X-Message-Number: 10699
Date: Wed, 04 Nov 1998 23:16:57 -0800
From: Brian Manning Delaney <>
Subject: Re: Calorie Restriction
References: <>

To Thomas Donaldson,

To continue this discussion when I said I was going to stop is
definitely not going to help my reputation for arguing people
into the ground , but.... well, maybe having started with this
line will help a little. :)

In your case, it should of course be "TRYING to argue someone
into the ground". You're serious. I want you on my team!

In all earnestness, I very much appreciate your rigor and
interest in this topic, and, as I always say, I will buy someone
his (his/her) weight in chocolate if he can convince I don't need
to be on CR. (No, wait, I'll buy MYSELF my weight in chocolate --
hmm, make that HIS weight :)

One of the things that's been helpful is that you're reminding me
that "ancient" (as I call them) life span studies shouldn't be
dismissed by dint of their age. They are often flawed, but can
yield very useful morsels.

A few quick (ha) points:

> None of the strains I've seen used for aging
> experiments suffers from any particular
> characteristic disease, either --- though some
> of the shortest lived strains, for  instance,
> have a strong tendency to die early of leukemia.

The point I was making before about problems using short-lived
strains in life-extension experiments can still apply even if the
autopsies reveal multiple causes of death, and even if the strain
is medium-lived, and not short-lived. There, though, my two human
equivalent analogies wouldn't apply, to be sure. But there are
plenty of genetic flaws which manifest themselves in a wide array
of diseases, and which might be corrected by one agent.
Congenital immune system weakness, for example, results in early
death my many causes.

This is why Walford has always insisted -- I think rightly --
that we can't make anti-aging claims about a life-extension
regimen unless the study on which the claims are based is done on
long-lived strains. A further condition I would add (the old
Steve Harris quote addresses this) is that the experimental group
actually live beyond the normal strain maximum life span. That
is, bad husbandry on a long-lived strain might shorten lives in a
way which some agent might _partially_ correct. You might find a
max. life span gain in the expt. group in comparison with
controls, but that doesn't mean it's slowing aging.

Something from the day before:

> If you actually read up on melatonin

It's only the two particular studies you cited that I haven't
read recently. Melatonin research I've followed keenly (though
I'm not totally up to date).

> you will
> discover that it is among the drugs which may
> mimic CR, at least in some respects. The reason
> for this is that CR retards changes in the
> pineal gland (which produces melatonin), and
> thus with CR your melatonin remains relatively
> high.

I just got into this question in Sci.life-extension. Self-quoting
is annoying but...

SLE> For (just about) each instance of a postulation
SLE> that the CR effect results from a change in
SLE> parameter X, say a slowing of the age-associated
SLE> decline in melatonin production [1], there's the
SLE> rejoinder that such prevention is "ultimately"
SLE> caused by a decrease in free-radical damage. (Of
SLE> course it could be the result of better repair
SLE> or neutralization, something quite different
SLE> from fewer radicals being generated.) That is,
SLE> the argument would go, pinealocytes are staying
SLE> youthful longer because of reduced free radical
SLE> damage. Of course one can easily test which is
SLE> primary, it would at first seem, by looking to
SLE> see whether cells elsewhere are also staying
SLE> younger longer. And they are. But then the
SLE> melatonin theorist says, "Ah but melatonin
SLE> itself prevents free radical damage _throughout_
SLE> the body, so...."
SLE> Thus the difficulty in nailing down the precise
SLE> mechanism of CR's action.

You've probably read this, but this was the reference:
[1] Stokkan KA, et al.
Food restriction retards aging of the pineal gland.
Brain Res. 1991 Apr 5;545(1-2):66-72.
PMID: 1713529; UI: 91316606.


The point -- I'm not saying you're taking issue with this -- is
that we simply don't yet know the relation among the relevant
variables yet. And: figuring it out is tricky. Some melatonin
researchers have, in my view prematurely, argued that CR works by
dint of its effect on the pineal gland. We simply can't yet
conclude that.

(Nevertheless, you've got me realizing that there are indeed a
lot of no-brainer experiments that haven't been tried, that
should be, even if I still think you underrate, or underrated,
the CR research agenda. Recently discovered set-point regulators,
for example, should be investigated with respect to CR. I do know
one group working on this, but these things take time to
complete, and publish....)

> Pierpaoli is far from the only person who
> has done lifespan experiments with melatonin.
> There is a popular book which you might get
> which  discusses these various issues, RJ Reiter
> and J Robinson, MELATONIN.

Yeah, I've glanced at it. I believe in peer-review....


> Pierpaoli has also written his own book on
> melatonin, THE MELATONIN MIRACLE. This, too,
> deserves a read, ESPECIALLY if you want to
> criticise his experiments.

Every time I reach for this book the title turns me off. But I
trust your judgement.

> One interesting experiment (which might --- or
> might not --- show that melatonin and CR are
> related) is to try CR on mice which lack a
> pineal gland. Since some strains of mice also
> make  melatonin elsewhere, you'd want to make
> sure that you don't do the experiment on such a
> strain.

I mentioned gland-mutilation AND'ed with CR previously. I owe you
a reference 9and a couple others), and you'll get one after I go
to the library. (It wasn't the pineal, though.) My recent move
caused file-loss (temporary, I hope).

> And I doubt very strongly that CR is the only
> strategy available to us if we wish personally
> to delay our aging.

To be clear: I've been claiming _specifically_ that CR is the
only strategy which we have good reason to believe slows aging
appreciably. This leaves open 1) the possibility that agents we
know about now _might_ work well but just need to be tested under
better circumstances; and 2) the actuality that the evidence we
DO have allows us to conclude with a significant probability that
some other agents slow aging somewhat -- but not as much as CR.
The evidence, even the guesswork, just isn't there.

It's all the same team,

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