CR Monkey Study Update
Ian Goddard
J Interferon Cytokine Res 2002 May;22(5):565-71
Cytokine responses in young and old rhesus monkeys: effect of
caloric restriction.
Mascarucci P, Taub D, Saccani S, Paloma MA, Dawson H, Roth GS,
Lane MA, Ingram DK.
Laboratory of Neurosciences, Gerontology Research Center,
National Institute on Aging, NIH, Baltimore, MD 21224.
Caloric restriction (CR) is the only known intervention demonstrated
to retard a great variety of aging processes, extend median and
maximum life-span, and decrease the incidence of age-associated
diseases in mammals. Paralleling findings from rodent studies,
studies in rhesus monkeys (Macaca mulatta) suggest that CR may
retard many age-sensitive parameters in primates. A recent study
in rhesus monkeys showed age-related dysregulation of cytokine
levels. Specifically, age-related increases in interleukin-10
(IL-10) and IL-6 proteins were observed in supernatants from
lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear
cells (PBMCs), and interferon-gamma (IFN-gamma) protein exhibited
an age-related decrease in phytohemagglutinin (PHA)-stimulated
PBMCs. To investigate effects of CR on age-related changes in
cytokine production, we obtained PBMCs from control and CR rhesus
monkeys aged 6-7 and 22-25 years. We evaluated IL-10 and IL-6
protein and gene expression after exposure to LPS and IFN-gamma
protein and gene expression after PHA stimulation. The results
revealed significantly higher levels of IFN-gamma protein and
gene expression in aged monkeys on CR for 2 years compared with
controls. No significant CR effects were observed on IL-10 and
IL-6 protein levels. IFN-gamma plays an important role in the
initial defense mechanism against viral and microbial disease
and cancer. Altered regulation of IFN-gamma in old CR rhesus
monkeys may be a key factor in reducing cancer incidence and
other age-associated diseases.
PMID: 12060495 [PubMed - in process]
Thanks to Alan Pater for posting the PMID on the crsociety list!
"To lengthen thy life, lessen thy meals." Ben Franklin
Brian
periodical fasting is preferable than each day caloric restriction.
Caloric restriction - not curative method, while periodical fasting
has great curative component at least in periods of fasting, when
reparation process are dominating.
Brian
Ian Goddard
>What is your opinion on fasting method? To extend the human life span
>periodical fasting is preferable than each day caloric restriction.
>
>Caloric restriction - not curative method, while periodical fasting
>has great curative component at least in periods of fasting, when
>reparation process are dominating.
IAN: My personal opinion is against fasting. Research points
to some potential CR risk factors, all of which, it seems to
me, would be maximized by short-term starvation. The main
risk for adult-onset CR is probably osteoporosis (while life-
long CR animals have less osteoporosis than controls). But
the main possible risk involves the possibility of negative
effects on the brain, which should be taken very seriously.
While the overall body of evidence clearly finds that CR
increases the lifespan of brain cells, and even increases
neurogenesis in some important areas such as the hippocampus,
a recent study found fewer synapses in layer 2 of sensorimotor
cortex of CR rats. While this did not result in any demonstrable
outcome in terms of impaired activities, it nevertheless points
to the potential that CR might have neurological risks. [1]
When we add to that research showing that actual malnutrition
involving both caloric and protein deficiency have been shown
to cause deleterious effects in the sensorimotor cortex, [2]
I feel that wise counsel points away from practices such as
fasting that involve actual malnutrition, even if short term.
I try to make sure that my body is not deprived of nutrition
by eating light but frequently and doing supplemental protein.
You say periodic fasting is preferable to daily CR for life
extension, but I am not aware of any basis for that claim
in research. I am, however, aware of research suggesting
that fasting may actually increase the risk of cancer. [3]
"To lengthen thy life, lessen thy meals." Benjamin Franklin
[1] Posting of Shi et al and thread debating their findings:
http://groups.google.com/groups?q=g:thl3102589553d&dq=&hl=en&lr=&selm=3ca65e2e.124225751%40news.erols.com
[2] Posted abstract showing sensorimotor-cortex impairment caused
by actual malnutrition involving caloric and protein deficiency:
http://groups.google.com/groups?selm=3ca951a4.101517504%40news.erols.com&output=gplain
[3] Carcinogenesis 2002 Feb;23(2):323-7
Enhanced growth of colorectal aberrant crypt foci in fasted/refed
rats involves changes in TGFbeta1 and p21CIP expressions.
Caderni G, Perrelli MG, Cecchini F, Tessitore L.
Dipartimento di Farmacologia Preclinica e Clinica, Universita
degli Studi di Firenze, Firenze, Italy.
We previously demonstrated that fasting/refeeding enhances the
initiation phase of liver and colorectal carcinogenesis in rats.
The present study was undertaken to establish whether cycles of
fasting/refeeding carried out during the promotion phase of
carcinogenesis may also affect the formation of aberrant crypt
foci (ACF), preneoplastic lesions induced in the colon by
azoxymethane (AOM). We were also interested in studying whether
this effect might be mediated by changes in the proliferation,
apoptosis or expression of TGFbeta1 and p21CIP genes in the colon.
44 male Fisher 344 rats were given a single dose of AOM (20 mg/kg
s.c.) and one week later, they were exposed to 5 cycles of 4 days
fasting followed by 7-10 days of refeeding (refed rats); controls
were regularly fed; the rats were killed 2, 8 or 30 days after the
last cycle of fasting. Fasting/refeeding caused a dramatic
increase in crypt multiplicity when compared with regularly fed
rats (AC/ACF was 4.30 +/- 1.3 in refed and 2.38 +/- 0.4 in
regularly fed rats, P < 0.005 means +/- SD), while no significant
changes were observed in the number of ACF/colon. In the two
experimental groups, cell proliferation was higher in ACF than in
the surrounding mucosa, but proliferative indexes were higher and
the apoptotic index lower in ACF of refed rats compared with
regularly fed rats. TGFbeta1 expression was higher in the ACF
of refed rats than in those of fully fed controls while p21CIP
was less expressed in refed rats than in controls. These results
suggest that fasting/refeeding is a risk factor for colon cancer
and must be taken into account for cancer prevention in humans.
PMID: 11872640 [PubMed - indexed for MEDLINE]
"To lengthen thy life, lessen thy meals." Benjamin Franklin
CBI
"Ian Goddard" <igod...@erols.mom> wrote in message
news:3d0b9168...@news.erols.com...
> On 15 Jun 2002, brian_an...@yahoo.com (Brian) wrote:
>
> >What is your opinion on fasting method? To extend the human life span
> >periodical fasting is preferable than each day caloric restriction.
> >
> >Caloric restriction - not curative method, while periodical fasting
> >has great curative component at least in periods of fasting, when
> >reparation process are dominating.
>
>
> IAN: My personal opinion is against fasting.
It is like the old joke - Wives live longer than their husbands. For the
husband it just seems longer. This would be worse. It would both be longer
and seem longer. Not everyone's goal is to live as long as possible.
--
CBI, MD
G EddieA95
>
>It is like the old joke - Wives live longer than their husbands. For the
>husband it just seems longer. This would be worse. It would both be longer
>and seem longer.
I don't know about that. Fasting one day out of three might be easier for some
than making the effort of a 33% CR regime.
>Not everyone's goal is to live as long as possible.
But in that case, why bother with this ng???
Ian Goddard
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. 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.
Of further import to the fasting question, the study finds that:
"After 14 weeks of restriction, total serum IGF-1 was lowest in
the LDF [limited-daily-feeding] group, and highest in the EOD and
PF groups." Shi et al -- who found reduced sensorimotor synapses
in CR rats -- proposed that the observed reduction was a result
of CR-induced reductions of IGF-1. This new study would therefore
suggest that every-other-day (EOD) fasting might be the preferable
route for the prevention of any sensorimotor-synaptic downregulation.
"To lengthen thy life, lessen thy meals." Benjamin Franklin
Tom Matthews
>
> 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. 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.
This is consistent with the notion that the CR benefit comes from the
stress of hunger which many have thought might be the case for some
time. Too bad, because on my regimen I am very seldom hungry. In
addition, I have tried EOD feeding and find that I am simply far too
disturbed on the fasting days to function adequately. Thus, on EOD
feeding my quality of life suffers too much for it to be worthwhile.
Still, I may try it again sometime to see if I can make it work.
> Of further import to the fasting question, the study finds that:
> "After 14 weeks of restriction, total serum IGF-1 was lowest in
> the LDF [limited-daily-feeding] group, and highest in the EOD and
> PF groups." Shi et al -- who found reduced sensorimotor synapses
> in CR rats -- proposed that the observed reduction was a result
> of CR-induced reductions of IGF-1. This new study would therefore
> suggest that every-other-day (EOD) fasting might be the preferable
> route for the prevention of any sensorimotor-synaptic downregulation.
It also suggests that perhaps supplementation of chemicals which
increase IGF-1 (DHEA) would be beneficial for LDF CR practitioners.
--Tom Matthews
MoreLife for the rational - http://morelife.org
Reality based tools for More Life in quantity & quality
Ian Goddard
>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. 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.
>
>
>This is consistent with the notion that the CR benefit comes from the
>stress of hunger which many have thought might be the case for some
>time. Too bad, because on my regimen I am very seldom hungry. In
>addition, I have tried EOD feeding and find that I am simply far too
>disturbed on the fasting days to function adequately. Thus, on EOD
>feeding my quality of life suffers too much for it to be worthwhile.
>Still, I may try it again sometime to see if I can make it work.
IAN: Same here. While I can't say I've tried an EOD regimen,
the times in my life I have fasted were usually marked by
periods during the fast that were unpleasant and that reduced
my ability to function at an optimal level. But some people
say that EOD CR causes them to be less hungry than LDF CR.
Currently I could not be more comfortable with LDF CR, and
seeing that this new study does not refute that it too can
extend LS, I do not see an overwhelming reason to go to EOD.
As you note, perhaps DHEA could counter any IGF-1 reductions.
The findings of the study at the AAA site are really exciting.
They might suggest a better potential of finding CR mimetics
versus if CR-induced +LS is a function of caloric intake. What
this new study suggests is that the +LS effect is a result of
something the body does, perhaps releasing some chemicals that
slow down aging. Here's a hypothesis to consider: the purpose
of a body is to maximize its chances of genetic replication.
Low-food supplies are correlated with reduced off-spring and
thus represent a threat to the organism's prime directive. So
an organism will react to reduced food supplies in a way that
will preserve the odds that it can maximize its procreative
potential, which requires (1) that it survive the food drought
and (2) that it slow down its aging so that it might still be
sexually potent when/if the food drought comes to an end.
In short, I expect and have seen others propose hypotheses
along the lines that CR, by EOD or LDF, initiates a program
that is hardwired into living organism that slows down aging,
which seems to suggest that CR-induced +LS is not a function
of reduced caloric-burning-induced ROS and mitochondrial damage.
This might also have significant ramifications with respect to
our pervious discussions regarding levels of body mass and LS.
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. The fact that we cannot
find any head-to-head tests also means we have nothing that
suggests their findings are questionable. The implication of
their findings are major with respect to understanding what
we're looking at regarding CR. It suggests, as they state,
that it's not about calories. Thus it's not about caloric-
burning-induced ROS and mitochondrial damage. In short, the
findings would completely overhaul leading theories about CR.
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."
7117847: "The mean life span of the EOD group
represented an 83% increase over that of the AL group."
2321437: "Furthermore, time-scheduled feeding
caused an important increase of the mean life
expectancy and a reduction in the incidences
of chronic nephropathy and purulent and chronic
forms of prostatitis. ... Time-scheduled feeding
did not cause a reduction in the incidence of
tumours, but it delayed their occurrence."
2682315 (EOD neuro-preservative effect):
Neurobiol Aging 1989 Jul-Aug;10(4):317-22
Dietary restriction suppresses age-related changes
in dendritic spines.
Moroi-Fetters SE, Mervis RF, London ED, Ingram DK.
Department of Pathology, Ohio State University
College of Medicine, Columbus 43210.
The effects of dietary restriction by every-other-day (EOD)
feeding on dendritic spines in the aging rat neocortex were
evaluated in Golgi preparations. After weaning, male Wistar
rats were offered a 24% protein diet either ad lib (AL) or
EOD. AL-fed groups were sacrificed at 6 and 24-25 months of
age. EOD-fed groups were sacrificed at 6, 24, and 30 months.
To assess the effects of EOD feeding late in life, another
group was fed AL for 19 months, then EOD for 5 months and
sacrificed when 24 months old. Spine density and configuration
were quantified along 20 microns terminal tip segments from
the basilar tree of layer V pyramidal cells of the parietal
cortex. Evaluation of spine densities from the 6 and 24
months AL-fed groups showed that there was a significant
loss of spines with normal aging (-38%). In EOD-fed rats,
spine density did not differ significantly from AL age-matched
controls at either 6 or 24 months of age. However, spine
densities in 24-month-old rats diet restricted late in life
and EOD-fed 30-month-old rats were the same as 6-month-old
AL-fed controls and EOD 6-month-old rats, an observation
suggesting protection of dendritic spines from age-related
loss. Spines were categorized as either L-type (lollipop-
shaped), which are more prevalent in young adults, or N-type
(nubbin). With normal aging (comparing 6- and 24-month-old
AL-fed groups) there was a significant decrease in L-type
spines. However, all dietarily restricted groups showed
retention of L-type spines.(ABSTRACT TRUNCATED AT 250 WORDS)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2682315&dopt=Abstract
"To lengthen thy life, lessen thy meals." Ben Franklin
Fat to Thin: http://IanGoddard.net/me-cr.htm
Chris Allen
> >Not everyone's goal is to live as long as possible.
> But in that case, why bother with this ng???
Curve squaring (squaring of the vitality decline curve) might be
considered by some to be life extension if what they want is extension
of life as it is lived by typical young people.
-Chris
Tom Matthews
This has been proposed before, but it does not help answer the
question of why, specifically, aging is slowed (ie by what exact
mechanisms.)
> In short, I expect and have seen others propose hypotheses
> along the lines that CR, by EOD or LDF, initiates a program
> that is hardwired into living organism that slows down aging,
> which seems to suggest that CR-induced +LS is not a function
> of reduced caloric-burning-induced ROS and mitochondrial damage.
I agree that such a "program" to enhance the chances of genome
propagation has been built into the genome of all lifeform over the
course of evolution. However, I don't agree that is an argument for or
against any particular mechanism. After all, what does evolution care
about how it happens, just so long as it does. In any case, the
extension of LS by CR can be (and probably is) the combined result of
multiple mechanisms, one of which may be reduced ROS and reduced
mitochondrial damage.
> This might also have significant ramifications with respect to
> our pervious discussions regarding levels of body mass and LS.
>
> 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. The fact that we cannot
> find any head-to-head tests also means we have nothing that
> suggests their findings are questionable. The implication of
> their findings are major with respect to understanding what
> we're looking at regarding CR. It suggests, as they state,
> that it's not about calories. Thus it's not about caloric-
> burning-induced ROS and mitochondrial damage. In short, the
> findings would completely overhaul leading theories about CR.
LS extension not being "about" calories (ie not proportional to total
calorie intake) does not imply that it is not being affected by the
manner of caloric intake. My own interpretation of the result is
something which I have often thought before. It may well be that the
stress of feeling hungry, including the biochemical regulatory changes
which occur when inadequate glucose is directly available from food or
glycogen resources, are the necessary factor for LE due to CR. That
would jibe with the new results because EOD fasting does give one more
hunger (stress) time than LDF CR. My own preference for the most
important derivative mechanism is the increased rate of protein
turnover which more quickly recycles the dysfunctional glycated and/or
oxidized proteins, preventing their build-up and creating new pristine
fully functional proteins in their place.
Ian Goddard
>> The findings of the study at the AAA site are really exciting.
>> They might suggest a better potential of finding CR mimetics
>> versus if CR-induced +LS is a function of caloric intake. What
>> this new study suggests is that the +LS effect is a result of
>> something the body does, perhaps releasing some chemicals that
>> slow down aging. Here's a hypothesis to consider: the purpose
>> of a body is to maximize its chances of genetic replication.
>> Low-food supplies are correlated with reduced off-spring and
>> thus represent a threat to the organism's prime directive. So
>> an organism will react to reduced food supplies in a way that
>> will preserve the odds that it can maximize its procreative
>> potential, which requires (1) that it survive the food drought
>> and (2) that it slow down its aging so that it might still be
>> sexually potent when/if the food drought comes to an end.
>
>
>This has been proposed before, but it does not help answer the
>question of why, specifically, aging is slowed (ie by what exact
>mechanisms.)
IAN: Yeah, I was just suggesting why, but not how, CR may work
(I use the word "how" in the same way you use the word "why").
>> In short, I expect and have seen others propose hypotheses
>> along the lines that CR, by EOD or LDF, initiates a program
>> that is hardwired into living organism that slows down aging,
>> which seems to suggest that CR-induced +LS is not a function
>> of reduced caloric-burning-induced ROS and mitochondrial damage.
>
>
>I agree that such a "program" to enhance the chances of genome
>propagation has been built into the genome of all lifeform over the
>course of evolution. However, I don't agree that is an argument for or
>against any particular mechanism. After all, what does evolution care
>about how it happens, just so long as it does. In any case, the
>extension of LS by CR can be (and probably is) the combined result of
>multiple mechanisms, one of which may be reduced ROS and reduced
>mitochondrial damage.
IAN: I agree with that. My point was along the lines that
CR may not +LS by simply causing fewer calories to be burned
resulting in fewer ROS, but by initiating a biological program
that by some unknown mechanism causes +LS. That unknown mechanism
could, as you point out, include reducing mitochondrial damage.
"To lengthen thy life, lessen thy meals." Benjamin Franklin
Ian Goddard
One thing I think we're somewhat overlooking is that the study
in question merely shows that EOD CR exerted protection against
kainic acid (KA) neurotoxicity that was independent of caloric
consumption. It is a leap to infer from this that the wide range
of CR benefits including +LS may therefore be calorie independent.
The study in question did not even compare LS effects of EOD & LDF.
I have yet to see a study that says EOD CR extended maximum LS and
there are some showing fasting/refeeding increases carcinogenesis.
One study found that EOD did not reduce cancers, which is contrary
to the vast majority of CR studies that presumably used LDF CR.
"To lengthen thy life, lessen thy meals." Benjamin Franklin
GeoWCherry
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. 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.
Of further import to the fasting question, the study finds that:
"After 14 weeks of restriction, total serum IGF-1 was lowest in
the LDF [limited-daily-feeding] group, and highest in the EOD and
PF groups." Shi et al -- who found reduced sensorimotor synapses
in CR rats -- proposed that the observed reduction was a result
of CR-induced reductions of IGF-1. This new study would therefore
suggest that every-other-day (EOD) fasting might be the preferable
route for the prevention of any sensorimotor-synaptic downregulation.
George Cherry wrote:
Okay, here's what I am going to try:
fasting every night! :o) Actually, I'm
not joking: eat an early dinner, about
4:00 PM and then eat breakfast the
next day about 9:00 AM. So, "break-
fast" ("breakfast") breaks the fast
every day! Hey, a 17 hour fast isn't
so shabby.
GeoWCherry
> 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. 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.
Tom Matthews wrote:
This is consistent with the notion that the CR benefit comes from the
stress of hunger which many have thought might be the case for some
time. Too bad, because on my regimen I am very seldom hungry. In
addition, I have tried EOD feeding and find that I am simply far too
disturbed on the fasting days to function adequately. Thus, on EOD
feeding my quality of life suffers too much for it to be worthwhile.
Still, I may try it again sometime to see if I can make it work.
George wrote:
Could you try a 15 hour fast every day:
Eat dinner at 4:00 PM and drink your
"break-fast" at 9:00 AM or something
like that?
GeoWCherry
>> 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. 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.
Tom Matthews:
George wrote:
Ian, your evolutionary argument does not
seem cogent to me. Most procreation of
our ancestors probably took place in their
teenage and eary twenties. Evolution and
its mechanism "survival of the fit enough"
just doesn't matter much for what happens
after you're thirty or forty. I don't think the
kind of "fine-tuning" you're hypothesizing
happens. We life extentionists are post-
Darwinian. On the other hand, our paleo-
lithic ancestors probably did have to fast
involuntarily quite often when they failed
to catch the rabbit or bird and ate all
the berries or nuts on the bush.
As an aside, my diet right now
is composed of a great deal of
sprouts (oat, quinoa, buckwheat, and
a few sunflower sprouts). Remarkably,
I'm not very hungry on this diet, even
though I'm eating far fewer calories
every day than I thought I ever could
without facing intolerable hunger. I also
have good energy and alertness. Could
sprouts help diminish appetite?
One thing I appreciate about sprouting
is how it lowers the calorie density of
the seeds by their absorbing a great deal
of water and increasing their volume
by producing roots. This helps satisfy
hunger with fewer calories. My wife
notices this also and we are both very
pleased by our CR progress.
George
Steve Harris
> On Sun, 16 Jun 2002, Tom Matthews <t...@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
--
I welcome Email from strangers with the minimal cleverness to fix my address
(it's an open-book test). I strongly recommend recipients of unsolicited
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& headers to "abuse@[offendingISP]."
Ian Goddard
Thanks Steve for your important reply. Just a couple hours
before I had noted the error inherent in my extrapolating
the effect of EOD on one neurotoxicity measure to CR per se.
You could not have provided more relevant insights. Thanks!
"To lengthen thy life, lessen thy meals." Ben Franklin
Tom Matthews
> On Sun, 16 Jun 2002, Tom Matthews <t...@morelife.org> wrote:
>
>
>>> The findings of the study at the AAA site are really exciting.
>>> They might suggest a better potential of finding CR mimetics
>>> versus if CR-induced +LS is a function of caloric intake. What
>>> this new study suggests is that the +LS effect is a result of
>>> something the body does, perhaps releasing some chemicals that
>>> slow down aging. Here's a hypothesis to consider: the purpose
>>> of a body is to maximize its chances of genetic replication.
>>> Low-food supplies are correlated with reduced off-spring and
>>> thus represent a threat to the organism's prime directive. So
>>> an organism will react to reduced food supplies in a way that
>>> will preserve the odds that it can maximize its procreative
>>> potential, which requires (1) that it survive the food drought
>>> and (2) that it slow down its aging so that it might still be
>>> sexually potent when/if the food drought comes to an end.
>>>
>>
>>This has been proposed before, but it does not help answer the
>>question of why, specifically, aging is slowed (ie by what exact
>>mechanisms.)
>>
>
>
> IAN: Yeah, I was just suggesting why, but not how, CR may work
> (I use the word "how" in the same way you use the word "why").
Interesting usage differences. Yours would be more correct in the
context of a volitional being, but since evolution is blind, "why" and
"how" mean essentially the same thing. Still, because I was not
talking about human decision making, I should definitely have used the
word "how". Your use of the word "why" as different than how is not
supportable about evolution and wrongly imputes a volitional decision
making role to evolution. IMO, this sort of thinking about evolution
should be rigidly abandoned because it can lead to logical errors.
>>> In short, I expect and have seen others propose hypotheses
>>> along the lines that CR, by EOD or LDF, initiates a program
>>> that is hardwired into living organism that slows down aging,
>>> which seems to suggest that CR-induced +LS is not a function
>>> of reduced caloric-burning-induced ROS and mitochondrial damage.
>>>
>>
>>I agree that such a "program" to enhance the chances of genome
>>propagation has been built into the genome of all lifeform over the
>>course of evolution. However, I don't agree that is an argument for or
>>against any particular mechanism. After all, what does evolution care
>>about how it happens, just so long as it does. In any case, the
>>extension of LS by CR can be (and probably is) the combined result of
>>multiple mechanisms, one of which may be reduced ROS and reduced
>>mitochondrial damage.
>>
>
>
> IAN: I agree with that. My point was along the lines that
> CR may not +LS by simply causing fewer calories to be burned
> resulting in fewer ROS, but by initiating a biological program
> that by some unknown mechanism causes +LS. That unknown mechanism
> could, as you point out, include reducing mitochondrial damage.
AFAIK, few people (likely no scientists) think that CR works by as simple
a mechanism as ROS reduction by means of burning fewer calories. That is
already refuted by the studies which show that the specific metabolic
rate, or number of ROS per mitochondria is hardly changed. At most, this
would only be one of the mechanisms.
Furthermore, I think few people look for only *one* mechanism. The
biochemical changes which occur from lack of immediate calories are
extremely many and varied, and surely have essential effects on many
initially independent body pathways. That is why I think it is very
simplistic (wishful thinking?) to imagine that there is only one or
even a very few mechanisms which can be adequately simulated by some
mimetic.
Tom Matthews
I agree. It should also be a way to reduce overall calorie intake. I
used to often do this sort of thing (13-14 hours between supper and
breakfast), but Kitty always has trouble going to sleep when she is
hungry (she is used to having often eaten near to bedtime before we
joined). We will have to see if she can train herself out of this or
we may have to split our eating routines which is something which
neither of us wants.
I have no problem going to sleep when feeling hungry. All it takes is
a glass of water to temporarily dilute the hungry feeling, and I wake
up feeling no more hungry than normal. Still, I think that I too would
have problems trying to accomplish anything or even feel relaxed in
the late evening, if I went 9 hours between supper and bedtime.
Tom Matthews
I used to have a triple decker sprouter many years ago which
worked beautifully, but when living alone and often traveling,
I could not keep it going. Recently, I looked for sprouters
again and could not find any in health food stores. However,
you have now convinced me to try harder and find one.
Thomas Carter
As Steve points out there has been a plenitude of studies which
taken in whole indicate that every other day feeding or fasting on
weekends do not extend life in rodents. Nor is every other day calorie
restricted feeding significantly better than limited daily feeding.
But the fasts may have been too short. Below I post a fairly recent
abstract indicating the efficacy of a four day fast. Unfortunately
this study shares a common fault with many others in that it compares
the intervention group with an ad lib (pig-out) control group rather
than a group on a more normal diet. I have put the lead author on my
author watch list in hopes that he will follow up this study with on
that restricts calories in both groups. If the results turn out to be
synergistic I will definitely consider the regimen. I have fasted
five days several times and once for seven days. In every case after
the second day I had no hunger at all, this is a commonly reported
phenominum.
A word of caution on growth hormone, whose effects are
largely mediated by IGF-1. This substance is now regarded by most as
pro-aging. A dearth of it and it's mediator, IGF-1 prolongs life and
an excess of it shortens life in rodents and is related to a shorter
life in humans (bigger humans have shorter lives). Its effects seem
to mediated in part by decreased insulin sensitivity. Insulin is bit
by bit coming to be regarded as a "death" hormone along with cortisol.
I also include three abstracts supporting this fact, which the second
one calls "well known". A reason for some past confusion on this
insulin link could be that insulin sensitivity seems to be increased
by GH in GH deficient humans. I include an abstract to this effect and
three others on GH and longevity which I happen to have.
Mech Ageing Dev 2000 May 18;115(1-2):61-71 Influence of short-term
repeated fasting on the longevity of female (NZB x NZW)F1 mice. Sogawa
H, Kubo C. Department of Psychosomatic Medicine, Graduate School of
Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku,
812-8582, Fukuoka, Japan. sog...@cephal.med.kyushu-u.ac.jp Caloric
restriction in rodents is well known to retard the rate of aging,
increasing mean and maximum life-spans, and inhibit the occurence of
many age-associated diseases. However little is known about the
influence of short term repeated fasting on longevity. In this study,
female (NZB x NZW)F1 mice were used to test the physiological effect
of short-term repeated fasting (4 consecutive days, every two weeks).
The results showed that fasting mice survived significantly longer
than the full-fed mice, in spite of the fasting group having a heavier
body weight than the control group. Mean survival times for fasting
control mice were 64.0+/-15.3 and 47.9+/-9.4 weeks, respectively.
Short-term repeated fasting manipulation was also effective on the
prolongation of lifespan in autoimmune-prone mice. PMID: 10854629
Wien Med Wochenschr 2001;151(18-20):426-9 [Growth hormone in the
elderly man] [Article in German] Riedl M, Kotzmann H, Luger A.
Klinische Abteilung fur Endokrinologie und Stoffwechsel,
Universitatsklinik fur Innere Medizin III, Wahringer Gurtel 18-20,
A-1090 Wien. Many symptoms being part of the growth hormone deficiency
syndrome in adults like decrease in muscle mass and bone mineral
content, increase in fat mass, and skin atrophy are observed also with
ageing. Indeed, short term trials with growth hormone administration
to persons over 60 years old revealed that many of these symptoms
could be reversed by growth hormone. However, recent reports of an
association of high insulin-like growth factor-1
(IGF-1)-concentrations and increased risk of prostate, lung, colon and
breast cancer as well as a possible decrease of insulin sensitivity
prohibit currently the use of growth hormone in an attempt to reverse
a normal ageing process. Prospective, randomised and
placebo-controlled long-term trials are necessary to prove safety and
efficacy of growth hormone therapy in the ageing population before it
can be recommended. In addition, no data are available as to the right
growth hormone dose and the correct monitoring. Expectations of the
society and the search for the fountain of youth should not motivate
physicians to leave the firm ground of evidence based medicine and
prescribe experimental therapies to healthy older persons. PMID:
11817251
Diabetes 2001 Aug;50(8):1891-900 Growth hormone induces cellular
insulin resistance by uncoupling phosphatidylinositol 3-kinase and its
downstream signals in 3T3-L1 adipocytes. Takano A, Haruta T, Iwata M,
Usui I, Uno T, Kawahara J, Ueno E, Sasaoka T, Kobayashi M. First
Department of Medicine, Toyama Medical and Pharmaceutical University,
Toyama, Japan. Growth hormone (GH) is well known to induce in vivo
insulin resistance. However, the molecular mechanism of GH-induced
cellular insulin resistance is largely unknown. In this study, we
demonstrated that chronic GH treatment of differentiated 3T3-L1
adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and
activation of Akt (also known as protein kinase B), both of which are
downstream effects of phosphatidylinositol (PI) 3-kinase, despite
enhanced tyrosine phosphorylation of insulin receptor substrate
(IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and
IRS-1-associated PI 3-kinase activity. In contrast, chronic GH
treatment did not affect 2-DOG uptake and Akt activation induced by
overexpression of a membrane-targeted form of the p110 subunit of PI
3-kinase (p110(CAAX)) or Akt activation stimulated by platelet-derived
growth factor. Fractionation studies indicated that chronic GH
treatment reduces insulin-stimulated translocation of Akt from the
cytosol to the plasma membrane. Interestingly, chronic GH treatment
increased insulin-stimulated association of IRS-1 with p85 and
IRS-1-associated PI 3-kinase activity preferentially in the cytosol.
These results indicate that cellular insulin resistance induced by
chronic GH treatment in 3T3-L1 adipocytes is caused by uncoupling
between activation of PI 3-kinase and its downstream signals, which is
specific to the insulin-stimulated PI 3-kinase pathway. This effect of
GH might result from the altered subcellular distribution of
IRS-1-associated PI 3-kinase. PMID: 11473053
Am J Obstet Gynecol 2002 Mar;186(3):512-7 Human placental growth
hormone causes severe insulin resistance in transgenic mice. Barbour
LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, Garrity M, Draznin
B, Friedman JE. Department of Medicine, University of Colorado Health
Sciences Center, Denver, USA. OBJECTIVE: The insulin resistance of
pregnancy is considered to be mediated by human placental lactogen,
but the metabolic effects of human placental growth hormone have not
been well defined. Our aim was to evaluate the effect of placental
growth hormone on insulin sensitivity in vivo using transgenic mice
that overexpress the human placental growth hormone gene. STUDY
DESIGN: Glucose and insulin tolerance tests were performed on 5
transgenic mice that overexpressed the human placental growth hormone
variant gene and 6 normal littermate controls. The body composition of
the mice was assessed by dual-energy radiograph absorptiometry, and
free fatty acid levels were measured as a marker of lipolysis.
RESULTS: The human placental growth hormone levels in the transgenic
mice were comparable to those attained in the third trimester of
pregnancy. These mice were nearly twice as heavy as the control mice,
and their body composition differed by a significant increase in bone
density and a small decrease in percentage of body fat. Fasting
insulin levels in the transgenic mice that overexpressed placental
growth hormone were approximately 4-fold higher than the control mice
(1.57 +/- 0.22 ng/mL vs 0.38 +/- 0.07 ng/mL; P <.001) and 7 times
higher 30 minutes after glucose stimulation (4.17 +/- 0.54 ng/mL vs
0.62 +/- 0.10 ng/mL; P <.0001) with no significant difference in
either fasting or postchallenge glucose levels. Insulin sensitivity
was markedly decreased in the transgenic mice, as demonstrated by an
insignificant decline in glucose levels after insulin injection
compared with the control mice, which demonstrated more than a 65%
reduction in glucose levels (P <.001). CONCLUSION: Human placental
growth hormone causes insulin resistance as manifested by fasting and
postprandial hyperinsulinemia and minimal glucose lowering in response
to insulin injection. Human placental growth hormone is a highly
likely candidate to mediate the insulin resistance of pregnancy. PMID:
11904616
J Clin Endocrinol Metab 2002 May;87(5):2121-7 Effects of seven years
of GH-replacement therapy on insulin sensitivity in GH-deficient
adults. Svensson J, Fowelin J, Landin K, Bengtsson BA, Johansson JO.
Research Centre for Endocrinology and Metabolism, Sahlgrenska
University Hospital, SE-413 45 Goteborg, Sweden.
johan.s...@medic.gu.se The few trials in GH-deficient (GHD) adults
that have investigated the long-term effects of GH-replacement therapy
on insulin sensitivity have shown conflicting results. In this study,
insulin sensitivity was determined using the hyperinsulinemic,
euglycemic clamp technique in 11 GHD adults at baseline and after 6
months, 1 yr, 2 yr, and 7 yr of GH-replacement therapy. Furthermore,
insulin sensitivity in the GHD patients was compared with that in 11
matched control subjects at baseline and with that in 11 other matched
controls at study end. The mean initial GH dose was 1.10 mg/d. The
dose was gradually lowered; and after 7 yr, the mean dose was 0.61
mg/d. A sustained reduction in body fat and a sustained increase in
fat-free mass were observed. Serum high-density
lipoprotein-cholesterol (HDL-C) increased, and serum low-density
lipoprotein-cholesterol (LDL-C) decreased, after 7 yr of treatment.
Fasting blood glucose was transiently increased during the first year
of GH replacement. The glucose infusion rate/body weight (GIR/BW), as
measured using the hyperinsulinemic, euglycemic clamp technique, was
unaltered during GH-replacement therapy. The comparisons with the
control subjects revealed that GIR/BW in the GHD patients was 45% of
that in the control subjects at baseline; whereas, at study end, the
GIR/BW was 71% of that in the control subjects (P = 0.06 vs.
baseline). This could suggest that GH-replacement therapy may prevent
the age-related decline in insulin sensitivity in GHD patients. PMID:
11994351
J Gerontol A Biol Sci Med Sci 2001 Aug;56(8):B340-9
Mutant mice with a combined deficiency of growth hormone (GH),
prolactin, and thyrotropin, and knockout mice with GH resistance, live
longer than their normal siblings. The extension of life span in these
animals is very large (up to 65%), reproducible, and not limited to
any particular genetic background or husbandry conditions. In addition
to demonstrating that genes control aging in mammals, these findings
suggest that GH actions, growth, and body size may have important
roles in the determination of life span. We describe the key
phenotypic characteristics of long-living mutant and knockout mice,
with an emphasis on those characteristics that may be related to
delayed aging in these animals. We also address the broader topic of
the relationship between GH, growth, maturation, body size, and aging,
and we attempt to reconcile the well-publicized antiaging action of GH
with the evidence that suppression of GH release or action can prolong
life.
Cell loss in glands (Bartke’s session). The 30% extension of
maximum lifespan by loss of genes involved in growth hormone
production is well known to the participants; it is a sterling example
of a spectacular breakthrough that was given virtually no airtime in
the science media. A recent advance of comparable significance was the
nearly complete reversal of thymic involution by IGF-7. Sample
literature reference: Aspinall et al, Biochem Soc Trans 28:250-254.
Mech Ageing Dev 2002 May;123(9):1229-44 Implications for the insulin
signaling pathway in Snell dwarf mouse longevity: a similarity with
the C. elegans longevity paradigm. Hsieh CC, DeFord JH, Flurkey K,
Harrison DE, Papaconstantinou J. Department of Human Biological
Chemistry and Genetics, The University of Texas Medical Branch, 613
Basic Science Building, Rt. 0643, 7755-0643, Galveston, TX, USA
Mutation analyses in the nematode, Caenorhabditis elegans, and mice
have identified genes that increase their life-span via hormonal
signal transduction, i.e. the insulin/insulin-like growth factor-1
(IGF-1) pathway in nematodes, and the growth hormone (GH)-thyriod
stimulating hormone (TSH)-prolactin system in Snell dwarf mouse
mutants. We have shown that the GH deficiency due to Pit1 mutation in
the long-lived Snell dwarf mice may decrease circulating insulin
levels, thereby resulting in a decreased activity of the insulin/IGF-1
signaling pathway. The data presented are consistent with our
hypothesis that the decreased circulating insulin levels resulting
from the Pit1 mutation mimics a physiological state similar to that
proposed to occur in the long-lived C. elegans, daf-2 mutant. Our
studies demonstrate a series of changes in components of the
insulin/IGF-1-signaling pathway that suggest a reduction-of-function
of this pathway in the aged dwarf. These include a decreased IRS-2
pool level, a decrease in PI3K activity and its association with IRS-2
and decreased docking of p85alpha to IRS-2. Our data also suggest a
preferential docking of IRS-2-p85alpha-p110alpha in the aged dwarf
liver and IRS-2-p85alpha-p110beta in the aged control. We speculate
that the preference for the p110alpha-containing complex may be a
specific characteristic of a downstream segment of the
longevity-signaling cascade. We conclude that the Pit1 mutation may
result in physiological homeostasis that favors longevity, and that
the Snell dwarf mutant conforms to the nematode longevity paradigm.
(Which is less IGF-1 equals longer life span) PMID: 12020945
GeoWCherry
> As an aside, my diet right now
> is composed of a great deal of
> sprouts (oat, quinoa, buckwheat, and
> a few sunflower sprouts). Remarkably,
> I'm not very hungry on this diet, even
> though I'm eating far fewer calories
> every day than I thought I ever could
> without facing intolerable hunger. I also
> have good energy and alertness. Could
> sprouts help diminish appetite?
>
> One thing I appreciate about sprouting
> is how it lowers the calorie density of
> the seeds by their absorbing a great deal
> of water and increasing their volume
> by producing roots. This helps satisfy
> hunger with fewer calories. My wife
> notices this also and we are both very
> pleased by our CR progress.
Tom Matthews wrote:
I used to have a triple decker sprouter many years ago which
worked beautifully, but when living alone and often traveling,
I could not keep it going. Recently, I looked for sprouters
again and could not find any in health food stores. However,
you have now convinced me to try harder and find one.
--Tom Matthews
MoreLife for the rational - http://morelife.org
Reality based tools for More Life in quantity & quality
George wrote:
Tom, a good online source for sprouts and
sprouters is
I like their "Easy Sprouter" very much. I
bought one, liked it, bought a second, and
then bought a third. Right now I'm sprout-
ing garbanzo beans in one, quinoa in an-
other, and soaking almonds in the third.
All these items came from sproutpeople.
All their seeds are organic (except for their
broccoli seeds).
George
Ian Goddard
> The findings of the study at the AAA site are really exciting.
> They might suggest a better potential of finding CR mimetics
> versus if CR-induced +LS is a function of caloric intake. What
> this new study suggests is that the +LS effect is a result of
> something the body does, perhaps releasing some chemicals that
> slow down aging. Here's a hypothesis to consider: the purpose
> of a body is to maximize its chances of genetic replication.
> Low-food supplies are correlated with reduced off-spring and
> thus represent a threat to the organism's prime directive. So
> an organism will react to reduced food supplies in a way that
> will preserve the odds that it can maximize its procreative
> potential, which requires (1) that it survive the food drought
> and (2) that it slow down its aging so that it might still be
> sexually potent when/if the food drought comes to an end.
>George wrote:
>Ian, your evolutionary argument does not
>seem cogent to me. Most procreation of
>our ancestors probably took place in their
>teenage and eary twenties. Evolution and
>its mechanism "survival of the fit enough"
>just doesn't matter much for what happens
>after you're thirty or forty.
IAN: And that's when the effects of CR diminish.
Steve Harris
news:a7b55247.02061...@posting.google.com...
> Mech Ageing Dev 2000 May 18;115(1-2):61-71 Influence of short-term
> repeated fasting on the longevity of female (NZB x NZW)F1 mice. Sogawa
> H, Kubo C. Department of Psychosomatic Medicine, Graduate School of
> Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku,
> 812-8582, Fukuoka, Japan. sog...@cephal.med.kyushu-u.ac.jp Caloric
> restriction in rodents is well known to retard the rate of aging,
> increasing mean and maximum life-spans, and inhibit the occurence of
> many age-associated diseases. However little is known about the
> influence of short term repeated fasting on longevity. In this study,
> female (NZB x NZW)F1 mice were used to test the physiological effect
> of short-term repeated fasting (4 consecutive days, every two weeks).
> The results showed that fasting mice survived significantly longer
> than the full-fed mice, in spite of the fasting group having a heavier
> body weight than the control group. Mean survival times for fasting
> control mice were 64.0+/-15.3 and 47.9+/-9.4 weeks, respectively.
> Short-term repeated fasting manipulation was also effective on the
> prolongation of lifespan in autoimmune-prone mice. PMID: 10854629
Comment:
And these aren't autoimmune prone mice? Their mean survival times SUCK
(about half the mean survival for decently-lived strains).
There's a big difference between the effect of mild DR on autoimmune
problems (big effect--- see the studies of Goode especially) and mild DR on
aging (not so great an effect). If you've got lupus or even rheumatoid
arthritis, you'd better be skinny first and foremost.
Also, fasting for four consecutive days is NOT a "short-term" fast for a
mouse that runs at 7 or even 10 times the metabolic rate of you and me. At
min it's human equivalent to 4 weeks, and at max it's up there with 40 days
and 40 nights.
Steve Harris
news:3D0DD364...@morelife.org...
Just stay away from the alfalfa sprouts, or you may find yourself doing CR
to try to fix your induced lupus from all that canavanine.
Sprouts don't WANT to be eaten. It wouldn't suprise me if canavanine isn't
the only nasty chem warfare thing they've developed. It's just the only one
we've found (or that I personally know about, anyway). So watch it.
GeoWCherry
Just stay away from the alfalfa sprouts, or you may find yourself doing CR
to try to fix your induced lupus from all that canavanine.
Sprouts don't WANT to be eaten. It wouldn't suprise me if canavanine isn't
the only nasty chem warfare thing they've developed. It's just the only one
we've found (or that I personally know about, anyway). So watch it.
George writes:
Sure, what survival value could there possibly
be for THEM to be wolfed down by US!
Michael
First, thanks to Steve for pointing out the near-irrelevance of this
study, & some of the evidence that alternate-day fasting is not an
improvement over regular, daily decreased Caloric intake. Actually,
there's significant evidence that EOD CR is actually INFERIOR to
"continuous" CR. I started a long post on this some time ago & never
finishted it; but see, for starters:
http://groups.yahoo.com/group/crsociety/message/2751
http://groups.yahoo.com/group/crsociety/message/5062
http://groups.yahoo.com/group/crsociety/message/4395
This posts goes over some of the same evidence & adds more. Bottom
line:
IMO, EOD CR is an inferior protocol, possibly ESP so in adult-onset
CRONies.
(1) put "male mice from the A/J and C57BL/6J strains and their F1
hybrid, B6AF1/J" on either AL or EOD CR diets at 1.5, 6 or 10 months
of
age (~ human ages 4.5, 18, or 31). Now, in the very genetically
longevous C57BL/6J strain & their F1 hybrid, "mean and maximum life
span
were incremented when the every-other-day regimen was initiated at 1.5
or 6 months of age[, but] When every-other-day feeding was introduced
at
10 months of age, ... mean life span was not significantly affected
although maximum life span was increased."
This would suggest that, while aging was slowed, the stress of the
shift
on adult organisms' less-adaptable bodies was sufficient to cause
other,
unsustainable damage.
"Among A/J mice, intermittent feeding did not reduce body weight
relative to ad libitum controls when introduced at 1.5 or 10 months of
age". This is not as incredible as one might think. Simply put, fast
one
day, you pig out the next. In most strains, EOD feeding results in
~30%
CR for just this reason; presumably, AJs just gorge better. Unless
you're going to track Calories (which, of course, would negate one of
the potential convenience advantages of EOD CR), you couldn't really
be
sure that you're even ON CR -- even if your weight drops (CR-induced
hyperactivity, etc).
"however, this treatment did increase mean and maximum life span [in
hte
AJs] when begun at 1.5 months, ... at 6 months of age, body weight
reduction compared to control values was apparent at some ages, but
the
treatment had no significant effects on mean or maximum life span ...
[and] it DECREASED mean and maximum life span when begun at 10
months."
The former is curious, obviously; I would hypothesize that the latter
2
are again perhaps attributable to the lesser metabolic flexibility of
older organisms, which results in sudden adult-onset CR NOT extending
lifespan (2), despite the success of GRADUAL adult-onset CR (2-5).
See also these refs:
Premoselli F, Sesca E, Binasco V, Caderni G, Tessitore L.
Fasting/re-feeding before initiation enhances the growth of aberrant
crypt foci
induced by azoxymethane in rat colon and rectum.
Int J Cancer. 1998 Jul 17;77(2):286-94.
PMID: 9650566
Tagliaferro AR, Ronan AM, Meeker LD, Thompson HJ, Scott AL.
Cyclic food restriction, insulin and mammary cell proliferation in the
rat.
Carcinogenesis. 1997 Nov;18(11):2271-6.
PMID: 9395231 [PubMed - indexed for MEDLINE]
Tagliaferro AR, Ronan AM, Meeker LD, Thompson HJ, Scott AL, Sinha D.
Cyclic food restriction alters substrate utilization and abolishes
protection
from mammary carcinogenesis female rats.
J Nutr. 1996 May;126(5):1398-405.
PMID: 8618136 [PubMed - indexed for MEDLINE]
-Michael
1: Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N.
Effects of intermittent feeding upon body weight and lifespan in
inbred mice:
interaction of genotype and age.
Mech Ageing Dev. 1990 Jul;55(1):69-87.
PMID: 2402168
2. Weindruch R, Walford RL.
Dietary restriction in mice beginning at 1 year of age: effect on
life-span and
spontaneous cancer incidence.
Science. 1982 Mar 12;215(4538):1415-8.
PMID: 7063854
Extracts from full text here:
http://groups.google.com/groups?hl=en&selm=69779556.0112131750.660ca49d%40posting.google.com
3. Pugh TD, Oberley TD, Weindruch R.
Dietary intervention at middle age: caloric restriction but not
dehydroepiandrosterone sulfate increases lifespan and lifetime cancer
incidence in mice.
Cancer Res. 1999 Apr 1;59(7):1642-8.
PMID: 10197641; UI: 99211498
4. Yu BP, Masoro EJ, McMahan CA.
Nutritional influences on aging of Fischer 344 rats: I. Physical,
metabolic, and
longevity characteristics.
J Gerontol. 1985 Nov;40(6):657-70.
PMID: 4056321; UI: 86035196
Tom Matthews
> Hi,
> As Steve points out there has been a plenitude of studies which
> taken in whole indicate that every other day feeding or fasting on
> weekends do not extend life in rodents. Nor is every other day calorie
> restricted feeding significantly better than limited daily feeding.
> But the fasts may have been too short.
Nevertheless, this last is the manner in which Walford himself
practices calories restriction. Albeit, he still makes sure to
restrict his calories sufficiently by not gorging himself on his days off.
The real question which needs to be answered in my mind is whether it
is necessary to "feel hungry" in order to benefit from CR. Too bad
that animals cannot tell us if the "feel hungry". Still, perhaps some
of their physiological parameters would mean essentially that.
> Below I post a fairly recent
> abstract indicating the efficacy of a four day fast. Unfortunately
> this study shares a common fault with many others in that it compares
> the intervention group with an ad lib (pig-out) control group rather
> than a group on a more normal diet. I have put the lead author on my
> author watch list in hopes that he will follow up this study with on
> that restricts calories in both groups. If the results turn out to be
> synergistic I will definitely consider the regimen. I have fasted
> five days several times and once for seven days. In every case after
> the second day I had no hunger at all, this is a commonly reported
> phenominum.
But in my experience, you go through hell (and a couple of days of
non-functionality) in order to reach that point.
> A word of caution on growth hormone, whose effects are
> largely mediated by IGF-1.
But not always, those on CR have higher GH secretion, but lower or
unchanged IGF-1.
J Anat 2000 Nov;197 Pt 4:575-85
The effects of growth hormone and IGF-1 deficiency on cerebrovascular
and brain ageing.
Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S, Ingram R.
Department of Physiology and Pharmacology, Wake Forest University
School of Medicine, Winston-Salem, NC 27157-1083, USA. wson...@wfubmc.edu
Research studies clearly indicate that age-related changes in cellular
and tissue function are linked to decreases in the anabolic hormones,
growth hormone and insulin-like growth factor (IGF)-1. Although there
has been extensive research on the effects of these hormones on bone
and muscle mass, their effect on cerebrovascular and brain ageing has
received little attention. We have also observed that in response to
moderate calorie restriction (a treatment that increases mean and
maximal lifespan by 30-40%), age-related decreases in growth hormone
secretion are ameliorated (despite a decline in plasma levels of
IGF-1) suggesting that some of the effects of calorie restriction are
mediated by modifying the regulation of the growth hormone/IGF-1 axis.
Recently, we have observed that microvascular density on the surface
of the brain decreases with age and that these vascular changes are
ameliorated by moderate calorie restriction. Analysis of cerebral
blood flow paralleled the changes in vasculature in both groups.
Administration of growth hormone for 28 d was also found to increase
microvascular density in aged animals and further analysis indicated
that the cerebral vasculature is an important paracrine source of
IGF-1 for the brain. In subsequent studies, administration of GHRH (to
increase endogenous release of growth hormone) or direct
administration of IGF-I was shown to reverse the age-related decline
in spatial working and reference memory. Similarly, antagonism of
IGF-1 action in the brains of young animals impaired both learning and
reference memory. Investigation of the mechanisms of action of IGF-1
suggested that this hormone regulates age-related alterations in NMDA
receptor subtypes (e.g. NMDAR2A and R2B). The beneficial role of
growth hormone and IGF-1 in ameliorating vascular and brain ageing are
counterbalanced by their well-recognised roles in age-related
pathogenesis. Although research in this area is still evolving, our
results suggest that decreases in growth hormone and IGF-1 with age
have both beneficial and deleterious effects. Furthermore, part of the
actions of moderate calorie restriction on tissue function and
lifespan may be mediated through alterations in the growth
hormone/IGF-1 axis.
Publication Types:
Review
Review, Tutorial
PMID: 11197531
And earlier:
J Reprod Fertil Suppl 1993;46:87-98
The regulation and mechanisms of action of growth hormone and
insulin-like growth factor 1 during normal ageing.
D'Costa AP, Ingram RL, Lenham JE, Sonntag WE.
Department of Physiology and Pharmacology, Bowman Gray School of
Medicine, Wake Forest University, Winston-Salem, NC 27157-1083.
The decrease in tissue function that is observed in ageing animals has
been linked to the decline in rates of protein synthesis. These
changes may be caused, in part, by reduced secretion of growth hormone
(GH) and insulin-like growth factor 1 (IGF-1). It is well established
that growth hormone-releasing hormone (GHRH) and somatostatin have an
important role in the regulation of GH secretion and results from
several studies suggest that an age-related increase in release of
somatostatin has an important role in altering the secretion of GH.
When the amounts of somatostatin mRNA were examined, there was a
decrease in the aged rats but the amount of somatostatin mRNA bound to
polysomes increased in these animals. This suggests that translational
regulatory mechanisms are compromised in ageing animals. Moderate
dietary restriction, which has been shown to increase life span,
increases the amplitude of GH pulses and the capacity of tissues to
synthesize protein. We have used the caloric restriction model to
investigate the regulation and roles of GH and IGF-1 during ageing.
Our results suggest that neuroendocrine regulation of GH secretion
plays an important role in the process of biological ageing and that
part of the beneficial effects of moderate dietary restriction may be
mediated by altering the GH, IGF-1 axis.
Publication Types:
Review
Review, Academic
PMID: 8315618
And here is one which describes the mechanisms involved:
Metabolism 1995 Oct;44(10 Suppl 4):50-7
Nutritional regulation of insulin-like growth factor-I.
Ketelslegers JM, Maiter D, Maes M, Underwood LE, Thissen JP.
Department of Internal Medicine, School of Medicine, Catholic
University of Louvain, Brussels, Belgium.
Several lines of evidence indicate that in the human, insulin-like
growth factor-I (IGF-I) is nutritionally regulated. Both energy and
protein availability are required for maintenance of IGF-I.
Measurements of serum IGF-I constitute a sensitive means for
monitoring the response of acutely ill patients to nutritional
intervention. Serum IGF-I may also serve as a marker for evaluation of
nutritional status. Our findings and those of others in animal models
suggest that nutrients influence synthesis and action of IGF-I and its
binding proteins (IGFBPs) at multiple levels. In fasting, liver growth
hormone (GH) binding is decreased, providing one explanation for
decreased IGF-I. In protein restriction, GH receptors are maintained,
but there is evidence for a postreceptor defects. The latter results
from pretranslational and translational defects. Amino acid
availability to the hepatocytes is essential for IGF-I gene
expression. Protein malnutrition not only decreases IGF-I production
rate, but also enhances its serum clearance and degradation. Finally,
there is evidence for selective organ resistance to the
growth-promoting effects of IGF-I in protein-restricted rats.
Publication Types:
Review
Review, Tutorial
PMID: 7476312
> This substance is now regarded by most as
> pro-aging.
Unless you accept the narrow gerontological definition of anti-aging
as something which increases the age of death of the longest lived
species member, I think that it is incorrect to say that something
with all the proven benefits enumerated in the following abstract is
"pro-aging".
Cardiovasc Res 2002 Apr;54(1):25-35
Growth hormone, insulin-like growth factor-1 and the aging
cardiovascular system.
Khan AS, Sane DC, Wannenburg T, Sonntag WE.
Department of Physiology and Pharmacology, Wake Forest University
School of Medicine, Medical Center Boulevard, 27157-1083,
Winston-Salem, NC, USA
There is a large body of evidence that biological aging is related to
a series of long-term catabolic processes resulting in decreased
function and structural integrity of several physiological systems,
among which is the cardiovascular system. These changes in the aging
phenotype are correlated with a decline in the amplitude of pulsatile
growth hormone secretion and the resulting decrease in plasma levels
of its anabolic mediator, insulin like growth factor-1 (IGF-1). The
relationship between growth hormone and biological aging is supported
by studies demonstrating that growth hormone administration to old
animals and humans raises plasma IGF-1 and results in increases in
skeletal muscle and lean body mass, a decrease in adiposity, increased
immune function, improvements in learning and memory, and increases in
cardiovascular function. Since growth hormone and IGF-1 exert potent
effects on the heart and vasculature, the relationship between
age-related changes in cardiovascular function and the decline in
growth hormone levels with age have become of interest. Among the
age-related changes in the cardiovascular system are decreases in
myocyte number, accumulation of fibrosis and collagen, decreases in
stress-induced cardiac function through deterioration of the
myocardial conduction system and beta-adrenergic receptor function,
decreases in exercise capacity, vessel rarefaction, decreased arterial
compliance and endothelial dysfunction leading to alterations in blood
flow. Growth hormone has been found to exert potent effects on
cardiovascular function in young animals and reverses many of the
deficits in cardiovascular function in aged animals and humans.
Nevertheless, it has been difficult to separate the effects of growth
hormone deficiency from age-related diseases and associated
pathologies. The development of novel animal models and additional
research are required in order to elucidate the specific effects of
growth hormone deficiency and assess its contribution to
cardiovascular impairments and biological aging.
PMID: 12062358
> A dearth of it and it's mediator, IGF-1 prolongs life and
> an excess of it shortens life in rodents and is related to a shorter
> life in humans (bigger humans have shorter lives).
Once again, "the dose makes the poison". As the first abstract above
and many others point out, IGF-1 is also brain beneficial. It levels
are also negatively associated with bone mineral density.
Clin Endocrinol (Oxf) 2001 Dec;55(6):759-66
The contribution of IGF-I to skeletal integrity in postmenopausal women.
Munoz-Torres M, Mezquita-Raya P, Lopez-Rodriguez F, Torres-Vela E, de
Dios Luna J, Escobar-Jimenez F.
Endocrinology Division, University Hospital San Cecilio, Granada,
Spain. m...@jet.es
OBJECTIVES: The pathogenic role of the decline in serum concentrations
of IGF-I in postmenopausal osteoporosis is not fully elucidated. We
investigated the associations among IGF-I, bone mineral density (BMD),
ultrasound parameters and prevalence of vertebral fractures in
postmenopausal women. DESIGN: A cross-sectional study. PATIENTS: One
hundred and fifty-four ambulatory postmenopausal women (61 +/- 7
years) referred for osteoporosis screening. MEASUREMENTS: IGF-I was
measured by radioimmunoassay and BMD using dual-energy X-ray
absorptiometry. Broadband ultrasound attenuation (BUA) and speed of
sound (SOS) at calcaneus were measured by a quantitative ultrasound
system. RESULTS: IGF-I was significantly lower in osteoporotic
subjects and correlated positively with BMD, BUA and SOS. After
adjusting for age, years since menopause and body mass index, IGF-I
accounted for 8.5% of the variance at lumbar spine BMD, 4.6% at
femoral neck and 7.1% at calcaneal BUA. BUA was associated with IGF-I
independently of BMD. IGF-I was lower in women with vertebral
fractures (91 +/- 39 microg/l vs. 114 +/- 44 microg/l; P = 0.003). The
osteoporosis densitometric criteria (t-score < or = -2.5 SD) was the
most strongly independent associated variable with prevalent vertebral
fractures [odds ratio (OR): 3.3 (1.4-7.6)], followed by IGF-I levels
below 75th percentile [OR: 3 (1-8.8)]. CONCLUSIONS: Our study shows
that IGF-I is strongly associated with bone mineral density and
reflects aspects of bone quality. The contribution of IGF-I to
skeletal integrity in postmenopausal women is clinically relevant.
PMID: 11895218
Perhaps this is a reason why CR people tend to have lower BMD. I don't
but then I also take DHEA which is known to increase IGF-1.
> Its effects seem
> to mediated in part by decreased insulin sensitivity. Insulin is bit
> by bit coming to be regarded as a "death" hormone along with cortisol.
I think this is going too far. Once again (as with IGF-1) insulin is
necessary and valuable. It is only too much that is negative.
Furthermore, even cortisol has beneficial effects.
Med Hypotheses 1991 Mar;34(3):198-208
Cortisol and immunity.
Jefferies WM.
The relationship between adrenocortical function and immunity is a
complex one. In addition to the well-known detrimental effects of
large, pharmacologic dosages of glucocorticoids upon the immune
process, there is impressive evidence that physiologic amounts of
cortisol, the chief glucocorticoid normally produced by the human
adrenal cortex, is necessary for the development and maintenance of
normal immunity. This evidence is reviewed, and the importance of
differentiating between physiologic and pharmacologic dosages and
effects is discussed. The popular use of synthetic derivatives of
cortisol, which differ greatly from the natural hormone in strength,
and the dynamic nature of the normal adrenocortical response, which
varies with the degree of stress being experienced, have contributed
to the confusion. Further studies of the nature of the beneficial
effect of cortisol, and possibly of other normal adrenocortical
hormones, upon immunity in humans are needed, especially in view of
recent evidence of a feedback relationship between the immune system
and the hypothalamic-pituitary-adrenal axis, and with the increasing
awareness not only that the immune process provides protection against
infection, but also that its impairment seems to be involved in the
development of autoimmune disorders, malignancies and the acquired
immunodeficiency syndrome (AIDS).
Publication Types:
Review
Review, Tutorial
PMID: 2062254
> I also include three abstracts supporting this fact, which the second
> one calls "well known". A reason for some past confusion on this
> insulin link could be that insulin sensitivity seems to be increased
> by GH in GH deficient humans. I include an abstract to this effect and
> three others on GH and longevity which I happen to have.
This may make sense for those on CR, but most other aged humans *are*
deficient in GH. Therefore, increase insulin sensitivity is one more
benefit of increasing their GH.
Furthermore, your last abstracs below describe a longevity enhancing
effect in animals specially bred to have low GH. Unless we all want to
be dwarfs, I don't see that this necessarily has relevance for humans.
Once again, I remind you that GH is increased by CR and its age
related decline is also inhibited.
--Tom Matthews
MoreLife for the rational - http://morelife.org
Reality based tools for More Life in quantity & quality
> Mech Ageing Dev 2000 May 18;115(1-2):61-71 Influence of short-term
Tom Matthews
Thanks Steve, but I have known about it for years, and don't ever eat alfalfa
sprouts for that reason. Still your point about sprouts not wanting to be eaten
is well taken and should be cautionary to everyone.
Tom Matthews
> All:
>
> First, thanks to Steve for pointing out the near-irrelevance of this
> study, & some of the evidence that alternate-day fasting is not an
> improvement over regular, daily decreased Caloric intake. Actually,
> there's significant evidence that EOD CR is actually INFERIOR to
> "continuous" CR. I started a long post on this some time ago & never
> finishted it; but see, for starters:
>
>
>
> http://groups.yahoo.com/group/crsociety/message/2751
>
> http://groups.yahoo.com/group/crsociety/message/5062
>
> http://groups.yahoo.com/group/crsociety/message/4395
>
> This posts goes over some of the same evidence & adds more. Bottom
> line:
> IMO, EOD CR is an inferior protocol, possibly ESP so in adult-onset
> CRONies.
Then why does Walford himself practice CR by fasting 2-3 days per week?
>
> (1) put "male mice from the A/J and C57BL/6J strains and their F1
> hybrid, B6AF1/J" on either AL or EOD CR diets at 1.5, 6 or 10 months
> of
> age (~ human ages 4.5, 18, or 31). Now, in the very genetically
> longevous C57BL/6J strain & their F1 hybrid, "mean and maximum life
> span
> were incremented when the every-other-day regimen was initiated at 1.5
> or 6 months of age[, but] When every-other-day feeding was introduced
> at
> 10 months of age, ... mean life span was not significantly affected
> although maximum life span was increased."
>
> This would suggest that, while aging was slowed, the stress of the
> shift
> on adult organisms' less-adaptable bodies was sufficient to cause
> other,
> unsustainable damage.
Perhaps, because as Steve pointed out EOD to a mouse is equivalent to every
other week to a human. But this says little about human EOD!
Similar comments apply to the rest of your mouse and rat studies.
--Tom Matthews
MoreLife for the rational - http://morelife.org
Reality based tools for More Life in quantity & quality
>
Thomas Carter
Hi Steve,
Good guess, These, are indeed Lupus prone mice.
"Systemic lupus erythematosus (SLE) is inherited as a complex
polygenic trait. (New Zealand Black (NZB) x New Zealand White (NZW))
F(1) hybrid mice develop symptoms that remarkably resemble human SLE,"
The lifespans seem reasonable for their strain. It seems the
fasting effect is probably less on aging than on immune function. I
guess it is a good idea to check out what is the particular
characteristic of the strain of mouse used for each study before
trying to understand the ramifications.
I attach another study on the same strain of mouse which might be
interesting.
Thomas
J Nutr 2001 Oct;131(10):2753-60 Life span is prolonged in
food-restricted autoimmune-prone (NZB x NZW)F(1) mice fed a diet
enriched with (n-3) fatty acids. Jolly CA, Muthukumar A, Avula CP,
Troyer D, Fernandes G. Division of Clinical Immunology, Department of
Medicine, The University of Texas Health Science Center at San
Antonio, San Antonio, TX 78229-3900, USA. Moderate food and/or energy
(calorie) restriction delays age-related immune dysfunction and
prolongs life span in multiple animal models. The amount and type of
dietary fatty acids can also profoundly affect life span.
Marine-derived fish oils contain (n-3) fatty acids, which have potent
anti-inflammatory properties. We therefore examined the influence of
food restriction (40% overall reduction in intake of all dietary
components) combined with substitution of fish oil for corn oil in a
factorial design. Autoimmune-prone (NZB x NZW)F(1) (B/W) mice, which
develop fatal autoimmune renal disease, were used. The
food-restricted/fish oil diet maximally extended median life span to
645 d (vs. 494 d for the food-restricted corn oil diet). Similarly,
fish oil prolonged life span in the ad libitum-fed mice to 345 d (vs.
242 for the ad libitum/corn oil diet). Increased life span was
partially associated with decreased body weight, blunting renal
proinflammatory cytokine (interferon-gamma, interleukins-10 and -12
and tumor necrosis factor-alpha) levels and lower nuclear
factor-kappaB (NF-kappaB). Reductions in NF-kappaB were preceded by
enhanced superoxide dismutase, catalase and glutathione peroxidase
activities. These findings demonstrate the profound additive effects
of food restriction and (n-3) fatty acids in prolonging life span in
B/W mice. These observations may have additional implications in the
management of obesity, diabetes, cancer and/or the aging process.
PMID: 11584100
Thomas Carter
> Thomas Carter wrote:
>
Snip
Hi Tom,
Interesting papers especially the first showing an increase in GH but
not IGF-1 with CR. The third shows that some functional aspects of
IGF-1 are mediated by things other than GH. But I meant to say only
that the majority of the effects of GH are mediated by IGF-1, not that
concentrations were tied together.
You meant to say positively, of course. I agree that both hormones
have many positive functions and also that they can be life extending.
I have meant to give what I think is the opinion of researchers in the
field, more than my own. My readings seem to me to show that current
thought is that GH and IGF-1 when supplemented in all but very
deficient people puts one at high risk for an increase in the rate of
age related pathologies. The most probable pathway of mediation seems
to be in part a decrese in insulin sensitivity. My own thought is that
GH will turn out to be beneficial only to normal people after they
reach a certain degree of age related frailty where they can enjoy the
benefits and not succumb rapidly to the detriments. It does seem
curious, but I see no inherent contradiction in the fact that they can
be life extending for some, say thru prevention of a hip fracture or
heart attact and life shortening for others thru an increase in the
basic physioligical aging process possibly mediated thru an excess of
insulin or thru direct action of IGF-1.
Cortisol has been called repeatedly the "death hormone" it is
what causes Salmon to die after mating, and is related to extreme old
age depression which seems to cause animals to wander off and die
almost "voluntarily" as well being a known cause of death in humans.
Yes, I guess it was going a bit too far to speculate that insulin will
be regarded in the same league as cortisol.
A good point, but much needs to be learned to know just when
supplementation shoud be started to increase insulin sensitivity, and
whether safer means are not or will not be available.
> Furthermore, your last abstracs below describe a longevity enhancing
> effect in animals specially bred to have low GH. Unless we all want to
> be dwarfs, I don't see that this necessarily has relevance for humans.
> Once again, I remind you that GH is increased by CR and its age
> related decline is also inhibited.
>
>
> --Tom Matthews
>
> MoreLife for the rational - http://morelife.org
> Reality based tools for More Life in quantity & quality
The relevance is quite apparent and is similar to that of many
other animal studies. A relation ship has been established which may
be relative to humans, nothing more. This same relationship is also
seen in humans, but is not as obvious because the GH levels in normal
humans are more nearly the same than they are in KO and normal mice.
Much will be revealed in next five to ten years on this issue. In
the meantime I will now be a bit more content to know that my IGF-1
level should be reduced by CR. As to the increase in GH with CR, I
have a question which is also pertinent to some other aging
parameters. If GH goes down with age, is the reason that an animal on
CR of a certain chronilogical age, has more GH than an ad lib animal
due to CR per se, or due to the fact that he is physiologically
younger? If the former, the increased GH could be a mechanism by which
longevity is mediated. If the latter, it is just a related affect
rather than a cause.
Thomas
Michael
Tom Matthews <t...@morelife.org> wrote in message news:<3D10572D...@morelife.org>...
> Michael wrote:
>
> > there's significant evidence that EOD CR is actually INFERIOR to
> > "continuous" CR. I started a long post on this some time ago & never
> > finishted it; but see, for starters:
> >
> > http://groups.yahoo.com/group/crsociety/message/2751
> > http://groups.yahoo.com/group/crsociety/message/5062
> > http://groups.yahoo.com/group/crsociety/message/4395
> >
> > This posts goes over some of the same evidence & adds more. Bottom
> > line: IMO, EOD CR is an inferior protocol, possibly ESP so
> > in adult-onset CRONies.
>
>
> Then why does Walford himself practice CR by fasting 2-3 days per week?
Well, first, I'm not sure that W actually does this anymore: several
folks on CR Society SEEM to recall reading that he'd quit this
protocol, but no one has yet produced documentation. Second, the
reason he gave in the 1986 _120 Year Diet_ was that he found it
easier. But third (and most importantly): Walford states, reccomends,
and/or practices all kinds of things which are irreconcilable with
available evidence. I have enormous respect for the Grand "Old" Man,
but the fact that he says, reccomends, or practices something is not,
itself, evidence in favor of it.
> >
> > [Cited evidence] would suggest that, while aging was slowed,
> > the stress of the shift on adult organisms' less-adaptable
> > bodies was sufficient to cause other, unsustainable damage.
>
>
> Perhaps, because as Steve pointed out EOD to a mouse is equivalent to every
> other week to a human. But this says little about human EOD!
I don't think that this is a reasonable extrapolation ("mouse days"
extrapolation like "mouse years"), for several reasons. First, there
is the obvious shared chronobiology between rodents and humans: we've
all evolved to "work" on a cycle not too far off from the spinning of
the earth, with endocrine and other rhuthms roughly attuned to (and
constantly re-adjusted to) the apparent rise & fall of Sol Invictus.
Second, a direct extrapolation of the sort proposed (granted mouse max
LS ~1200 days vs human ~120 yrs) would actually be a 48h mouse fast
equating to a 10.4 week human one -- which would be quite deadly.
Similarly, rodents normally eat once a day in CR studies, but this
doesn't mean that they are undergoing continuous human-equivalent 5.4
week starvatioin diets. Heck, even the mouse's normal nibbling style
of eating (when food is available) and going hungry when food is
scarce would leave mouse "weeks" of starvation unless food were
continuously provided in the wild. And, again, we know from some of
the studies tha you can fast a rodent for a day or 2 without altering
its body mass; the same, again, is inextrapolable to the human
situation. Etc.
Again, EOD CR clearly DOES when begun shortly after weaning, but no
one would suggest that keeping human children unfed for even the 1-2
weeks previously suggested would not lead to considerable frank
nutritional deficiencies and increased mortality.
Like it or not, the rodent data is what we've got. Until someone shows
otherwise, I'm going to take the data at face value unless there is a
clear reason not to; I don't think that the line of argumentation
based on "mouse days" constitutes such clear-cut a case.
> Similar comments apply to the rest of your mouse and rat studies.
Right ;)
-Michael
Thomas Carter
This study I got today from the LEF site has some relevance to our
issue.
Thomas
Blood Tests May Help Determine Which Older Women Are at Higher Risk
for Disability and Death
AScribe Newswire
University of Maryland Medical System
June 20, 2002
BALTIMORE, June 20 (AScribe Newswire) -- Older women with abnormal
levels of two substances -- a growth hormone and a biological marker
tied to inflammation -- may be at higher risk for becoming disabled or
dying, according to the results of a new study. The study, led by a
University of Maryland School of Medicine researcher, will be
presented June 22 at an international endocrinology conference in San
Francisco.
Using data from a three-year study of 718 women over age 65 with
physical disabilities, researchers found that those who had low levels
of a hormone called insulin-like growth factor-1 (IGF-1) and high
levels of interleukin-6 (IL-6) were more likely to have serious
problems walking and caring for themselves than women with normal test
results.
"These women were also twice as likely to die within five years
compared to those with normal levels of IGF-1 and IL-6," says the lead
investigator, Anne R. Cappola, M.D., Sc.M., an endocrinologist at the
University of Maryland Medical Center and an assistant professor of
medicine at the University of Maryland School of Medicine.
"We do not know whether the abnormal levels contribute to the decline
in health of elderly women or are just markers," she says. "If they
are a cause, some kind of intervention or drug therapy might help
those at risk. It could be that they just need to be monitored more
closely."
But, she adds, if the abnormal levels are only markers, that would
still help to identify patients at risk of developing problems.
"Because it is an observational study, we can't prove cause and
effect. But if other studies confirm our findings, testing for IGF-1
and IL-6 could be clinically useful in the future to identify older
people at risk for disabilities and death," says Dr. Cappola, who will
present the results at ENDO 2002, the 84th annual meeting of The
Endocrine Society, in San Francisco, Calif.
Dr. Cappola and researchers from the National Institute on Aging and
the Johns Hopkins Medical Institutions looked at levels of IGF-1 and
IL-6 in 718 moderately to severely disabled women, who took part in
the Women's Health and Aging Study I. The study, funded by the
National Institute on Aging, was conducted from 1992 to 1995 in
Baltimore.
"We discovered that older women with both low IGF-1 levels and high
IL-6 levels were five times more likely to have difficulty walking a
quarter of a mile or climbing stairs compared to women who had normal
test levels," says Dr. Cappola.
She says that these at-risk women were 10 times more likely to have
severe limitations in their ability to walk. They had a 27 percent
increased risk of having difficulty or being unable to perform daily
tasks, such as bathing, dressing, eating and using the toilet, and a
68 percent increased risk of having problems with other chores, such
as light housework, shopping and preparing meals.
According to Dr. Cappola, previous studies have detected abnormal
levels of IL-6 or IGF-1 in older people who become disabled, but this
is the first study to look at both factors together.
Levels of IGF-1 and IL-6 change as people age, but the degree to which
this occurs appears to signal problems. The growth hormone IGF-1,
which is produced in the liver, affects bone mass and strength.
Interleukin-6 is associated with an inflammatory response by the body.
Neither is routinely measured clinically.
In analyzing the data, researchers tried to factor out all other
possibilities for the women's disabilities, taking into account not
only their age, race, education and body mass, but also whether they
smoked or had chronic medical conditions, such as diabetes or heart
disease.
The average age of the women was 77.6 years, and 28.9 percent of them
were African-American. Twelve percent smoked, 10.2 percent had
congestive heart failure and 15.7 percent had diabetes. Seventy-two
percent of them had difficulty caring for themselves on a daily basis,
while 47 percent had problems walking or climbing stairs.
"The bottom line is that it seems that the women were worse off if
they had both a low level of IGF-1 and a high level of IL-6 than if
they had neither, but we're not sure what causes that," Dr. Cappola
says. "Our work represents an initial step toward understanding what
is really going on physiologically with older women who are disabled
and for developing a risk profile for frailty in older women."
-30-
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Tom Matthews
> Tom Matthews <t...@morelife.org> wrote in message news:<3D10539...@morelife.org>...
>
>>Thomas Carter wrote:
>>
>>
> Snip
>
>>> A word of caution on growth hormone, whose effects are
>>>largely mediated by IGF-1.
Thanks for the correction of my slip above. Based on you paragraph above, I
think we are in agreement.
But it can't be too bad because is seems to be increased in those on CR.
> The relevance is quite apparent and is similar to that of many
> other animal studies. A relation ship has been established which may
> be relative to humans, nothing more. This same relationship is also
> seen in humans, but is not as obvious because the GH levels in normal
> humans are more nearly the same than they are in KO and normal mice.
> Much will be revealed in next five to ten years on this issue. In
> the meantime I will now be a bit more content to know that my IGF-1
> level should be reduced by CR. As to the increase in GH with CR, I
> have a question which is also pertinent to some other aging
> parameters. If GH goes down with age, is the reason that an animal on
> CR of a certain chronilogical age, has more GH than an ad lib animal
> due to CR per se, or due to the fact that he is physiologically
> younger? If the former, the increased GH could be a mechanism by which
> longevity is mediated. If the latter, it is just a related affect
> rather than a cause.
I have thought the same. My opinion is that it is partly the latter, ie an
effect of CR producing a younger phenotype at an older age. After all, the same
is true for DHEA - while it is reduced by CR at younger ages, its age related
decline is inhibited.
However, increased GH may also have a major causal effect on CR reduced aging
rate since more GH stimulates a higher rate of protein turnover, which I
maintain is the major effect of CR - dysfunctional proteins get replaced more
quickly!.
All that I was pointing out is that its occurrence (high GH in CR) argues
against GH, per se, being negative for aging.