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How the world got lost on
the road to an anti-aging pill
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March 13, 2017: by Bill Sardi
Some skeptics have called resveratrol pills a “hopeless illusion.” They claim resveratrol is hiding behind “non-human research as a cover” for back-door marketing of resveratrol supplements.” Resveratrol “may indeed turn out to be nothing more than a sleight of hand.” [Pharmacological Research Dec 2014]
Helping to sort out fact from fiction, researchers in Germany have recently attempted to compare and contrast the alleged health benefits of pharmaceuticals versus nutraceuticals like resveratrol. [Applied Microbiology Biotechnology, Feb 2017.
Generally, nutraceuticals like garlic, resveratrol, quercetin, curcumin, are secondary metabolites of plants that are produced to defend against environmental threats like fungi, insects and solar radiation. Most nutraceuticals are concentrated forms of these protective plant molecules.
Polyphenolic nutraceutical compounds like resveratrol are better shown to work in epidemiological (population) studies in context with a traditional diet and with other synergistic molecules, as found in wine. But controlled studies have produced mixed results.
It’s possible favorable alteration of gut bacteria plays a role in positive, negative or null human studies involving resveratrol.
Only recently understood is that nutraceutical molecules produce metabolites in the gut (intestines) that activates a profound indirect biological effect, which overcomes the criticism that these molecules are not biologically available. As such, high blood plasma levels may be of no consequence. Usually nutrition studies are considered less valid if they do not determine whether there is a nutrient deficiency in a subgroup that may benefit from nutritional therapy. But in this instance, blood levels may be immaterial.
In the animal laboratory, diets are controlled, whereas in human studies diets obviously vary. So differences in gut bacteria may be an explanation as to why results in animal studies aren’t always confirmed in human studies.
Recently researchers assessed the biological effects of resveratrol in men. Males given 500 mg resveratrol twice a day (1000 mg/day total) exhibited robust changes in gut bacteria. [International Journal Molecular Sciences 2017]
Indeed, another recent study confirms fecal matter from animals fed resveratrol transplanted to other animals produces beneficial health effects, which suggests some unidentified metabolite of resveratrol is the mechanism of action. [Diabetes Feb 2017]
Furthermore, even though almost all resveratrol is metabolized in the liver and conjugated with detoxification molecules (sulfate, glucuronate) in the liver, rendering resveratrol non-bioavailable, these liver metabolites (resveratrol-sulfate, resveratrol-glucuronate) have been found to exert biological activity as strong as free unbound resveratrol.
Moreover, nutraceuticals like garlic, quercetin and resveratrol, may actually work by initially exerting pro-oxidant rather than antioxidant action, therefore acting as perceived biological threats that activate internal enzymatic antioxidants (glutathione, catalase, SOD) that are far more protective than any oral antioxidants that can be consumed. Living every day with a measured amount of biological stress (heat-sauna, radiation-sunlight, food deprivation-fasting) or a molecular mimic of biological stress (resveratrol) may have profound health benefits.
Furthermore, extracts from plants may produce more powerful effects than foods that contain the same molecules. It is not coincidence that fermented foods where various molecules are concentrated, such as phytoestrogens in miso and tempeh that have been shown to exert greater biological effect than tofu. Wine exerts far greater biological action than an equal dose of grape juice.
More so, wine is an alcohol extract of grape skins that is presented with other synergistic molecules. Roger Corder, Professor at the William Harvey Institute in London and author of The Red Wine Diet, says it is the total molecules in aged red wine (resveratrol, quercetin, catechin, gallic acid, kaempferol, ferulic acid, melatonin, proanthocyanidins) that produce such a profound effect. [Nature Nov 30, 2006]
Which leads this discussion to the topic of appropriate or optimal dosage. Mega-dose resveratrol may or may not be safe (there have been no reports of major side effects in human studies involving up to 1000 mg/day). But mega-dose resveratrol may nullify the well-described hormesis effect where a mild biological stressor activates an endogenous (internal) enzymatic antioxidants (glutathione, catalase, SOD) via the Nrf2 gene that are far more protective than oral antioxidants like vitamin E.
Wine exerts a demonstrable reduction in mortality from coronary artery disease when 3-5 five-ounce glasses of aged red wine are consumed that provide 60 milligrams of total polyphenols per glass or 180-300 mg total. Beyond 5 glasses a day results in higher risk.
Similarly, when resveratrol or resveratrol + synergistic molecules were put to the test, the human equivalent of 175-350 mg protected the heart from damage induced by an experimental heart attack whereas a 10-fold increased dose (1750-3500 mg) increased the area of damage to heart muscle. [PLoS One Dec 23, 2010]
In fact, a combination of resveratrol + other small molecules (Longevinex®) was able to preserve 40% more heart muscle tissue from fibrosis (scarring) after an experimentally induced heart attack at less than half the dose of resveratrol. [PLoS One Dec 23, 2010]
It is no wonder that Longevinex®, being a resveratrol pill accompanied by other synergistic natural molecules and dosed properly, exhibits superior biological action.
And finally, while it may be more difficult for biologists to measure the broad effects resveratrol has on hundreds of genes compared to drugs, single gene-targeted drugs have been met with failure as most chronic disease involves many genes. Resveratrol cannot be easily traced to a single molecular event. Complex biological problems are addressed by resveratrol, whereas drug molecules only offer a partial remedy.
Instead of injecting stem cells eye researchers now pose the prospect of natural regeneration of the aged human retina without the implantation of stem cells.
Zebrafish contain a chemical that regenerates their eyes. The same regrowth and repair chemical at the back of zebrafish eyes can be found in humans, lending hope for regenerative therapies for hopeless eye disorders like macular degeneration. Blinded zebrafish rapidly recover vision within days.
An anti-regenerative molecule is gamma amino butyric acid (GABA) that is a nerve transmitter. GABA is a nerve and mood-relaxing chemical activated by drinking alcohol. GABA is now understood to interfere with regenerative factors at the back of the eyes. Treatment with a GABA inhibitor might stimulate retinal repair like what is observed in zebrafish say eye researchers. [Daily Mail UK March 10, 2017; Stem Cell Reports April 11, 2017] Resveratrol is a potent GABA inhibitor. [Neuroscience Bulletin Feb 4, 2017; Proceedings Nutrition Society Feb 1, 2017; ResveratrolNews.com]—Copyright 2017 Bill Sardi, ResveratrolNews.com