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Life Extension Magazine

LE Magazine March 2001

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Very Berry - and Grape too!
Benefits Abound: An Update on Blueberries, Bilberry Extract, Cranberry Extract, and Grape Seed Extract

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My grandmother was a folk healer. She knew a lot about herbs. But her favorite medicinal potions were home-made wines, which she prepared herself. She favored black currant, elderberry and blackberry wine. Tart cherries and small, dark navy-blue grapes were also acceptable, but black currants and elderberry were credited with greater preventive and healing power. “For a strong heart and long life,” my grandmother explained.

Modern science has confirmed that dark-colored berries and red, purple and dark-blue grapes are a treasure house of health-giving and possibly even life-extending phenolic compounds, including proanthocyanidins, anthocyanins and quercetin. And while the days of home-made wine may be over, we now have excellent extracts that provide standardized doses of the active polyphenols in berries and grapes. Bilberry extract and grape seed extract are the best known; cranberry extract and elderberry extract are also available for special therapeutic uses.

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Dry red wine is now recommended for diabetics, and is thought to be one reason for the greater slenderness of the French compared with other Europeans.

Before we look at some of these benefits, a quick note on the often confusing current terminology. Different authors use different terms. Proanthocyanidins, being short chains of catechin subunits, are also called oligomeric condensed tannins and are occasionally referred to as “oligomeric proanthocyanidin complexes,” or OPCs. Anthocyanins, which are larger molecules, are sometimes called polymeric condensed tannins. Both types of compounds, often referred to by the general term such as polyphenols, polyphenolics, or flavonoids, or even simply “plant pigments,” are widely distributed in plants, including peel, seeds, flowers and bark. Various berries, dark grapes and pine bark are particularly rich sources of proanthocyanidins and anthocyanins. Plants usually contain complex mixtures of phenolic compounds, including simple phenolic acids, quercetin, catechins, epicatechins, proanthocyanidins and anthocyanins. Wine is estimated to contain over two hundred phenolic compounds, though it is known that proanthocyanidins are the major bioactive polyphenols.

I find the broad term polyphenols to be the most convenient. The range of health benefits of polyphenols is extremely wide. Known primarily as potent antioxidants, they have also been reported to show antibacterial and antiviral action, to be anticarcinogenic, antiangiogenic, anti-inflammatory and anti-allergic. Various polyphenols have been shown to inhibit platelet aggregation and lipid peroxidation, as well as promote vasodilation and improve microcirculation. They can also chelate metals. Other benefits of high intake of polyphenols may include fewer cavities (an anti-caries action), improved kidney function, younger- looking skin and even the promotion of hair growth.

Cardiovascular benefits


A recent study done in Brazil showed that red wine as well as wine polyphenols without alcohol can provide marked protection against atherosclerosis. Rabbits were fed a high-cholesterol diet to produce a marked increase in their LDL cholesterol. One group of rabbits received red wine with their diet, another group was given non-alcoholic wine products and the third group served as control. All animals showed an increase in LDL cholesterol and some arterial plaque formation. The rabbits receiving red wine, however, fared best: on the average, only 38% of their arterial surface was covered with plaque (in some wine-fed animals, only 29%). Non-alcoholic wine products placed second, with 47%. Control animals showed plaque in 69% of their arterial surface. Thus, red wine and non-alcoholic but polyphenol-rich wine products were shown to inhibit arterial plaque formation even in the presence of high LDL cholesterol.

In addition, the authors checked the thickness of the inner arterial lining, the so-called “intima” layer. A thickening of the intima indicates excess smooth muscle proliferation, one of the many pathological processes involved in atherosclerosis. In terms of the ratio of the intima to the middle layer, the control group showed the greatest thickening (.60). The wine-fed group showed the least thickening (.14). The group consuming no alcohol but fed red wine polyphenols also showed significantly less thickening than the controls (.39). (The greater degree of protection provided by wine is probably due to the synergy between the wine polyphenols and ethanol. Ethanol, the alcohol found in wine, has been shown to have some cardioprotective properties when consumed within a moderate dose range.)

A similar Japanese study found that a proanthocyanidin-rich extract from grape seeds significantly reduced the severity of atherosclerosis in cholesterol-fed rabbits. The rabbits receiving grape seed extract in their cholesterol-laden diet showed less atherosclerosis in general and less oxidized LDL cholesterol in their foam cells (a component of plaque).

If a heart attack should happen, there is reason to think that those patients who have been consuming plenty of polyphenols would do better than those who do not have the help of those powerful antioxidants. A recent American study showed that the hearts of rats that had been fed grape seed extract were much more resistant to the injury caused by reperfusion (the return of blood to the tissue after of period of oxygen deprivation), as evidenced in greater ability to resume contractions. Likewise, a study on rats that focused specifically on the cardioprotective effects of resveratrol, found that pretreatment with resveratrol before inducing ischemia-reperfusion injury reduced the incidence and duration of arrhythmias and ventricular fibrillation. The authors concluded that resveratrol is a potent antiarrhythmic agent.

Anti-atherosclerotic benefits have been reported for purple grape juice as well. A study done at the University of Wisconsin, Madison, showed that when coronary patients consumed a large quantity of purple grape juice for 14 days, their flow-mediated vasodilation significantly improved, while their LDL cholesterol showed less susceptibility to oxidation. However, it takes a lot of juice to provide the same benefits as those of one glass of red wine - and a lot of juice means a lot of sugar. Grape seed extract, providing a rich mix of proanthocyanidins and other phenolic compounds, is a practical alternative for those who wish to avoid either the alcohol in wine or the sugar in grape juice.

A French study found that both red-wine proanthocyanidins and certain anthocyanins were able to produce a relaxation of the rat aorta, an effect due most likely to the ability of various phenolics to promote the production of nitric oxide. Proanthocyanidins turned out to be generally effective. However, one of the anthocyanins tested, delphinidin, showed exceptional effectiveness. A more recent American study done at Tufts University showed that the four anthocyanins found in elderberry extract were taken up by the membranes of the cells lining blood vessels, providing increased protection against oxidative stress. Another Tufts study found that blueberry anthocyanins protected red blood cells against oxidative stress by hydrogen peroxide both in vitro and in vivo.

Yet another way in which polyphenols help prevent atherosclerosis is by boosting the activity of vitamin C, which in turns increases the levels of vitamin E. This synergy increases the overall resistance to oxidative stress. It is oxidized LDL cholesterol and not cholesterol by itself, that is harmful. Thus the effort to lower LDL cholesterol is only part of the prevention of cardiovascular disease; reducing the oxidation of cholesterol is at least as important.

Besides the need to minimize the oxidation of LDL cholesterol, one needs to consider the role of platelet aggregation in arterial disease. Platelet aggregation is the first step in the formation of clots, which may lead to heart attack or stroke. Part of the effectiveness of aspirin in preventing heart attacks lies in its ability to inhibit platelet aggregation and thus the formation of clots. Dr. Lester Packer demonstrated that Pycnogenol, an extract from pine bark that is similar in composition to grape seed extract, “works better than aspirin in terms of controlling platelet aggregation, but without the unwanted side effects associated with aspirin. Pycnogenol reduced human smoking-induced platelet aggregation to the same extent as a five-time-higher dose of aspirin” (p. 127). This is a very dramatic finding, suggesting that cardiac patients especially should consider taking Pycnogenol or grape seed extract for preventive purposes.

Another study found that alcohol (ethanol) and wine polyphenols synergize in inhibiting platelet aggregation both in vitro and in vivo. Alcohol itself can inhibit platelet aggregation, but at rather high blood plasma concentrations (blood alcohol content of .2 or higher). In a study using dogs, it was found that a beneficial effect could be detected at much lower concentrations (blood alcohol content of .028) with polyphenol-rich red wine.

What might be the mechanism by which certain polyphenols in grape seed extract or pine bark extract inhibit platelet aggregation? Here we go back to the potent antioxidant properties of various phenolic compounds. If fewer free radicals are present, there is less inflammatory cascade that starts with the release of arachidonic acid from cell membranes and ultimately results in greater mobilization of platelets, creating a risk of a heart attack-inducing clot.

It is only recently that we have learned that heart disease is largely inflammatory in nature. Inflammation de-stabilizes the arterial plaque. Here again polyphenols turn out to be relevant, since they are known to have anti-inflammatory action. The main mechanism appears to be the inhibition of the metabolism of arachidonic acid. Studies have shown that various phenolic compounds can inhibit both the cyclooxygenase and the lipoxygenase inflammatory pathways, thus reducing the production of inflammatory prostaglandins and leukotrienes. In addition, some polyphenols (including resveratrol) have the ability to inhibit the activation of nuclear factor kappa-B, thus inhibiting the production of inflammatory cytokines. Proanthocyanidins have also been found to protect against a nitrogen-based free radical, peroxynitrite, one of the mediator molecules in inflammation. Yet another anti-inflammatory mechanism may involve the inhibition of cell adhesion molecule proteins, thus dampening over-recruitment of immune cells.

As has already been mentioned, excess proliferation of smooth muscle cells in the arterial lining also plays an important role in the progression of atherosclerosis. Here again wine polyphenols have been shown to have a anti-atherosclerotic effect. Japanese scientists have demonstrated that the polyphenols extracted from red wine had a powerful inhibitory effect on smooth muscle proliferation in the rat aorta. A more recent Japanese study focused on the effects of resveratrol and found that this potent phenolic antioxidant (found chiefly in red wine, grape skins and, in lower concentrations, in peanuts) was able to inhibit smooth muscle proliferation induced by high levels of AGEs in the plasma. AGEs is an acronym for advanced glycation end-products that result from the crosslinking of proteins by simple sugars. This, again, suggests that grape seed extract could be of special importance to diabetics.

Finally, polyphenols play a role in the regulation of nitric oxide production. The correct amount of nitric oxide is crucial for relaxing the smooth muscles of blood vessels, thus producing vasodilation. Polyphenols found in red wine and grape seed extract, including resveratrol, have been shown to upregulate nitric oxide production by healthy arterial endothelium (cells lining the inner surface of blood vessels). Excess production of nitric oxide by macrophages (a type of immune cell), however, is associated with inflammation and various inflammatory diseases, including arthritis and atherosclerosis. If macrophages drawn to the vascular walls produce too much nitrogen oxide, the result is damage to the lining of the blood vessel. Excess nitric oxide gives rise to dangerous nitrogen-based free radicals such as peroxynitrite, which damages proteins and destroys glutathione. Packer places great emphasis on the ability of polyphenols to help regulate the production of nitric oxide, as well as help protect against not only oxidation, but also nitration. New findings indicate that alcohol can synergize with phenolic compounds found in red wine in inhibiting excess nitric oxide production by macrophages.

While a lot of research has concentrated on single phenolic compounds such as quercetin and resveratrol, it is likely that a rich mixture of various polyphenols is more effective in providing cardiovascular protection than any single compound. As Dr. Packer points out, “In almost every circumstance, combinations of antioxidants have been proven to be more effective than single antioxidants” (p. 118).

Potent anticarcinogens

Epidemiological studies confirm that those who consume plenty of polyphenol-rich foods and beverages have a lower risk of cancer. We are always being urged to eat more fruits and vegetables. There has been little guidance, however, as to which fruits and vegetables should be particularly emphasized. There is reason to think that berries should be very high on the list.

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Raspberries and strawberries contain a potent anti-carcinogenic compound called ellagic acid, which is well documented, however flavonoids in general are known to inhibit the bioactivation of carcinogens.

Blueberries and other berries, notably raspberries and strawberries, contain a potent anticarcinogenic compound called ellagic acid. While the anticarcinogenic properties of ellagic acid are particularly well documented, polyphenols in general are known to inhibit the bioactivation of carcinogens. They also exert antiproliferative (anti-mitotic) effects that are particularly pronounced in tumor cells. Add to this the growing evidence that some classes of phenolic compounds, including anthocyanins and proanthocyanidins, have an anti-angiogenic effect (that is, they prevent the development of new blood vessels).

Red wine and grape seed extract also show a great promise in the prevention of cancer. Resveratrol in particular has been extensively studied for its anticarcinogenic properties. Its action on tumor cells has been found to be dose-dependent. Very low doses appeared to increase proliferation; higher doses decreased proliferation and induced apoptosis (programmed cell death). Exposure of colon cancer cells to resveratrol resulted in growth inhibition through cell-cycle arrest and an inhibition of polyamine synthesis, apparently through inhibition of a crucial enzyme, ornithine decarboxylase. Resveratrol also strongly inhibited the proliferation of liver-cancer cells. Interestingly, ethanol (the alcohol present in wine) lowered the threshold for the effectiveness of resveratrol, again showing that alcohol can enhance the action of polyphenols. Resveratrol and quercetin have also been shown to some effectivess against leukemia.

Grape seed extract has been found to provide greater protection against DNA damage than vitamins C, E and beta-carotene. In addition, grape seed extract has proven effective in vitro in arresting the growth of human breast cancer, lung and gastric adonocarcinoma. In animal studies, topical application of grape seed extract has been shown to provide excellent protection against skin cancer. Of special interest is the recent finding that grape seed extract may also work against prostate cancer. Up to 98% growth inhibition was obtained in a dose- and time-dependent manner. Another study found that resveratrol downregulates androgen-upregulated genes, thus inhibiting androgen-stimulated cell growth. It should be stressed that while resveratrol is often referred to as a phytoestrogen, it has no feminizing side effects.

The fact that polyphenols raise glutathione levels is also of great importance in cancer prevention. Glutathione is one of the chief factors in the defense of DNA. In fact, one of the many jobs performed by glutathione is activating the enzymes that repair damaged DNA. The liver also needs enormous amounts of glutathione to detoxify the endless carcinogens and other toxins to which we are constantly exposed. By boosting glutathione levels with various polyphenols, we increase our ability to detoxify harmful chemicals.

People who show a slow rate of aging and a resistance to cancer (both thought to be due to “centenarian genes”) tend to have higher levels of glutathione than their chronological peers. Conversely, people suffering from age-related diseases are deficient in glutathione. Likewise, animal studies have shown that raising glutathione levels can extend life span. Thus, if we can keep our glutathione levels from declining with age, it is likely that we will age more slowly and will be more resistant to cancer. Dr. Packer, for one, thinks that reaching 100 should not be a difficult feat as long as we can maintain youthful levels of glutathione. Dr. Packer, of course, advocates the boosting of the entire antioxidant network, which means consuming an antioxidant-rich diet and supplementing with a variety of antioxidants, including a mix of polyphenols.

Supplementation with oral glutathione is controversial because of uncertainty as to its absorption in the reduced state. However, there is reason to think that if glutathione is taken together with sufficient amount of bilberry extract, it can be absorbed in the reduced (antioxidant) state. It may still be more cost-effective, however, simply to consume a lot of polyphenol-rich food and/or take supplements that contain a mixture of various phenolic compounds, along with lipoic acid, also known to be very effective at raising the levels of glutathione.

Packer also reports the findings that Pycnogenol enhances the immune function, increasing the production of Interleukin 2 and stimulating natural killer cell activity. A healthy immune system is regarded as one the crucial factors in resistance to cancer.


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