mutant mtDNA. This is probably not useful
against aging, given the large number of different mutations that arise
in different cells. I'm not all that optimistic about its efficacy
against mitochondrial diseases (involving just one mutation) either,
but that's another matter.
Aubrey de Grey
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