From: rbradbur@hardy.u.washington.edu (Robert Bradbury)
Newsgroups: bionet.molbio.ageing
Subject: Why does calorie restriction reduce the rate of aging?
Summary: An adaptive mechanism or something else?
Date: 21 Aug 92 12:56:39 GMT
Organization: University of Washington, Seattle

This group may be moribund but it isn't completely dead.

I've been studying the mechanisms by which calorie restriction retards
the aging rate and extends life and thought I would toss out some thoughts
for consideration.

As many of us know calorie restriction in a variety of species extends
lifespan.  A 40% restriction of calories for mice/rats can lead to a
30-50% extension in lifespan.  This process does not work by reducing the
specific metabolic rate (there is a slight drop in the metabolic rate
per unit of lean body mass initially and then it returns to normal).
There is a slightly lower average temperature in CR animals but the
1-2 deg difference hardly seems enough to account for the large extension
in life.  There does seem to be a shift in fat/carbohydrate/protein
metabolism which may explain much of the extension.

CR animals exhaust their fat stores and do not have sufficient calorie
intake to rebuild them.  Normal cells seem to up-regulate insulin
receptors and become more efficient at taking up sugar when it is
available and little remains for adipocytes to store as fat.  CR
seems to result in the hypothalmus/pituitary/adrenals up-regulating
glucocorticoid (cortisol) production which results in increased
gluconeogenesis (sugar production) by the liver.  Since there isn't
any glucose or fat to serve as an energy source the liver uses amino
acids from proteins broken down in other tissues (initally muscle but
perhaps other tissues as well).

This process has two interesting consequences:
  1) Since there is little fat, there are few fatty-acids to breakdown
     for energy.  The first step in B-oxidation of fatty-acids in
     peroxisomes involves the production of hydrogen peroxide (H2O2)
     which is "supposed" to be cleaned up by catalase and glutathione.
     However, there some evidence that indicates that this process is
     not perfect and may end up causing approx. 50% of the oxygen
     related damage we see in cells.

  2) The increased amino-acid requirements of the liver cause an increase
     in protein turnover in other tissues.  One can presume that this
     results in a reduction in oxidized/glycosylated proteins with
     diminished function and an increase in spiffy new proteins which
     perform their intended tasks better.

The combination of reduction in DNA damage and increased protein
efficiency could explain much of the extension in life one sees
in CR.  Interestingly enough, Holliday and others have pointed
out that this could be a general adaptive mechanism in many species
because of its evolutionary advantages.  When food is scarce, reproduction
is not a particularly good idea.  Instead an organism would have a
selective advantage if it could put the resources which would normally
go into reproduction into preserving the organism until such time as
times got better and food resources would allow better offspring survival.

Now, there are two interesting paradoxes I have yet to resolve for myself:
  1) Glucocorticoides/cortisol are stress hormones which are normally
     associated with a number of harmful effects in organisms.  E.g. long
     term exposure results in increased neuron death in the hypothalmus.
     The only thing I can hypothesize is that either the good effects
     outweigh the bad or else there is some mechanism by which the low
     levels of glucose/insulin/T3 offset the high GC levels.

  2) Protein synthesis is expensive from an energy requirement standpoint.
     How can an organism get less overall energy and yet increase its
     protein breakdown and synthesis?  One saves some energy because
     you do not have the losses associated with building up/breaking
     down fatty acids.  There also seems to be a less cell replication
     due to lower growth hormone/T3 levels.  Do these and the slightly
     lower temperatures provide enough energy savings to be able to
     increase protein synthesis with 40% less calories or is there
     something I am missing?

If the above explanation for why CR works is accurate then there is no
reason to think that it should not work in humans as well.  And to throw in
my inevitable political comment (to which you should *NOT* reply in this
forum), since the lifetime health care costs of both CR (thin?) and
non-CR (!thin?) individuals are roughly the same (heavily skewed towards
the last few years of life) but because CR individuals will have longer
lives and thus lower disease incidence rates, should not the CR individuals
have much lower health insurance costs?  Conversely, I suspect that non-CR
humans would not want to pay the retirement costs of CR humans.
Newsgroups: bionet.molbio.ageing