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  • RESVERATROL: REWRITING THE SCIENCE

    October 22, 2018: by Bill Sardi

    Over 7 million results for “resveratrol” on the Google search engine.  Sixty years of research; 133 human clinical trials; twenty thousand (20,000) published research papers plus symposia, conferences, patents and attempts to produce analog drugs (synthetic resveratrol-like molecules).  Doses ranging from 5-5000-milligrams have been put to the test in humans. This is what a recent landmark retrospective report reveals (Biomolecules & Therapeutics, Oct. 2018).  But that portrayal of resveratrol needs to be re-written not only to correct misinformation but to reveal valid science that modern medicine has never dared to put into practice.

    The author of that report is a leading researcher whose groundbreaking research opened the door to study resveratrol.  His worldwide investigation on behalf of the American Cancer Society concluded that among all of the thousands of natural molecules studied, resveratrol deserved singular attention because it halted cancer at all three stages of development – initiation, growth and metastasis (spread), something no existing cancer drug can say some two decades later.  The author, Professor John M. Pezzuto PhD, has written 38 published papers about resveratrol since 1997 and has applied for a number of patents as well.

    If any single molecule ever threatened to put modern medicine out of business, which is the highest ethical calling of the practice of medicine, it is resveratrol. Harvard professor David A. Sinclair, a pioneer resveratrol researcher, says this red wine molecule would address 20 different diseases associated with aging.  The current paradigm of one drug for one disease in modern medicine would be disrupted.

    Heart disease: resveratrol remains on the sidelines

    With all of the cardiac drugs and medical and surgical technologies in modern cardiology, the same rate of mortal heart attacks is reported from year to year.  Ambulances are rushed to deliver paramedics to initiate treatment to fresh heart attack patients and to deliver them to the emergency room within minutes of the event, yet cardiac mortality rates haven’t changed.  Beyond use of baby-size aspirin tablets, which are ineffective, true prevention of mortal heart attacks does not exist.  Despite an effort to lower cholesterol levels with statin drugs, 244 healthy patients need to take statin drugs for 5-years to prevent one death from any cause.  Why not intravenous resveratrol for every heart attack victim?

    Resveratrol limits the damage caused by a heart attack via a known epigenetic mechanism (Nrf2), that of activation of internal enzymatic antioxidants (glutathione, catalase, superoxide dismutase), a phenomenon called cardiac preconditioning that remarkably protects the heart muscle from damage both prior to and following a heart attack.  Resveratrol may also eliminate heart attacks altogether via its ability to transiently provoke nitric oxide gas in coronary arteries, similar to administering a nitroglycerine pill.  Furthermore, resveratrol concomitantly inhibits the aggregation of blood platelets that form blockages in coronary arteries, which is what happens in virtually all heart attacks.

    To put it bluntly, many people are having heart attacks and dying needlessly for the lack of resveratrol.

    Resveratrol for longevity: will it ever be put to the test?

    Prevention of mortal heart attacks would directly affect life expectancy in the US, but resveratrol’s initial calling was as an anti-aging pill, a molecular mimic of a lifespan/healthspan-doubling calorie restricted diet.  Even if such a claim could be made for resveratrol, that it prolongs human life, the federal government has stepped in and now forbids any dietary supplement from making any longevity claims or face expulsion from online merchant accounts, enforced by bankers.

    Instead of putting resveratrol to the test, modern medicine posits metformin, an inexpensive anti-diabetic drugs that is only expected to prolong human life by ~8% and induces a deficiency of vitamin B12, making it problematic for broader use by the public.  Furthermore, resveratrol activates the cell energy-sensing molecule AMPK 50-200 times better than metformin.

    Self-interested skeptics who have a financial interest in maintaining the status quo demand conclusive data to show resveratrol is a true longevity pill.  But convincing data would take 50-70 years to accomplish.   So markers of aging must suffice.

    The real problem is, if you fix aging, you fix virtually every chronic age-related disease, which represents most of the income and profits generated by the healthcare industry.

    Even though translation and application of resveratrol from the research laboratory to the clinic appears to be stalled, the research community keeps eating up grant money to churn out endless studies.

    There have been so many research studies that professor Pezzuto asks: “why publish yet another manuscript?”

    Shall we close the door on resveratrol?

    Dr. Pezzuto says controversy comes with any molecule that has gained such colossal attention.  But did the research community conjure up controversy to stall its progress?  For one thing, as Dr. Pezzuto describes, from a chemical viewpoint, “very little enthusiasm was engendered by a simple molecule that was devoid of structural novelty” (paraphrased).

    Molecular promiscuity

    Researchers denigrate resveratrol by using the term “promiscuous” to describe its broad effect upon the animal and human genome.  Compared to the one-drug/one-gene target drugs, Pezzuto stated: “the number of molecular targets influenced by resveratrol is immense.”

    How many genes are significantly altered over a lifetime when lab animals are given a lifespan-doubling calorie-restricted diet? Answer: 831.

    A telling short-term (12-week) study compared a calorie restricted (CR) diet against resveratrol or resveratrol + other small molecules (Longevinex®).

    The CR diet altered 198 genes.

    Resveratrol altered 225 genes

    The resveratrol matrix (Longevinex®) 1711 genes (681 or 82% of those 831 genes activated by life-long CR).

    Resveratrol combined with quercetin and rice bran IP6 far exceeded the biological action of a life-long CR diet in only 12 weeks.

    This astounding animal study published in 2008 has only been referred 31 times in other published papers over a 10-year period.

    Biologists say there are 295 genes involved in the human aging process, far fewer than in rodents.

    That is the closest the field of biology has come to epigenetically mimic a calorie restricted diet, yet it continues to go unmentioned.   Pezzuto made no mention of it.  That study published in 2008 takes on greater significance in light of another animal study that showed life-long plain resveratrol did not significantly prolong survival of laboratory mice.  Maybe resveratrol by itself is not the answer.

    Resveratrol: is/isn’t bioavailable

    Then came the bogus idea that resveratrol is not biologically available – that it may be absorbed in the digestive tract but can’t make it past the liver detoxification system.

    It is a surprise that the broad review of 60 years of resveratrol science by Dr. Pezzuto quotes professor David M. Goldberg of the University of Toronto to say: “It doesn’t matter how potent a compound is in the test tube.  If it doesn’t get into the blood stream, it won’t have any effect.”

    Yes, research paper after research paper condemns resveratrol for not being bioavailable, that is, its inability to get past the liver detoxification system as a free unattached molecule.  Dr. Pezzuto does set the record straight.   Resveratrol is metabolized as it passes through the liver being perceived as a biological threat.  So detoxification molecules glucuronate and sulfate attach to resveratrol, theoretically rendering it an inactive molecule, too large to enter the nucleus of cells where genetic material resides.

    However Dr. Pezzuto does cite the fact liver metabolites resveratrol sulfate and resveratrol glucuronate have been found to be equal to if not superior to unbound free resveratrol.

    But there is no scientific traffic cop to halt the continued myth that resveratrol is not biologically available and use that fable to justify the development of analogs – resveratrol-like drugs.

    Pezzuto’s paper does mention the fact a black pepper extract (piperine) allows more resveratrol to pass through the liver and be initially bioavailable before all resveratrol is metabolized.  Quercetin is another molecule that does this also.

    So bottom line, resveratrol is bioavailable as a free unbound molecule and as a liver metabolite and works more rapidly when accompanied with other molecules that permit instant bioavailabity and that synergize its biological activity.

    But that is only the half of it.  Modern medicine now knows polyphenols like resveratrol exert a profoundly broad effect on gut bacteria.  Resveratrol doesn’t have to enter the blood stream to exert a biological effect.  It is a prebiotic – it influences the bacterial composition the gut (intestines) rather than the limited effect of probiotics like acidophilus and bifidus that are only one strain of bacteria.  In one animal experiment resveratrol altered gut bacteria which in turn negated a toxin in the liver that is involved in the accumulation of arterial plaque.  Who would have imagined this a decade or two ago?

    Resveratrol and diabetes

    Resveratrol is convincingly a remedy for diabetes but it has yet to enter the clinic.

    A lab dish study demonstrated that resveratrol “completely substitutes for insulin.”  A review of 11 published human studies reveals resveratrol significantly reduces fasting glucose (blood sugar), insulin, oxidized (glycated) hemoglobin, and insulin resistance levels among diabetics.  But resveratrol was mischaracterized as being ineffective when it didn’t lower blood sugar levels in healthy individuals – i.e. it doesn’t induce hypoglycemia.   (That sounds like an added level of safety.)

    Researchers note that metformin can restore oxygen consumption levels in sugar-laden tissues via the energy-sensing molecule AMPK.  By the 4th decade of life our ability to process oxygen is decreased by 10%; by the 5th decade by another 20%; by the 7th decade we lose yet another 30%.  Presumably resveratrol would be far better suited to address this problem than metformin.

    Molecular synergism

    An interesting study was reported a few years back.  Wine and resveratrol were studied for their effect upon vascular smooth muscle cells that control the inner lumen size of arteries.  Both wine and resveratrol inhibited blood platelet aggregation (blood clotting), activated Nrf2 internal antioxidant production, reduced oxidation and induced nitric oxide, a transient gas that dilates (widens) blood vessels.  However wine was more effective than resveratrol.

    Professor Roger Corder of the William Harvey Research Institute (London) has written that resveratrol is a minor component of wine and could not possibly exert the reduction in coronary artery disease mortality attributed to wine whereas the entire concentrated assemblage of molecules in wine (resveratrol, quercetin, catechin, gallic acid, and many other molecules, even melatonin).

    It has been authoritatively documented that individual doses of resveratrol, quercetin and catechin were ineffective in reducing cancer in laboratory mice but the combination of these three molecules demonstrably reduces tumor growth.  Recall the animal lab study where three molecules (resveratrol, quercetin, IP6 rice bran) activated 1711 genes compared to just 225 for plain resveratrol over a 12-week period.  Molecular synergism is well validated.

    Dose response

    Dr. Pezzuto only makes one lone mention of hormesis in his authoritative paper.  Hormesis is low-dose toxin exposure in living systems that activates a responsive antioxidant defense as evidenced by Nrf2 triggering of internal enzymatic antioxidants.

    Dosing of resveratrol appears to be critical.  It was the late Dipak Das PhD who was falsely accused of research fraud (Das was exonerated when other research teams produced the experiments with the same results) who conducted dosage studies in an animal model of heart attack.

    The human equivalent dose of 175 and 350 milligrams of resveratrol protected heart muscle from reperfusion (re-supply of oxygen) damage.  The combination of resveratrol + quercetin + IP6 rice bran produced a more protective effect (millions more heart muscle cells survived and did not produce scar tissue –fibrosis).

    A ten-fold greater amount of resveratrol (1750 mg & 3500 mg human equivalent dose) actually induced greater heart muscle damage presumably from a pro-oxidant effect.  Resveratrol binds to copper and exerts an antioxidant effect in modest doses and releases copper to produce a pro-oxidant effect in mega doses.

    Of particular interest is the Longevinex®, a commercial brand of resveratrol, produced no toxicity or tissue damage at 2800 mg, a dose that normally “kills” the rodent heart.  Obviously, Longevinex has unidentified ingredients or other trade secrets that renders it completely non-toxic even in mega-doses.  This was validated in a separate toxicity study, making it the safest resveratrol pill.

    Yet modern medicine keeps resveratrol hidden in the research closet, never to fully enter the daily practice of medicine.

    Given that dark aged red wine provides ~60 milligrams of polyphenols (resveratrol, quercetin, catechin, others) per 5-oz. glass, and 3-5 glasses of wine providing 180-300 milligrams total polyphenols produces the lowest mortality rate for coronary heart disease, it would appear to be obvious that a similar dose of wine solids sans alcohol would produce the most beneficial effect.

    This is similar to the 175-350 mg dose of resveratrol found to protect the animal heart from damage by experimentally induced heart attacks.  Longevinex exerted an even more protective effect at 100 mg of resveratrol, likely due to the synergistic effects of accompanying molecules.

    Resveratrol: Safe but not without side effects

    While oral resveratrol dietary supplements are magnanimously safe and have not resulted in hospitalizations for deaths – having a “pristine” safety record as Dr. Pezzuto notes, they are not completely devoid of side effects at all doses.

    A study involving 40 subjects who consumed varying doses of pure synthetic resveratrol (500 mg, 1000 mg, 2500 mg, 5000 mg) resulted in only 4 individuals dropping out of the study and no serious side effects.  However, 28 of the 40 subjects did report mild side effects, 21 of those on doses of 1000-5000 mg.  Mild and transient side effects included nausea, flatulence, abdominal discomfort and diarrhea, which could have been diminished by consumption with meals.

    Some 531 available brands of resveratrol pills ranging from 25 to 1000 milligrams per serving are commercially offered but there have been few human clinical studies on branded resveratrol products.   It would appear that 1000 mg resveratrol pills are potentially problematic.  They wouldn’t cause a heart attack but if one should occur, it could induce greater tissue damage in the heart.

    With over a decade of marketing resveratrol pills, I can authoritatively inform readers of the following:

    Resveratrol is a very strong TNF inhibitor and produces the same side effects as Enbrel (etanercept), an injected drug used to treat autoimmune diseases.  TNF (tumor necrosis factor is a protein capable of inducing death of tumor cells and thus is part of the human immune response.  Over-inhibition of TNF  induces side effects include anxiety, skin rash, cough, headache, sweating, sore throat,  and flu-like symptoms.  These same symptoms are reported among resveratrol users, though uncommonly.  Excessive dose of resveratrol is the likely cause of these symptoms.

    Resveratrol may inhibit sulfotransferase enzymes that keep a lid on stress hormones secreted by the adrenal glands.  In modest doses, resveratrol would therefore make users more mentally alert.  But in high doses may induce sleeplessness, a racing heart and anxiety.  Coffee and tea provide molecules that have a similar effect to resveratrol.  Overconsumption of wine, coffee and tea during holidays is linked to “holiday heart syndrome.”  Migraine headaches may also emanate from overdoses of resveratrol via this same mechanism.

    Achilles heel tendonitis (soreness) is also widely but rarely reported among resveratrol supplement users.

    Because resveratrol, like molecules in grapefruit juice, inhibit (cytochrome p450) liver enzymes that detoxify drugs and other potentially noxious agents, it can initially heighten the effects of drugs, for example cause blood pressure to drop too far when taking a blood-pressure lowering medication, an effect that is only transient as resveratrol is rapidly metabolized in the liver.

    Reports of loose stool with the use of resveratrol supplements is attributed to the emodin content of Giant knotweed extracts (botanical name Polygonum cuspidatum) which is largely eliminated in more pure (85%+) extracts.

    Resveratrol: nothing more than snake oil?

    Dr. Pezzuto ridicules “bombastic” advertising claims for resveratrol –based products that “protect you from head to toe,” yet his review of 20 years of research and development describes potential applications for this red wine molecule for acne, memory, inflammation, heart disease, cancer and sun damage to the skin.

    Yet he concludes: “at the present time, the consensus of expert opinion does not yet support the use of resveratrol for the treatment or prevention of any human ailment,” a claim that would categorize resveratrol as a drug, not a dietary supplement.  Not anything unexpected from a noted pharmacologist. He equates resveratrol with “snake oil.”

    Extortion by another name

    He alludes to the sale of Harvard-based Sirtris Pharmaceuticals to a major drug company for $720 million as evidence of resveratrol’s commercial value but falls short of characterizing that acquisition for what is was – Big Pharma being extorted by Harvard to extract a price to keep this molecule and its analogs off the market.

    No better than placebo?

    Dr. Pezzuto makes a soft suggestion that some of the reported benefits of resveratrol emanate from a placebo effect.  This is a bit preposterous considering a great deal of resveratrol research has been conducted among animals that cannot possibly be influenced by any imagined placebo effect.  In fact, the very existence of a placebo effect needs to be called into question given the revelation that placebo and “no treatment” groups match 100% of the time.  In fact, it appears the placebo effect has been conjured up to explain away the beneficial effects of dietary supplements.

    It appears resveratrol could rescue thousands of elderly subjects from the threat of legal blindness caused by a lack of blood circulation at the back of the eyes that results in blood vessel invasion of the visual center (macula) of the retina.  Resveratrol inhibits the formation of new blood vessels (aka angiogenesis or neovascularization) at the back of the eyes.

    While this condition is successfully treated with injections of anti-angiogenic drugs, ~15% of patients fail treatment and face impending impaired vision.  One brand of resveratrol (Longevinex®,) has been reported in a pilot study to improve various measures of vision in 16 of 17 subjects.  But a petition to the Food & Drug Administration to study resveratrol among patients who have failed conventional treatment was rejected.

    It is what goes unsaid about resveratrol that reveals its true promise and intentional mischaracterization within the ranks of the research and clinical practice community.  At least readers of this article now have more information to ascertain its value. ####

    Chart: Resveratrol effectiveness - toxicity

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