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Resveratrol doesn't Improve Survival in mice


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#31 Mixter

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Posted 05 July 2008 - 10:06 AM

It seems to me that the relevant link would be:
resveratrol -> higher mitochondrial function -> higher overall metabolism

Resveratrol induces many beneficial changes, but overall you're IMO
left with a faster metabolism due to its action in the mitochondria,
which leads to more metabolic byproducts and perhaps local ROS.

My impression is that no max lifespan increase happens at least because
the effects of a higher metabolism aren't mitigated by an additional regimen.

It'd be very interesting to see mouse studies with combinations of
supplementation and resveratrol at once, which should have a larger
effect than the sum of its parts. I wonder why nobody is doing it?
Eg. GliSODin-glutathione-ALCAR-RALA-resveratrol mice? I suspect
it may even be an easy way to initially win some of the Mprize fund :)

Edited by mixter, 05 July 2008 - 10:08 AM.


#32 kenj

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Posted 05 July 2008 - 12:25 PM

What about resveratrol, benaGene, and metformin. Seems to me to be serious contenders in mimicking a CR environment, if you cut down just a lil on cals simultaneously.

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#33 Matt

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Posted 05 July 2008 - 01:36 PM

First of all Calorie Restriction in this study DID extend lifespan, but low dose (not high!) with resveratrol extended lifespan a little more, but definitely looks promising addition to a CR diet!

Posted Image

Calorie restriction (EOD) with High does resveratrol improved early survival but then closely matched EOD until the end of the study.

Calorie Restriction plus Low dose Resveratrol (EODLR) looks superior at all times. Early survival, average, and max was all better.

Lets look at another survival curve for the B6 mice from another study. These are two screen shots for those that want to have the mouse years translated into human years. The B6 mice were subjected to 27% Calorie Restriction from 12.5 months of age. B6 mice started CR at a human-age equivalence of 40 years.

Posted Image

Posted Image


References can be found
http://iangoddard.net/cr.htm


It does get me thinking, maybe I should add a glass of wine to my CR regimen :)

Edited by Matt, 05 July 2008 - 01:49 PM.


#34 wydell

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Posted 05 July 2008 - 01:54 PM

I know that folks have posted estimated rodent - human conversion dosage tables before. And I recognize that the tables are somewhat hypothetical. But does anyone have a guess as to what the low dosage in humans would equate to.

First of all Calorie Restriction in this study DID extend lifespan, but low dose (not high!) with resveratrol extended lifespan a little more, but definitely looks promising addition to a CR diet!

Posted Image

Calorie restriction (EOD) with High does resveratrol improved early survival but then closely matched EOD until the end of the study.

Calorie Restriction plus Low dose Resveratrol (EODLR) looks superior at all times. Early survival, average, and max was all better.

Lets look at another survival curve for the B6 mice from another study. These are two screen shots for those that want to have the mouse years translated into human years. The B6 mice were subjected to 27% Calorie Restriction from 12.5 months of age. B6 mice started CR at a human-age equivalence of 40 years.

Posted Image

Posted Image


References can be found
http://iangoddard.net/cr.htm


It does get me thinking, maybe I should add a glass of wine to my CR regimen :)



#35 wydell

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Posted 05 July 2008 - 02:02 PM

If that is true, that would seem to be against Sinclair's and his company's business interest to design a study in this manner. You would also think that Sinclair and Glaxo would at least point this fact out in the study themselves (or maybe they did?).


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.



#36 Matt

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Posted 05 July 2008 - 03:17 PM

Heres another study using the same mice, it reports a 15% increase in maximum lifespan was achieved.
Dietary Intervention at Middle Age
Caloric Restriction but not Dehydroepiandrosterone Sulfate Increases Lifespan and Lifetime Cancer Incidence in Mice
http://cancerres.aac.../full/59/7/1642


So why would they use a mouse that doesn't respond well to mid-life calorie restriction and try using resveratrol? Did they think that resveratrol would have bigger effects over CR alone and tried to prove that point? Hopefully they have plans to test the compound on other mice than this model.

#37 stephen_b

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Posted 05 July 2008 - 03:23 PM

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.

Glisodin claims to greatly boost glutathione.

Stephen

#38 stephen_b

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Posted 05 July 2008 - 03:31 PM

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.

It could have been revealing though had it turned out differently. If the mice that normally don't respond to CR had responded to resveratrol, then researchers would have had evidence that resveratrol doesn't work through the same pathways for life extension as CR. Now they have more evidence supporting the claim that any life extension properties of resveratrol would have to work through the same pathways as CR does.

Stephen

#39 stephen_b

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Posted 05 July 2008 - 03:54 PM

So why would they use a mouse that doesn't respond well to mid-life calorie restriction and try using resveratrol?


Maybe the Sinclair quote from your first post has the answer: "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". It sounds like they achieved their objective.

I also think that they are purposely underemphasizing the maximum lifespan angle since from the FDA's point of view aging isn't a disease, and doing so might detract from their business plan of fighting the diseases of aging. I think that Sirtris' marketing division not unaware of the market for life extenstion, thinking 'that's what off-label prescriptions are for'.

Stephen

#40 sUper GeNius

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Posted 05 July 2008 - 06:15 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.


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.


"To answer these questions, we examined
the effects of resveratrol on mice fed SD ad libitum, subjected
to EOD feeding, "

Please correct me if I'm incorrect, but it seems to me that the EOD mice were allowed to eat as much as they wanted. No CR.

#41 maxwatt

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Posted 05 July 2008 - 09:39 PM

....snip...

"To answer these questions, we examined
the effects of resveratrol on mice fed SD ad libitum, subjected
to EOD feeding, "

Please correct me if I'm incorrect, but it seems to me that the EOD mice were allowed to eat as much as they wanted. No CR.


The total calorie intake matches that of CR mice; nothing one day, lots the next = same as restricted for two days. Oversimplifies, but EOD is considered a form of calorie restriction, and imparts the same benefits as per a number of studies looking at gene expressiona nd other parameters.

PS: perhaps Sirtris want to deemphasize resveratrol for life extension. Who will pay for an expensive prescription medicine if low-cost extract from a weed does the same thing?

Edited by maxwatt, 05 July 2008 - 09:41 PM.


#42 sUper GeNius

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Posted 05 July 2008 - 09:45 PM

....snip...

"To answer these questions, we examined
the effects of resveratrol on mice fed SD ad libitum, subjected
to EOD feeding, "

Please correct me if I'm incorrect, but it seems to me that the EOD mice were allowed to eat as much as they wanted. No CR.


The total calorie intake matches that of CR mice; nothing one day, lots the next = same as restricted for two days. Oversimplifies, but EOD is considered a form of calorie restriction, and imparts the same benefits as per a number of studies looking at gene expressiona nd other parameters.


I don't think the amount of calories is the same between CR and EOD. Do you think those mice, having fasted an entire day, would eat the same amount the following day as unfasted animals? Unless you assume that the mice were fed exactly twice the amount calories on the second day, how can you come to your conclusion? It is either assumed that the total caloric intake was the same, or they wer allowed to eat as much as they desired on the feeding day. Does it state in the study one way or another, or are you saying your conclusion is a reasonable or usual assumption?

#43 Fredrik

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Posted 06 July 2008 - 12:53 AM

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.

Meth-free protein powder? Hehe.

I haven´t been able to reduce my intake below 1.9 gram of methionine a day. And that is a normal level. It would be great to reduce that by 50% but that is hard when on a high-protein (1.3-1.5 g/kg) CR diet. I´m near vegan already. And less protein makes me hungry (hungrier).

Edited by Fredrik, 06 July 2008 - 12:56 AM.


#44 sUper GeNius

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Posted 06 July 2008 - 01:14 AM

If that is true, that would seem to be against Sinclair's and his company's business interest to design a study in this manner. You would also think that Sinclair and Glaxo would at least point this fact out in the study themselves (or maybe they did?).


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.



Sinclair is trying to get FDA approval. The FDA does not approve drugs for "life extension." They do approve drugs that help with heart disease and bone aging, as this study showed.

#45 Matt

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Posted 06 July 2008 - 01:29 AM

Whether or not it will extend human lifespan or work in other strains of mice... It has the potential to dramatically reduce medical costs associated with being over weight/obese or being elderly. And maybe people can indulge a bit if resveratrol really does prevent the negative consequences of eating badly.

#46 maxwatt

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Posted 06 July 2008 - 02:21 AM

....snip...

"To answer these questions, we examined
the effects of resveratrol on mice fed SD ad libitum, subjected
to EOD feeding, "

Please correct me if I'm incorrect, but it seems to me that the EOD mice were allowed to eat as much as they wanted. No CR.


The total calorie intake matches that of CR mice; nothing one day, lots the next = same as restricted for two days. Oversimplifies, but EOD is considered a form of calorie restriction, and imparts the same benefits as per a number of studies looking at gene expressiona nd other parameters.


I don't think the amount of calories is the same between CR and EOD. Do you think those mice, having fasted an entire day, would eat the same amount the following day as unfasted animals? Unless you assume that the mice were fed exactly twice the amount calories on the second day, how can you come to your conclusion? It is either assumed that the total caloric intake was the same, or they wer allowed to eat as much as they desired on the feeding day. Does it state in the study one way or another, or are you saying your conclusion is a reasonable or usual assumption?


Somewhere it's documented, but they do not eat twice as much the next day. overall reduction can be 30 to 40%.

#47 notox

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Posted 07 July 2008 - 05:25 AM

It seems to me that most people take resveratrol in 1-2 singles dose/day.
But can we compare this with mice feeding experiments?

I do not know exactly, but I do not believe that mice are eating their food all at
once in 1-2 single doses/day and isn't it their food that contains the RSV?

I would guess they are eating all day long if food is available and this would never
result in peak plasma levels of resveratrol rather than in a continuous (very?)
low RSV plasma curve spread over the day.

You are invited to proof me false, but isn't there a fundamental difference in the
way mice are exposed to resveratrol (in these experiments) in contrast to what
we do when taking pills/powder with enhanced delivery systems such as
HPMC/Lecithin/alcohol/micronization etc...

Edited by notox, 07 July 2008 - 05:29 AM.


#48 TianZi

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Posted 07 July 2008 - 08:15 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.


You continue to misunderstand the posts you are replying to. You assume all mice are created equal, so to speak, but that's not true--mice used in studies are often "mutant", inbred strains that can differ vastly from one another, with the particular strain of mice used in a study identified by a serial number, as was the case here. The strain used in the study you found so disappointing doesn't even respond to CR (probably because it has been bred or otherwise altered so as to knock out particular genes), quite unlike the typical mouse and most animals generally.

Differences in dosage of resveratrol and breed of mice used can lead to vastly different results between two studies, just as they can when comparing studies measuring the effects of CR (there is no precise definition of "caloric restriction", so researchers in one study may reduce daily caloric intake by much more than researchers in another study).

#49 wydell

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Posted 07 July 2008 - 02:41 PM

According to Matt's post, the mice in this particular study responded quite well to CR and I recall it being around a 10% - 20% extension in life. Did you read that post?



[

You continue to misunderstand the posts you are replying to. You assume all mice are created equal, so to speak, but that's not true--mice used in studies are often "mutant", inbred strains that can differ vastly from one another, with the particular strain of mice used in a study identified by a serial number, as was the case here. The strain used in the study you found so disappointing doesn't even respond to CR (probably because it has been bred or otherwise altered so as to knock out particular genes), quite unlike the typical mouse and most animals generally.

Differences in dosage of resveratrol and breed of mice used can lead to vastly different results between two studies, just as they can when comparing studies measuring the effects of CR (there is no precise definition of "caloric restriction", so researchers in one study may reduce daily caloric intake by much more than researchers in another study).



#50 tom a

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Posted 07 July 2008 - 04:02 PM

I guess I'm wondering what Michael Rae, our resident resveratrol basher, is going to say about this latest result.

It can hardly be good for his overall take on CR vs resveratrol that the CR in this case did not enable longer life -- at least not to the point of statistical significance -- but that CR plus resveratrol did.

He was happily making the point earlier that "silence was golden" with respect to the absence of any report from Sinclair's group about the increased longevity of mice on standard diets using resveratrol. Now it looks like the same mice even on CR diets did not show statistically significant gains!

I expect his brain to explode over the concept that it was only CR combined with resveratrol that showed the statistically significant effect.

Not sure how he's going to trash the apparent results of this study, but I gotta guess he'll come up with something, however implausible.

#51 Matt

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Posted 07 July 2008 - 04:49 PM

Tom a... CR still on its own extended lifespan in Sinclair's study and Weindruch's study... see survival curves.

#52 Mind

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Posted 07 July 2008 - 04:50 PM

I know Michael is extremely cautious with regards to supps in general, however, I figure it is good to get all sides/angles to the argument.

#53 Matt

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Posted 07 July 2008 - 04:56 PM

Here is a using the C57BL/6 mice (B6) Mice and starting CR at 12 months...

Attached Files


Edited by Matt, 07 July 2008 - 05:14 PM.


#54 tom a

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Posted 07 July 2008 - 05:25 PM

Tom a... CR still on its own extended lifespan in Sinclair's study and Weindruch's study... see survival curves.


Well, at least according to the curves I see on this page on the Sinclair study, whatever effect CR by itself has on longevity is roughly doubled when combined with low levels of resveratrol -- if you take the curves simply as they stand. Insofar as one is willing to ignore the whole issue of statistical significance, and try to draw inferences from the curves as if they represent true underlying dispositions, one would have to say that CR looks like a piker compared to CR & resveratrol in terms of extending life.

Of course, ignoring statistical significance, at least at some level of real confidence, is a dangerous thing.

And the only real statistically significant effect is, again, CR combined with resveratrol.

#55 malbecman

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Posted 07 July 2008 - 08:32 PM

Wow, you go away for a little vacation and the whole board lights up...... :)


I, for one, will take these positive effects. Certainly no bad news from the feeding study. Yes, its a disappointment that the life extension was not really shown but this is in just 1 mouse strain (which seems like it has its own questions as to why it was chosen) but
an improvement in quality of life is not to be sneezed at. Lets consider it a preliminary positive result.

I am also glad to see that GSK has not surrounded Sinclair et al with a cone of silence after buying the company but that we are still getting some results/insights from them. and yes, they want to prove medical benefits, not life extension, for their formulation/NCEs, at least for now....

Finally, in regards to the question about dosing in the food vs. the single dosing regimen most of us follow. Trust me, all animal studies of this kind are done by placing the agent in the food (usually after stability studies to show it does not break down in the chow). There are typically at least dozens if not hundreds of animals in these studies and it is much, much, much, easier to mix the agent in the food and weigh 100+ food cups every day (to get an estimate of their dosage) than it is to try and get a grad student or postdoc to orally gavage 100+ mice every day. That would be untenable. I also actually think that in terms of gene activation (like the SIRT genes), a single large dose is preferable rather than a dose dribbled out over the day. You want to get maximal receptor binding here, basically, so the more resveratrol that reaches the target receptors/genes, the better, IMHO.......

edit for typos

Edited by malbecman, 07 July 2008 - 08:33 PM.


#56 krillin

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Posted 08 July 2008 - 12:05 AM

First of all Calorie Restriction in this study DID extend lifespan, but low dose (not high!) with resveratrol extended lifespan a little more, but definitely looks promising addition to a CR diet!

How do we measure maximum lifespan, anyway? I've always considered it to be when the last subject keels over, but the text of this paper as quoted by Hedgehog says "maximum life span (final 20% surviving)". 20% surviving happens to be just about the only part of the graph where the EOD and SD curves meet. Hence their statement that EOD wasn't any better than SD.

#57 Matt

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Posted 08 July 2008 - 12:16 AM

First of all Calorie Restriction in this study DID extend lifespan, but low dose (not high!) with resveratrol extended lifespan a little more, but definitely looks promising addition to a CR diet!

How do we measure maximum lifespan, anyway? I've always considered it to be when the last subject keels over, but the text of this paper as quoted by Hedgehog says "maximum life span (final 20% surviving)". 20% surviving happens to be just about the only part of the graph where the EOD and SD curves meet. Hence their statement that EOD wasn't any better than SD.


I thought it was the last 10% survivorship that determines max.... but anyway, the survival curve from the same strain of mouse does show an effect in weindruch's study; see this again;

Posted Image

#58 maxwatt

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Posted 08 July 2008 - 01:34 AM

First of all Calorie Restriction in this study DID extend lifespan, but low dose (not high!) with resveratrol extended lifespan a little more, but definitely looks promising addition to a CR diet!

How do we measure maximum lifespan, anyway? I've always considered it to be when the last subject keels over, but the text of this paper as quoted by Hedgehog says "maximum life span (final 20% surviving)". 20% surviving happens to be just about the only part of the graph where the EOD and SD curves meet. Hence their statement that EOD wasn't any better than SD.


I thought it was the last 10% survivorship that determines max.... but anyway, the survival curve from the same strain of mouse does show an effect in weindruch's study; see this again;


This difference in Sinclair's study was not considered statistically significant. Even though you can see a difference, it could be due to chance.

WRT resveratrol in mouse chow: when I worked in a lab, we fed the rodents once a day. Most of it was eaten in the first half hour or so. This could approximate once-a-day dosing.

#59 Ethan

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Posted 08 July 2008 - 01:53 AM

Lets consider it a preliminary positive result.


Can't do it. I do admire your optimism. I agree, high marks that the study appears to suggest that res improves quality of life, but the question has always been about quantity.

A few people have mentioned that this is just one mouse strain. They certainly didn't select it because they thought it had the best chance for failure. These are the people who participated:


the laboratories of Rafael de Cabo, Ph.D., of the Laboratory of Experimental Gerontology at the NIA; David A. Sinclair, Ph.D., of the Glenn Laboratories for Molecular Biology of Aging at Harvard Medical School; and an international group of researchers. In addition to scientists from the NIA and Harvard Medical School, researchers from the following institutions collaborated in this study: New York Medical College, Valhalla, N.Y.; University of Michigan, Ann Arbor; University of Sydney in Australia; Thomas Jefferson University, Philadelphia; University of California, San Diego, La Jolla; Hospital for Special Surgery, New York, N.Y.; University of Cincinnati, Ohio; University of Texas Health Science Center at San Antonio and Audie Murphy VA Hospital, San Antonio, Texas; Universidad Pablo de Olavide, Sevilla, Spain; Pennington Biomedical Research Center, Baton Rouge, La.; University of Washington, Seattle; and Sirtris Pharmaceuticals of Cambridge, Mass., a company founded by Harvard University co-lead author Sinclair.

With a list this long you can bet they weren't looking to disprove any of their theories. There are a lot of positive things shaping up in LE; this is a big negative. Until they provide proof otherwise, the headline is Resveratrol Does Not Extend Lifespan in Mice.

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#60 tom a

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Posted 08 July 2008 - 02:17 AM

Until they provide proof otherwise, the headline is Resveratrol Does Not Extend Lifespan in Mice.


Given what the data show and don't show, the headline equally well could be CR Does Not Extend Lifespan in Mice.

Which isn't what you'd want to conclude, I'd expect.




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