some questions from Aubrey's book
Aubrey de Grey
ag24 at mole.bio.cam.ac.uk
Fri Jan 14 09:54:46 EST 2000
Michael Sherman wrote:
> To move off theory for a moment, do you think that this implies
> a danger for humans who intentionally increase their dietary
> consumption of unsaturated fats, especially the trendy w3 polys?
> Are these likely to find their way into mitochondrial membranes
> or is the composition of these membranes fixed for a species?
I think there would be such an effect, yes. However, it it vital to
bear in mind that the effect would be on the relative amounts of the
various polyunsaturated fatty acids, rather than on the proportion of
saturated to unsaturated. There was a study in 1986 (McMurchie et al,
Lipids 21:315) which showed that the former is indeed altered by diet
but the latter is not. This is no big surprise when one bears in mind
that one side chain of a typical phospholipid is saturated and the
> I presume you are referring to improved *nuclear* DNA repair, since
> that is the topic of the paper you referenced. It seems unsatisfying
> to me that if MiFRA with SOS is the primary cause of aging, and CR
> the only known way to slow aging, that CR should do so in a manner so
> remote from the fundamental cause. Is there a mechanism for
> mitochondrial DNA repair, and if so is this also upregulated by CR?
Good question, and sorry to have been over-concise before. Certainly,
I claim that if MiFRA is correct then CR must work by retarding the
accumulation of mtDNA mutations. (It must also retard nuclear DNA
mutations so as to retard cancer, but according to MiFRA this would
be somewhat achieved just by retarding mtDNA mutations, since that
would reduce systemic oxidative stress which would benefit the nucleus
like anywhere else.) Unfortunately, not nearly so much work has yet
been done on mtDNA repair enzymes -- indeed, for a long while a lot of
people thought there were none! -- and I know only one article that has
looked specifically at mtDNA damage in CR (Chung et al, Free Rad Biol
Med 12:523), which did not look at enzyme levels, only at steady-state
However, it has recently become apparent that nuclear and mitochondrial
DNA repair enzymes are often encoded by alternatively spliced versions
of the same gene. Thus it is quite likely that a rise in nuclear DNA
repair enzyme levels indicates a concomitant rise in mtDNA ones.
> If nuclear DNA repair were CR's primary mechanism, then I would expect
> CR animals to contain roughly the same proportion of anaerobic "poison"
> cells as ad lib animals at the same age. The CR ones would be less
> sensitive to the induced oxidative damage in healthy cells due to their
> superior repair ability.
> Do you know if any research has been done to determine whether CR
> reduces the production of anaerobic cells?
Yes, and indeed it does: Aspnes et al, FASEB J 11:573.
> My prediction would be that it does so, because otherwise wouldn't
> CR animals be expected to age rapidly if fed ad lib late in life?
> They would have built up the usual supply of anaerobic cells for
> their chronological ages so should (I think) begin to accumulate
> damage at rates matching ad lib controls of the same age. I do not
> believe this is observed in practice.
> A random thought: suppose an otherwise-harmless substance X could be
> found which INDUCES occasional oxidative damage to mitochondrial
> membranes. Take X in a concentration at which, on average, any given
> mitochondrion can expect to be ruined in about a month. This would, I
> think, modestly increase the mitochondrial recycling rate. However, if
> (as I understand SOS) lysosomes are attracted to damaged mitochondrial
> membranes, this would cause them to destroy the non-OXPHOS mitochondria
> on a monthly basis, along with all the others. I believe that might
> have a dilutive effect similar to the effect of cell division you
> discuss in 8.5.3, and thus prevent the production of anaerobic cells.
This is most ingenious. I believe it has two flaws, though. The first
is that since the membrane damage from OXPHOS would still be present,
there would still be more membrane damage (hence recycling) to the
working mitochondria than to the mutant ones. The more potent an X is
used, the less this difference would be when considered as a ratio,
which is probably the right way to consider it. But this is offset by
the second problem, which is that raising the rate of turnover would
raise the risk of mtDNA replication error in a given time period, so
SOS might work more slowly in a given cell but might be happening in
more cells, so do more harm overall. There is also a third probable
problem: the mechanism by which lysosomes are attracted to membrane-
damaged mitochondria is not known, and it may well involve detection
of an effect of respiration, such as a rise in temperature or depletion
of oxygen in the mitochondron's vicinity. This would be absent in the
mutant mitochondria even if they are membrane-damaged by X, so those
mitochondria would not necessarily be destroyed.
Aubrey de Grey
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