Copper and Ageing?

Robert Bradbury bradbury at sftwks.UUCP
Fri Oct 23 22:04:49 EST 1992

In article <1992Oct8.184920.28808 at gserv1.dl.ac.uk>
>It is well established that copper, and another transition metal, iron, 
>promote the production of free-radicals in vitro.
Although Cu does promote free radical formation better than Fe does,
the problem is there is 20x as much iron in the body as copper.
The best reference on this is:
  Free Radicals in Biology and Medicine, 2nd Ed
  B Halliwell, JMC Gutteridge
  ISBN 0-19-855294-7, Clarendon Press, Oxford 1989
The authors have done a number of experiments in this area over the
last 10 years and I think they currently prefer Fe over Cu as a source
of damage due to its higher levels in the body.

>Cellular systems for handling copper will sequester most of
>the metal from the potential to cause damage. However, it is tenable 
>that some low level of 'free' copper occurs in cells, due to the
>affinity of copper for various cell components. So it can be proposed 
>that some of this metal is bound to the DNA. 
Yes, Cu is sequestered by ceruloplasmin among other things.  The *really*
interesting part is that Fe is normally stored in ferritin as Fe+++; when
it is released it must be converted to Fe++.  Ceruloplasmin functions as
a ferrioxidase since it converts Fe++ to Fe+++ which can be stored back
in ferritin.  So here you have a case of a protein which protects from
oxidative damage from 2 different metals by 2 different methods.
What is the probability of this from an evolutionary perspective???

>Then, co-agents could act with copper to catalyze radical induced 
>damage to the cellular DNA. These co-agents might be metabolic 
>substrates or products, which are reduced in concentration under 
>a calorie restricted diet.
Yes, one probably reduces H2O2 formation under CR.  It is questionable
whether superoxide production is reduced as under CR protein synthesis
activities increase and so "in theory" energy requirements go up, as
I mentioned before this may be offset by a slight decrease in temperature.

>Finally, it is necessary to assume that the DNA repair systems of
>the cell are not 100% efficient in rebuilding the damaged DNA 
>without error, at least under a non calorie restricted diet.
Even when under CR it is still imperfect.
>I would be glad of any comments on these ideas about the
>possible involvement of copper in the ageing process.
The experiment waiting to be done is to restrict animals intake of Fe and Cu
and determine the relative modification to DNA damage/life-span.  Of course
given the Fe & Cu both have "good" uses, this approach cuts both ways.
Another possibility would be the up-regulation of the ferritin/ceruloplasmin
proteins to see if DNA damage is reduced by increasing the probability that
the metals will be in stored form rather than drifting around the cell.

Robert Bradbury			uunet!sftwks!bradbury

Death is an imposition on the human race, and no longer acceptable
				Alan Harrington, The Immortalist (1969)

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