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
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
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
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
bulk Email ad spam use "http://combat.uxn.com" to get the true corporate
name of the last ISP address on the viewsource header, then forward message
& 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.
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
> 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
>
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