Michael Sherman wrote:
> I have read your new MiFRA book and found it fascinating,
> at least to what little degree I could grasp its contents.
> I expect to have to read it a few more times.
Great. I tried to make it intelligible to the scientifically-minded
layman while also being valuable to the specialist; I'm glad it's not
too intimidating.
> In section 6.5.3.1 (pg 71) you discuss the finding that long-lived
> species use less (oxidation susceptible) unsaturated fats in their
> mitochondrial membranes. "This is thus very suggestive of the
> importance of oxidative stress in aging ..."
>> But if I understand MiFRA correctly, oxidative damage to mitochondrial
> membranes seems relatively harmless. Mitochondria damaged in that way
> should be preferentially mopped up by the lysosomes. Only damage to
> mitochondrial DNA can produce the anaerobic mitochondria which can
> accumulate in the cell. One might even postulate an anti-aging effect
> for an easily-oxidized membrane: its ability to absorb LECs might keep
> them away from the mitochondrial DNA and signal lysosome cleanup.
>> So my question is: do you think the preferential use of saturated fats
> in mitochondrial membranes slows the aging rate, and if so why?
OK, you've come up against what many specialists also find difficult
about my "survival of the slowest" model (Chapter 8). It is essential
to distinguish (1) the situation before there have been any mutations
and (2) the situation after a mutation has occurred. Before there are
mutations, you're absolutely right, oxidative damage to mitochondrial
membranes is harmless according to this model: an organism with more
highly unsaturated membranes will just recycle its mitochondria more
rapidly. But faster recycling means more frequent replication of the
mtDNA, which in turn means a greater chance of producing mutant mtDNA.
Moreover, from then on any mutation will be amplified faster by the
faster turnover. Your idea that easily-oxidized membranes would be
protective to mtDNA is also wrong, but again for a subtle reason: when
a lipid is attacked by a free radical it becomes a free radical itself,
and a chain reaction ensues, which can propagate into DNA as well as
into other lipids, so lipids cannot be protective in this way.
I hope that's clear; please feel free to follow up if not.
> Section 6.5.4 on calorie restriction left me unclear as to whether
> MiFRA suffices to explain the slowdown in aging rate produced by CR. As
> you pointed out, the cellular metabolic rate is apparently not reduced
> in calorie restricted animals. Does that mean that each mitochondrion
> is respiring at the same rate in a CR animal as in a normally-fed one?
> If so, wouldn't they be expected to fumble electrons and damage their
> DNA at the same rate?
Excellent question, and the reason I wasn't specific on this point is
that I don't think the answer is known. We know that what you call the
cellular metabolic rate [which is usually called the specific metabolic
rate (i.e. rate per unit mass) in order to factor out variations in cell
size] is about the same in CR as in ad lib. We don't know whether the
number of mitochondria per unit mass goes up, as in Section 10.1, but
you're quite right that that would lower the rate of respiration of each
mitochondrion, and that should lower the rate of free radical production
per unit mass. (Actually there are circumstances in which this would
not be the result, but that's a big digression which I'll defer.) But
there are other, equally realistic, ways in which CR might retard free
radical damage without lowering specific metabolic rate. One that I
mentioned in that section is raising the assiduousness of DNA repair,
which would slow down the rate at which damage matures into mutations.
See for example Guo et al, 1998, Exp. Cell Res. 245:228-238.
Aubrey de Grey
