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Resveratrol doesn't Improve Survival in mice


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#1 Matt

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Posted 03 July 2008 - 06:07 PM


Resveratrol is a fairly hot topic these days and many expected we'd see good
life extending effects of mice on a normal diet when being given high doses
of Resveratrol. However it appears this is not the case...but overall health
is generally improved. I haven't got the paper so don't know the details,
the dose or anything.

I wonder if Resveratrol alters core body temperature in rodents? Because
isn't this a quite a big factor in cancer prevention in mice?

And another point, maybe we are still quite a way off from a 'true CR
mimmetic'

Ohwell! I don't take the stuff anyway


Eurekalert.org

Long-term study of middle-aged mice shows
Resveratrol improves health and mimics some benefits of dietary restriction

CAMBRIDGE, Mass., July 3, 2008 -- Sirtris, a GlaxoSmithKline company focused on discovering and developing small molecule drugs to treat diseases of aging such as Type 2 Diabetes, is included among a research team that reported in today's online edition of Cell Metabolism that mice treated at middle-age to the end-of-life with resveratrol showed an overall health improvement, including improved bone health, a reduction in cataracts and cardiovascular dysfunction, and improved balance and motor coordination.

"In this study, we wanted to determine whether or not resveratrol, which imparts many of the same health benefits as caloric restriction in mice, does so by inducing a physiology similar to dietary restriction," says study co-author David Sinclair, Ph.D., a Sirtris co-founder and Harvard Medical School Associate Professor of Pathology. "The data show that resveratrol does induce many similar pathways," says Sinclair, who is co-chair of Sirtris' Scientific Advisory Board. The study was co-led by Rafael de Cabo, Ph.D. at the National Institute on Aging and David Sinclair.

The research team began testing of mice at one year, the mouse equivalent of middle-age, as that is when a small molecule drug mimicking dietary restriction might be given to humans.

The mice were placed on different diets: a standard diet (SD); every-other-day feeding (EOD); and a high-calorie diet (HC). Mice in each dietary regime were divided into treated and untreated subgroups, with some not receiving resveratrol and others receiving different dosage levels of resveratrol.

The study showed that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by dietary restriction, a diet known to slow aging and extend lifespan in rodents and dogs. The study also found a significant increase in lifespan in both the resveratrol treated group on a high-calorie diet and the resveratrol treated group on a calorie restriction diet, but the treatments did not extend lifespan of mice on a standard diet when started at one year of age. This study was funded by the National Institute on Aging.

In developed countries, much of the population now survives to the point where chronic age-associated diseases such as cardiovascular disease, cancer, diabetes, osteoporosis, stroke, and kidney disease are the major determinants of illness and death. Studies in numerous species have demonstrated that a reduction in calorie intake of 30 to 50 percent below normal levels can delay the onset of age-related diseases.

"A small molecule SIRT1 activator that safely mimics the ability of dietary restriction to delay age-related diseases would be of great benefit," says study team member Peter Elliott, Ph.D., Sirtris Senior Vice President of Development.

The research team found that among the notable changes were gene sets representing an increase in mitochondrial gene expression in liver and muscle and a decrease in apoptosis, or cell death, across four of the tissues. The team also found that many genetic pathways were similarly altered by EOD feeding or resveratrol treatment: 82 percent (liver); 76 percent (muscle); 96 percent (fat); and 64 percent (heart). This finding supports the idea that resveratrol can mimic many effects of dietary restriction in vivo.

Specifically, researchers found that resveratrol decreased functional decline often seen in the frail and elderly, such as osteoporosis, cataracts, and motor coordination. For example, in general, femurs from the resveratrol-treated mice trended toward better bone properties, suggested that resveratrol could reduce age-induced bone loss in normal mice. Cataract formation was also lessened by resveratrol in a dose-dependent manner. The mice on a SD treated with resveratrol also showed a significant improvement in balance and motor coordination. The resveratrol treated mice also had improved markers for cardiovascular health. Their arteries were more youthful, and they had reduced aortic stiffness. They also had fewer free radicals and DNA damage.

"Frailty in humans is an important health concern," says Christoph Westphal, M.D., Ph.D., Chief Executive Officer, Sirtris, a GSK Company. "This study informs us how frailty in mice can be delayed, and this knowledge could help us translate preclinical benefits to humans. We are in clinical trials with SRT501, our proprietary formulation of resveratrol that has shown efficacy signs in humans in Phase 1b testing, and we are also testing a novel SIRT1 activator in a human clinical trial."

Edited by Matt, 03 July 2008 - 06:41 PM.


#2 Hedgehog

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Posted 03 July 2008 - 06:25 PM

More...

major finding of the study reported today is that resveratrol prevented age-related and obesity-related cardiovascular functional decline in the mice as determined by several parameters. Total cholesterol was significantly reduced in 22-month-old non-obese mice after 10 months of resveratrol treatment, although triglyceride levels had only a slight, non-significant trend toward a decrease. Further, the aortas of 18-month-old obese and non-obese mice treated with resveratrol functioned significantly better than untreated mice. Resveratrol also moderated inflammation in the heart. In addition to cardiovascular function, the scientists found resveratrol to have a variety of positive effects on other age-related problems in mice:

  • Treated mice tended to have better bone health, as measured by thickness, volume, mineral content and density, and bending stiffness compared to the non-treated control group.
  • At 30 months of age, resveratrol-treated mice were found to have reduced cataract formation, a condition found to increase with age in control-group mice.
  • Resveratrol enhanced balance and motor coordination in aged animals. Scientists found significant improvement in performance at 21 and 24 months versus 15 months in the resveratrol-treated mice but not in the untreated mice.
  • Resveratrol partially mimicked the effects of dietary restriction on the gene expression profiles of liver, skeletal muscle and adipose (fatty) tissue in mice.
Along with determining the effect of resveratrol on the health of mice, scientists also studied the effect of resveratrol on longevity.

"We found that while quality of life improved with resveratrol, the compound did not significantly affect overall survival or maximum lifespan for mice on a standard diet, compared to mice on the same diet without resveratrol," said de Cabo.

Resveratrol did not have a significant effect on lifespan in animals fed standard chow, suggesting that the intervention did not affect all aspects of the basic aging process. 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. However, for mice on a high-calorie diet, mean and maximum lifespan increased for mice on resveratrol when compared with the control mice. Researchers found that resveratrol's effects on longevity could be completely uncoupled from changes in body weight, meaning that mice on a high-calorie diet with resveratrol did not necessarily lose weight but did experience a longer (and healthier) life than mice on the same high-calorie diet not taking resveratrol. They speculate that improved cardiovascular health and reduced fatty changes in the liver may have contributed to the increased lifespan of resveratrol-treated mice.

Researchers still have much to learn before resveratrol can be recommended for human use. Basic questions of safety and biological effect in humans remain to be studied experimentally.

"We are learning a great deal about how resveratrol affects the health and survival of mammals," said Sinclair. "Continued study of calorie restriction mimetics such as resveratrol may eventually point the way to new medicines to treat diseases of aging."



http://www.nia.nih.g...resveratrol.htm





If people want the article to view and delete PM me....


actually don't PM me its free

http://www.cellmetabolism.org/
http://www.cellmetab...550413108001824
http://download.cell...13108001824.pdf

another interesting article

The Ongoing Saga of Sirtuins and Aging

Matt Kaeberlein1,

1Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA




So what's the "take-home message" from all this? Is more SirT1 good, or is less SirT1 good? The answer, as is often the case in biology, is that there's no simple answer. Activating SirT1 is probably a good thing in some cells under some conditions and is probably a bad thing in other cells under other conditions. SirT1 activators may be good for diabetes but may cause cancer due to p53 inhibition, SirT1 inhibitors may protect against cancer but cause metabolic disease, and there is evidence supporting the idea that both activators and inhibitors of SirT1 can confer protection against neurodegeneration in different contexts. 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 SirT1—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.


Edited by Hedgehog, 03 July 2008 - 06:36 PM.


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#3 forever freedom

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Posted 03 July 2008 - 06:58 PM

That's sad. So the way to extend maximum lifespan is still with CR only. Someone has got to change that, i don't want to starve!

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#4 Matt

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Posted 03 July 2008 - 07:14 PM

For those that already look after our health taking resveratrol may to little or nothing to increase life span further. However for the general population who are mostly overweight and obese, it could possibly extend their lifespan by a few years, as it did with the over fed mice. Also lets not forget those that have some predisposition to diseases or already have diseases, it could extend their lifespan. So not all bad, just not very good either!

Edited by Matt, 03 July 2008 - 07:15 PM.


#5 theone

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Posted 03 July 2008 - 07:16 PM

That's sad. So the way to extend maximum lifespan is still with CR only. Someone has got to change that, i don't want to starve!



What Resveratrol dosage did these mice get? If it's a lower does nothing surprising here. Have these numbers been published?

Edited by theone, 03 July 2008 - 07:18 PM.


#6 Mind

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Posted 03 July 2008 - 07:36 PM

So the way to extend maximum lifespan is still with CR only.


This is true in most mammals but has not been proven in humans. Even if CR does not extend maximum lifespan but only extends healthspan, then it is probably worth it to those who don't mind starving themselves. This study would also seem to indicate an increase in healthspan from taking resveratrol - which is a good thing.

#7 Hedgehog

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Posted 03 July 2008 - 08:22 PM

That's sad. So the way to extend maximum lifespan is still with CR only. Someone has got to change that, i don't want to starve!



What Resveratrol dosage did these mice get? If it's a lower does nothing surprising here. Have these numbers been published?



Sorry I guess that link doens't work my PM still applys if you want it

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


Survival
We have reported that resveratrol treatment increased the survival
of mice fed a HC diet to 114 weeks of age (Baur et al.,
2006). Here, we provide the complete Kaplan-Meier survival
analysis (Figures 4B–4D) and maximum life span (final 20% surviving)
for the HC groups, as well as mice fed a standard diet or
placed on an EOD feeding regimen (Figure 4E). In the context of
the HC diet, resveratrol increased remaining life span of 1-yearold
mice by an average of 26% for the HCLR group (p = 0.005)
and 25% for HCR (p = 0.001) to the point where survival was
not significantly different from that of nonobese SD controls. In
the lower-dose (HCLR) group, maximum life span was also increased,
while this effect did not reach significance for the higher
dose (HCR) (Figure 4E). 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).
Interestingly, the increases in longevity could be completely
uncoupled from changes in body weight. While the HCR group
had a very slight decrease in body weight that was not statistically
significant, the HCLR group displayed a significant increase
in body weight, despite consuming a similar amount of food (Figures
4A, S4, and S5). Thus, the beneficial effects of resveratrol on
health and life span are not dependent on weight loss.
In the context of the standard diet, resveratrol did not increase
overall survival or maximum life span (Figures 4B and 4E). Importantly,
the SD control group had a life span similar to that of
a much larger cohort of C57BL/6NIA mice (Turturro et al.,
1999). EOD feeding produced a trend toward increased longevity
compared to the SD control group, but the effect did not
reach statistical significance. 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). Notably, EOD feeding in combination with the lower
dose of resveratrol did extend both mean and maximal life
span by 15% compared to SD controls (Figures 4C and 4E).
We have also tested the effect of a higher dose of resveratrol beginning
at 12 months of age (SDHR) on life span, and again found
that longevity was not significantly affected. (Figure 4F).

Edited by Hedgehog, 03 July 2008 - 08:32 PM.


#8 steelheader

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Posted 03 July 2008 - 08:51 PM

"Resveratrol enhanced balance and motor coordination in aged animals. "

I experienced this effect strongly, as reported in an earlier post.

For you non yet aged animals this may not seem significant. But for aged animals who wish to continue to participate
in activities requiring good balance and motor coordination, the payoff is huge.

#9 sUper GeNius

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Posted 03 July 2008 - 09:40 PM

"Notably, EOD feeding in combination with the lower
dose of resveratrol did extend both mean and maximal life
span by 15% compared to SD controls (Figures 4C and 4E)."

Hey, 15% increase in max and mean is nothing to sneeze at. I'm 24 hr fasting, but the study's "low dose" of 100 mg/kg is a whole not more than I'm taking.

Overall though, I think this study largely bodes well for us. Also, remember this is only one data point. Several studies on worms showed max-life extension, yet there was one posted here that showed none. We need more mice studies.

Edited by FuLL meMbeR, 03 July 2008 - 09:40 PM.


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#10 niner

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Posted 03 July 2008 - 09:55 PM

In the context of the standard diet, resveratrol did not increase
overall survival or maximum life span (Figures 4B and 4E). Importantly,
the SD control group had a life span similar to that of
a much larger cohort of C57BL/6NIA mice (Turturro et al.,
1999). EOD feeding produced a trend toward increased longevity
compared to the SD control group, but the effect did not
reach statistical significance. 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). Notably, EOD feeding in combination with the lower
dose of resveratrol did extend both mean and maximal life
span by 15% compared to SD controls
(Figures 4C and 4E).
We have also tested the effect of a higher dose of resveratrol beginning
at 12 months of age (SDHR) on life span, and again found
that longevity was not significantly affected. (Figure 4F).

This is pretty interesting. These mice don't live longer with CR! Doesn't that kind of blow the whole comparison? Also, getting a 15% increase in mean and maximal lifespan when combined with EOD feeding is worth considering. There is something going on here that is important. I do not believe this is the death knell for resveratrol by any stretch of the imagination.

#11 sUper GeNius

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Posted 03 July 2008 - 10:03 PM

In the context of the standard diet, resveratrol did not increase
overall survival or maximum life span (Figures 4B and 4E). Importantly,
the SD control group had a life span similar to that of
a much larger cohort of C57BL/6NIA mice (Turturro et al.,
1999). EOD feeding produced a trend toward increased longevity
compared to the SD control group, but the effect did not
reach statistical significance. 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). Notably, EOD feeding in combination with the lower
dose of resveratrol did extend both mean and maximal life
span by 15% compared to SD controls
(Figures 4C and 4E).
We have also tested the effect of a higher dose of resveratrol beginning
at 12 months of age (SDHR) on life span, and again found
that longevity was not significantly affected. (Figure 4F).

This is pretty interesting. These mice don't live longer with CR! Doesn't that kind of blow the whole comparison? Also, getting a 15% increase in mean and maximal lifespan when combined with EOD feeding is worth considering. There is something going on here that is important. I do not believe this is the death knell for resveratrol by any stretch of the imagination.


Isn't the author saying that that data, in older mice, mirrors early data published by Walford?

#12 edbear

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Posted 03 July 2008 - 11:23 PM

In a small pilot study using 7.5 times our highest dose (18,000 mg/kg resveratrol in the food), five out of six mice died within 3–4 months, consistent with an earlier study of extremely high doses in rats (Crowell et al., 2004 J.A. Crowell, P.J. Korytko, R.L. Morrissey, T.D. Booth and B.S. Levine, Resveratrol-associated renal toxicity, Toxicol. Sci. 82 (2004), pp. 614–619. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (28)Crowell et al., 2004).


This combined with the unimpressive results of resv on the SD mice argues against arbitrarily giving yourself crazy high doses (though that level is probably beyond what anyone would actually try, I hope).

I like the sound of EOD - it seems slightly less arduous for those of us with poor overall self-control.

#13 DaffyDuck

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Posted 03 July 2008 - 11:48 PM

In a small pilot study using 7.5 times our highest dose (18,000 mg/kg resveratrol in the food), five out of six mice died within 3–4 months, consistent with an earlier study of extremely high doses in rats (Crowell et al., 2004 J.A. Crowell, P.J. Korytko, R.L. Morrissey, T.D. Booth and B.S. Levine, Resveratrol-associated renal toxicity, Toxicol. Sci. 82 (2004), pp. 614–619. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (28)Crowell et al., 2004).


This combined with the unimpressive results of resv on the SD mice argues against arbitrarily giving yourself crazy high doses (though that level is probably beyond what anyone would actually try, I hope).

I like the sound of EOD - it seems slightly less arduous for those of us with poor overall self-control.


I believe EOD (every other day) refers to how often the mice ate food, not resveratrol.

#14 sUper GeNius

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Posted 04 July 2008 - 12:33 AM

In a small pilot study using 7.5 times our highest dose (18,000 mg/kg resveratrol in the food), five out of six mice died within 3–4 months, consistent with an earlier study of extremely high doses in rats (Crowell et al., 2004 J.A. Crowell, P.J. Korytko, R.L. Morrissey, T.D. Booth and B.S. Levine, Resveratrol-associated renal toxicity, Toxicol. Sci. 82 (2004), pp. 614–619. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (28)Crowell et al., 2004).


This combined with the unimpressive results of resv on the SD mice argues against arbitrarily giving yourself crazy high doses (though that level is probably beyond what anyone would actually try, I hope).

I like the sound of EOD - it seems slightly less arduous for those of us with poor overall self-control.


I believe EOD (every other day) refers to how often the mice ate food, not resveratrol.


I think that's what he meant, hence the 'poor self control" comment.

An aside, Sardi just sent out an email summarizing the study, and he said the doses used were for mg/kg of *food,* not body weight. If this is correct, then those doses are achievable in humans.

#15 Hedgehog

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Posted 04 July 2008 - 12:59 AM

An aside, Sardi just sent out an email summarizing the study, and he said the doses used were for mg/kg of *food,* not body weight. If this is correct, then those doses are achievable in humans.



Yes that is what I posted above it was mg/kg of food.... Here is the details of the diet

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.

#16 niner

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Posted 04 July 2008 - 04:27 AM

In the context of the standard diet, resveratrol did not increase
overall survival or maximum life span (Figures 4B and 4E). Importantly,
the SD control group had a life span similar to that of
a much larger cohort of C57BL/6NIA mice (Turturro et al.,
1999). EOD feeding produced a trend toward increased longevity
compared to the SD control group, but the effect did not
reach statistical significance. 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). Notably, EOD feeding in combination with the lower
dose of resveratrol did extend both mean and maximal life
span by 15% compared to SD controls
(Figures 4C and 4E).
We have also tested the effect of a higher dose of resveratrol beginning
at 12 months of age (SDHR) on life span, and again found
that longevity was not significantly affected. (Figure 4F).

This is pretty interesting. These mice don't live longer with CR! Doesn't that kind of blow the whole comparison? Also, getting a 15% increase in mean and maximal lifespan when combined with EOD feeding is worth considering. There is something going on here that is important. I do not believe this is the death knell for resveratrol by any stretch of the imagination.

Isn't the author saying that that data, in older mice, mirrors early data published by Walford?

Well, they're just saying that this kind of mouse (C57BL/6) doesn't respond to EOD feeding, just like it doesn't respond to regular CR. So I think it's really interesting that resveratrol is doing something that completes the dietary restriction puzzle for this mouse species, such that when the mouse is on EOD feeding and it takes a low dose (like 500mg in a human) of resveratrol, it lives 15% longer. This is a good argument for people doing CR to take resveratrol, too, in case humans turn out to be like C57BL/6 mice.

#17 Matt

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Posted 04 July 2008 - 10:18 AM

I'm quite happy that I started reducing calories when I was 18 (by following a healthier diet), followed by more serious CR when I was 20. Hopefully this should have much bigger benefits.


Check out the B6 survival curve here : http://iangoddard.net/cr.htm The graph is extrapolated into human equivalent years every 10 or so seconds, so keep an eye on it.

Adult-onset CR: Only adult-onset-CR data are relevant for human consideration, and life extension is less when CR is initiated in midlife, approaching nil when initiated in late life. [10] The next graphs show the lifespans of two long-lived mouse types gradually subjected to 44% (B10) and 27% (B6) CR starting at 12.5 months of age versus controls. B10 mice started CR at a human-age equivalence of 30, while B6 mice started CR at a human-age equivalence of 40.

Edited by Matt, 04 July 2008 - 10:21 AM.


#18 maxwatt

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Posted 04 July 2008 - 11:43 AM

In the context of the standard diet, resveratrol did not increase
overall survival or maximum life span (Figures 4B and 4E). Importantly,
the SD control group had a life span similar to that of
a much larger cohort of C57BL/6NIA mice (Turturro et al.,
1999). EOD feeding produced a trend toward increased longevity
compared to the SD control group, but the effect did not
reach statistical significance. 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). Notably, EOD feeding in combination with the lower
dose of resveratrol did extend both mean and maximal life
span by 15% compared to SD controls
(Figures 4C and 4E).
We have also tested the effect of a higher dose of resveratrol beginning
at 12 months of age (SDHR) on life span, and again found
that longevity was not significantly affected. (Figure 4F).

This is pretty interesting. These mice don't live longer with CR! Doesn't that kind of blow the whole comparison? Also, getting a 15% increase in mean and maximal lifespan when combined with EOD feeding is worth considering. There is something going on here that is important. I do not believe this is the death knell for resveratrol by any stretch of the imagination.

Isn't the author saying that that data, in older mice, mirrors early data published by Walford?

Well, they're just saying that this kind of mouse (C57BL/6) doesn't respond to EOD feeding, just like it doesn't respond to regular CR. So I think it's really interesting that resveratrol is doing something that completes the dietary restriction puzzle for this mouse species, such that when the mouse is on EOD feeding and it takes a low dose (like 500mg in a human) of resveratrol, it lives 15% longer. This is a good argument for people doing CR to take resveratrol, too, in case humans turn out to be like C57BL/6 mice.


It seems like a poor choice, that the strain of mouse they chose for these studies does not show increased life-span with CR or EOD feeding. It tells us little directly about whether resveratrol will extend life span with a normal diet. That the cobination of EOD feeding and resveratrol did increase max and avg lifespan is therefore somewhat startling.

One statement in the paper caught my eye: "One clear difference between EOD and resveratrol was that EOD strongly upregulated glutathione metabolism, whereas resveratrol had no effect."

Some things that are supposed to increase one's glutathione levels are 1) consumption of certain foods (broccoli, asparagus, garlic, et al.) 2) N-acetyl cystein 3) alpha-lipoic acid 4) Curcumin 5) Silymarin.

Curiously, of these, Silymarin has been shown to activate Sirt1.

Another gene panel study showed CR regulated IGF-1 where resveratrol did not. Some things that regulate Sirt1 are EGCG in green tea, and folate.

So if one is supplementing resveratrol, the addition of EGCG (in moderation), curcumin and silymarin could be helpful.

#19 Mind

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Posted 04 July 2008 - 04:58 PM

I do not believe this is the death knell for resveratrol by any stretch of the imagination.


The study indicates health benefits (in mice) from resv. I can't see why this should be viewed in a negative light.

#20 DukeNukem

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Posted 04 July 2008 - 05:16 PM

>>> An aside, Sardi just sent out an email summarizing the study...

Are you on a special mailing list with him?

#21 sUper GeNius

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Posted 04 July 2008 - 05:44 PM

>>> An aside, Sardi just sent out an email summarizing the study...

Are you on a special mailing list with him?


I guess I am on a list. He periodically sends me emails. You think maybe the emails he's sending to his mother-in-law are being misrouted by his ISP?? Hmmm. That would explain a few things, including the salutation.


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#22 Ethan

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Posted 04 July 2008 - 10:00 PM

This is vastly disappointing. I presume these results will translate into any modifications made by Sinclair's group to the compound. I remember hearing about resveratrol at a conference years ago where all the speakers assumed that these compounds would give us years of extra life. Indeed, resveratrol sales are probably in the tens of millions by now, purchased by people who wanted to get a head start on life exstention, not improve bone density and cardiovascular health. Oh well.

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#23 Mind

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Posted 04 July 2008 - 10:10 PM

This is vastly disappointing.


I suppose it is disappointing to some, however, there is currently no proven way to increase maximum lifespan in humans - only ways to increase healthspan - and if you want to stay alive long enough to partake in real rejuvenation therapies then CR, resveratrol, certain diets, exercise, etc. all seem to help.

#24 AgeVivo

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Posted 04 July 2008 - 10:15 PM

That's sad. So the way to extend maximum lifespan is still with CR only. Someone has got to change that, i don't want to starve!


I believe that diets that are low methionine works too: eat protein sources that are low in diet, no need to fast (although I guess fasting would further extend lifespan). One low-methionine diet was tested in several strains of rats that extended lifespans by 40% or more. Low methionine diet is already used in humans in case of some genetic diseases and recently against various cancers (methionine is required for any synthesis of proteins and particularly cell division).

In practice it is difficult to do it with 'normal' food because animal proteins contain much methionine and vegetable/beans/soja do not contain much proteins. So patients partially reduce meat/fish intake and buy meth-free protein powders, they do it in the long term and it is reported to be quite safe actually

I'm reading stuff on it. Help would be great. I started a post/project about it on MFoundation's website: http://mfoundation.o...hread.php?t=745 .

Best.

#25 maxwatt

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Posted 05 July 2008 - 03:57 AM

This is vastly disappointing. I presume these results will translate into any modifications made by Sinclair's group to the compound. I remember hearing about resveratrol at a conference years ago where all the speakers assumed that these compounds would give us years of extra life. Indeed, resveratrol sales are probably in the tens of millions by now, purchased by people who wanted to get a head start on life exstention, not improve bone density and cardiovascular health. Oh well.


You have missed the following points:

- the mice on restricted calorie diet (EOD -every other day- feeding) also lived no longer than controls; this species' life is not extended by CR.
- resveratrol plus EOD CR did extend the lifespan by 15% over EOD or CR alone, or ad libium.

You cannot translate results regarding resveratrol or CR alone to this strain of mice, nor extrapolate to humans. But the two together did extend lifespan, somehow overcoming the genetic defect in this strain that prevents CR from working. And there was an increase in health.

#26 VP.

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Posted 05 July 2008 - 04:01 AM

This is vastly disappointing. I presume these results will translate into any modifications made by Sinclair's group to the compound. I remember hearing about resveratrol at a conference years ago where all the speakers assumed that these compounds would give us years of extra life. Indeed, resveratrol sales are probably in the tens of millions by now, purchased by people who wanted to get a head start on life exstention, not improve bone density and cardiovascular health. Oh well.


As pointed out earlier these mice are not optimised for mimicking caloric restriction so I don't believe this study has in any way ruled out an increase in human lifespan. Also mice don't die of the same diseases that humans do. 35% of human deaths are from Heart disease and stroke, something not usually seen in mice. Sinclair makes the same conclusion:

“I was most sur­prised by how broad the ef­fects were,” added Sin­clair. “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.


Edited by velopismo, 05 July 2008 - 04:07 AM.


#27 Ethan

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Posted 05 July 2008 - 05:11 AM

This is vastly disappointing. I presume these results will translate into any modifications made by Sinclair's group to the compound. I remember hearing about resveratrol at a conference years ago where all the speakers assumed that these compounds would give us years of extra life. Indeed, resveratrol sales are probably in the tens of millions by now, purchased by people who wanted to get a head start on life exstention, not improve bone density and cardiovascular health. Oh well.


You have missed the following points:

- the mice on restricted calorie diet (EOD -every other day- feeding) also lived no longer than controls; this species' life is not extended by CR.
- resveratrol plus EOD CR did extend the lifespan by 15% over EOD or CR alone, or ad libium.

You cannot translate results regarding resveratrol or CR alone to this strain of mice, nor extrapolate to humans. But the two together did extend lifespan, somehow overcoming the genetic defect in this strain that prevents CR from working. And there was an increase in health.


When a compound is a failure in mice during pharmacuetical testing, typically that compound is dropped and not brought to human trials. The reaon mice are used by everyone from Glaxo Smith Kline to the M Prize is because their biology reacts similiarly enough to humans that they have become the gold standard. Now maybe, there is a more promising effect in humans, but because our biology is more complex I certainly wouldn't bet on it.

The statements you have listed indicate that CR plus resveratrol equals some life extension, but resveratrol has been touted precisely because it was suppose to be an alternative to CR, not an addendum.

#28 sUper GeNius

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Posted 05 July 2008 - 06:11 AM

This is vastly disappointing. I presume these results will translate into any modifications made by Sinclair's group to the compound. I remember hearing about resveratrol at a conference years ago where all the speakers assumed that these compounds would give us years of extra life. Indeed, resveratrol sales are probably in the tens of millions by now, purchased by people who wanted to get a head start on life exstention, not improve bone density and cardiovascular health. Oh well.


You have missed the following points:

- the mice on restricted calorie diet (EOD -every other day- feeding) also lived no longer than controls; this species' life is not extended by CR.
- resveratrol plus EOD CR did extend the lifespan by 15% over EOD or CR alone, or ad lib.

You cannot translate results regarding resveratrol or CR alone to this strain of mice, nor extrapolate to humans. But the two together did extend lifespan, somehow overcoming the genetic defect in this strain that prevents CR from working. And there was an increase in health.


When a compound is a failure in mice during pharmacuetical testing, typically that compound is dropped and not brought to human trials. The reaon mice are used by everyone from Glaxo Smith Kline to the M Prize is because their biology reacts similiarly enough to humans that they have become the gold standard. Now maybe, there is a more promising effect in humans, but because our biology is more complex I certainly wouldn't bet on it.

The statements you have listed indicate that CR plus resveratrol equals some life extension, but resveratrol has been touted precisely because it was suppose to be an alternative to CR, not an addendum.


Was it CR plus t-res, or was it EOD (with ad-lib on the feeding days) plus t-res? I think it was the latter. If mice are the gold standard, then my current regimen is very promising indeed. On the other hand, if these mice are the gold standard, then CR for humans is in jeopardy too, as these mice experienced no life extension when on the CR diet alone.

Edit: As far as mice being the gold standard, is that true of life-extension trials? Have there been many life-extension trials with mice? Isn't it possible, as Sinclair intimated, that life extension trials on mice might not be as valuable for such trials in determining the effects in humans? There's certainly a basis for that, as markers for heart aging were reduced, yet mice don't have much heart disease to begin with.

Edited by FuLL meMbeR, 05 July 2008 - 06:21 AM.


#29 Ethan

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Posted 05 July 2008 - 08:13 AM

This is vastly disappointing. I presume these results will translate into any modifications made by Sinclair's group to the compound. I remember hearing about resveratrol at a conference years ago where all the speakers assumed that these compounds would give us years of extra life. Indeed, resveratrol sales are probably in the tens of millions by now, purchased by people who wanted to get a head start on life exstention, not improve bone density and cardiovascular health. Oh well.


You have missed the following points:

- the mice on restricted calorie diet (EOD -every other day- feeding) also lived no longer than controls; this species' life is not extended by CR.
- resveratrol plus EOD CR did extend the lifespan by 15% over EOD or CR alone, or ad lib.

You cannot translate results regarding resveratrol or CR alone to this strain of mice, nor extrapolate to humans. But the two together did extend lifespan, somehow overcoming the genetic defect in this strain that prevents CR from working. And there was an increase in health.


When a compound is a failure in mice during pharmacuetical testing, typically that compound is dropped and not brought to human trials. The reaon mice are used by everyone from Glaxo Smith Kline to the M Prize is because their biology reacts similiarly enough to humans that they have become the gold standard. Now maybe, there is a more promising effect in humans, but because our biology is more complex I certainly wouldn't bet on it.

The statements you have listed indicate that CR plus resveratrol equals some life extension, but resveratrol has been touted precisely because it was suppose to be an alternative to CR, not an addendum.


Was it CR plus t-res, or was it EOD (with ad-lib on the feeding days) plus t-res? I think it was the latter. If mice are the gold standard, then my current regimen is very promising indeed. On the other hand, if these mice are the gold standard, then CR for humans is in jeopardy too, as these mice experienced no life extension when on the CR diet alone.

Edit: As far as mice being the gold standard, is that true of life-extension trials? Have there been many life-extension trials with mice? Isn't it possible, as Sinclair intimated, that life extension trials on mice might not be as valuable for such trials in determining the effects in humans? There's certainly a basis for that, as markers for heart aging were reduced, yet mice don't have much heart disease to begin with.


"Was it CR plus t-res, or was it EOD (with ad-lib on the feeding days) plus t-res?"

Looks like an EOD CR.

"As far as mice being the gold standard, is that true of life-extension trials?"

I would say the so-called Methuselah mouse is the gold standard, yes.

"Have there been many life extension trials with mice?'

Not sure of the numbers, but all of these groups are guilty by association http://www.mprize.or...=mp_competitors

"Isn't it possible, as Sinclair intimated, that life extension trials on mice might not be as valuable for such trials in determining effects on humans?"

I suppose. I believe Sinclair has good reasons, rooted in science, to believe that, if that is what he stated. However, as side note, anyone who stands to profit from the LE effects of resveratrol, trials on mice are certainly less valuable in this particular case.

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#30 maxwatt

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Posted 05 July 2008 - 09:21 AM

This is vastly disappointing. I presume these results will translate into any modifications made by Sinclair's group to the compound. I remember hearing about resveratrol at a conference years ago where all the speakers assumed that these compounds would give us years of extra life. Indeed, resveratrol sales are probably in the tens of millions by now, purchased by people who wanted to get a head start on life exstention, not improve bone density and cardiovascular health. Oh well.


You have missed the following points:

- the mice on restricted calorie diet (EOD -every other day- feeding) also lived no longer than controls; this species' life is not extended by CR.
- resveratrol plus EOD CR did extend the lifespan by 15% over EOD or CR alone, or ad lib.

You cannot translate results regarding resveratrol or CR alone to this strain of mice, nor extrapolate to humans. But the two together did extend lifespan, somehow overcoming the genetic defect in this strain that prevents CR from working. And there was an increase in health.


When a compound is a failure in mice during pharmacuetical testing, typically that compound is dropped and not brought to human trials. The reaon mice are used by everyone from Glaxo Smith Kline to the M Prize is because their biology reacts similiarly enough to humans that they have become the gold standard. Now maybe, there is a more promising effect in humans, but because our biology is more complex I certainly wouldn't bet on it.

The statements you have listed indicate that CR plus resveratrol equals some life extension, but resveratrol has been touted precisely because it was suppose to be an alternative to CR, not an addendum.


Was it CR plus t-res, or was it EOD (with ad-lib on the feeding days) plus t-res? I think it was the latter. If mice are the gold standard, then my current regimen is very promising indeed. On the other hand, if these mice are the gold standard, then CR for humans is in jeopardy too, as these mice experienced no life extension when on the CR diet alone.

Edit: As far as mice being the gold standard, is that true of life-extension trials? Have there been many life-extension trials with mice? Isn't it possible, as Sinclair intimated, that life extension trials on mice might not be as valuable for such trials in determining the effects in humans? There's certainly a basis for that, as markers for heart aging were reduced, yet mice don't have much heart disease to begin with.


Most strains of mice live longer on CR. (Weindruch et al, referenced in Sinclair's paper.) EOD feeding is a form of CR. The strain of mouse used in Sinclair's study does not respond to CR, lacking a particular genetic pathway. Why they chose it to test resveratrol as a CR mimetic is a good question, but obviously if the mice do not respond to CR you cannot test the live extending properties of a putative CR mimetic like resveratrol using this strain of mouse. The study is null and void for this purpose.

That EOD feeding plus EOD feeding as a form or CR, DID extend the mice's lifespan is worth further study. But it is quite likely that at least some humans lack the same metabolic pathways as these mice. Like many scientific studies, this one raises as many questions as it answers and will keep graduate students busy for the next few years. The study needs to be repeated with a strain of mouse that does respond to CR. An attempt should be made to elucidate what resveratrol does in these mice, to make up for the missing genes that prevent CR from working.

In the meantime, from this and other studies, we know there is a broad overlap in the gene expression caused by resveratrol and that caused by CR. "Plugging the holes" with one or two more supplements to get a more perfect overlap seems a good strategy.




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