Why does calorie restriction reduce the rate of aging?

Robert Bradbury bradbury at sftwks.UUCP
Mon Aug 24 19:01:41 EST 1992


In article <Pine.2.4.9208211519.B25086 at mcmail>
  charley at MCMAIL.CIS.MCMASTER.CA (Calvin Harley) writes:
> ... comments on ad lib consumption of food increasing morbidity...

In the "natural environment" you rarely have "ad lib" food consumption.
That would imply that "typical" lab rat and human diets are "unnatural".
You can argue that this results in the abuse of the system which was
designed to store and metabolize fats in that most animals never have
enough food to become "overweight".

I agree that this is a philosophical point, obviously evolutionary fitness
is increased by being able to store fats and metabolize them when the sugar
supply is exhausted.  Medawar's/Williams' pleiotropic deleterious genes
theory with its recent support by Steve Austad clearly makes sense.  There 
has been no selection against beta-oxidation of fatty acids because the
benefits are so high compared with the negative effects of H2O2 production
given the coevolution of catalase protection against the H2O2.  Individuals
who might have mutations which resulted in better defenses (e.g. higher
catalase levels) rarely survive to old age where the effects of those
"good genes" become apparent and can lead to selection which increases
their frequency in the gene pool.

> ... which leads one to predict that many (perhaps thousands) of
>genes have co-evolved to dictate a certain maximum genetic lifespan.

George Martin at the Univ. of Washington has studied this.  He predicts
that there may be a few thousand genes involved in the genetic diseases
which exhibit some of the symptoms of aging.  He has also indicated that
he feels that a few (50-100?) play key roles and the rest are secondary
players.  If some of these genes are involved in the same biochemical
pathways one can begin to feel that there are only a few critical pathways
which may play a key role in much of the aging process.  If you look
at man's large increase in lifespan relative to the other primates in
a relatively short evolutionary timespan you can also begin to suspect that
only a few genes are involved.

>thus is unlikely that a single alteration in lifestyle or diet or a "pill"
>will have a dramatic effect on the genetically determined lifespan. Maybe
>the lab animals on which the caloric restriction theory has been tested
>all have curtailed "normal" lifespans because of ad lib feeding.

I've already given you a single alteration (caloric restriction) which
extends lifespan 30-40% in not only mammals but fish and insects as well.
Anything which acts across that wide a variety of species has to be working
on a general principal which to my mind is something like, "excess food
leads to putting resources into reproduction at the expense of protection
and repair resulting in a diminished lifespan".  Since reproduction is
the "normal" mode in which nature expects us to operate, I prefer to
think of the "well-fed" lifespan as being "normal" while the caloric
restricted lifespan extension is what results from the long term activity
of an adaptive mechanism to resource scarcity which nature has included
as a backup system to increase overall fitness.

>If 120 y is our genetic
>maximum, then I would predict that CR would allow more of us to live closer
>to 120 y, but it would not push the tail of the curve out to 150-200 y or
>more, as some have predicted.

The predictions are based on an examination of the lifepsan curves.  CR
doesn't result in a rectangularization of the lifespan curves which is what
would happen if you eliminated death by various causes until you reached
a maximum "programmed" lifespan at which point all of the animals would die.
Instead the lifespan curve retains the same shape but the development of
disease and death occurs after a much longer life.  This is what you would
expect if we have sufficient reserve to keep things functioning normally
until a point is reached that the accumulated damage breaks a critical
component in a weakened system.  If CR acts to reduce the rate of damage
accumulation then lifespan extension would be a logical result.

Of course it is interesting to ask question, "Why doesn't CR extend lifespan
more than 40%?", one begins to see some interesting things.  If we assume
that aging is due to the following factors:
 * 1) Oxidative DNA and protein damage from B-oxidation
 * 2) Glycosylation of proteins from high glucose levels
 * 3) DNA damage resulting from mutagenic substances in the diet
 * 4) Cell replication (breast, colon, etc.) leading to mutations from
      errors in DNA replication or repair
   5) DNA damage resulting from free radical generation by the mitochondria
      (DNA damage in the mitochondria itself will lead to reduced energy
       supplies and diminished ability for cells to tolerate stress)

Those items with asterisks are reduced by CR, but to different degrees.
#5 may in fact be increased by CR due to the higher levels of protein
synthesis required when proteins are broken down to provide the amino
acids for gluconeogenesis in the liver.  So CR isn't a perfect solution
but it does provide an important pointer to some of the mechanisms whose
control could lead to a reduction in the aging rate.

-- 
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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