X-Message-Number: 10675
Date: Mon, 02 Nov 1998 01:07:18 -0800
From: Brian Manning Delaney <>
Subject: Re: Calorie Restriction
References: <>

In Message #10664, Thomas Donaldson wrote:

> Yes, the effects of drugs on lifespan is
> obscured by the fact that mice come in all kinds
> of breeds. However your claim that the
> comparison is with (say) hypercholesterolemics
> versus normals is WAY too much exaggerated.

(To be clear: my comparison was with short-lived strains only --
those used in the melatonin studies.)

Why do you think that? If anything, the example isn't strong
enough, when it comes to many strain differences. Short-lived
strains of rodents are often very sickly; indeed, far MORE sickly
than hypercholesterolemics (and sickly in a way that's
attributable to just one disease, or one condition that
predisposes them to disease). Therein lies precisely their
research value, and often is the reason they were
bred/developed/isolated in the first place.

If you want an analogy that's an equality along more axes --
though I don't see how it would make a difference to the point I
was making -- think of a group of women all of whom have a gene
that predisposes them to getting breast cancer at a very early
age. Give half of them melatonin. The women in the melatonin
group may well live much, much longer than those in the control
group. Maximum life span could even be increased. Yet we wouldn't
be able to conclude from a such a study that aging was slowed at

Here's part of a very old post (May, 1995) to Sci.life-extension
by Steve Harris, whom I think many people on Cryonet know and
trust (well they should!). (This was in response to my claims in
_support_ of melatonin, as it turns out -- I do still think
melatonin is very much worth further research.)

(Apologies to Steve if this no longer represents his views.)

SBH> Again, [the melatonin experiments] are not done
SBH> on long lived strains. At the Walford lab our
SBH> mice on mild (10%) restriction (necessary to
SBH> keep them from getting hugely fat) have max
SBH> lifespans of 42 months. Restrict them and they
SBH> go out to 54 months. The longest lived animals
SBH> getting melatonin in the Pierpaoli studies went
SBH> to less than 33 months. This is silly....
SBH> ..To me, it's about like a report of men who
SBH> lived to be 65 on some drug, as opposed to 55.
SBH> It's a life extending effect, but no way are
SBH> you going to convince me it's an antiaging effect.
SBH> Any group of people all dead by 65 are not
SBH> being well taken care of, period. Any group of
SBH> mice all dead by 33 months are a joke....

> Furthermore, if a drug causes some of the same
> effects as CR, it may well show some of the
> symptoms of CR in animals receiving it.

Yes, of course -- "IF".

> As a
> matter of fact, most of the drugs I listed were
> not found to have an effect on aging by
> established researchers into aging. That has
> always seemed to me to be a very interesting
> fact which tells us something about motivations.

Yes, I agree. It tells us something about problems in aging
research (especially pre-90's research).

> The only way to decide, in such experiments,
> whether or not CR may have played some implicit
> role is to study the actual experiment in detail.

Yes. In many cases, however, especially where weight changes are
not reported, no amount of detailed studying will enable us to
say more than: "Because the study was badly conducted (assuming
it's primarily an aging study), CR _may_ have caused any
anti-aging effect seen. Let's do another one with the same agent,
but this time do it right." Where a second study is not done, we
can't say the agent slows aging -- nor, obviously, can we say it
does not slow aging. Thus my original statement which started
this thread.

> Most important, even when the animals show a
> slight loss of weight, it does not match that of
> CR animals.

But neither does the maximum life span gain match. Indeed, the
weight loss -- in the case of at least all but the L-dopa and
dilantin studies, I'm certain (where the weight loss was
reported) -- it matches that of animals CR'd to a degree to cause
the same small increase in maximum life span. But, to be sure -->

> Please read the articles again.

I certainly plan to look up the L-dopa and dilantin studies soon!
Though in the case ofr most of the studies you mentioned, my
memory is clear: the studies did not control for CR, which,
regardless of weight findings, makes an anti-aging study suspect
-- though not worthless, of course. If my memory of the L-dopa
and dilantin studies proves to be appreciably at variance with
reality, I'll report back.

> As for glucose metabolism, yes, it's true that
> experiments with the drugs I suggested have been
> done. If that is all you mean, then I agree with
> you.

That's half of what I mean. The other half is the CR studies
themselves, which attempt to discover in more detail which
physiological parameters are altered by CR. These two halves
together enable us to see two important things. 1) When we
uncover more CR-induced physiological changes, we have a better
idea of which drugs to try in anti-aging experiments (or to
develop for anti-aging purposes). 2) When we test putative
anti-aging drugs which alter some parameter thought to be part of
the CR response, we learn more about which of the many changrse
seen in CR actually matter.

So then I'm not sure how the combination of these two types of
studies -- the first of which you're aware of, and the second of
which you can find by the hundreds with a Medline search [1] --
wouldn't also do what you're asking about here:

> However if there are scientific papers
> actually looking at the relation of these (or
> other metabolism-changing drugs) in relation
> specifically to CR, then please give me the
> references at once.

That is to say, researchers doing an aging study (in the last few
years) of say, chromium -- even if the experiment didn't have an
additional control group of CR'd animals -- would of course
examine the question of whether their findings answer the
question of the mechanism of CR. For example, if chromium lowers
fasting glucose, but doesn't increase maximum life span, fasting
glucose can't be the explanation, or certainly not all of the
explanation, of how CR retards aging.

The way CR research has gone has been: 1) Make sure it works, and
that it's energy-restriction, and not something else
(fat-restriction, protein-restriction, etc.), that causes the
anti-aging effect. That it's energy-restrction was fairly clearly
established by the late 80's (though a few people have recently
tested the idea that meal-timing, or the source of the Calories,
that makes the difference: it isn't, for the most part). 2) At
the same time, and later, researchers were looking at which
particular physiological parameters are altered by CR. Dozens
were discovered (and more are still being discovered). 3) Since
then, researchers have been trying to figure out which of the
many parameters altered by CR is actually responsible for the
anti-aging effect. This has involved doing precisely the sort of
things you've been asking about (with respect to drug studies),
and also, as I mentioned, various other types of CR-elucidating
interventions. Some interesting examples can be found in this
review article:

Neurobiol Aging 1995 Sep-Oct;16(5):845-7; discussion 855-6. "Use
of caloric restriction to investigate neuroendocrine involvement
in aging." Weindruch R, May P.

> There is a problem with using CR to explain
> results with drugs. Usually the lifespan
> extension found is too large to be explained
> simply by CR, given the condition of treated
> animals.

If you're thinking of any but the dilantin and L-dopa studies,
I'm fairly certain you're wrong. If not, I'll respond after I get
my hands on the dilantin and L-dopa studies.

Before continuing, let me note that we've been exploring two

1) Whether there is reason to believe that any putative
aging-intervention about which we now have any experimental
evidence produces an effect that approximates that of CR. The
answer here is clearly No, I contend.
2) The nature of anti-aging research priorities -- both those
connected with CR, and others.

> Not only that, but CR explains nothing at all.
> We just have to go back a step and ask why CR
> might increase lifespans.

This does not speak to the first issue, unless I'm not following
you, but rather to the second. Insofar as it speaks to the second
issue, I agree with you completely, as does everyone I know who's
interested in anti-aging research or life-extension. You may know
some life-extensionist technophobes who argue that
life-extensionists should be doing CR, and nothing else, AND
think that research shouldn't be looking into alternatives, or
into the mechanism by which CR works. I suggest we save time by
making the reasonable assumption that such people are not
included among the readers of this discussion, and stop making
the point that we need to discover how CR slows aging.

The flow of your argument, however, suggests that you might have
made the above-quoted claim in connection with issue (1). If so,
I don't see the connection. If this is how you intended your
comment, please explain the connection.

The two issues above are of course related, and I suppose this
relation may have something to do with your comment. The relation
between the two, as I see it, would be something like the

Assuming a life-extensionist wants to live a long, healthy life,
and that cryonics currently offers only a small possibility of
success (a most distinct issue!) s/he needs to slow aging, NOW.
As I write, there is no reason to believe with more than a very
small probability that any intervention can achieve -- or even
come close to achieving (not quite as tiny a probability here) --
the anti-aging effect of CR. Thus, for a person for whom the many
possible reasons not to do CR (pregnancy, desire to get pregnant,
concerns about food obsession, love of eating to excess or
satiation, etc.) don't apply, CR should be practiced. (And many
would argue that cryonics is also a smart anti-aging choice.)

Obviously, even for someone who _enjoys_ CR, reflection on future
anti-aging interventions can't stop here. For the average person
on CR, the diet will buy an additional two or three decades at
most. Thus, anyone wanting more than a modest increase in life
span would need to support further research into anti-aging.

Estimations of the odds of success, however, of future research,
could certainly affect someone's motivation to go on CR. This is
where the connection between issues (1) and (2) becomes trickier.
If I knew with certainty that some intervention that equals or
exceeds CR's effectiveness were going to be developed (and
verified) in say, ten years, I might make the decision to stop
doing CR now.

Perhaps, then, your repeated stressing of the need to elucidate
the CR mechanism is in the service of turning my No answer to the
question of current CR alternatives into a Yes by the year 2004,
instead of 2008 or 2010. If so, I understand, and very much

Once again, though, I'm puzzled. You're preaching to the
converted, and I don't see why you would think otherwise.
Research is good; more research is better: Why would any
life-extensionist disagree with that?

(Maybe there are financial stakes here of which I'm ignorant? --
not nec'ly a cynical comment, so please don't take offense.)

God, pardon the length. I may bow out here.


Doing Medline searches for CR articles can be a bit tricky. Using
MeSH terms, the following catches most, but not all CR studies:

"energy intake"[MeSH Terms] AND ("aging"[MeSH Terms] OR
"longevity"[MeSH Terms])

This is a bit better, but still misses some, and includes a few
that aren't CR aging studies:

((Calorie[All] OR caloric[All] OR dietary[All] OR food[All] OR
energy[All]) AND (restriction[All] OR restricted[All]) AND
("longevity"[MeSH Terms] OR "aging"[MeSH Terms])

Brian Manning Delaney
(No need to CC articles to me.)

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