WASHINGTON - Huge amounts of a red wine extract seemed to help obese
mice eat a high-fat diet and still live a long and healthy life,
suggests a new study that some experts are calling "landmark" research.
The big question is, can it work the same magic in humans?
Scientists say it's far too early to start swilling barrels of red
wine. But some are calling the latest research promising and even
"spectacular."
The study by the Harvard Medical School and the National Institute of
Aging shows that heavy doses of red wine extract lowers the rate of
diabetes, liver problems and other fat-related ill effects in obese
mice.
Fat-related deaths dropped 31 percent for obese mice on the supplement,
compared to untreated obese mice, and the treated mice also lived long
after they should have, the study said.
Astoundingly, the organs of the fat mice that got the wine extract
looked normal when they shouldn't have, said study lead author Dr.
David Sinclair of Harvard Medical School. And Sinclair said other
preliminary work still being done in the lab shows the wine ingredient
has promise in lengthening the life span of normal-sized mice, too.
Sinclair has a financial stake in the research. He is co-founder of a
pharmaceutical firm, Sirtris Pharmaceuticals Inc. of Cambridge, Mass.,
which is testing the safety of using the extract on humans for
treatment of diabetes.
For years, red wine has been linked to numerous health benefits. But
the new study, published online in the journal Nature on Thursday,
shows that mammals given ultrahigh doses of the red wine extract
resveratrol can get the good effects of cutting calories without having
the pain of actually doing it.
"If we're right about this, it would mean you could have the benefit of
restricting calories without having to feel hungry," Sinclair said.
"It's the Holy Grail of aging research."
Resveratrol, produced when plants are under stress, are found in the
skin of grapes and in other plants, including peanuts and some berries.
The resveratrol-treated 55 obese mice on a high-calorie diet (one
scientist called it a "McDonald's diet") are not only about as healthy
as normal mice, they are as agile and active on exercise equipment as
their lean cousins, showing what can be considered a normal quality of
life, higher than usual for obese mice, said study co-author Rafael de
Cabo of the National Institute on Aging.
"These fat old mice can perform as well on this skill test as young
lean mice," Sinclair said.
The only major body measurement that didn't improve - aside from
weight - was cholesterol and that didn't seem to matter in the
overall health of the mice, Sinclair said.
The study is so promising that the aging institute this week is
strongly considering a repeat of the same experiment with rhesus
monkeys, coming the closest to humans, after successful resveratrol
experiments on yeast, worms, fruit flies and now mice, said institute
director Dr. Richard Hodes.
Hodes cautions that it's too early for people to start taking
non-regulated resveratrol supplements because safety issues haven't
been addressed adequately. He pointed to past hyped medical treatments,
such as estrogen, that turned out to cause more harm than good.
Sirtris Pharmaceuticals is working on a high-dose resveratrol pill that
unlike unregulated supplements on the market now, would be used as a
drug and require Food and Drug Administration approval, said
company chief executive officer Dr. Christoph Westphal. And that
development and federal approval is about five years away, he said.
Sinclair's results are so promising that he rushed the study into the
science journal while the obese mice are still alive, not waiting
several more weeks or months until they die. That raises some issues,
including specific figures about mortality, but is understandable, said
outside experts. The obese mice still lived past the median age for
mice of their weight.
Even would-be competitors are praising the study.
"It's a fairly spectacular result," said University of Wisconsin
medical professor Dr. Richard Weindruch, who co-founded another biotech
company that looks at the genetics of aging and drugs that could expand
life spans. "People will go to McDonald's and afterwards they'll do
super-sized resveratrol."
"This is fantastic," said Brown University molecular biology professor
Stephen Helfand, who was the first reviewer for the journal Nature and
not part of the team. "This is a historic landmark contribution."
Helfand said he won't be taking red wine extract supplements - but he
has put his elderly mother on them. He said he's waiting to see if
there are long-term ill effects for humans. Mice, he said, are good
initial test subjects for human drugs because their bodies function
more similarly to humans than differently. However, he added that those
differences can prove crucial.
Sinclair said he takes resveratrol supplements, but doesn't recommend
it for others. Sinclair's mice took such high doses of resveratrol that
it would be the equivalent of an adult drinking 100 bottles of wine
daily.
Resveratrol works by spurring activity and regrowth in cells'
mitochondria, which Sinclair called "the energy powerhouses of the
cell."
Some scientists, such as Weindruch and Hodes, worry that the research
may encourage people to forget about their diets and wait for a red
wine cure-all that may never come.
"It's not an excuse to overeat," Sinclair said. But he added that for
mice at least, this shows you can be "fat, happy, healthy and vigorous."
Erich Brueschke
In any case, there are probably lots of things (e.g., green tea,
magnesium, pomegranate juice, l-arginine, etc.) that would dramatically
improve the health of an animal on a "McDonald's diet".
I think Sinclair et al. see dollar signs and go a little crazy.
Arbor
The mice were fed a hefty dose of resveratrol, 24 milligrams per
kilogram of body weight. Red wine has about 1.5 to 3 milligrams of
resveratrol per liter, so a 150-lb person would need to drink 750 to
1,500 bottles of red wine a day to get such a dose.
http://www.nytimes.com/2006/11/02/science/02drug.html?ei=5087%0A&em=&en=5c3164a8ce76e512&ex=1162616400&pagewanted=all
So a 150-lb person would need about 1636 mg per day of resveratrol to
mimic this study.
Wish they would have done one more step and seen what a standard diet
plus resveratrol would do.
Erich
You have forgotten the metabolic conversion factor from mice to humans,
which would almost certainly apply to supplementing resveratrol. Using
this factor (about 7.5 depending on the weight of mice used) the human
dosage would be around 220 mg daily. This is still a considerable
amount, but not too difficult to manage from currently sold
supplements.
> Wish they would have done one more step and seen what a standard diet
> plus resveratrol would do.
Yes, that appears to be the major problem with the study (as I just
commented in a message which is nearly ready for posting to the Yahoo
group MoreLife). The reason for this appears to be that Sinclair is far
more interested in fame and money making than he is in extending the
lifespan of healthy humans.
--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
Rational freedom by self-sovereignty & social contracting
Pete
You are quite correct.
Sinclair did not do that presumably because he is not really interested
in having humans take resveratrol. He is only interested in getting
sufficient interest and investment money in his work and company so
that he can produce a patentable resveratrol analog drug which his
company can then market and make enormous amounts of money from the
coercive power of governments enforcing his patent and from the
authoritarian/coercive power of establishment medicine to prescribe it
and maintain that most unpatentable medicines are useless.
Unfortunately, in the current social climate where people have no
understanding of why trying to get something without paying for what
value it has to one, is not in one's widest thinking longest range best
interest, this method of research and drug development is the only one
available to a person who wishes to do such work and gain the value
that his work and efforts are worth.
--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
Rational freedom by self-sovereignty & social contracting
>
Does anyone here happen to know how much longer
they lived?
Thanks,
Kingsley
From the NYT article:
>One person who is not following this prudent advice,
>however, is Dr. Sinclair, the chief author of the study.
> He has long been taking resveratrol, though at a dose
> of only five milligrams per kilogram. Mice given that
> amount in a second feeding trial have shown similar,
> but less pronounced, results as those on the
> 24-milligram-a-day dose, he said.
Assuming he weights about 180 lb, I calculate
he is taking about 410 mg/day.
The least expensive online source for resveratrol
that I am aware of is Beyond a Century, and my
calculation suggests that it would cost about
$1.30/day for Sinclair's dose.
Better check my math!
It appears that the NYT is also not aware of the metabolic scaling
between mice and men.
the 5 mg/kg that Sinclair is taking would be equivalent to about 37.5
mg/kg for a mouse.
> Assuming he weights about 180 lb, I calculate
> he is taking about 410 mg/day.
That appears to be correct - almost twice as much as in the latest
mouse study.
The fact that he is taking is a such a high dose also makes it doubly
reprehensible that he states that others should not supplement
resveratrol, but instead should wait for his patented drug to be
developed.
> The least expensive online source for resveratrol
> that I am aware of is Beyond a Century, and my
> calculation suggests that it would cost about
> $1.30/day for Sinclair's dose.
I used to be a customer of BAC for many years when it was run by Warren
Cochrane, but after experiences of a few years back with his son Eric
who now runs the company, some of which experiences were posted by
Kitty on sci.life-extension and are documented at the MoreLife.org
website, I do not recommend them for anything except products
formulated and produced by others.
No, because Sinclair published the study before they had all died and
AFAIK, has not yet reported the final lifespan results. However,
remember that he did not do a test of mice on a standard healthy diet
also fed resveratrol. Therefore, unless the lifespan of the "McDonald's
Diet" mice plus resveratrol exceeds that of the control normally fed
mice, the result will not be of any value for those of us who eat very
healthy diets to begin with.
> Assuming he weights about 180 lb, I calculate
> he is taking about 410 mg/day.
I thought that much resveratrol would thin your blood too much.
Bob
I have now received the full text of the nature paper courtesy of a
member of the Yahoo group MoreLife and so can report that according to
the following introductory text, my statement above may not be true
after all.
"Cohorts of
middle-aged (one-year-old) male C57BL/6NIA mice were provided
with either a standard diet (SD) or an otherwise equivalent highcalorie
diet (60% of calories from fat, HC) for the remainder of their
lives. To each of the diets, we added resveratrol at two concentrations
that provided an average of 5.260.1 and 22.460.4 mg kg21 day21,
which are feasible daily doses for humans. After 6 months of treatment,
there was a clear trend towards increased survival and insulin
sensitivity. Because the effects were more prominent in the higher
dose (22.460.4 mg kg21 day21, HCR), we initially focused our
resources on this group and present the results of those analyses
herein. Analyses of the other groups will be presented at a later
date."
Although nothing more was mentioned in the reported results about any
other cohorts of mice, the about appears to me as if the experiment
(not yet compete) is actually running 6 different cohorts of mice in
parallel:
1. SD
2. SD + 5 mg/kg resveratrol
3. SD + 22 mg/kg resveratrol
4. HC
5. HC + 5 mg/kg resveratrol
6. HC + 22 mg/kg resveratrol
The current Nature report only contains data and comparisons of groups
1. 4, and 6 (referred to in the paper as (SD, HC, and HCR
respectively).
The diet is described as:
"Briefly, one-year-old male C57BL/6NIA mice were maintained on AIN-93G
standard diet (SD), AIN-93G modified to provide 60% of calories from
fat (HC),
or HC diet with the addition of 0.04% resveratrol (HCR)."
And weight differences between HC and HCR were at most a very mild
factor:
"Mice on the HC diet steadily gained weight until ,75 weeks of age,
after which average weight slowly declined (Fig. 1a). Although mice
on the HCR diet were slightly lighter than the HC mice during the
initial months, there was no significant weight difference between the
groups from 18-24months, when most of our analyses were performed.
There was also no difference in body temperature (Table 1),
food consumption (Supplementary Fig. 1a, b), total faecal output or
lipid content (Supplementary Fig. 1c, d), or post-mortem body fat
distribution (Supplementary Fig. 2)."
I do not have the supplementary information, but here is the whole of
Table 1 edited and formatted a little:
Table 1 | Effects of a high-fat diet and resveratrol on various
biomarkers in plasma
Parameter.............................SD...................HC.......................HCR...........Fed
or Fasted
Free fatty acids (mequiv.)......0.27 (0.04) .....0.59 (0.06)
.........0.53 (0.03) Fed
..............................................0.83 (0.10) .....0.45
(0.20)......... 0.54 (0.05) Fasted
Triglycerides (mg/d).............. 76.6 (6.8)....... 81.4
(6.6)............ 88.2 (10.8) Fasted
Cholesterol (mg/dl)................135 (7)............183
(20)............... 204 (16)... Fasted
Insulin (ng/ml)........................1.77 (0.64) ......9.21
(1.95).......... 2.46 (0.47) Fed
.............................................0.73 (0.14)....... 2.70
(0.36).......... 1.06 (0.30) Fasted
Glucose (mg/dl).................. 129.0 (5.4) ......118.3
(4.7)........... 114.8 (6.3) Fed
..............................................94.5 (3.3)....... 125.3
(11.6) .........85.6 (10.3) Fasted
IGF-I (ng/ml)......................... 346 (40) ..........534
(12).............. 482 (21)... Fed
...............................................625 (33).......... 999
(102)............ 929 (81)... Fasted
IGFBP-1 (AU)........................ 1.0 (0.3).......... 1.7
(0.3)............... 1.7 (1.0) Fed
...............................................1.0 (0.2).......... 0.5
(0.3)............... 0.3 (0.1){ Fasted
IGFBP-2 (AU)........................ 1.0 (0.2)............0.7
(0.04)............ 0.9 (0.1) Fasted
Leptin (ng/ml)........................ 2.0 (1.1).......... 21.6
(7.2)........... 11.6 (6.5) Fasted
Adiponectin (mg/ml).............. 12.1 (1.6)......... 9.5
(0.5)............. 9.0 (0.8) Fed
Amylase (U/l) .......................2,060 (150)..... 2,960
(320)........ 2,190 (230) Fasted
Ala aminotransferase (U/l).... 347 (119)......... 390 (61).............
446 (88) Fasted
Asp aminotransferase (U/l).... 448 (85).......... 425 (90).............
512 (46) Fasted
Creatine phosphokinase (U/l) 4,260 (1820). 2,010 (810)......... 2,520
(680) Fasted
Lactate dehydrogenase (U/l) 1,530 (240)... 1,610 (170).......... 2,020
(180) Fasted
Alkaline phosphatase (U/l)...... 43.8 (3.4)........44.6
(6.0)............ 34.2 (1.4) Fasted
Bilirubin (mg/dl)....................... 0.16 (0.02)..... 0.10
(0.03)......... 0.16 (0.02) Fasted
Albumin (g/dl)...........................2.78 (0.16)..... 2.88
(0.19)......... 2.66 (0.14) Fasted
Creatinine (mg/dl)................... 0.54 (0.02)...... 0.48
(0.04)......... 0.46 (0.04) Fasted
Cyclo-oxygenase (liver, AU/mg) 1.00 (0.14).... 0.80 (0.11).........
0.83 (0.11) Fed
Citrate synthase (liver, AU/mg) 141 (14) ..........128
(21).............. 138 (11)....Fed
Body temperature (uC)............34.71 (0.14)..... 35.52 (0.17)......
35.57 (0.15).. Fed
Once again however, the text of the paper suggests that Sinclair et al
are not after life extension per se but instead only in health
extension and reduced mortality for those who are either too stupid or
too lazy to eat a healthy diet.
"The number of overweight individuals worldwide has reached 2.1
billion, leading to an explosion of obesity-related health problems
associated with increased morbidity and mortality1,2. Although the
association of obesity with increased risk of cardiovascular disease
and diabetes is well known, it is often under-appreciated that the
risks
of other age-related diseases, such as cancer and inflammatory
disorders,
are also increased."
"On the basis of the unprecedented ability of resveratrol to improve
health and extend lifespan in simple organisms, we have asked
whether it has similar effects in mice. We hypothesized that
resveratrol
might shift the physiology of mice on a high-calorie diet towards
that of mice on a standard diet and provide the associated health
benefits without the mice having to reduce calorie intake."
"Discussion
The ability of resveratrol to prevent the deleterious effects of excess
caloric intake and modulate known longevity pathways suggests that
resveratrol and molecules with similar properties might be valuable
tools in the search for key regulators of energy balance, health and
longevity. As a case in point, the most highly upregulated gene in the
HC group and second most highly downregulated gene in the HCR
group was Cidea, which regulates energy balance in brown fat and
provides resistance to obesity and diabetes when knocked out43.
Taken together, the findings in this study show that resveratrol
shifts the physiology of mice consuming excess calories towards that
of mice on a standard diet, modulates known longevity pathways,
and improves health, as indicated by a variety of measures including
survival, motor function, insulin sensitivity, organ pathology, PGC-
1a activity, and mitochondrial number. Notably, all these changes
occurred without a significant reduction in body weight. Whether
these effects are due to resveratrol working primarily through SIRT1,
which is the case for simpler metazoans, or through a combination
of interactions, as predicted by the xenohormesis hypothesis6,44,
remains to be determined. In either case, this study shows that an
orally available small molecule at doses achievable in humans can
safely reduce many of the negative consequences of excess caloric
intake, with an overall improvement in health and survival."
Paul,
You're correct; the supplementary information refers to the 3 groups
that you mentioned
I was curious about the source of the resveratrol given to the mice, as
it might be also the source used by Longevinex (?), whether it was
given in the food or as gavage, stability etc. Here is the part of the
Supplementary Information linked to the online version of the paper
related to your question and the resveratrol source.
Arbor
http://www.nature.com/nature/journal/vaop/ncurrent/extref/nature05354-s1.doc
Supplemental Methods
Animals and diets.
Male C57BL/6NIA mice at 11 months of age were purchased from the
National Institute on Ageing Aged Rodent Colony. The mice were
maintained on a standard purified mouse diet (AIN-93G) for one month
prior to the start of the experiment. The groups presented in this
study were fed the standard AIN-93G diet or AIN-93G plus 0.04%
resveratrol ad libitum for an additional six weeks while high-calorie
diets were prepared. Animals on AIN-93G either continued on the
standard diet (SD), or were switched to high-calorie AIN-93G (modified
by the addition of hydrogenated coconut oil to provide 60% of calories
from fat, HC), and the group receiving AIN-93G plus 0.04% resveratrol,
was switched to the high-calorie diet plus 0.04% resveratrol (HCR).
Coconut oil was chosen to avoid high levels of dietary cholesterol
associated with animal fats such as lard and because it is solid at
room temperature so that a large quantity can be added to the food
pellets without much change in the consistency. This helps prevent
overgrowth of the teeth, which can happen with high fat paste-like
diets over an extended period. For the PGC-1a experiments, mice at a
similar age were fed the HC diet or HC plus resveratrol at a
concentration that delivered ~ 186 mg/kg/day for six weeks.
Resveratrol (> 98%) was purchased from Orchid Pharmaceuticals
(Aurangabad, India) and mixed to homogeneity during manufacturing of
the diets (Dyets Inc., Bethlehem, PA). Chow was never permitted to
exceed 50°C and was kept away from light whenever possible to ensure
the stability of resveratrol (the light/dark cycle in the mouse
facility was not altered). Stock resveratrol and all chow were stored
in the dark at -80°C or 4°C respectively, and food was provided in
cages for no more than 1 week. Every 3-4 months the stability of
resveratrol in the stored food was assessed using either HPLC and/or
the Fluor-de-Lys SIRT1 assay (Biomol, Plymouth Meeting, PA)."
The mice were maintained on a 12 hour light/dark cycle and maintained
between 68 -72°F according to animal protocols and NIH guidelines.
Food intake and body weight were measured on a weekly basis for the
duration of the study. Survival curves were plotted using the
Kaplan-Meier method, which includes all available animals at each time
point. Statistical analyses were performed using JMP IN (SAS, Cary,
NC). The criteria for euthanasia were based on an independent
assessment by a veterinarian according to AAALAC guidelines and only
cases where the condition of the animal was considered incompatible
with continued survival are represented in the curves. The SD group
initially contained 60 mice. Of the 34 mice that have died in this
group, 13 were sacrificed for experiments and censored, 14 were found
dead and counted, 6 were euthanized and counted, and 1 was euthanized
for a tooth root abscess and censored. The HC group started with 55
mice. Of the 40 mice that have died, 13 were sacrificed for
experiments and censored, 18 were found dead and counted, 8 were
euthanized and counted, and 1 was euthanized for ulcerative dermatitis
and censored. The HCR group began with 55 mice. Of the 36 mice that
have died in this group, 15 were experimental and censored, 3 deaths
were accidental (cage flooding) and censored, 7 were found dead and
counted, 8 were euthanized and counted, and 3 were euthanized and
censored (2 for ulcerative dermatitis and 1 for an inner ear infection).
Paul,
<<<snip>>>
Well, their treatment of resveratrol is even more careful than Longivenex's.
Longivenex doesn't store nor ship its product in dry ice packs to maintain
their product at -80 to +4 C. Either the researchers were overly and
unjustifiably cautious with it or it really is that unstable. What we've
got is an interesting study that would be very costly for the average LEer
to test the benefits of in his own LE program considering the 400-500mg. per
day dosage needed. LEF is well respected for their procurement and
processing of quality products most of the time. Their resveratrol comes in
20 mg. capsules 60 for USD 22.13. Assuming that resveratrol isn't as
unstable as the researchers implied and LEF's product would be good, we're
looking at spending USD 7.38 to USD 9.22 a day.
> Well, their treatment of resveratrol is even more careful than Longivenex's.
> Longivenex doesn't store nor ship its product in dry ice packs to maintain
> their product at -80 to +4 C. Either the researchers were overly and
> unjustifiably cautious with it or it really is that unstable.
(I have never purchased resveratrol and have no connection to the
company.) Longevinex site claims the following below. In the study
however, resveratrol was incorporated into the pellets and thus
required the extra measures mentioned above.
(from: http://www.longevinex.com/article.asp?story=QA)
"Question? How can consumers be assured the resveratrol in
Longevinex® remains stable during encapsulation?
Answer: Liquid Longevinex® is produced in an oxygen-free, nitrogen
environment and then sealed in an airtight capsule (Licaps) with an
internal nitrogen bubble. Other red wine products do not go to this
extent to ensure stability and preservation of resveratrol. An
independent assay conducted by Plant Bioactives Research Institute
confirms that "red wine polyphenols" have been preserved in the
finished Longevinex® product. Shelf-life studies conducted by an
independent laboratory confirm that Longevinex capsules exhibit the
ability to up-regulate Sirtuin 1 gene enzymes 10 months after date of
manufacture (at the date of this writing, Longevinex has only been
marketed for about 12 months)."
Googling the keywords Resveratrol +"Sigma Aldrich" brought
references to several other research studies that used Sigma
Aldrich's 3,4',5-Trihydroxystilbene [see 1 below]. In one of
these studies [2] it was "suspended in 0.9% saline solution and
administered by gavage (p.o.)".
My point is that apparently there are trans-resveratrol molecules that
are stable enough to be given in water (This is an assumption only
since the full study [2] isn't available to me). [3] links to 5 such
molecules. Interestingly, these other resveratrol rodent studies
didn't receive any media splash when published. The association
between resveratrol and Sinclair's name is already set in stone so
that is part of it, however, it might be due to the fact that he uses
stilbene molecule a.k.a wine extract, and others used the above
derivative/s[3]. That certainly makes consideration of which
supplement to choose more difficult given that such information is not
available.
Arbor
1. http://tinyurl.com/y3sbdo
2. Martin AR, Villegas I, Sanchez-Hidalgo M, de la Lastra CA.
The effects of resveratrol, a phytoalexin derived from red wines, on
chronic inflammation induced in an experimentally induced colitis
model.
Br J Pharmacol. 2006 Apr;147(8):873-85.
PMID: 16474422]
3. http://molpharm.aspetjournals.org/cgi/content/full/67/5/1451/FIG1
In an email exchange with Dayna Dye that happened over the last few minutes,
Danya, 2nd in command (it appears) after Bill Faloon) at LEF, said that
periodic assays are made of their resveratrol offering which show that it
contains what the label claims. Now to investigate, when I have time, if
there's is from grapes. Many products aren't and may fit the results and
conclusions of your investigations. As I have COTS bottles of Huperzine A
(bought from iHerb, producted by Life Enhancement) that were sampled,
assayed and showed no evidence of what is on the label, one must becareful
when going for the cheap. If an offering sounds too good to be true, it
most probably isn't.