Unless you are a died-in-the-wool resveratrol pill user, you are likely having doubts over whether you should continue taking these so-called red wine pills now that the science published by a leading researcher in the field has been called into question (more about that below). Strangely enough, the science behind resveratrol’s miraculous ability to protect the human heart is very well founded, but when did solid science ever influence consumers anyway?

The record shows consumers of resveratrol pills are more likely to fall for a phony sales pitch rather than phony science. Except for a brief period in 2009 when online spammers falsely claimed their products were endorsed by Oprah Winfrey, pandered resveratrol pills as a cure-all for whatever ails mankind, made free bottle offers that came with fine print and unwanted monthly $85 credit card billings for more resveratrol pills and sold millions of bottles of these pills, consumers of dietary supplements have not widely adopted resveratrol pills into their daily pill regimens and appear to be paying a steep price for it with their lives.

Compare resveratrol with statin drugs. While cardiologists look directly into the eyes of their patients and admonish them if they do not take statin cholesterol-lowering drugs, saying the consequences could be death, there is simply no evidence that statin drugs prevent mortal heart attacks among healthy adults. Harvard Professor John Abramson reviewed the ten largest statin drug studies and found these pills do not reduce mortality rates among healthy adults. Even among high-risk individuals, 70 patients need to take statin drugs for 5 years to prevent one non-mortal heart attack. Up to 250 low-risk adults must take statin drugs to prevent one non-mortal heart attack over a 5-year period.

Also, aspirin tablets, the most relied-upon preventive measure against mortal heart attacks, may not be working as advertised. This revelation comes on the heels of a recent scientific review showing aspirin, the most relied-upon preventive measure against heart attacks, does not avert mortal heart stoppages, only non-mortal attacks.

Resveratrol pills remain mired as the 109^th best-selling dietary supplement despite its promise as a miracle molecule. Now resveratrol pill sales are plunging with word a resveratrol researcher allegedly faked his experiments. While these allegations have no bearing on the scientific conclusions that were drawn – that resveratrol can potentially turn mortal heart attacks into non-mortal events, there is a major pause in resveratrol pill sales as consumers wonder if these pills are a waste of their money.

There is no shortage of supply. According to the Natural Medicines Comprehensive Database, there are nearly 350 brands of resveratrol pills. But most of these companies sell less than $50,000 of resveratrol pills or potions at wholesale price in an entire year. It’s hardly a booming business.

Most brands of resveratrol pills rely upon borrowed science, hoping that tomorrow’s news headlines about the latest advance in resveratrol science will make them rich. But few brands have ventured to put their products to the test. Ironically, good science doesn’t equate with sales, so it doesn’t pay for pill makers to spend money on science.

The false appearance of science is what sells. All online spammers had to do is misleadingly claim their pills were shown on the Oprah Winfrey TV show and that Dr. Oz blessed them, and that Harvard Medical School had apparently studied them, and lure consumers with bogus free bottle offers, and sales of these fermented grape pills temporarily boomed. Sadly, resveratrol is fast becoming another fad like coral calcium or hoodia.

Most consumers choose brands based upon price. The big-box discount stores mount up a great deal of the resveratrol pill business, but these economical brands often only pretend to provide resveratrol. Based upon animal lab experiments, the dose of resveratrol required to avert a mortal heart attack is somewhere in the range of 50-350 milligrams, with higher doses actually worsening the damage to the heart in laboratory experiments. But many mega-dose resveratrol pills are widely promoted as “more for your money,” About 90% of purchases of resveratrol pills are for untested brands and about 70% provide the wrong dose to fully benefit.

Cardiology Shows Its True Colors

Evaluate the level of enthusiasm among cardiologists in the following statements:

“The potential public health benefits are huge. It really changes the way we have to think about prevention of heart attack and stroke.”

~ Paul M. Ridker of the Brigham and Women’s Hospital in Boston

“It’s a breakthrough study, it’s a blockbuster. It’s absolutely paradigm-shifting.”

~ Steven E. Nissen of the Cleveland Clinic
(These are the words drug companies want to hear.)

“This takes prevention to a whole new level.”

~ W. Douglas Weaver,
president of the American College of Cardiology

“These are findings that are really going to impact the practice of cardiology in the country.”

~ Dr. Elizabeth G. Nabel,
director of the National Heart, Lung and Blood Institute, which was not involved in the research

Were these leading cardiologists expressing their enthusiasm over resveratrol? No, they were talking about a new and more powerful statin drug. Modern cardiology has expressed little or no interest in resveratrol, despite its unique mechanism to insulate humans from a mortal heart attack.

The mechanism that protects the human heart when taking resveratrol pills is not like aspirin. Aspirin is best taken during a heart attack to thin the blood and break up a clot that is blocking blood circulation to the heart. Resveratrol works in a different manner.

Actually, resveratrol is perceived as something slightly noxious to the heart which triggers defenses and provokes release of antioxidant molecules that protect the heart prior to a heart attack. This is a unique protective mechanism called cardioprotection or preconditioning. Cardiologists first noticed this when they induced small heart attacks in animals which had a life-sparing effect for a major heart attack that followed.

It is not like modern cardiology does not know what cardiac preconditioning is. Cardiologists have been talking about it for years. Cardiac preconditioning has been known since its discovery in 1986. It is widely practiced prior to heart surgery. Cardiac surgeons use a pressure cuff on extremities to intentionally create a slight shortage of oxygen (called ischemia) just prior to heart surgery to trigger the heart’s defenses to produce protective antioxidants. This is done in an effort to avoid deaths on the operating table. Some heart surgeons administer adenosine, an antioxidant that is released during cardiac preconditioning, instead of using a pressure cuff to produce the same effect.

Dr Alberto Bertelli of Italy was one the pioneers to demonstrate how resveratrol protects the heart prior to a heart attack by releasing protective antioxidants, namely adenosine and nitric oxide. This animal experiment, conducted over a decade ago, is a landmark study. It showed that an infusion of resveratrol increases the natural release of adenosine by 68%. Other researchers have also shown that resveratrol remarkably limits the damage to the heart during a blockage in a coronary artery and increases survival in animals. More remarkably, even if resveratrol is administered to a heart attack patient after the event it should limit damage to the heart and reduce the risk of mortality.

In 2006 a paper was published in the Annals of Cardiology and Angiology (Paris) under the title: “Cardiologists are living through exciting times.” That report said short bouts of repeated exposure to ischemia (lack of oxygen) protects the heart against a serious heart attack. These French cardiologists described how they looked forward to the day when “cardiologists are fully awoken to the idea of preventing heart muscle cell death” that occurs when circulation is re-established to a blocked coronary artery and oxygenated blood creates a massive amount of oxygen free-radicals that damage the tissue.

However, cardiology is talking out of two sides of its mouth. It will practice preconditioning just prior to heart surgery, but it hasn’t taken to the idea of using resveratrol pill, which is a proven preconditioning agent, to prevent mortal heart attacks altogether.

A Brown University researcher expounds on the promise of resveratrol to prevent deaths associated with coronary artery disease and says: “extensive research in the past several decades has identified multiple mechanisms by which resveratrol modifies the cardiovascular risk factors that lead to coronary artery disease, yet translation to the clinical arena has been unexpectedly slow…. To date, there have been no clinical trials investigating the effect of resveratrol on cardiovascular risk or co-morbidities.” Translation: modern cardiology is dragging its feet.

Cardiology has had sufficient evidence for over a decade that resveratrol convincingly turns mortal heart attacks in the animal lab into non-mortal events. But it hasn’t been able to muster up one human clinical study involving resveratrol in all this time. Millions of at-risk patients may be needlessly dying.

In 2008 cardiologists in Australia disingenuously said “there remains a paucity of evidence that this protective paradigm is clinically exploitable.” Inexplicably, cardiologists are reluctant to launch a study using resveratrol in humans to prove or disprove this.

Now for the zinger. While there have been strong accusations of scientific fraud against a University of Connecticut heart researcher who demonstrated in animals that a carefully measured dose of resveratrol can turn a mortal heart attack in animal into a non-mortal event, not one of the prior scientific studies I’ve cited herein involved that same researcher.

But not to matter, radio talk show host Rush Limbaugh, referring to the accused researcher, said: “He just made it up! He literally just made it up.” The science involving resveratrol and the heart is not made-up science. Modern cardiology is showing its true colors here. It loathes to put resveratrol to the test while demanding human studies be performed. Don’t run to any cardiologist and ask if any of this is true, you will get a predictable answer that it is still unproven.

Over 2200 Americans die prematurely of heart and blood vessel disease each day, one every 39 seconds. A blockage in a coronary artery, that feeds the heart with oxygenated blood, causes over 400,000 deaths annually (2007 data). Less than an estimated 100,000 Americans take resveratrol pills daily out of an at-risk population of over 100 million American adults over age 50, less than 1/10^th of one-percent of the at-risk population.

Unless the public makes a bee line for resveratrol pills in a self-guided effort to prevent mortal heart attacks it is going to miss out on one of nature’s most remarkable molecules, a molecule that can save millions of lives.

Is there any evidence resveratrol pills protect humans from mortal heart attacks?

Does resveratrol really prevent mortal heart attacks in humans? Nate E. Lebowitz, MD, FACC, Director of Preventive Cardiology at the Advanced Cardiology Institute, a division of Hackensack University Medical Center Cardiovascular Partners in New Jersey, in writing to the American Heart Association, said: “I have started to see patients taking a resveratrol pill, anecdotal as it may be, who exhibit literally the same heart-sparing effect during a heart attack that has been demonstrated in mice.”

Ed Skonezny, age 70, may have resveratrol to thank for his life. Ed had none of the common symptoms of coronary artery disease. He was regularly driving a golf ball over 280 yards off the tea at his Palm Desert, California golf resort home. But a routine angiogram (dye test of coronary arteries that supply the heart with oxygenated blood) revealed narrowed coronary arteries, probably caused by a prior smoking habit conquered years ago. One major coronary artery was 99% blocked, four others partially, yet Ed experienced no angina chest pain and no damage (scarring) to his heart. Heart surgeons performed open heart surgery on this man who had no symptoms. His doctors were totally baffled.

Ed had been taking a resveratrol pill for the past few years, a resveratrol pill that had been shown in animal experiments to convert mortal heart attacks into non-mortal events. In an animal study conducted by researchers at the National Institutes of Health, this microencapsulated and micronized brand of resveratrol pill (Longevinex®) protected the heart prior to a blockage in a coronary artery and restored a normal gene activation pattern to heart muscle twice as well as plain resveratrol. Copyright 2012 Bill Sardi, ResveratrolNews.com

Resveratrol-Meter

Timeline of positive and negative events involving resveratrol

The recent checkered past of resveratrol is presented below (Resveratrol Meter) with up-arrows (⇧) identifying positive information that gained public attention, while down-arrows (⇩) signify negative information that has created consumer doubt or confusion. It’s been a rocky public relations road for resveratrol.

⇧Nov. 17, 1991, CBS’s “60 Minutes” broadcasts a report on the correlation between consumption of red wine in France and lower rates of heart disease. Shortage of red wine reported that year in USA.

⇧Jan 1997: Researcher John M Pezzuto searches the planet for natural anti-cancer molecules, analyzes 30,000 molecules for anti-cancer properties; advises cancer researchers to study resveratrol, the most promising of all.

⇧Sept 2003: Harvard professor David Sinclair and Konrad Howitz of Biomol make link between sirtuin1 survival gene, longevity produced by calorie-restricted diets and resveratrol, a red wine molecule. Discovery is covered widely in Wall Street Journal, NY Times, etc.

⇧Nov 2006: Resveratrol increases survival in overfed laboratory mice.

⇩Aug 2007: Researchers Matt Kaeberlein and Brian Kennedy cannot duplicate earlier Howitz/Sinclair activation of Sirtuin1 survival gene with resveratrol. It is found that a dye used in the gene activation test stimulated this gene, not resveratrol. Resveratrol continues to astound, but its gene target is questioned.

⇧April 22, 2008: GlaxoSmithKline announces purchase of Sirtris Pharmaceuticals and its experimental resveratrol-based drug, SRT501, plus synthetic “new chemical entities” for $725 million.

⇩July 2008: Leonard Guarente of MIT reports a calorie restricted diet does not activate the sirtuin1 survival gene in all tissues and organs, making it an unreliable marker as a longevity gene. Resveratrol is still miracle molecule but its gene target is in question. A major advantage of resveratrol is its ability to affect many genes, not single genes.

⇩Aug 2008: High-dose resveratrol fails to prolong the life of laboratory mice on a normal calorie diet.

⇧Jan 25, 2009: CBS’ 60-Minutes TV program revisits the topic of red wine and health and focuses on a special molecule – resveratrol. The idea of a resveratrol pill to prolong human life is presented. A university researcher interviewed on the program fails to report that his lab tested a particular brand of resveratrol pill that activated 9-fold more genes in laboratory mice than plain resveratrol.

⇧Dr. Oz appears on Oprah TV show extolling resveratrol as an anti-aging pill.

⇩Spammers flood computers all over the world with misleading claims their brand of resveratrol was shown on the Oprah Show and Google allows these online scammers to make deceptive sales pitches that their resveratrol pills cure cancer, remedy wrinkles, produce weight loss, etc. A leading online site attracts 833,000 visitors in a month selling a 30-day supply trial bottle of resveratrol for $2.94 which is too tempting for most consumers. Consumers fall for this offer but don’t read the small type that they will be shipped and billed $85/month thereafter for resveratrol pills. This becomes the only upsurge in consumer demand for resveratrol pills.

⇩On August 19, 2009, Harpo, Inc., producers of The Oprah Winfrey Show and The Dr. Oz Show, along with Dr. Mehmet Oz, filed a trademark infringement complaint against 40 Internet marketers of dietary supplements, for using their names as a false endorsement for their products.

⇩Cancer researchers employ mega-dose (5000 mg) resveratrol among terminal bone marrow (multiple myeloma) cancer patients and are forced to halt the study due to immediate kidney failure experienced by the patients.

⇩August 12, 2010: Two former Sirtris Pharmaceutical executives begin selling resveratrol as a dietary supplement. GlaxoSmithKline, who purchased Sirtris, halts sale of resveratrol supplement and censures its executives.

⇩Dec 1, 2010: GlaxoSmithKline announces it will discontinue research & development of its SRT501 resveratrol-based drug.

⇧Nov 2011: Researchers report a 30-day trial of resveratrol mimics metabolic health benefits of a calorie restricted diet in humans.

⇩Jan 2012: Pall is cast over resveratrol research as a University of Connecticut releases document alleging leading resveratrol scientist has committed scientific fraud. The science in question would not have altered the conclusions of the research studies that were published, yet news reporters trash the whole idea of taking resveratrol pills. The research in question has no bearing on the fact resveratrol can potentially turn mortal heart attacks into non-mortal events, a fact that goes overlooked in the controversy.

Copyright 2012 Bill Sardi, ResveratrolNews.com

While researchers have argued over whether Sirtuin1 is the direct or indirectly-activated gene responsible for its molecular mimicry of calorie restriction, researchers now claim resveratrol works directly by inhibiting enzymes called cAMP-dependent phosphodiesterases which then triggers a cascade of events that includes Sirtuin1. You also see the name of a pharmaceutical company in Japan participating here. (see attached paper)

Cell 148, February 3, 2012

Finding a Target for Resveratrol

Ruth I. Tennen,1,2 Eriko Michishita-Kioi,3 and Katrin F. Chua1,2,*
1Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University, Stanford, CA 94305, USA
2Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA
3R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
*Correspondence: kfchua@stanford.eduDOI 10.1016/j.cell.2012.01.032

Despite resveratrol’s well-documented health benefits, its mechanism of action remains controversial.
In particular, the direct molecular target of resveratrol has been elusive. Park et al. now show that resveratrol directly inhibits cAMP-dependent phosphodiesterases, triggering a cascade of events that converge on the important energy-sensing metabolic regulators AMPK, SIRT1, and PGC-1a.

1. In recent days, Rush Limbaugh has suggested maybe the whole idea of drinking wine for heart health, and certainly red wine resveratrol pills, should be abandoned, that this idea is based upon data that has been found to be faulty. First, what about wine, you at least respond positively if patients with heart disease inquire about wine drinking?

Answer: Not only do I respond positively when patients inquire about drinking red wine, but I will occasionally encourage them to take resveratrol based up the individual patient’s profile and medical condition. The health benefits of red wine, especially in cardiovascular disease, have been well known for centuries if not thousands of years. Research in this field has clearly been accelerating over the last several years and recent events do not deter me in the least. After an extensive review of the literature, including recent events at the University of Connecticut, I am undeterred in my conclusion, which is entirely based upon scientific evidence, that resveratrol and red wine have the potential to be extraordinarily beneficial in the fight against cardiovascular disease.

2. What about red wine resveratrol pills, are they still a good idea? What is your experience with them?

Answer: I have been prescribing a specific resveratrol pill for the last few years for a very large number of my patients. This has entirely been prompted by over 10 years of science coming out of Harvard University and then subsequently studies sponsored by the National Institute of Health. It is rare for me to specify that a patient take one particular brand of a supplement. However, in the case of resveratrol, I have been rather strict that patients specifically take Longevinex® as their resveratrol supplement. I believe that, and I tell patients this, that Longevinex® seems to me to be the one supplement that best replicates the decade of science that has come out of Harvard on resveratrol with regard to longevity and cardiovascular protection. In addition, there has been National Institute of Health trials on resveratrol in which Longevinex® was the source of resveratrol chosen for the study. Clinically, I have seen extraordinary benefit in a number of patients. One specific anecdote which occurred recently is in a 90-year-old patient who has been on resveratrol, specifically Longevinex®, suffered a heart attack, but at cardiac catheterization and later on at subsequent nuclear perfusion stress testing, there was so little damage that it was almost nonexistent. This exactly replicates animal data with resveratrol.

3. In recent weeks a report published in the Archives of Internal Medicine suggests a baby aspirin may be widely effective in reducing non-mortal heart attacks but not sudden death heart attacks. What do you now tell your heart patients about aspirin?

Answer: I take care of a lot of patients who are considered “primary prevention”, meaning that they are at risk of heart disease but have not had any clinical cardiac events. In addition, I take care of a lot of “secondary prevention” or patients who have known cardiovascular disease and are trying to prevent recurrence, which is always considered a high risk. A number of studies have shown that up to 70% of people taking aspirin are doing so for no good clinical benefit and are therefore putting themselves at risk. I counsel patients carefully on the risks and benefits of aspirin in their individual case, and I can tell you that I prescribe far less aspirin than the average physician. For the patients in whom clinical testing has found a predisposition towards clotting or “sticky” platelets, then of course aspirin can be life saving. However, the vast majority of patients who are taking aspirin, especially those in the primary prevention arena, are doing so unnecessarily.

4. It has been said that the best type of prevention for the heart would be something called “cardio prevention” where the defensive systems in the heart are activated prior to a heart attack. Exactly what is this?

Answer: Everything that we are trying to do, whether in the primary prevention or secondary prevention arena, is to restore a system of health to arteries that are otherwise unhealthy. This latter is sometimes called “endothelial dysfunction” in which arteries constrict in response to signals telling them to relax and are therefore prone to damaging the lining of the arteries leading to cholesterol accumulation. A number of substances have been found to restore endothelial function, ranging from healthy diets to omega 3 fish oil. One of the most exciting areas of cardio prevention, however, is the idea of “ischemic preconditioning.” The ability to recruit collateral blood vessels and improve endothelial function is often mediated by a molecule called adenosine. Adenosine is often reduced or compromised in people with endothelial dysfunction and arterial disease. Resveratrol has been found to significantly improve ischemic preconditioning, possibly though improved adenosine release. In the clinical scenario that I mentioned earlier of the 90-year-old heart attack patient, I believe that this is likely the mechanism through which he suffered so little if any damage.

5. How have your patients taken to the idea of a red wine pill?

Answer: They love it. They love the idea that their cardiologist is always looking at cutting edge and especially non-pharmaceutical science. The fact that this is so new and scientific with the potential to help them in so many ways is exciting to them. They also have all heard about the fact that people in France and Italy live to old ages and often have lower rates of heart disease, possibly attributable to their red wine consumption. They do not necessarily want to have to drink 3 to 5 glasses a day of red wine, and therefore they are enthusiastic about the idea about taking it in pill form.

6. Will any resveratrol pill do or are there doses that are recommended or special brands?

Answer: As I mentioned above, this is one supplement in which I am very strict that patients take one specific resveratrol brand, called Longevinex. This is because after looking at all of the resveratrols on the market, many of which have come from off shore and are fraudulent, it is critically important to find a supplement that is both safe and has the right mix of ingredients. Taking resveratrol correctly is very tricky. Too little does not work and too much can be toxic. The therapeutic window is somewhat narrow. In addition, resveratrol alone may not do very much. Rather, it has to be combined with several of the “small molecules” found in red wine. The one supplement that I think makes extraordinary effort to replicate all of the above and the over 10 years of science that has come out of Harvard University on resveratrol, is indeed Longevinex®.

Nate E. Lebowitz MD, FACC

Advanced Cardiology Institute
Diplomates in Cardiovascular Disease
American Board of Internal Medicine
9W Office Center, 2200 Fletcher Avenue
Ft. Lee, NJ 07024
(210) 461-6200
www.acicardio.com

* Dr. Lebowitz received no compensation for the above statements and is not commercially affiliated with Longevinex®.

Note: The Food & Drug Administration deems dietary supplements like Longevinex® to narrowly support heart health and only FDA-approved drugs can be said to prevent, treat or cure diseases, such as heart disease. This interviews was released in the public interest given aspirin has now been shown to be largely ineffective in preventing mortal heart attacks and at least in the animal laboratory resveratrol has been demonstrated to turn mortal heart attacks into non-mortal events. It will take years to prove whether resveratrol prevents sudden-death heart attacks in humans. If that is proven at some future date in time, resveratrol pills would likely be declared a drug by the FDA. During that time millions of adults will meet their early demise due to a sudden unexpected heart seizure. Given that there is no current impetus to put resveratrol to the test in cardiology, inquiring consumers, using the best available science, must embark upon their own self-guided efforts to determine whether resveratrol would be beneficial for their heart health. – Bill Sardi, ResveratrolNews.com Jan 29, 2012

According to the following report, 25% of accepted manuscripts contained at least one “inappropriately manipulated figure,” but obviously the authors of these papers did not all face expulsion from their institutions as did Dr. Das. This report in Nature Methods does not say that editors also reject papers where western blot images that are not of sufficient quality to be reproduced, forcing authors to enhanced the images. But it should. Furthermore, apparently most of these cases involve researchers who did not have intent to deceive.

The question arises, why didn’t the editors of the 11 journals involving 26 papers submitted by Dr. Das ever catch these “altered images” in their peer review and scientific integrity efforts? It seems to me researchers should submit raw images and let the journals take all the ethical criticism rather than risk their careers over this. Would firing 25% of the researchers fix the problem? Obviously no. But it’s OK to pillory Dr. Das.

The western blot test is a political can of worms. There have been dismissals and sanctions issued over western blot images for a number of years now and the scientific community is no closer to resolving the problem than when the issue first came to light a few years back. Today we have better though more expensive tests that can be performed, to measure protein levels in tissues. The most sophisticated is microRNA. NIH researchers validated by microRNA Dr. Das’ work which involved the use of resveratrol in excised rodent hearts that were subjected to experimental heart attack. Resveratrol restored the normal microRNA gene expression pattern following a heart attack in animals.

The western blot test was only one of other tests performed to demonstrate the benefits of resveratrol. The most remarkable were direct photo images of the heart which showed that resveratrol reduced the area of scarring (fibrosis) following an experimental heart attack. These photo images themselves provide observable evidence that resveratrol protects the heart prior to a heart attack and can turn a mortal heart attack into a non-mortal event. This is jaw-dropping science.

Given that aspirin was recently found to be ineffective at reducing the risk for mortal heart attacks, cardiology should be focusing on resveratrol. The release of accusations against the leading resveratrol researcher in cardiology was perfectly timed. In the 8 years since a Harvard professor indicated resveratrol is a key molecule in red wine responsible for the French Paradox (the fact the wine-drinking French have a much lower rate of coronary artery disease mortality despite their high fat diet and high cholesterol levels), not one human study involving resveratrol in cardiology has ensued. The higher crime appears to be foot dragging by modern medicine. – Bill Sardi, managing partner, Resveratrol Partners LLC, dab LONGEVINEX

Nature Methods – 3, 237 (2006)
doi:10.1038/nmeth0406-237
http://www.nature.com/nmeth/journal/v3/n4/full/nmeth0406-237.html

A picture worth a thousand words (of explanation)

While the dust slowly settles over a staggering case of scientific fraud, a bitter aftertaste lingers with scientists and editors alike—that of having been deceived by grossly manufactured evidence. It is clear that fraud is a shameful exception, but this climate may be conducive to a little reflection on some less extreme practices of figure manipulation, which—if seemingly more innocuous—are largely more common. With current processing software, a few clicks of the mouse make possible a spectrum of image manipulations, from innocent embellishment to scientific misconduct. Nature journals have prepared new guidelines in an attempt to clarify boundaries of acceptability in preparing images for publication (http://www.nature.com/nmeth/about/ed_policies/index.html).

We do believe that in the vast majority of cases intentions are good: authors seek to present data more clearly. But good intent does not make all practices acceptable, and the few numbers available to quantify the unacceptable are surprisingly high.

Particularly informative are the statistics gathered by the Journal of Cell Biology, which for almost 4 years has been applying a systematic search for image manipulation in its accepted papers before publication (The Scientist 20, 24; 2006). This scrutiny led to 1% of accepted papers to be revoked on the grounds that image manipulation affected the interpretation of data. Surprisingly, 25% of accepted manuscripts contained at least one inappropriately manipulated figure for which a satisfactory replacement could be obtained from the authors upon further investigation. These rates have not declined since the policy was implemented. Such numbers together with anecdotal evidence suggest that a large proportion of authors are not aware of what does and does not constitute inappropriate image manipulation.

The new Nature journal guidelines are an attempt to clarify these limits. Their principle is that no modification can be made that selectively affects only a portion of the image, removes information or adds information obtained in a different experiment. Even without affecting the paper’s conclusion, such modifications may have consequences. For example, hiking up the contrast of a western blot image to decrease the appearance of background will provide the community with a false idea of the antibody quality. Moreover, some observations that do not appear to make sense in the context of the current body of knowledge may turn out to be logical once the biology of the system is understood. Removing such peripheral information from images today will lead to contradictions tomorrow.

Thanks to electronic submission and publication processes, much more information may be presented to editors, reviewers and ultimately readers. When modifications are unavoidable, authors should provide a clear description of the manipulation in the figure legend and are encouraged to provide original images as supplementary information.

Distortion of data can also occur before the figures are prepared, that is, at the time of image acquisition. This is particularly true for fluorescence microscopy (Nat. Methods 2, 889; 2005). Unless properly trained, many researchers may not fully understand the consequences of adjusting instrument settings. To allow readers to fully comprehend the context of an experiment, we request that the parameters affecting image acquisition be recorded in the paper. Additionally, Nature Methods has recently published a special focus issue (http://www.nature.com/nmeth/focus/fluorescence/index.html) with the goal of providing a reference of best practices for new users of fluorescence microscopy.

Several documented cases of published papers containing manipulated images, whether intentionally deceptive or not, have reflected a disconnect between the people who acquire the results and those who report them (Nature 434, 952; 2005). When even a single person distorts evidence unbeknownst to their coauthors, the reputation of honest, unsuspecting scientists is at stake. To avoid such damaging situations, corresponding authors need to acknowledge their responsibility to be accountable for the scientific veracity of the work.

From now on, Nature Methods will also be requesting, upon conditional acceptance of a paper, a statement by the corresponding author assuring that the figures provided for publication accurately represent the original data in agreement with our guidelines. This will be viewed as bureaucratic nonsense by some, but nevertheless, we hope it will promote a dialog within research groups and improve awareness of the acceptable limits of image modification.

We encourage you to read these guidelines, discuss them with your peers and perhaps reconsider some practices that you have been applying without contemplating their consequences. We hope that this is a solid step forward in dismantling the myth that more-than-perfect images are needed to gain the approval of reviewers and editors.

GUIDE FOR DIGITAL IMAGES

Images submitted with a manuscript for review should be minimally processed (for instance, to add arrows to a micrograph). Authors should retain their unprocessed data and metadata files, as editors may request them to aid in manuscript evaluation. If unprocessed data are unavailable, manuscript evaluation may be stalled until the issue is resolved. All digitized images submitted with the final revision of the manuscript must be of high quality and have resolutions of at least 300 dpi.

A certain degree of image processing is acceptable for publication (and for some experiments, fields and techniques is unavoidable), but the final image must correctly represent the original data and conform to community standards. The guidelines below will aid in accurate data presentation at the image processing level; authors must also take care to exercise prudence during data acquisition, where misrepresentation must equally be avoided. Manuscripts should include a single Supplementary Methods file (or a subsection of a larger Supplementary Methods file) labeled ‘equipment and settings’ that describes for each figure the pertinent instrument settings, acquisition conditions and processing changes, as described in this guide.

1. Authors should list all image acquisition tools and image processing software packages used.
2. Authors should document key image-gathering settings and processing manipulations in the Supplementary Methods.
3. Images gathered at different times or from different locations should not be combined into a single image, unless it is stated that the resultant image is a product of time-averaged data or a time-lapse sequence. If juxtaposing images is essential, the borders should be clearly demarcated in the figure and described in the legend.
4. The use of touch-up tools, such as cloning and healing tools in Photoshop, or any feature that deliberately obscures manipulations, is to be avoided.
5. Processing (such as changing brightness and contrast) is appropriate only when it is applied equally across the entire image and is applied equally to controls. Contrast should not be adjusted so that data disappear. Excessive manipulations, such as processing to emphasize one region in the image at the expense of others (for example, through the use of a biased choice of threshold settings), is inappropriate, as is emphasizing experimental data relative to the control.
6. When submitting revised final figures upon conditional acceptance, authors may be asked to submit original, unprocessed images.

In recent days a clear message has been sent to laboratory investigators – cooperate with a resveratrol pill maker and your career will be over. And this is not the first time this has happened.

Leading resveratrol researcher accused of fraudulent science

If you were listening to Rush Limbaugh on the radio in the past week you heard him impugn the work of East-Indian born researcher, Dipak Das PhD., a University of Connecticut researcher widely known for his work in studying resveratrol (rez-vair-ah-troll), a red wine molecule, for heart health.

According to Limbaugh and over 300 news agencies, Dr. Das is unequivocally guilty of doctoring tests that measure the amount of proteins in tissues, a test called a western blot. The University of Connecticut, Dr. Das’ employer, released a damning report that appears to present undeniable evidence that Dr. Das had doctored images on his office computer and published those images in a scientific journal in 2008.

The fraud that wasn’t fraud

But hold on. The alleged faulty tests in no way altered the outcome of his research studies. The western blot test was only one of many tests used to draw scientific conclusions in published studies. Furthermore, other independent labs, including the National Institutes of Health (NIH) itself, validated Dr. Das’ work, as did researchers in Europe and Japan.

What would the motive have been to doctor the tests? University of Connecticut alleges it was grant money from the NIH. But Dr. Das alleges there had been long-standing jealously of his work within the University of Connecticut dating back to 1984. He says everyone in his laboratory and many others knew of this.

University of Connecticut reviewers had brought this particular published report into question more than two years prior. Dr. Das had refuted all the allegations then. So why was it resurrected? There is obviously more to the story.

Anonymous letters received

This writer first became aware of allegations against Dr. Das about two years ago when he received an anonymous letter was received in the US mail claiming that investigators were examining Dr. Das for scientific fraud. The letter originated from Farmington, Connecticut, where the University of Connecticut Health Center is located. It was typewritten on photocopied university letterhead.

This was certainly an odd occurrence. Dr. Das was out of the country at the time, so I contacted University officials and faxed them a copy of the letter. I said this was unusual for an outsider to receive a potentially slanderous letter like this and I wanted to know if there truly was any investigation going on and I wanted to know who sent me this letter.

I was informed by a doctor at the university that they thought they knew who was responsible for issuing this anonymous letter. So it was someone the university knew. I later found it was an East Indian-born researcher who worked in Dr. Das’ lab who is also the informant or whistle blower in this case During subsequent investigations I found that other research students in Dr. Das’ lab had also received similar anonymous letters alleging Dr. Das was under investigation.

Dr. Das is unpaid consultant

Since Dr. Das had volunteered to study the resveratrol pill my company makes, and test it alongside pure research-grade resveratrol, I thought that any investigation may have negative repercussions on my company. I was assured by a university official that our company was not under investigation.

Dr. Das: mentor to many

Dr. Das, who is widely known for mentoring students who later become full professors university-based research laboratories around the world, repeatedly said he wanted no money from my company. We as a company could provide some free product to test and maybe some testing supplies, but his stated desire was to test a commercially available brand of resveratrol and, if the tests warranted, see it come into common use before his research career was over.

Dr. Das is 66 years of age and approaching retirement. Upon his retirement he had hoped to return to India to conduct further studies at the food and nutrition institute he established at Jadavpur University in Kolkata (the old Calcutta), the city of his birthplace.

Getting to the truth

Fortunately, I was in a unique place when the news media first blasted their recent reports claiming scientific fraud by Dr. Das. I was attending a meeting of resveratrol researchers in Kolkata, India and had direct access to Dr. Das, as he was in attendance at the meeting. Furthermore, two of his former laboratory students whose names are published alongside his in some papers, were also attending the meeting in Kolkata. So I could conduct an extensive inquiry of all three parties.

I first hesitated to inform Dr. Das of what was happening on a worldwide basis. I wondered how he would take the news. The issuance of a 600-page document that provided evidence of his alleged wrong-doing had previously been placed on his desk at the university. The stress of all this resulted in two small strokes which he has remarkably recovered from. But this ordeal was certainly taking its toll.

I took him aside and asked if he knew that his name was in a headline story published by over 300 news agencies around the globe, claiming he had committed scientific fraud. At the meeting in Kolkata I was informed by others that legislators in India were also considering censure of Dr. Das as he had shamed East Indian scientists around the world. The swiftness with which the news media operated and the unusual sanctions were unprecedented. It suggested this was an orchestrated hit job.

Dr. Das says all researchers alter western blot tests

I asked Dr. Das directly, had he altered western blot images, or directed others in his lab to do so. While his initial answer was no, meaning he had not fabricated or altered any scientific finding, altering western blot images are a common practice in laboratories for reasons other than deception. The university chose to present its findings in a derogatory manner. Dr. Das explains that editors at scientific publications commonly request researchers to enhance faded images of western blot tests so they can be duplicated in their publications. Western blot tests are frequently altered to remove backgrounds, enhance contrast and increase dots-per-inch resolution so that they are suitable for publication. This had been fully explained to university officials long ago.

Alteration of western blot tests is not a “Dr. Das” issue, it is a widespread issue that has been discussed widely among scientists. There are even online courses on how to use Photoshop to alter western blot images. An online report says: “There is a difference between figures in a research article and the actual data. Scientists will quantify changes in protein levels, for example, but show the prettiest image they have to visually convey those changes in the paper. So even if you falsify an image but your data is solid, you can still stick with your scientific claims (although your intelligence could be fairly questioned).”

Were the western blot images in question altered to gain further NIH grants as the University of Connecticut alleges? How so? The western blot data would have not changed the positive outcomes of the studies as they were only one of many tests performed to draw conclusions.

The other set of keys

The document produced by the university claims only Dr. Das had access to his office; that only he had the keys to his office and his computer. So he, and he alone, was responsible for the alleged western blot images that had been altered, says the university report.

But I inquired about this with the two former students attending the meeting in India. They said, no, that another party in Dr. Das’ office also had a set of keys and that this party is the very same informant who issued the anonymous letters slandering Dr. Das’ work. I was told that the informant stands to be promoted if the university fires Dr. Das. News reports claim the university will soon fire Das, if this has not already taken place.

Did Dr. Das dismiss a researcher for not cooperating?

Another allegation is that Dr. Das “de-funded” a student who conducted Western blot testing when he didn’t like the results she produced. But all three of my sources, including Dr. Das, claim this lab worker spent most of her hours working for the co-researcher who was the informant in this case and that since the worker was not doing any work on his experiments, he removed her from his budget. The de-funding had nothing to do with the results of the western blot tests.

Students are solely responsible for data

As I drilled Dr. Das’ former students with questions, I found that lead researchers like Dr. Das do not do any lab bench experiments. Students do all the work and submit their results to him via e-mail or by directly downloading data into his computer. Dr. Das says that when he is not traveling his office is open and students can enter and download data directly onto his computer. I had previously visited Dr. Das at the University of Connecticut and noticed his office door was left open and anyone could have access to his computer.

One former student told me that typically lead researchers like Dr. Das write the introduction and conclusion of experiments and the students enter all the data, before publication in scientific journals. Dr. Das, who is busy lecturing all over the globe because of his groundbreaking studies, does not directly oversee tests that are performed, and neither do most other lead researchers. The University of Connecticut report says the university holds Dr. Das responsible for all of the data. Probably most lead researchers in scientific laboratories around the globe are vulnerable to errors or even fabrication of data by their students.

Factitious report

Why would the university issue a report that contained erroneous and misleading information itself? Not only did another senior researcher in his lab have a set of keys, and his students widely knew of this, but also another university investigator had broken the locks on his office door and removed data from his computer as well as private information such as bank account records and his passport, according to Dr. Das.

Let’s examine the level of evidence here. An analogy could be a murder case in a court of law where prosecutors may find a gun involved in the murder in a defendant’s desk drawer, they may find his finger prints on the gun, and the bullet that killed the deceased may have come from the same gun. But this evidence is circumstantial. It does not place the accused at the site of the crime or reveal a motive. Furthermore, just how a person could be held responsible for the real possibility that someone else using his gun (computer) goes unexplained, but that is the university’s position. Furthermore, in this instance, the murder (intended alteration of data with intent to deceive) was never committed. The western blot test was altered only for the purpose of meeting publication clarity requirements. It appears that scientific publications need to add a caveat to altered western blot images that they publish, saying something like “these western blot images have been altered for the purpose of better visualization and reproduction and are not exact replicas of the original western blots. Refer to the actual numerical data in the report.” This would de-criminalize this practice.

University allegations fall apart

The more I asked questions the more that the university’s allegations were falling apart. The news media, in a rush to get their story out to the world, simply reported that Dr. Das had not returned their phone calls, which was pejorative. He was in no position to answer calls at his home or office in the US as he was attending a scientific conference in India. He was blindsided by the release of the report to the news media. He could not defend himself in a timely manner. The timing of the release of the University of Connecticut report appeared to be cunningly intended to limit Dr. Das’ ability to reply to these accusations.

The informant

Just what was the motive of the university’s informant? This is where this case turns into East Indian Bollywood intrigue without the dancers and singers. According to a former student of Dr. Das, the informant, an East Indian whose career had been furthered by Dr. Das, was quite jealous of other East Indian students whom Dr. Das appeared to favor. The student says this informant even attempted to “pour wine directly down my throat” in an attempt to inebriate her and get her to reveal negative information about Dr. Das. Well, well.

Colleagues don’t believe the university

Dr. Das says many editors at scientific journals don’t believe the University of Connecticut report. They full-well know that editing of western blot tests is common practice and that the tests in question in no way invalidate his work and were only one part of the evidence provided in his papers from which Dr. Das drew conclusions. This is the case of scientific fraud that wasn’t.

The University of Connecticut gave Dr. Das 30-days to respond to its report, but given his busy lecturing schedule, established and made known to the university months in advance, and given that he had refuted all prior questions asked of him, he was perplexed how to provide the university with further convincing rebuttal. I also think Dr. Das was too frightened to respond. He wrote two letters which feebly defended his work which are included in the university report. It was only when I was able to conduct an extended interview with Dr. Das that all of these other details came to light. Dr. Das was doing a poor job of defending himself.

Will Dr. Das obtain legal representation and demand embarrassing depositions from university personnel that will reveal what has been revealed in this report? An attorney called me to suggest that Dr. Das file a worldwide defamation case against the university.

The best way for Dr. Das to prevail in this travesty against him is to continue to work with his colleagues overseas and to write scientific papers that savvy editors of scientific publications will publish. If his colleagues publish his work, it would be fitting justice against a university and a scientific community that drew forgone conclusions and didn’t conduct a thorough investigation.

Not the first time

Was this the first time a resveratrol pill faced such back-door opposition? No. In 2004 a professor at a prestigious Ivy League institution announced to the news media that he had developed a nutriceutical version of resveratrol which would soon be marketed. It ultimately evolved into the pill my company now makes. But institution authorities intercepted this professor’s e-mails and phone calls and directly informed him, if he chose to work with a dietary supplement company, that he would never become tenured.

There have been other sour experiences my company has had with the research community.

• A South Florida testing lab conducted a human clinical trial of the pill my company makes and appeared to intentionally botch the study. The lab forgot to monitor whether subjects took the pills on schedule and blood samples that were sent to an outside lab were said to have been contaminated. When contacted, the outside lab said this had never occurred in their laboratory. Our company spent $60,000 for a study that produced unreportable data.
• In 2006 the a prestigious Midwestern university gained NIH approval to test resveratrol for Alzheimer’s disease. The university had selected the pill my company makes for the study. I had met personally with the lead researcher. However, a major pharmaceutical company used its influence over the university and the study never commenced.
• In 2008 researchers affiliated with a major university appeared on CBS’ 60 Minutes TV program about resveratrol and failed to mention that the pill our company makes was found to activate 9-times more genes than plain resveratrol in a mouse study, exceeding the effect of plain resveratrol or a calorie-restricted diet. To this day these researchers refuse to lecture on this published discovery.
• In 2011 Dr. Das traveled to an out-of-state university-based animal laboratory to conduct special studies involving resveratrol and arterial health. Our company provided samples of our resveratrol pill for the test. Laboratory tissue samples obtained during these experiments were then shipped to Dr. Das’ laboratory in Connecticut, but had been completely contaminated prior to shipping. Was this another case of scientific sabotage?

Modern medicine in lock-step

Dr. Das is the man who demonstrated that resveratrol can turn a mortal heart attack into a non-mortal event and that a particular brand of resveratrol pill did this more so than plain resveratrol in laboratory mice. How many billions of dollars of heart drugs are threatened by Dr. Das’ discoveries?

Modern medicine is marching in lock-step to make sure a resveratrol pill never gains public acceptance. That is because resveratrol pills exhibit much broader biological action than any gene-targeted drug, or a drug aimed at a single cell receptor site. This is how most modern drugs are designed.

Resveratrol is an antidepressant, an anti-inflammatory, an anti-bacterial, anti-fungal, anti-viral, anti-cancer, cholesterol-lowering, liver-cleansing, brain enhancing molecule. If Americans embraced resveratrol pills en masse, many prescription drugs would not be needed. Modern pharmacology and its model of developing individual synthetically-made molecules to specifically treat each and every disease, would become antiquated.

The real resveratrol story

What the public heard about resveratrol in the news media in the past week is far from the real story.

Resveratrol and blindness

As many as 150,000 older Americans needlessly lost their sight in the past four years due to foot-dragging by eye doctors in recommending resveratrol for a condition known as wet macular degeneration. Billions of dollars in medication costs to treat this eye disease could also have been saved had the resveratrol pill my company makes been widely used as a substitute treatment.

In an NIH study our pill had been shown to exhibit six times greater effect than plain resveratrol in inhibiting the formation of abnormal retinal blood vessels which can destroy vision at the back of the eyes.

In 2007 eye physicians discovered the resveratrol pill my company makes rapidly restored sight to patients who either refused to undergo needle injections into their eyes or who failed drug treatment. Drug treatment fails in one in six patients with macular degeneration and these patients go on to suffer permanent vision loss.

But suddenly these eye doctors denied the pill worked, they said the effect didn’t last and abandoned the use of the pill. Thereafter eye physicians began injecting a more expensive drug to treat this eye disease and began collecting billions of dollars of Medicare funds for these injections.

Mary is an 88-year old patient with wet macular degeneration who is among the first to benefit from the use of a resveratrol-based pill to save her sight. She was hospitalized at a veterans health center primarily for unstable blood pressure and her failing vision. Initially the veterans health center said our pill could not be used there because it was not an FDA-approved drug. Mary’s eye doctor appealed, having successfully treated a number of other patients with our pill. The hospital chief of staff intervened and said if the patient acquired our pill on her own, and elected to take it as a dietary supplement, there would be no objections.

Mary called our company and we rush-shipped the pills. Within four days Mary was able to read the hospital meal menu for the first time. She was able to visualize her doctor’s face and see her own handwriting. As things progressed, her unstable blood pressure, which had been causing her to black out, normalized. She also experienced remission of life-long migraine attacks and was later discharged from the hospital. Other therapies had failed to produce these health benefits.

Resveratrol and heart attacks

Hundreds of thousands of Americans could possibly avert a sudden mortal heart attack annually if resveratrol was substituted for aspirin among patients at high risk for heart attacks. Neither statin cholesterol-lowering drugs nor aspirin tablets prevent mortal heart attacks according to the most authoritative data. Strikingly, with all of the sophisticated pharmaceutical armamentarium against heart disease, there is not one proven way to prevent sudden-death heart attacks. Cardiologists show virtually no interest in using resveratrol in clinical practice. Outside of one non-invasive cardiology practice in Ft. Lee, New Jersey, no others are known to regularly recommend resveratrol.

Resveratrol and cancer

If animal data can be translated to humans, countless cancer patients could have survived longer or even experienced total remissions if resveratrol were used commonly either alongside existing cancer treatments or used solely as cancer therapy. Oncologists also express no interest in using resveratrol in cancer therapy now that a major pharmaceutical company abandoned further research and development of its resveratrol drug. Specifically, a mega-dose (5000 mg) resveratrol pill induced kidney failure among patients with bone marrow cancer (multiple myeloma), which scared patients and doctors away from resveratrol pills. But a particular brand of resveratrol pill, the one my company makes, was found to be non-toxic in animal and human kidneys, even in high doses, and protected the mouse heart from damage caused an intentionally-induced heart attack while the same high dose of plain resveratrol caused damage to the rodent heart. Cardiologists and oncologists paid no attention.

An Ivy League medical school researcher laments that 8 years following the announcement that resveratrol may be the key molecule responsible for the French Paradox ( i.e., the fact the French who eat a high cholesterol/high-fat diet experience a much lower rate of coronary artery disease mortality than North Americans), there is still no human trial involving resveratrol for heart disease. Resveratrol works better than aspirin, preventing blood clots, reducing inflammation, widening (dilating) blood vessels, and releasing protective chemicals before a heart attack occurs. No drug comes close to what resveratrol can do in the heart.

A researcher in the field of resveratrol suggests there is not enough human data to bring resveratrol from the laboratory bench to the hospital bedside as yet. But thousands of consumers have leaped ahead of foot-dragging researchers to experience the many health benefits posed by this miraculous small molecule found in red wine. Modern medicine is demanding evidence that it loathes to produce.

Patients are convinced

Some patients already are convinced of the health benefits of resveratrol:

Joyce B, age 77, of Mesquite, Nevada, was losing her sight and had undergone 17 injections of a drug directly into her eyes without success. There were no other options for Joyce. All other treatment options had been exhausted. Having learned of the possibility that resveratrol may save her sight, she obtained a brand of resveratrol pill that had been uniquely shown to inhibit abnormal blood vessels that destroy the visual center (the macula) at the back of the eyes. Within days her vision was restored and she passed a driver’s license test. Her eye doctor insisted the medicine he injected was responsible for her recovery. Her aged husband also took the pill and experienced measurably improved vision, resolution of his fragile diabetic condition and disappearance of a fluttering heart condition (atrial fibrillation) that stubbornly could not be conquered by conventional treatments.

Ed S, age 70, had none of the common symptoms of coronary artery disease. He was regularly driving a golf ball over 250 yards off the tea at his Palm Desert, California golf resort home. But a routine angiogram (dye test of coronary arteries that supply the heart with oxygenated blood) revealed narrowed coronary arteries, probably caused by a prior smoking habit conquered years ago. One major coronary artery was 99% blocked, yet Ed experienced no angina chest pain and no damage (scarring) to his heart. Heart surgeons performed open heart surgery on this man who had no symptoms or heart damage. Doctors were totally baffled. Ed had been taking a resveratrol pill for the past few years, a resveratrol pill that had been shown in animal experiments to convert mortal heart attacks into non-mortal events, the very pill my company makes. In studies conducted by researchers at the National Institutes of Health, this resveratrol pill protected the heart prior to a blockage in a coronary artery and restored a normal gene activation pattern to heart muscle.

Dr. S, in his 80s, a retired Albany, New York eye physician, developed a parotid gland tumor that oncologists said would require surgery. He began taking a resveratrol pill and some other dietary supplements and his tumor completely vanished. Surgeons persisted with the idea of surgical removal of this salivary gland even though there was no evidence of a tumor and the planned treatment does not address the cause of the disease nor has treatment been shown to meaningfully prolong survival.

Long-term controlled studies demanded

The scientific community keeps begging for long-term, controlled human studies compared against an inactive placebo pill before rushing to use resveratrol pills. But here is the crux of the situation. If a resveratrol pill is not harmful and it is the only remaining therapy after all other treatments have been exhausted, and patients face irreversible harm to their eyes or hearts unless something is done, why would modern medicine demand that studies be completed, which may take years to complete, before recommending it for otherwise hopeless patients? How many will needlessly go blind or die of sudden heart attacks before resveratrol undergoes long-term studies?

Can you find an honest doctor to conduct studies?

As managing partner for a company that makes a resveratrol pill I have been repeatedly advised to make our pill into a drug and spend 3 or 4 years and millions of dollars to prove it works for a narrowly defined disease. But the problem is, I don’t think eye or heart physicians could be recruited to honestly conduct these studies given their foot-dragging and denial of the evidence.

When the National Institutes of Health sought to determine which of two injectable eye drugs worked the best in treating wet macular degeneration, ophthalmology drug its feet for three years before recruiting patients and then took another two years to complete the study. The drug that costs $200 (Avastin) was found to work equally well as a drug (Lucentis) that costs $1500 per injection. But eye physicians often elect to use the more expensive drug, thus gouging Medicare. Eye physicians typically inject patients 6-8 times a year and earn a fee for injecting the medication into the eye. The introduction of an oral pill would take billions of dollars away from eye physicians.

I don’t think eye physicians or cardiologists are going to conduct any study that puts them out of business.

The real story about resveratrol isn’t being told. Resveratrol isn’t being adequately studied. Will consumers see through all this subterfuge? The real scandal does not involve Dr. Das. The real resveratrol scandal is that modern medicine is obviously fearful of this molecule and is loathe to put resveratrol to the test.

Bill Sardi is managing partner of Resveratrol Partners LLC, dba LONGEVINEX®, a Las-Vegas-based dietary supplement company.

Scott Tips, a California-based attorney representing the accused, Dr. Dipak Das, calls into question the following irregularities in the University’s 600-page report which claims Dr. Das doctored images of tests conducted at his laboratory or instructed others to doctor them. Some of these irregularities include:

• The claim that only Dr. Das had access to his computer which was in his locked office. In fact, Dr. Das claims the chief informant in this case, whom the university does not reveal, also had a key to Dr. Das’ office. Dr. Das asserts his office was not private and “anyone could use it.”
• The university’s report stems from a paper published in a 2008 issue of Free Radical Biology & Medicine, a peer-reviewed journal. Why did the university choose to wait three years to publish these allegations that were refuted by Dr. Das over two years ago? No retraction of that published report was called for at that time.
• Dr. Das was blind-sided by the university, being completely unaware of the release of these allegations to the news press. Dr. Das had to be informed of the negative news reports by his colleagues. He was prevented from making a timely response to all of these charges. The news press reports Dr. Das did not return phone calls, which is pejorative, as he was away from his desk and was not monitoring his calls.
• The University of Connecticut report alleges Dr. Das “defunded” the work of a student in his lab because she did not produce results that he wanted. Investigation into this matter shows that Dr. Das “defunded” the work of this researcher from his budget because she was devoting all of her time to another researcher in the same laboratory, who turns out to be the informant or “whistle-blower” in this case, the very same person who also had a key to Dr. Das’ office.
• Another student researcher who worked in Dr. Das’ laboratory in 2008 discloses that the informant in this case was a trouble maker who chased away many other researchers by intentionally causing friction in Dr. Das’ lab. The former student says the university informant in this case even attempted to “pour wine down her mouth,” hoping to get her to reveal negative things about Dr. Das. The student says she did not witness any scientific irregularities in Dr. Das’ lab during her tenure there, which included Western Blot tests that were alleged to be doctored.
• Another party, a university internal investigator whom Dr. Das accuses of long-standing prejudice against foreign-born researchers, reportedly broke the lock on Dr. Das’ office door, removed computer files and personal items such as bank records and a passport, and could have manipulated data in his computer files. Dr. Das says this university investigator has had a long-standing vendetta against him going back to 1984.
• Dr. Das says he has not personally conducted laboratory bench tests for many years now and that his students and other subordinates conducted all the tests, including the allegedly doctored Western Blot tests. Even if doctored and inaccurate, these tests in no way invalidate the many health claims associated with resveratrol, a red wine molecule. Dr. Das says most of his work has been corroborated by other researchers including his important finding that resveratrol protects the heart against damage prior a heart attack.
• While the news media made quick association between Dr. Das and a particular brand of resveratrol pill he has tested, Dr. Das has no commercial relationship and does not serve as a paid consultant to any manufacturer of resveratrol pills. He served as an unpaid expert for an online interview of a particular brand of resveratrol, a pill that his laboratory found to be superior to plain resveratrol in laboratory studies. A spokesman for that company, Bill Sardi, managing partner for Resveratrol Partners LLC, dba Longevinex®, says his company has donated product to researchers including Dr. Das’ lab and has underwritten some of the expenses involved in conducting tests, but no researchers have received pay offs or have personally profited from their studies involving his product. Mr. Sardi says his company has not sought to influence the outcome of any independent or sponsored studies. Resveratrol Partners LLC is a private company based in Las Vegas, Nevada. ####

“May the force be with you.” – Star Wars

Strange as it may seem, largely because of difficulties in figuring out how to commercialize on what it promises, both alternative and conventional medicine fail to put into practice a compelling discovery that promotes health and longevity in an unmatched fashion.

It’s not a high-tech invention. It is not a patentable process. It is not a machine or a drug. Nor is it new. It has been recognized in the medical literature for decades now.

It is an adaptive internal response to mild biological threats that trigger incomparable defenses in the human body.

Despite considerable personal investigation into this topic, even the most avid health nut or PhD pursuer of longevity is likely to have missed the greatest mechanism to promote the human healthspan and lifespan ever discovered because it is not found in our external world but is rather a built-in adaptive response within the human body that has many triggers.

Historically this life force dates back to reports published in the 1940s, but it still has not hit the public’s radar of awareness. A few reports of people bathing in radium hot springs or spending time at the bottom of old mine shafts, to be exposed to sub-lethal amounts of radon gas, have been published. These practices are examples of mild biological stressors that tap into this life force, but the power of this mechanism and its numerous environmental triggers goes largely unrecognized and untapped.

This “life force” promises to make super humans who can think faster and more cogently, who are resistant to pain via production of endorphins, and who are resistant against disease in a manner that would antiquate most prescription drugs in use today.

Pray tell, what is it? And why hasn’t the public been alerted to it sooner?

This “life force” is called hormesis, which is defined as exposure to a low level toxin that triggers biological defenses.

The historical father of hormesis is Swiss-born Phillippus Aureolus, who used the pseudonym “Theophrastus Bombastus von Hohenheim” and later went by the pen name Paracelsus (1493-1541 AD), was among the first to utilize chemicals as medicines and became famous for saying “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” His statement has been shortened to say “the dose makes the poison.”

The absence of a hormetic agent will obviously produce no biological response, while a low dose produces a profoundly measurable protective effect and a stronger dose is toxic and even deadly.

The dose response of hormesis is visualized in the so-called U-shaped or J-shaped risk curve where maximum biological survival is produced at a low dose and with increased dosage the protective effect vanishes and toxicity becomes worse than if the living organism were not exposed to it at all.

In an antioxidant world ushered in by researcher Denham Harman in the 1950s, when antioxidants were first posed as antidotes to all disease given that about 5% of the oxygen humans breathe becomes unstable oxygen that can damage living tissues, stronger antioxidants were often posed as superior.

But there is a growing body of scientific evidence to show that the competitive commercial war to produce products that offer stronger and stronger antioxidant protection in various health food supplements may be counterproductive. There is a body of evidence showing certain natural plant extracts, particularly polyphenols found in grapes, berries and spices, are antioxidants at low dose and promote oxidation (pro-oxidant) at high doses.

Only recently has it been recognized that dietary antioxidants may exert the majority of their protective properties via activation of hormesis.

The first time the word hormesis is used is in 1943 when researchers were studying an antibiotic substance extracted from Western Red Cedar which stimulated rather than killed off certain organisms at certain concentrations. The next year other researchers reported the bacteria count of a refrigerated sample containing red blood cells was much higher when exposed to higher rather than lower doses of penicillin.
As researchers explain, “novel types of innovative, mild, repeated stress or stimulation that challenge a biological system in a dose-response manner are likely to have an effect that, properly harnessed, can be used to delay, prevent, or reverse age-related changes in humans.”
Toxicologists have now identified a number of environmental triggers of hormesis which includes exposure to low amounts of:

• Radon gas or other forms of gamma or x-ray radiation.
• Low-oxygen environments, such as at high altitudes.
• Heat, such as in sauna baths.
• Near starvation or so-called calorie restriction, practiced regularly in some human cultures as fasting.
• Molecular mimics of hormesis, that is, molecules that trigger the same defensive genes. These are small molecules found in the diet that can get into genetic machinery within living cells, molecules from grapes, spices and other botanicals.

If humans can activate this adaptive response on a regular basis, keeping themselves in survival mode, they would tap into the most powerful life enhancing mechanism apparently designed into living organisms.

In humans hormesis activates antioxidant mechanisms more powerful than taking a whole bottle of antioxidant vitamin pills. In fact, hormesis may explain why some studies show high-dose antioxidant pills begin to lose their effect compared to low doses.

Hormesis demonstrated

It was Moscow-based biologist Felix Meerson who first described protective adaptation among animals and humans exposed to high-altitude, low-oxygen environments. Meerson’s research led to athletes being coached to “train high and live low,” that is, to train in mountainous environments and then return to low-altitudes for everyday living, in order to achieve optimum physical performance.

Exposure to low amounts of radon gas has been shown to be effective in the treatment of chronic pain and glandular and circulatory diseases. Whole body exposure to low-dose ionizing radiation (gamma rays, x-rays) appears to decrease overall cancer incidence.

Some researchers also believe physical exercise causes inflammation that triggers hormesis.

Mechanism of hormesis

A specific internal mechanism of hormesis is the activation of the Nrf2 protein, or what is known as a transcription factor that binds to DNA and controls the dynamic protein-making property of genes called epigenetics rather than the better known inherited alterations in the sequence of DNA known as mutations.

Nrf2 activates powerful internally-produced enzymatic antioxidants, namely superoxide dismutase (SOD), catalase, glutathione, and heme oxygenase. Transient gases produced in the circulatory system, namely hydrogen sulfide and nitric oxide are also recognized hormetic triggers.

Other biological pathways that trigger hormesis are also described involving the sirtuin/FOXO gene pathway and the NF-kappaB pathway.

This all may sound a bit technical but this simply means that modern biologists have even identified the chief mechanism which activates hormesis. Hormesis is not some spooky unknown biological phenomenon.

Hormesis = preconditioning

Another way of describing hormesis is pre-conditioning, that is, turning on defenses in the body prior to an adverse event such as a heart attack or a stroke. It has been known for some time now that if a person experiences a mild circulatory blockage in an artery that supplies the heart with oxygenated blood and then experiences a later full-blown blockage of that artery (a heart attack), the damage to that area of the heart will be minimized because the heart turned on its defenses prior to the event.

Felix Meerson was the first to describe cardioprotection where the animal or human heart increases protective mechanisms if exposed to brief periods of low oxygen (hypoxia) prior to a full-blown blockage of blood circulation (a heart attack) in a coronary artery that supplies the heart with oxygenated blood.

It has been known for some time now that upon blockage of oxygenated blood to heart muscle (a heart attack) that the heart responds by producing strong antioxidants internally, namely heme oxygenase, adenosine and nitric oxide. Resveratrol, a red wine molecule, does this prior to a heart attack and therefore “cardio-protects.” This is described as the best form of prevention for the heart.

Antioxidant theory of aging and disease

A reason why molecules extracted from plants have produced perplexing results is that while they are often widely known as antioxidants they may initially provoke oxidation that triggers hormesis. This runs counter to what Denham Harman, the father of the antioxidant theory of aging proposed, which was a simple straightforward explanation that aging and its accompanying chronic diseases are a consequence of oxidation and are countered by antioxidants. Dietary antioxidants that initially promote an increase in destructive reactive oxygen species known as free radicals within the mitochondria or cellular power plants may actually extend life by switching on internal defenses.

There are a number of molecules extracted from plants, called phytochemcials, which exhibit a hormetic effect. The most studied are curcumin from turmeric spice, resveratrol from red wine grapes, catechins from green tea and sulforaphane from broccoli.

There are more than 60 molecules that induce the Nrf2 network of antioxidants, most of them found in the daily diet. Although known as typical antioxidants, researcher Marc Birringer says a closer look reveals that these molecules initially induce unstable forms of oxygen “and thereby trigger an adaptive stress response and hormesis.” This leads to higher levels of antioxidants within living cells such as glutathione and antioxidant enzymes such as glutathione peroxidase, thioredoxin reductase, and superoxide dismutase.

Researchers have progressed in their understanding of hormesis and describe a phenomenon called xenohormesis (xeno = foreign; hormesis = control) whereby plants are exposed to harsh conditions that result in their increase of protective molecules that resist sunlight, fungi and attacks by insects. Then humans consume these plant molecules which provoke a low toxin response in the human body and therefore acquire by transfer the hormetic or protective effect

What surprised biologists is that oxygen free radicals, known to be tissue-damaging agents, “may be necessary to trigger a sequence of events that result in benefits… that produce cellular longevity” within the mitochondrial power plants within living cells. Overzealous use of antioxidants, particularly among healthy individuals, may be counterproductive.

Pharmaceutical researchers now give nod to the idea of xenohormesis, saying “xenohormetic plant compounds can, when ingested, improve longevity and fitness by activating the animal’s cellular stress response and can be applied in drug discovery, drug production, and nutritional enhancement of diet.”

Hormesis has caught the attention of Big Pharma. Pharmaceutical companies now want to profiteer off of hormesis.

Resveratrol and hormesis

Resveratrol (rez-vair-ah-troll), known as a red wine molecule, is the best studied molecule known to induce hormesis and the only such small molecule where some dosage data is available.

Researchers say “many effects induced by resveratrol are dependent on dose and that opposite effects occur at low and high doses, being indicative of a hormetic dose response.”

Then disappointment came in 2008 when researchers reported that resveratrol did not extend lifespan in laboratory mice on a normal calorie diet. Yet these same researchers were also talking about resveratrol as a xenohormesis agent (plant-based hormetic agent).

It is as if researchers intentionally over-dosed the lab animals to produce a pro-oxidant rather than antioxidant effect. Resveratrol is an antioxidant at low dose and pro-oxidant at high dose, exhibiting a toxic but cancer killing/germ killing effect. The demonstration of the pro-oxidant effect of resveratrol in lab dishes may not be relevant under physiological conditions where other antioxidants exist to counter any pro-oxidant action.

However, some plant-based antioxidants may, when provided in high-dose concentration, induce destructive oxidation that is capable of killing cancer cells. However, there may be trade offs in that the favorable generation of free radicals to kill cancer cells produced by high-dose resveratrol may also result in a much greater concentration of resveratrol in the kidneys where it is rapidly shuttled for excretion, potentially resulting in kidney failure. While resveratrol has generally been demonstrated to protect the kidneys in animal experiments, mega-dose resveratrol (5000 mg) caused rapid kidney failure among patients with bone marrow cancer (multiple myeloma) that resulted in immediate cessation of the study.

Whether mega-dose concentration of resveratrol has a future in cancer therapy is unknown at the present time. However, there may be a way to use high-dose resveratrol to cause cancer cells to die off without toxic cell killing action (see below).

Among healthy individuals it appears a lower dose more favorably mimics the desirable effects of a calorie restricted diet.

Resveratrol, a grape skin and red wine-derived polyphenolic phytoalexin, exhibits hormetic action delivering numerous health benefits at lower doses while being detrimental at higher doses. Some researchers recognize that human clinical trials need to be based on the clear understanding of hormetic health benefits of resveratrol.

The most exacting research involving resveratrol has been conducted in the animal lab by Dipak Das and colleagues at the University of Connecticut. Higher than dietary doses, but lower than mega-doses, produce a protective effect in the rodent heart. Low doses, equivalent to 175 to 350 mg for a 160-pound human, reduced the size (area of scarring) of a heart attack whereas a dose ten-times that (1750 mg) increases the area of heart muscle damaged by an intentionally induced heart attack.

Of considerable interest is a unique commercial brand of resveratrol (Longevinex®) that protects the heart at an even lower dose (100 mg resveratrol) and continues to protect the heart even at high doses that typically kills 100% of hearts tested with plain resveratrol. In other words, there is no toxicity at very high dose. This is the first time in biology an L-shaped toxicity curve has been exhibited. The same results were produced in long and short-term studies on two different species of animals.

Outside of resveratrol there is little instruction as to dosage required to product hormesis with other molecules. However, red wine is a concentrated source of polyphenolic antioxidants via grape fermentation which can serve as a model for dosing. There are many antioxidant molecules in wine which can trigger the Nrf2-controlled survival response (resveratrol, quercetin, catechin, ferulic acid, gallic acid, malvidin, kaempferol, others).

The optimal beneficial effect of red wine is produced within a dosage range of 3-5 five-ounce glasses. Aged red wine provides around 60 milligrams of antioxidant molecules per glass, or 180-300 milligrams total in 3-5 glasses. This appears to be a safe and potentially effective range for aggregate dietary and dietary supplement intake of plant molecules that trigger hormesis in healthy individuals.

While there are numerous hormetic molecules in the human diet it is unlikely that most people will consume enough of them to produce a hormetic effect as they are generally provided in microgram (1/1000^th of a milligram) doses. It is in fermented products such as wine from red grapes or hot water extracts in teas that milligram-strength doses are achieved and unusual health benefits are noted. The most reliable way to achieve hormesis on a regular basis is the wise selection of a properly-doses dietary supplement designed and tested to produce hormesis.

Homeopathy

A naïve and mistaken thought is that evidence for hormesis validates homeopathy. While some aspects of hormesis apply to homeopathy, they should not be confused. Basically homeopathy asserts that dilutions of a molecule exert a biological effect while hormesis is confirmed with dose-response curves. There are five cardinal differences between homeopathy and hormesis:

• Hormesis is a universal phenomenon, while homeopathy is highly specific;
• Hormesis uses only measurable quantities of compounds, as opposed to homeopathy, where medicines are employed at dilutions far beyond the measurable range;
• Preparation of hormetic solutions follows standard laboratory procedure, while homeopathy requires a sequential series of dilutions, each followed by vigorous shaking (called ‘succussion’);
• The effects of hormesis are moderate and temporary, while homeopathy claims curative and permanent responses and
• Hormesis is a lab phenomenon observed primarily in healthy organisms, whereas homeopathy is a mode of treatment administered primarily to ailing individuals.

Transhumanism

Strangely, transhumanists have not widely embraced hormesis.

Transhumanism is a loosely defined effort to understand opportunities to advance the human organism via technology to create super-intelligent, disease-resistant, long-living humans, or so-called “posthumans” with vastly greater capacities than present human beings.

As Nick Bostrom explains, transhumanists believe humanity is “not at the end of evolution.” Rather than searching for God as a way out of the human dilemma of suffering and death, all mortality would be seen as premature by transhumanists that could be delayed indefinitely by technological advances.

Transhumanism is not elitist, not driven to create a small group that rises above the human condition, but rather values the idea that everybody should have opportunity to become posthuman. As such, any technology that accomplishes this would have to be an economical cure given the estimated high cost of creating 7 billion posthumans.

Transhumanists appear to be more interested in the pursuit than the attainment of their goal. Transhumanists are searching for a technological breakthrough rather than an existing natural phenomenon like hormesis. Maybe standing in a deep mine shaft to soak up radium is just not the type of technology transhumanists envision.

Final comments

The take home lesson here is not to over-do consumption of dietary or supplemental antioxidants.

Modern humans won’t be the first to benefit from hormesis. Those who practice fasting or regularly take baths in hot saunas or radium springs would have already put hormesis into practice. Looking back historically, Moses may have activated hormetic triggers by fasting and climbing a mountain where there was less oxygen. Jesus not only fasted and climbed mountains but drank unfiltered wine, a molecular activator of hormesis.

Whether humanity makes a course correction to embrace the powerful health and longevity properties of hormesis is to be determined. It has been over 50 years since hormesis was first described in scientific journals. In this modern world there may be a need to commercialize hormesis to build awareness and allow insurance plans to pay for associated costs of delivery. The calorie restriction society with its small membership is the only known group that advocates a particular hormetic activator. The biologist Felix Meerson once advocated use of hypobaric (low-oxygen) chambers to treat aging and disease as an alterative to drugs. It is not anticipated that the American Medical Association will embrace hormesis anytime soon. Whether individuals learn about hormesis and choose to adopt hormesis as a self-guided strategy to achieve health and longevity is also unknown.

There are doctors who practice psychiatry, and doctors who practice internal medicine, and geriatric physicians who take care of the aged, but we have no category for doctors who practice hormesis. There is the International Dose Response Society that talks about hormesis from a scientific standpoint. Maybe if hormesis can be translated into insurance billing codes then it will gain credence within the institution of modern medicine and be put into practice. For now, hormesis is a self-guided pursuit.

In an informal survey, this author has inquired whether people would want to know about a health force such as hormesis that would heighten measureable markers of health and longevity in an incomparable way. The response has been mixed. Most people who are financially challenged felt the idea of hormesis is of little interest to them because their primary focus is on meeting everyday needs. Others who already pursue healthy longevity through various means expressed more interest in learning about hormesis.
–© 2011 Bill Sardi, ResveratrolNews.com

Drs. Haime Otani at Kansai Medical University in Moriguchi, Japan and lead researcher Dipak K Das at the University of Connecticut Medical School, say “currently available pharmacological drugs are frequently not sufficiently effective.” They go on to say: “A salient finding of the present study is that the improvement of endothelial function was observed in patients taking Longevinex® whose disease conditions were already being managed by standard therapy for lifestyle-related disease.” The endothelium is in inner lining of arterial walls that controls arterial diameter and blood flow.

The study involved 34 patients, half of whom took Longevinex® for 3 months while the others took a placebo, and then both groups switched and received Longevinex® or the inactive placebo pills. The positive health effects produced by Longevinex® followed the group that was taking the pill with active ingredients. Neither group knew which one was taking the pill with active ingredients.

Longevinex®, providing low-dose microencapsulated/micronized resveratrol and other polyphenols produced a 40% greater increase in flow mediated dilatation (4.4% to 10.0%) than a prior human study (4.1% to 7.7%) that employed a much larger dose (270 mg) of plain resveratrol among a similar group of subjects who were not taking prescription medications.

The very earliest sign of blood vessel disease is inability of blood vessels to widen as the heart pumps faster and blood flow increases, a phenomenon called flow mediated dilatation, which was first described in 1933 and first measured using modern methods in 1992.

To measure flow mediated dilatation requires a pressure cuff that is applied to the forearm for a few minutes to impair blood flow and then relaxed, which results in rapidly increased blood flow and the release of a transient gas called nitric oxide that dilates (widens) blood vessels. A key ingredient in Longevinex®, resveratrol, is known to produce nitric oxide.

Flow mediated dilatation controls blood pressure when the heart rate increases. An ultrasound device measures in millimeters the ability of an artery in the forearm to dilate. Essentially the test measures arterial stiffness which actually precedes plaque formation in arteries.

Smoking (even second-hand smoke), elevated blood sugar and circulating cholesterol are known to impair flow-mediated dilatation. Estrogen, magnesium, the amino acid arginine and red wine are known to enhance flow-mediated dilatation. Cholesterol-lowering drugs and ACE inhibitors are known to reverse impaired flow-mediated dilatation.

Studies measuring the effect of wine upon flow mediated dilatation provide mixed results have been inconclusive. This could be due to the wide variation in content of red wine solids (polyphenols) such as resveratrol, quercetin and catechin, the most commonly-found molecules in red wine.

Age-related or disease-related decline in flow mediated dilatation is also predictive for arterial plaque that can impair circulation and induce stoppage of circulation to the heart and brain. In fact, flow-mediated dilatation is considered a way to evaluate artery-unclogging drugs. Favorable blood flow mediated dilatation measures are also predictive of survival following a heart stoppage.

The results of this study were published in Nutrition Research November; Volume 31(11): pages 842-7, 2011.

Further information can be found at www.longevinex.com

Copyright 2011 Resveratrol Partners LLC

Nutrition Research 2011 Nov; 31(11):842-7.

Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment.

Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M, Nishikawa M, Iwasaka T, Das DK.

Source

Second Department of Internal Medicine, Kansai Medical University, Moriguchi 570-850, Japan.

Abstract

Resveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors underlying endothelial dysfunction. We hypothesized that the modified resveratrol, Longevinex, improves endothelial function in patients with MetS. Thirty-four patients who had been treated for MetS and lifestyle-related disease were randomly assigned to group A, in which Longevinex was administered for 3 months and then discontinued for 3 months, whereas in the time-matched group B, Longevinex was administered between 3 and 6 months. These 2 groups of patients received similar drugs at baseline for diabetes mellitus, dyslipidemia, or hypertension. Flow-mediated dilatation significantly increased during the administration of Longevinex but decreased to baseline 3 months after the discontinuation of Longevinex in the group Apatients. Conversely, in the group B patients, flow-mediated dilatation remained unchanged for the first 3 months without Longevinex but was significantly increased 3 months after the treatment with Longevinex. Longevinex did not significantly affect blood pressure, insulin resistance, the lipid profile or inflammatory markers during 6-month follow-up. These results demonstrate that Longevinex specifically improves endothelial function in subjects with MetS who were receiving standard therapy for lifestyle-related disease. PMID: 22118755

In the Darwinian model an individual might have a genetic mutation inherited from their mother or father or both which is passed on to them. A gene mutation is defined as a substitution, deletion or insertion of an incorrect nucleotide on the DNA ladder. Adenine, guanine, cytosine and thymine represent the four nucleotide proteins that comprise the rungs on the DNA ladder. For example, a genetically similar group of short-statured people in Ecuador exhibit a gene mutation in a growth factor gene that confers unusual longevity upon them.

Contrary to static genes, epigenetics is the dynamic protein-making property of genes where genes produce (express) or negatively produce (silence) proteins. Alterations in genes that do not change the sequence of DNA nucleotides describe epigenetics.

Epigenetics was not known at the time of Darwin who postulated that observed changes in bird beaks over a two-month period of time served as evidence for the gradual development of new species. But what Darwin observed and then eloquently sketched in his field notebook could not have been the result of gene mutations but rather adaptation emanating from epigenetics.

Environmental factors such as food or lack of food, temperature or solar radiation can switch genes on or off.

What happens during conception and early development may epigenetically imprint genes which can be transferred on to following generations. Epigenetic imprinting may not last forever but it still has an inheritance.

Genetic imprinting has to do with the wrapping of bundles of genes called chromatic around what are called histone bodies, what would look like a double-coiled cable wrapped around a tennis ball. If the DNA coil (chromatin) is wrapped tightly around histone bodies than the genetic information is non transferable, much like a non-read file on your computer. If the DNA coil is loosely wrapped around histone then the genetic information can be accessed and epigenetic protein-making ensues.

In a groundbreaking experiment, researchers at Stanford University worked with roundworms that had mutations in one of three genes (ASH-2, WDR-5 and SET-2), genes which control how DNA is packaged or wrapped around histone bodies. By epigenetically altering the wrapping of chromatin around histones researchers were able to extend the lifespan of roundworms and then observe that epigenetic inheritance for longevity was passed on to succeeding generations. Genetically normal worms (no mutations) lived as long as long-lived grandparents who had mutations.

The red wine molecule resveratrol has been shown to be a dietary agent that helps to control epigenetic gene activity via its ability to alter chromatin wrapping around histones.

Bottom line, your biological inheritance does not doom you to a long or short life per se. There is even evidence that genes can be switched to produce longevity proteins among aged individuals. – © 2011 Bill Sardi, ResveratrolNews.com

But suddenly a striking study in humans has brought resveratrol, well, back to life. Researchers in the Netherlands not only report for the first time that low-dose resveratrol mimics a calorie restricted diet in humans, but it significantly lowered blood pressure, favorably altered resting metabolic rate and activated over 450 genes, something no pharmaceutical drug has demonstrated to date. Furthermore, it was shown that the dose employed in the study, 150 milligrams, achieved the same blood concentration as much higher doses in laboratory animals. A growing body of research now points to low-dose resveratrol as being beneficial and mega-doses as being counterproductive.

One of the key aspects of resveratrol is that it is known as a hormetic agent. Hormesis is where a low-dose toxin triggers defenses in the body that produce profound health effects. This is the magic of resveratrol. At high doses resveratrol is no longer a hormetic agent.

Now that the world’s largest publication, the AARP Magazine (circulation 24.2 million) online blog chose to mention the recent breakthrough in anti-aging science involving the red wine molecule resveratrol, one wonders if senior Americans will begin to add resveratrol pills to their daily regimen of pills. So far scientific reports surrounding resveratrol have been confusing or inconclusive. But even with a green light to take resveratrol pills, few senior Americans are expected to swallow down resveratrol pills, for a number of reasons.

First and foremost, an AARP online survey taken a few years back shows senior Americans desire more life in their remaining years than years in their remaining life. They desire a pill that would restore youthfulness (smooth skin, thick hair, viagra effects) over a pill that might cause them to live another twenty years in a debilitated state. Resveratrol does improve the human healthspan and promise quality along with quantity of life, but seniors have missed that message.

There are many other reasons why seniors aren’t going to add resveratrol pills to their daily pill regimen. Among these are:

1. The average 65-year old already takes 5 prescription medications and hates the idea of taking yet another pill.
2. The cost of resveratrol pills, while affordable, cost more than the co-pay for prescription drugs. Most seniors are laggards and are waiting for the day these pills are paid for by health insurance plans.
3. Even if effective, in the back of many seniors’ minds is that they may never know if these pills work as it will take years to determine that and even if they do extend their lifespan they fear running out of retirement money.

But that isn’t the crux of why I’m writing this report. All these points have been made in prior articles written here at ResveratrolNews.com. For those individuals who do opt to take resveratrol pills, the promise of an anti-aging pill may still be imaginary.

Most resveratrol pills on the market today are largely untested or provide the wrong dose, often an overdose or a miniscule dose. The bargain brands of resveratrol pills sold at big-box stores, which most senior buy, provide resveratrol in name only. Examine of the supplement facts box on the back pane of these products reveals resveratrol is not even a major ingredient and it would take a number of these res-pills to approximate the 150 mg used in the recently reported human trial. So the cost savings are also imaginary.

I’ve had the task of formulating a proprietary brand of resveratrol pill and I can tell you, misleading labels and untested products abound. The more this is said the more consumers feel, why take them at all?

To make matters worse, most of the 345 brands of resveratrol pills on the market today use borrowed science to scientifically substantiate their products. One brand owns most of the published science (a brand I am proud to be associated with). But the grade of resveratrol in laboratory studies is provided in frozen sealed vials and certified by testing. This is critically important since resveratrol is an unstable molecule that can degrade when exposed to ultraviolet light. Testing labs only test for the amount of trans resveratrol, the un-degraded form. But if they tested for cis resveratrol they would likely find quite a bit of the degraded form in the mix. Some form of protection for resveratrol (microencapsulation, opaque capsules) needs to be utilized to retain the molecular integrity of this herbal extract. This is just another reason why consumers may miss out on the resveratrol revolution. The science they read about is based upon lab-grade resveratrol which not being offered in dietary supplements.

But there is even another tidbit of science that says most consumers taking mega-dose resveratrol pills aren’t going to achieve their desired objective. In the prior report published online at ResveratrolNews.com it was reported that researchers demonstrated a way to remove senescent cells that no longer replicate themselves and therefore showed for the first time that senescent cell removal actually slows progressive aging changes in the eyes, muscles and skin. ResveratrolNews.com is the first to uncover research also showing resveratrol targets the very same gene that controls cellular senescence and theoretically slows the rate of aging. The take-home lesson here is that youth seekers need not wait for researchers to come up with a drug that will accomplish this.

A monkey wrench has been thrown into the promise of an anti-aging pill. A newly published study entitled “Resveratrol… induces premature senescence in primary human fibroblasts” (Age, Volume 33, pages 555-64, 2011) indicates high-dose resveratrol actually induces cellular senescence which would negate the promise of slowing the rate of aging. Dosage is even more important now that we know mega-dose resveratrol is going to undermine the alleged benefits of supplementation. A summary of that study is provided below.*

If consumers only knew the behind-the-scenes battles I have had in communicating with a number of irresponsible makers of mega-dose resveratrol pills that they risk bringing down the whole resveratrol revolution with their oversized pills. But they are obstinate and persist in misinforming consumers that “more is better.” In fact, low-dose resveratrol is an antioxidant but mega-dose resveratrol unfavorably promotes oxidation. If undesirable side effects are reported the FDA could use this as an excuse to force resveratrol pills off the market for being toxic.

The makers of these mega-dose pills have no scientific counsel, sometimes work out of a garage or a home and have others write books and other literature to give their products a false air of scientific authority. It is nauseating.

The consumer caveat is: “resveratrol pills get scientific green light, but check dose.” - © 2011 Bill Sardi, ResveratrolNews.com Not for posting on other websites.

*AGE (2011) 33:555–564

Resveratrol, but not dihydroresveratrol, induces premature senescence in primary human fibroblasts

Resveratrol, trans-3,5,4′-trihydroxystilbene, is a polyphenolic compound which has been reported to mimic the gene expression patterns seen in whole animals undergoing dietary restriction. The mechanism of action of resveratrol remains poorly understood, but modulation of both cellular proliferation and apoptosis has been proposed as important routes by which the molecule may exert its effects. This study reports the effects of both resveratrol and dihydroresveratrol (a primary in vivo metabolite) on the proliferative capacity of human primary fibroblasts. No generalized reduction in the growth fraction was observed when fibroblasts derived from three different tissues were treated with resveratrol at concentrations of 10 μm or less. However, concentrations above 25 μm produced a dose-dependent reduction in proliferation. This loss of the growth fraction was paralleled by an increase in the senescent fraction as determined by staining for senescence associated beta galactosidase and dose recovery studies conducted over a 7-day period. Entry into senescence in response to treatment with resveratrol could be blocked by a 30-min preincubation with the p38 MAP kinase inhibitor SB203580. No effects on proliferation were observed when cells were treated with dihydroresveratrol at concentrations of up to 100 μm.