From: ((Steven B. Harris))
Subject: Re: Sci.life-extension Calorie Restriction FAQ
Date: 07 Jun 1995

In <3r328q$ct@soenews.ucsd.edu> barry@starfire.ucsd.edu (Barry Merriman)
writes:

>I'm curious as to exactly how lifespan varies with
>caloric intac in CR experiments. Its not clear exactly what
>the caloric variable should be, but either calories consumed
>per unit of time (e.g. calories per day) or total calories
>consumed during the lifetime would be reasonable choices. Does
>one obtain some characteristic graph of lifespan vs. either of
>these variables? In particular, do you die after eating a certain
>number of calories?


Answer: Well, mice on CR get far more calories/gram of mouse/lifetime
than do fully fed ones.  They do get about the same number of calories
per mouse per lifetime, due to being smaller.  I suspect that CR
initiated at weaning is a different kind of thing than CR initiated in
young adulthood, and probably has additional mechanistic effects
(perhaps developmental clock effects as well as energy/ metabolic
effects).  Weening-CR results in mice which are structurally different,
with most organs (though not, significantly, the brain) smaller in
weening CR mice.  Life extention here is radically longer.  By contrast
adult restriction results in much less life extension (even calculated
on the basis of lifetime calories), and body composition changes showing
radical fat loss (and I suspect probably slower specific metabolic
rate), but not greatly decreased size of vital organs.


                                         Steve Harris, M.D.



>--
>Barry Merriman
>UCSD Fusion Energy Research Center
>UCLA Dept. of Math
>bmerriman@fusion.ucsd.edu (Internet; NeXTMail is welcome)

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: sci.life-extension,sci.med.nutrition
Subject: Re: Calorie Restriction and Exercise (was The Exercise Paradox)
Date: 3 Nov 1998 09:54:01 GMT

In <363E977D.96960BA8@notarealaddr.ess> Brian Manning Delaney
<bmdelaney@notarealaddr.ess> writes:

>Holloszy's most recently published study provides the extra
>Calories to CR'd exercisers. In the previously (repeatedly)
>established relationship among the three variables, exercise,
>degree of restriction, and longevity, C and D, below, differ
>appreciably. In Holloszy's lastest study (and in the other one I
>cited) they look quite similar, but extra Calories to group C
>were provided (or fewer to D, depending on how you look at it):
>
>A. Non-CR'd, sedentary rodents. (Shortest-lived.)
>B. Non-CR'd, exercised. (Between)
>C. CR'd and exercised. (Longest-lived.)
>D. CR'd and sedentary. (Longest-lived.)
>
>Holloszy's most recent study (not the one I referred to in the
>previous post) fed group D to be WEIGHT-matched with group C.
>They ate a lot less food. Group C was restricted by 30%. Group D
>ended up being restricted by about 50%. Yet the difference in
>mortality was not significant (the most long-lived of D lasted a
>tiny bit longer than the most long-lived of C).
>
>Holloszy speculates, however, that with a different strain the
>same results might not apply. The reason he gives is that in the
>strain used here, the Long Evans rat, CR beyond 30% doesn't
>produce additional significant life span gains -- at least his is
>what he found in his previous study [2].
>
>Either way, if this finding proves repeatable, it weakens the
>idea that exercise is not good for people on severe CR.
>
>Best wishes,
>Brian.



   Very interesting.  It also strengthens what some of us have long
thought, which is that CR is not just a matter of "decrease in calorie
generated free radicals".  Rather, the driving factor is some metabolic
consquence (hormones, temperature, glucose, etc) of the body weighing
less than it wants to, so that it thinks it is starving.  Body
composition (the ob/ob mouse data) and exercise, and indeed, even total
caloric intake, are almost irrelevent.  If you can run more calories
through without changing the body's relationship to its own striven-for
"set point", you'll get the same life span extending effect.  Yes, the
experiment needs to be repeated to see if the relationship is between
calories taken in and calories the body WANTS to take in (so that the
excercised group has the chance to show even more effect).  But I doubt
it will happen.  I don't think the body really has any way to know how
many calories have been eaten.  It only knows how much storage energy
is available at any given time, and (of course) also how well the
homeostatic mechanisms are keeping up with the necessity to maintain
body temperature.

                                        SBH

-------------------------------------------------------------------

"I know of no better life's work than to run the insignificant and
 easily destroyed newgroup opinion to ground."

                      -- Usenet Addicts Anonymous. Credo #1

--------------------------------------------------------------------

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.life-extension,sci.med.nutrition
Subject: Re: EU vitamin ban -can cutting vitamin intake be dangerous?
Date: Mon, 25 Mar 2002 10:47:01 -0800
Message-ID: <a7nr90$3pe$1@slb3.atl.mindspring.net>

michaelprice wrote in message
<4ABn8.18030$Dr3.2460445@news6-win.server.ntlworld.com>...

>Steve's "controls" - for which criticism (a) applies!! - were on 10%
>restriction.  Tragic since CR improves glucose tolerance.


Actually, it doesn't (at least in mice): you should see the glucose
tolerance curves in my 40% CR animals-- horrible (abstract is below, but it
really takes looking at the graphs to get the full impact).  Being on severe
CR doesn't give you a pancreas with a lot of reserve (not surprisingly).
It's the average and fasting glucoses that are low in CR.  10% gives
intermediate fasting glucoses, and the best glucose tolerance to acute
challenge. Ad lib animals are pre-diabetic.  Incidentally I did run some of
these on Cr picolinate for a while and got no glucose effect. I couldn't get
ANY effect of this stuff in my model on ANY parameter.

Thanks to Michael for answering the other parts of your question and doing a
lot of work for me. I will add only that the literature of gerontology is
litered with claims for life span improving properties of all kinds of
things: Vitamins C and E,  DMAE, cysteine, cysteamine, BHT,
ethoxyquin, deprenyl, CoQ10, lots of other stuff.  It proved to be
unrepeatable, by and large. I don't even completely believe my own results
until they've been confirmed; it's too easy to fool yourself in science.
There are also old reports from the 40's, 50's and 60's like the ones you
cite: never confirmed and there they sit.  My guess is that if they were
repeatable they also would have been confirmed. Since they haven't, we can
ignore them.  If you want to try repeating them yourself and maybe be
famous, be my guest.

Mech Ageing Dev 1994 Mar;73(3):209-21 Related Articles, Books, LinkOut


Serum glucose, glucose tolerance, corticosterone and free fatty acids during
aging in energy restricted mice.

Harris SB, Gunion MW, Rosenthal MJ, Walford RL.

Department of Pathology, University of California at Los Angeles 90024.

Energy restriction, the only method known to increase maximum life span in
laboratory animals, was used as a tool to test hypotheses regarding possible
mechanisms of aging. Serum glucose and corticosterone (CS) concentrations in
mice of a long-lived hybrid mouse strain, aged 7, 17, and 29 months, and on
50%, 80%, and 100% of ad libitum intake, were measured. Serum glucose and CS
concentrations were also measured in response to intraperitoneal (i.p.)
glucose challenge in mice at ages 7 and 29 months. Serum glucose and CS
concentrations were also measured at several time points over 36 h, to
assess their diurnal variation. There were no differences in single fasting
glucose concentrations in 7- and 29-month-old mice at the same degree of
energy restriction, but energy restriction decreased glucose concentrations.
Serum CS concentrations were generally increased restricted animals with
respect to fully fed ones. Average serum glucose concentrations were found
to be significantly decreased by dietary restriction. Glucose tolerance
curves were unchanged by age in ad libitum fed or 50% restricted animals,
but in 80% ad libitum groups, older animals showed evidence of decreased
glucose tolerance with respect to young animals. For each age, peak serum
glucose concentrations after i.p. glucose loading varied with degree of
energy restriction, with more severely restricted animals showing less
glucose tolerance. Average serum CS concentrations were elevated at 7 months
by restriction, especially at night and long after feeding, but we found no
differences with age or diet in average CS concentrations. Our serum glucose
results support the hypothesis that nonenzymatic glycation is
mechanistically involved in normal aging. Our serum CS results do not
support the hypothesis that CS contributes significantly to the
pathophysiology of normal aging in mice.

PMID: 8057691 [PubMed - indexed for MEDLINE]


--
I welcome email from any being clever enough to fix my address. It's open
book.  A prize to the first spambot that passes my Turing test.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.life-extension,sci.med.nutrition
Subject: Re: EU vitamin ban -can cutting vitamin intake be dangerous?
Date: Mon, 25 Mar 2002 15:21:47 -0800
Message-ID: <a7obc7$rt4$1@slb6.atl.mindspring.net>

michaelprice wrote in message ...

>> Actually, it doesn't (at least in mice): you should see the glucose
>> tolerance curves in my 40% CR animals-- horrible (abstract is below,
>> but it really takes looking at the graphs to get the full impact).  Being
>> on severe CR doesn't give you a pancreas with a lot of reserve
>> (not surprisingly).
>> It's the average and fasting glucoses that are low in CR.  10% gives
>> intermediate fasting glucoses, and the best glucose tolerance to acute
>> challenge. Ad lib animals are pre-diabetic.  Incidentally I did run
>> some of these on Cr picolinate for a while and got no glucose effect.
>
>Old,  young or both?


Both as I recall.

>> I couldn't get ANY effect of this stuff in my model on ANY parameter.
>
>Including insulin levels?


I didn't look at that. My assay for insulin was not the most sensitive, and
I really couldn't reliably "see" any fasting insulin level differences even
among various fasting restriction groups. I saw a clear insulin signal only
with glucose challenge, and didn't look at glucose tolerance with chromium.


>You really should publish since it is impossible to critique unpublished
>word-of-mouth stuff.

Yep.



--
I welcome email from any being clever enough to fix my address. It's open
book.  A prize to the first spambot that passes my Turing test.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.life-extension,sci.med.nutrition
Subject: Re: EU vitamin ban -can cutting vitamin intake be dangerous?
Date: Sun, 31 Mar 2002 20:04:11 -0700
Message-ID: <a88je0$5i7$1@slb4.atl.mindspring.net>

"michaelprice" <michaelprice@ntlworld.com> wrote in message
news:2uMp8.31201$gj7.4928174@news2-win.server.ntlworld.com...

> Second, the lower fasting glucose levels of Steve's CR "controls" is also
> an effect produced by chromium picolinate, so they are not good controls.


How do you you figure?  The CR animals got the same amount of brewer's yeast
per animal per day as the others.

Believe me, little bits of brewers yeast give or take make no difference in
this system. We tried giving non restricted and slightly restricted mice a
lot more of brewer's yeast; and we tried giving them a hellava lot of
straight red Cr-picolinate powder ("Chromax II"), as the pure chemical
provided from the nice people at Nutrition 21 in La Jolla, CA, 12.5%
chromium by weight (I'm sitting here, looking at the bottle as I type). And
we did both. There was no effect on glucose whatsoever. The restriction
effect on glucose is NOT a chromium effect. If it were, we've have swamped
it 3 ways from Sunday.

SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.life-extension,sci.med.nutrition
Subject: Re: EU vitamin ban -can cutting vitamin intake be dangerous?
Date: Mon, 1 Apr 2002 10:23:24 -0700
Message-ID: <a8a5g8$gp2$1@slb1.atl.mindspring.net>

"michaelprice" <michaelprice@ntlworld.com> wrote in message
news:TeTp8.34766$gj7.5248199@news2-win.server.ntlworld.com...
> "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com> wrote in message
> news:a88je0$5i7$1@slb4.atl.mindspring.net...
> > "michaelprice" <michaelprice@ntlworld.com> wrote in message
> > news:2uMp8.31201$gj7.4928174@news2-win.server.ntlworld.com...
> >
> >> Second, the lower fasting glucose levels of Steve's CR "controls"
> >> is also an effect produced by chromium picolinate, so they are
> >> not good controls.
> >
> > How do you you figure?  The CR animals got the same amount
> > of brewer's yeast per animal per day as the others.
>
> Sorry, you'll have to clue me in here.  Brewer's yeast was used as
> a source of B-vitamins or chromium GTF?

Of GTF only. We had suspicions about the CrCl3 (as I remember) being used in
the AIN-76 mineral mix of the time. Or perhaps there was no Cr at all in
that mix-- I no longer remember.  Anyhow restricted animals got about 60% of
the food of ad lib animals, so they were given a diet which was more dense
in vitamins, minerals and yeast by a factor of 1/0.6 = 5/3.



> Another thought, is the
> strain you used susceptable to diabetes, like humans?


Not really. The ad libs ran glucoses around 120 mg/dL, which wouldn't
formally give them the diagnosis, even in todays' more conservative
atmosphere (where you need to be above 129).  Perhaps a few were above 129,
but we'd have ignored them since the criteria then was 139. As a group, old
ad-lib fed C57Bl10/C3H hybrids are near diabetics, at best. For a real
diabetic, this control would be excellent with A1c's in the 6's.

SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.life-extension,misc.health.alternative,alt.health
Subject: Re: CR Research Update
Date: Mon, 8 Apr 2002 15:56:11 -0600
Message-ID: <a8t3lr$rus$1@slb6.atl.mindspring.net>

"Ian Goddard" <igoddard@erols.mom> wrote in message
news:3cadb458.31640034@news.erols.com...
>   IAN: McCay's findings were not seen as discovering a method
>   of anti-aging. It was assumed that what was happening with
>   life-long CR was that by delaying the onset of puberty, all
>   the subsequent phases of life were delayed, including death.


Not everybody assumed that. Even McCay, if I am to credit hearsay. I once,
10 years ago at UCLA, heard a lecture by gerontologist James E. Birrin, in
which he mentioned that he's served in WWII aboard a destroyer with the very
same Clive McCay, and McCay spent a lot of time telling people they would do
better to eat less if they wanted to live longer!

That's a hell of a good story, if true.

SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.life-extension,alt.health,misc.health.alternative,sci.med
Subject: Re: CR & Fasting
Date: Sun, 16 Jun 2002 22:13:40 -0600
Message-ID: <aejo1p$djq$1@slb6.atl.mindspring.net>

"Ian Goddard" <igoddard@erols.mom> wrote in message
news:3d0ce20c.42516749@news.erols.com...
> On Sun, 16 Jun 2002, Tom Matthews <tom@morelife.org> wrote:
>
> >Ian Goddard wrote:
> >
> >>  This soon-to-be published study just posted to the crsociety list
> >>  presents strong evidence contrary to the case I made aginst fasting:
> >>
> >>   http://www.americanaging.org/abs/Anson2.htm
> >>
> >>  The study suggests that every-other-day fasting yields life-extension
> >>  effects comparable to daily-feeding CR but with only a 9% reduction
> >>  in total caloric intake.

COMMENT
No, as this study did not look at life span directly, but only very dubious
markers.  Do not take wooden nickels in this game-- the *only* gold standard
in calorie restriction studies is life span.

Yes, this study CLAIMS that you can get the same life span by every other
day (EOD) ad lib feeding as by (some other level) of caloric restriction. I
know of no evidence that every other day feeding gives you any life span
advantage at all over any other kind of feeding which results in the same
calorie intake (which is a bit less than total ad lib, as noted, but not
that much less). EOD ad lib feeding is a very mild sort of CR, but it only
produces mild CR effects also, if you do it ad lib. Nobody has yet been able
to reproduce the tremendous effects of the 82 Goodrick paper. At Walford's
lab the restricted animals got fed 3x per week, to be sure, but that was
only a matter of convenience-- their portions on the days they were fed were
restricted. Even the "ad lib" animals only got fed 5x a week, with a double
portion before the weekend (which they ate in 12 hours) after which they
went 2 days without anything. They were big fat animals and didn't get any
life span extension by comparison with known curves for that breed.


>>This of course immediately suggests that
> >>  the effects of CR may come from periods of food depravation per se
> >>  rather than from (or only from) an overall reduction of calories.

COMMENT:
Not until we see a LOT more data, it doesn't!

Remember, we haven't all been running out to do feeding frequency studies in
DR, because enough of them have already been done to suggest that
time-between-meals is not a big part of the answer. In the 90's we were all
aware of the Nelson and Halberg study quoted below.  I wrote a bunch of
grants in the early 90's to do much the same work you see that Masoro
finally did in 1995 below (mine got turned down, his obviously didn't). More
or less, Masoro failed to find any effect either between once a day and
twice a day restriction. Nelson, as a bit of trivia, had to build a cute
little machine which was basically a gear and clock driven Archimedes screw
which delivered tiny powder meals 6x a day, but totaling out to an energy
restricted diet. He got the full CR effect anyway.


IAN:
>   The following is from a reply I made on the crsociety list...
>
>
>   IAN: Yeah, I wasn't able to find any research testing EOD vs
>   daily-feeding CR. While the study at the AAA site is not yet
>   published, the NIA researchers are a reliable group, I would
>   take their findings at face value.

Yep.


IAN:
>The fact that we cannot
>   find any head-to-head tests also means we have nothing that
>   suggests their findings are questionable.

Harris: Burden of proof is on them. They are not doing what anybody these
days would call "CR,"  so it remains up to them to show it is a
significantly life span prolonging therapy. They can't just cite one paper
from 1982.


IAN
>   I was not able to find any studies showing that EOD extended
>   Maximum LS, but I would be surprised if there was a difference
>   in this respect between EOD and LDF mice that went unmentioned
>   in the abstract. These researchers know CR and would most surely
>   observe mean vs max LS and note any differences. I found these:
>
>      6641783: "...EOD-fed rats had a mean lifespan of
>      124 weeks compared to 103 weeks for AL-fed rats."


But would be expected to have a slightly smaller food intake.


>      7117847: "The mean life span of the EOD group
>      represented an 83% increase over that of the AL group."

COMMENT:
This is the Goodrick et al paper of 1982, and it probably represents the
best findings for EOD ad lib in the literature. Even here, though, the EOD
animals weight less, so were somewhat restricted.


==================

J Nutr 1986 Nov;116(11):2244-53

Meal-timing, circadian rhythms and life span of mice.

Nelson W, Halberg F.

The possibility that circadian rhythm alteration may contribute to the
life-prolonging effect of food restriction was investigated in female CD2F1
mice housed in a room with a 12-h span of fluorescent lighting daily. A
control group was allowed to feed ad libitum throughout life while three
other groups began lifelong restriction to about 75% of ad libitum intake
when 6 wk old. The daily schedule of food accessibility differed among these
three groups: a single meal during early darkness; a single meal during
early light; six smaller meals at about 2-h intervals during darkness. Food
restriction as such clearly prolonged life, but there were no statistically
significant differences in overall mean life span or in 10th-decile life
span among the three restricted groups. Telemetered body temperature data
confirmed marked differences in the effects of these different restricted
feeding schedules on circadian rhythms. The effect of food restriction on
survival is probably not due to altered relations among circadian rhythmic
variables. Possible contributing factors suggested by the results are a
lower body temperature, a reduced overall metabolic rate and an increased
circadian amplitude. PMID: 3794831 [PubMed - indexed for MEDLINE]


===================================


J Gerontol A Biol Sci Med Sci

1995 Jan;50A(1):B48-53

Temporal pattern of food intake not a factor in the retardation of aging
processes by dietary restriction.

Masoro EJ, Shimokawa I, Higami Y, McMahan CA, Yu BP. Department of
Physiology, University of Texas Health Science Center at San Antonio.
Long-term dietary restriction programs which retard aging processes in
rodents usually involve meal eating rather than the nibbling pattern of food
intake of ad libitum fed rodents. Thus, the possibility arises that the
antiaging action may at least in part result from an altered temporal
pattern of food intake. This possibility was investigated using male F344
rats maintained on the following dietary regimens: Group A rats fed ad
libitum; Group B rats fed 60% the ad libitum intake in a single meal at 1500
h; Group B-2 rats fed 60% of the ad libitum intake in two meals (0700 h and
1500 h). The diurnal pattern of plasma corticosterone concentration differed
among the groups as did that of the plasma glucose concentration. The median
length of life and age of tenth percentile survivors were similar for Group
B and B-2 rats and much greater than those for Group A rats. Both modes of
dietary restriction influenced age-associated disease processes in a similar
fashion. Thus, although the temporal pattern of food intake influenced
circadian rhythms of food-restricted rats, it did not significantly affect
the antiaging action. PMID: 7814779 [PubMed - indexed for MEDLINE]


SBH

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: soc.support.fat-acceptance,alt.support.big-folks,soc.singles,
	alt.support.diet,sci.med
Subject: Re: Massive study links excess weight, cancer risk
Date: Thu, 24 Apr 2003 14:24:59 -0700
Message-ID: <b89kn9$c7j$1@slb6.atl.mindspring.net>

"Crazy Mullet" <jadey@my-deja.com> wrote in message
news:VMWpa.114801$MB4.39768002@news4.srv.hcvlny.cv.net...
> "The morbidly obese are harder to operate on, harder to plan radiation
> therapy for -- often, they don't even fit into a radiation therapy
> machine," Mayer said. He said it also is hard to decide the right
> chemotherapy dose for the obese, because fat tissue sometimes absorbs
> the chemicals."
>
> I don't see this as being a hunch.
>
> Jade



Calorie restriction as long been known as an anti-aging
treatment in lab animals (rodents, and now also primates).
It is known that much if its life-prolonging effects are due
to its cancer preventative properties for many kinds of
tumors.  As Ben Franklin said: "To lengthen thy life, lesten
they meals."

SBH