Resveratrol supplementation does not extend lifespan in ad libitum-fed rodents.
rs1...@yahoo.com
http://www.sciencedaily.com/releases/2008/07/080703120402.htm
jc101
> So they published it afterall....
>
> http://www.sciencedaily.com/releases/2008/07/080703120402.htm
" Resveratrol did not have a significant effect on lifespan in animals
fed standard chow,....However, for mice on a high-calorie diet, mean
and maximum lifespan increased for mice on resveratrol when compared
with the control mice."
Maybe I am reading it wrong, but doesn't that say high calorie diet
with resveratrol lived longer than standard diet alone? Anyone looked
at the study?
JLC
Taka
failure ... Well I think the RSV has to be titrated to the PUFAs and
particularly AA in the body. Profound benefits were found in mice who
were engorged with a very-high fat diet - 60% fat calorie - of course,
60% Omega-6 will produce huge oxidative stress!
Taka
--------------------------------------
From Longevinex:
Follow-Up Resveratrol Mouse Study Confirms Red Wine Molecule Exerts
Profound Positive Effects Upon Health, But Also Produces A Surprise
Finding
In a follow-up study to the widely publicized 2006 mouse/resveratrol
study published in Nature Magazine (November 1, 2006), researchers now
provide more complete long-term analysis of the biological effects of
resveratrol as a molecular mimic of calorie restriction in animals.
The results, published in the journal Cell Metabolism, are jaw-
dropping, but they also come with a surprise. Resveratrol-fed elderly
mice show a marked reduction in signs of aging, including:
• Reduced albumin (a blood protein; elevated albumin often occurs with
heart failure)
• Decreased inflammation
• Superior blood-vessel health
• Increased elasticity of the aorta (the first blood vessel
outside the heart)
• Greater balance and coordination (motor function)
• Strikingly reduced cataract formation (even better than a
reduced-calorie diet)
• Preserved bone mineral density.
But surprisingly, while supplemental resveratrol did, as previously
reported, prolong the lifespan of mice who were engorged with a very-
high fat diet (60% fat calories, which no human could tolerate),
resveratrol did not prolong life in mice fed a standard calorie diet.
Two doses of resveratrol were employed in the mouse study, lower-dose
resveratrol (100 mg/kilogram of food (or ~364 milligrams for a 160-
pound/70 kilogram adult), or 400 mg/kilogram of food (~1565 milligrams
for the 160-pound/70 kilogram adult). While there were no long-term
detrimental effects noticed at modest doses, the lower-dose
resveratrol group appeared to consistently live a bit longer in all
groups than the higher-dose resveratrol groups (see chart). The
authors of the paper cite another animal study which showed that
18,000 mg/kilogram of body weight (likely to be difficult for humans
to even intentionally achieve) did increase mortality due to heart
failure in a mouse study. So there may be decreasing health benefits
with increasing dosage.
The effects of a calorie-restricted diet on longevity are diminished
when the regimen is initiated at increasing ages. This drawback may
be overcome by resveratrol.
Of great interest is the effect resveratrol exerted over the Sirtuin1
gene, the gene that is activated when calorie restricted diets are
employed. However, “microarray data on the effects of SIRT1 over-
expression in these tissues are not available, making it currently
difficult to assess whether SIRT1 is a mediator of these effects,”
said researchers.
Matt Kaeberlein, a noted Sirtuin gene researcher at the University of
Washington in Seattle, offered his commentary, entitled “The Ongoing
Saga of Sirtuins and Aging,” in an accompanying article in Cell
Metabolism. Dr. Kaeberlein said:
Unfortunately, what has often been lost in reviews of the sirtuin
literature and reports in the popular media are the many complexities
and inconsistencies in our understanding of sirtuin biology as it
relates to aging. For example, in yeast, Sir2 over-expression
increases replicative life span (the span of time when a mother yeast
cell produces daughter cells, but shortens chronological life span,
which is a measure of the length of time a yeast cell can survive in a
non-dividing state.
Multiple labs have reported that sirtuins are not always
required for life-span extension from dietary restriction in either
yeast or worms. What makes the study by Li et al. particularly
interesting is the observation that Sirtuin1 gene inhibition causes
some phenotypes (groups with inherited genetic mutations) more
consistent with a slower rate of aging. For example, they show that
Siruin1 inhibition leads to increased IRS-2 acetylation, decreased
Insulin Growth Factor-1 signaling, and decreased Ras/ERK signaling.
Decreased Ras gene signaling increases life span in yeast, and reduced
insulin/Insulin Growth Factor-1-like signaling is associated with
increased life span in worms, flies, and mice. Supporting the idea
that inhibition of Sirtuin1 may slow aspects of aging in mice, studies
show enhanced resistance to oxidative stress in neuronal cells after
Sirtuin1 knockdown and reduced oxidation of proteins and lipids in
brains of Sirtuin1 knockout animals.
Taken together, these data may indicate that inhibition of
Sirtuin1 can be nerve-protective in aging animals and that some
features of aging are slowed rather than accelerated in animals whose
Sirtuin1 gene has been eliminated.
The one thing that seems clear is that sirtuin activators are
unlikely to be a ‘‘magic bullet’’ for aging. A more realistic hope is
that, as we continue to unravel the complexities of sirtuin biology,
targeted activation or inhibition of Sirtuin1—and perhaps other
sirtuins as well—will prove therapeutically useful toward a subset of
age-associated diseases. Such an achievement would be a huge step
forward in the transition of aging-related science from the laboratory
to the clinic, and we eagerly await the next chapter in the unfolding
saga that is sirtuin biology. --Matt Kaeberlein. (Cell Metabolism
July 2008)
The next chapter will be written by Longevinex®, which will unveil its
mouse study which measures the global-gene array effects of a calorie-
restricted diet, a resveratrol-fortified diet and a Longevinex®-
fortified diet. Of considerable interest, this upcoming study, to be
published in Experimental Gerontology, does not show that resveratrol
increases Sirtuin1 gene activity, as measured by messenger RNA. –
Copyright 2008 Resveratrol Partners LLC
rj...@my-deja.com
Although this summary says "resveratrol did not prolong life in mice
fed a standard calorie diet. ", two points are worth noting. 1)
resveratrol plus CR in the form of every-other-day (EOD) feeding DID
extend lifespan by 15%, and 2) the strain of mice used in this study
have previously been shown to not respond to either EOD or 40% caloric
restriction.
One cannot draw definite conclusions as to what exactly resveratrol
will do in other species of mice, much less in human beings, from this
study. It does seem likely to be beneficial.
ironjustice
beneficial <<
These guys seem to agree.
---------------
Red Wine Ingredient Wards Off Effects Of Age On Heart, Bones, Eyes And
Muscle
Article Date: 06 Jul 2008 - 4:00 PDT
Large doses of a red wine ingredient can ward off many of the vagaries
of aging in mice who begin taking it at midlife, according to a new
report published online on July 3rd in Cell Metabolism, a Cell Press
publication. Those health improvements of the chemical known as
resveratrol - including cardiovascular benefits, greater motor
coordination, reduced cataracts and better bone density - come without
necessarily extending the animals' lifespan.
Sinclair and de Cabo's team further show evidence that resveratrol
mimics the beneficial effects of eating fewer calories. In mice, they
found that resveratrol induces gene activity patterns in multiple
tissues that parallel those induced by dietary restriction and every-
other-day feeding.
" From a health point of view, the quality of life of these mice at
the end of their days is much better," said Rafael de Cabo of the
National Institute on Aging. It suggests that resveratrol may "extend
productive independent life, rather than just extending life span."
" I was most surprised by how broad the effects were in the mice,"
added David Sinclair of Harvard Medical School. "Usually, you focus on
slowing down or ameliorating one disease at a time. In this case,
resveratrol influences a whole series of seemingly unrelated diseases
associated with aging." Sinclair said he expects some of the effect
seen in the mice would have even greater impact if they hold in
humans. That's because, unlike people, mice usually don't die as a
result of heart disease, or suffer from weakening bones.
Earlier studies showed that reducing calorie intake by 30%-50%, or
eating a nutritious diet every other day, can delay the onset of age-
related diseases, improve stress resistance, and decelerate functional
decline, the researchers said. Although dietary restriction has
beneficial effects in humans, such a diet is unlikely to be widely
adopted and would pose a significant risk to the frail, critically
ill, or the elderly.
Therefore, the researchers are on a quest for "dietary restriction
mimetic" compounds that provide some of the benefits without cutting
calories. One contender has been compounds like resversatrol that
activate SIRT1, a protein linked to long life in many species, from
yeast to mammals.
Indeed, studies have shown resveratrol can extend the lives of yeast,
worms, flies and fish. It also improves the health and survival of
obese mice fed a high-calorie diet. Now, de Cabo and Sinclair show
that those effects do indeed seem to take place by inducing the
physiology of dietary restriction. They placed one-year-old mice on a
standard control diet or every-other-day feeding with or without
resveratrol.
Resveratrol produced changes in the gene expression profiles of key
metabolic tissues, including liver and muscle, that closely resemble
those induced by dietary restriction, they report. Overall, the
animals' health improved under all dietary conditions, as reflected by
a reduction of osteoporosis, cataracts, vascular dysfunction, and
declines in motor coordination. However, the mice lived longer only
when they were fed a high-calorie diet, consistent with earlier
reports.
" In conclusion, long-term resveratrol treatment of mice can mimic
transcriptional changes induced by dietary restriction and allow them
to live healthier, more vigorous lives," they wrote. "In addition to
improving insulin sensitivity and increasing survival in [high-calorie
fed] mice, we show that resveratrol improves cardiovascular function,
bone density, and motor coordination, and delays cataracts, even in
nonobese rodents. Together, these findings confirm the feasibility of
finding an orally available dietary restriction mimetic."
Resveratrol treatment is already being tested in clinical trials for
type II diabetes, the researchers noted, and more potent molecules
with effects similar to resveratrol are also under development.
----------------------------
Article adapted by Medical News Today from original press release.
----------------------------
The researchers include Kevin J. Pearson, National Institute on Aging,
National Institutes of Health, Baltimore, MD; Joseph A. Baur, Harvard
Medical School, Boston MA; Kaitlyn N. Lewis, National Institute on
Aging, National Institutes of Health, Baltimore, MD; Leonid Peshkin,
Harvard Medical School, Boston MA; Nathan L. Price, National Institute
on Aging, National Institutes of Health, Baltimore, MD, Harvard
Medical School, Boston MA; Nazar Labinskyy, New York Medical College,
Valhalla, NY; William R. Swindell, University of Michigan, Ann Arbor,
MI; Davida Kamara, National Institute on Aging, National Institutes of
Health, Baltimore, MD; Robin K. Minor, National Institute on Aging,
National Institutes of Health, Baltimore, MD; Evelyn Perez, National
Institute on Aging, National Institutes of Health, Baltimore, MD;
Hamish A. Jamieson, Centre for Education and Research on Ageing, and
the ANZAC Research Institute University of Sydney, Concord, Australia;
Yongqing Zhang, Gene Expression and Genomics Unit, National Institute
on Aging, National Institutes of Health, Baltimore, MD; Stephen R.
Dunn, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,
PA ; Kumar Sharma, Translational Research in Kidney Disease, UCSD, La
Jolla, CA; Nancy Pleshko, Hospital for Special Surgery, New York, NY;
Laura A. Woollett, University of Cincinnati Medical Center,
Cincinnati, OH; Anna Csiszar, New York Medical College, Valhalla, NY ;
Yuji Ikeno, University of Texas Health Science Center at San Antonio,
and Research Service, Audie Murphy VA Hospital (STVHCS), San Antonio,
TX; David Le Couteur, Centre for Education and Research on Ageing, and
the ANZAC Research Institute University of Sydney, Concord, Australia;
Peter J. Elliott, Sirtris Pharmaceuticals Inc, Cambridge, MA; Kevin G.
Becker, Gene Expression and Genomics Unit, National Institute on
Aging, National Institutes of Health, Baltimore, MD; Placido Navas,
Centro Andaluz de Biologia del Desarrollo, and Centro de Investigacion
Biomedica en Red: Enfermedades Raras, Instituto de Salud Carlos III,
Sevilla, Spain; Donald K. Ingram, Nutritional Neuroscience and Aging
Laboratory, Pennington Biomedical Research Center, Louisiana State
University System, Baton Rouge, LA; Norman S. Wolf, University of
Washington, Seattle, WA; Zoltan Ungvari, New York Medical College,
Valhalla, NY ; David A. Sinclair, Harvard Medical School, Boston MA;
and Rafael de Cabo, National Institute on Aging, National Institutes
of Health, Baltimore, MD.
Source: Cathleen Genova
Cell Press
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
> study. It does seem likely to be beneficial.- Hide quoted text -
>
> - Show quoted text -
François Rose
<snip>
>
> Although this summary says "resveratrol did not prolong life in mice
> fed a standard calorie diet. ", two points are worth noting. 1)
> resveratrol plus CR in the form of every-other-day (EOD) feeding DID
> extend lifespan by 15%, and 2) the strain of mice used in this study
> have previously been shown to not respond to either EOD or 40% caloric
> restriction.
>
> One cannot draw definite conclusions as to what exactly resveratrol
> will do in other species of mice, much less in human beings, from this
>
> - Show quoted text -
I can't find where you get your 15%.
I only get this from the given link:
http://www.sciencedaily.com/releases/2008/07/080703120402.htm
"Mice on a high-calorie diet without resveratrol lived the shortest
length of time and mice on an every-other-day regimen lived the
longest, regardless of resveratrol treatment."
I can't find either the name of the strain.
If anyone has access to the data of the different groups, I would be
interested
François Rose
PS to rs1000: just curious, when you wrote "So they published it
afterall....
did you mean that the authors were possibly a bit reluctant to publish
these results (because the resveratrol life extending effect was not
seen in normal diet and CR diet animals)?
rj...@my-deja.com
You have to read the paper, not a news report based on a press
release.
Pearson et al., Resveratrol Delays Age-Related Deterioration and
Mimics Transcriptional Aspects of Dietary
Restriction without Extending Life Span, Cell Metabolism (2008), doi:
10.1016/j.cmet.2008.06.011
http://www.cellmetabolism.org/content/article/fulltext?uid=PIIS1550413108001824
rj...@my-deja.com
You have to read the paper. not the summary from the press release.
Pearson et al., Resveratrol Delays Age-Related Deterioration and
Mimics Transcriptional Aspects of Dietary
Restriction without Extending Life Span, Cell Metabolism (2008), doi:
10.1016/j.cmet.2008.06.011
François Rose
>
> - Show quoted text -
The abstract is avalaible for free at the link you've provided
but the full text is not free (it can be purchased for 31,50$)
So I won't pay this in order to have the stats.
So once again,
I now know where you get your 15%.
but I can't find the name of the strain.
François Rose
>
> > > François Rose
> > > PS to rs1000: just curious, when you wrote "So they published it
> > > afterall....
> > > did you mean that the authors were possibly a bit reluctant to publish
> > > these results (because the resveratrol life extending effect was not
> > > seen in normal diet and CR diet animals)?
>
>
> - Show quoted text -
Thanks, Jay, for the copy of the full text
MAX LIFESPAN (= mean of the final 20% mice !!!!!!!!!!)
standard diet (regardless resveratrol):139 +/- 1 weeks
every other day feeding (without RSV):144
every other day feeding (with low dose RSV((100 mg/kg of
food)(7.6 ± 0.2 mg/kg/day which equals 1.27mg/kg/day for a human (I
have to divide by 6 because the animals were mice):147 weeks
every other day feeding (with high dose RSV (400 mg/kg of
food)(30.4 ± 0.6 mg/kg/day which equals 5mg/kg/day for a human):143
weeks
high caloric (without RSV):130
high caloric (with low dose RSV((100 mg/kg of
food)(7.6 ± 0.2 mg/kg/day which equals 1.27mg/kg/day for a human (I
have to divide by 6 because the animals were mice):137 weeks
high caloric (with high dose RSV (400 mg/kg of
food)(30.4 ± 0.6 mg/kg/day which equals 5mg/kg/day for a human):135
Regarding max lifespan:
EOD with low RSV is significantly higher than standard diet
High caloric is significantly lower than standard diet
High caloric with low RSV is not significantly different to standard
diet
IOW:
The high dose of resveratrol is not useful for max lifespan (this is
quite questioning about the right dose of resveratrol in
humans!!!!!!!!)
A low dose of resveratrol enhance the max lifespan
* of High caloric group to the one of the standard group
* of every other day feeeding to a significantly higher than the one
of standard group
SURVIVAL RATE CURVES:
EOD and EOD (with high RSV) are almost superposed and these two ones
square a bit the curve of the standard diet survival
EOD with low RSV squares a bit more the curve (and this is significant
when it was compared to the standard diet)
standard diet (with low RSV or no RSV) are almost superposed (low RSV
survival is a bit lower at the beginning!!)
standard diet (with high RSV) squares the curve a little but
all these 3 standard diets survival do not differ significantly with
regard to resveratrol use
High caloric survival is significantly lower than the one of the
standard diet
High caloric with low or high dose of resveratrol do not differ
significantly to the standard diet
Conclusion: quite identical to those of the max lifespan
NOTES FROM THE FULL TEXT:
"At 1 year of age, C57BL/
6NIA mice were placed on a standard control diet (SD) or DR
by every-other-day feeding (EOD) with or without resveratrol."
Once again, this question has to be asked: how was the every other day
procedure implemented? Would that change something?
"Our results are consistent with
the previous observation that the effect of EOD on longevity is
diminished
in older C57BL/6 mice (Goodrick et al., 1990), which is
also true of DR by 40% restriction (Weindruch and Walford,
1982)."
On Jul 9, 11:47 am, r...@my-deja.com wrote:
> Although this summary says "resveratrol did not prolong life in mice
> fed a standard calorie diet. ", two points are worth noting. 1)
> resveratrol plus CR in the form of every-other-day (EOD) feeding DID
> extend lifespan by 15%, and 2) the strain of mice used in this study
> have previously been shown to not respond to either EOD or 40% caloric
> restriction.
The point 2) above is wrong: C57BL/6 mice respond correctly to either
EOD or 40% CR (you can check that in PubMed). If initiated in older
mice, they respond less. (something very normal)
Here they start the restriction or the resveratrol use at 52 weeks
(which can be compared to the survival ratio median : 120 weeks +/-5
weeks)
"The effects of DR on longevity are diminished when the regimen
is initiated at increasing ages (Goodrick et al., 1990; Weindruch
and Walford, 1982), although many of the characteristic
transcriptional changes can be induced rapidly regardless of
age (Cao et al., 2001). Indeed, our EOD feeding regimen was
initiated at 12 months of age, and while average life span was
increased,
the effect did not reach statistical significance, except
in combination with resveratrol (EODLR versus SD). Thus, it is
possible that the age of our animals at the start of the experiment
might have diminished the potential effects of resveratrol on lifespan
in nonobese mice. To address this question, we are following
up with life-span studies in which resveratrol treatment is
begun at weaning. It may also be that resveratrol slows the general
age-related decline but does not impact the specific causes
of death in these mice. Indeed, resveratrol did not suppress
lymphoma, a major cause of mortality in C57BL/6 mice."
>
> One cannot draw definite conclusions as to what exactly resveratrol
> will do in other species of mice, much less in human beings, from this
> study. It does seem likely to be beneficial
I agree with the above;
From the full text: "The major factor contributing to life span
extension in the resveratrol-treated HC groups was a reduction
in the number of deaths attributed to cardiopulmonary distress
(specifically, fatty changes in the liver combined with severe
congestion and edema in the lungs; Table S3)."
So I don't know if it would be more (or less) benefical in humans in
terms of survival rate and max lifespan.
BENEFITS OF RESVERATROL
Resveratrol use shows a significant effect on osteoporosis, cataracts,
locomotor function and vascular function (in standard diet (we don't
have the data for the other diets); so though it did not add lifespan
or survival to the standard diet mice, it improved their lifetime
conditions (I haven't been very deep into that point).
François Rose
Olafur Pall Olafsson
> On Jul 10, 12:59 pm, François Rose <fr.r...@free.fr> wrote:
>
>
>
> > > > François Rose
> > > > PS to rs1000: just curious, when you wrote "So they published it
> > > > afterall....
> > > > did you mean that the authors were possibly a bit reluctant to publish
> > > > these results (because the resveratrol life extending effect was not
> > > > seen in normal diet and CR diet animals)?
>
> > François Rose- Hide quoted text -
>
> > - Show quoted text -
>
> Thanks, Jay, for the copy of the full text
Thanks for the report Francois.
> MAX LIFESPAN (= mean of the final 20% mice !!!!!!!!!!)
> standard diet (regardless resveratrol):139 +/- 1 weeks
> every other day feeding (without RSV):144
> every other day feeding (with low dose RSV((100 mg/kg of
> food)(7.6 ± 0.2 mg/kg/day which equals 1.27mg/kg/day for a human (I
> have to divide by 6 because the animals were mice):147 weeks
Your calculations are not very accurate. Dividing by 7,3 rather than 6
should give more accurate numbers since the metabolism of mice is
approximately 7,3 times faster than that of humans. This would give a
dose of:
7,6mg/kg / 7,3 = 1,0mg/kg for humans if one calculates the dose based
on the amount per body weight. You can also see that your number is
suspiciously high if you calculate the dose based on the amount per kg
of food given in the full text. As you report the dose was 100mg/kg
food. Usually this is on a dry weight basis. On a dry weight basis a
70kg adult human eats roughly 500g of food daily which gives about
50mg per day or 50mg/70kg = 0,71mg/kg body weight of resveratrol. This
is even further from your number of 1,27mg/kg/day than what I get
using the conversion factor of 7,3. To see how I estimated that a 70kg
adult human eats roughly 500g of food daily on a dry weight basis see
the last post in this discussion: http://tinyurl.com/5ryqad
> every other day feeding (with high dose RSV (400 mg/kg of
> food)(30.4 ± 0.6 mg/kg/day which equals 5mg/kg/day for a human):143
> weeks
Using a conversion factor of 7,3 the numbers for the high dose
resveratrol group amount to:
30,4mg/kg / 7,3 = 4,2mg/kg body weight daily for humans if one
calculates the dose based on the amount per body weight, and
400mg/kg x 0,5kg / 70kg = 2,9mg/kg body weight daily for a 70kg human
if one calculates the dose based on the amount per kg of food given.
François Rose
>
> - Show quoted text -
Thanks for the correction, Olafur
I wasn't sure about my calculations; that's why I wrote them so that
I
could be corrected.
I don't not know yet very well the conversion and I got to work more
on
this.
Thanks for the link
I say it once again because I think it is an important point, IMO:this
study really casts doubt upon the use of high dose resveratrol
(regarding life extending effect AND health span)
François
rj...@my-deja.com
Yo cannot use relative metabolic rates alone except as a starting
point for safe dosage. Mice, rats and humans all differ significantly
in the rate and amount of glucuronidation and sulfonation bin the
intestines and liver. Humans are much more efficient at this than
rodents, so the amount of free resveratrol in the blood is
significantly lower than in rodents at metabolically equivalent
doses. I've seen it estimated that the metabolic rate and the
glucoronidation rate cancel out, so mouse and human dose per kg should
be about the same. One would have to compare blood serum levels of
resveratrol over time to get an idea. Even then, there is speculation
that the metabolic by-products of resveratrol are also active.
The most extensive human trials were with a formulation (and hence
more bio-available form) of resveratrol, SRT501, by Sirtris. They
used 2.5 and 5 gram doses for dealing with disease. I wonder if
they've published data on blood-serum levels?
Paul Antonik Wakfer
Some additional information from the paper needs to be given from what
François provided, and some additional consideration of the data needs
to be done with respect to that given by Olafur and François.
The full paper states:
"Here, we test the hypothesis that resveratrol imparts health
benefits by inducing DR physiology. At 1 year of age, C57BL/
6NIA mice were placed on a standard control diet (SD) or DR
by every-other-day feeding (EOD) with or without resveratrol.
We present evidence that long-term resveratrol treatment slows
age-related degeneration and functional decline and mimics the
gene expression patterns induced by DR. We discuss the potential
implications of these findings for human health.
RESULTS
We previously reported that resveratrol improves the health and
survival of obese mice fed a high-calorie diet (Baur et al., 2006).
This raised two key questions: (1) Can resveratrol improve the
health of nonobese mice, and (2) if so is this due to an ability to
mimic the effects of DR? To answer these questions, we examined
the effects of resveratrol on mice fed SD ad libitum, subjected
to EOD feeding, or fed a high-calorie diet (HC) ad libitum.
Initially, each dietary group was divided into no resveratrol
(negative
control; SD, EOD, or HC), low resveratrol (100 mg/kg of
food, SDLR, EODLR, or HCLR), or resveratrol (400 mg/kg of
food, SDR, EODR, or HCR). Later, additional groups of mice
were given a higher dose of resveratrol along with the standard
or HC diets (2400 mg/kg of food, SDHR, or HCHR). The HC
plus resveratrol (HCR) group was the subject of a previous
report, and that nomenclature is preserved herein (Baur et al.,
20"06)."
And from the EXPERIMENTAL PROCEDURES section:
"Animals and Diets
Male C57BL/6NIA were purchased from the National Institute on Aging
Aged
Rodent Colony (Harlan Sprague-Dawley, Indianapolis, IN). Beginning at
1 year of age, mice were fed a standard AIN-93G diet (SD and EOD) or
AIN-93G modified to provide 60% of calories from fat (HC) plus 0%,
0.01%,
or 0.04% resveratrol. Average daily doses over the course of the study
(mg/kg/day) were: 7.9 ± 0.2 (SDLR), 30.9 ± 0.6 (SDR), 7.6 ± 0.2
(EODLR),
30.4 ± 0.6 (EODR), 5.4 ± 0.2 (HCLR), 24.2 ± 0.8 (HCR), 204 ± 4 (SDHR),
and
167 ± 16 (HCHR, ages 12–18 months). Additional details are provided in
the
supplemental material."
Therefore it is clear that there are two groups of mice: standard diet
high resveratrol (SDHR) and high calorie high resveratrol (HCHR)
(unfortunately no EODHR group), about which there is only fragmentary
information given in the paper, some of which is in tables and figures
in the supplemental material, and for which the experimenters
apparently did not test survival. (However, when I attempted to access
the supplemental material I found nothing there. Hopefully, it will
appear later.)
This means that it may distort the facts and intention of the paper
when Francois and Olafur refer to the 400mg/kg food groups as having
been fed a *high* dosage of resveratrol. Therefore, in the rest of my
comments, I will use the terms "low resveratrol" and "resveratrol" for
the 100mg/kg and 400mg/kg groups, respectively, just as the paper
authors did.
Note also in the first paragraph of the above that the abbreviation
"DR" (for dietary restriction) was used as a general description of
what every other day (EOD) feeding was intended to accomplish. And the
actual amounts of resveratrol ingested daily in mg/kg body weight by
the EOD groups (something not generally provided when dosages are
already given in mg/kg food) shows that the EOD groups consumed
substantially less food than the SD groups *without any extra
supplementation of vitamins/minerals* (ie the EOD groups were
effectively food restricted!). And this is confirmed by the average
weights shown in figure 4A of the paper. As shown there the EOD groups
weighed about 30g on average while the SD groups weight about 34g - an
average weight reduction of 12%!. (Exact numbers cannot be determined
because no tabular weight data is provided - perhaps in the missing
supplementary material.)
The dosage data given above together with these average weights can
then be used to calculate the ratio of the daily food intake. By my
calculation from these figures, the EODLR group was actually 15% food
restricted with respect to the SDLR group, while the EODR was only 13%
food restricted with respect to the SDR group. This also shows that
not only were the dosages for the EOD groups less than for the
corresponding SD groups but the absolute daily intake of resveratrol
was considerably lower (because of the lower food intake).Without more
exact weight data it is impossible to tell, but from the dosage
figures above it may even be true that the resveratrol had a small
crypto-CR effect on both the SD groups and the EOD groups. The weight
difference from figure 4A (34g versus 30g) amounts to a weight
reduction of about 12% of the EOD groups from the SD groups, is
consistent with the food restriction effect. (and is consistent with
what has been found for EOD in general - it is hard to do EOD and not
get some CR effect as well). Also note that the weight bar graph of
figure 4A clearly shows that the amount of weight decrease (from
whatever physiological causes) was proportional to resveratrol dosage.
Based on this additional analysis of the data from the paper, in the
context of the small lifespan differences between the groups, the lack
of any supplemental vitamins/mineral going along with this restriction
and the fact that EOD feeding for a mouse is much more strenuous than
EOD feeding for a human (due their relative metabolic rates and even
more drastic lifespan differences), I think that it is both premature
to say that resveratrol is a CR mimetic (see more on this below), and
also premature to suggest that the lower dosage of resveratrol may be
more healthful and life extending for humans.
It is also important to realize that, since the authors did do the
necessary work to determine actual daily animal dosages (for which I
commend them), it is these figures that should be used for the
purposes of relating to human dosages rather than the amount of
resveratrol per kg of food.
Also note that if one uses the actual weights of the experimental mice
(average 34g for the SD mice) to calculate the mouse to human (70 kg
standard) dosage conversion factor for this experiment, one gets
(70000/34)**0.25 = 6.7 (the 7.3 figure supplied by Olafur is based on
a 25g mouse and the mice of this experiment were a 36% heavier type).
Since mice are, in many ways, not a good model for the study of
longevity in humans - for example "resveratrol did not suppress
lymphoma, a major cause of mortality in C57BL/6 mice", the relevance
of these results for humans is not likely strong.
In summary, although this paper does give some reason for pause to
those who are espousing that healthy people with BMI's under 25 should
take resveratrol dosages of at least 5 mg/kg to achieve maximum
benefit, and I have reduced my personal dosage of resveratrol somewhat
as a result of it, I think that it is premature for any very definite
conclusion and that many more studies will be needed before optimal
human dosages can even be realistically guessed at.
BTW, with respect to the thought of resveratrol being a CR mimetic,
note the following paragraph from the discussion section:
"One clear difference between EOD and resveratrol
was that EOD strongly upregulated glutathione metabolism,
whereas resveratrol had no effect. Thus, there may be differences
in mechanisms by which EOD and resveratrol reduce oxidative
stress. Another difference was that while both increased
expression of ribosomal proteins in liver, heart, and adipose, only
EOD had this effect in skeletal muscle. Since increased protein
synthesis in skeletal muscle has previously been implicated as
a major effect of DR (Lee et al., 1999), this result highlights a
potentially
important difference in the resveratrol-treated animals."
In every study of CR (or DR) mimetics that I have seen the result were
similar.
"Whether it is possible to find a DR mimetic that is also safe for
long-term consumption is of considerable debate in the field."
In some ways the protocol was a mimetic, but not in all ways, which
means there is no complete CR mimetic yet and, IMO, there is not
likely to be any one chemical that is a complete mimetic.
In closing I think that the experimental results and even the above
text is contradictory to the author's concluding statements about
resveratrol being a CR mimetic (which conclusion text is even self
contradictory, IMO). Ie. the author's conclusions are not supported by
their results when these results are carefully analyzed.
"In conclusion, long-term resveratrol treatment of mice can
mimic transcriptional changes induced by dietary restriction
and allow them to live healthier, more vigorous lives. In addition
to improving insulin sensitivity and increasing survival in HC
mice, we show that resveratrol improves cardiovascular function,
bone density, and motor coordination, and delays cataracts,
even in nonobese rodents. Together, these findings confirm
the feasibility of finding an orally available DR mimetic.
Since cardiovascular disease is a major cause of age-related
morbidity and mortality in humans but not mice, it is possible
that DR mimetics such as resveratrol could have a greater impact
on humans. However, resveratrol does not seem to mimic
all of the salutary effects of DR in that its introduction into the
diet of normal 1-year-old mice did not increase longevity."
--Paul Wakfer
MoreLife for the rational - http://morelife.org
Reality based tools for more life in quantity and quality
The Self-Sovereign Individual Project - http://selfsip.org
Self-sovereignty, rational pursuit of optimal lifetime happiness,
individual responsibility, social preferencing & social contracting
jc101
Persons who have been overdosing on resveratrol will now have to eat
crow and back down on dosages. These are essentially 'plant derived
poisons' and are used hormetically to stimulate the mammal. You can
get too much.
We have used for years 1/4 tsp of resveratrol extract and 1/4 tsp of
fisetin extract. These run about 40-50% potency by our lab analysis,
so around 250 mg of each chemical net; use with food.
JLC
Jefferson
>>BENEFITS OF RESVERATROL
>>Resveratrol use shows a significant effect on osteoporosis, cataracts,
>>locomotor function and vascular function ...
>>
>>François Rose
The Microsoft word document that I have referenced uses information like
that above to support it's study design.
>
>
> Persons who have been overdosing on resveratrol will now have to eat
> crow and back down on dosages. These are essentially 'plant derived
> poisons' and are used hormetically to stimulate the mammal. You can
> get too much.
>
> We have used for years 1/4 tsp of resveratrol extract and 1/4 tsp of
> fisetin extract. These run about 40-50% potency by our lab analysis,
> so around 250 mg of each chemical net; use with food.
> JLC
The following is a Microsoft Document and is the 3rd item listed at
http://tinyurl.com/636fb9:
Contract: NCI Division of Cancer Prevention N01-CN-25025-3
TASK 2 A
Phase I repeat-dose clinical study of safety, pharmacokinetics and
pharmacodynamics of resveratrol
Protocol Version 3.2
June 2, 2006 (This is a 75 page document, but not all of it needs to be
reviewed.)
It was basically a design for the protocol to use in human subjects. It
gives the rationale for the dosages of resveratrol to be used.
1.0 Objectives of Task 2A
1.1 Objective 1
Measure concentrations of resveratrol and its metabolites in the plasma,
urine and stool of humans, and establish resveratrol pharmacokinetics
after at least 20 days of dosing. Characterize changes in
pharmacokinetics between the first and last dose.
Hypothesis: Resveratrol given once daily at a dose of 1 gm for at least
20 days will generate a Cmax at steady state of 50 μM combined
resveratrol + glucuronide metabolites in 80% or more of human participants.
1.2 Objective 2
Establish the effect of a single dose and steady state concentrations of
resveratrol obtained after a minimum of 20 days of dosing on COX-2
activity and M1G concentration in circulating white blood cells,
compared to pre-dose.
Hypothesis: A Cmax steady state resveratrol + glucuronide
concentrations of 50 μM or greater at steady state after a minimum of 20
days of dosing will be sufficient to cause a 50% or more reduction in
Cox-2 activity in circulating white blood cells compared to pre-dosing.
Hypothesis: A resveratrol + glucuronide concentration of 50 μM or
greater at steady state after a minimum of 20 days of treatment will be
sufficient to cause a 60% or more reduction in M1G concentrations in
circulating white blood cells compared to pre-treatment.
1.3 Objective 3
To obtain a preliminary toxicity profile of resveratrol given at doses
up to 5 gm per day.
Hypothesis: A daily resveratrol of 5.0 gm given for 29 days will result
in less than 5% incidence of any grade 2 or greater NCI Common Toxicity
scale toxicity in healthy human participants.
In addition Siritis used 2.5 and 5 gram doses in a phase I trial in
India of type 2 diabetics to test resveratrols safety. They are doing a
phase II trial using the same doses plus metformin.
Also a clinical trial is being conducted by the University of California
San Francisco in subject with metabolic syndrome at 5 grams of
resveratrol per day - http://tinyurl.com/578zjp.
We should have more reliable information of resveratrol dosages and
safety in humans in the near future.
Frank