Resveratrol does [NOT] directly activate SIRT1

[NO HYPE]

J Biol Chem (2010) 0: .
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

M Pacholec, BA Chrunyk, D Cunningham, D Flynn, DA Griffith, M Griffor, P Loulakis, B Pabst, X Qiu, B Stockman, V Thanabal, A Varghese, J Ward, J Withka, K Ahn

Sirtuins catalyze NAD+-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism and aging. There are seven human sirtuins (SIRT1-7) and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full length protein substrates, while they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

http://www.mitochondrial.net/showabs...y%2BNewsletter

[nunes]

J Biol Chem (2010) 0: .
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

M Pacholec, BA Chrunyk, D Cunningham, D Flynn, DA Griffith, M Griffor, P Loulakis, B Pabst, X Qiu, B Stockman, V Thanabal, A Varghese, J Ward, J Withka, K Ahn

Sirtuins catalyze NAD+-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism and aging. There are seven human sirtuins (SIRT1-7) and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full length protein substrates, while they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

http://www.mitochondrial.net/showabs...y%2BNewsletter

good post nh but whats your personal comments on that?

[SIRT1]

Interesting

[GeneGnomeX]

This and a couple other relevant articles posted in this thread: http://forum.bodybuilding.com/showth...#post437942981

It seems that resveratrol directly activates AMPK which then activates sirt1. Experimental artifact it appears.

[ElHombre]

check out this blog post by arguably the best known drug developer blogger:

http://pipeline.corante.com/archives...ess_really.php

^^lot's of interesting comments and links following his post


http://pipeline.corante.com/archives...eratrol_do.php
^an earlier post on these suspicions

i just say: drink the damn wine itself.

[Sldge]

i just say: drink the damn wine itself.

This is probably the best idea when it comes to res. IMO people are over extracting it trying to isolate higher amounts of res not realizing that there is obviously something else in wine that either helps in its use or another compound all together like pterostillbene. Either way lower extracts or wine itself would be better then most of the 50%+ extracts we see being used now.

[GeneGnomeX]

This is probably the best idea when it comes to res. IMO people are over extracting it trying to isolate higher amounts of res not realizing that there is obviously something else in wine that either helps in its use or another compound all together like pterostillbene. Either way lower extracts or wine itself would be better then most of the 50%+ extracts we see being used now.

There is an interventional study ongoing that prescribes a daily dose of alcohol (presumably wine will be one of them) and is watching CVD risk apparently (according to this article). Will be interesting to see if it confirms the correlational and short term research.

[Sldge]

There is an interventional study ongoing that prescribes a daily dose of alcohol (presumably wine will be one of them) and is watching CVD risk apparently (according to this article). Will be interesting to see if it confirms the correlational and short term research.

Ill have to watch for it.

[Bane]

This is probably the best idea when it comes to res. IMO people are over extracting it trying to isolate higher amounts of res not realizing that there is obviously something else in wine that either helps in its use or another compound all together like pterostillbene. Either way lower extracts or wine itself would be better then most of the 50%+ extracts we see being used now.

Ii wonder if we can sell concentrated wine 99%alcohol as a supplement

[Sldge]

Ii wonder if we can sell concentrated wine 99%alcohol as a supplement

Wouldnt that be great, more like a "gel", .

[Bane]

i just say: drink the damn wine itself.

But I hate alcohol Sir






(not serious)

[potionmaster]

here's an idea...how about wine without the alcohol(removed)

[SIRT1]

here's an idea...how about wine without the alcohol(removed)

Grape juice

[nunes]

well I always take my res with a glass of wine...hope it helps and I just love that damn wine

[GeneGnomeX]

here's an idea...how about wine without the alcohol(removed)

Like those weirdly shaped colored things that you see when first entering a grocery store? They can't be healthy!

[Synapsin]

Like those weirdly shaped colored things that you see when first entering a grocery store? They can't be healthy!

I always try my best to avoid those and the other weirdly shaped colored things at the grocery store.

[NO HYPE]

Resveratrol and Nampt - What is Resveratrol's true target?, Will taking niacinamide decrease Sirt1 function?

Niacinamide without resveratrol has been shown to downregulate Sirt1 expression (here), and increase adipocity (fat). Apparently, niacinamide doesn't actually turn on Nampt, despite it being Nampt's substrate. However, there may be some tipping point where an overabundance of niacinamide does activate Nampt through other cellular watch dogs. However, what are those controllers of Nampt expression? That is, how did resveratrol increase Nampt expression? Is there an even more upstream target that resveratrol is really working on, or does Nampt feed back on itself for activation? Actually, it seems that Nampt might actually feed back on itself. For instance, Nampt activity activates AMPK, and this activation of AMPK is inhibited by niacinamide (see here again). Yet, on the other hand, AMPK activity is required to activate the transcription of Nampt in response to glucose restriction. Here we have a chicken or the egg problem. Does AMPK activate Nampt which activates AMPK, or does Nampt activate Sirt1 which activates AMPK, which then activates more Nampt production? The latter is what fits the evidence best in my opinion. However, it's still possible resveratrol is actually turning on AMPK. So then, if resveratrol acted directly to activate Nampt, that activity would snow ball into an increase in Nampt and efficient processing of niacinamide into NAD+. On the other hand, a high enough amount of niacinamide will inhibit AMPK and break this process. If resveratrol turned on AMPK which then turned on Nampt, niacinamide wouldn't be expected to break the process and stop AMPK activation, as resveratrol already would have done it. Let's look at this another way and ask what other ways are Nampt turned on?

Apparently, as stated before, Nampt transcription is activated by stress and CR, via such factors as IL-1beta (see here) and other proinflammatories. Since resveratrol is an anti-inflammatory molecule, it's not very likely that resveratrol is acting on higher inflammatory responsive pathways to turn on Nampt. Moreover, resveratrol activated Sirt1 actually protects from NF-kB activation, while IL-1beta causes damage, so it's unlikely NF-kB, which is the main responder to proinflammatory signals, turns on Nampt, and neither does IL-1beta in the same way. Even if IL-1beta upregulates Nampt mRNA, other pathways turned on by IL-1beta may outweigh it, or perhaps IL-1beta leads to Nampt secretion into the media instead of increase intracellularly.

Now we've moved into the realm of pure speculation and need to stop here, as I don't have the papers to address these questions. More research must be done, but it seems that for now, until higher targets in the pathway are found, I feel, and this is only my opinion, we can say resveratrol's real target is possibly Nampt, and only Sirt1 by consequence.

http://www.imminst.org/forum/index.php?showtopic=27350

[acecombact1]

Has anyone thought about freeze dried wine.......i think that would make an awesome product!!!

[Runner710]

Very interesting post..Iam very much enjoyed by reading your site..this article has provided a useful info..

[Motley_Muscle]

This is probably the best idea when it comes to res. IMO people are over extracting it trying to isolate higher amounts of res not realizing that there is obviously something else in wine that either helps in its use or another compound all together like pterostillbene. Either way lower extracts or wine itself would be better then most of the 50%+ extracts we see being used now.

Great point. Below is an article I've had saved for a while. Can't remember where I got it, but it does cite many references and makes for an interesting read.



The “Other” Resveratrol A Novel Method to Simulate the Genetic Effects of Caloric Restriction
By Tiesha D. Johnson, RN, BSN

Scientists have discovered a plant extract related to resveratrol that mimics many of the beneficial effects of caloric restriction. This natural compound favorably regulates genes involved in the development of cancer, atherosclerosis, diabetes, and the system-wide inflammation that underlies a variety of age-related disorders.

Pterostilbene (terro-STILL-bean), found in blueberries, grapes, and in the bark of the Indian Kino Tree, has been used for centuries in Ayurvedic medicine. Pterostilbene and resveratrol are both stilbene compounds, closely related structurally, which gives them similar but not identical functions. Researchers have found that these two compounds work in a synergistic fashion to activate one’s “longevity genes.”

Pterostilbene produces its beneficial effects on gene expression in ways that enhance those produced by resveratrol. That is why pterostilbene functions particularly well when combined with resveratrol.

This article first examines the unique ways in which pterostilbene simulates conditions produced by caloric restriction. Then it will describe how these effects translate into a broader spectrum of benefits than otherwise provided by resveratrol alone.

Pterostilbene and Gene Expression: The Key to Longer Life

You’re probably used to thinking of genes as fixed units of hereditary information that determine physical characteristics like hair and eye color.
Scientists now know that you can change the messages your genes transmit to your body. This process is known as gene expression. It occurs when stimuli from within or outside your body switch certain genes “on” or “off.” Switching on protective genes or switching off harmful ones (modulating gene expression) is one of the most exciting areas of medical research.

Calorie restriction turns on genes directly related to long term survival. This includes genes that reduce the activity of certain cancer-promoting agents, genes that induce programmed death of cancer cells, and genes that confer neuroprotection.1
The incredible news is that many of the same genes that confer a longer life span can be favorably modulated with plant extracts such as resveratrol and pterostilbene.
How Pterostilbene and Resveratrol Work Together

Scientists have found that resveratrol activates genes near the beginning of the molecular cascade precipitated by caloric restriction. These in turn activate a broad array of disease-preventing genes. In essence, resveratrol’s beneficial genetic action takes place “upstream.”
Pterostilbene directly activates genes “downstream” from the sites of resveratrol’s action. This complements resveratrol’s ability to help prevent cancer and diabetes, and support healthy blood lipids. Acting together, resveratrol and pterostilbene produce potent longevity-promoting effects across the cycle of gene expression through complementary mechanisms.

How Pterostilbene Mimics Caloric Restriction

It’s truly remarkable how closely pterostilbene can mimic the beneficial effects of calorie restriction on a molecular level. Calorie restriction directly suppresses cancer-causing genes while up-regulating genes that suppress cancer development.1-21 In numerous studies pterostilbene modulates exactly the same genes, up-regulating those that stimulate the programmed cell death known as apoptosis, and down-regulating those that allow cancer cells to invade and metastasize.22-31

Calorie restriction changes expression of genes throughout the metabolic process. It increases activity of powerful fat-sensing complexes that lower blood lipids and sugar levels.32-35 Pterostilbene naturally activates these same fat-sensing complexes and was found to favorably affect lipid profiles in hamsters with elevated cholesterol.36,37
In the liver, calorie restriction favorably modifies several vital glucose-regulating enzymes, which helps to control blood sugar.38 Pterostilbene produces identical beneficial changes in many of those enzymes. It also reduces markers of dangerous glucose-damaged proteins (glycosylated hemoglobin).39

Calorie restriction dramatically reduces production of inflammatory mediators linked to age-related conditions such as atherosclerosis, chronic inflammatory diseases, and even cognitive decline.8,40-51 At the level of gene expression, pterostilbene exerts virtually identical effects, suppressing those same genes in studies of inflammation-related conditions.23,31,52-54 And like calorie restriction, pterostilbene up-regulates specific brain proteins associated with improved memory.55,56

Cancer Chemoprevention

There’s growing evidence that pterostilbene provides chemoprevention by many routes. Pterostilbene has powerful antioxidant capacity equivalent to resveratrol, and its anti-inflammatory actions help it block the inflammation/cancer connection.57 In addition, pterostilbene inhibited the growth of highly malignant human melanoma cells and prevented metastatic spread of those cells to the liver in laboratory animals. It thus enhanced survival.27

As with so many nutraceuticals, pterostilbene achieved this dramatic effect by multiple mechanisms. It inhibits production of molecules that cancer cells use to “stick” to vessel walls, and also makes them vulnerable to immune-system destruction.
Other mechanisms include: blocking enzymes that activate carcinogens;58,59 up-regulating pro-apoptotic activity in highly resistant leukemia cells (while showing no toxicity at all to normal blood-forming cells);29 blocking metastatic spread of aggressive and invasive human breast cancer cells;25 and enhancing nitric oxide-induced cell death in human melanoma.28

At the whole-organism level, pterostilbene suppresses formation of pre-cancerous cells in the colons of carcinogen-exposed animals.60 More excitingly, pterostilbene and quercetin dramatically enhanced elimination by radiation and chemotherapy treatment of implanted colon cancers.54 Cancer cells communicate with each other across special connectors called gap junctions. Pterostilbene disrupts those gap junctions, thereby interfering with inter-cellular communication that cancers need to direct their renegade growth.60-61 Disruption of gap junctions is a mechanism that appears to be truly unique to pterostilbene, one not shared by other chemopreventive or chemotherapy agents. Clearly there’s substance to the recent conclusion by Korean cancer researchers that “pterostilbene may be a functional chemopreventative agent and that dietary exposure of pterostilbene would be helpful for improving health.” 24

Cognition and Memory

Both resveratrol and pterostilbene have remarkable effects on learning and memory. Pterostilbene was the most efficacious of a group of resveratrol-like compounds at preventing loss of the neurotransmitter dopamine from memory centers in aged rats.62 Supplementation with pterostilbene reversed cognitive behavioral deficits. This study showed working memory function was correlated with levels of pterostilbene in the hippocampus, a key brain location where memory is processed.

A closer look reveals yet again the astonishing correspondence between pterostilbene and caloric restriction on gene expression. Supplementation with blueberries (one of the richest sources of pterostilbene) improved performance of aged animals in working memory after just three weeks.55 The improvement was closely correlated with activation of a brain-signaling protein in the hippocampus. Improvement in memory performance was just recently shown to be another direct result of caloric restriction!56 Improved spatial memory during times of low food availability might be a very appropriate adaptive response, making animals more efficient at locating scarce food resources. If so, then pterostilbene’s ability to mimic these fundamental changes in brain chemistry is a powerful modern take on an ancient survival mechanism.
Pterostilbene affects gene expression similarly to caloric restriction in multiple ways … all key in the battle against age-related disease.

[Motley_Muscle]

Part 2:

Summary

In the words of Dr. Agnes M. Rimando, a leading expert in the biology of the stilbenes (resveratrol, pterostilbene, and related compounds): “Stilbenes have diverse pharmacological activities, which include cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span.”63

What is so exciting to modern researchers is the way in which both resveratrol and pterostilbene achieve these benefits by mimicking the actions of caloric restriction, which produces similar effects on gene expression.

Even more exciting is the series of discoveries showing that resveratrol and pterostilbene produce similar results by acting at different locations in the control of gene expression. This means that these two phytonutrients likely complement one another in increasing both the quantity and the quality of life. Along with responsible calorie control and exercise, both belong in the regimens of people who are serious about improving health and longevity.
To find out how much pterostilbene you may need, please read below.

HOW MUCH PTEROSTILBENE DO YOU NEED?

Pterostilbene is found in minute quantities in certain plant foods. A typical cup of blueberries, for example, contains only about 20 mcg of pterostilbene.
Even in these tiny amounts, pterostilbene is believed to provide some of the benefits related to ingesting these healthy foods.

Like resveratrol, in order to significantly impact one’s health, it is desirable to consume more pterostilbene than what one would normally obtain from dietary sources.
A dose of 125–500 micrograms of pterostilbene provides an amount of this nutrient comparable to consuming from five to twenty cups of blueberries every day.
Research is underway to determine the optimal dose of pterostilbene for health benefits. Gene expression studies in animal models with pterostilbene show favorable effects upon similar genes up-regulated by calorie restriction. Similar to resveratrol, a close chemical ‘cousin’ of pterostilbene, higher concentrations of pterostilbene may be necessary for optimal effects in gene expression studies.1 A dose of 3 mg a day of pterostilbene provides the equivalent of eating over 140 cups of blueberries each day. These super-high potency pterostilbene formulas are expected to soon become available as dietary supplements.

The good news is that pterostilbene provides so much biological activity in a relatively small dose, that it is being added to resveratrol and other supplement formulas today without significantly affecting the cost to the consumer.

Reference:
1. BMC Med Genemics 2008 MAR 20;1:7.

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[gekkoboy14]

Wouldnt the amount of wine you need to drink negate the effects of resveratrol, or not make it worth while?