Resveratrol: Pfizer Study

Found this, but was surprised the only property they talk about is ‘anti-ageing’
Anyway thought some of you may be interested, BTW I found it on Pharmaceutical & Medical Packaging news.

Pfizer muddies the waters of red wine’s fountain of youth: Study casts doubt on ability of resveratrol to slow aging
Feb. 1–A key ingredient in red wine may not unlock the fountain of youth after all.

That’s the conclusion from a study by Pfizer Inc. scientists in Groton who looked at a component of red wine called resveratrol. The scientists, led by Kay Ahn, published a paper last month in the Journal of Biological Chemistry that called into question previous research suggesting compounds like resveratrol may boost an enzyme that slows down the aging process.

“Efforts to slow the march of old age with a pill have been dealt a blow,” concluded an article about the study in New Scientist magazine.

Nature magazine says the new study about resveratrol “deepens the divide between those who are confident in its potential and those who think it is too good to be true.”

Despite the Pfizer study, authorities such as Philip Norrie, an Australian doctor who has written books about wine and health, said people shouldn’t give up on resveratrol or the good health effects of drinking moderate amounts of their favorite red vintages.

Norrie, in an e-mail, questioned the Pfizer study, saying that it looked at resveratrol only as a direct activator of beneficial biochemical pathways.

“If it is an indirect activator/stimulator of a certain pathway, it would thus not show up as a direct activator to researchers such as in this instance with Pfizer, but it would still be causing the same resultant beneficial effect,” he said. “Biochemical pathways are very complex with many interactions, checks and balances – it is not always simple and in a straight line.”

“The overwhelming evidence is that moderate consumption of red wine leads to better health and lowers mortality,” added Thomas Matthews, executive editor of Wine Spectator magazine, in a phone interview.

Dipak Das, a researcher at the University of Connecticut Health Center in Farmington and a national expert on resveratrol, agreed about the benefits of red wine and said in a phone interview that his research shows resveratrol in small doses can promote good health. He said there appears to be something about the way wine delivers resveratrol to the body that helps people derive benefits not seen in experimental scenarios.

“The benefit is without a doubt,” said Das, who has been invited to address a National Institutes of Health seminar about the resveratrol controversy next month.

Das said resveratrol has to be delivered in a relatively small dose; larger doses can actually do damage. The formulation of the compound must also be as pure as possible to show the best effect, he said.

Bill Sardi, partner in a California firm that markets a so-called nutraceutical formulation of resveratrol called Longevinex, added that 60 milligrams of the drug can be found in a 5-ounce glass of wine, with maximum benefits derived by those who drink three to five glasses daily.

Sardi, a former health journalist, said studies of resveratrol have been hampered in the past by the lack of a biomarker to determine a beneficial effect. But he said in the past two years scientists have focused on the width of red blood cells as a good marker for how we age, giving hope that progress will be made.

Scientists have targeted resveratrol for study because it appears to activate an enzyme that protects cells from the kinds of damage that lead to aging. Resveratrol can be found in the skin of red grapes, though apparently not in significant enough quantities to explain the so-called “French paradox” noted by researchers looking to explain the low incidence of heart disease in France, despite the population’s high-fat diet.

“Activation of this enzyme is thought to play a role in delaying the onset and reducing the incidence of age-related diseases including type 2 diabetes, as had been reported in scientific publications,” Pfizer said in a statement.

But Ahn’s team at Pfizer’s research campus in Groton found, after “extensive biochemical and biophysical studies,” that resveratrol as well as several other similar chemicals “are not direct activators” of this enzyme, according to company spokeswoman Liz Power.

Specifically, low doses of resveratrol did not help mice on a high-fat diet cut their blood-sugar levels, according to Ahn’s study. And high doses of the drug killed three of the eight mice studied, Pfizer researchers said.

Pfizer did not make the local researchers available for interviews.

But Ahn, quoted in an article last month in Nature magazine, downplayed the significance of her study.

“Under our conditions we didn’t see beneficial effects, but we don’t want to make a big conclusion out of those results,” she said.

The Pfizer team’s research contradicted a highly publicized study done by Harvard University researcher David Sinclair and calls into question the assumptions behind new drugs being developed by Sirtris, a Massachusetts-based company purchased two years ago by GlaxoSmithKline for $720 million.

Sirtris has three experimental compounds in early- and mid-stage development that use proteins known as sirtuins against such diseases as cancer and diabetes.

Glaxo said in a statement that “scientific debate around the interpretation of data is a normal part of discovery in emerging areas of research.”

But Glaxo said Pfizer’s interpretation of data “is at odds with multiple studies conducted at Sirtris and those published by independent investigators.”

The company added that the “purity of the compounds that were used in their study … cannot be ascertained due to the lack of data provided. The publication also does not cite nor discuss multiple scientific publications which are in direct contrast to their primary conclusions; as such it is unclear how to place this work in perspective of what has been found by other investigators.”

Glaxo said the Pfizer study appeared to be trying to prove a negative.

“The study falls short of that goal while adding little to the advancement of sirtuin biology,” the company said.

The Pfizer scientists involved in the resveratrol study were listed as Michelle Pacholec, Boris A. Chrunyk, David Cunningham, Declan Flynn, David A. Griffith, Matt Griffor, Pat Loulakis, Brandon Pabst, Xiayang Qiu, Brian Stockman, Venkataraman Thanabal, Alison Varghese, Jessica Ward and Jane Withka.

Another study, published in an October issue of Chemical Biology & Drug Design by scientists from Amgen, found results similar to Pfizer’s research.

As the science behind the ties between red wine and longevity becomes more controversial, resveratrol continues to be a favorite “miracle product” of fly-by-night marketers, said Sardi, the California businessman.

“Spammers have done more to sell resveratrol pills than any science,” he said.

A one-month supply of the dietary supplements can sell for as little as $5, he reports, which is much cheaper than buying the aged red wines that he says bring the most beneficial health effects.

Still, Sardi conceded that marketing the benefits of red wine in pill form has drawbacks.

“You can’t replace the romance and relaxation of wine,” he said.

“Wine is our oldest medicine and best preventative medicine,” added Norrie, a researcher known as The Wine Doctor.

Oh oh, they found that if the dose is high enough, you can kill 3 of 8 mice with it.

Perhaps the next big Pfizer discovery will be that too much water provided by gavage can kill even a higher percentage of mice than this.

Their effort sounds like sour grapes – no pun intended.

Wow this is pretty stunning. I had heard there had been some uneasiness for the Sirtris folk lately, probably a sign things were going to take a turn for the worse.

Their initial Nature paper in 2007 was pretty remarkable. Perhaps now we see there is a new side to the story than is not what they initially claimed.

I find the Pfizer result at the end of the paper particularly interesting where they see the four molecules (resveratrol and the 3 Sirtris compounds) have all sorts of activity at various targets, although the analysis is not very detailed (only one concentration is tested, lame). You have to wonder what the Sirtris people were doing with their development of their 3 compounds given this result. You would almost have to purposely design this sort of thing (so much activity at so many targets) for it to occur, that or be seriously messing up your screening technique.

Either way, this does not look good for Sirtris.

PS - This does not sound like “sour grapes!”

The Pfizer study is a very detailed analysis of the work claimed by Sirtris and published in a very high quality biochemistry journal. The seminal 2007 Nature paper by Sirtris is in a journal that loves gushy anti-aging-type work, especially centered around “next-generation media-hyped” molecules like resveratrol has become. Look at it and tell me they didn’t just go ga-ga when Sinclair/Westphal submitted it to them. Sometimes things get published without enough questioning…

But you never know Bill, Sirtris might have lied their way right into the 700$ million GSK deal. And if their stuff is bunk, someone needs to publish it. This is more about the Sirtris molecules, their claims of them producing anti-diabetic and anti-obesity in rodents and their claims of how the molecules are direct SIRT1 activators than anything. They are not saying resveratrol is worthless; it clearly produces very interesting effects in people but is probably not the SIRT1 activator Sirtris has made it out to be.

Maybe you should read the text for yourself?

http://www.jbc.org/content/early/2010/01/08/jbc.M109.088682.long
http://www.jbc.org/content/suppl/2010/01/08/M109.088682.DC1/jbc.M109.088682-1.pdf

J Biol Chem. 2010 Jan 8.
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

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

Pfizer, United States;

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.

The “sour grapes” comment was with reference to making a point of having found a dose high enough to kill mice, as if it were remarkable that such a dose can be found for a substance.

Which was the only point addressed in my post, so I thought it was clear that that was what the “sour grapes” comment referred to.

I’m not really sure if you are trying to be sarcastic or what, but Pfizer appears to be far more in the right than Sirtris on this one, even if they toot their own horn to the media a little when they announce something this big.

I think I was clear enough on the meaning of what I said: pretty straightforward.

On some occasions it will happen that someone will seem set on reading into a post, whether mine or someone else’s, things that simply aren’t there. It seems to me that that is what is happening here.

Not only did my post rather clearly address one point and only one point, the followup said plainly that that was what it was doing, yet above there seems to still be imagined possible sarcastic comments on other points. That there is just no basis of whatsoever in my posts: not even the dot of an i’s worth.

When I’m being sarcastic (generally actually not, but either sardonic or ironic) I do make clear what the thing is that I am talking about. Here, it was their making an issue of there having been an LD50. As if Pfizer drugs don’t have LD50’s.

It seems to me I’ve done all I can to be clear on what I was saying and that it was limited to the very thing being said.

I’m sure that this isn’t intentional on your part, but it seems to be what’s happening.

Nah I just think there’s a lot more important things to be said about this story than Pfizer finding they could kill mice with resveratrol.

But why assume I was saying these things you think more important when clearly I wasn’t, and I even re-iterated that I wasn’t.

I assume that the actual factual, scientific statements in the article are correct and have not the slightest inkling of reason to dispute them.

By the way, I never at any time claimed the SIRT proteins as relevant to resverattrol, I don’t think Biotest ever did, and I never claimed life extension for resveratrol and I don’t think Biotest ever did. I also never had much of an opinion of what Sirtris was doing, actually had a rather negative instinctive sort of take on it, though I really had not looked much into it.

What I cared to comment on was exactly what I did: the absurdity of acting as if a compound having an LD50 value was a shocking and scary thing.

But why assume I was saying these things you think more important when clearly I wasn’t, and I even re-iterated that I wasn’t.

Maybe you had some expectation (I don’t know why you would) that I would dispute the factual, scientific statements in the article rather than object to the pretending of it being a shocking and alarming thing that resveratrol has an LD50. But I have no reason to object to the scientific findings reported. I assume they are correct.

By the way, I never attributed anything to the SIRT proteins for resveratrol. I also never had a positive opinion of what Sirtris was doing and though I hadn’t looked into it sufficiently to have a firm conclusion, my instinctive (so to speak) take of it was negative.

[quote]Bill Roberts wrote:
But why assume I was saying these things you think more important when clearly I wasn’t, and I even re-iterated that I wasn’t.

Maybe you had some expectation (I don’t know why you would) that I would dispute the factual, scientific statements in the article rather than object to the pretending of it being a shocking and alarming thing that resveratrol has an LD50. But I have no reason to object to the scientific findings reported. I assume they are correct.

By the way, I never attributed anything to the SIRT proteins for resveratrol. I also never had a positive opinion of what Sirtris was doing and though I hadn’t looked into it sufficiently to have a firm conclusion, my instinctive (so to speak) take of it was negative.
[/quote]

Just admit it…

You couldn’t resist making the pun.

Okay, well now I checked the Rez-V article to see if perhaps Biotest had ever mentioned the SIRT proteins. (I hadn’t remembered that being done.)

Turns out that does comprise a small part of the article, so although it still isn’t the case that anything in my posts at all looked like I was talking about anything other than what I said I was, you could have had a reason for thinking I’d have wanted to discuss the SIRT proteins.

When it’s something that I’m writing myself, or am cowriting, I have the option of deciding not to include things that look good but which I think are unproven and I am unsure of, and that’s the option that I take. Aside from principle, from the practical standpoint of effective presentation of positions, I very much believe that the Marcia Clark approach of dumping an absolute ton of details and lines of argument on the listener is the wrong way to go. Having even one poor point that results in a “if the glove doesn’t fit, you must acquit” response is just not the way to go.

While it’s logically incorrect, in the minds of most it results in casting doubt on all the completely valid points you did make that the other side cannot refute.

So myself, I wouldn’t have put the SIRT thing in there.

However, when it comes to me seeing articles go up by others, it’s one thing for me to see something that is in fact incorrect and point this out so it can be corrected, if need be.

It would be another thing entirely for me to object that while I can’t prove that a given thing is wrong and sure there are references that support it and none that prove it wrong, still I say you should slice out of your article because I think it’s dubious. The thought must never have even crossed my mind when reading the Rez-V article. It was a completely reasonable article. It is not as if there weren’t references supporting what was said. It does turn out I was right to think that line of possible benefit to be questionable, but I didn’t find that worth commenting on as it wasn’t a major opinion of mine to say the least: probably something like #1000 or more down the list, not that there is a list or I could really count such things.

[quote]chimera182 wrote:

Just admit it…

You couldn’t resist making the pun.[/quote]

It wasn’t conscious, but I guess it’s likely that the expression or even the general thought came to mind from the resveratrol/wine/grapes thing :slight_smile:

[quote]Bill Roberts wrote:

[quote]chimera182 wrote:

Just admit it…

You couldn’t resist making the pun.[/quote]

It wasn’t conscious, but I guess it’s likely that the expression or even the general thought came to mind from the resveratrol/wine/grapes thing :)[/quote]

Puns are a beautiful thing, as well as being very… pun to make.

(groan) :wink:

I have real difficulty with much of the information that comes out of this drug company. Back some years ago when Linus Pauling Phd was making news with vitamin C. The drug companies tried to discredit the vitamin C, going so far as to pour vitamin C into open mice lesions to attempt to cause a cancer. When something says “Pfizer says…” be very alert, and keep a hand over your wallet.

Here’s an insider’s point of view on the Sirtris scenario:

http://pipeline.corante.com/archives/2010/01/15/sirtuin_scenarios.php

I heard another company knocked out SIRT1 in mice a while back and nothing happened. :stuck_out_tongue_winking_eye:

I’ll go with the “720$ million disappears” option. It is quite unfortunate but the guy nailed the scenario in saying that CEOs a lot of times don’t have the time to be scientists. Or worse in a case like this where you need real experience to make good decisions for your company, are not even scientists at all. I think this is changing in the drug industry somewhat (although my personal experiences are pretty limited) as people become more multi-skilled in today’s increasingly demanding workplace, where you see a person become a CEO - or thrusting themselves into the role after building successful drugs - after starting as a scientist, but situations like this suggest that it is still far, far from the commonplace.

[quote]Rusty Barbell wrote:
I heard another company knocked out SIRT1 in mice a while back and nothing happened. :stuck_out_tongue_winking_eye:

I’ll go with the “720$ million disappears” option. It is quite unfortunate but the guy nailed the scenario in saying that CEOs a lot of times don’t have the time to be scientists. Or worse in a case like this where you need real experience to make good decisions for your company, are not even scientists at all. I think this is changing in the drug industry somewhat (although my personal experiences are pretty limited) as people become more multi-skilled in today’s increasingly demanding workplace, where you see a person become a CEO - or thrusting themselves into the role after building successful drugs - after starting as a scientist, but situations like this suggest that it is still far, far from the commonplace.

[/quote]

Pharmaceutical companies are primarily business industries, not scientific ventures. It would be nearly impossible for a CEO to be a scientist and an executive, since the education and training experience required for either of these careers is lengthy and intensive. Unless you get Buckaroo Banzai to head GSK, leave the business decisions to the Wharton alums and let the PhD’s from Berkeley get the drugs through the pipeline. That’s the historical paradigm for Big Pharma, and they’re slow to change.

I think the best decisions should arise from a collaboration team of business executives and scientists to insure the future of Pharma. Makes sense to me, in an ideal world. Because right now, there are very few scientists in top management positions that have influence in the boardroom.

The Ceo’s job is to please the shareholders. The scientist’s job is to plunge crappy compounds through the pipeline. Both are under high pressure to deliver a drug to market in a short timeline. This culture of urgency over quality in the name of science, that requires shortcuts and tolerates bad data is why Big Pharma has become the Evil Empire.

Please check out my article on resveratrol and caloric restiction which pertains, in part, to the Pfizer constroversy. It also concerns cancer research, the Warburg hypotesis and how resveratrol and caloric restriction create a rejuvenation metabotype enabling efficient mitochondrial biogenesis.

The link is: