some questions from Aubrey's book

Paul S. Brookes. brookes at uab.edu
Fri Jan 21 19:26:54 EST 2000


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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