Nutrisearch Comparative Guide Product Rating Criteria

Product Rating Criteria

This chapter explains the Health Support Profile, a comprehensive set of mathematical algorithms that are based on 18 health support criteria described below. The Health Support Profile ranks each product that is included in theNutriSearch Comparative Guide to Nutritional Supplements in accordance with nutrient intake recommendations described in the Blended Standard. As previously mentioned, this standard forms the basis of our analytical model. For a detailed explanation of the Blended Standard, please refer to the previous chapter.

When a product is evaluated, the rating for each criterion is calculated and pooled to provide a raw product score. This score is then used to rank each product against its peers. With four new criteria added to our analysis and all criteria strengthened, the revised Health Support Profile represents a significant enhancement from previous editions of theComparative Guide. These revised criteria effectively raise the bar for nutritional excellence by which all products are evaluated in this guide.

Changes to the Criteria

In previous editions of the Comparative Guide, we gave full credit for nutrient potencies that met or exceeded 50% of the potency for each nutrient relative to the Blended Standard. For this edition of the guide, the benchmark has been raised considerably. Full credit for the potency of a given nutrient is now based on 100% of the value for that nutrient as described in the Blended Standard. In addition, we have added four new criteria, based on evolving scientific evidence. These new criteria are:

• Gamma Tocopherol Profile
• Ocular Health
• Inflammation Control
• Glycation Control

Furthermore, several of the previous criteria have been enhanced to accommodate new scientific findings. For example, the number of nutrients included in the criteria for Antioxidant Support, Heart Health, Metabolic Health, Liver Health (formerly called Glutathione Support), and Methylation Support formerly called Homocysteine Reduction Support) has been increased. As well, the penalty-imposition point for excessive iron, which is part of the Potential Toxicities criterion, has been lowered. This decision is based upon recent evidence of cumulative iron toxicity at a dosage as low as 5 mg/day.¹

To receive a full point for any single criterion, the product must meet or exceed the benchmark established for that criterion. Each criterion is rated using an ordinal (sliding) scale, where partial points are awarded for the partial fulfillment of each criterion. The last criterion, Potential Toxicities, penalizes the product if the formulation exceeds defined limits for those nutrients (vitamin A and iron) that demonstrate a potential cumulative toxicity.

The following is an overview of each criterion used in our Health Support Profile. For each criterion, we also provide the analytical question that addresses the criterion. Each question posed constitutes the logical argument that is embedded in the mathematical algorithm, and each algorithm evaluates the product based on the specified criterion.

Show Me the Science

For each Health Support Profile criterion, we provide a review of the scientific justification for those nutrients included in the criterion. This review is a more comprehensive overview than is available in the printed 4^th edition of theComparative Guide to Nutritional Supplements; it is provided for those wishing to delve deeper into the available scientific evidence supporting the value of supplementation with a particular nutrient or nutrient group.

1.   Completeness

Over the years, scientific research has documented numerous micronutrients that are required for optimal health. We now know that the body requires approximately 17 vitamins and vitamin-like substances, a diverse group of plant-based antioxidants, at least 14 trace elements and minerals, and several essential fats necessary for proper cellular function. The body cannot manufacture many of these substances; they must be obtained through the diet. In all, 47 essential nutrients and nutrient categories are referenced in this guide, based upon the recommendations of our 12 cited authorities, and enhanced by emergent research that, in some instances, has eclipsed their published recommendations. These 47 nutrient categories comprise the cornerstone of our Blended Standard—the definitive benchmark upon which our analysis is built.

The criterion for Completeness poses the following question:

Does the product contain the full spectrum of nutrients and nutrient categories listed in the Blended Standard and considered essential for optimal health? To qualify, a nutrient or nutrient category must be present at a dosage that is at least 20% of the value in the Blended Standard.

Due to the technical challenges, including tableting, stability, and shelf-life, involved in the addition of high levels of essential fatty acids (fish oils and plant seed oils) in tableted products, the levels of these nutrient categories are only included in the Completeness criterion for those products categorized as Combination Products.

2.   Potency

Recent epidemiological studies reveal that there is considerable genetic variation in the functionality of several key coenzymes in human cells.[*] In many instances, these genetic variations will hinder the ability of a coenzyme to bind to the active site of other enzymes, thus impairing the reactions that these enzymes control. This, in turn, can increase susceptibility to disease. Individuals affected with these genetic defects (polymorphisms) require supplementation with those nutrients serving as precursors for the affected coenzymes at potencies that may be substantially greater than their recommended dietary intakes (DRIs).

The potencies for the 47 essential nutrients and nutrient categories referenced in this guide are based upon the recommendations of our 12 cited authorities and reflect the need for supplementation with some nutrients at levels considerably higher than their DRIs. In those few instances where a specific recommendation is not definitive, but where there is clear support for the inclusion of the nutrient or nutrient category (such as in the case of phenolic compounds), we turn to emergent research for guidance.

The criterion for Potency poses the following question:

For each nutrient in the product, what is the level of potency relative to the potency for that nutrient in the Blended Standard?

Due to the technical challenges, including tableting, stability, and shelf-life, involved in the addition of high levels of essential fatty acids (fish oils and plant seed oils) in tableted products, the levels of these nutrient categories are only included in the Potency criterion for those products categorized as Combination Products.

3.   Mineral Forms

Minerals are essential components of our cells and serve as cofactors in the thousands of enzyme-controlled reactions that power the machinery of the cell. Throughout the body, minerals form critical structural elements, regulate the action of nerves and muscles, maintain the cell’s osmotic (water) balance, and modulate the pH (acidity) of the cell and extracellular fluids. While minerals comprise only 4% to 5% of our total body weight, life would not be possible without them.

During the digestive process, minerals separate from the food and dissociate into ions (electrically charged atoms in solution). Ionized minerals can then pass freely through the intestinal wall and into the blood. They also attach themselves to amino acids, or other organic acids, and “hitch a ride” with these carriers, which are preferentially absorbed by the cells lining the small intestine. From here, the carriers and their attached minerals enter the blood and then travel to the liver to be readied for use by the cells of the body.

When nutritional supplements are consumed, the minerals are naturally conjugated (joined) to amino acids available in the gut during the digestive process.² This is why it is best to consume your supplements with a meal. This suggests that there should be no differences in mineral bioavailability[†]  between supplements that use chelated mineral complexes and those that use less expensive inorganic mineral salts. However, such is not the case. For one thing, as people age, they lose their ability to produce sufficient stomach acid, making it increasingly difficult to dissolve and ionize common mineral salts. For another, complex mineral interactions can inhibit absorption and influence mineral bioavailability.

Many components of our daily diet, including other minerals, can interfere with, and sometimes block, the absorption of certain minerals, making them unavailable to the body.³ Natural fibre, such as that found in fruits and cereals, has a depressing effect on the absorption of minerals supplied as inorganic mineral salts. Surprisingly, recent evidence shows that a fibre-rich diet can even deplete the body’s mineral status when minerals are provided as inexpensive mineral salts, resulting in a negative mineral balance.^{4, 5} Considering the ready availability of dietary supplements that use inexpensive mineral salts, these mineral-mineral and mineral-substrate interferences take on considerable importance. Imagine taking a mineral supplement in good faith and going into a negative mineral balance—actuallylosing ground for the very minerals you consumed! The short of it is this: avoid the use of supplements that provide minerals in the form of inorganic mineral salts (such as oxides, carbonates, sulphates and phosphates). While less expensive to manufacture, supplements using mineral salts do not appear to provide optimal nutritional value.

To resolve mineral-mineral interferences and increase the bioavailability of minerals, many manufacturers chemically bond the mineral to an amino acid or organic acid carrier. These chelated minerals are believed to mimic the natural mineral chelates that form during the digestion process. Beyond their reported superior bioavailability, chelated minerals appear to have lower absorptive interference and better tolerance in the gut than the less expensive mineral salts.⁶ Moreover, minerals delivered in chelated form avoid the competitive inhibitions to absorption and the mineral-mineral interactions experienced by less expensive mineral salts.

While not chelates in the true sense of the word, minerals joined to organic acids, such as citrate, malate, succinate, alpha-ketoglutarate and aspartate (known, collectively, as Krebs cycle intermediates), are also believed to be preferentially absorbed. These organic acids are essential to the central metabolic pathway of the cell. Consequently, they are selectively absorbed through the gut, along with the attached mineral (which piggybacks along for the ride). Minerals chelated to Krebs cycle intermediates are better utilized and tolerated than inorganic or relatively insoluble mineral salts. Both Krebs cycle intermediates and amino-acid chelates fulfill all the requirements for an optimal carrier molecule:⁷ they are easily metabolized; non-toxic; helpful in increasing the absorption of the mineral carried; and efficiently degraded and employed in other areas of the cell’s metabolism. Organic-acid complexes also provide needed acidity to promote absorption in the gut. Moreover, both the mineral/amino-acid chelates and the mineral/organic-acid complexes appear to be better tolerated by the human gut than simple mineral salts.⁸

The Bottom Line

The question of mineral form versus bioavailability has been an issue of contention within the scientific community for some time. This is largely because of the complexities of the human digestive process and the multitude of interactions between minerals and other digestive products. Some studies appear to refute the claims of superior bioavailability of mineral chelates;^{6, 9, 10} other studies provide convincing evidence that chelated minerals are preferentially absorbed.^11-16 While recognizing the controversy that continues to surround this issue, this guide acknowledges the consensus of our selected nutritional authorities, which supports the use of mineral/amino-acid chelates and mineral/organic-acid (Krebs cycle) complexes as superior mineral forms with respect to bioavailability^{2, 17-20} 

The criterion for Mineral Forms poses the following question:

For those minerals included in a formulation, how many are found in their most bioavailable forms as amino-acid chelates or organic-acid complexes?

4.   Bioactivity of Vitamin E

Vitamin E is a fat-soluble vitamin that exists in eight different structural forms (four tocopherols and four tocotrienols). Each form, or isomer,[‡] has its own biological activity, which is the measure of potency or functional use in the body. Alpha-tocopherol is the name of the most active form of vitamin E in humans. It is the only form of vitamin E actively maintained in the human body and is, therefore, the form of vitamin E found in the largest quantities in the blood and tissue. Consequently, the type of vitamin E used in nutritional supplements is generally the alpha-tocopherol form.

Alpha-tocopherol functions as a chain-breaking antioxidant that prevents the propagation of lipid oxidation within the cell membrane. Found in leafy green vegetables, vegetable oils, and nuts, intakes of small quantities of this fat-soluble vitamin—as little as 100 IU per day—have been associated with a significantly reduced risk of heart disease in both men and women.²¹ Natural alpha-tocopherol is called d-alpha-tocopherol. Synthetic vitamin E, also known as d/l-alpha-tocopherol, or all-rac tocopherol, is produced commercially in a process that yields both the d- and l-isomers. Like your right and left hands, these isomers are mirror images of each other.

Until recently, synthetic vitamin E was believed to possess a biological activity about two-thirds that of natural vitamin E. However, new evidence regarding the biological activity of synthetic vitamin E has prompted the National Academies of Science to recognize synthetic (d/l) alpha-tocopherol as possessing only one-half the biological activity of natural (d) alpha-tocopherol.²²

As well as showing the highest level of biological activity, natural vitamin E appears to be quickly absorbed into human cells. In contrast, the synthetic forms are metabolized (broken down) and excreted in the urine. The assimilation of natural vitamin E appears to be a result of the action of specific binding proteins produced in the liver. These proteins preferentially bind and transport d-alpha-tocopherol, to the exclusion of other forms of the vitamin. According to researchers at the Linus Pauling Institute, some of the forms of tocopherol present in synthetic vitamin E are simply not useable by the body. Consequently, d/l-alpha-tocopherol is less bioavailable and only about half as potent as natural d-alpha-tocopherol.

The Bottom Line

The evidence demonstrating the greater bioavailability, preferential absorption and assimilation, and lower rates of excretion of d-alpha-tocopherol compared to the synthetic form of the vitamin is persuasive. Despite the use of the IU measure to account for differences in biological activity of natural versus synthetic vitamin E, the weight of evidence favours d-alpha-tocopherol as the standard by which to judge nutritional quality. Accordingly, differentiation between these isomeric forms of vitamin E is incorporated, where applicable, throughout the product-rating criteria used in this guide.

The criterion for Bioavailability of Vitamin E poses the following question:

Does the product contain the natural (d) isomer of alpha-tocopherol or does the product contain the synthetic (d/l) isomers of alpha-tocopherol?

5.   Gamma Tocopherol

Regular consumption of natural vitamin E, with its complex mixture of tocopherols and tocotrienols, has long been known to lower the risk of degenerative disease. A good deal of laboratory evidence and data from epidemiological and retrospective studies show that a high dietary intake of vitamin E can ward off heart disease^23-26 and keep several cancers at bay.^27-29 Findings from several prospective studies and clinical trials, however, have been ambiguous, failing to show consistent results.^30-34 One plausible explanation for this ambiguity may be that virtually all clinical trials have used alpha-tocopherol, the primary form of vitamin E in dietary supplements, and many trials have used synthetic (d/l) vitamin E—known to cause adverse effects at high dosage—rather than the natural tocopherols found in the diet.³⁵Researchers at Johns Hopkins University point out that the benefits of alpha-tocopherol may, in fact, be compromised by a decrease in the levels of gamma-tocopherol that is known to occur during high-dose supplementation with alpha-tocopherol.³⁶

Gamma-tocopherol possesses distinctive chemical properties that differentiate it from its alpha analogue and may explain the observed differences in the physiologic effects of the two vitamin E forms. Gamma-tocopherol has been shown to be more effective than alpha-tocopherol in:

• reducing several prothrombotic events associated with oxidative stress;^{37, 38}
• reducing platelet aggregation and clot formation;³⁹
• enhancing the activity of the antioxidant enzyme, superoxide dismutase (SOD), and inhibiting the proinflammatory COX-2 enzyme;⁴⁰
• regulating the expression of genetic factors that can influence cancerous growth; and^{41, 42}
• subduing nitric oxide-induced oxidative stress by removing toxic nitrogen-based free radicals.⁴³

Not surprisingly, gamma-tocopherol is emerging as an important partner to alpha-tocopherol in the science of preventive health. Both forms of vitamin E are recognized nutritional thoroughbreds, each possessing protective talents based upon their individual chemistries; however, it is their work as a team—at once both complementary and synergistic—that is the likely “power behind the punch” of vitamin E observed in epidemiologic, retrospective, and laboratory studies. The Bruce Ames research group at the University of California, Berkeley, contends that consumers taking vitamin E supplements containing an imbalance of the two principal forms of vitamin E are depriving themselves of the protection afforded by a mixture of tocopherols. Accordingly, the researchers argue that vitamin E supplements should contain a ratio of alpha/gamma-tocopherol that is closer to what is found in nature.^44-46

The Bottom Line

There are few studies that allude to an optimal alpha/gamma-tocopherol ratio; however, some researchers have proposed a 2:1 to 1:1 blend.⁴⁷ We support the need for the inclusion of gamma-tocopherol in any supplement containing high levels of the alpha-form. Consequently, we are adding the recommendation for the inclusion of gamma-tocopherol at an alpha/gamma ratio of 2:1 as a new component in the class="EmphasisItalic">Blended Standard.

The criterion for Gamma Tocopherol poses the following questions:

Does the product contain gamma-tocopherol (or a mixture of gamma, beta, and delta-tocopherols) at a potency of up to one-half the potency of alpha-tocopherol in the same product? What is the potency of gamma-tocopherol or mixed tocopherols in the product, compared to the potency for gamma-tocopherol in the Blended Standard?

6.   Antioxidant Support

The scientific evidence supporting the health benefits of supplementing with a balanced spectrum of antioxidants is impressive. Consequently, many health practitioners have begun to recommend higher dietary intakes of these important nutrients as a prudent preventive measure against oxidative stress. As was anticipated over two decades ago by leading researchers,⁴⁸ high-dose supplementation with antioxidants is gaining a significant role in the prevention and treatment of many of today’s common ailments. However, antioxidants do not work in isolation. When an antioxidant neutralizes a free radical, it is, itself, oxidized and must be replenished by another antioxidant before it can be used again. For this reason, it is vital to supplement with a wide spectrum of antioxidants—an approach that is reflective of what occurs in nature.

As an aqueous-phase antioxidant, vitamin C (ascorbic acid) is the principal sentry against oxidative attack in the extra-cellular matrix and within the cytoplasm of the cell. Vitamin C is a cofactor or substrate for eight separate enzyme systems involved in various cellular functions, including collagen synthesis, ATP synthesis in the mitochondria, and hormone biosynthesis. Its primary antioxidant partners include vitamin E and beta-carotene, which help regenerate vitamin C.

Of all the antioxidants, vitamin E may offer the greatest protection against heart disease because of its ability to imbed itself into the LDL-cholesterol molecule and protect it from oxidative damage. Its solubility in lipids (fats) makes the vitamin an important component of the cell membrane, where it works to protect the cell against lipid peroxidation and attenuate oxidation-induced inflammatory events. More recently, the gamma-tocopherol form of vitamin E has shown great promise in reducing the risks of several cancers including colorectal and prostate. {Campbell, 2006 95 /id;Jiang, 2004 18 /id Researchers at the University of Uppsala, Sweden, found that gamma-tocopherol proved even more effective than alpha-tocopherol in reducing several prothrombotic events associated with oxidative stress.⁴⁹

Beta-carotene (Provitamin A)

Beta-carotene is the best-known member of the carotenoids, a group of accessory photosynthetic plant pigments that absorb blue-violet and blue-green light. In human nutrition, the beta-carotene plays a dual role. As an antioxidant, beta-carotene’s extensive conjugated double-bond structure reacts effectively with singlet oxygen radicals, absorbing and diffusing their destructive energy {Handelman GJ, 1996 244 /id}As a precursor for vitamin A (retinol), beta-carotene contributes in an entirely different way, supplying a portion of the body’s requirement for the vitamin. Through its conversion to the active forms of retinol (retinal and retinoic acid), beta-carotene plays a central role in the chemistry of vision, the activation of gene expression and the control of cell differentiation (task specialization). Beta-carotene also affects immune function, taste, hearing, appetite, skin renewal, bone development and growth, and embryonic development.

Inadequate beta-carotene levels in the blood have been associated with impairment of immune function. ^{50, 51}Supplementation produces regression of leukoplakia (precancerous lesions in the mouth) and demonstrates a strong inverse association with the risk of cervical cancer and dysplasia. ^{52, 53} Many epidemiological and clinical studies support the long-term benefits of beta-carotene intake. Similar findings pertain to its protective actions in heart disease and immune health. ⁵⁴

The Triad of Vitamin C, E and beta Carotene

While vitamins C, E and beta-carotene each carry out important antioxidant functions on their own, their synergistic activities provide some startling evidence regarding their efficacy.

Heart Disease

The triad of vitamins C, E and beta-carotene has proven effective in the reduction and prevention of heart disease. In one large study of over 5,000 Finnish adults, the relationship between dietary intake of vitamin C, vitamin E, beta-carotene and the reduction in risk of coronary mortality was significant for both sexes. ⁵⁵Another large population study, relating antioxidant intake to the prevalence of coronary artery disease, found that blood levels of vitamins C, E and beta-carotene were significantly lower and oxidized lipids significantly higher in coronary disease patients, compared to the normal population. ⁵⁶ Research indicates that the protective action of this triad of antioxidants may be exerted through the quenching of the oxidation of low density (LDL) lipoproteins. This protective mechanism has been noted in several studies, ^57-59 providing evidence of a preventive role in reducing the fatty plaque build up characteristic of atherosclerosis. Other studies provide more evidence of the preventive role of vitamins C, E and beta-carotene in the reduction of the risk of ischemic heart disease⁶⁰ and myocardial infarction (heart attack). ⁶¹The evidence for the mitigation of risk is so strong that some investigators conclude that a major determinant for heart attack may, in fact, be vitamin deficiency. Accordingly, they have recommended nutritional supplementation for the prevention of cardiovascular disease.

Cancer

Several epidemiological studies have shown that the combination of vitamins C, E and beta-carotene is capable of significantly reducing the risk of dying from a heart attack or stroke. ⁶²Conversely, low levels of these nutrients have been associated with an increased risk of mortality from numerous cancers. ⁶³As well, several studies confirm that alpha tocopherol and beta-carotene play a central role in preventing cancers in the oral cavity. ^64-66Other investigators report that vitamins C, E and beta-carotene are important in the regulation of cancer cell differentiation.

These three vitamins exhibit powerful cytotoxic (cell killing) effects on cancerous cells and may even revert cancer cells back to normal cell types. ⁶⁷Research shows that supplementation with this antioxidant triad can inhibit liver carcinogenesis, ⁶⁸ reduce the incidence of reappearance of precancerous polyps found in the colon, ⁶⁹ and provide a significant reduction in cancer mortality. ⁷⁰ Numerous studies also confirm a strong inverse relationship between circulating levels of vitamin A, beta-carotene, vitamin E and vitamin C and the risk of cancer mortality.

Several studies confirm that low levels of antioxidants in the blood are associated with a high risk for cancer mortality.⁷¹,⁶⁸,^72 73,⁷⁴,⁷⁵All three nutrients appear to exert their anti-cancer effects through their individual and collective ability to quench free radical species  ⁷⁶and prevent lipid peroxidation. ⁷⁷

Other Important Antioxidants

• Alpha-lipoic acid (ALA) is a powerful antioxidant that can act in both the aqueous and lipid-phases of the cellular environment. Able to cross the blood-brain barrier with ease, ALA is capable of removing heavy metal toxins from the CNS. ALA also acts as a “recycler” of vitamin E and vitamin C, stimulates the production of the endogenous antioxidant, gluatathione, and aids in the absorption of coenzyme Q10. ⁷⁸ and its reduced form, dihydrolipoic acid, are powerful antioxidants. ALA scavenges hydroxyl radicals, hypochlorous acid, peroxynitrite, and singlet oxygen. Dihydrolipoic acid, the reduced form of ALA, scavenges superoxide and peroxyl radicals and can regenerate thioredoxin, vitamin C, and glutathione, which can, in turn, recycle vitamin E ⁷⁹
• Lycopene, the red pigment found in ripe tomatoes, exhibits the highest overall ability of all the carotenoids to quench singlet oxygen and may exhibit even more impressive anti-cancer benefits. Increased dietary consumption of lycopene has been shown to provide significant protection against cancers of the prostate, pancreas, and gastrointestinal tract.⁸⁰
• Coenzyme Q10 is structurally similar to vitamin E and plays a crucial role in the creation of cellular energy and protection of mitochondrial membranes from oxidative damage caused by the respiratory processes. The antioxidant has a sparing effect on vitamin E and works with vitamin E to prevent lipid peroxidation. It is also a significant immunological stimulant and cardiovascular protectant.
• Selenium is an essential trace mineral that functions as an antioxidant in partnership with vitamin E. An integral component of the antioxidant glutathione peroxidise, it enhances the activity of this important endogenous antioxidant enzyme. Selenium is also antagonistic to heavy metals, such as lead, mercury, and cadmium.

The Bottom Line

The criterion for Antioxidant Support poses the following question:

Does the product contain vitamin C, vitamin E (including alpha-tocopherol and gamma-tocopherol, or mixed tocopherols), vitamin A, beta-carotene, alpha-lipoic acid, lycopene, coenzyme Q₁₀, and selenium at potencies up to 100% of the potencies for these nutrients in the Blended Standard?

7.   Bone Health

As living tissue, healthy bones require at least 24 bone-building materials, including trace elements and protein. The most important minerals are calcium, magnesium, phosphorus, and potassium. Equally important is the balance between these minerals. Strong bones need lots of calcium, but calcium supplementation also requires the presence of magnesium, which increases calcium retention in the bone. Phosphorus, another important component in bone formation, must be in proper balance with calcium. Too much of it, from soft-drink consumption or high protein intake, will suck calcium out of the bone and weaken its integrity. Vitamins D and K are also vital for enhanced calcium deposition⁴⁹ while silicon, boron, and zinc are required to strengthen the bone’s mineral matrix.⁸¹ Vitamin C stimulates formation of the collagen matrix, an important protein component that creates a framework for calcium crystallization.⁴⁹ Silicon increases bone-mineral density and appears to have a role in the prevention and treatment of osteoporosis. Silicon deposition is found in areas of active bone growth, suggesting that it may be involved in the growth of bone crystals and the process of bone mineralization. Zinc is essential for the proper action of vitamin D; its status plays a central role in bone health. Increased zinc excretion, common in osteoporosis sufferers, is a likely consequence of accelerated depletion of bone-mineral content. Diets low in zinc have been shown to slow adolescent bone growth.⁸²Last but not least, vitamins B₆, B₁₂, and folic acid reduce mineral loss by modulating blood homocysteine levels.⁴⁹  Let’s look at each of this important nutrients in more detail:

Vitamin D

Vitamin D stimulates the absorption of calcium. As a steroid hormone synthesized in the skin, vitamin D regulates calcium absorption from the gut, the deposition of calcium in the bone, and the re-absorption of calcium from the urine. In the skin, sunlight changes 7-dehydrocholesterol, the precursor of vitamin D, into active vitamin D3, or cholecalciferol. Sunlight’s central role in the manufacture of vitamin D is one of the reasons that people living in northern climates or confined indoors often have a deficiency of this important nutrient. Several studies show that vitamin D, used in combination with calcium, reduces the rate of osteoporotic hip fractures and improves bone mineral status.1 One study, conducted in 1995, showed that supplementation with 700 IU of vitamin D reduced the rate of hip fractures by nearly sixty percent ⁸³

Recent evidence has challenged the current recommended daily intakes for vitamin D established by Canada and the United States. Gallagher⁸⁴ argues that the current recommended levels of vitamin D intake might be too low in the elderly, noting that doses of 800 IU per day can lower the incidence of osteoporotic fractures. In a 1999 study, Vieth⁸⁵suggests that the recommended dietary allowance for adults of 5 μg (200 IU) of vitamin D is insufficient to prevent osteoporosis and consequent damage to the parathyroid glands, responsible for regulating blood calcium levels. Recent disclosure of a high prevalence of hypovitaminosis D (low levels of vitamin D) in medical in-patients, including those with vitamin D intakes greater than the recommended daily allowances, has led other researchers to conclude that maintaining recommended intakes at current levels may be insufficient to ensure adequate nutrient stores. ⁸⁶

There is merit in these arguments. The original scientific basis for the limited-dose recommendation of vitamin D was arbitrary and based largely on anecdotal reports. While it is reasonable that the daily vitamin D intake could be up to 800 IU per day, Murray⁸⁷ recommends a daily intake of 400 IU because the level of active vitamin D does not differ substantially between 400 IU and 800 IU. According to Murray, dosages exceeding 800 IU/day may adversely affect magnesium levels. Other researchers suggest that, except for those with vitamin D hypersensitivity, there is no evidence of adverse effects in doses up to 10,000 IU per day. ⁸⁶

Calcium

Through bone remodelling, an ongoing process of bone deposition and resorption, our bones replace much of their mineral content every few years. ⁸⁸However, if this dynamic balance is disturbed, through dietary and lifestyle choices or through the side effects of pharmaceutical drugs used to treat other disorders, we can rapidly deplete our calcium stores and our bones will become progressively weaker. In fact, poor calcium nutrition is now recognized as a leading risk factor in osteoporosis, a disease that is becoming epidemic in our aging society. Numerous studies confirm that calcium supplementation at 500 to 1200 mg per day can significantly reduce bone loss and the risk of accidental fracture ^{83, 83, 89} Calcium supplementation has also been found to increase the bone mineral content of children and adolescents. ^90-92 Several studies confirm that good calcium nutrition during our adolescent years leads to improved bone health and reduced risk of osteoporosis later in life. ^93-95According to Dr. Paul Ullom-Minnich, University of Kansas School of Medicine: “Based on cost-effectiveness and clinical efficacy, calcium and vitamin D should be the first-line therapy in patients at risk for osteoporotic fractures.”

Vitamin K

A deficiency in vitamin K leads to impaired bone mineralization due to inadequate osteocalcin levels (osteocalcin is the major, non-collagen protein in the bone). In a 1988 study, Bitensky and co-workers⁹⁶ found a strong association between the severity of osteoporotic fracture and reduction in the level of vitamin K in the blood. A 1997 study of Japanese post-menopausal women found that those women with reduced bone mineral density had significantly lower levels of vitamin K than those with normal bone density⁹⁷ Low levels of the vitamin have also been found in osteoporotic men.⁹⁸ Research suggests that intakes much higher than the current recommended levels improve bone formation and bone mineral density. ⁹⁹Other studies have shown a high correlation between the levels of vitamin K in the blood and the level of bone density.⁹⁷ In the blood, vitamin K is involved in the manufacture and conversion of prothrombin to the active enzyme, thrombin, which initiates clot formation. Because of its propensity to increase the clotting ability of blood and its potential for interference with pharmaceutical anticoagulants, such as warfarin, vitamin K in nutritional supplements sold in Canada is limited to a daily dose not exceeding 80 µg.

Boron

Boron is a trace mineral that has recently gained attention as a protective factor against osteoporosis because of its ability to activate estrogen and vitamin D. In one study, dietary supplementation with as little as 3 mg per day reduced urinary excretion of calcium by 44 percent and dramatically increased blood levels of estrogen¹⁰⁰ Boron deficiency appears to affect calcium and magnesium metabolism, leading to alterations in the structure and strength of bone01.¹⁰⁰ When combined with magnesium deficiency, boron deficiency appears to be particularly damaging to bone mineral density.¹⁰⁰ While the daily requirement for boron is small, the standard North American diet is severely deficient in boron-rich food sources. Supplementation at 3-5 mg/day will provide an adequate intake.¹⁰¹ Because of its novel status, current U.S. and Canadian dietary standards do not yet recognize boron as an essential micronutrient. While allowed in U.S. dietary products, at the time of this writing, Health Canada has not allowed boron to be included in nutritional supplements sold in Canada.

Magnesium

There is growing evidence that magnesium supplementation is just as important as calcium supplementation in the prevention and treatment of osteoporosis. Several studies confirm that women with osteoporosis exhibit a marked depletion in their bone magnesium content,^{102, 103} and reveal other clinical indicators of magnesium deficiency. Magnesium is essential for the normal function of the parathyroid glands. Deficiency of this mineral modifies the action of parathyroid hormone, consequently affecting calcium balance and bone formation. In a study of elderly women, Tucker¹⁰⁴ showed that those women with low dietary intakes of magnesium had significantly lower bone mineral density than those with higher intakes.

Magnesium deficiency impairs vitamin D metabolism, which, in turn, adversely affects bone health.¹⁰⁵Supplementation with magnesium improves bone mineral status. A two-year placebo-controlled trial, using a relatively low maintenance dose of magnesium, at 250 mg/day, revealed improved bone density of adult post-menopausal women. In contrast, the placebo group demonstrated a slight decrease in bone density.¹⁰³

B-Complex Vitamins

Low levels of vitamins B6, B12 and folic acid, common in the elderly, are risk markers for cardiovascular disease and appear to contribute to osteoporosis.¹⁰⁶ As discussed previously, these nutrients are essential to the modulation of blood homocysteine levels. High levels of homocysteine interfere with the cross-linking of collagen proteins, necessary to build a strong bone matrix, and thereby contribute to the onset of osteoporosis. Supplementation with folic acid appears to reduce blood homocysteine levels in post-menopausal women, regardless of their B-vitamin status before treatment.¹⁰⁶ Supplementation with all three vitamins provides even better results than with any single nutrient¹⁰⁷—further evidence of the synergy provided by the “teamwork” approach to supplementation.

Potential damage isn’t limited to senior citizens, though. Researchers have found that low cobalamin (vitamin B12) levels in adolescents may lead to low bone mineral density.¹⁰⁸ Proper nutrition, exercise, and supplementation is an important part of building and maintaining health throughout our lives.

Silicon

Studies show that silicon increases bone mineral density and appears to have a role in the prevention and treatment of osteoporosis. Silicon deposition is found in areas of active bone growth, suggesting that it may be involved in the growth of bone crystals and the process of bone mineralization.¹⁰⁹ The mineral is responsible for cross-linking of the collagen strands in the organic matrix and contributes greatly to the final strength and integrity of the bone matrix. ¹¹⁰Recalcification in bone remodelling may be dependent on adequate dietary levels of silicon, suggesting a preventive role for supplementation with this mineral.

Zinc

A component in over 200 enzymes, zinc is involved in more metabolic reactions than any other mineral. Zinc also modulates the action of several hormones and is necessary for the proper functioning of the immune system. Because the mineral is essential for the proper action of vitamin D, its status plays a central role in bone health. Increased zinc excretion, common in osteoporosis sufferers, is a likely consequence of accelerated depletion of bone mineral content. Diets low in zinc have been shown to slow adolescent bone growth, ¹¹⁰ suggesting that supplementation with zinc during the growth years may help optimize peak bone mineral density.

The Bottom Line

The scientific evidence supports the need for long-term supplementation with several key nutrients in the maintenance of bone health. This is particularly true for women in their peri- and post-menopause years. Accordingly, supplementation with vitamins D, K, C, B₆, B₁₂, folic acid, and the minerals boron, calcium, magnesium, silicon, and zinc, at levels deemed suitable for optimal nutritional health by our cited nutritional authorities, is included as an important component of our product-rating criteria.

The criterion for Bone Health poses the following question:

Does the product contain vitamin D, vitamin K, vitamin C, vitamin B₆, vitamin B₁₂, folic acid, boron, calcium, magnesium, silicon, and zinc at potencies up to 100% of the potencies for these nutrients in theBlended Standard?

8.   Heart Health

Epidemiological research has consistently revealed that individuals with a high dietary intake of antioxidant vitamins have a lower-than-average risk of cardiovascular disease.¹¹¹This evidence is particularly consistent for vitamin E.¹¹² As well, many clinical studies show magnesium supplementation to be of significant benefit in the treatment of cardiac arrhythmias (irregular heart beat) and in reversing the depletion of potassium that accompanies a magnesium deficit. Many cardiovascular events, such as angina pectoris (chest pain), congestive heart failure (failure to pump blood efficiently), and cardiomyopathy (weakening or damaging of the heart muscle), are related to low magnesium status.¹¹³ Coenzyme Q₁₀ (CoQ₁₀), an essential component in cellular energy production, is also prevalent in the heart muscle. Low tissue levels of CoQ₁₀ have been associated with several cardiovascular complications, including angina, congestive heart failure, cardiomyopathy, hypertension (high blood pressure), and mitral valve prolapse (failure of the valve to close properly). Research suggests that this triad of nutrients—coenzyme Q₁₀, vitamin E, and magnesium—plays a central role in the maintenance of cardiac health and the prevention of disease states.

Vitamin E

Vitamin E’s cardio-protective effect appears to stem from its ability to bind to LDL cholesterol, protecting it from free-radical-induced oxidative damage and the consequent build-up of atherogenic plaque. Low levels of vitamin E in the blood are predictive of a heart attack almost 70% of the time. ¹¹⁴ A large study, conducted by the Harvard School of Public Health, showed that men who consumed at least 67 mg (100 IU) of vitamin E per day for at least two years had a 37 percent lower risk of heart disease than those who did not take supplements. ¹¹⁵

Calcium

Population studies suggest a link between calcium intake and blood pressure.¹¹⁶ While results have not been consistent, several studies show that calcium supplementation can lower blood pressure in hypertensive individuals.¹¹⁷ A recent review on the effects of mineral intakes in reducing hypertension concludes that a decrease of sodium and concurrent increase of calcium, along with increased potassium and magnesium intakes, characteristic of the Dietary Approaches to Stop Hypertension (DASH) diet, has an excellent blood pressure lowering effect.¹¹⁸Regulation of intracellular calcium appears to play a key role in hypertension and obesity.¹¹⁹ Overall, sub-optimal calcium intakes contribute to the aetiology of hypertension. Dietary calcium appears to reduce blood pressure by normalizing intracellular calcium.

Magnesium

A cofactor for over 300 enzyme systems and one of several nutrients responsible for carbohydrate metabolism, magnesium is a mineral essential for many fundamental processes in the body. ¹²⁰ All enzymatic reactions involving the cell’s principal energy storage molecule, ATP (adenosine triphosphate), require magnesium. The metallic mineral is also required for protein synthesis, the manufacture of DNA and fatty acids, the breakdown of glucose, and the elimination of toxic wastes. ¹²¹ Magnesium is also essential for the formation of healthy bones, and it interacts with calcium in the regulation of blood vessels, the contraction of skeletal and cardiac muscle, and the conduction of nerve impulses. Many individuals with congestive heart failure (CHF) have a magnesium deficiency. The level of the mineral in the blood is associated with the ability of the heart muscle to beat properly. Survival rates of CHF patients correlate directly to magnesium status. ¹¹³Supplementation with magnesium has been shown to be of benefit in the treatment of cardiac arrhythmias and the prevention of potassium depletion; both minerals play an important role in the proper functioning of the heart ^122-125Deficiency in magnesium has been observed in cardiomyopathy and mitral valve prolapse. In fact, over 85% of patients with mitral valve prolapse exhibit a chronic magnesium deficiency, which is relieved through supplementation. ^{126, 127} Several other studies confirm improvement in heart function in patients with cardiomyopathies when supplemented with magnesium. ^{123-125, 128} Because the mineral acts in so many ways to enhance cardiac function and optimize cellular metabolism, magnesium is widely recognized as a critical nutrient for general cardiac support.

Coenzyme Q₁₀

Coenzyme Q10 is an energy coenzyme that plays a central role the respiratory pathway within the mitochondria (energy centres) of the cell. As such, the coenzyme is fundamental for energy production. Not surprisingly, the heart muscle, liver, kidneys and pancreas contain the highest levels of CoQ10. Synthesized by all cells of the body, particularly the liver, the coenzyme is also a powerful antioxidant. Its ability to quench free radical damage helps maintain the structural integrity of cellular and mitochondrial membranes, where it serves to reduce oxidation of low-density lipoprotein (LDL) cholesterol. ¹²⁹However, as aging proceeds the body’s ability to synthesize this get-up-and-go nutrient diminishes, which may partially explain our loss of vitality as we age.

CoQ10 supplementation confers therapeutic benefits in several disease states, including heart failure, ischemic heart disease (reduced blood supply), hypertension and certain muscular dystrophies (progressive weakening of the skeletal muscles). ¹³⁰Deficiency of CoQ10 results from impaired synthesis of the coenzyme, a consequence of more general nutritional deficiencies; it is common among individuals with heart disease and many other cardiovascular dysfunctions, including angina pectoris, hypertension, mitral valve prolapse and congestive heart failure. Such individuals respond well to increased tissue levels of CoQ10. In one study, CoQ10 proved effective in reversing mitral valve prolapse, with relapse rarely occurring in patients who had taken CoQ10 supplementation for over three months¹³¹

Several double-blind studies in patients with various cardiomyopathies also show the benefits of CoQ10 supplementation. Langsjoen and co-workers reported an 89 percent improvement rate in 80 cardiomyopathy patients treated with CoQ10 ¹³²The coenzyme also appears to moderate blood pressure through an unusual mechanism of action: by lowering cholesterol levels and stabilizing the vascular system through its antioxidant properties, thereby reducing vascular resistance. Several studies confirm a lowering of both systolic (pumping) and diastolic (resting) pressures in the range of 10 percent through CoQ10 supplementation^133-135

One of the most metabolically active tissues of the body, the heart muscle is particularly susceptible to the effects of CoQ10 deficiency. In one study, patients with stable angina treated with 150 mg/day of CoQ10 reduced their frequency of attacks by 53% and markedly increased their treadmill exercise performance. ¹³⁶Other clinical studies have shown that supplementation with 100 mg/day of CoQ10 in patients with congestive heart failure can provide results more positive than those obtained from conventional drug therapy.¹³⁷ In short, coenzyme Q10 is an antioxidant powerhouse with clinically-demonstrated efficacy in restoring and enhancing cardiac function and in protecting against oxidative damage to the energy centres in myocardial (heart muscle) and other tissues.

Other nutrients play important roles in optimizing cardiovascular health and reducing hypertension. These include gamma-tocopherol, l-carnitine and acetyl-l-carnitine, procyanidolic oligomers (PCOs), phenolic compounds, and lycopene.

Other Important Heart Protective Nutrients

• Gamma-tocopherol has been shown to be more effective than α-tocopherol in reducing several prothrombotic events associated with oxidative stress;^138,38reducing platelet aggregation and clot formation;¹³⁹enhancing the activity of the antioxidant enzyme, superoxide dismutase (SOD), and inhibiting the proinflammatory COX-2 enzyme, ^40,45 all of which can effect proper cardiovascular function.
• Carnitine is a vitamin-like compound responsible for the transport of fatty acids into the mitochondria for conversion to energy. Normal heart function depends on the presence of carnitine, a deficiency of which will starve the heart muscle for fuel.¹⁴⁰Procyanidolic Oligomer (PCO) extracts demonstrate a wide range of biological activities that are cardioprotective. They scavenge free radicals, increase cellular vitamin C levels, decrease capillary permeability and fragility and attenuate inflammation. Dietary intakes of PCOs demonstrate an inverse correlation with the risk of heart attack.¹⁴¹
• Phenolic compounds, including extracts of olive oil, curcumin, and green tea, demonstrate remarkable cardioprotective actions. Consumption of olive oil reduces the risk of breast and colon cancer^{142, 143} and lowers blood pressure. ¹⁴⁴ Their high bioavailability¹⁴⁵ and the ability to protect LDL cholesterol from oxidative damage^{146, 147} makes phenolic compounds from olives potent antioxidants, ¹⁴⁸ a likely reason for their strong cardio-protective characteristics. Curcumin, the yellow-orange pigment long used in Chinese and Ayurvedic (Indian) medicine is a potent antioxidant with anti-inflammatory, anticarcinogenic, and cardioprotective properties. Green tea lowers cholesterol levels and reduces the clotting tendency of the blood. The cetechins of green tea also possess anti-mutagenic properties, protecting the cellular DNA from oxidative damage.¹⁴⁹Consumption of green tea may also protect against pancreatic and colorectal cancers. ¹⁵⁰
• Lycpoene is associated with reduced risks of degenerative disease. In several recent studies, dietary intakes of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risks of chronic diseases such as cancer and cardiovascular diseases.¹⁵¹ Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial properties, evidence is accumulating to suggest other mechanisms such as modulation of hormonal and immune system and metabolic pathways may be involved. Low serum levels of lycopene have been associated with an increased risk of atherosclerotic vascular events in middle-aged men previously free of CHD and stroke.¹⁵² In a recent study conducted on healthy middle-aged Finnish men, it was found that a deficiency of lycopene may play a role in early stages of atherogenesis.¹⁵³ It is believed that the antioxidant property of lycopene may be one of the principal mechanisms for its effect; however, other mechanisms may also be responsible. The evidence is supportive of the need for controlled clinical and dietary intervention to provide definitive evidence for the role of lycopene in the prevention of CHD.^154-157

The Bottom Line

The scientific evidence supports the need to supplement with a variety of heart-protective nutrients as a means of reducing cardiovascular risks. Accordingly, supplementation with these nutrients, at levels deemed suitable for optimal nutritional health by our cited nutritional authorities, is included as an important component of our product-rating criteria.

The criterion for Heart Health poses the following question:

Does the product contain vitamin E (including alpha-tocopherol and gamma-tocopherol, or mixed tocopherols), beta-carotene, coenzyme Q10, calcium, magnesium, l-carnitine or acetyl-l-carnitine, procyanidolic oligomers (PCOs), phenolic compounds, and lycopene at potencies up to 100% of the potencies for those nutrients and nutrient categories in the Blended Standard?

9.   Liver Health (detoxification)

From birth to death, our bodies must prevail against an unrelenting assault from these harmful exogenous agents—the thousands of toxic substances that we breathe, consume in our foods and absorb through our skin everyday. Fortunately, nature, in her wisdom, has evolved mechanisms through which the cells of our bodies can rid themselves of this toxic debris. Unfortunately, modern humankind, in its ignorance, has created such a flood of xenobiotics (materials foreign to the cell) that these natural protective systems are often overwhelmed.

The liver is the organ most involved with the detoxification of xenobiotics, and it is the main repository for glutathione. In the specialized hepatocyte cells of the liver glutathione is conjugated (joined) to many of the toxic chemicals, including heavy metals, solvents and fat-soluble pesticides. Conjugation of a toxin with glutathione renders the toxin water-soluble and prepares it for excretion from the body via the kidneys and the bile. The power of glutathione in the conjugation and elimination of toxins is prodigious, accounting for up to 60% of all liver metabolites in the bile. While our cells use six different detoxification pathways, conjugation with glutathione appears to be the primary route employed. According to Parris Kidd, PhD, “The glutathione status of a cell … will perhaps turn out to be the most accurate single indicator of the health of the cell. That is, as glutathione levels go, so will go the fortunes of the cell.”

Glutathione (GSH) is a simple tripeptide, a small protein that consists of three amino acids: glutamic acid, cysteine, and glycine. Because of the chemical nature of sulphur-containing cysteine, glutathione effortlessly donates electrons, accounting for its powerful antioxidant properties.[§] Intracellular glutathione status is a sensitive indicator of cellular health and of the cell’s ability to resist toxic challenges. An important water-phase antioxidant, glutathione is an essential component in the glutathione peroxidase system, one of three vital free-radical scavenging mechanisms in the cell. Glutathione peroxidase enzymes serve to detoxify peroxides, including hydrogen peroxide (H₂O₂), generated within cellular membranes and lipid-dense areas of the cell, particularly the mitochondrial membrane. Severe glutathione depletion quickly leads to cell death; experimental glutathione depletion has been found to induce cellular apoptosis (suicide).^{158, 159}

Glutathione depletion at the cellular level invokes extensive damage to the mitochondria, the energy centres of the cell. Depletion of mitochondrial glutathione, in fact, may be the ultimate factor determining a cell’s vulnerability to oxidative attack.¹⁶⁰ Nowhere is glutathione’s presence more vital than in these cellular “furnaces,” where a cascade of oxidation-reduction reactions complete the final steps in respiration—a process known as oxidative phosphorylation. Throughout this process, electrons invariably escape and react with ambient oxygen to generate toxic free radicals.¹⁶¹It is estimated that 2% to 5% of the electrons that enter the mitochondrial “furnaces” are converted to reactive oxygen species (oxygen-based free radicals),¹⁶¹ generating considerable oxidative stress for the cell.^{162, 163} These free radicals, like sparks from a fire, pose an immediate threat to other cellular components, such as the DNA, enzymes, structural proteins, and lipids.

The cumulative damage wrought by oxygen and other free radical species is now recognized as a principal contributor to the degenerative disease process and the progressive loss of organ function, commonly recognized as aging.¹⁶³ Consequently, the cell is constantly challenged to destroy these free-radical “sparks” before they can inflict lasting damage. Minimizing such oxidative assaults may prove to be the ultimate challenge of being alive. For this reason, the formidable reducing power of glutathione is of profound importance to the cell.

Glutathione helps regenerate other antioxidants that become depleted from their task of fending off free radical challenges. Glutathione-induced regeneration, in fact, may be the mechanism used by the cell to conserve the lipid-phase antioxidants, vitamin A, vitamin E, and the carotenoids.¹⁶⁴ Recent investigations confirm that dietary vitamin C can protect against tissue damage resulting from glutathione depletion; likewise, supplementation with glutathione or its precursors can quickly replenish vitamin C deficiencies.^{165, 166} Thus, glutathione and ascorbic acid—two of the pre-eminent cellular antioxidants—are tightly linked: glutathione can conserve vitamin C and vitamin C can conserve glutathione. Together, these two antioxidant powerhouses protect the entire spectrum of biomolecules within the cell and facilitate the cell’s optimal performance.¹⁶⁰

Glutathione Depletion — Exogenous Stresses

Because of its twin roles as a lipid-phase antioxidant and as a primary agent for detoxification, the demands on the cellular glutathione pool can be overwhelming, frequently leading to depletion. Many pharmaceutical products are known to diminish glutathione from the liver, kidneys, heart and other tissues. ¹⁵⁰ For example, overuse of acetaminophen, a common over-the-counter painkiller, can dangerously deplete liver glutathione, rendering the organ vulnerable to acute damage from other exogenous toxins, such as alcohol. ¹⁶⁰

Many other exogenous factors have been shown to deplete glutathione stores, including a dietary deficiency of methionine (a glutathione precursor),¹⁶⁷ionizing radiation,¹⁶⁸ acute tissue injury^{169, 170} iron overload from haemochromatosis¹⁶³ and excessive alcohol intake.¹⁷¹Even strenuous aerobic exercise can rapidly deplete glutathione and other antioxidant stores from muscle tissue. For habitual exercisers and elite athletes, supplementation with glutathione precursors appears to be a prudent preventive measure.¹⁷²

Probably more than for any single nutrient, lifestyle choices and their effects on glutathione status can prove fateful. A combination of negative lifestyle factors, including smoking, alcohol and drug abuse, prolonged emotional and physical stress, and unhealthy dietary choices, can summon a sustained oxidative assault to the body, depleting glutathione reserves to the point of distress. Beyond this, the body’s defences are quickly overwhelmed and free radical damage compounds, with grim consequences for the cell. Here is how it appears to unfold: as tissue levels of glutathione and other antioxidants diminish, cells (usually those enduring the highest level of oxidative attack) begin to die. Zones of damaged tissue appear and begin to spread as free radical damage spreads outward, eventually encompassing other tissues and organs. This propagating wave of destruction is the manifestation of degenerative disease.

Glutathione Deficiency and Disease

According to several studies, glutathione depletion is a major contributory factor in diseases of the liver.^{167, 173}Shigesawa and co-workers¹⁷⁴ documented marked decreases in plasma and liver glutathione levels in individuals with viral hepatitis, alcoholic and non-alcoholic liver disease. Studies of a number of pulmonary diseases, including obstructive pulmonary disease and pulmonary fibrosis, also note glutathione deficiencies. ¹⁶⁷ Other studies document a reduced capacity to detoxify free radicals in individuals with multiple sclerosis; the key factor appears to be a reduced level of the glutathione peroxidase enzyme system. ^175-177 Many of these studies note that supplementation with selenium significantly enhances glutathione peroxidase activity. One study, conducted on AIDS patients, found that supplementation with selenium provided a dramatic elevation of glutathione peroxidase activity in HIV-positive subjects. ¹⁷⁸ The likely mechanism is via selenium-induced activation of the glutathione peroxidase enzyme. Correlations also exist between depleted levels of glutathione, low glutathione peroxidase activity and the onset of atherosclerosis.

Glutathione depletion also dramatically inhibits immune functions^{179, 180} and increases vulnerability to infection. As well, chronic viral infections deplete glutathione stores. Patients diagnosed with hepatitis C and early HIV infection have been found to be deficient in blood glutathione.^{165, 181} Depletion of glutathione stores is also implicated in the development of several neurological disorders. Because the brain is highly oxygenated and rich in polyunsaturated lipids, it is a fertile area for nutrient deficiency-induced free radical assault. Correlations between the level of lipid peroxidation in Parkinson’s disease¹⁸²and glutathione status point toward glutathione depletion as a causative factor.¹⁸³ Alzheimer’s patients show similar patterns of abnormally low glutathione.

While dietary glutathione is efficiently absorbed in the gut, the same may not be the case for nutritional supplementation. Oral dosing appears to raise glutathione levels, albeit with great variability between subjects. In one study, oral supplementation raised glutathione levels from two to five-fold.¹⁸⁴ In another study, absorption of a single dose of 3,000 mg was negligible.¹⁸⁵ Such variations raise concern about the efficacy of supplementing with glutathione itself. As a tripeptide (protein fragment), glutathione would tend to be hydrolyzed (broken down) during the digestive process. This leads some researchers to conclude that oral supplementation with glutathione does not appear to be cost effective in light of other methods available.¹⁶⁰

Nutrients that Enhance Cellular Glutathione Levels

The following nutrients have been found effective at enhancing cellular glutathione levels. Inclusion of these nutrients in a regimen of daily supplementation is believed to be a more effective means of boosting tissue glutathione than does dosing with oral glutathione:

Vitamin C

Daily supplementation with vitamin C appears sufficient to enhance and maintain good tissue glutathione levels, provided the necessary metabolic precursors for glutathione synthesis are also available. One double-blind study found that red blood cell glutathione levels increased nearly 50 percent when subjects were given 500 mg per day of ascorbic acid (vitamin C).¹⁸⁶ In patients with hereditary glutathione insufficiency, Jain and co-workers found vitamin C to be more effective and less costly in raising glutathione levels than N-acetyl cysteine, another well-known and effective glutathione booster.¹⁸⁷ Vitamin C appears to boost glutathione levels by helping the body manufacture it.

Cysteine

Cysteine, the metabolic precursor that most severely limits the synthesis of glutathione, is another nutrient that has proven very effective in boosting glutathione levels.¹⁸⁸ Unfortunately, at high doses cysteine has been found to auto-oxidize, raising questions about its safety as an oral supplement.¹⁶⁰ N-acetyl cysteine (NAC), however, is another story.

N-Acetyl Cysteine

N-Acetyl Cysteine (NAC) is a cysteine precursor that appears to avoid the problems of auto-oxidation attributed to cysteine. In the cell, NAC converts easily to cysteine, which, in turn, converts to glutathione. NAC is well absorbed in the intestinal tract and has been found to significantly boost glutathione levels in deficient subjects. As well, NAC demonstrates strong antioxidant, anti-mutagenic and anti-carcinogenic properties. Doses of up to 600 mg per day have proven to be an effective and safe means of optimizing tissue glutathione levels. ¹⁸⁹ Interestingly, while both NAC and vitamin C are effective in boosting tissue glutathione insufficiency, one study demonstrated that vitamin C was both more effective and less expensive than NAC. ¹⁸⁷The use of NAC products has become increasingly popular as a means of optimizing tissue glutathione; however, caution against too much of a good thing is advised. ¹⁹⁰ There is evidence that, at high doses (exceeding 1-2 g/day), NAC can also act as a pro-oxidant and begin contributing to the level of oxidative stress. ¹⁹¹ To avoid this, people supplementing with NAC should ensure that the daily dose of vitamin C is two to three times the dose of NAC.

SAM-e

When given orally, S-adenosyl methionine (SAM-e) is also effective in raising red blood cell and liver glutathione.^167,192

Other Nutritional Factors

Other nutrients play a vital role in glutathione metabolism through their participation in the glutathione peroxidase pathway. Selenium, essential for the activation of glutathione peroxidase, acts as a cofactor for the enzyme; its supplementation markedly boosts enzyme activity. Selenium dosing significantly enhances the activity of glutathione peroxidase in HIV-positive individuals who exhibit abnormally low enzyme activity.¹⁷⁸ As well, a study of patients with multiple sclerosis found that supplementation with high doses of selenium, vitamin C and vitamin E raised glutathione peroxidase activity five-fold, conferring a marked enhancement of cellular antioxidant status.¹⁹³

Riboflavin (vitamin B₂) and niacin (vitamin B₃) are also required for the optimal functioning of the glutathione peroxidase system. Both nutrients are important for their role in the energy transfer reactions that are a part of this vital antioxidant enzyme system.

The Bottom Line

As the body’s pre-eminent detoxicant, glutathione is essential for cellular health. While dietary glutathione is efficiently absorbed in the gut, the same may not be the case for nutritional supplementation. Oral dosing appears to raise glutathione levels, albeit with great variability between subjects. In one study, oral supplementation raised glutathione levels two- to five-fold.¹⁸⁴ In another study, absorption of a single dose of 3,000 mg was negligible.¹⁸⁵ Accordingly, supplementation with glutathione precursors and with those nutrients involved in the glutathione peroxidase pathway, including vitamin C, cysteine and n-acetyl-cysteine, selenium, vitamin B₂ (riboflavin), and vitamin B₃ (including niacin and niacinamide), at levels deemed suitable for optimal nutritional health by our cited nutritional authorities, is included as a component of our product rating criteria. For further information on the scientific evidence supporting the use of these nutrients, please log on to www.NutriSearch.ca.

The criterion for Liver Health poses the following question:

Does the product contain vitamin C, n-acetyl-cysteine (including cysteine), selenium, vitamin B₂, and vitamin B₃ (including niacin and niacinamide), at potencies up to 100% of the potencies for these nutrients in the Blended Standard?

10.  Metabolic Health (glucose control)

Diabetes, now the seventh leading cause of death in the United States and Canada, is a chronic disorder of carbohydrate, fat, and protein metabolism. The disease first appears as a constellation of metabolic changes associated with hyperinsulinemenia (elevated insulin levels) and hyperglycemia (elevated blood-sugar levels). This condition, a precursor to full-blown diabetes, is called Insulin Resistance Syndrome. Untreated, insulin resistance will develop into full-blown diabetes; with it comes greatly magnified risks of heart disease, stroke, eye and kidney disease, and loss of nerve function. Frank diabetes is the principal cause of adult blindness and limb amputation.

Non-insulin-dependent (type 2) diabetes mellitus is a disease strongly associated with a sedentary lifestyle and the modern western diet. Inadequate physical activity, combined with a diet high in refined sugars, saturated fats, and proteins, and low in dietary fibre, has resulted in an epidemic of obesity throughout Canada and the United States. With it has risen the prevalence of type 2 diabetes. Obesity is, in fact, a hallmark of the disease: almost 90% of those diagnosed with type 2 diabetes are obese at the time of diagnosis.^{194, 195} While there is disagreement as to whether obesity causes type 2 diabetes or whether diabetes begets obesity, one thing is clear: the disease involves a profound disturbance in the metabolic balance of the body, with dramatic consequences for the individual.

To reduce the risk of frank type 2 diabetes, one must prevent the onset of insulin resistance. However, millions of North Americans suffer unknowingly from this syndrome, placing them at an increased risk for cardiovascular and neurological dysfunctions. The development of insulin resistance is multi-factorial; however, research shows that complications associated with this pre-diabetic disorder may be mitigated effectively through conscientious dietary and lifestyle changes. Several nutrients are involved in the day-to-day regulation of glucose metabolism:

Chromium

Chromium is an essential mineral known to increase the efficiency of insulin, one of the hormones responsible for the control of blood sugar. Chromium enhances cellular sensitivity to the hormone by binding with several amino acids to form a complex known as Glucose Tolerance Factor (GTF).^196-198 GTF allows insulin to bind with its receptor sites, resident on the surface of the cell membrane.

Studies show that supplementation with chromium improves insulin action, decreases fasting blood sugar levels and decreases total cholesterol and triglyceride levels.¹⁹⁹ Reversing chromium deficiency through nutritional supplementation has been found to lower body weight while, at the same time, increase lean muscle mass. Sub-clinical chromium deficiency is widespread in North America, and it is a likely contributor to the increasing prevalence of Insulin Resistance Syndrome and type-2 diabetes. According to Murray,²⁰⁰ at least 200 micrograms of elemental chromium per day appears necessary for optimal blood sugar regulation.

According to Dr. Michael Murray, vitamin B6 supplementation is especially important to diabetics, whose condition can mask a deficiency in this important nutrient.²⁰¹  Many other studies also support supplementation with vitamin B6 for diabetics.^202-204 Murray recommends a daily intake of 150 mg to ensure adequate levels are maintained.
Vitamin B6 may also prove to be important in preventing other diabetic complications because it inhibits glycosylation of proteins.²⁰² Vitamin B6 supplementation should be tried as a safe treatment for gestational diabetes (diabetes caused by pregnancy).  In one study of 14 women with gestational diabetes, taking 100 milligrams of vitamin B6 for 2 weeks resulted in eliminating the diagnosis in 12 of  the 14 women.”²⁰⁵

Vitamin C

High dose vitamin C (2,000 mg per day) has been shown to reduce the accumulation of sorbitol, a metabolic by-product of glucose metabolism, known to cause chronic complications in the diabetic patient.²⁰⁶ Studies also show that vitamin C supplementation inhibits the glycosylation of proteins (the complexing of protein with sugar), a process that is elevated several-fold in diabetes. Because insulin facilitates the transport of ascorbic acid into cells, many diabetics do not have sufficient vitamin C within their cells despite adequate dietary intake. This chronic deficiency of vitamin C in the diabetic is problematic and leads to vascular disorders, elevated blood cholesterol and depression of the immune system.²⁰⁶ Accordingly, high dose supplementation with vitamin C is an issue of primary concern for the diabetic or pre-diabetic sufferer. Recent studies reveal that vitamin C supplementation, alone, provides a more effective means of correcting sorbitol accumulation than current pharmaceutical approaches.^{200, 207}

Alpha and gamma Tocopherols

The two principal forms of Vitamin E are also important in the prevention of diabetes. Studies show that low vitamin E status results in a marked increase in the risk of developing the disease.²⁰⁸ Supplementation improves insulin sensitivity and helps reduce long-term complications. One study of elderly patients concluded that high dose supplementation with alpha-tocopherol improves insulin sensitivity and glucose tolerance in healthy patients, with an even more dramatic improvement evident in diabetic patients.²⁰⁹ Gamma-tocopherol may also play a role in protecting against the onset of type 1 diabetes. In one study the gamma-form was found to be more effective than its alpha-analog in protecting pancreatic cells from the damaging effects of interleukin 1β, an inflammation-signaling protein secreted by macrophages (specialized white blood cells responsible for the destruction of pathogens) activated by exposure to RNOs.^{210, 211}

Vitamin B₃

Like chromium, vitamin B₃ (niacin) is an important component of the GTF and is central in enhancing the body’s sensitivity to insulin. A cofactor in many energy transfer reactions, niacin assists in energy production, fat and carbohydrate metabolism, and several other metabolic processes. There is evidence that supplementation with the niacinamide form of B₃ prevents the onset of diabetes in experimental animals.²¹² Similar findings are reported in human clinical trials, where some newly diagnosed type-1 diabetics experienced a complete reversal of their condition through dietary supplementation with niacinamide.²¹³ Mitigation of damage to the insulin-producing beta-cells within the pancreas appears to be its “modus operandi.”²¹⁴ Europeans have long used inositol hexaniacinate, a safe and effective form of niacin that has been found to lower elevated blood lipids associated with both forms of diabetes. This form of B₃ appears to improve blood flow and blood sugar levels better than standard niacin.²¹⁵

Biotin

An essential cofactor for several enzymes, biotin is vital for normal carbohydrate metabolism and the biosynthesis of fatty acids and proteins. Supplementation may help improve blood sugar control in the diabetic and pre-diabetic individual by enhancing insulin sensitivity and increasing the activity of enzymes involved in the breakdown of glucose.²¹⁶ As little as 16 mg per day of biotin results in a marked lowering of blood sugar levels in type I diabetics; similar results are reported at doses as low as 9 mg per day in type-2 diabetics

Magnesium 

Several minerals are involved in the prevention and treatment of insulin resistance and full-blown type-2 diabetes; one of the most important is magnesium. Magnesium deficiency is common in insulin resistance and diabetes. The mineral is intimately involved in several areas of glucose metabolism. Accordingly, the pre-diabetic and diabetic patient may require double the current recommended daily intake for this mineral.²¹⁵

Manganese 

Like magnesium, manganese is involved in many of the enzymatic reactions controlling glucose metabolism. Important in the enzyme, superoxide dismutase (SOD), manganese enhances SOD activity and, in turn, increases the level of antioxidant protection. Deficiency in manganese, common in Insulin Resistance Syndrome and type-2 diabetes, leads to bone and joint abnormalities, impaired pancreatic function, reduced reproductive capacity, and abnormal carbohydrate and lipid metabolism. Studies reveal that diabetics have only half the manganese levels of normal individuals.²¹⁷

Zinc

Zinc is critical for proper insulin action. The mineral protects the beta-cells of the pancreas, where the hormone is manufactured. Diabetics excrete excessive amounts of zinc, and the mineral must be replaced through diet or supplementation.²¹⁷ Supplementation with zinc improves insulin levels and accelerates wound healing.

Coenzyme Q10

Research has proven that diabetics can also benefit from CoQ10 or Ubiquinone. The National Cancer Institute states that Coenzyme Q10 is present in most tissues, but the highest concentrations are found in the heart, the liver, the kidneys, and the pancreas.²¹⁸

In 2002, a 12 week study of 40 patients with type II diabetes demonstrated improved endothelial dysfunction of the brachial artery: The authors concluded that:  Coenzyme Q(10) supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes.²¹⁹ A second study in 2002 indicated that type II diabetics given 100 mg of CoenzymeQ10 twice daily had improved glycemic control.²²⁰

Dr. James Balch and Phyllis Balch recommend 80 mg daily as part of a multi nutritional approach to improving type II diabetes.²²¹

According to the Mayo Clinic, “preliminary evidence suggests that CoQ10 does not affect blood sugar levels in patients with type-1 or type-2 diabetes and does not alter the need for diabetes medications.”²²²

The Bottom Line

Vitamins B₃, B₆, B₁₂, C, E, biotin, coenzyme Q10, and the trace elements chromium, magnesium, manganese, and zinc are all essential for proper metabolic support and the regulation of glucose metabolism. Accordingly, supplementation with these nutrients, at levels deemed suitable for optimal nutritional health by our cited nutritional authorities, is included as an important component of our product-rating criteria. For further information on the scientific evidence supporting the use of these nutrients, please log on to www.NutriSearch.ca.

The criterion for Metabolic Health poses the following question:

Does the product contain vitamin B₃ (including niacin and niacinamide), vitamin B₆, vitamin B₁₂, vitamin C, vitamin E (including alpha-tocopherol and gamma-tocopherol, or mixed tocopherols), biotin, coenzyme Q_10, chromium, magnesium, manganese, and zinc at potencies up to 100% of the potencies for these nutrients in the Blended Standard?

11.  Ocular Health

Our eyes are our window to the world.  Just as vision can be affected by the same free radicals that affect other organ function, vision must also be provided protection.

Inasmuch as we provide optimal nutrition for our general well-being, our eyes can benefit from nutritional support.  It is thought that vision problems such as macular degeneration, glaucoma and cataracts can be both prevented and improved by certain nutrients. Prevention is key, support with such nutrients as B vitamins, vitamins A, C, E, beta-carotene, lutein, and zeaxanthin can maintain ocular health for our lifetime.

Vitamin A is best known for its effects on the visual system. There are four types of photopigments produced from vitamin A, which are present in the retina of the eye. Rhodopsin is found in the retinal cells responsible for night vision, and three iodopsins (sensitive to red, yellow, and blue wavelengths) regulate colour vision during daylight. These four forms of vitamin A are isomers of retinal, an active (aldehyde) form of the vitamin.²²³ Poor adaptation to changes in light intensity and poor night vision are indicative of a low vitamin A status. In developed countries, vitamin A deficiency usually results from malabsorption; supplementation induces a rapid restoration of vision.^{224, 225} Beta-carotene, once converted into the active form of vitamin A by oxidative cleavage via the enzyme beta-carotene monooxygenase, also contributes to the chemistry of vision.²²⁶

People who eat foods rich in lutein and zeaxanthin (including broccoli, collard, kale, spinach, and turnip greens) are much less likely to suffer from age-related cataracts[**] than those who do not. These carotenoid pigments are also effective in reducing the incidence of macular degeneration,[††] likely a consequence of their ability to quench oxidative damage within the eye. Recent studies show that these auxiliary photosynthetic pigments may also slow down age-related increases in lens density.²²⁷

Low circulating levels of vitamins C, E, and beta-carotene are implicated in the development of cataracts in the eye;²²⁸conversely, high serum levels have been shown to reduce the prevalence of cataract formation.^{229, 230} Beta-carotene also acts as a natural biological solar filter, protecting against light-induced UV damage to the eye.²³¹ There is substantial evidence that, when used in combination, the actions of these antioxidant partners are synergistic in nature, providing a level of protection that strikingly exceeds the sum of their individual contributions.²³²

The Bottom Line

Accordingly, supplementation with vitamin C, E, and A, and the carotenoids, beta-carotene, lutein, and zeaxanthin, at levels deemed suitable for optimal nutritional health by our cited nutritional authorities, is included as an important component of our product-rating criteria.

The criterion for Ocular Health poses the following question:

Does the product contain the antioxidants, vitamin C, vitamin E (including alpha and gamma tocopherol, or mixed tocopherols), vitamin A (including beta-carotene) and the carotenoids, lutein and zeaxanthin, at potencies up to 100% of the potencies for these nutrients in the Blended Standard?

12.   Methylation Support

Over 40 major clinical studies confirm that homocysteine levels are a predictive marker for heart disease, stroke, and peripheral artery disease. A powerful oxidizing agent, homocysteine is now believed to be responsible for the initial damage to the inner walls of the arteries and the subsequent initiation of atherosclerotic plaque formation. Twenty to 40% of patients with heart disease have elevated levels of homocysteine.^{233, 234} Deficiencies in vitamin B₆, vitamin B₁₂, and folic acid can increase circulating levels of homocysteine; conversely, together, these nutrients reduce circulating homocysteine levels by helping to convert it to methionine, a harmless amino acid used by the cell for other functions. For more information on homocysteine metabolism and the particular biochemical functions of these nutrients, please refer to the discussion in Chapter 6 or log on to www.NutriSearch.ca.

Most individuals with high levels of homocysteine respond well to supplementation with vitamins B₆, B_12, and folic acid; however, a significant proportion of the population is resistant to this nutritional intervention. Persons with homocysteine resistance often suffer from a common genetic defect (polymorphism) that impairs the enzyme, methylene tetrahydrofolate reductase (MTHFR). A defect in the MTHFR enzyme creates a metabolic bottleneck that limits the conversion of homocysteine to methionine and results in elevated levels of homocysteine in the blood (see Figure 6-2, Chapter 6; and Figure 9-1, Chapter 9). Supplementing with vitamins B₆, B₁₂, and folic acid cannot effectively alleviate this bottleneck; however, studies show that the defective enzyme is sensitive to riboflavin deficiency.²³⁵ Consequently, it has been suggested by the Ames group of Berkeley that mega-dose therapy with riboflavin, the precursor vitamin to the flavin adenine dinucleotide (FAD) coenzyme required by the defective enzyme, would prove beneficial (see Figure 6-2, Chapter 6).²³⁶

When provided as a dietary supplement, trimethylglycine (TMG), commonly known as betaine, can also address homocysteine resistance, which is experienced in about 15% to 20% of the population. Supplementation with TMG creates a bypass to the MTHFR bottleneck, providing an alternate route for the methylation of homocysteine. By donating one of its three methyl (CH₃-) groups to homocysteine in a process mediated by the enzyme, betaine-homocysteine methyltransferase, TMG effectively regenerates methionine and lowers homocysteine levels (see Figure 9-1).²³⁷ The subsequent decrease in blood homocysteine can be maintained as long as the supplement is taken.²³⁸

Vitamin B₂

Vitamin B₂ (riboflavin) is an important component of the cyclic conversion of tetrahydrofolate. It acts as a cofactor for the enzyme methylene tetrahydrofolate, which drives the methylation of homocysteine to harmless methionine. Riboflavin is converted in the body to flavin adenine dinucleotide (FAD), which acts as a hydrogen donor in the reaction process.

Figure 6-2 on page 30 (reproduced below) of the NutriSearch Comparative Guide to Nutritional Supplements, 4^thedition, shows methylation reactions in detail.

Most individuals with high levels of homocysteine respond well to supplementation with vitamins B₆, B_12, and folic acid; however, a significant proportion of the population is resistant to this nutritional intervention. This is because they possess a defective enzyme that creates a biochemical “bottleneck” in the conversion of methylene tetrahydrofolate to methyl tetrahydrofolate (see Figure 6-1). Supplementing with, vitamins B₆, B_12, and folic acid cannot effectively alleviate this bottleneck. However, studies show that the defective enzyme is sensitive to riboflavin deficiency.²³⁹Consequently, it has been suggested by the Ames group of Berkeley that mega-dose therapy with riboflavin, the precursor vitamin to the FAD coenzyme required by the defective enzyme, would prove beneficial.²⁴⁰

Vitamin B₆

Vitamin B₆ (pyridoxine) is one of the essential, water-soluble B-complex vitamins. It functions as a coenzyme, working with over one hundred other enzyme systems in the cell. With a central role in amino acid metabolism, B₆ is vital in regulating blood homocysteine levels. ²⁴¹ In one study, a six-week supplementation program with vitamin B₆ and folic acid showed that treatment with both vitamins normalized blood homocysteine levels in 92 percent of participants, significantly reducing the risk of adverse cardiovascular events. ²⁴² A more recent study, reported in 1998 in the American Heart Association journal, Circulation, provides further evidence of the importance of vitamin B₆ in preventing heart disease. Researchers measured blood levels of homocysteine, folic acid, vitamin B₁₂ and vitamin B₆ and showed conclusively that those with high levels of homocysteine or with low levels of folate and B₆ had an appreciably greater risk of heart disease. ²⁴³ A large-scale study of 80,082 women taking part in the Nurses’ Health Study supports these findings. The results of this investigation showed that those with the highest intake of vitamin B₆ had 30 percent less risk of heart attack than those in the low intake group. Combining vitamin B₆ and folate dropped the level of risk by over 50 percent. ²⁴⁴

Folic Acid

One of the water-soluble B vitamins, folic acid (folate) plays a central role in regulating cellular metabolism and cell division. Folic acid deficiencies are related to a number of disease states, most of which can be avoided or reversed through proper diet or supplementation. Epidemiological studies show a strong association between folic acid status, cancer risk ²⁴⁵and neural tube defects in infants. ²⁴⁶ There is also convincing evidence that folic acid plays a major role in determining the level of risk for cardiovascular disease and stroke.^{247, 248} However, Ubbink and co-workers¹⁰⁷found that supplementation with folic acid will lower homocysteine levels only if adequate blood levels of vitamins B₆and B₁₂ are also present. This apparent synergy between the vitamins B₆, B₁₂ and folic acid, in reducing cardiovascular risk, has been reported in several recent studies.^{234, 242, 249}

Vitamin B₁₂

Vitamin B₁₂ (cobalamin) is another of the water soluble B-vitamins and one of the few essential substances in the human body that contains the trace element cobalt. As a coenzyme, vitamin B₁₂ activates an enzyme responsible for the cyclic metabolism of folic acid. Consequently, a dietary deficiency of B₁₂ will result in an interruption of folic acid production. For this reason, a deficiency of vitamin B₁₂ can mimic a folic acid deficiency. Dietary supplementation with both vitamin B₁₂ and folic acid results in markedly lower levels of homocysteine. One study found that supplementing with both B₁₂ and folate lowered homocysteine levels even in individuals with normal blood levels of these nutrients. ²³³Human nutritional requirements for vitamin B₁₂ are small; however, it is estimated that a significant percentage of individuals — particularly vegetarians — may be deficient. Vitamin B₁₂ deficiency is also common in the elderly and can result in impaired nerve function, depressed mental acuity and the development of symptoms mimicking Alzheimer’s disease. In fact, it is estimated that up to 42 percent of the elderly may be deficient in this important nutrient, which may also explain the prevalence of age-related depression in seniors. ²⁵⁰ The likelihood of widespread sub-clinical deficiencies of vitamin B₁₂, particularly in the elderly, provides a strong argument for daily supplementation.

The Bottom Line

A high level of homocysteine in the blood is a primary risk factor for cardiovascular disease and warrants supplementation with vitamins B₂, B₆, B₁₂, and folic acid as a prudent preventive measure. This is particularly so for the elderly, with respect to noted age-related declines of vitamin B₁₂. Accordingly, supplementation with these nutrients at levels deemed suitable for optimal nutritional health by our cited nutritional authorities is included as an important component in our product rating criteria.

The criterion for Methylation Support poses the following question:

Does the product contain vitamin B₂, vitamin B₆, vitamin B₁₂, folic acid, and trimethylglycine at potencies up to 100% of the potencies for these nutrients in the Blended Standard?

13.  Lipotropic Factors

In our toxic world, we are exposed to ever-increasing levels of contaminants and harmful chemicals that, once ingested, accumulate in fatty deposits within the body. The liver and the brain are two primary targets for the bioaccumulation of lipid-soluble toxins, such as pesticides and metals. Vitamins C, E, and beta-carotene, the water-soluble B-complex vitamins, and some of the trace minerals consumed in the diet play important roles in protecting these tissues from the damage caused by oxidative assault from such toxins.^{251, 252} However, it is the liver—the body’s toxic filtration and purification unit—that does most of the heavy lifting. First in line to deal with the contaminants consumed in our foods and drinking water, the liver is subject to a daily onslaught of noxious challenges. In addition to the external toxic load (a function of lifestyle and environment), the liver must also deal with a range of endogenous (internal) toxins produced by the metabolic processes of our body. Normally, the liver can cope quite handily; however, when things go wrong—a result of chronic nutritional deficiencies, disease, or overuse of over-the-counter drugs such as acetaminophen—the workload for the liver can increase dramatically.

Fortunately, proper diet, nutritional supplementation, and treatment with herbal remedies can fortify the liver to withstand this toxic stress. Within the liver, choline and inositol assist with the elimination of toxins, helping to mobilize the fatty tissue and remove metals and other noxious compounds. Such agents are known as lipotropic (fat-moving) factors because of their ability to mobilize fats and bile (a secretion from the liver that helps emulsify fats during the digestive process). Lipotropic factors have a long history of use within the naturopathic community, helping to restore and enhance liver function and treat a number of common liver ailments. Dietary lipotropic factors work by increasing the levels of S-adenosylmethionine (SAM-e), the liver’s in-house lipotropic agent, and glutathione, the premier detoxicant in the body. They have been used preferentially because, until recently, dietary SAM-e has not been widely available and because oral glutathione is not well absorbed in the digestive tract.

Choline

Choline acts as a methyl donor, transferring methyl (-CH₃) groups to other molecules essential in the process of lipid mobilization. While it can be manufactured by the conversion of other amino acids, choline has recently been designated an essential nutrient. ^{253, 254}Without choline, fats become trapped in the liver, where they accumulate, along with the fat-soluble toxins they carry, and disrupt proper liver function. Choline also plays an important role in the transmission of signals inside cells and is an essential component of cell membranes. Studies confirm that choline supplementation, primarily as phosphatidylcholine (P-choline), has proven effective in improving mental acuity and as a treatment for asthma²⁵⁵ and bipolar disorder.  Choline also increases levels of acetylcholine, an important neurotransmitter in the brain. Studies indicate that supplementation with choline counteracts anatomical changes in the brain associated with aging. ²⁵⁶ Unfortunately, trials with the treatment of Alzheimer’s disease have yielded inconsistent results. ²⁵⁷

During the digestive process, lecithin is converted to choline and fatty acids. Once in the body, however, choline is easily re-converted to phosphatidylcholine (P-choline). P-choline entertains several important physiological functions, including increasing the solubility of cholesterols, lowering blood cholesterol levels, removing cholesterol from tissue deposits, and reducing the tendency of blood platelets to aggregate and clot ²⁵⁸

Inositol 

Inositol is an unofficial member of the B-complex family and works closely with choline in the task of lipid mobilization and detoxification in the liver. An essential component of cell membranes and the myelin sheath protecting nerve cells, inositol plays an important role in proper nerve action and the regulation of brain and muscle functions. Inositol’s presence is required for the proper action of several neurotransmitters in the brain, including serotonin and acetylcholine. Several studies confirm inositol’s anti-depressive actions in the brain, ^{259, 260} including general panic disorder²⁶¹ and obsessive-compulsive disorder. ²⁶² Inositol therapy may prove, in fact, to be a useful treatment in the management of clinical depression.²⁶³

The Bottom Line

Our selected nutritional authorities recognize the lipotropic factors, choline and inositol, as essential because of the pivotal roles these nutrients play in lipid mobilization and detoxification within the liver. Eight out of our twelve cited authors recommend daily supplementation with choline at a median level of 94 mg/day and nine out of the twelve recommend inositol at a median intake of 125 mg/day. Lecithin (phosphatidylcholine), which converts to choline during the digestive process, is recommended at 350 mg/day. Accordingly, supplementation with these nutrients, at the levels deemed suitable for optimal nutritional health by our cited authorities, is included as an important component in our product rating criteria. For further details on the scientific evidence supporting the use of each of these nutrients, please log on to www.NutriSearch.ca.

The criterion for Lipotropic Factors poses the following question:

Does the product contain the important lipotropic factors, choline or lecithin (phosphatidylcholine), and inositol at potencies up to 100% of the potencies for these nutrients in the Blended Standard?

14.  Inflammation Control

Chronic inflammation, frequently induced by uncontrolled oxidative stress, is a principal mechanism by which degenerative disease takes root. Reducing oxidative stress and changing the balance within the body to favour the production of anti-inflammatory chemical messengers is, therefore, important in lowering the levels of inflammation. This can be attained through conscious changes to diet and lifestyle, including appropriate supplementation.

Consuming foods rich in the omega-3 essential fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), derived from fish oil, has a profound impact on reducing inflammation. When an appropriate balance of omega-3 to omega-6 essential fats is consumed, production of anti-inflammatory prostaglandins[‡‡] is favoured and inflammation is kept in check.²⁶⁴ Increasing the consumption of foods rich in omega-3 fats, such as salmon and other cold-water fish, or supplementing with a high quality, ultra-refined fish oil, suppresses the formation of harmful prostaglandin E-2 (PG-E2) while promoting the synthesis of beneficial prostaglandins (PG-E1 and PG-E3).^{265, 266}Because the modern North American diet contains 10 to 20 times the amount of omega-6 oils that we need, the most sensible dietary approach is to reduce sources of omega-6 oils and supplement with high-dose omega-3 oils to bring us back to an optimal 4:1 ratio of omega-6:omega-3.²⁶⁷

Supplementing with flaxseed oil is another effective means of optimizing your omega-6:omega-3 ratio. Anti-inflammatory EPA can be manufactured in the body via the enzymatic conversion of alpha-linolenic acid that is prevalent in flaxseed oil. Supplementation with the oil, along with restriction of omega-6 fatty acid intake, raises tissue EPA levels to those comparable to fish-oil supplementation. In fact, flaxseed oil contains more than twice the omega-3 fats as fish oil. Alpha-linolenic acid can be found in a variety of other plant sources, such as pumpkin seeds, walnuts, and other nuts; however, flaxseed—by far the richest source of this important omega-3 oil—contains a whopping 58% by weight.²⁶⁷

Gamma-tocopherol is another nutrient that plays a pivotal role in quenching inflammation.²⁶⁸ Acting through a mechanism unavailable to alpha-tocopherol, gamma-tocopherol reacts with and expunges toxic reactive nitrogen oxide (RNO) radicals, subduing inflammation.²⁶⁹Gamma-tocopherol can also reduce inflammation by inhibiting cyclooxygenase-2 (COX-2), an enzyme central to the inflammatory process. COX-2 controls the synthesis of inflammatory prostaglandin E2 (see Figure 4-1, Chapter 4). Administration of gamma-tocopherol has been found to reduce several other powerful inflammatory protagonists at the site of inflammation—strong evidence that this form of vitamin E exhibits potent anti-inflammatory properties that have important implications for human disease prevention and therapy.²⁷⁰

Lipoic acid (LA) is both a water-soluble and fat-soluble antioxidant. Capable of preventing oxidative damage in the cytosol (the fluid portion) of the cell and within the cell’s membranous structures, LA is able to neutralize reactive nitrogen oxide and oxygen species, including one of the most damaging free radicals of all—the hydroxyl (OH) radical.²⁷¹ While all antioxidants possess some anti-inflammatory properties, LA’s aptitude as an anti-inflammatory agent is highly regarded. LA is a potent inhibitor of nuclear factor kappa beta (NFkB), the nuclear transcription factor activated in response to oxidative stress. As we learned in Chapter 4, NFkB, once activated, switches on genes that manufacture several pro-inflammatory cytokines. For that reason, the presence of LA is critical to the cell’s ability to reduce inflammation.²⁷² Very recently, researchers investigating the use of LA as a therapeutic agent against bone loss associated with systemic inflammation found that the antioxidant can also reduce the production of pro-inflammatory PG-E2 via inhibition of cyclooxygenase-2 enzyme.²⁷³

There is substantial evidence from human trials and animal-model studies that supplementation with physiological doses (doses in the range provided in a normal diet) of vitamin C can depress clinical markers of inflammation, including tumor necrosis factor-beta (TNF-beta)²⁷⁴and C-reactive protein.²⁷⁵In an investigation of the effect of antioxidant therapy in the recurrence of atrial fibrillation, vitamin C dramatically lowered the rate of recurrence from 36.3% to 4.5% and attenuated the associated low-level inflammatory response.²⁷⁶ Importantly, intracellular vitamin C can inhibit the activation of NFkB.²⁷⁷ High-dose supplementation with vitamin C can also reduce dysfunction of the endothelial lining of blood vessels, caused by acute inflammation,²⁷⁸ and suppress apoptosis (cell death) of endothelial cells damaged from an inflammatory response.²⁷⁹

New research has revealed that flavonoids and other polyphenols not only serve as effective antioxidants, they also modulate cell-signalling processes that direct inflammatory events and may, themselves, serve as signalling agents to attenuate such events.²⁸⁰ Several recent studies reveal that, as a group, flavonoids possess remarkable anti-inflammatory abilities, including the capacity to inhibit the expression of cellular adhesion molecules and the ability to subdue the generation of prostaglandin E-2.^281-283Numerous studies also report that flavonoids inhibit the activity of the inflammation-promoting enzyme cyclooxygenase-2,^{282, 284} attenuate activation of the inflammation-signalling molecule, NFkB, and inhibit the synthesis of the inflammatory mediator, nitric oxide (NO).²⁸⁵ Resveratrol, a type of polyphenol found in grapes, has been shown to inhibit the expression of inflammatory cytokines[§§] in vivo (within the body)  and block the activation of other cell-signalling molecules, including NFkB and activator protein-1[***] (AP-1).²⁸⁶{ Through its ability to inhibit NFkB activation, resveratrol, along with other flavonoids, can effectively choke off inflammation at a critical control point, thereby influencing a wide variety of inflammatory pathways. In a study on experimental colitis, resveratrol significantly reduced the degree of colonic injury and suppressed the expression of the pro-inflammatory COX-2 enzyme.²⁸⁷

Similar to resveratrol, green tea polyphenols can also inhibit the activation of NFkB and, through this mechanism, control a wide variety of inflammatory pathways. They are also believed to be neuroprotective, invoking a spectrum of cellular mechanisms, including the chelation of metals, scavenging of free radicals, activation of anti-inflammation signalling pathways, and modulation of mitochondrial function in nervous tissues.²⁸⁸ Green tea polyphenols are now being considered as therapeutic agents to alter brain processes and to serve as neuroprotective agents in progressive neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease.²⁸⁹

A recent review by Bengmark (2006) shows that almost 1500 papers dealing with curcumin have been published in recent years—an indication of the level of interest this simple herb is attracting within the scientific community.²⁹⁰Curcumin is completely non-toxic, possesses potent antioxidant activity, and has been shown to inhibit such mediators of inflammation as NFkB, phospholipase, cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). Moreover, studies also show that a number of inflammation-signalling cytokines (proteins) are also inhibited by curcumin.

Recent studies have examined the anti-inflammatory nature of virgin olive oil and of the olive vegetation water expressed from the processing of the oil. The findings show that, similar to the polyphenols found in green tea, grapes, and turmeric, olive oil phenols can reduce the expression of a key inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), and decrease the production of the inflammation-promoting enzyme, inducible nitric oxide synthase (iNOS).²⁹¹ In several recent studies, olive oil phenols have demonstrated protective anti-inflammatory effects by reducing atherosclerotic lesions,²⁹²improving major risk factors for cardiovascular disease (including endothelial function),²⁹³ and lowering the expression of inflammation-signalling molecules in human inflammatory bowel disease.²⁹⁴ Several researchers consider the consumption of virgin olive oil and olive extracts a valued strategy in the prevention of inflammation.

The Bottom Line

There are, indeed, a wide variety of nutrients that are involved in fighting systemic inflammation, and we have included these in our Inflammation Control criterion. These nutrients and nutrient categories include eicosapentaenoic and docosahexaenoic acids; linolenic acid; gamma-tocopherol; alpha-lipoic acid; vitamin C; flavonoids; procyanidolic oligomers; and the phenolic compounds found in green tea, turmeric (curcumin), and olive extracts. All are proven inflammation antagonists. Together, these nutrients and nutrient categories, at potencies prescribed in the Blended Standard, comprise the Inflammation Control criterion.

The criterion for Inflammation Control poses the following question:

Does the product contain eicosapentaenoic and docosahexaenoic acids, linolenic acid, gamma-tocopherol, alpha-lipoic acid, vitamin C, flavonoids, procyanidolic oligomers, and the phenolic compounds from green tea, olive, and turmeric extracts, at potencies up to 100% of the potencies for these nutrients or nutrient categories in the Blended Standard?

Due to the technical challenges, including tableting, stability, and shelf-life involved in the addition of high levels of essential fatty acids (fish oils and plant seed oils) in tableted products, the levels of these nutrient categories are only included in the Inflammation criterion for those products categorized as Combination Products.

15.  Glycation Control

Aging—the outcome of the conflict between chemistry and biology in living systems—introduces chronic, cumulative chemical modifications that compromise the structure and function of important biomolecules within our cells. We now know that changes to these molecular structures, driven by unrelenting oxidative stress, can render them dysfunctional. Their accumulation, the detritus of an ongoing oxidative war within the cell, is a hallmark of the aging process.

Proteins with long life spans serve as molecular repositories for cumulative oxidative damage, which is detectable in the form of advanced glycation and lipoxidation end-products (AGEs and ALEs).²⁹⁵ A telltale sign of protein oxidation is the addition of carbonyl groups (>C=O) to particular amino acids within a protein’s structure. Carbonylation is an irreversible process;²⁹⁶ just as you cannot unscramble an egg, carbonylated proteins, once formed, must be destroyed and expunged from the cell. Normally, they are marked for degradation by the cell’s proteolytic enzymes; however—depending on the vitality of the cell’s removal processes—they can escape to form aggregates that accumulate with age. Carbonylation of proteins occurs through direct oxidative attack from free radicals and metal ions, from reactions with oxidized sugars and lipid peroxides (oxidized fats), and through the process of glycation.²⁹⁷

Glycation (also called glycosylation) is the complexing of a protein with a sugar to form a molecular arrangement that irreversibly alters the structure of the protein and destroys its functionality. The effects of glycation can be seen in the browning of a glazed ham or turkey during the cooking process. Essentially, the same things happen in the body, which acts much like a low-temperature oven (37^oC) with a 76-year cooking cycle.²⁹⁸ Over time, non-enzymatic reactions between sugars and proteins generate a “browning” of our cells with a consequent accumulation of dysfunctional glycosylated proteins. Excessive glycation is a common occurrence in diabetes. Fuelled by high blood-sugar levels, glycation is responsible for much of the damage to tissues and organs that is a hallmark of the disease, including disruption of the transport of blood gases, development of cataracts and diabetic retinopathy, destruction of the myelin sheath of nerve cells, and the development of diabetic neuropathy. For the diabetic, the consequences of uncontrolled glycation can prove deadly, indeed.

The build-up of glycosylated proteins also leads to molecular cross linking and further oxidative modifications, resulting in the formation of AGE deposits. These high-molecular-weight aggregates can become cytotoxic.²⁹⁹ A growing body of evidence suggests that AGEs and similar toxic rubble from lipid peroxidation (ALEs) contribute to the progress of several degenerative diseases, including Parkinson's disease, Alzheimer's disease, and cancer.^{134, 139-142}

Carnosine

Carnosine, a simple dipeptide of the amino acids, beta-alanine and l-histidine, has emerged as the most promising broad-spectrum shield to date against the oxidative modification of proteins.³⁰⁰ In multiple studies, the peptide has been shown to inhibit lipid peroxidation, free radical induced oxidative damage, protein glycation, AGE formation, and protein-protein cross linking.^301-304 As an antioxidant, it reduces carbonylation; as a chelator of metal ions, it interrupts their ability to catalyze other forms of oxidative protein modification. Carnosine acts as a natural scavenger of toxic reactive aldehydes produced from the degradation of fats, sugars, and proteins. As well, carnosine inhibits the cross linking of proteins that leads to the formation of AGEs.³⁰² Senile plaque formation of amyloid-beta protein is stimulated in the presence of metal ions, such as copper and zinc; as a chelator of transition metals, carnosine can prevent the cross linking of these proteins that leads to such plaque formation.

Most importantly, carnosine shields normal proteins from the toxic reach of AGEs already present in the cell.³⁰⁵By offering itself as a sacrificial target and binding preferentially to glucose, carnosine spares important cellular proteins from oxidative degradation.³⁰⁶ In the process, carnosine, itself, becomes glycosylated, forming a non-mutagenic derivative that can be safely degraded by the cell.³⁰⁷  Some researchers have observed that carnosine’s ability to address the challenges of protein modification fit the bill so well, it appears that the molecule was designed by Nature’s hand to address this unique need.³⁰⁰

While carnosine is available in the US market, it is restricted in products manufactured for the Canadian market. Regardless of this, our Health Support criteria are evidence-based and do not consider the regulatory question. Consequently, we have included carnosine as a critical component of our Glycation Control criterion. We recognize that this places Canadian products at a very slight disadvantage in the final product rankings. This is unfortunate; Health Canada will, hopefully, see reason to allow this important anti-aging nutrient to be made available in Canada in the near future.

Other Nutrients

High doses of vitamin C and E, both powerful antioxidants in their own right, separately and in combination have been found to confer protection against glycation.^{221, 308} The combination of vitamins C and E was found to block the formation of protein cross links and delay collagen aging in young mice,³⁰⁹and to reduce levels of glycosylated haemoglobin and low-density lipoproteins in diabetic animals.³¹⁰ A cross-sectional study investigating the association of diet and lifestyle with levels of glycated blood proteins in non-diabetic, middle-aged adults demonstrated that a high intake of these antioxidants correlated with a reduced level of glycation.³¹¹

In animal-model studies, alpha-lipoic acid has been found to prevent hypertension and hyperglycemia.³¹² Other studies have demonstrated the antioxidant’s ability to prevent glycation and inactivation of proteins.³¹³ It has been proposed that supplementation with alpha-lipoic acid and vitamin E may directly strengthen the anti-glycation defense mechanisms in the brain to protect against AD.³¹⁴  When human blood cells are treated with alpha-lipoic acid, they demonstrate a marked reduction in lipid peroxide levels. This finding is supported by a recent animal-model study. Laboratory rats given intraperitoneal injections of alpha-lipoic acid, at 35mg/kg of body weight, had significantly less glycation and accretion of AGEs in their diaphragm muscles than did control animals. According to the authors, the findings provide strong evidence for the therapeutic utility of alpha-lipoic acid in reducing protein glycation. ³¹⁵

The Bottom Line

Glycation and other processes of protein degradation, including oxidative carbonylation and AGE formation, are principal pathways for the onset of degenerative disease. Carnosine, a simple dipeptide of beta-alanine and histidine, has emerged as an effective and natural means of reducing such protein damage and guarding against age-related proteolytic decline, which retards the removal of damaged proteins. Supplementation with carnosine provides the added benefit of cellular rejuvenation—the reason it has been dubbed as Nature’s “pluripotent life extension agent.” Carnosine, along with vitamins E and C, and alpha-lipoic acid, demonstrate powerful antioxidant and anti-glycation effects. These four important nutrients, at doses recommended in the Blended Standard, comprise our Glycation Control criterion.

The criterion for Glycation Control poses the following question:

Does the product contain l-carnosine, vitamin E (including alpha-tocopherol and gamma-tocopherol, or mixed tocopherols), vitamin C, and alpha-lipoic acid at potencies up to 100% of the potencies for those nutrients or nutrient categories listed in the Blended Standard?

16.  Bioflavonoid Profile

Biochemical, clinical and epidemiological studies all confirm that a diet rich in animal products and saturated fats, common to western and northern European cultures, raises atherogenic LDL cholesterol levels and increases the prevalence of heart disease. In contrast, a diet rich in carbohydrates and fibre, where the principal sources of fats are the monounsaturated fatty acids (MUFAs)—as found in the olive-oil rich Mediterranean diet common to southern Europe—modulates cholesterol levels and is associated with a low incidence of heart disease. ^{{Assmann, 1997 632 /id;Hu, 2001 633 /id;Keys, 1986 502 /id;Murray MT, 1996 500 /id}}The evidence clearly shows that a diet enriched with MUFAs lowers LDL (bad) cholesterol, enhances HDL (good) cholesterol and provides resistance to oxidative damage^{316, 317}

The traditional Mediterranean diet is characterized by an abundance of plant foods, such as bread, pasta, vegetables, salad, legumes, fruits and nuts. Olive oil is the principal source of fat. Meat consumption consists of low to moderate amounts of fish and poultry, with little red meat. Eggs, dairy products and red wine are also consumed in low to moderate amounts. Epidemiological comparisons reveal the striking health benefits provided by such a diet. In adult Greek men in 1960, premature mortality from coronary heart disease was 90 percent lower than that for men in the United States; the life expectancy for Greek men, at the time, was the highest in the world. ³¹⁸Among Greek women, breast cancer rates were less than half those in the United States. The overall prevalence of several other chronic diseases was also markedly lower than for individuals in northern and central European countries. ³¹⁹

Apart from the expected cardio-protective effects of a diet low in saturated fats, additional health benefits of the Mediterranean diet are derived from its favourable fatty acid profile³²⁰ and its rich composition of natural antioxidant compounds, known as polyphenols. Natural constituents of many fruits and vegetables, polyphenols are particularly prevalent in red wine and olives. The inverse relationship noted between polyphenol intake and mortality is likely due to favourable effect of polyphenols on blood lipids, including their reduced ability to oxidize. ¹⁴⁶The antioxidant actions of polyphenols appear to protect blood lipids from oxidative damage by quenching free radical-induced lipid peroxidation.^{,321, 322}These properties complement and enhance the antioxidant prowess of vitamin C, vitamin E and the carotenoids. Polyphenols possess several other important pharmacological properties. They are anti-bacterial, anti-viral, anti-inflammatory, anti-allergic, anti-hemorrhagic, and vasodilatory.^323-327

Polyphenols are a diverse class of compounds found naturally in the leaves, bark, roots, flowers, and seeds of plants. Citrus fruits, grapes, olives, tea leaves, bark, vegetables, dark berries, whole grains, and nuts are particularly rich sources of these natural antioxidants. Polyphenol pigments are largely responsible for the brightly coloured hues of ripened fruits and vegetables. Within the plant, they guard the cells from disease, filter out harmful ultraviolet light, and protect the delicate plant seeds until germination. When consumed in the diet, polyphenols become prodigious free radical scavengers, conferring numerous health benefits. There is evidence that some phenolic compounds also help detoxify the body by chelating with metals and facilitating their removal.^{146, 328}

There are two major groups of polyphenols, differentiated on the basis of their structural formula: the flavonoids and the phenolic compounds (derived from phenolic acids). The flavonoids are known as “Nature’s biological response modifiers” because of their ability to alter the body’s reactions to allergens, viruses and carcinogens, and to protect cellular tissues against oxidative attack. Flavonoids, found in the edible pulp of many fruits and vegetables, impart a bitter taste when isolated. Citrus fruits, such as oranges, lemons, limes, grapefruit, and kiwi, are particularly rich sources of flavonoids. Rose hips, cherries, black currents, grapes, green peppers, broccoli, onions, and tomatoes are also high in these compounds, as are many herbs, including bilberry, ginkgo, yarrow, hawthorn, and milk thistle. Other flavonoid compounds are found in the leaves, bark, and seeds of various plant species. The leaves of Camellia sinensis(dried to make green and black tea), the bark of the maritime (Landes) pine, and the seeds of ripened grapes are excellent sources of a variety of flavonoid compounds. As well, soybeans, nuts, and whole grains are replete with a class of flavonoids known as isoflavones.

Flavonoids are important for the health and integrity of blood vessels. Through their ability to decrease permeability, flavonoids can reduce microvascular haemorrhaging and enhance capillary strength. The flavonoids confer cardio-protective benefits specifically through their ability to prevent oxidation of cholesterol. This ability is reported to be similar to, and possibly more potent than, the antioxidant powers of vitamins C and E. The scientific literature is filled with studies reporting the beneficial effects of dietary flavonoids in human health. Flavonoids, along with beta-carotene, vitamin C, and vitamin E, may be the cell’s principal cancer chemopreventive agents. Their abundance in fruit and vegetables underlies the strong correlation between high fruit and vegetable consumption and reduced cancer risk.^{329, 330}

Citrus flavonoids, also called bioflavonoids, are, perhaps, the largest of the flavonoid groups. Studies indicate they can relax smooth muscles in the arteries, reduce vascular permeability, and enhance the strength of capillaries, thereby lowering blood pressure and improving circulation. As well as possessing anti-inflammatory properties, citrus flavonoids exhibit powerful antioxidant properties and protect the cardiovascular system from harmful lipid peroxidation. Quercetin, one of the most biologically active of the flavonoids, serves as the backbone for many of the citrus flavonoids. Quercetin is indicated in the prevention of diabetes, due to its ability to enhance insulin production, protect the insulin-producing beta-cells in the pancreas, and inhibit platelet aggregation (a principle cause of blood clotting in diabetics).³³¹ In animal studies, quercetin has proved effective against a wide variety of cancers.³³²  Unfortunately, there is little human research available to assess its efficacy. Other important citrus flavonoids, including rutin, quercitrin, and hesperidin, are derivatives of quercetin. The subtle differences in the chemistry of these compounds are a consequence of the various sugar molecules attached to the quercetin backbone.

According to Bagchi,³³³ the flavonoids found in grape seed extract (GSE) are highly bioavailable. Proanthocyanidins, the active components of GSE, from a complex of bioflavonoid compounds, known as procyanidolic oligomers (PCOs). This unique group of flavonoids appears to confer the cardio-protective benefits noted in consumers of red wine. PCO compounds also exhibit cytotoxicity (cell-killing ability) against several types of cancer cells, increase intracellular levels of vitamin C, enhance capillary stability, and inhibit the destruction of collagen.^{334, 335}

The antioxidant actions of flavonoids appear to protect blood lipids from oxidative damage by quenching lipid peroxidation.^{322, 324} These properties complement and enhance the antioxidant powers of vitamin C, vitamin E, and the carotenoids. Flavonoids also possess several other important pharmacological properties: they are anti-bacterial, anti-viral, anti-inflammatory, anti-allergic, anti-hemorrhagic, and vasodilatory.^{323, 325-327, 336} All in all, not bad for a day’s work!

The Bottom Line

Accordingly, the bioflavonoids (citrus flavonoids, soy isoflavones, quercetin, quercitrin, hesperidin, rutin,  bilberry, and assorted berry extracts) are combined with the PCOs (including resveratrol, grape seed and pine bark extracts) to form an important component of our product rating criteria, listed collectively under the category of Mixed Bioflavonoids.

The criterion for the Bioflavonoid Profile poses the following question:

Does the product contain a mixture of bioflavonoids (citrus flavonoids, soy isoflavones, quercetin, quercitrin, hesperidin, rutin, bilberry, and assorted berry extracts) and PCOs (including resveratrol, grape seed, and pine bark extracts) at potencies up to 100% of the recommended potencies for mixed bioflavonoids and PCOs in the Blended Standard?

17.  Phenolic Compounds Profile

Phenolic compounds are derivatives of the phenolic acids, hydroxycinnamic acid and hydroxybenzoic acid. These compounds differ from the flavonoids in that they are composed of a single six-carbon ring, known as an aromatic or cyclic ring, which provides them with a strong electron-donating ability. The many different phenolic compounds found in nature are variations of these basic structures, with a wide variety of different groups attached to this basic hydrocarbon skeleton. The difference in the ring structure in the phenolic compounds, compared to the flavonoids, provides for a slightly different (but equally valuable) chemical nature.

The most intensely studied of the phenolic compounds include:

• Green tea, for centuries a staple of the oriental diet, is a rich source of a class of polyphenolic compounds, called catechins. Note the structural similarities between d-catechin and quercetin. These antioxidant compounds possess an anti-mutagenic potential, protecting the cellular DNA from oxidative damage. ¹⁴⁹Epidemiological evidence suggests that consumption of green tea may also protect against pancreatic and colorectal cancers.  ¹⁵⁰In one population-based controlled study, consumption of green tea appeared to significantly lower the risk of stomach cancer. What’s more, the effect was independent of the age at which consumption began. ³³⁷ Green tea is a fusion of the leaves from the tea plant, Camellia sinensis.
• Black tea, produced by the fermentation of green tea leaves, does not contain the high levels of catechins found in unfermented green tea and, consequently, may not afford the same benefits. However, recent evidence suggests that the antioxidant activity of black tea preparations is higher than that of most reported dietary agents, based on daily intake; in one study, one cup of black tea was found to provide 262 mg of polyphenols per serving. ^{337, 338} Therefore, like green tea, black tea is also a rich source of polyphenolic antioxidants.
• olive extracts containing tyrosol, hydroxytyrosol, and the oleuropeine glycosides, found in the fruit of the olive tree. Extra Virgin olive oil, extracted from the first cold press of the olive, derives its unique aroma, pungent taste, and high thermal stability from these complex aromatic compounds.¹⁴⁶
• turmeric, a perennial herb of the ginger family and a major ingredient in curry. Long used in Chinese and Ayurvedic (Indian) medicine as an anti-inflammatory, it is an effective antioxidant, anticarcinogenic, cardiovascular, and hepatic agent.

The weight of scientific evidence supporting the health benefits of the dietary consumption of polyphenols is immense. Their power as free radical antagonists, their recognized efficacy in reducing cardiovascular and cancer risks, and their demonstrated pharmacologic properties as anti-inflammatory, anti-viral, anti-bacterial, anti-allergic, anti-hemorrhagic, and immuno-enhancing agents, make an exceptionally strong case for their inclusion in nutritional supplementation. The International Consensus Statement, issued recently by the European Commission, promoting the adoption of the Mediterranean diet, echoes the scientific findings: the consumption of olive oil and the phenolic compounds derived from the humble fruit of the olive tree confers profound health benefits.

The Bottom Line

The biochemistry of polyphenols is an emerging area of nutritional research; because of its novel nature, there is not yet a quantitative consensus among our cited nutritional authorities with respect to daily intake. While there is definitive recognition that supplementation with polyphenols is highly desireable, no median recommended daily intake specific to phenolic compounds is yet available. For this reason, we have turned to the emergent scientific literature^328,339  in order to establish a recommended daily intake of 25 mg of phenolic compounds as the basis for ourBlended Standard.

Accordingly, the phenolic compounds include the olive-based phenolic compounds and the phenolic-acid derivatives, curcumin, and the green tea catechins. Together, they form another important component of our product rating criteria, listed under the Phenolic Compounds Profile.

The criterion for the Phenolic Compounds Profile poses the following question:

Does the product contain phenolic compounds (polyphenolic acids and their derivatives, which include olive, curcumin, and the green tea extracts) at the potency for this nutrient category established in the Blended Standard?

18.  Potential Toxicities

In order to optimize preventive-health benefits, the strategy of nutritional supplementation is to encourage long-term use. Consequently, there exists a potential risk for consumers with regard to the cumulative toxicity of particular nutrients. It would be folly, indeed, to supplement with high levels of certain nutrients, only to find down the road that your investment, instead of promoting wellbeing, has jeopardized your health. Most nutrients used in nutritional supplements have a high degree of safety; however, some nutrients require a degree of prudence when it comes to long-term use.

Vitamin A (retinol), because of its solubility in fatty tissues, can become toxic when taken in high doses over a long period. As well, chronic iron overload can significantly increase the level of oxidative damage to cells. Accidental overdose of iron-containing supplements is, in fact, a leading cause of fatal poisoning in children (see Table 5-1, Chapter 5). This is not to say that vitamin A and iron are not important to the health of our cells; both nutrients play crucial roles in cellular metabolism. However, it is important to be aware that there exist safe and effective alternatives for meeting the daily requirements for these nutrients without compromising one’s health through imprudent use. Because of their importance in cellular health and their potential for cumulative damage, either too much or too little vitamin A and iron is problematic.

Vitamin A

Despite the prevalence of vitamin A deficiency, retinol toxicity is a common occurrence. As many as 5% of those who supplement with vitamin A unknowingly suffer from toxicity symptoms.³⁴⁰ Supplementation at 5,000-10,000 IU per day of pre-formed vitamin A—a dose well within the range offered in many popular vitamin supplements—may lead to acumulative toxic overdose.³⁴¹ As well, accidental ingestion of a single, large dose of vitamin A can produce acute toxicity in children. One large study of over 22,000 pregnant women who supplemented with vitamin A during early pregnancy found that among the babies born to women who took more than 10,000 IU of preformed vitamin A per day in the form of supplements, about 1 infant in 57 had a malformation attributable to the supplement.^{180, 181}

Consumption of more than 10,000 IU of vitamin A carries a five-fold greater risk of birth defects than does consumption of less than 5,000 IU per day. Rothman and co-workers³⁴² found that the prevalence of birth defects appears greatest in those women who consume high levels of the pre-formed vitamin within the first seven weeks of their pregnancy. The authors conclude that women who might become pregnant should limit their retinol intake to below 5,000 IU, or—better yet—supplement with beta-carotene.

Beta-carotene, the orange/yellow-coloured pigment found in many garden vegetables, is a retinol precursor. The body easily converts beta-carotene into vitamin A by cleaving the carotene molecule into two molecules of retinol as needed, thereby avoiding the toxic accumulation of pre-formed vitamin A. Once transformed into active retinol, beta-carotene confers the same beneficial effects. Other than occasional loose stools or slight discoloration of the skin, even high doses of beta-carotene do not exhibit toxicity. As an added benefit, beta-carotene is a much more potent antioxidant than retinol and provides even greater protection against oxidative challenge. If you take too much beta-carotene you might turn orange like a carrot—but provided you’re not around any large rabbits, you’ll be just fine!

Iron

Iron plays an important role in the physiology of the body. As a central part of the haemoglobin and myoglobin molecules, iron is indispensable to the body’s ability to transport gases into and out of the cell. It is also needed in several important enzymes involved in energy production, metabolism, and DNA synthesis. Some iron is lost through the breakdown of red blood cells and excretion in the bile. However, due to its importance, the body conserves iron at all costs; the kidneys do not eliminate the metal.

The dark side of iron supplementation arises when it is consumed in amounts excessive to the body’s needs. While unbound (non-heme) iron is more likely to generate oxidative challenges through free radical generation, excessive iron supplementation in any form can create profound problems for the cell. Iron overload can cause deterioration of the gut lining, vomiting and diarrhoea, abdominal and joint pain, liver damage, loss of weight, and intense fatigue.³⁴³ Acute doses as low as 3 g can cause death in children.

Approximately one out of every 250 North Americans suffers from haemochromatosis, a genetic defect common in those of northern European descent. The disorder causes the body to accumulate and store abnormally high levels of iron. People with haemochromatosis store twice as much iron as others, placing themselves at increased risk for iron-related diseases. Symptoms generally occur after 50 years of age and include fatigue, abdominal pain, achy joints, impotence, and symptoms that mimic diabetes. Evidence from several studies suggests that high levels of iron contribute to a noticeable increase in the risk for cardiovascular disease, likely due to non-haeme iron’s aggressive pro-oxidant nature. Serum ferritin (iron) levels are, in fact, one of the strongest biochemical markers for the progression of atherosclerosis, a consequence of dramatically increased oxidation of LDL cholesterol.³⁴⁴ A 1995 study, conducted on Finnish men, found that those with high body stores of iron had a substantially increased risk of heart attack. Men with the highest levels of stored iron showed a level of risk three times that of men with the lowest levels.³⁴⁵

Iron accumulation disorders contribute to a variety of other disease states, all of which are degenerative in nature. Studies reveal that chronic iron overload contributes to increased infections, cancer, arthritis, osteoporosis, diabetes, and various cognitive dysfunctions.^{346, 347} Data obtained from the first National Health and Nutrition Examination Survey (NHANES I), linking body-stores of iron and cancer, found an elevated risk was associated with high iron levels.³⁴⁸ Unless you are a woman with regular menses (menstrual periods), the only way to remove excess iron is through blood letting. That is why, for men, iron overload can prove quite problematic to resolve. Very recent research has found that long-term supplementation with iron at doses less than 5 mg/day can lead to iron-overload toxicity.¹Consequently, this guide has adopted an upper limit of iron intake at 5 mg/day when considering a product’s rating. Any product containing iron at a daily dose greater than this limit is penalized in this rating criterion.

The Bottom Line

The majority of nutrients used in supplementation have a large measure of safety; however, the use of vitamin A and iron warrants prudence and caution, particularly when consumed by children or pregnant women. Accordingly, consideration of the levels of vitamin A in excess of the median value in the Blended Standard (5,000 IU/day) and iron in excess of 5 mg/day forms the final criterion in the 18-point product rating used in this guide. This criterion penalizes any product whose daily dose of either vitamin A or iron exceeds these established limits.

The criterion for Potential Toxicities poses the following questions:

Does the nutritional supplement contain vitamin A and iron (which is no longer included in theBlended Standard)? Does the potency of vitamin A exceed 100% of the potency for that nutrient in theBlended Standard? Does the potency of iron exceed 5 mg/day?

Summary

From these 18 criteria, a Final Product Rating, based on a five-star scale, is determined. A five-star rating highlights those products whose characteristics for optimal nutrition are clearly superior to the majority of products on the market and that approach or meet the pooled recommendations of the Blended Standard. Conversely, a one-star rating or less represents products possessing few, if any, of the characteristics for optimal nutrition reflected in the Blended Standard. We believe that this five-star scale, divisible in half-star increments, provides an intuitive means by which the consumer can compare products, based on product content.

In the 4^th edition of the NutriSearch Comparative Guide to Nutritional Supplements, we have employed this rating schema in our comparison of over 1600 nutritional products available in Canada and the United States. The guide is available through your local bookstore (ISBN: 978-0-9732538-6-3), Amazon.com, or the Comparative Guide online store at http://www.comparativeguide.com.

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style='font-size:12.0pt;font-family:AGaramond'>[*]Coenzymes are small organic non-protein molecules that carry chemical groups between enzymes. Many coenzymes are activated water-soluble vitamins that have a phosphate group attached to the vitamin. Non-vitamins, such as ATP—the energy currency of the cell—can also act as coenzymes. While coenzymes are consumed in the reactions in which they assist, they are constantly regenerated and their concentration maintained at a steady level in the cell.

[†] Bioavailability is the ability of a given nutrient to be absorbed by the gut and to be utilized by the cells of the body.

style='font-size:12.0pt;font-family:AGaramond'>[‡]Isomers are molecules with the same chemical formula and often with the same kinds of bonds between atoms, but in which the atoms are arranged differently to provide either a different structural formula (structural isomerism) or a different three-dimensional shape (stereoisomerism).

[§] Oxidation-reduction reactions in biological systems involve a transfer of electrons from one chemical species to another. The ease by which an antioxidant donates an electron to reduce (neutralize) a free radical is, therefore, its defining prowess.

[**] A cataract is a clouding of the eye's natural lens, which focuses light onto the retina at the back of the eye. The lens is mostly made of water and protein, with the protein fibers arranged in a precise way to keep the lens clear and transparent. Oxidative damage to these proteins causes them to clump together and start to cloud the lens. This is known as a cataract. In time, the cataract may grow larger and cloud more of the lens, making it translucent or milky. The consequence is blurred and darkened vision.

[††] Macular degeneration is the development of blurred or distorted central vision due to degeneration of the macula of the eye. This small area in the center of the retina makes sharp-detail vision possible from the central portion of the eye.

[‡‡]  Prostatglandins belong to a large class of oxygenated fatty acids, called the eicosanoids. They are derived from the essential fatty acids supplied through our diet. Eicosanoids are actually primitive hormones from our evolutionary past that act as localized cellular signalling molecules.

[§§] Cytokines are proteinaceous signalling compounds, similar to hormones and neurotransmitters, which are used extensively for localized inter-cellular communication.

AP-1 is a pro-inflammatory cytokine that acts as a transcription factor, controlling the transfer of genetic information from the cell’s DNA to molecules of messenger RNA (mRNA), which subsequently direct the manufacture of other inflammatory proteins.