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How the world got lost on
the road to an anti-aging pill
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December 29, 2014: by Bill Sardi
2014 was another year of great promise and inexcusable dawdling by the research community as well as intentional disparagement of what may be the most profound health and longevity molecule ever discovered — resveratrol. Strikingly, there are no human clinical trials for resveratrol for heart disease or cancer, two of its most promising applications. For now, lab rats will be the primary beneficiaries of this remarkable molecule.
One thing is for sure, the research community isn’t taking its foot off the pedal – just over one thousand published studies, commentaries and reviews about resveratrol were posted at the National Library of Medicine this year. That is out of a pool of 7000 published reports dating back to 1978. [PubMed.gov Accessed 12/18/2014]
But test tube and animal studies prevail over applied science. And the thrust of the research, based upon the false premise resveratrol is not bioavailable, is to invent a synthetic resveratrol-like molecule that can be turned into a blockbuster drug, not use of resveratrol as an economical nutraceutical.
The most disappointing study of the year turned out to deliver a bogus conclusion, that resveratrol failed to reduce mortality. In fact, its authors overlooked a major health discovery.
Not a single news reporter challenged this study, namely because it emanated from the most prestigious health institution in the country, Johns Hopkins University. The report errantly claimed resveratrol (no, in fact it was red wine not solely resveratrol) did not reduce overall mortality over a 9-year period among residents living in a wine-making region of Italy. The undisclosed reason: more than three times as many study participants smoked tobacco in the heavy wine-drinking group (25.1%) versus teetotalers and occasional wine drinkers (7.7%). [JAMA Internal Medicine July 2014]
If the conclusions of this study were true, the French paradox, the fact the wine-drinking French have far lower mortality rates despite their relatively high-fat high-calorie diet, would no longer be valid. That would have been mind-boggling.
The hidden discovery was that those Italians who drank the most wine (2.6+ glasses/day) were half as likely to experience mental decline over the 9 years of the study compared to teetotalers. [ResveratrolNews.com May 16, 2014; Johns Hopkins Medicine May 12, 2014] That is a remarkable finding.
This study serves as evidence the scientific community wants to malign resveratrol. The lack of criticism of this study is indicative of a culture in the research community that uses science for its own ends.
The most prominent application of resveratrol is as an anti-aging molecule. While not directly related to resveratrol, the award for the grandest absurdity of the year went to Dr. Ezekiel Emanuel, age 57, a co-drafter of the Affordable Care Act, who claims he will do nothing after he reaches age 75 to prolong his life. He hopes to set an example for others. No resveratrol pills for him. Living an extra 30 years to achieve superlongevity is pointless says Dr. Ezekiel. This writer has penned a critique of Dr. Ezekiel’s “we know what’s best for you” position. [ResveratrolNews.com Sept 24, 2014]
Second place in the absurdity category went to the Harvard biologist who started the resveratrol quest for longevity over a decade ago and now says it is best to wait for synthetic “new chemical entities.” [ResveratrolNews.com April 7, 2014] By the way, that scientist has been religiously taking resveratrol pills for over a decade now.
Third place on the absurdity meter went to the research team that reported the infusion of blood from a young animal into an old one invigorated the memory and learning of the older animal. Before you go out and coax your grandchildren to donate blood and have it infused back into your circulatory system, further investigation reveals low-dose resveratrol addresses the same biological mechanism that this experiment identified. [ResveratrolNews.com May 5, 2014]
Fourth place went to the UCLA research team that now claims healthy longevity is now within reach and all that needs to be done is elevate an enzyme called AMPK, a cellular energy-sensing protein. [UCLA Newsroom Sept 8, 2014] However, they said “we are not there yet” and “it could take many years” before biologists figure out how to raise AMPK. They were remiss in not saying the anti-diabetic drug metformin does that very well. Of interest, a mild dose of resveratrol elevates AMPK 50-200 times more than metformin. [Diabetes Aug 2006]
A decade after a Harvard biologist connected the scientific dots between a lifespan-doubling calorie-restricted diet and the red wine molecule resveratrol with activation of the Sirtuin1 survival gene [Nature Sept 11, 2003], human studies are slowly being reported.
Short-term small-group studies are being reported on the use of resveratrol among humans for diabetes [International Journal Biochemistry Biophysics Oct 27, 2014], fatty liver disease [Nutrition Research Oct 2014], macular degeneration [Nutrients Oct 17, 2014], age-related muscle shrinking (sarcopenia), for estrogen replacement among postmenopausal women [Journal Translational Medicine Aug 14, 2014]and as an exercise mimic. [American Journal Physiology Heart Circulation & Physiology Oct 15, 2014; Applied Physiology Nutrition Metabolism Oct 2014] A full-blown large-scale study is also underway for Alzheimer’s disease. [National Institute on Aging]
Yet some researchers wonder if this miracle molecule will ever get to market. Researchers ask: how can a drug that promises to slow aging gain FDA approval when aging is not defined as a disease? [Translational Research May 2014] The answer is that it is already on the market as a nutraceutical, it just isn’t paid for by health insurance nor regularly prescribed by doctors.
There is no question now that the potential exists to delay human aging.
However, other researchers wonder if resveratrol is going to be confined to use among lab rats given some conflicting studies and its alleged low-bioavailability. [Journal Translational Medicine June 2014]
But biologists write that the unprecedented prolongation of the human lifespan over recent decades has been achieved by means not linked to genetic mechanisms involved with life prolonging calorie-restricted diets. Therefore there is still opportunity to dramatically extend the human lifespan and healthspan. [PLoS One Jan 6, 2014] Resveratrol as an anti-aging agent hasn’t been disproven, it is just unproven (uninvestigated).
The scientific community keeps falsely alleging resveratrol is not biologically available and asserts synthetic analogs (look-alike molecules) need to be developed into drugs to overcome this problem. [Molecules Oct 24, 2014] This is despite growing evidence resveratrol’s liver metabolites, often said to be biologically inactive, produce beneficial health effects in humans as well as laboratory animals.
Over 68 scientific reports published in 2014 referred to resveratrol’s lack of bioavailability. [PubMed.gov] This has resulted in scientific doublespeak. One faction in science believes resveratrol is nearly worthless because of its lack of bioavailability. Only by making it a patentable synthetic molecule (analog) will it work. While another faction convincingly reports resveratrol bound to detoxification proteins (sulfate, glucuronate) produced in the liver does indeed yield health benefits. [Autophagy March 10, 2014] The latter discovery cancels out the former.
Even if there were a growing body of positive human studies for resveratrol this may not translate into the medical community embracing resveratrol and prescribing it, at least not when it conflicts with their own vested interests. For example, preliminary case reports show a resveratrol-based dietary supplement spares hopeless patients with wet macular degeneration from going blind when conventional medical therapy fails. But that fact has not prompted interest among eye doctors because it takes away revenues for injecting medicine into the eye.
Let’s move on with highlights of resveratrol science published in 2014 instead of airing a continual rant about things that are unlikely to change.
Calling the promises of resveratrol in the field of cardiology a “hopeless illusion,” researchers in Hong Kong say they “tried to remain as neutral as possible” in drawing their conclusions. [Pharmacological Research Dec 2014] The editor of journal Pharmacological Research called it “the resveratrol fiasco” and decried back-door marketing of resveratrol dietary supplements based upon non-human research. This author wrote a lone rebuttal to those assertions. [ResveratrolNews.com Sept 5, 2014] It is a farce to demand research studies the cardiology community refuses to conduct.
In an intriguing study, researchers in Turkey gave 250 grams of red grapes (about 9 ounces or a little over a half-pound as a source of resveratrol) to adults over age 55 with cardiovascular disease and found this dietary regimen produced a similar reduction in risk for heart disease (-2.2 fold) as an hour of exercise per week (-2.5 fold). [Anatolian Journal Cardiology April 8, 2014] The news media played dead on this one probably because it emanates from a little-known foreign cardiology journal. Grape growers ought to get behind this discovery.
Research teams worldwide continue to validate the studies initially conducted by discredited researcher Dipak Das PhD (deceased) who showed that resveratrol reduces the area of scarring in experimentally induced heart attacks in lab animals [PLoS One Dec 23, 2010]. Resveratrol at a human equivalent dose of 140 milligrams activates cellular defenses prior to a heart attack in lab animals, a phenomenon known as cardiac preconditioning. [Molecular Medicine Reports June 2014; Molecular Nutrition Food Research Dec 9, 2014]
A 350 milligram equivalent human dose (5 mg/kilogram/2.2-lbs of body weight) produced almost complete recovery” of cardiac function in animals with long-term diabetes. [Nutrition Metabolism Cardiovascular Disease April 2014]
For the first time researchers have demonstrated that a modest dose of resveratrol (2.5 mg per kilogram/2.2-lbs of body weight, equivalent to 175 mg in a 154-lb human) activates the Sirtuin1 survival gene that in turn activates the cell energy sensing enzyme AMPK in lab animals whose left coronary artery was surgically closed off to induce heart failure. Resveratrol-fed mice experienced an increase in the pumping action of the heart (left ventricular ejection fraction 46.84 versus 34.44 among animals given resveratrol or no resveratrol) and survival increased dramatically from 36% to 82%! This is with the laboratory researchers intentionally attempting to kill these lab animals! [Genetics & Molecular Research Jan 21, 2014]
Recognize that for ethical reasons studies involving cardiac mortality must be done with laboratory animals, not humans. So these animal studies represent the best available science.
Researchers in Canada say “preclinical studies provide convincing evidence that resveratrol has beneficial effects in animal models of heart disease” and that the primary mechanisms have been identified, namely activation of the Sirtuin1 survival gene to elevate AMPK and activate internal antioxidant enzymes (heme oxygenase, catalase, SOD, glutathione).
These researchers also write that: “despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, clinical studies are still limited.” They are calling for large-scale, long-term controlled studies (can placebos ethically be used when the measured outcome is death?), which are unlikely to ever occur.
Since heart attacks maybe occur in 1-to-3 out of 1000 adults over age 50 over a 5-year period, a study group of 50,000 would be required to produce 50-150 cases of heart attack that can be analyzed to determine risk reduction. [International Journal Biochemistry & Biophysics Nov 1, 2014] We are talking about a $50 million study! It will never happen.
Cardiology ineffectively employs non-prescription aspirin to prevent heart attacks and resveratrol is far safer than aspirin (doesn’t induce bleeding gastric ulcers or brain hemorrhages). So why not prescribe resveratrol instead of aspirin?
In 2014 it was reported that resveratrol increases the immune response among animals receiving conventional vaccines. [American Journal Veterinary Medicine Aug 2014] Resveratrol may serve as a safer adjuvant than toxic mercury that is often added to provoke an immune response to vaccines.
Candida albicans, a yeast (fungus) that overgrows in the digestive tract with consumption of refined sugar, is highly prevalent among Americans. For the first time researchers report that resveratrol induces death of this potential pathogen by a method called apoptosis (programmed cell death). [Current Microbiology Nov 21, 2014] The anti-Candida action of resveratrol by other mechanisms had been reported earlier. [Journal Microbiology & Biotechnology Aug 2007]
It was also reported that HIV infection confers high-level resistance to anti-viral agents and resveratrol may help control this problem. [AIDS Jan 28, 2014]
Researchers in Australia report resveratrol is not effective among patients with non-alcoholic fatty liver disease. [Clinical Gastroenterology Hepatology Dec 2014] However, this negative study may be due to over-dosing. Subjects were given 3000 milligrams of resveratrol/day, which is a pro-oxidant dose. In a similar study patients with fatty liver disease were given 500 milligrams of resveratrol per day. Resveratrol supplementation + lifestyle changes was superior to diet and lifestyle changes alone. [Nutrition Research Oct 2014]
It is sad to hear researchers saying “there is no proof of any therapeutic properties of resveratrol in prostate diseases” [Central European Journal Urology 2013] when simply no human studies have commenced to analyze.
What harm could come of taking resveratrol under the promise it may inhibit the growth and spread of prostate cancer? There is currently no preventive medicine for the vast majority of men who live with this disease.
Aspirin modestly reduces the risk for prostate cancer but it also carries the risk for mortal bleeding gastric ulcers and brain hemorrhage. Resveratrol is safer than aspirin and works to inhibit cancer by many of the same mechanisms as aspirin. Chemotherapy inevitably results in treatment resistance. Resveratrol sensitizes prostate tumor cells to chemotherapy. [Annals New York Academy Science Jan 2011] Should urologists sit and watch their patients die of treatment resistant tumors till there is sufficient evidence resveratrol may be of benefit? That evidence may be over a decade away.
Researchers at the University of Wisconsin postulate that resveratrol may help restore zinc levels to prostate tissue that may reverse or even abolish malignancy. Experimental animal studies are proposed. [Cell Cycle June 15, 2014]
With so many senior Americans now living into the 8th decade of their lives the challenge to maintain bone and muscle mass is considerable. In 2014 researchers reported that resveratrol has a therapeutic potential against osteoporosis as evidenced in an animal study, but exceptionally high doses were required to demonstrate an effect. [Acta Biochimica et Biophysica Sinica Dec 2014]
Another study showed that old male rats given the human equivalent of 700 milligrams/day of resveratrol experienced an increase in bone volume. [Rejuvenation Research Oct 2014]
Resveratrol has also been demonstrated to produce modest improvement in muscle mass among animals whose hind limbs were suspended to produce a totally sedentary condition. [PLoS One Dec 12, 2014]
Preliminary human clinical trials show that resveratrol holds great potential to treat diabetes and would also amplify conventional therapy. [Biochimica Biophysica Acta Oct 27, 2014] An analysis of 11 small human trials involving 388 patients total concludes that resveratrol improves glucose control and improves cellular usage (sensitivity) of insulin. [American Journal Clinical Nutrition April 2, 2014]
A 90-day trial of 300 mg and 3000 mg/day of resveratrol among a small group of older diabetic patients results in lower blood glucose levels at both dosage levels with greater reduction in body weight and waist circumference for subjects that consumed 300 mg/day of resveratrol. [Experimental Gerontology Sept 2014]
In animal studies resveratrol was shown to prevent adverse effects caused by high-fat, high-sugar (cane sugar sucrose and corn syrup fructose) diets. [Cell Metabolism July 1, 2014; European Journal Nutrition Sept 11, 2014; Canadian Journal Physiology Pharmacology Dec 2014] Resveratrol was also shown to help control blood pressure in fructose-fed animals. [British Journal Pharmacology June 2014]
Resveratrol was also reported to prevent complications of diabetes in the eyes (focusing lens: cataracts) and kidneys of animals. [Pharmacology Reports Oct 2014; PLoS One Dec 3, 2014; Oxidative Medicine Cell Longevity 2013]
A review of six studies involving 247 total subjects found that more than 150 milligrams/day of resveratrol reduces systolic blood pressure by -11.80 points whereas lower-dose resveratrol did not exhibit a significant effect. [Clinical Nutrition March 31, 2014] That reported result was as good or better than most prescription drugs employed to control blood pressure.
Researchers lament that research involving resveratrol and blood pressure have been narrowly confined to its ability to widen (dilate) blood vessels in distant arteries with almost no studies involving the effects of resveratrol upon the kidneys which play an essential role in regulation of blood pressure. [Frontiers Physiology Aug 2014]
There were over 200 published reports involving the search terms resveratrol and cancer posted as the National Library of Medicine in 2014. Most were lab dish studies with a few animal experiments.
The only human investigations involved resveratrol in wine and cancer. While resveratrol is a small component of wine (about 1 milligram per 5-ounce glass of the best dark aged red wine), alcohol in wine negates much of its cancer fighting properties. [International Journal Cancer Jan 1, 2014] However red wine was found to significant suppression of lung cancer cells in lab dish assays. [Cancer Cell International Jan 23, 2014] The anti-cancer effect of wine is modest at best and not as strong compared to its ability to reduce mortality from heart disease. [Critical Review Food Science Nutrition Sept 10, 2014] Some researchers even claim information about cancer-preventive properties of resveratrol in wine is “misleading and must be prohibited.” [International Journal of Cancer Jan 1, 2014]
In 2014 researchers reported that resveratrol eliminates the abnormal formation of tetraploid cells that encompass twice as many chromosomes as normal cells. Tetraploidy has been detected at early stages in multiple types of cancer which is also correlated with the inactivation of tumor suppressors. Resveratrol has been found to selectively kill tetraploid cells and leave normal cells unharmed. [Proceedings National Academy of Science Feb 25, 2014]
Researchers now report AMPK, the key cellular energy-sensing enzyme in living cells, is activated by resveratrol and is believed to be the primary target for anti-cancer treatment. [Mini Review Medicinal Chemistry 2014]
Currently there is no drug to reverse tumor resistance to chemotherapy drugs used in cancer treatment. Two reports published in 2014 show that resveratrol reverses mechanisms that induce cancer drug resistance [Current Drug Metabolism Sept 26, 2014; Experimental & Therapeutic Medicine June 2014], though this has been known for over a decade.
One published study of particular interest conducted by researchers in Spain showed that mild-dose resveratrol increases a tumor suppressor known as PTEN (phosphatase and tensin homolog) which in turn prevents cancer by activation of internal antioxidant enzymes (catalase and superoxide dismutase SOD) and reduction of destructive hydrogen peroxide. [Biomedical Research International 2014]
The anti-depressant effect of resveratrol has been widely reported since 2006. In 2014 researchers reported yet another mechanism by which resveratrol acts as an antidepressant. [Behavior Brain Research July 15, 2014] Resveratrol was also reported to exhibit the identical antidepressant effect of a widely prescribed drug (desipramine/Norpramin). [Behavioral Brain Research May 1, 2014]
Abnormal development of the pancreas during fetal development of animals strongly suggests resveratrol supplements be avoided by pregnant women. [FASEB Journal June 2014]
Stuart Richer OD, PhD, continues to report on his successful series using a resveratrol-based nutraceutical (Longevinex®) for eyes who have failed to respond to drugs that inhibit destructive invasion by new blood vessels at the back of the eyes (macula). [Nutrients Oct 2014]
Topically applied resveratrol eye drops were reported to reduce elevated eye fluid pressure by 15.1%-25.2% in laboratory animals. [Clinical Experimental Ophthalmology July 3, 2014] Resveratrol may one day be used in eye drops to treat glaucoma.
Periodontitis is the term used to describe chronic gum infection. The experimental use of resveratrol in laboratory animals prevents the progression of this condition. [Free Radical Biology Medicine Oct 2014]
Chemical pollutants, namely phthalates used in the plastics industry, are linked to diminished semen quality in males. Resveratrol protects against the potentially deleterious effects of phthalates. [Indian Journal Pharmacology Jan-Feb 2014]
Researchers in China report that resveratrol helps to normalize gut bacteria among mice fed a high-fat diet. Resveratrol elevates the number of protective Lactobacillus and Bifidobacteria while decreasing antibiotic-resistant strains of bacteria that are potentially pathogenic. [Food & Function June 2014]
Bacteria In Gut Of Laboratory Animals
Rice has been genetically altered to produce resveratrol. Mice fed with resveratrol-enriched rice experienced a 20.0% reduction in body weight and a 31.3% reduction in abdominal fat). [Scientific Reports Jan 27, 2014]
Gastrointestinal side effects are frequently reported among resveratrol consumers. For example, one study showed 77% of healthy subjects taking resveratrol pills experienced gastrointestinal side effects versus 15% among non-users. [Applied Physiology Nutrition Metabolism Oct 2014] Another study reported that 20-33% of resveratrol users experienced loose stool (compared to 10% among placebo users) and 10-17% experienced constipation (compared to zero among placebo group). [Experimental Gerontology Sept 2014] A significant percentage of resveratrol supplements derived from giant knotweed (sbotanical name Polygonum cuspidatum) contain emodin, a molecule that induces loose stool. [Journal Agriculture Food Chemistry June 25, 2014] Purer extracts avoid this problem. Some brands of resveratrol dietary supplements have minimized emodin content and reduced the occurrence of this problem to nil. [Longevinex.com]
Bottom line, there is no scientific reason why resveratrol shouldn’t be recommended to every patient being treated for diabetes, heart disease, cancer, retinal problems and mental and mood decline, at the very least to augment existing therapy. Resveratrol is the best tonic against the ravages of aging. However, resveratrol fails to become a part of the everyday practice of modern medicine because commercial interests rather than good science dominate the health industry today. © 2104 Bill Sardi, ResveratrolNews.com
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