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Resveratrol doesn't Improve Survival in mice


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#61 krillin

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Posted 08 July 2008 - 02:31 AM

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.

In the 6-3-08 thread it was shown that for both mice and rats, multiplying the mg/kg dose by 3.9 gives the human dose that yields an equivalent Cmax.

SDLR 7.9 mg/kg * 3.9 = 31 mg/kg
EODLR 7.6 mg/kg * 3.9 = 30 mg/kg
HCLR 5.4 mg/kg * 3.9 = 21 mg/kg

So it's about 2 grams.

#62 niner

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Posted 08 July 2008 - 02:54 AM

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.

In the 6-3-08 thread it was shown that for both mice and rats, multiplying the mg/kg dose by 3.9 gives the human dose that yields an equivalent Cmax.

SDLR 7.9 mg/kg * 3.9 = 31 mg/kg
EODLR 7.6 mg/kg * 3.9 = 30 mg/kg
HCLR 5.4 mg/kg * 3.9 = 21 mg/kg

So it's about 2 grams.

It may be a lot less than that. I computed the factor of 3.9 from a rat study by Marier and a human study by Boocock. Boocock's people were dosed with straight resveratrol, but Hedgehog pointed out that Marier's rats got theirs in a cyclodextrin formulation. The formulation differences change the picture such that the human doses probably need to be only about 30% higher than what the mice were given. (This is still nine times as much as the HED conversion factor would suggest, but the HED conversion factors aren't intended to be used for obtaining equivalent blood levels, so that's not all that surprising.) This is pretty good news, at any rate, because it says that less than a gram a day should get you a decent result. (690mg/day for 70kg human, EODLR dosage rate)

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#63 sUper GeNius

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Posted 08 July 2008 - 02:55 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.


A big negative? What, for CR? The researchers have proven that these mice don't realize any life extension doing CR? Seriously, don't you think that last fact confounds things a bit? No, a whole lot...

#64 Ethan

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Posted 08 July 2008 - 04:18 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.



Except the primariy focus of the study was not to make a point about resveratrol, not about CR.

#65 tom a

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Posted 08 July 2008 - 04:53 AM

Except the primariy focus of the study was not to make a point about resveratrol, not about CR.


Look, the data show what they show. The "purpose" of the study is basically irrelevant to what the data demonstrate, or don't.

The simple fact is that, just as there was no effect of resveratrol in isolation on longevity in this type of mouse that was statistically significant, there was likewise no such effect of CR in isolation that was statistically significant. They are completely on a par in that basic sense. Only the combination of CR and resveratrol showed a statistically significant effect.

Why this result should reflect badly only on resveratrol with respect to longevity and not on CR as pertaining to this type of mouse is something that is entirely of your own making.

#66 Ethan

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Posted 08 July 2008 - 06:02 AM

Except the primariy focus of the study was not to make a point about resveratrol, not about CR.


Look, the data show what they show. The "purpose" of the study is basically irrelevant to what the data demonstrate, or don't.

The simple fact is that, just as there was no effect of resveratrol in isolation on longevity in this type of mouse that was statistically significant, there was likewise no such effect of CR in isolation that was statistically significant. They are completely on a par in that basic sense. Only the combination of CR and resveratrol showed a statistically significant effect.

Why this result should reflect badly only on resveratrol with respect to longevity and not on CR as pertaining to this type of mouse is something that is entirely of your own making.


This will be my last post on this matter, because this is getting silly and irrelevant. Again, why this reflects on resveratrol more so than on CR is because it is the topic at hand. It is why we are having this discussion on the supplement subsection and not in the CR. The people who funded this study did so to primarily elucidate the effects of resevertrol on mice and to capitalize on the prospects that res works as a life extender without CR. You cannot claim that intent is an objective matter.

If I set out to prove a+b=c and in the process I prove x+y=z, well great, in the end that extra equation may help me. But it doesn't change the fact that my original hypothesis wasn't true and subjectively and objectively it is a detour to my original purpose.

#67 sUper GeNius

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Posted 08 July 2008 - 06:48 AM

Except the primariy focus of the study was not to make a point about resveratrol, not about CR.


Look, the data show what they show. The "purpose" of the study is basically irrelevant to what the data demonstrate, or don't.

The simple fact is that, just as there was no effect of resveratrol in isolation on longevity in this type of mouse that was statistically significant, there was likewise no such effect of CR in isolation that was statistically significant. They are completely on a par in that basic sense. Only the combination of CR and resveratrol showed a statistically significant effect.

Why this result should reflect badly only on resveratrol with respect to longevity and not on CR as pertaining to this type of mouse is something that is entirely of your own making.


This will be my last post on this matter, because this is getting silly and irrelevant. Again, why this reflects on resveratrol more so than on CR is because it is the topic at hand. It is why we are having this discussion on the supplement subsection and not in the CR. The people who funded this study did so to primarily elucidate the effects of resevertrol on mice and to capitalize on the prospects that res works as a life extender without CR. You cannot claim that intent is an objective matter.

If I set out to prove a+b=c and in the process I prove x+y=z, well great, in the end that extra equation may help me. But it doesn't change the fact that my original hypothesis wasn't true and subjectively and objectively it is a detour to my original purpose.


Sorry. whether or not the study is valid has nothing to do with which forum we are discussing it in. Now THAT is silly.

#68 Ethan

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Posted 08 July 2008 - 07:19 AM

Except the primariy focus of the study was not to make a point about resveratrol, not about CR.


Look, the data show what they show. The "purpose" of the study is basically irrelevant to what the data demonstrate, or don't.

The simple fact is that, just as there was no effect of resveratrol in isolation on longevity in this type of mouse that was statistically significant, there was likewise no such effect of CR in isolation that was statistically significant. They are completely on a par in that basic sense. Only the combination of CR and resveratrol showed a statistically significant effect.

Why this result should reflect badly only on resveratrol with respect to longevity and not on CR as pertaining to this type of mouse is something that is entirely of your own making.


This will be my last post on this matter, because this is getting silly and irrelevant. Again, why this reflects on resveratrol more so than on CR is because it is the topic at hand. It is why we are having this discussion on the supplement subsection and not in the CR. The people who funded this study did so to primarily elucidate the effects of resevertrol on mice and to capitalize on the prospects that res works as a life extender without CR. You cannot claim that intent is an objective matter.

If I set out to prove a+b=c and in the process I prove x+y=z, well great, in the end that extra equation may help me. But it doesn't change the fact that my original hypothesis wasn't true and subjectively and objectively it is a detour to my original purpose.


Sorry. whether or not the study is valid has nothing to do with which forum we are discussing it in. Now THAT is silly.



Of course it is valid. I have never questioned the validity of the study. Why fabricate an argument I didn't make and then call it silly?

#69 sUper GeNius

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Posted 08 July 2008 - 07:51 AM

Except the primariy focus of the study was not to make a point about resveratrol, not about CR.


Look, the data show what they show. The "purpose" of the study is basically irrelevant to what the data demonstrate, or don't.

The simple fact is that, just as there was no effect of resveratrol in isolation on longevity in this type of mouse that was statistically significant, there was likewise no such effect of CR in isolation that was statistically significant. They are completely on a par in that basic sense. Only the combination of CR and resveratrol showed a statistically significant effect.

Why this result should reflect badly only on resveratrol with respect to longevity and not on CR as pertaining to this type of mouse is something that is entirely of your own making.


This will be my last post on this matter, because this is getting silly and irrelevant. Again, why this reflects on resveratrol more so than on CR is because it is the topic at hand. It is why we are having this discussion on the supplement subsection and not in the CR. The people who funded this study did so to primarily elucidate the effects of resevertrol on mice and to capitalize on the prospects that res works as a life extender without CR. You cannot claim that intent is an objective matter.

If I set out to prove a+b=c and in the process I prove x+y=z, well great, in the end that extra equation may help me. But it doesn't change the fact that my original hypothesis wasn't true and subjectively and objectively it is a detour to my original purpose.


Sorry. whether or not the study is valid has nothing to do with which forum we are discussing it in. Now THAT is silly.



Of course it is valid. I have never questioned the validity of the study. Why fabricate an argument I didn't make and then call it silly?


The summary of the study says the aim was to see whether t-res would produce effects that would mimic CR. And in fact, the researchers say it did, and they enumerate the benefits. Max lifespan extension was not one of them.

Tell me why a study with mice that do not respond to CR has any relevance for humans?

I wonder why this strain was used at all. Is there an clue as to why this strain does not respond to CR? Anyone check the paper referenced, Weindruch and Walford, 1982? Therein lies the secret.

Edited by FuLL meMbeR, 08 July 2008 - 07:52 AM.


#70 Michael

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Posted 08 July 2008 - 11:21 AM

All:

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

No shit!

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!

No: as I just got thru' explaining, there was no CR in this study, and EOD (not CR) did not extend lifespan.

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....

Contrary to what one always hears in the press, "maximum lifespan" does not mean the single longest-lived organism, but is operationally defined as the mean longevity of the last n% of survivors. This is to avoid outlier effects from single exceptional organisms (spontaneous longevity mutants, misassigned animals, etc), which would otherwise bugger up the study and make statistical significance tricky to calculate. Often, therefore, the smaller the cohort size, the larger the % of animals used.

This is why saying that Jeanne Calmet proves the max human LS to be >120 is wrong; the proper equivalent is probably centenarianship.

but anyway, the survival curve from the same strain of mouse does show an effect in weindruch's study

... and many others. Again, what this study shows is that neither EOD without a net reduction in Calories, nor resveratrol, provide the age-delaying, life-extending benefits of CR (though there may have been a very mild benefit from the combination).
-Michael

Edited by Michael, 08 July 2008 - 11:27 AM.
clarification


#71 tom a

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Posted 08 July 2008 - 02:47 PM

Again, what this study shows is that neither EOD without a net reduction in Calories, nor resveratrol, provide the age-delaying, life-extending benefits of CR (though there may have been a very mild benefit from the combination).
-Michael


How about looking at it another way?

If, as you argue, there was no relevant net reduction of calories, then what this study shows conclusively is that there are methods of extending life that do not in any way involve calorie restriction?

And I'm not sure why a 15% increase in the longevity is "very mild", considering that the regimen was started toward middle age for these mice.

#72 sUper GeNius

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Posted 08 July 2008 - 04:59 PM

Again, what this study shows is that neither EOD without a net reduction in Calories, nor resveratrol, provide the age-delaying, life-extending benefits of CR (though there may have been a very mild benefit from the combination).


How about looking at it another way?"

Okay.

"If, as you argue, there was no relevant net reduction of calories, then what this study shows conclusively is that there are methods of extending life that do not in any way involve calorie restriction?"

Yes, so this could be interpreted as a milestone! Funny how some don't see it that way.

"And I'm not sure why a 15% increase in the longevity is "very mild", considering that the regimen was started toward middle age for these mice."

Very true! A question. Has full-blown CR started in middle age done any better than 15%? Again, I'm surprised Michael wouldn't describe this as a milestone, for the reasons you listed. I await his response to your post.

Seems to be an exciting time. We are honing in on the holy grail, a chemical mimetic to CR, and this study is one notch in the belt.

Edited by Michael, 05 December 2009 - 12:44 PM.
Trim quotes


#73 inawe

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Posted 08 July 2008 - 05:33 PM

This subforum is about RSV but it turned (again) into a comparison with Calorie Restriction (CR). There is this myth that CR is doing
something and so it should be considered the gold standard (for something). It's clear that overeating is bad for ones health. On the
other extreme there is starving, which is also bad. In between it's Satiety(S), 80%S, anorexia ... Somewhere over there there is CR which by
being hard to define has a cult following.
For myself I like 80%-90% S plus exercise. I feel a little hunger, to which I got accustomed.
Any procedure, treatment or supplemental program should be analyzed on it's own merits. Without comparing it to CR which can be dangerous as shown in:
"Chronic food restriction in young rats results in depression- and anxiety-like behaviors with decreased expression of
serotonin reuptake transporter", PMID: 17383614.

#74 krillin

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Posted 09 July 2008 - 12:04 AM

It may be a lot less than that. I computed the factor of 3.9 from a rat study by Marier and a human study by Boocock. Boocock's people were dosed with straight resveratrol, but Hedgehog pointed out that Marier's rats got theirs in a cyclodextrin formulation. The formulation differences change the picture such that the human doses probably need to be only about 30% higher than what the mice were given. (This is still nine times as much as the HED conversion factor would suggest, but the HED conversion factors aren't intended to be used for obtaining equivalent blood levels, so that's not all that surprising.) This is pretty good news, at any rate, because it says that less than a gram a day should get you a decent result. (690mg/day for 70kg human, EODLR dosage rate)

But this is a mouse study, and the 3.9 factor for mice was calculated from resveratrol delivered in glycerol formal. Would glycerol formal give a similar 3x Cmax?

#75 stephen_b

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Posted 09 July 2008 - 02:41 AM

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.

Why not take them at their word? Sinclair: "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." If the mice on resveratrol had lived longer than the CR mice, they would have disproved their hypothesis that resveratrol's health benefits arise "by inducing a physiology similar to dietary restriction". I think they hoped that these CR unresponsive mice would have a similar response on CR as on resveratrol.

If on the other hand the resveratrol mice had outlived the CR mice, it would have disproved their hypothesis by providing evidence that resveratrol provides its health benefits by mechanisms different from CR's mechanisms.

Stephen

#76 maxwatt

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Posted 09 July 2008 - 03:24 AM

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.

Why not take them at their word? Sinclair: "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." If the mice on resveratrol had lived longer than the CR mice, they would have disproved their hypothesis that resveratrol's health benefits arise "by inducing a physiology similar to dietary restriction". I think they hoped that these CR unresponsive mice would have a similar response on CR as on resveratrol.

If on the other hand the resveratrol mice had outlived the CR mice, it would have disproved their hypothesis by providing evidence that resveratrol provides its health benefits by mechanisms different from CR's mechanisms.

Stephen


Then does the 15% increase in max life span for resveratrol + EOD feeding, over either by itself, indicate that CR and resveratrol act by different but complementary mechanisms? I rather think so. Differences noted in the paper on gene expression were up-regulation of glutathione by EOD CR, not by resveratrol. Would adding a glutathione up-regulator suchas NAC or ALA to resveratrol be a desireable addition to one's regimen?

(And EOD feeding is a form of mild caloric restriction; food consumption overall is slightly less than ad libidum-fed mice, even if the EOD mice get all they want on non-fast days.)

#77 notox

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Posted 09 July 2008 - 05:09 AM

EOD alone -> no life extension
EODLR -> Life extension

But have they also tested normal diet with every other day resveratrol ?

If not, how can someone rule out that RSV given in low dose every other day
would have done the trick alone....

#78 niner

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Posted 09 July 2008 - 05:25 AM

It may be a lot less than that. I computed the factor of 3.9 from a rat study by Marier and a human study by Boocock. Boocock's people were dosed with straight resveratrol, but Hedgehog pointed out that Marier's rats got theirs in a cyclodextrin formulation. The formulation differences change the picture such that the human doses probably need to be only about 30% higher than what the mice were given. (This is still nine times as much as the HED conversion factor would suggest, but the HED conversion factors aren't intended to be used for obtaining equivalent blood levels, so that's not all that surprising.) This is pretty good news, at any rate, because it says that less than a gram a day should get you a decent result. (690mg/day for 70kg human, EODLR dosage rate)

But this is a mouse study, and the 3.9 factor for mice was calculated from resveratrol delivered in glycerol formal. Would glycerol formal give a similar 3x Cmax?

Krillin, I don't know how we missed this after all of our resveratrol bioavailability hacking, but glycerol is a good solvent for resveratrol, is pretty cheap and essentially nontoxic. It might be a terrific way to take resveratrol. In Sale's study, as you noted here and I noted here, they got the same Cmax/mg/kg with glycerol in mice as Marier's rats using cyclodextrin. Is glycerol the poor man's cyclodextrin? It should function as a solvent/antisolvent micronization scheme like ethanol, I'd think. Anyway, to answer your question, yeah, glycerol might jack up the PK parameters in the rodents, but it could be used in humans too. We don't have human data with glycerol, so the closest straight comparison between humans and rodents is using rat data from a Sirtris patent, fig 27 in this thread. They used 50mg/kg oral dosing of unprocessed resveratrol in methylcellulose, and got a Cmax of about 2.2 uM. (I think MC is not as good as HPMC as a resveratrol formulating agent, but it's probably better than nothing.) Boocock used oral dosing of 5 gm unprocessed resveratrol with no formulation, and got 2.4 uM. Estimating 70 kg gives 71.4mg/kg, so...

rat, res + MC, oral: 2.2 uM / 50 mg/kg = 0.044
human, unformulated res, oral: 2.4 uM / 71.4 mg/kg = 0.0336

rat/human = 0.044/0.0336 = 1.3

So, if we use a non-formulated resveratrol and we want to compare to rats getting dosed in their food or some other non-optimal formulation, then we should take approximately 1.3 times the rat mg/kg dose.

To recap, my earlier figure of 3.9 was too high because it didn't take into account the formulation differences between Marier's rats and Boocock's humans. When formulations are equivalent, it looks like humans might need only 30% more than the rodents. Bear in mind that this is an approximation, and the exact factor will depend on a lot of things.

#79 sUper GeNius

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Posted 09 July 2008 - 05:45 AM

Niner,

Would you consider t-res in water with a small pinch of HPMC a "formulated" version or not?

#80 Matt

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Posted 09 July 2008 - 12:06 PM

Then does the 15% increase in max life span for resveratrol + EOD feeding, over either by itself, indicate that CR and resveratrol act by different but complementary mechanisms? I rather think so. Differences noted in the paper on gene expression were up-regulation of glutathione by EOD CR, not by resveratrol. Would adding a glutathione up-regulator suchas NAC or ALA to resveratrol be a desireable addition to one's regimen?

(And EOD feeding is a form of mild caloric restriction; food consumption overall is slightly less than ad libidum-fed mice, even if the EOD mice get all they want on non-fast days.)


I think Michael has explained this issue well enough but hasn't seemed to have been acknowledged yet. The EOD MICE in this study were NOT on a CR diet. They compensated for calories, their body weights remained the same as the standard diet group, and other studies on the normal CR with the b6 mice has shown benefits in many studies [all referenced in michaels post].

Read:

there was no CR in this study, and EOD (not CR) did not extend lifespan.
http://www.imminst.o...o...st&p=249624

Edited by Michael, 05 December 2009 - 12:45 PM.
Trim quotes


#81 maxwatt

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Posted 09 July 2008 - 01:19 PM

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.

Why not take them at their word? Sinclair: "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." If the mice on resveratrol had lived longer than the CR mice, they would have disproved their hypothesis that resveratrol's health benefits arise "by inducing a physiology similar to dietary restriction". I think they hoped that these CR unresponsive mice would have a similar response on CR as on resveratrol.

If on the other hand the resveratrol mice had outlived the CR mice, it would have disproved their hypothesis by providing evidence that resveratrol provides its health benefits by mechanisms different from CR's mechanisms.

Stephen


Then does the 15% increase in max life span for resveratrol + EOD feeding, over either by itself, indicate that CR and resveratrol act by different but complementary mechanisms? I rather think so. Differences noted in the paper on gene expression were up-regulation of glutathione by EOD CR, not by resveratrol. Would adding a glutathione up-regulator suchas NAC or ALA to resveratrol be a desireable addition to one's regimen?

(And EOD feeding is a form of mild caloric restriction; food consumption overall is slightly less than ad libidum-fed mice, even if the EOD mice get all they want on non-fast days.)


I think Michael has explained this issue well enough but hasn't seemed to have been acknowledged yet. The EOD MICE in this study were NOT on a CR diet. They compensated for calories, their body weights remained the same as the standard diet group, and other studies on the normal CR with the b6 mice has shown benefits in many studies [all referenced in michaels post].

Read:

there was no CR in this study, and EOD (not CR) did not extend lifespan.
http://www.imminst.o...o...st&p=249624


Splitting hairs? EOD affects many markers in the same way as 40% CR. It is not the same as 40% CR. True, and to my knowledge no study has followed EOD feeding in mice to determine life extension. However, note a quote from the paper:

. 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).


40% CR in Weindruch's study had a diminished life extension effect in these mice.
BUT EOD + resveratrol extended both mean and maximal life span by 15%.

And EOD feeding did increase lifespan in these mice but not to the point of achieving statistical significance.

This study raises some intriguing questions, more than it answers.

There is nothing in the paper specifying comparative weights or calorie consumption of the different groups of mice; I do not have access to the supplementary data for this paper, but unless it is there, it is unwarranted to state that "they compensated for calories, their body weights remained the same as the standard diet group". If you have access to the supplementary data, would you please share it?

#82 Matt

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Posted 09 July 2008 - 01:24 PM

There is nothing in the paper specifying comparative weights or calorie consumption of the different groups of mice; I do not have access to the supplementary data for this paper, but unless it is there, it is unwarranted to state that "they compensated for calories, their body weights remained the same as the standard diet group". If you have access to the supplementary data, would you please share it?


Michael had already attached it to his post, get the attachment here: http://www.imminst.o...t...ost&id=3162

So we know that EOD + Low dose resveratrol extended lifespan, but EOD alone failed to do anything much. Now you have to gauge the correct resveratrol dose to have the desired effect, it seems there is a window to get this right, do you know at which dose that is for humans?

Edited by Matt, 09 July 2008 - 01:25 PM.


#83 maxwatt

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Posted 09 July 2008 - 02:09 PM

There is nothing in the paper specifying comparative weights or calorie consumption of the different groups of mice; I do not have access to the supplementary data for this paper, but unless it is there, it is unwarranted to state that "they compensated for calories, their body weights remained the same as the standard diet group". If you have access to the supplementary data, would you please share it?


Michael had already attached it to his post, get the attachment here: http://www.imminst.o...t...ost&id=3162

So we know that EOD + Low dose resveratrol extended lifespan, but EOD alone failed to do anything much. Now you have to gauge the correct resveratrol dose to have the desired effect, it seems there is a window to get this right, do you know at which dose that is for humans?


That attachment appears to be from a different paper, not the supplemental information to the Pearson, Sinclair, et al paper in Cell Metabolism. However looking at the graphs, it seems that EOD resulted in reduced food intake as compared to SD (standard diet.)

#84 Michael

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Posted 09 July 2008 - 03:39 PM

There is nothing in the paper specifying comparative weights or calorie consumption of the different groups of mice; I do not have access to the supplementary data for this paper, but unless it is there, it is unwarranted to state that "they compensated for calories, their body weights remained the same as the standard diet group". If you have access to the supplementary data, would you please share it?

Michael had already attached it to his post, get the attachment here: http://www.imminst.o...t...ost&id=3162

That attachment appears to be from a different paper, not the supplemental information to the Pearson, Sinclair, et al paper in Cell Metabolism.


I'm not sure what gives you that impression; I know that it's hard to read, but if you look carefully you'll see all the cohorts involved: HighCalorie, StandardDiet, EveryOtherDay, all with and without resv[eratrol] or low[dose] resv[eratrol] . IAC, I can assure you that this is Supplementary Figure S5 from :

Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R.
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metab. 2008 Jul 2. [Epub ahead of print]
PMID: 18599363 [PubMed - as supplied by publisher]

However looking at the graphs, it seems that EOD resulted in reduced food intake as compared to SD (standard diet.)

... very marginally. And maybe that explains (some of?) the minor numerical differences (not statistically significant, and dubious on historical control grounds) in longevities :) .

-Michael

#85 sUper GeNius

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Posted 09 July 2008 - 05:14 PM

Michael,

There is still one point to which you did not respond. You characterized the 15% extension in EOD & resveratrol mice as "mild," despite the fact that this regimen was started in middle age. Does full-blown CR provide any better results than this, applied at middle age? A 15% extension from two additions, that on their own, did not extend life.

To me, this outcome seems remarkable.

Edited by FuLL meMbeR, 09 July 2008 - 05:17 PM.


#86 krillin

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Posted 09 July 2008 - 10:01 PM

Krillin, I don't know how we missed this after all of our resveratrol bioavailability hacking, but glycerol is a good solvent for resveratrol, is pretty cheap and essentially nontoxic. It might be a terrific way to take resveratrol. In Sale's study, as you noted here and I noted here, they got the same Cmax/mg/kg with glycerol in mice as Marier's rats using cyclodextrin. Is glycerol the poor man's cyclodextrin? It should function as a solvent/antisolvent micronization scheme like ethanol, I'd think.

They actually used glycerol formal (product mixture from reaction of glycerol and formaldehyde). Straight glycerol is so sticky and viscous that I wouldn't enjoy trying to drink it, and diluting it might cause the resveratrol to drop out of solution. So I agree it might be a good ethanol substitute.

#87 Michael

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Posted 09 July 2008 - 10:08 PM

There is still one point to which you did not respond. You characterized the 15% extension in EOD & resveratrol mice as "mild," despite the fact that this regimen was started in middle age.

Actually, I did address this in my post:

The modest increase in lifespan observed in the EOD + resveratrol group is interesting, and I'd like to see it further investigated, but even that result is somewhat weakened by the fact that the controls did not reach the historical benchmark for lifespan in laboratory mice (and this strain in particular), which is ~900 d mean and ~1200 d max (10th-decile survivorship) (see again my ([references]) below for examples); this might suggest that the benefit allowed them to compensate for suboptimal husbandry conditions, but would not actually benefit animals that were better-cared-for in the first place.

To eyeball from (3), Fig. 4 [C] and [E], mean and max LS for EOD-fed, "low"-dose resveratrol were ~132 and 147 weeks, or 924 and 1029 d. That is: these animals lived about as long, on average, as the controls of the same strain in numerous previous studies, including the adult-onset CR studies op cit -- and had a lower maximum LS. So a claim of "extended" LS is dubious.

As a close analogy: if I ran a clinical trial of "anti-aging" drug in humans, and at the end of the trial the placebo group's mean and max LSs were 50 and 70, vs. 80 and 90 in verum, we wouldn't hail it as a breakthrough against aging; we'd instead try to figure out what was wrong with either the controls, or the study population as a whole, and whether this meant that the drug was worthless, or protected against some disease or environmental stress, or really was an anti-aging drug that just needed to be tested in a healthier population.

This problem plagues all the claims of "extended" lifespan from non-genomic interventions other than CR, such as the "Melatonin Miracle" of the 1990s ( (1) -- gosh, from your photo, FuLL meMbeR, you might not even remember this one! I'm an old fart! Come on, SENS ... ). That's why the biogerontology literature keeps somberly saying stuff like “caloric restriction (CR) is the only intervention repeatedly demonstrated to retard the onset and incidence of age-related diseases, maintain function, and extend both lifespan and health span in mammals, including brain and behavioral function” (2), even tho' supplement vendors keep making contrary claims for everything from selenium to BHT.

And, of course, so far it's only one study ...

A 15% extension from two additions, that on their own, did not extend life.

To me, this outcome seems remarkable.

If it's for real, and not a statistical fluke or the result of letting the animals tolerate poor husbandry, it will be. As I said, I'd like to see further investigation.

-Michael

1. Pierpaoli W, Dall'Ara A, Pedrinis E, Regelson W.
The pineal control of aging. The effects of melatonin and pineal grafting on the survival of older mice.
Ann N Y Acad Sci. 1991;621:291-313.
PMID: 1859093 [PubMed - indexed for MEDLINE]

2. Ingram DK, Young J, Mattison JA.
Abstract
Calorie restriction in nonhuman primates: assessing effects on brain and behavioral aging.
Neuroscience. 2007 Apr 14;145(4):1359-64. Epub 2007 Jan 16. Review.
PMID: 17223278 [PubMed - indexed for MEDLINE]

3. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R.
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metab. 2008 Jul 2. [Epub ahead of print]
PMID: 18599363 [PubMed - as supplied by publisher]

Edited by Michael, 09 July 2008 - 10:23 PM.
Added citation and hard numbers on LS; explicated analogy.


#88 sUper GeNius

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Posted 09 July 2008 - 10:38 PM

[quote name='Michael'

from your photo, FuLL meMbeR, you might not even remember this one! I'm an old fart! Come on, SENS ... ).

[/quote]

Hey, that photograph was taken on my 67th birthday!








Edit: Nah. It's a pic of Ozzy Osbourne, and probably taken many years ago.

#89 stephen_b

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Posted 10 July 2008 - 02:32 AM

Sardi's reply about why the resveratrol fed mice didn't live longer -- no vitamin D3:

Caloric restriction (CR) is known to oppose cancer development and increase maximum life span in rodents. A prior study conducted by Richard Weindruch PhD, now of LifeGen Technologies in Madison, Wisconsin, showed that a calorie-restricted diet increased maximum life span by approximately 15%, however the incidence of the most prevalent cancer, myeloma (cancer of the blood plasma cell in bone marrow) was higher (66%) in calorie-restricted mice versus normal-fed mice (41%).[1]

In order for any agent to significantly prolong the lifespan of laboratory mice it is going to have to address lymphomas that characteristically develop in these laboratory animals in late adulthood.

Other prior experiments conclusively show that the addition of vitamin D3 to the diet of laboratory mice almost doubles the survival time among lymphoma-bearing mice (37 days for untreated mice, 68 days for vitamin D3-treated mice).[2],[3]

Vitamin D is a key independent factor that controls the innate immune system.[4]

Resveratrol has also been shown to stimulate the response to vitamin D and inhibit myeloma tumors in mice by a mechanism that sensitizes the vitamin D3 cell-surface receptor site. So resveratrol is a bit hampered without vitamin D3 in regard to lymphoma inhibition. The combination of resveratrol and vitamin D3 has application for treatment or prevention of myeloma.[5]


Stephen

Tried uploading the email with no luck. :(

Click HERE to rent this advertising spot to support LongeCity (this will replace the google ad above).

#90 sUper GeNius

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Posted 10 July 2008 - 02:38 AM

Sardi's reply about why the resveratrol fed mice didn't live longer -- no vitamin D3:

Caloric restriction (CR) is known to oppose cancer development and increase maximum life span in rodents. A prior study conducted by Richard Weindruch PhD, now of LifeGen Technologies in Madison, Wisconsin, showed that a calorie-restricted diet increased maximum life span by approximately 15%, however the incidence of the most prevalent cancer, myeloma (cancer of the blood plasma cell in bone marrow) was higher (66%) in calorie-restricted mice versus normal-fed mice (41%).[1]

In order for any agent to significantly prolong the lifespan of laboratory mice it is going to have to address lymphomas that characteristically develop in these laboratory animals in late adulthood.

Other prior experiments conclusively show that the addition of vitamin D3 to the diet of laboratory mice almost doubles the survival time among lymphoma-bearing mice (37 days for untreated mice, 68 days for vitamin D3-treated mice).[2],[3]

Vitamin D is a key independent factor that controls the innate immune system.[4]

Resveratrol has also been shown to stimulate the response to vitamin D and inhibit myeloma tumors in mice by a mechanism that sensitizes the vitamin D3 cell-surface receptor site. So resveratrol is a bit hampered without vitamin D3 in regard to lymphoma inhibition. The combination of resveratrol and vitamin D3 has application for treatment or prevention of myeloma.[5]


Stephen

Tried uploading the email with no luck. :(


Yep, i got that email too. That guy tries to spin everything into more geld in his pocket.




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