William Amzallag, M.D.

The Resveratrol Story; July 2011

The Resveratrol Story

William Amzallag M.D. In 1997 a French woman Jeanne Calment died at the age of 122 years. Her death has led many to conclude that Nature has already reached the outer limit of the human lifespan.Cell biology, however, indicates something quite different; many biologists are coming to believe that human beings have not been optimized by long life at all, and our potential for longevity may be largely untapped. Recognizing the potential for longer life and bringing it about, however, are two very different things. In 2006 headlines around the world blared the news of a series of scientific breakthroughs: could it really be possible that natural substances found in red wine could extend life, avert cancer and heart disease, help people maintain or even lose weight and create the muscles of an athlete? All these extraordinary effects were being observed in laboratory animals, offering reason to believe the same would hold true for humans. A new fountain of youth? Scientists saw this as a distinct possibility. In 2002 David Sinclair and Joseph Baur from Harvard University published in the prestigious scientific journal Nature a revolutionary discovery: they discovered that Resveratrol substance found in red wine grape skins could activate certain animal-cell genetic pathways and produce amazing benefits which include: Increased memory, reduced fat cells (despite a high calorie diet); boosted energy and endurance in muscle cells; enhanced muscle strength and decrease fatigue; improved coordination and mobility. But most remarquably, those molecules was also found to reduce the incidence of certain cancers, vascular diseases; brain degeneration and prolonged the lives of treated mices by 25%. The groundwork for these discoveries date back to the 1930s when scientists at Cornell University discovered that rodents placed on a near-starvation diet lived up to 50% longer; maintained youthful activity levels and appearance, and showed delays in age related diseases. Later in the mid 1990s researchers found specific sets of genes that kept cells from wearing out, from free radicals. For the first time it became clear that a single gene could alter the rate of aging and can be activated by caloric restriction or other stresses. These genes found in animals exist also in human and were called survival or scarcity genes. Unfortunately, this near starvation diet, despite its dramatic benefits, is intolerable for most people. But substances found in red wine grape skins can activate these survival genes, without calorie restriction. The secret of those compounds may be traced 4 million years ago, when our ancestors were exposed to severe stress from environmental and climatic changes, specific human genes will be activated that controlled carbohydrates, proteins, and fat metabolism in order to improve their chances of survival. In times of plenty, our body typically burn food carbohydrates for energy and store energy in the form of fat; during food shortages, these special genes mobilize this stored fat to survive. Coexisting with our ancestors were plants that recognized and responded to environmental stresses such as drought, infection, pests and harsh sun. To survive, these stressed plants activated their own survival genes, producing natural molecules to increase their own cellular defenses and repair
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William Amzallag, M.D. The Resveratrol Story; July 2011 mechanisms. The plant molecules that we find in red wine grape skins (resveratrol) are produced by stress to fight invaders. Laboratory mices that consumed these plant molecules also benefited from the same stress response. In other words, when ingested plants communicate with animals and people, using the language of molecular genetics and activating the survival genes. Mapping the system of human genes which was completed in 2001, has led to a new scientific field called nutrigenomics, which seeks to explain how nutritional substances, from french fries to blueberries activate our genes for better and for worse. This branch of biology explains how plants that have triggered their own protective response due to environmental stress talk to people, stimulating human genes to set in motion similar cellular activities to promote survival. Aging appeared to be a highly regulated mechanism which is genetically controlled by genes called sirtuins (SIR2), activating the production of specific proteins/enzymes called: SIR2 enzymes. This enzyme enhance the stability of the DNA and suppresses the formation of abnormal DNA.It became apparent that all living organisms from bacteria to humans, possesses genes for the production of SIR2 like enzymes.

What are polyphenols?

On November 1991, the CBS TV program 60 minutes broadcast a story suggesting that French peoples consumption of red wine was the reason for the lower rate of heart disease in France, they coined this phenomenonFrench paradox. It is now agreed that red wines contain polyphenols known as resveratrol, quercitin, cathechins and others, all of which have powerful activities, including prevention of heart attack, cancer and strokes. Polyphenols are the most abundant antioxidants in our diet, and they promote health through a variety of gene activating mechanisms. Polyphenols give the red to the red wines; the dark brown to chocolate; the green to the green tea. Grapes, apples, onions, soy, peanuts, berries, and many other fruits and vegetables are loaded with polyphenols. Resveratrol highly active polyphenol found in high concentration in the skin of red grapes is now playing a major role in the antiaging revolution. Those small molecules found in red wine can activate the sirtuins gene in the absence of caloric restriction to provide the same cardio protective effect than wine, without the alcohol.

Health benefits of Resveratrol

Living longer
It is crucial that we understand the role of genes in aging and longevity; there are two different processes: genes govern the cellular repair of damaged cells and regulate new cell growth, and so they, indirectly determine longevity. In other words, if we lose our ability to repair damaged cells, aging occurs prematurely. It is in this context that the sirtuins gene activators found in plant polyphenols molecules work. They help to repair genes and make them more resistant, thereby increasing longevity by reducing cell death. The recent work from David Sinclair (Harvard Medical School) showed that plant based molecules slow aging, reduce the consequence of obesity and enhance strength and endurance opening up incredible new opportunities in preventing aging and enhancing longevity.

William Amzallag, M.D. The Resveratrol Story; July 2011

Increasing endurance
Resveratrol dramatically increase the number of energy-producing mitochondria in muscle cells and convert type II, or fast-twitch muscle cells( common in sprinters) to type I ,or slow-twitch muscle cells (found in endurance athletes),it also enhance muscle strength and reduce muscle fatigue, along with improved coordination. Currently underway is a study evaluating elite athletes, to determine if these same natural compounds may enhance endurance and strength under competitive conditions.

Enhancing memory
Much the same way that we lose strength, endurance in our muscles as we age, we also see a gradual decline in memory, reaction time, and processing of information. One on three people over fifty wild experience mild cognitive impairment (MCI).Scientists from New Delhi University discovered in 2005 that animals engineered and grown to have Alzheimers like impairment had improved memory and cognitive function when given Resveratrol. They also found that the age dependant decrease in cognitive ability had been stopped. It appears also that Resveratrol enhance memory and reaction time in normal, healthy individuals.

Diabetes
Diabetes is a disease of sugar and fat metabolism caused by problems with insulin secretion by the pancreas, or with the insulin sensitivity of the cells. Insulin, a hormone, facilitates the uptake of sugar required by every cell to produce energy. There are two primary types of diabetes: type I, which is the most serious, develops when the bodys immune system destroys the insulin-secreting cells in the pancreas; type II diabetes, called adult onset diabetes begins when cells do not use insulin properly and develop resistance to it. To compensate, the pancreas attempts to produce more insulin and gradually loses the ability to do so. In type I diabetes ,injection of insulin keep the bodys level of blood sugar under control; in type II ,where cells still produce insulin, but not enough, oral medications are the first line of treatment. In 1985 in Australia, scientists discovered that two components of the red wine: quercitine and epicatechin enhanced insulin release in rats by 50%.In 2003 scientists showed that quercitine regenerated pancreatic cells and increased insulin release. In 2005 scientists in Canada discovered that Resveratrol appears to counter the effects of elevated free fatty acids, allowing normal uptake in muscle cells. In 2006 scientist from Taiwan showed that Resveratrol stimulated the uptake of glucose by liver, fat, and muscle cells. Resveratrol appeared to act through a mechanism different from that of insulin. In 2005 scientists from Chile confirmed that not only quercitin but other polyphenols found in grape skins also slowed sugar absorption in the intestines. All of those molecules hold great potential for diabetic management.

Cardio protection
Coronary artery disease, or hardening of the coronary artery, is the cause of most heart attacks .The problem is that half of the time, sudden death is the first symptom of heart disease. It was well established that elevated cholesterol levels, high blood pressure, diabetes, tobacco use, obesity, and sedentary lifestyles were all major risk factors associated with progressive artery blockage, but they showed up in only half of all fatal heart attacks. So what caused the rest?
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William Amzallag, M.D. The Resveratrol Story; July 2011 In 1990 scientists began to look beyond the composition of the clots blocking blood vessels to the lining of the vessels themselves, called the endothelium. Its functions include regulating inflammation and immune reactions, the tone of blood vessels. Many components circulating in the blood can damage the endothelium. These include glucose, Trans fatty acids, low-density lipoproteins (LDL), free radicals, and cytokines, signaling molecules that can turn inflammation on and off. There are 5 stages leading to a heart attack: 1/ The accumulation and oxidation of fat by free radicals 2/ Inflammation in the blood vessel 3/ A markedly decreased vascular tone and decrease elasticity of blood vessels 4/ Increased clotting that results in coronary thrombosis 5/ The damage or death of the heart muscle itself .Polyphenols and especially Resveratrol has shown remarquably effects on the 5 stages 1/ The antioxidant effect: Reducing free radicals Diet high in fat and Trans fatty acids appear to increase the risk of heart attack more than any other food product, even at very low level: a 2% increase in calories from trans fatty acids is associated with a 23% increase in the incidence of heart attacks. . After being processed by the liver, fats accumulate in the blood in the form of cholesterol and triglycerides. There are 2primary types of cholesterol molecules: LDL or bad low density lipo proteins, and HDL or good high density lipoproteins. If the balance tips toward LDL the endothelium become irritated and causes microscopic cracks to develop in the lining of blood vessel. Theses cracks release free radicals that oxidize or degrade the LDL. The accumulation of free radicals leads to the next stage of the coronary disease. In 1995 scientists from the University of Massachusetts Medical Center found that people drinking one and a half glass of red wine per day, lowered their level of lipid peroxidation (the toxic material) by 40%.In 1998 researcher from Cambridge University(UK) showed that an alcohol free powder of a red wine polyphenols extract had similar antioxidant effects. 2/ The anti-inflammatory effect: When oxidized LDL and fat attract white blood cells circulation in the blood stream. These white cells (called macrophages) ingest the cholesterol in an attempt to remove it. Those macrophages create significant inflammatory reaction. Smooth muscle cells form a cap over the injury site in the blood vessel lining; calcium accumulates and forms a material similar to bone, hardening the arteries. Nuclear factor kappa B molecule is a protein that acts as a switch to turn inflammation on and off. Known as the bodys smoke detector it can detect substances such infectious agents, free radicals, and other bad actors. In response, it turns on special genes that promote production of inflammatory cytokines that in turn kill or neutralize the invading agent through the inflammatory response. It is through blocking Nuclear factor kappa B that Resveratrol and Quercitin act as a potent anti-inflammatory agent. 3/ The vasoconstriction effect The coronary arteries widen and constrict to vary blood supply to the heart muscle.A substance called nitric oxide, produced by the endothelium, promote relaxation and constriction of the arterial
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William Amzallag, M.D. The Resveratrol Story; July 2011 muscle. In atherosclerosis, the endothelium is not able to produce nitric oxide. Polyphenols including Resveratrol enhance the production of nitric oxide, allowing the arteries to dilate when needed. 4/ The blood clotting effect As material continues to build up, it can accumulate to a point where blood flow is markedly reduced and then finally blocked. More commonly the arterial plaque can break up, exposing the underlying cellular debris to the rapidly flowing bloodstream. The body senses this as an injury and send platelets to form protective clots .These sticky platelets quickly pile up.A sudden heart attack occurs when blood is cut off by the platelet thrombus or clot. In 2002 scientists from the University of Peking showed that Resveratrol blocked platelet aggregation. In 2000 Italians researchers evaluating quercitin and catechin also found similar actions. 5/ Stopping the heart attack A heart attack occurs when a coronary artery no longer supplies blood to a particular part of the heart. In 2005 scientists from the University of Chicago and from Saint Louis University found that a specific enzyme found in cardiac cells is activated by free radical released by cellular injury from a heart attack. When this enzyme is over activated it results in heart cell death, this enzyme reduces also the activity of the enzyme SIRT 1. Resveratrol protect the heart cell against this specific enzyme by activating SIRT gene In sum, Resveratrol can help protect us against heart disease at every stage of its development, and can help ameliorate its life threatening effects when a heart attack occurs

The anticancer effect

There is a constant balance in every cell between so called oncogenes (genes involved in uncontrolled cell growth) and tumor suppressor genes (genes that turn off division and replicating mechanisms).When the balance tips in favor of the oncogenes, cells escape to normal control mechanisms of the body. The reactive nature of free radicals, and their ability to destabilize almost every molecule they contact, makes them harmful to normal human cells. Free radicals are normal by-products of the cells energy-producing mitochondria, much like the exhaust from burning gasoline in a combustion engine. The body has systems to remove them, but to combat the overproduction of free radicals accelerated by improper diet, environment pollution the body turns to external antioxidants like Vit C,E and beta Carotene to neutralize their destructive effects. In 1997 scientists from Purdue University published a paper in Sciences called Cancer Chemopreventive Activity of Resveratrol Natural Product Derived from Grapes .For the first time, researchers demonstrated that a polyphenols could interfere with the 3 major stages of cancer production: it neutralize free radicals in the initiation stage, acted as an anti-inflammatory during the promotion stage ,and inhibited the formation of new blood vessels supplying the tumor during the progression stage.

William Amzallag, M.D. The Resveratrol Story; July 2011 Thousands of scientific papers have been published and polyphenols are now evaluated for the treatment of many cancers.

Stroke prevention
A stroke is the loss of function that results from cell death caused by a blockage or rupture in a blood vessel supplying oxygen to the brain. Because a stroke is similar to a heart attack, it is now commonly referred to as brain attack .Polyphenols and in particular Resveratrol act as an antioxidant, an antiinflammatory, a blood vessel dilator, and an inhibitor of clot formation all should contribute to a reduction in brain attack .Also numerous studies have demonstrated that various polyphenols can protect brain cells and prevent stroke.

Rserve : Super Antioxidant Power

Rserve was formulated to fight against natural and disease-related aging. It is a specially-designed anti-aging system. The most important reason supporting our formulation of Rserve is to address a fundamental aging problemchronic inflammation at the cellular level. This chronic inflammation is a leading cause of most of todays significant diseases. Rserve is a very powerful product for the following reasons: The nutritional benefits reach the cellular level of the body, The synergistic combination of ingredients penetrates the bodys red blood cells, Strengthens the cell wall against the negative consequences of inflammation, Helps to repair cellular damage arising from the natural aging process, and Extends the life of healthy cells. Consuming Rserve daily restores the vitality of red blood cells. This leads to better health and an overall sense of well-being. The ingredient combination in Rserve is very important. These super antioxidants including resveratrol, acai, dark sweet cherries, blueberries, concord grapes, pomegranate, aloe vera and green tea help: Reduce bone and joint problems, Increase the natural flexibility of arteries, Lower blood pressure, Increase memory function, Enhance immune cell responsiveness, and Prevent bacteria from adhering to the cell walls. The gel delivery system of Rserve is very important for two reasons:

William Amzallag, M.D. The Resveratrol Story; July 2011 Significantly increases the bioavailability of the powerful ingredients. This means that the minerals and nutrients in the product are dispersed quickly throughout the body. This creates a much better result than gelatin-type capsules, tablets or pills. It creates a very delicious, natural fruit flavor. Because of the antioxidant potency of Reserves ingredients and the nutritional science supporting this formulation, Rserve is a very strong cellular-level protection against the effects of oxidative stress and free radical damage. There is a final and impressive benefit resulting from the ingenious ingredient combination in this remarkable anti-aging product. These ingredients help to combat the negative effects of elastase, a potent enzyme in the body. This helps to prevent the skin from aging too quickly. This is critical because elastase is responsible for the breakdown of the protein elastin which is vital in preserving skin tone and texture. Simply stated, Jeunesse has created the next revolutionary internal beauty product with Rserve. Because of this compelling benefit, Rserve becomes the perfect companion product to Luminesce, Jeunesses flagship skin care product.

CAP-e Testing
The CAP-e test measures the antioxidant potential of natural products. It is a cell-based test to determine if those antioxidants can penetrate and protect living cells from oxidative damage. This test is designed to measure the antioxidant bioavailability of a product at the cellular level. Rserve has obtained a remarkable CAP-e score of 37.1 units per cc. This score is the highest ever seen by our product formulator and is a tremendous indicator of the antioxidant properties of Rserve and the ability of this product to penetrate and protect living cells from oxidative damage. Such a high score is evidence of the antioxidant bioavailability of Rserve at the cellular level. The data from the Rserve CAP-e Test can be used to make the following statement: Antioxidants in our product can enter into and protect live cells.

Conclusions
Dramatic new scientific discoveries have unlocked the genetic secrets to a longer and healthier life. As so often happens with great discoveries, the answers turn out to be based on an incredibly simple idea: by ingesting natural plant molecules with which we have coexisted for millions of year, we can switch genes on and off to benefit from their anti-inflammatory, anticancer, antibacterial, and blood sugar normalizing effectand live longer! The concept of food as fuel only no longer holds. Even the simplest foods contain hundreds of specialized molecules. Some are nutritional by providing energy, other are bioactive, capable of effecting changes in hormone levels and in fat, carbohydrate and protein metabolism. This plant-toanimal interaction is as ancient as humankind itself.25% of our prescription drugs .Those molecules in our food can have significant health and longevity enhancing effects that surpass anything current medication can achieve