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A Low Dose of Dietary Resveratrol Partially Mimics CR


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#1 mikeinnaples

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Posted 04 June 2008 - 12:50 AM


A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

http://www.plosone.o...al.pone.0002264

Published today. Key point 4.9mg/kg was used in the study.

(edited by Matthias: meaningful title)

Edited by Matthias, 08 July 2008 - 09:58 AM.


#2 mikeinnaples

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Posted 04 June 2008 - 02:04 AM

I am not sure exactly what to make of this atm, I need to let it soak in a bit.

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

#3 niner

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Posted 04 June 2008 - 03:11 AM

Wow. This is huge. As measured by changes in gene expression, resveratrol is a CR mimetic in mice. It looks like really nice work. Yes, there was some funding by DSM, a manufacturer of, among other things, resveratrol, but from the disclosure it doesn't look like the study is corrupted by it. I haven't finished reading it, but so far I don't see anything wrong. Now all we need to see is life extension in well-husbanded mice with a healthy diet. Based on the results of this study, it would not be unexpected. (But is not a given.) It would be straightforward to run this experiment on humans, with a restricted set of tissues. (No heart or brain) The dose employed here was a quite reasonable 5mg/kg body weight, or 350 mg/day for the canonical 70kg human. However, given the difference in ability to conjugate resveratrol between mice and humans, a comparable human dose might be 1-2g/day. This might be reduced by improved formulation.

Mike, thanks for a great find.

#4 sUper GeNius

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Posted 04 June 2008 - 03:19 AM

Wow. This is huge. As measured by changes in gene expression, resveratrol is a CR mimetic in mice. It looks like really nice work. Yes, there was some funding by DSM, a manufacturer of, among other things, resveratrol, but from the disclosure it doesn't look like the study is corrupted by it. I haven't finished reading it, but so far I don't see anything wrong. Now all we need to see is life extension in well-husbanded mice with a healthy diet. Based on the results of this study, it would not be unexpected. (But is not a given.) It would be straightforward to run this experiment on humans, with a restricted set of tissues. (No heart or brain) The dose employed here was a quite reasonable 5mg/kg body weight, or 350 mg/day for the canonical 70kg human. However, given the difference in ability to conjugate resveratrol between mice and humans, a comparable human dose might be 1-2g/day. This might be reduced by improved formulation.

Mike, thanks for a great find.



Sardi sent an email around today touting the study, presumably to support his low dose product. No mention of conjugation differences between mice and men in his email though. Hmmm...

#5 hmm

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Posted 04 June 2008 - 05:24 AM

Thanks Mike. This is my favorite passage from the study: "We note that unlike CR, resveratrol did not reduce circulating IGF-1 levels (Figure 2B), and there was also no decrease in spontaneous tumors at the time of sacrifice (Supplemental Table S2). In particular, spontaneous liver tumors were abundant in mice fed the control diet or resveratrol, but rare in CR mice. Thus, although a low dose of resveratrol can improve quality of life by retarding aging parameters such as cardiac dysfunction, a nutritional or pharmaceutical strategy to also increase lifespan in mice will likely require blockage of the IGF-1 axis or its targets."

And yet RSV does appear to fight cancer at higher dosage levels, does it not? So I would love to see this exact study done at about 10 different dosage levels with this study's dosage level being the lowest one. At what dosage level does RSV fight cancer? Does it fight cancer by reducing circulating IGF-1 levels or through some other means? And how does the extra RSV make a difference in outcomes?

#6 mikeinnaples

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Posted 04 June 2008 - 12:40 PM

Thanks Mike. This is my favorite passage from the study: "We note that unlike CR, resveratrol did not reduce circulating IGF-1 levels (Figure 2B), and there was also no decrease in spontaneous tumors at the time of sacrifice (Supplemental Table S2). In particular, spontaneous liver tumors were abundant in mice fed the control diet or resveratrol, but rare in CR mice. Thus, although a low dose of resveratrol can improve quality of life by retarding aging parameters such as cardiac dysfunction, a nutritional or pharmaceutical strategy to also increase lifespan in mice will likely require blockage of the IGF-1 axis or its targets."

And yet RSV does appear to fight cancer at higher dosage levels, does it not? So I would love to see this exact study done at about 10 different dosage levels with this study's dosage level being the lowest one. At what dosage level does RSV fight cancer? Does it fight cancer by reducing circulating IGF-1 levels or through some other means? And how does the extra RSV make a difference in outcomes?



Hmm, I agree. I would like to see this study expanded upon too, for the same reasons. Given the other studies regarding cancer I would speculate that different dosages of resveratrol can be taken for different reasons. An example of what I am thinking based on speculation of some of the studies we have seen and effects of increasing dose. CR Mimetic -> Life Extension -> Diabetes tx -> Cancer/Tumor supression .....yes this is pure speculation (and I repeat), but we have all seen studies showing these things. If everything translates over to humans ...... I would like to see Hedge's thoughts on this.

#7 mikeinnaples

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Posted 04 June 2008 - 12:48 PM

On a side note, I wonder if a heads up on this is what led the Sincalir group to sell to GSK. If low dosages of a readily available nutritional supplement can achieve a CR mimetic role, who needs 501? Well there were the NCE's, so .....

#8 maxwatt

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Posted 04 June 2008 - 01:46 PM

On a side note, I wonder if a heads up on this is what led the Sincalir group to sell to GSK. If low dosages of a readily available nutritional supplement can achieve a CR mimetic role, who needs 501? Well there were the NCE's, so .....


Low dose in mice does not translate to low dose in humans. Because humans have much more efficient mechanisms of glucuronidation and sulfonation, higher doses of resveratrol per unit body weight are needed in people vs. rodents. Many of us made the assumption that human dietary levels needed to be but 1/4 to 1/5 that of rodents, based on relative mass and surface area. Negatory. Based on relative serum levels for a given dose, humans would need perhaps 20 times the mg/kg level of a mouse. (Niner posted extensively on this.)

The paper (http://www.plosone.o...al.pone.0002264) did not specify the serum levels achieved in the mice, but I believe the mouse doses in this study translate to around 3 or 4 grams a day for a human.

NB, I think the reason Sirtris sold to Glaxo was the principles wanted the financial benefits of success up front, not after many years. I never thought I'd complain about doubling my money....

#9 Alistair

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Posted 04 June 2008 - 02:35 PM

More discussion here:

http://www.eurekaler...w-air060208.php

Best Regards,

Alistair

#10 mikeinnaples

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Posted 04 June 2008 - 02:48 PM

Low dose in mice does not translate to low dose in humans. Because humans have much more efficient mechanisms of glucuronidation and sulfonation, higher doses of resveratrol per unit body weight are needed in people vs. rodents. Many of us made the assumption that human dietary levels needed to be but 1/4 to 1/5 that of rodents, based on relative mass and surface area. Negatory. Based on relative serum levels for a given dose, humans would need perhaps 20 times the mg/kg level of a mouse. (Niner posted extensively on this.)

The paper (http://www.plosone.o...al.pone.0002264) did not specify the serum levels achieved in the mice, but I believe the mouse doses in this study translate to around 3 or 4 grams a day for a human.


3/4 grams with or without micronization/dispersing agent. If its 3/4 grams without, that could translate into under 1-2 grams easily through that.


I never thought I'd complain about doubling my money....


I hear you loud and clear. I am complaining about it too. ;)

Edited by mikeinnaples, 04 June 2008 - 02:48 PM.


#11 maxwatt

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Posted 04 June 2008 - 04:01 PM

Low dose in mice does not translate to low dose in humans. Because humans have much more efficient mechanisms of glucuronidation and sulfonation, higher doses of resveratrol per unit body weight are needed in people vs. rodents. Many of us made the assumption that human dietary levels needed to be but 1/4 to 1/5 that of rodents, based on relative mass and surface area. Negatory. Based on relative serum levels for a given dose, humans would need perhaps 20 times the mg/kg level of a mouse. (Niner posted extensively on this.)

The paper (http://www.plosone.o...al.pone.0002264) did not specify the serum levels achieved in the mice, but I believe the mouse doses in this study translate to around 3 or 4 grams a day for a human.


3/4 grams with or without micronization/dispersing agent. If its 3/4 grams without, that could translate into under 1-2 grams easily through that.


No, the human dose needs to be nearly 20 times the rodent dose per kg to achieve the same blood serum levels...

4.9 mg kg−1 day−1 * 75 kg * 20 = 7.5 grams. That is assuming humans need around 20 times the mouse dose to achieve the same serum levels due to metabolic differences in metabolism. I believe this is the figure (20x) that niner came up with given our efficiency compared to rodents at sulfonation and glucuronadation. It could be less, with micronization and other strategies to improve bioavailability, but not by an order of magnitude.

#12 Hedgehog

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Posted 04 June 2008 - 05:11 PM

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

http://www.plosone.o...al.pone.0002264

Published today. Key point 4.9mg/kg was used in the study.



Here is a dose calculator from the FDA. It allows you to put your weight and also height.

http://www.fda.gov/c...animalframe.htm

#13 maxwatt

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Posted 04 June 2008 - 05:58 PM

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

http://www.plosone.o...al.pone.0002264

Published today. Key point 4.9mg/kg was used in the study.



Here is a dose calculator from the FDA. It allows you to put your weight and also height.

http://www.fda.gov/c...animalframe.htm


This allows for different body masses. but it does not allow for different metabolic pathways in different species. That's the problem with trying to use the calculator other than as a first approximation. I also am not sure that they are using the right algorithm on the FDA website.

#14 inawe

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Posted 04 June 2008 - 06:07 PM

From reading the paper I only know they fed the mice about 4.9 mg/Kg per day of RSV. I cannot guess if the effects were due to the RSV in plasma and/or of any or all of the metabolites. So it's not easy to figure out what the equivalent human dose would be.
At the relatively low dose they used, RSV behaves as a partial CR mimetic as far as several metabolic markers. Except that "there was also no decrease in spontaneous tumors at the time of sacrifice". Since most mice die from cancer we can guess that RSV is not life extending for them.
They probably spent a lot of time on this work with more researchers than mice. So we can trust their conclusions. Like that they haven't seen much involvement of sirtuins in their analysis. Hopefully they are repeating the work with higher doses to see if there is an inverse U curve as far as benefits vs. dose.
"Both CR and resveratrol supplementation lowered blood glucose levels" in these mice. So how come there was no blood glucose lowering reported in ImmInst humans?

#15 mikeinnaples

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Posted 04 June 2008 - 06:15 PM

So how come there was no blood glucose lowering reported in ImmInst humans?


Didn't Sirtris release finding on glucose?

#16 maxwatt

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Posted 04 June 2008 - 06:21 PM

Thanks Mike. This is my favorite passage from the study: "We note that unlike CR, resveratrol did not reduce circulating IGF-1 levels (Figure 2B), and there was also no decrease in spontaneous tumors at the time of sacrifice (Supplemental Table S2). In particular, spontaneous liver tumors were abundant in mice fed the control diet or resveratrol, but rare in CR mice. Thus, although a low dose of resveratrol can improve quality of life by retarding aging parameters such as cardiac dysfunction, a nutritional or pharmaceutical strategy to also increase lifespan in mice will likely require blockage of the IGF-1 axis or its targets."

And yet RSV does appear to fight cancer at higher dosage levels, does it not? So I would love to see this exact study done at about 10 different dosage levels with this study's dosage level being the lowest one. At what dosage level does RSV fight cancer? Does it fight cancer by reducing circulating IGF-1 levels or through some other means? And how does the extra RSV make a difference in outcomes?


I believe resveratrol fights cancer by inhibiting the wnt pathway.

Folic acid modulates IGF-1; perhaps folic acid combined with resveratrol would more closely mimic caloric restriction?

Endocr Relat Cancer. 2006 Jun;13(2):571-81. Links
Folic acid and its metabolites modulate IGF-I receptor gene expression in colon cancer cells in a p53-dependent manner.Attias Z, Werner H, Vaisman N.
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

The insulin-like growth factor-I receptor (IGF-IR) has an important role in colorectal cancer development and progression. IGF-IR displays a potent anti-apoptotic activity and is overexpressed in primary tumors and colon cancer-derived cell lines. Folic acid, a member of the vitamin B family, is a chemopreventive agent whose deficiency has been linked to an enhanced colon cancer risk. The present study was aimed at testing the hypothesis that part of the modulatory effect of folic acid on malignant transformation may be attributed to its ability to regulate IGF-IR gene expression. Regulation of IGF-IR gene expression by folic acid was assessed using western blots, RT-PCR, transient transfections and chromatin immunoprecipitation assays. Activation of the IGF-IR signaling pathway was evaluated by measuring phosphorylation of ERK, and apoptosis was assayed using poly (ADP-ribose) polymerase cleavage and annexin V-FITC staining. Results obtained showed that folic acid induced a dose-dependent decrease in IGF-IR protein and mRNA levels in the HCT116 +/+ colon cancer cell line. This effect was associated with a significant reduction in IGF-IR promoter activity. Similar effects were elicited by the folic acid metabolites dihydrofolic acid and tetrahydrofolic acid. In addition, folic acid abrogated the IGF-I-stimulated phosphorylation of the downstream signaling molecule ERK1/2 and exhibited a pro-apoptotic activity. Moreover, folic acid induced a significant decrease in Sp1 binding to the IGF-IR promoter region. Finally, folic acid had no effect in wild-type p53-depleted HCT116 -/- and Caco-2 cells. In conclusion, the mechanism of action of folic acid involves regulation of IGF-IR gene expression. The ability of folic acid to downregulate the IGF-I signal transduction pathway may allow the micronutrient to function as a chemopreventive agent. Folic acid deficiency, on the other hand, may lead to increased IGF-IR gene expression, with ensuing pathological activation by endocrine and/or autocrine/paracrine IGF-I.

PMID: 16728583



#17 Anthony_Loera

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Posted 04 June 2008 - 06:23 PM

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

http://www.plosone.o...al.pone.0002264

Published today. Key point 4.9mg/kg was used in the study.



Here is a dose calculator from the FDA. It allows you to put your weight and also height.

http://www.fda.gov/c...animalframe.htm


This allows for different body masses. but it does not allow for different metabolic pathways in different species. That's the problem with trying to use the calculator other than as a first approximation. I also am not sure that they are using the right algorithm on the FDA website.



Maxwatt is right,
I would also say that once you have human plasma data (amount of res after oral dosage), it trumps any approximate calculations that do not use the data.

A

#18 krillin

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Posted 04 June 2008 - 07:56 PM

Folic acid modulates IGF-1; perhaps folic acid combined with resveratrol would more closely mimic caloric restriction?

Folate also prevents the age-related decline of insulin-like growth factor binding protein 3.

Gynecol Oncol. 2003 Nov;91(2):410-5.
In vitro downregulation of growth factors by insulin-like growth factor binding protein-3 in cervical cancer.
Mathur RS, Mathur SP.
Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC 29425, USA. mathurs@musc.edu

OBJECTIVES: Our hypothesis is that insulin-like growth factor binding protein 3 (IGF-BP3) would downregulate epidermal growth factor receptor (EGF-R) levels in cervical cancer cell lines, thereby reducing cellular IGF-II and angiogenesis-related vascular endothelial cell growth factor (VEGF). As folate deficiency is a risk factor in cervical cancer, we sought to determine if folic acid treatment might increase IGF-BP3 production, thereby inhibiting malignant cell proliferation. METHODS: We determined the cellular levels of EGF-R, IGF-II, and VEGF in the cervical cancer cell lines HeLa, ME-180 (both positive for human papilloma virus; HPV), and HT-3 (HPV-negative), following their treatment with IGF-BP3. Levels of IGF-BP3 in these cells before and after treatment with folic acid and VEGF were also enumerated, using a computerized semiquantitative immunofluorescent antibody assay. RESULTS: Treatment with IGF-BP3 significantly reduced the levels (mean intensity per pixel) of EGF-R, IGF-II, and VEGF in all three cell lines and IGF-I receptor (IGF-IR) in representative ME-180 cell line. Treatment with antiproliferative folic acid increased IGF-BP3 levels while the proliferative VEGF depleted cellular IGF-BP3 in all the cell lines. CONCLUSIONS: Levels of EGF-R, IGF-II, IGF-IR, and VEGF are significantly reduced following treatment with IGF-BP3 in cervical cancer. We observed increased levels of IGF-BP3 by folic acid, and decreased IGF-BP3 levels by VEGF. Downregulation of EGF-R by IGF-BP3 suggests an IGF-independent action. Folate deficiency is a risk factor in cervical cancer. Our results suggest that folic acid supplementation can lead to inhibition of cervical cancer cell growth by promoting increased IGF-BP3 levels.

PMID: 14599874

Carcinogenesis. 2004 Jan;25(1):69-76.
Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis.
Crott JW, Choi SW, Ordovas JM, Ditelberg JS, Mason JB.
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. jimmy.crott@tufts.edu

Folate depletion and aging are risk factors for colorectal cancer. We investigated the effects of folate status and aging on gene expression in the rat colon. Young (weanling) and older (12 month) rats were fed folic acid depleted (0 mg/kg) and supplemented (8 mg/kg) diets for 20 weeks. Gene expression was measured in colonic mucosal scrapings (n = 3 per group) using oligonucleotide arrays (Affymetrix U34A). Folate depletion induced the up-regulation of immune-related genes, urokinase and inducible nitric oxide synthase and the down-regulation of adhesion molecules (protocadherin-4, nidogen and integrin alphaV) and vascular endothelial growth factor in young rats. The abbreviated response to depletion in old rats (62 changes versus 136 in the young) included up-regulation of caspase-2 and deleted in colon cancer. Gene expression changes due to aging were more abundant in folate depleted than supplemented rats (38 versus 119 genes, respectively). In folate-deficient rats, aging induced the down-regulation of immune-related genes, urokinase, p53, insulin-like growth factor binding protein-3 and vav-1 oncogene. In folate supplemented rats, aging induced the down-regulation of vascular endothelial growth factor and caspase-2. Lower expression of adhesion molecules and higher expression of urokinase with folate depletion in young rats may indicate that cell detachment and migration, cancer-related processes, may be modulated by folate status. An age-related decline in p53 and IGF-BP3 expression was only observed in folate depleted animals, indicating that folate supplementation may reduce the risk for age-associated cancers by suppressing deleterious changes in the expression of certain genes.

PMID: 12970065

#19 maxwatt

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Posted 04 June 2008 - 08:17 PM

Folic acid modulates IGF-1; perhaps folic acid combined with resveratrol would more closely mimic caloric restriction?

Folate also prevents the age-related decline of insulin-like growth factor binding protein 3.
...
PMID: 14599874
...
PMID: 12970065


The question is what dose of folate would be appropriate combined with resveratrol?

I think it would be between 400 and 800 mg per day.

#20 stephen_b

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Posted 04 June 2008 - 08:32 PM

think it would be between 400 and 800 mg per day.

Ortho-core has 800 mcg of folic acid. Are you possibly off by a factor of 1000?

Stephen

#21 Hedgehog

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Posted 04 June 2008 - 10:41 PM

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

http://www.plosone.o...al.pone.0002264

Published today. Key point 4.9mg/kg was used in the study.



Here is a dose calculator from the FDA. It allows you to put your weight and also height.

http://www.fda.gov/c...animalframe.htm


This allows for different body masses. but it does not allow for different metabolic pathways in different species. That's the problem with trying to use the calculator other than as a first approximation. I also am not sure that they are using the right algorithm on the FDA website.



Maxwatt is right,
I would also say that once you have human plasma data (amount of res after oral dosage), it trumps any approximate calculations that do not use the data.

A


For a person 150lbs, 68inchs and wants 4.9mg/kg this FDA calculator says you need a dose of 334.09mg of

Based on a rat model that took 50mg/kg you get a plasma concentration of 548ng/mL and if you scale it down you could assume you get a plasma concentration of 53.68ng/mL if you give a rat a 4.9mg/kg dose.

Assume that the boocock paper (human plasma data) is correct which in a 500mg dose they achieved a 72ng/mL level. If we assume the average person in the study is 150lbs or 68kg then the dosage per kg is 7.4mg/kg. This also achieves a higher plasma concentration then what is seen in the rat model. If you do the conversion you need to take about 350mg dose to achieve a plasma concentration of 53ng/mL.

The FDA formula suggested 334mg human dose would be equivalent. So IMO it is pretty close

This math assumes lots of things.... (mainly weight of a person and of the rats they used)

Edited by Hedgehog, 04 June 2008 - 10:42 PM.


#22 Hedgehog

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Posted 04 June 2008 - 10:47 PM

Wow. This is huge. As measured by changes in gene expression, resveratrol is a CR mimetic in mice. It looks like really nice work. Yes, there was some funding by DSM, a manufacturer of, among other things, resveratrol, but from the disclosure it doesn't look like the study is corrupted by it. I haven't finished reading it, but so far I don't see anything wrong. Now all we need to see is life extension in well-husbanded mice with a healthy diet. Based on the results of this study, it would not be unexpected. (But is not a given.) It would be straightforward to run this experiment on humans, with a restricted set of tissues. (No heart or brain) The dose employed here was a quite reasonable 5mg/kg body weight, or 350 mg/day for the canonical 70kg human. However, given the difference in ability to conjugate resveratrol between mice and humans, a comparable human dose might be 1-2g/day. This might be reduced by improved formulation.

Mike, thanks for a great find.



I just spent a bunch of time doing a calculation of a the human dosage based on human and animal plasma studies... You got the same value as me... Did you just guess this value?

#23 niner

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Posted 05 June 2008 - 12:30 AM

Wow. This is huge. As measured by changes in gene expression, resveratrol is a CR mimetic in mice. It looks like really nice work. Yes, there was some funding by DSM, a manufacturer of, among other things, resveratrol, but from the disclosure it doesn't look like the study is corrupted by it. I haven't finished reading it, but so far I don't see anything wrong. Now all we need to see is life extension in well-husbanded mice with a healthy diet. Based on the results of this study, it would not be unexpected. (But is not a given.) It would be straightforward to run this experiment on humans, with a restricted set of tissues. (No heart or brain) The dose employed here was a quite reasonable 5mg/kg body weight, or 350 mg/day for the canonical 70kg human. However, given the difference in ability to conjugate resveratrol between mice and humans, a comparable human dose might be 1-2g/day. This might be reduced by improved formulation.

Mike, thanks for a great find.


I just spent a bunch of time doing a calculation of a the human dosage based on human and animal plasma studies... You got the same value as me... Did you just guess this value?

It's just 5mg/kg * 70kg = 350mg. That appears to be all the FDA calculator is doing; I don't know what it uses height for.

#24 niner

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Posted 05 June 2008 - 12:43 AM

Low dose in mice does not translate to low dose in humans. Because humans have much more efficient mechanisms of glucuronidation and sulfonation, higher doses of resveratrol per unit body weight are needed in people vs. rodents. Many of us made the assumption that human dietary levels needed to be but 1/4 to 1/5 that of rodents, based on relative mass and surface area. Negatory. Based on relative serum levels for a given dose, humans would need perhaps 20 times the mg/kg level of a mouse. (Niner posted extensively on this.)

The paper (http://www.plosone.o...al.pone.0002264) did not specify the serum levels achieved in the mice, but I believe the mouse doses in this study translate to around 3 or 4 grams a day for a human.


3/4 grams with or without micronization/dispersing agent. If its 3/4 grams without, that could translate into under 1-2 grams easily through that.


No, the human dose needs to be nearly 20 times the rodent dose per kg to achieve the same blood serum levels...

4.9 mg kg−1 day−1 * 75 kg * 20 = 7.5 grams. That is assuming humans need around 20 times the mouse dose to achieve the same serum levels due to metabolic differences in metabolism. I believe this is the figure (20x) that niner came up with given our efficiency compared to rodents at sulfonation and glucuronadation. It could be less, with micronization and other strategies to improve bioavailability, but not by an order of magnitude.

Maxwatt, I think you misremembered that. The ratio I came up with here, based on blood levels was about 4x the rodent dose. So that would be in the 1-2 gram ballpark.

#25 edward

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Posted 05 June 2008 - 04:22 AM

handy Rat to Human dose calculation. I forget where I found this, I think it was on some FDA toxicity and lethality of compounds article but it seems to work well. I've used it for Res Calculations, Deprenyl Calculations and pretty much anything that I take that I want to mimic a Rat study. Once you get the final answer then you will need to look at the specific compound being used and its metabolism to see if there are any differences between Rats and Humans in the breaking down of the compound.

Rat Dosage in mg * (human kg/.344kg)^.667 = human dosage for given kg

.344 kg is the average lab rat weight

so in this case using me as an example

4.9 mg (74 kg/.344 kg)^.667 = 176.234 mg per day (pretty darn small dose)

So "if" it is the case that you need 4x the amount of an equivalent rat dosage due to Res' specific metabolism then by my calculation that would be

4x 176.2304 = 704.936

#26 edward

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Posted 05 June 2008 - 04:27 AM

... but I am far from an expert in animal to human dosages, I work with humans, so I defer to Niner, but 705 mg seems like a reasonable equivalent

edit: I will still be taking my daily 2 grams + though

Edited by edward, 05 June 2008 - 04:29 AM.


#27 TianZi

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Posted 05 June 2008 - 06:53 AM

From my perspective as an unlettered layman, I noticed many interesting findings in this study.

1. The CR diet used in the study seems rather mild, as it only increased average and maximum lifespan by 13%, a result that was "expected" by the researchers. So when the study refers to CR, it refers to the specific diet used in this study. I wonder if a stricter CR diet triggers further anti-aging effects different not only in magnitude but in kind.

2."CR and resveratrol do not alter SIRT1 levels"

Quite the opposite of Sirtris' findings. Or are we comparing apples and oranges? As per the conclusion of this study, "It is likely that the effects of resveratrol feeding at lower doses reported here are distinct than [sic] those observed with higher doses, with particular relevance to the induction of SIRT1 activity."

Sirtris has claimed, I believe, that a fairly significant dose of resveratrol is required to trigger increased SIRT1 activity. Could it be that certain anti-aging effects of resveratrol are independent of SIRT1 activity (i.e., those supported by the findings in this study), while others, not discovered by this study perhaps because the dose of resveratrol was too low to trigger SIRT 1 activity, are dependent on it?

3. "Surprisingly, because we observed a large overlap of transcriptional shifts induced by resveratrol and CR in all organs examined, our findings also suggest that a large component of the transcriptional program induced by CR may be independent of CR-mediated alterations in plasma IGF-1, or insulin. This conclusion is supported by the finding that dwarfism and CR may impact lifespan through independent mechanisms [19], and the finding that GH deficiency and CR display minimal overlap at the gene expression level [20]."

I believe U. of Wisconsin researchers have argued for a while that low growth hormone levels are not a prerequisite for extension of lifespan via CR. Good news since higher levels of growth hormone (triggered endogenously by things like deep sleep and especially vigorous weight training) have a number of beneficial anti-aging effects, and numerous studies have shown anti-aging and life extending effects resulting from increased levels of GH (although levels that are too high are certainly dangerous, a problem with exogenous supplementation of GH). However, the finding of "abundant liver tumors" only in the resveratrol and control groups, but not the CR group, is troubling.

I note in passing that other resveratrol studies have found a cancer inhibiting effect not found in this study, perhaps because the dose of resveratrol was too low here. Also, there is a conflict among studies regarding GH levels in mice on a CR diet--at least two studies have found higher GH levels in mice on a CR diet (I've posted before about this conflict).

4. "... [O]ur observations do not indicate lowering of spontaneous levels of oxidative damage by either CR or resveratrol."

How did the dose of resveratrol given in studies that found a lowering of oxidative damage compare with that used in this study? Were the same breeds of mice being used?

5. "Long-lived F1 hybrid mice" were used in the study. Are these particular "hybrid" mice similar, or substantially different, from mice used in other similar studies?

#28 maxwatt

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Posted 05 June 2008 - 10:25 AM

Low dose in mice does not translate to low dose in humans. Because humans have much more efficient mechanisms of glucuronidation and sulfonation, higher doses of resveratrol per unit body weight are needed in people vs. rodents. Many of us made the assumption that human dietary levels needed to be but 1/4 to 1/5 that of rodents, based on relative mass and surface area. Negatory. Based on relative serum levels for a given dose, humans would need perhaps 20 times the mg/kg level of a mouse. (Niner posted extensively on this.)

The paper (http://www.plosone.o...al.pone.0002264) did not specify the serum levels achieved in the mice, but I believe the mouse doses in this study translate to around 3 or 4 grams a day for a human.


3/4 grams with or without micronization/dispersing agent. If its 3/4 grams without, that could translate into under 1-2 grams easily through that.


No, the human dose needs to be nearly 20 times the rodent dose per kg to achieve the same blood serum levels...

4.9 mg kg−1 day−1 * 75 kg * 20 = 7.5 grams. That is assuming humans need around 20 times the mouse dose to achieve the same serum levels due to metabolic differences in metabolism. I believe this is the figure (20x) that niner came up with given our efficiency compared to rodents at sulfonation and glucuronadation. It could be less, with micronization and other strategies to improve bioavailability, but not by an order of magnitude.

Maxwatt, I think you misremembered that. The ratio I came up with here, based on blood levels was about 4x the rodent dose. So that would be in the 1-2 gram ballpark.


Thanks. That also seems to be the dose I've settled on for my own use based on trying different doses and gauging my body's response.
And yes the folate dose I mentioned should have been mcg not mg.

#29 mikeinnaples

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Posted 05 June 2008 - 12:49 PM

Think about a monsoon rain.....a few drops cools things down a bit and freshens the air, a light drizzle causes plants to grow, a down pour causes puddles and localized flooding, and a torrential blinding rain causes wide spread flooding and mudslides.

The conversation in this thread reinforces my logical thoughts on the subject about scale. I think the trick is going to revolve around figuring out what dosage gives which set of desired responses.

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

#30 inawe

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Posted 05 June 2008 - 06:05 PM

This paper by Weindruch et al. doesn't seem to jibe with previous
papers by the Sinclair group. Am I the only one bothered by this?
Furthermore, Weindruch and Sinclair get together at events and carry
on as if they were on the same page. There was a longevity event at
the New York University hall. Among others, both these guys were in
attendance and gave talks. From a report of the event:
[Weindruch said his research, which began by showing how consuming little food could
greatly increase the life spans of mice, moved on in 1989 to a
long-term study on monkeys that can live up to 40 years. "Just now
we're starting to see statistically significant improvements in
survival and resistance to disease and favorable effects on brain
aging," he said. He said his team hopes to publish these results soon.
Sinclair said that based on Weindruch's work, he set out a decade ago
to find the genes involved in caloric restriction and find a pill that
can provide the benefits "without you feeling hungry all the time." He
described how his research found that mice given large doses of
resveratrol "live longer, they're almost immune to the effects of
obesity. They don't get diabetes, cancer, Alzheimer's as frequently.
We delay the diseases of aging." Sinclair showed video of mice on
resveratrol running on a treadmill far more vigorously than those who
didn't get the substance. He called them "our Lance Armstrong mice."]
Now, if I understood anything from Weindruch's paper, one of the
conclusions was "neither CR nor resveratrol feeding significantly altered the
levels of SIRT1 protein in brain or liver of mice, and SIRT1 abundance
was actually significantly decreased in both heart and muscle of CR
mice".
So SIRT1 has nothing to do with what RSV is doing? Are Weindruch and
Prolla going to start a new company SIRTISN"T?




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