Original Date: Wed, 24 May 2000 18:34:25 -0700
Original From: "Michael J Rae"

All:
--

Apologies in advance for pedantry.

On Sat, 20 May 2000 16:46:32 Brian Manning Delaney wrote:
>
>
>Peter Bell wrote:
>> Q. What is the proposed mechanism [of the CR effect]?
>>
>> CR: Shift body resources away from reproductive fitness
>> towards extending life.
>
>There are TONS of proposed mechanisms. That's just one. (And,
>indeed, it's an unusually "high level" description of something
>we'd want to call a "mechanism.")

Really, it isn't a mechanism per se: it's an answer to WHY it works,
rather than HOW it works: an ultimate, rather than a proximate,
explanation of the phenomenon. There are indeed many, many candidates
for a possible HOW: reduced oxidative stress, the immunomodulatory
effects of glucocorticoids, reduced AGE accumulation, increased DNA
synthesis, etc etc -- but only a very, very few answers to WHY it
works.

This is complicated by the fact that in some cases, 'whys and 'hows'
may coincide -- or, rather, there may be 'hows' which do not
require 'whys.' These are cases where it would seem that the food
redction itself is DIRECTLY responsible for one change which
just 'happens' to positively influence aging. Thus, being
physiologically (as opposed to subjectively) 'hungry' is a stressful
situation, which leads to glucocorticoid production; this, in turn,
has the effects which make this a possible 'how' of CR, and we may
not need any further explanation for it. Likewise, should it turn out
that CR does, indeed, lower metabolic rate, then this is likely to be
(certainly in large part) due to sheer stoichiometry: fewer electrons
available to scoot thru' the ETS, so fewer are fumbled, so the
mitochondria (and other anatomical components) get less mangled (at
whatever level actually turns out to be important); again, no
ultimate cause need be invoked. And, up to a point, blood glucose, AG!
Es, and aging may be the same way.

But then there are aspects of the CR effect which appear to be
clearly adaptive: where the organism is clearly DOING something,
actively, to slow down aging. Yes, fewer e- rushing through the MIM
may mean less damage -- but those mitochondria also burn what
calories they do process more cleanly, and they mop up the damage
more efficiently. The latter, certainly (and the former, probably --
as perhaps via thyroid hormones) is a process which involves the
active INVESTMENT of energy, where the intuitive thing to think is
that the organism would certainly not spend any more energy than it
had to on anthing when food is scarce. Ditto for upregulated DNA
repair and protein turnover (ie. both synthesis and degradation)
Again, to what extent is lower AGE due to less carb, and to what
extent isit due to (hypothetical) increases in enzymatic Amadori
product degradation? And there is no obvious reason why sheer lack of
calories should, in & of itself, drive down reproductive hormones so!
drastically. Etc.

So, why do we see what we see? Evolutionary theory suggests that,
when we see the organism actively altering its investment of limited
energy supplies, it must increase the organism's reproductive
fitness. The two things we clearly (IMHO) see in CR animals which
demand a 'why' are the increase in preventative maintenance and the
decrease in investments in reproduction and growth. Any candidate for
an ultimate cause must explain both these data -- and Occam's Razor
suggests that it ought to explain them both with a single thesis,
rather than seperately.

Solution: resources are limited. Those genetic combinations which
result in organisms which in vest them in the manner which most often
allows their genes to be passed on will become the dominant genes in
the pool. When food is scarce, organisms which invest the resources --
from gamete production, to maintenance of a sexy bod, to seekign out
and competing for mates, to sacrificing foods for the kids -- in
reproduction at the same rate they do when fed are going to often die
off without leavign viable offspring, while those who cool off and
keep the body in the best possible conditions will live to breed
another day.

In rodents, we not only see just this happening in food scarcity, but
we also see the predicted reverse: when food is plentiful, they
breed, and breed, and breed some more.

I cannot think of any other true WHY of CR, with the pseudo-
explanation of the hibernation cross-adaptation hypothesis -- which
is really more a matter of emphasis than a real difference.

-Michael