Just my two-cent's worth, having read those earlier mails on this topic.....
It should not be taken for granted that lipid peroxidation is a bad thing
because lipid radicals can propagate. Nitric oxide is a very effective
terminator of lipid peroxidation reactions, and there's increasing evidence
that due to its hydrophobicity, NO is preferentially partitioned into
membranes - some estimates are as much as 300-fold. Thus it is entirely
possible that sacrificial lipid peroxidation with termination by NO is a
very effective antioxidant mechanism, especially in the mitochondrion where
there are a lot of lipids susceptible to peroxidation, and the free
radicals themselves are made at the membrane level.
It is entirely possible to modulate mitochondrial lipid composition by
diet. However, a lot of the work that's been done on this uses
non-specific mixtures like fish oil or coconut fat, so its very difficult
to see what's actually producing the effect. It has also been argued
that these things may work by negative feedback. This might certainly be
the case for thyroid hormones, which make membranes more stiff in the
short term and may thus promote a counter-acting production of fluidy
polyunsaturates. It shouldn't be forgotten of course that fatty acid
composition is exquisitely related to proton leak. Depending on who you
beleive, proton leak either increases or decreases mt ROS production. I
proposed a while back that there might be a feedback loop: More
peroxidised lipids result in a higher proton leak (lots of evidence from
russian groups of the 60's), and this in turn serves to decrease ROS
generation. Once ROS generation falls then the lipids get repaired and
proton leak falls again and the whole cycle comes around. This would
account for the observations that animals with higher proton leak are also
the ones that produce the most mt ROS and the ones with the most
polyunsaturated membranes.
As for the mechanism of CR, would it make sense to say that the body, via
as yet unidentified mechanisms, senses that things are tight and switches
off such luxuries as replacing one's mitochondria every few months. This
would lead to slowing down of mitochondrial replication, which is where
most of the mutation occurs. The message for this could be something as
simple as the transmitters released when one's stomach is full. Because
CR diets usually involve less actual food bulk, has anyone done studies
looking at caloric restriction when the volume and density of the food are
the same (e.g. , just make the rats eat low fat low sugar chow with the
same amount of fiber).
Paul
_________________________________________
Dr. Paul S. Brookes. (brookes at uab.edu)
UAB Department of Pathology, G004 Volker Hall
1670 University Blvd., Birmingham AL 35294 USA
Tel (001) 205 934 1915 Fax (001) 205 934 1775
http://peir.path.uab.edu/brookes
The quality of e-mails can go down as well as up
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