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Effect of 36 Polyphenols on SIRT1 p53 deacetylase


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#1 maxwatt

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Posted 01 January 2011 - 01:19 AM


I would like to call attention to this paper. The abstract gives just a hint of what the authors have actually accomplished. Biomol's Fluor de Lys peptide was shown to be necessary for resveratrol to activate SIRT1(1), casting doubt on the SIRT1 activity of this and of many other substances that had shown a positive response. The authors developed an alternate assay for SIRT1 activity, using an acetylated peptide of p53 as a substrate. They then evaluated 36 substances, including many that Sirtris had evaluated, and came up with somewhat different conclusions.

It turned out that resveratrol was not the most potent activator of SIRT1; piceatannol was almost three times more potent. Several other substances were about as effective as resveratrol. Some substances that had been reported as activators or SIRT1 turned out to inhibit its activity; among these was quercetin, as I've long suspected. I am going to post the tables showing relative potencies in a follow-up.

J Pharmacol Sci. 2008 Nov;108(3):364-71. Epub 2008 Nov 13.

A novel chalcone polyphenol inhibits the deacetylase activity of SIRT1 and cell growth in HEK293T cells.
Kahyo T, Ichikawa S, Hatanaka T, Yamada MK, Setou M.

Mitsubishi Kagaku Institute of Life Sciences (MITILS), Machida, Tokyo, Japan.

Abstract
SIRT1 is one of seven mammalian orthologs of yeast silent information regulator 2 (Sir2), and it functions as a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase. Recently, resveratrol and its analogues, which are polyphenols, have been reported to activate the deacetylase activity of SIRT1 in an in vitro assay and to expand the life-span of several species through Sir2 and the orthologs. To find activators or inhibitors to SIRT1, we examined thirty-six polyphenols, including stilbenes, chalcones, flavanones, and flavonols, with the SIRT1 deacetylase activity assay using the acetylated peptide of p53 as a substrate. The results showed that 3,2',3',4'-tetrahydroxychalcone, a newly synthesized compound, inhibited the SIRT1-mediated deacetylation of a p53 acetylated peptide and recombinant protein in vitro. In addition, this agent induced the hyperacetylation of endogenous p53, increased the endogenous p21CIP1/WAF1 in intact cells, and suppressed the cell growth. These results indicated that 3,2',3',4'-tetrahydroxychalcone had a stronger inhibitory effect on the SIRT1-pathway than sirtinol, a known SIRT1-inhibitor. Our results mean that 3,2',3',4'-tetrahydroxychalcone is a novel inhibitor of SIRT1 and produces physiological effects on organisms probably through inhibiting the deacetylation by SIRT1.

PMID: 19008647


(1) Chem Biol Drug Des. 2009 Dec;74(6):619-24. Epub 2009 Oct 20. Resveratrol is not a direct activator of SIRT1 enzyme activity. Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M.

Edited by maxwatt, 01 January 2011 - 04:46 PM.
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#2 maxwatt

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Posted 01 January 2011 - 02:06 AM

Attached File  Table 1 Polyphenols' effect on deacetylase activity of SIRT1.JPG   47.68KB   340 downloads

Attached File  Figure 1 Chemical Structures of Polyphenols.JPG   70.59KB   293 downloads

Unfortunately the polyphenols in Table 1 are not named, but their structures can be found from Figure 1.

Compound 1 is resveratrol, 2 is piceatannol. Butein is compound 11, isoliquiritigenin compound 12, fisetin compound 29, and quercetin is compound 30. Myricetin is compound 35. Luteolin is 27.


(click on the images to enlarge; there will be a button in the lower right to download.)

Edited by maxwatt, 01 January 2011 - 02:08 AM.

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#3 niner

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Posted 01 January 2011 - 04:21 AM

Nice find.. Maybe we would have found it sooner if it didn't have such a nondescript title. One thing that strikes me is that all these compounds were run at 100 uM, which is non-physiological. Considering that, aside from a couple of the chalcones, these compounds don't really have that big of an effect on deacetylation, one way or the other- It's all within a factor of 3, mostly less than that. I wouldn't expect to see much at all at physiologic concentration. This all seems to say that Sirt's not the whole story.

#4 mikeinnaples

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Posted 01 January 2011 - 03:52 PM

This explains a few recent sales from certain supp manufacturers.

#5 maxwatt

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Posted 01 January 2011 - 05:10 PM

This explains a few recent sales from certain supp manufacturers.

Probably not. It's like any boom-and-bust; while resveratrol sales were growing rapidly, the price was high. The increase in sales has slowed, though it is still rising. Meanwhile manufacturers have stocked up in anticipation of an increase in demand that did not happen. While they work off their inventory, there will be bargains.

Quercetin is perhaps another matter, but it does seem to have some beneficial effects, and I recall a rodent study where it extended life-span. And as niner pointed out, Sirt1 is not the whole story. Besides Sirt1 (and 3,4,5, and I believe 7) resveratrol activates CLK1 and CLK2, inhibits nf-Kappa-B, agonizes PPAR-alpha, etc.

Luteolin seems to be a more potent activator of SIRT1 than resveratrol, but is much less studied. Pubmed shows cardio-protective effects and some anti-tumor activity. However a researcher I obtained some for found it had no effect on skin tumors in nude mice; perhaps too low a dose? it was administered in drinking water, and it is not really water soluble.

Myricetin according to Setou's paper inhibits SIRT1, yet it has very positive effects for lowering blood glucose and improving insulin sensitivity in rodents. Herbs high in myricetin content are used in Chinese medicine to treat diabetes. There are papers showing a very potent anti-cancer effect.

Perhaps cycling varous polyphenols, such as resveratrol and myricetin, would be beneficial. Or maybe not; it's not been studied.

#6 david ellis

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Posted 02 January 2011 - 05:59 PM

Attached File  Table 1 Polyphenols' effect on deacetylase activity of SIRT1.JPG   47.68KB   340 downloads

Attached File  Figure 1 Chemical Structures of Polyphenols.JPG   70.59KB   293 downloads

Unfortunately the polyphenols in Table 1 are not named, but their structures can be found from Figure 1.

Compound 1 is resveratrol, 2 is piceatannol. Butein is compound 11, isoliquiritigenin compound 12, fisetin compound 29, and quercetin is compound 30. Myricetin is compound 35. Luteolin is 27.


(click on the images to enlarge; there will be a button in the lower right to download.)


Thanks for this post, Max. Your post resulted in some encouraging reading in polyphenol research for me.

#7 maxwatt

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Posted 02 January 2011 - 08:28 PM

Glad you found the paper helpful. FWIW, the strongest SIRT1 agonist in the study, piceatannol, is a major metabolite of resveratrol. It's possible this accounts for the effects some of us have noted with resveratrol despite studies showing consistently low serum levels with oral administration: CYP1A1 and CYP1A2 convert it to piceatannol, which in turn is biologically active.

#8 PWAIN

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Posted 03 January 2011 - 06:18 AM

Does anyone know what compounds 6 and 7 are? Is there a way to find out? Might be worth using a combination of compounds. Also may be either cheaper or more easily available.

#9 mikeinnaples

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Posted 03 January 2011 - 12:57 PM

Does anyone know what compounds 6 and 7 are? Is there a way to find out? Might be worth using a combination of compounds. Also may be either cheaper or more easily available.


Looking at the paper briefly, I couldnt see a way to determine what all the others were. A few were explicitly listed, but umm yeah.

#10 maxwatt

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Posted 03 January 2011 - 01:42 PM

Does anyone know what compounds 6 and 7 are? Is there a way to find out? Might be worth using a combination of compounds. Also may be either cheaper or more easily available.

They are not available in quantity, and their effects have not been evaluated as thoroughly as resveratrol's. As piceatanol (compound 2, the most potent SIRT1 agonist) is a major metabolite of resveratrol, you make your own internally when you take resveratrol.

I find it interesting that luteolin (compound 27) is slightly more potent an activator of SIRT1. It is also a PDE4 inhibitor, possibly useful for asthma, but again it's not been as well studied as resveratrol, particularly in humans. It inhibits sulfotransferase enzymes, which in theory would make resveratrol more bioavailable since it would slow down its elimination from the body. Having taken it in conjunction with resveratrol, I can say that it seemed to increase the effects of resveratrol. Unfortunately this included the joint pain that some experience as a side-effect from resveratrol, said pain resolved once I increased my D-25 hydroxy levels by taking vitamin D3. Whether the effects were from increasing resveratrol levels or by virtue of luteolin's effects on Sirt1 and P53 deacetylase, I do not know. I've not resumed luteolin use, though I am considering it.

#11 maxwatt

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Posted 06 March 2011 - 10:55 AM

Compound 10 is pterostilbene, its SIRT1 activity is reported as 1.86 vs 1.29 for resveratrol. It is also more readily absorbed, in that blood serum levels are reported to be four times as high as an equivalent dose of resveratrol (pmid 21116625). Pterostilbene has also been reported to inhibit nf-kappa-B (like resveratrol), and to lower blood sugar in rodents as effectively as metformin.

#12 peteo

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Posted 08 March 2011 - 09:58 PM

Attached File  Table 1 Polyphenols' effect on deacetylase activity of SIRT1.JPG   47.68KB   340 downloads

Attached File  Figure 1 Chemical Structures of Polyphenols.JPG   70.59KB   293 downloads

Unfortunately the polyphenols in Table 1 are not named, but their structures can be found from Figure 1.

Compound 1 is resveratrol, 2 is piceatannol. Butein is compound 11, isoliquiritigenin compound 12, fisetin compound 29, and quercetin is compound 30. Myricetin is compound 35. Luteolin is 27.


(click on the images to enlarge; there will be a button in the lower right to download.)


Thanks for this post, Max. Your post resulted in some encouraging reading in polyphenol research for me.


So are there any piceatannol supplements? or can you get enough just taking pure resveratrol

#13 bernard

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Posted 15 December 2012 - 06:17 PM

It turned out that resveratrol was not the most potent activator of SIRT1; piceatannol was almost three times more potent. Several other substances were about as effective as resveratrol. Some substances that had been reported as activators or SIRT1 turned out to inhibit its activity; among these was quercetin, as I've long suspected. I am going to post the tables showing relative potencies in a follow-up.


How come you think that Quercetin inhibist Sirt1 ? Quercetin exerts many of the effects of sirt1 activators such as mitochondrial biogenesis. While several papers state that quercetin is very mild sirt1 activator how much state that it actually inhibits sirt1 ?

#14 maxwatt

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Posted 15 December 2012 - 09:27 PM

It turned out that resveratrol was not the most potent activator of SIRT1; piceatannol was almost three times more potent. Several other substances were about as effective as resveratrol. Some substances that had been reported as activators or SIRT1 turned out to inhibit its activity; among these was quercetin, as I've long suspected. I am going to post the tables showing relative potencies in a follow-up.


How come you think that Quercetin inhibist Sirt1 ? Quercetin exerts many of the effects of sirt1 activators such as mitochondrial biogenesis. While several papers state that quercetin is very mild sirt1 activator how much state that it actually inhibits sirt1 ?


Read the paper; it was their finding using a more accurate assay than Biomol's test kit. But Sirt1 is not the only target of resveratrol (or quercetin) and may not even be the most important one,

#15 bernard

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Posted 15 December 2012 - 10:26 PM

Resveratrol was actually debunked as a Sirt1 activator. GSK dropped the research on it. Latest hype are small molecules.

#16 Fred_CALICO

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Posted 16 December 2012 - 01:14 AM

Attached File  Table 1 Polyphenols' effect on deacetylase activity of SIRT1.JPG   47.68KB   340 downloads

Attached File  Figure 1 Chemical Structures of Polyphenols.JPG   70.59KB   293 downloads

Unfortunately the polyphenols in Table 1 are not named, but their structures can be found from Figure 1.

Compound 1 is resveratrol, 2 is piceatannol. Butein is compound 11, isoliquiritigenin compound 12, fisetin compound 29, and quercetin is compound 30. Myricetin is compound 35. Luteolin is 27.


(click on the images to enlarge; there will be a button in the lower right to download.)


Thanks for this post, Max. Your post resulted in some encouraging reading in polyphenol research for me.


So are there any piceatannol supplements? or can you get enough just taking pure resveratrol


Resveratrol is hydroxylated piceatannol (3,5,3 ', 4'-tetrahydroxystilbene) and X tetrahydroxystilbene unidentified.
http://books.google....AAJ&redir_esc=y

#17 Fred_CALICO

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Posted 16 December 2012 - 01:34 AM

Extract from a thesis in my "neighborhood" ... the french paradox

http://ressources-nu...DERIC_00_00.pdf


Complex natural mixtures of red wine polyphenols show their ability to stop the proliferation of cancer cells in vitro. But this slowdown seems less specifically related to a blockage in one particular phase of the cell cycle, as can be seen with resveratrol or quercetin for example, but rather an overall slowdown in all phases of the cell cycle. The diversity of phenolic compounds present in wine and diversity of activities are also an argument in favor of this hypothesis. Each of these molecules using multiple channels and each channel is used by several molecules, red wine polyphenols may together form a mesh and biological pathways of great complexity. Synergistic effects may exist between certain molecules in some ways, but also contradictory effects, as we have seen with combinations of resveratrol, quercetin and catechin on HCT116 cells. We have not clearly demonstrated strong synergy of actions of wine polyphenols on a specific mechanism, but this study has revealed a set of effects (such as
antiproliferative synergy between resveratrol and quercetin) that individually could be considered minimal, but which together combine to inhibit the proliferative activity of tumor cells.


...


Concentrates and extracts all exhibit antiproliferative capacity of cells SW480 human colon cancer from. The inhibition of proliferation is correlated with the total polyphenol concentration for the same wine. The extract appears wine Corbières able to act effectively in relatively low doses. Although variations in sensitivity between different cells tests make it impossible for a direct comparison with experimental wines of Burgundy, it seems that this extract Corbières wine is much more efficient in terms of inhibition of cell proliferation. Should be Repeat testing in similar conditions to clarify this point.
In addition, extracts of Burgundy wines of 2008 and 2009 do not have the same capabilities at antiproliferative concentrations of polyphenols equal. Wines that have undergone the maceration longest show an inhibitory power more important. If the IC50 is not correlated perfectly with the maceration time, these variations indicate all of well as the quality of polyphenols is an essential element in their effectiveness. Wines and the most effective are those whose contents gallic acid, catechin and epicatechin are the most important.
Cancer cells are sensitive to resveratrol and quercetin, which may act synergistically in limiting their proliferation. This inhibition is at least partly due to blocking S phase of the cell cycle, but studies of the cell cycle does not explain the synergistic 133effets. Low concentrations used in these tests do not induce cell death real either by necrosis or apoptosis, this mechanism does not seem to be taken into account to explain the decrease in the number of cells.
Paradoxically, wines with the lowest levels of quercetin and resveratrol are those for which we observed the best efficiencies against the antiproliferative
SW480 cells.

#18 bernard

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Posted 16 December 2012 - 01:28 PM

You should know that the french paradox is a term coined to describe not the health of the french but the fact that french cuisine is rather greasy and heavy but the majority of the french people are not fat. This was attributed to some effects in the wine, however I can tell you straight away that all alcohols are linked with negative calorie partitioning (meaning more energy becomes fat and less becomes glycogen in lean tissue) so I'm not sure that wine is any good. Plus there are multiple studies showing that even miniscule amounts of alcohol are detrimental for brain cell health. That's why most of the longevity experts nowaday have shied away from the "little alcohol every day is good" thesis.
Important: My parents drink 3-4 glasses of quality wine every day. However both have major health issues. One has it all (diabetes, gout, high blood pressure etc.) and the other has a benign tumor growing - so much for the anti-tumor properties of wine and resveratrol.

#19 Fred_CALICO

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Posted 16 December 2012 - 01:47 PM

I moved the conversation to :

http://www.longecity...choose-why-bye/

#20 maxwatt

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Posted 16 December 2012 - 02:48 PM

Resveratrol was actually debunked as a Sirt1 activator. GSK dropped the research on it. Latest hype are small molecules.


I think this is misleading; there were papers claiming resveratrol did not activate Sirt1 from competing labs to Sinclair's, but several times as many showing that it did. Possibly a matter of technique used in different labs. If you the read the paper I linked to in the first post in this thread, as I suggested you do earlier, they found resveratrol was a strong Sirt1 activator. As this was an assay by a different technique than Biomol's I would say the evidence leans strongly toward resveratrol activating Sirt1. Glasco dropping resveratrol was based on commercial considerations, they continued to work on Sirtris' other lead Sirt1 activating compounds before ultimately dropping them to. I hope Sinclair was laughing all the way to the bank.

And again, Sirt1 is not everything, as Sell58 was pointing out.

#21 Hebbeh

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Posted 16 December 2012 - 02:53 PM

I thought I remember research indicating resveratrol activated Sirt1 not directly but through downstream pathways?

#22 maxwatt

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Posted 16 December 2012 - 02:55 PM

Attached File  Table 1 Polyphenols' effect on deacetylase activity of SIRT1.JPG   47.68KB   340 downloads

Attached File  Figure 1 Chemical Structures of Polyphenols.JPG   70.59KB   293 downloads

Unfortunately the polyphenols in Table 1 are not named, but their structures can be found from Figure 1.

Compound 1 is resveratrol, 2 is piceatannol. Butein is compound 11, isoliquiritigenin compound 12, fisetin compound 29, and quercetin is compound 30. Myricetin is compound 35. Luteolin is 27.


(click on the images to enlarge; there will be a button in the lower right to download.)


Thanks for this post, Max. Your post resulted in some encouraging reading in polyphenol research for me.


So are there any piceatannol supplements? or can you get enough just taking pure resveratrol


Resveratrol is hydroxylated piceatannol (3,5,3 ', 4'-tetrahydroxystilbene) and X tetrahydroxystilbene unidentified.
http://books.google....AAJ&redir_esc=y


I believe piceatannol is a major metabolite of resveratrol.

#23 maxwatt

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Posted 16 December 2012 - 03:06 PM

You should know that the french paradox is a term coined to describe not the health of the french but the fact that french cuisine is rather greasy and heavy but the majority of the french people are not fat. This was attributed to some effects in the wine, however I can tell you straight away that all alcohols are linked with negative calorie partitioning (meaning more energy becomes fat and less becomes glycogen in lean tissue) so I'm not sure that wine is any good. Plus there are multiple studies showing that even miniscule amounts of alcohol are detrimental for brain cell health. That's why most of the longevity experts nowaday have shied away from the "little alcohol every day is good" thesis.
Important: My parents drink 3-4 glasses of quality wine every day. However both have major health issues. One has it all (diabetes, gout, high blood pressure etc.) and the other has a benign tumor growing - so much for the anti-tumor properties of wine and resveratrol.


Sorry to hear about your parents.

Most here are well aware of the French paradox being impossible to draw any conclusions from.
At this point Doctor seem to recoment 1 to 1.5 glasses of wine, if one already drinks wine. It does seem to provide some protection against fat deposition in arteries, but the evidence is based on population studies, which are not predictive for any one individual.

More on wine polyphenols here:
http://www.longecity...ne/#entry547943

As for ethanol killing brain cells, maybe it only kills the weak ones? :p

Posted Image

Edited by maxwatt, 16 December 2012 - 03:11 PM.


#24 bernard

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Posted 16 December 2012 - 06:06 PM

Sounds like you've already made your mind on the topic and don't want to let go of that idea.
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#25 maxwatt

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Posted 16 December 2012 - 08:23 PM

Sounds like you've already made your mind on the topic and don't want to let go of that idea.

Sounds like you've already made your mind on this and other topics and don't want to let go of your ideas despite any evidence to the contrary.

In any case the topic has drifted from its original subject, calling attention to an alternate Sirt1 assay to Biomol's possibly faulty Fleur de Lys assay. It was bumped by Sell58's post on the effects of mixed polyphenols which now has its own discussion topic here. http://www.longecity...choose-why-bye/

If you want to start a topic on the effects, benefits or lack thereof from wine or alcohol, please do. i have no iron in that fire, others may. But i am closing this topic so what information came to light does not get buried under irrelevant posts, and any new topics introduced can stand on and be considered on their own.

Edited by maxwatt, 16 December 2012 - 08:38 PM.

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