Aubrey's "survival of the slowest" hypothesis

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Tue May 8 15:09:25 EST 2001

Iuval Clejan wrote:

> Is the decrease in both mitochondial and cytosol lipid peroxidation he
> finds in MnSOD(+/-) mice in going from middle to old age consistent
> with RHH?

Yes, because of the substantial drop in membrane potential after middle
age (figure 3).  A lowered membrane potential will sharply retard lipid
peroxidation, and of course what's there already will be diluted away
by turnover so the steady-state level of peroxidation will fall.  (Note
that it's not mitochondrial and non-mitochondrial lipids in Figs 5A and
5B respectively, it's mitochondrial and total, so given the error bars
of the measurements we're not in fact told that non-mitochondrial lipids
change much in their peroxidation status.)

What that doesn't explain, unfortunately, is that the control livers
had a parallel decline in mt membrane potential after middle age but
showed a sharp RISE in lipid peroxidation.  This is where I think that
substantial apoptosis may play a stabilising role in the MnSOD(+/-),
as you say.  The membrane potential can only be dropped so far, of
course, before OXPHOS stops working.  In control mice, the oxidative
damage is slow until after middle age and then rises rather fast, and
this rise will be attenuated but not stopped by lowering the membrane
potential, but that's good enough to keep cells going.  In the mutants,
peroxidation gets into the rapidly rising phase a lot sooner, and the
trick of lowering the membrane potential is insufficient, so a lot of
cells apoptose, which of course triggers compensatory cell division
that dilutes out peroxidation.  I think that probably covers this data
-- the only wrinkle is that it seems to predict that membrane potential
would fall at an earlier age in the mutants than in the controls, but
with just three time points we don't really know that it doesn't.

Aubrey de Grey

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