Dr. Hank Liers here considers mechanisms involved in the activation of transcription factor Nrf2. Nrf2 is encoded by the NFE2L2 gene. Nrf2 can induce expression of genes encoding for antioxidant enzymes. Thus, it contributes to regulation of oxidative stress. Dr. Liers’ interest regards use of natural phytochemical Nrf2 activators for improving health. Also, see his post, “New Directions for Preventing Free-Radical Damage”(06.27.19).
Nrf2 SIGNALING, FOODS, AND HEALTH
Despite progress in the early detection and treatment of cancer, overall mortality rates for most cancers of epithelial origin have not declined during the past three decades. Consequently, in recent years attention has been directed to cancer prevention.
Carcinogenesis can be viewed as a multistep process in which the genes controlling proliferation, differentiation, and apoptosis are transformed and altered under selective environmental pressures.
Tumor development involves three distinct, yet closely linked, phases: initiation, promotion, and progression. The initiation phase is a rapid and irreversible event that occurs when a normal cell is exposed to a carcinogenic event. Frequently, unrepairable or misrepaired DNA damage happens in the initiation phase.
Promotion and progression processes are relatively longer processes than the initiation stage, and are considered reversible. Using various animal cancer models, scientists found that all three cancer development stages can be intervened by treatment with natural (or synthetic) chemicals.
Epidemiological and population studies also establish a close relationship between incidence of cancer and consumption of certain types of food.
The term “chemoprevention” was first coined in 1976 by Michael Sporn, when he referred to prevention of malignancy development by vitamin A and its synthetic analogs. Since then, chemoprevention has been adopted as one of the major tactics to modulate the process of carcinogenesis. Many research studies have proven this strategy is effective in reducing the incidence of cancer in well-defined high-risk groups.
Chemoprevention is by definition the use of natural (or pharmacologic) agents to inhibit the development of invasive cancer. The chemicals with a cancer preventive activity are referred to as chemopreventive agents. A chemopreventive agent can inhibit carcinogenesis either by blocking the DNA damage at initiation stage or by arresting or reversing the processes at promotion and progression stages. Most of the chemical substances used in cancer chemoprevention studies are natural phytochemicals found in food.
On the basis of the inhibition stages, chemopreventive agents have been classified into two categories, namely blocking agents and suppressing agents. Blocking agents act by preventing carcinogens from reaching the target sites, from undergoing metabolic activation, or from subsequently interacting with crucial cellular macromolecules such as DNA, RNA, and proteins at initiation stages.
Suppressing agents, on the other hand, inhibit the malignant transformation of initiated cells at either the promotion or the progression stage. Some agents may work on all three stages of carcinogenesis, and are hence classified into both categories.
DIETARY PHYTOCHEMICALS ARE NATURE’S CHEMOPREVENTIVE AGENTS
Many different animal models and cancer cell lines have been used to evaluate the chemopreventive values of phytochemicals, and have led to the discovery of new classes of chemopreventive agents. These agents include isothiocyanates (such as sulforaphane) from cruciferous vegetables, polyphenols from green and black tea, curcuminoids (from turmeric root), stilbenes such as resveratrol (from giant knotweed plant), flavonoids such as quercetin, and anthocyanidins (from many fruits and soybeans).
Progress also has been made in understanding the mode of action of newly identified chemopreventive agents. Exposure to the chemopreventive agents produces certain level of reactive oxygen species (ROS) or electrophiles, and causes mild oxidative/electrophilic stresses in cells.
Such mild oxidative stresses are sufficient to initiate the signaling pathways that, in turn, can activate a variety of cellular events, such as induction of phase II detoxification enzymes and antioxidant enzymes, expression of tumor-suppressor genes, and inhibition of cell proliferation and angiogenesis.
In order to survive under a variety of environmental or intracellular stresses, our cells have developed highly efficient protective mechanisms to protect themselves from oxidative or electrophilic challenges. Proteins that comprise phase II detoxification and antioxidant enzymes provide an enzymatic line of defense against reactive oxygen species. These enzymes include superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione S-transferase (GST), and glutamate cysteine ligase.
Induction of phase II and antioxidant enzymes are regulated at the DNA/gene level by antioxidant responsive element (ARE). ARE-mediated gene expression plays a central role in the cellular defense against cellular oxidative damage.
Experimental evidence supports the view that induction of ARE-mediated cytoprotective enzymes is a critical and sufficient mechanism to enable protection against carcinogenesis provoked by environmental and endogenous insults.
One of the key ARE-binding transcription factors is Nrf2. Induction of cytoprotective enzymes in response to ROS, electrophiles, and chemopreventive agents is a cellular event that is highly dependent on Nrf2 protein.
Nrf2 BOOSTS CELL DETOXIFICATION AND ANTIOXIDANT ENZYMES
By activating Nrf2 signaling, chemopreventive agents can increase cellular detoxification and antioxidant enzymes, thereby enhancing removal of reactive carcinogens and blocking carcinogenesis. This hypothesis has been tested in many studies.
For example, a study with sulforaphane (an isothiocyanate present abundantly in cruciferous vegetables) has shown that oral administration of this phytochemical could effectively block benzo[a]pyrene-induced forestomach tumors in mice. This protective effect was abrogated in mice that could not produce Nrf2, supporting a critical role of phase II detoxification and antioxidant enzymes in the prevention of carcinogenesis by chemopreventive agents.
Nrf2 is normally bound in the cytoplasm of cells to a protein called KEAP1. However, when an appropriate phytochemical agent attaches to a kinase receptor on the cell wall a phosphate group is released that causes the Nrf2 to be released. The Nrf2 then migrates into the cell nucleus and causes an antioxidant enzyme, such as SOD, to be released. This endogenously produced enzyme then can protect against ROS, electrophiles, and chemopreventive agents.
In practice, it has been found that a combination of multiple polyphenols works significantly better than single ingredients at activating Nrf2. In fact, in one experiment it was found that a combination of five ingredients all known to be Nrf2 activators was 18 times more effective than any single ingredient. Furthermore, it was found that this combination of five ingredients increased levels of SOD by 30% and catalase by 56% after 120 days.
A POWERFUL, NATURAL Nrf2 ACTIVATION FORMULA FOR GREATER HEALTH
In view of the above information and the fact that new and more effective ingredients are available, we have updated our exceptional formula designed to maximize activation of Nrf2 in the body. This new product is ULTIMATE PROTECTOR+. It is among the most advanced, natural Nrf2 activator formula on the market today.
We include a broad range of Nrf2 activators in ULTIMATE PROTECTOR+. These activators source from a wide variety of freeze-dried and concentrated fruits, vegetables, and herbs. These include USP-grade non-GMO Vitamin C , SFB® standardized fruit blend (~50% polyphenols, high-ORAC powder: 9,000 µmole TE/g) from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry), Curcumin(standardized extract with 95% curcuminoids), Trans-Resveratrol(98% from Giant Knotweed), Green Tea Extract(90% polyphenols, 50% EGCG), and VinCare® Whole Grape Extract (>80% polyphenols, ORAC>19,000 µmole TE/g). In addition the product contains Calcium Malate and Magnesium Malate, that support ATP and enzyme product and Bioperine® (a patented black pepper extract that significantly enhances absorption of all ingredients and is a known Nrf2 activator).
Phytochemicals provided by the array of freeze-dried and concentrated fruits, vegetables, and herbs in the formula include: Polyphenols, Phenolic acids, Proanthocyanidins (OPCs), Anthocyandins, Catechins, Glucosinolates, Zeaxanthin, Lutein, Lycopene, Beta Carotene, Chlorogenic acid, Ellagic acid, Quercetin, Quinic acid, Trans-Resveratrol, Ferulic acid, Punicalagins, Phloridzin, Polysaccharides, Xanthones and more.
In addition to these Nrf2 activators (above), ULTIMATE PROTECTOR+ contains an extremely broad array of plant based antioxidants from the same sources described above, as well as from non-GMO USP grade Vitamin C. All ingredients in this product have been used in chemoprevention protocols, as well as in protocols aimed at preventing free-radical damage in the body.
“Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells.” Am J Physiol Lung Cell Mol Physiol 294: L478–L488, 2008.
“Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.” Planta Med. 2008 Oct; 74(13): 1526–39. Epub 2008 Oct 20.
“Nrf2: a potential molecular target for cancer chemoprevention by natural compounds.” Antioxid Redox Signal. 2006 Jan–Feb; 8(1–2):99–106.
“Cancer chemoprevention by phytochemicals: potential molecular targets, biomarkers and animal models.” Acta Pharmacol Sin. 2007 Sep; 28(9): 1409–21.
“Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells.” Acta Pharmacol Sin. 2007 Apr; 28(4): 459–72.
“Anticarcinogenesis by dietary phytochemicals: cytoprotection by Nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-kappa B and AP-1 in abnormal cancer cells.” Food Chem Toxicol. 2008 Apr; 46(4): 1257–70. Epub 2007 Sep 15.
“Signal transduction events elicited by cancer prevention compounds.”Mutat Res. 2001 Sep 1; 480–481: 231–41.
“Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention.”Toxicology. 2010 Dec 5; 278(2): 229–41. Epub 2009 Oct 20.
“NF-kappa B and Nrf2 as potential chemopreventive targets of some anti-inflammatory and antioxidative phytonutrients with anti-inflammatory and antioxidative activities.” Asia Pac J Clin Nutr. 2008; 17 Suppl 1:269–72.
“Regulation of NF-E2-Related Factor 2 Signaling for Cancer Chemoprevention: Antioxidant Coupled with Antiinflammatory.” Antioxid Redox Signal. 2010 Dec 1; 13(11): 1679–98. Epub 2010 Aug 17.
“Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention.” AAPS J. 2010 Mar; 12(1): 87–97. Epub 2009 Dec 15.
“Dietary chemopreventive compounds and ARE/EpRE signaling.”Free Radic Biol Med. 2004 Jun 15; 36(12): 1505–16.
“Multiple molecular targets in cancer chemoprevention by curcumin.”AAPS J. 2006 Jul 7; 8(3): E443–9.
As you may know, free radical damage is associated with virtually every major health condition. For many years we have recommended taking antioxidants to protect against free radicals and for preventing free radical damage to the body.
Antioxidants we recommend include Vitamin C, Vitamin E, plant polyphenols (e.g., grape seed extract), green tea extract, rutin and other bioflavonoids, and amino acids and peptides (e.g., n-acetyl-l-cysteine and glutathione) to deal with free radicals. Using this approach, individuals often achieve excellent results.
In the last ten years, a new approach has become a major topic of scientific interest and research. This approach utilizes substances that induce strong activation of the body’s own enzyme systems. Some natural substances under study include turmeric (curcumin), sulforaphane (found in broccoli sprouts), transresveratrol (found in red wine and giant knotweed), and green tea extracts.
Nrf2 Activators Produce Antioxidant Enzymes Combating Free Radicals
Researchers specifically are studying how enzyme-activating substances activate a transcription factor known as Nrf2 that causes the body to produce higher levels of enzymes including superoxide dismutase (SOD), catalase, heme oxygenase, and glutathione peroxidase.
A human clinical trial of a nutritional supplement containing turmeric, milk thistle extract, green tea extract, bacopa, and ashwaganda showed this combination of phytochemicals can reduce lipid peroxides in the body by significant amounts after only one month. Further research on this same supplement has shown these enzyme inducers affect the function of up to 4,000 genes in the body related to internal protection systems.
Currently there are several supplements on the market that are classified as Nrf2 activators. My own approach to this includes a combination approach using very powerful antioxidants (for example, those with extremely high ORAC5.0 values such as whole grape extract) in combination with Nrf2 activators derived from plant extracts (such as transresveratrol and curcumoids).
My updated product (Ultimate Protector+) using this approach will be available in July 2019 so be on the look out for it!
Ultimate Protector+™ is a next-generation cell protection formula providing high levels of non-GMO Vitamin C, calcium and magnesium malate (supports ATP and enzyme production), a full spectrum of exceptionally high potency antioxidants (in accordance with ORAC6.0 testing), many of the most powerful natural Nrf2 protective enzyme activators, and Bioperine® to facilitate absorption of all ingredients – all in a single product! This potent combination of characteristics distinguishes our formula so that no other single product available today offers such complete protection. This is the best formula available for countering free radical damage. 100% non-GMO. 180 veggie caps per bottle.
ULTIMATE PROTECTOR+™ contains USP-grade non-GMOAscorbic Acid, SFB® standardized fruit blend (~50% polyphenols, high-ORAC powder: 9,000 µmole TE/g) from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry), Curcumin (standardized extract with 95% curcuminoids), Trans-Resveratrol (98% from Giant Knotweed), Green Tea Extract (>90% polyphenols, 50% EGCG), VinCare® Whole Grape Extract (>80% polyphenols, ORAC>19,000 µmole TE/g), Calcium Malate, Magnesium Malate, and Bioperine® (a patented black pepper extract that enhances absorption of all ingredients and is a known Nrf2 activator).
ULTIMATE PROTECTOR+ CONTAINS THREE MODES OF ACTION
ULTIMATE PROTECTOR+provides completecoverage for free-radical protection by satisfying three distinct needs in single cell protection formula:
Mode 1) A non-GMO Vitamin C product. Ultimate Protector+contains a Vitamin C formula without genetically modified sources of corn, potatoes, or beets. 100% Non-GMO Vitamin C!
Mode 2) A single, powerful antioxidant formula. Ultimate Protector+ provides a powerful antioxidant formula offering a broad range of extremely high-ORAC plant source antioxidants. These antioxidants should protect against the full range of free radicals found in the human body including: superoxide anion (O2·-), peroxyl radicals (ROO·), hydroxyl radicals (HO·), singlet oxygen (1O2), peroxynitrite (ONOO-), and hypochlorite (HOCl).
Antioxidants function as a vital line of defense against free radicals by blocking their attack on DNA, vital proteins, lipids, and amino acids. Until now, efforts to identify the effect of antioxidants on all six types of free radicals were constrained by limited testing procedures. However, new technological developments have resulted in a comprehensive testing method called the Total ORAC6.0 assay. Because of the development of the Total ORAC6.0™ test, it is now possible to target and measure the effects of antioxidants on the six major types of free radicals found in the body. Recently [8/2019] Brunswick Labs has tested ULTIMATE PROTECTOR+™ using the new ORAC6.0 test. The results reveal an incredible overall ORAC6.0 value of 272,743 µmole TE/gram (i.e., 272,743 per gram!). This corresponds to a total ORAC6.0 value per of over 968,000 μmole TE per serving of six small capsules. In addition, the ORAC5.0 value was measured to be over 950,000 μmole TE per serving. The results have shown that the formula offers excellent protection against all of the six major types of free radicals found in the body.
Mode 3) A full spectrum of Nrf2 activators. Ultimate Protector+ is a supplement providing a broad range of the most powerful natural Nrf2 transcription factor activators that allow the body to make its own antioxidant enzymes (e.g., superoxide dismutase (SOD), catalase, heme oxygenase, and glutathione peroxidase). Scientific research has shown that these are found in a wide range of fruits, vegetable, and herbs and that products which provide a wide range of Nrf2 activators give significantly higher levels of the endogenously produced antioxidant enzymes.
Ultimate Protector+ ingredients include pomegranate extract, as well as components from 12 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article I will explore the ingredient pomegranate, which is a component of SFB® – Standardized Fruit Blend from Ethical Naturals, Inc.
Ultimate Protector+ Includes Pomegranate
SFB® – Standardized Fruit Blend
SFB® is a proprietary formula that combines extracts from Grape, Cranberry, Pomegranate, Blueberry, Apple, Mangosteen, Bilberry, Chokeberry, and Goji Berry. High in fruit polyphenols, anthocyanins, proanthocyanins, ellagic acid, chlorogenic acid, resveratrol, and quinic acid. With its diverse blend, SFB® offers over 40-50% polyphenols as well as 9,000 ORAC units in a single gram.
Polyphenols and Anthocyanins are powerful plant ingredients associated with a variety of areas of human health, including healthy aging, healthy glucose metabolism, cardiovascular health, and inflammation management.
HEALTH BENEFITS OF POMEGRANATE
The pomegranate (Punica granatum L.) is native from Iran to the Himalayas in northern India and was cultivated and naturalized over the whole Mediterranean region since ancient times. It is widely cultivated throughout India and the drier parts of southeast Asia, Malaya, the East Indies and tropical Africa. The tree was introduced into California by Spanish settlers in 1769.
For thousands of years, the pomegranate has been extensively used as a source of food and medicine. Full of antioxidants, vitamin C and potassium, pomegranate has been used to control body weight, reduce cholesterol, fight against cell damage, and inhibit viral infections. Pomegranate extracts have anti-bacterial effects.
Pomegranates are rich in ellagic acid, gallic acid, lignans, polyphenols and other bioactive compounds, and have been shown to lower blood pressure and enhance vascular function. Furthermore, it can offset some of the negative effects of medications and chemicals. These compounds occur naturally in its peel, seeds, leaf and juice. The seeds are high in p-coumaric acid, plant sterols, tannins and fatty acids. In addition to their antihypertensive effects, they may help reduce blood sugar levels.
Pomegranate fruit is a rounded berry with a thick reddish skin covering approximately 200–1400 white to deep red or purple seeds. Pomegranate seeds are edible and hold strong antioxidant and anti-inflammatory properties due to their high content of hydrolysable tannins and anthocyanins. As compared to the antioxidant activity of vitamin E, β-carotene, and ascorbic acid, the pomegranate antioxidants appear unique due to combinations of a wide array of polyphenols, having a broader range of action against several types of free radicals. As compared to the recognized antioxidants in red wine and green tea, anthocyanins from pomegranate fruit possess significantly higher antioxidant activity.
Pomegranate has been used in various medicinal systems of medicine for the treatment and therapy of a multitude of diseases and ailments. In the ancient Indian medicinal system, i.e., in Ayurvedic medicine, the pomegranate was considered to be a whole pharmacy unto itself. It was recommended to be used as an antiparasitic agent and to treat diarrhea and ulcers. The medicinal properties of pomegranate have sparked significant interest in today’s scientific community as evidenced by the scientific research relating to health benefits of pomegranate that have been published in last few decades.
Studies have shown that pomegranate and its constituents can efficiently affect multiple signaling pathways involved in inflammation, cellular transformation, hyperproliferation, angiogenesis, initiation of tumorigenesis, and eventually suppressing the final steps of tumorigenesis and metastasis. The pomegranate constituents are shown to modulate transcription factors, pro-apoptotic proteins, anti-apoptotic proteins, cell cycle regulator molecules, protein kinases, cell adhesion molecules, pro-inflammatory mediators, and growth factors.
Pomegranate Chemical Constituents
The pomegranate fruit consists of white to deep purple seeds embedded in a white spongy astringent membrane surrounded by a thick reddish skin, or pericarp. Pericarp constitutes almost 50% of the fruit weight and is a rich source of bioactive constituents, such as phenolics, flavonoids, ellagitannins, and proanthocyanidin compounds. It also contains various minerals, mainly potassium (K), nitrogen (N), calcium (Ca), phosphorus (P), magnesium (Mg), and sodium (Na), as well as complex polysaccharides. The remaining 50% of the fruit consists of seeds (constituting 10% of the fruit weight) and arils (constituting 40% of the fruit weight).
Pomegranate seeds hold strong antioxidant and anti-inflammatory properties due to the high content of hydrolysable tannins (punicalagin, pedunculagin, punicalin, gallagic acid, ellagic acid, and esters of glucose) and anthocyanins (delphinidin-3-glucoside, cyanidin-3-glucoside, delphinidin-3,5-diglucoside, cyanidin-3,5-diglucoside, pelargonidin-3,5-diglucoside, and pelargonidin-3-glucoside).
Various organic acids, such as ascorbic acid, citric acid, and malic acid, etc., are also reported to be present in the seed coat, while the arils contain water (85%), sugars (10%), mainly fructose and glucose, and pectin (1.5%). Arils are a rich source of bioactive compounds such as phenolics and flavonoids, principally anthocyanins.
Pomegranate seed oil consists of mainly conjugated linolenic acid. Interestingly, punicic acid, a conjugated isomer of linolenic acid found uniquely in pomegranate oil, constitutes 70%–76% of the seed oil. Sterols, steroids, and cerebroside, a key component of mammalian myelin sheaths, constitute the minor share of the seed oil.
Scientific Studies on the Antioxidant Effects of POMEGRANATE
Databases of scientific studies (like the National Institutes of Health (NIH) PubMed database) contain thousands of up-to-date studies and abstracts about pomegranate.
We provide a few relevant scientific studies on the antioxidant effects of pomegranate.
Accumulating data clearly claimed that Punica granatum L. (pomegranate) has several health benefits. Pomegranates can help prevent or treat various disease risk factors including high blood pressure, high cholesterol, oxidative stress, hyperglycemia, and inflammatory activities. It is demonstrated that certain components of pomegranate such as polyphenols have potential antioxidant, anti-inflammatory, and anti-proliferative effects. The antioxidant potential of pomegranate juice is more than that of red wine and green tea, which is induced through ellagitannins and hydrosable tannins. Pomegranate juice can reduce macrophage oxidative stress, free radicals, and lipid peroxidation. Moreover, pomegranate fruit extract prevents cell growth and induces apoptosis, which can lead to its anticarcinogenic effects. In addition, promoter inhibition of some inflammatory markers and their production are blocked via ellagitannins. In this article, we highlight different studies on the therapeutic effects of pomegranate and their suggested mechanisms of actions.
J Nutr Biochem. 2005 Jun;16(6):360-7.
In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. Authors: Seeram NP1, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D.Seeram NP1, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D.
Pomegranate (Punica granatum L.) fruits are widely consumed as juice (PJ). The potent antioxidant and anti-atherosclerotic activities of PJ are attributed to its polyphenols including punicalagin, the major fruit ellagitannin, and ellagic acid (EA). Punicalagin is the major antioxidant polyphenol ingredient in PJ. Punicalagin, EA, a standardized total pomegranate tannin (TPT) extract and PJ were evaluated for in vitro antiproliferative, apoptotic and antioxidant activities. Punicalagin, EA and TPT were evaluated for antiproliferative activity at 12.5-100 microg/ml on human oral (KB, CAL27), colon (HT-29, HCT116, SW480, SW620) and prostate (RWPE-1, 22Rv1) tumor cells. Punicalagin, EA and TPT were evaluated at 100 microg/ml concentrations for apoptotic effects and at 10 microg/ml concentrations for antioxidant properties. However, to evaluate the synergistic and/or additive contributions from other PJ phytochemicals, PJ was tested at concentrations normalized to deliver equivalent amounts of punicalagin (w/w). Apoptotic effects were evaluated against the HT-29 and HCT116 colon cancer cell lines. Antioxidant effects were evaluated using inhibition of lipid peroxidation and Trolox equivalent antioxidant capacity (TEAC) assays. Pomegranate juice showed greatest antiproliferative activity against all cell lines by inhibiting proliferation from 30% to 100%. At 100 microg/ml, PJ, EA, punicalagin and TPT induced apoptosis in HT-29 colon cells. However, in the HCT116 colon cells, EA, punicalagin and TPT but not PJ induced apoptosis. The trend in antioxidant activity was PJ>TPT>punicalagin>EA. The superior bioactivity of PJ compared to its purified polyphenols illustrated the multifactorial effects and chemical synergy of the action of multiple compounds compared to single purified active ingredients.
High blood pressure, or “hypertension,” is associated with high levels of oxidative stress in the paraventricular nucleus of the hypothalamus. While pomegranate extract is a known antioxidant that is thought to have antihypertensive effects, the mechanism whereby pomegranate extract lowers blood pressure and the tissue that mediates its antihypertensive effects are currently unknown. We have used a spontaneously hypertensive rat model to investigate the antihypertensive properties of pomegranate extract. We found that chronic treatment of hypertensive rats with pomegranate extract significantly reduced blood pressure and cardiac hypertrophy. Furthermore, pomegranate extract reduced oxidative stress, increased the antioxidant defense system, and decreased inflammation in the paraventricular nucleus of hypertensive rats. We determined that pomegranate extract reduced mitochondrial superoxide anion levels and increased mitochondrial function in the paraventricular nucleus of hypertensive rats by promoting mitochondrial biogenesis and improving mitochondrial dynamics and clearance. We went on to identify the AMPK-nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) pathway as a mechanism whereby pomegranate extract reduces oxidative stress in the paraventricular nucleus to relieve hypertension. Our findings demonstrate that pomegranate extract alleviates hypertension by reducing oxidative stress and improving mitochondrial function in the paraventricular nucleus, and reveal multiple novel targets for therapeutic treatment of hypertension.
Cancer is the second leading cause of death in the United States, and those who survive cancer may experience lasting difficulties, including treatment side effects, as well as physical, cognitive, and psychosocial struggles. Naturally-occurring agents from dietary fruits and vegetables have received considerable attention for the prevention and treatment of cancers. These natural agents are safe and cost efficient in contrast to expensive chemotherapeutic agents, which may induce significant side effects. The pomegranate (Punica granatum L.) fruit has been used for the prevention and treatment of a multitude of diseases and ailments for centuries in ancient cultures. Pomegranate exhibits strong antioxidant activity and is a rich source of anthocyanins, ellagitannins, and hydrolysable tannins. Studies have shown that the pomegranate fruit as well as its juice, extract, and oil exert anti-inflammatory, anti-proliferative, and anti-tumorigenic properties by modulating multiple signaling pathways, which suggest its use as a promising chemopreventive/chemotherapeutic agent. This review summarizes preclinical and clinical studies highlighting the role of pomegranate in prevention and treatment of skin, breast, prostate, lung, and colon cancers.
Pomegranates are an important fruit full of polyphenols, anthocyanins, antioxidants, and Nrf2 activators that help to make Ultimate Protector+ such an outstanding nutritional supplement.
I previously wrote METHYLATION CYCLE, GENETICS, B VITAMINS in which I considered in-depth how the Methylation Cycle functions, how genetics affect metabolic pathways, and how B vitamins (including vitamin B12, folate, vitamin B6, and vitamin B2) are used in Methylation Cycle pathways. In today’s article, I take an in-depth view of what you need to know about vitamin B12, including the effects of not having sufficient amounts of Vitamin B12 in the body.
Vitamin B12 is one of eight B vitamins. It is the largest and most structurally complicated vitamin. It consists of a class of chemically related compounds (vitamers), all of which show physiological activity. It contains the biochemically rare element cobalt positioned in the center of a chemical ring structure.
Vitamin B12 (also called cobalamin) is a water-soluble vitamin that is involved in the metabolism of every cell of the human body. It is a cofactor in DNA synthesis, and in both fatty acid and amino acid metabolism. It is particularly important in the normal functioning of the nervous system via its role in the synthesis of myelin and in the maturation of developing red blood cells in the bone marrow.
Vitamin B12 contains the biochemically rare element cobalt positioned in the center of a chemical ring structure.
YOUR NEED FOR VITAMIN B12
Vitamin B12 deficiency is thought to be one of the leading nutritional deficiencies in the world. An extensive 2004 study showed that deficiency is a major health concern in many parts of the world, including the North America, Central and South America, India, and certain areas in Africa. It is estimated that 40 percent of people may have low levels of vitamin B12.
Vitamin B12 affects your mood, energy level, memory, nervous system, heart, skin, hair, digestion and more. It is a key nutrient regarding adrenal fatigue and multiple metabolic functions including enzyme production, DNA synthesis, and hormonal balance.
Because of vitamin B12’s extensive roles within the body, a vitamin deficiency can show up in many different symptoms, such as chronic fatigue, mood disorders such as depression, chronic stress, and low energy.
SOURCES OF VITAMIN B12
The only organisms to produce vitamin B12 are certain bacteria and archaea. Some of these bacteria are found in the soil around the grasses that ruminants eat. They are taken into the animal, proliferate, form part of their gut flora, and continue to produce vitamin B12.
Products of animal origin such as beef (especially liver), chicken, pork, eggs, dairy, clams, and fish constitute the primary food source of vitamin B12. Older individuals and vegans are advised to use vitamin B12 fortified foods and supplements to meet their needs.
Salmon is a good source of Vitamin B12
Commercially, Vitamin B12 is prepared by bacterial fermentation. Fermentation by a variety of microorganisms yields a mixture of methylcobalamin, hydroxocobalamin, and adenosylcobalamin. Since multiple species of propionibacterium produce no exotoxins or endotoxins and have been granted GRAS status (generally regarded as safe) by the United States Food and Drug Administration, they are the preferred bacterial fermentation organisms for vitamin B12 production.
Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 used in the human body (called coenzyme forms). The form of cobalamin used in many some nutritional supplements and fortified foods, cyanocobalamin, is readily converted to 5-deoxyadenosylcobalamin and methylcobalamin in the body.
Hydroxocobalamin is the direct precursor of methylcobalamin and 5-deoxyadenosylcobalamin. In mammals, cobalamin is a cofactor for only two enzymes, methionine synthase (MS) and L-methylmalonyl-coenzyme A mutase (MUT).
Unlike most other vitamins, B12 is stored in substantial amounts, mainly in the liver, until it is needed by the body. If a person stops consuming the vitamin, the body’s stores of this vitamin usually take about 3 to 5 years to exhaust. Vitamin B12 is primarily stored in the liver as 5-deoxyadenosylcobalamin, but is easily converted to methylcobalamin.
ABSORPTION OF VITAMIN B12
Vitamin B12, bound to protein in food, is released by the activity of hydrochloric acid and gastric protease in the stomach. Intestinal absorption of vitamin B12 requires successively three different protein molecules: Haptocorrin, Intrinsic Factor and Transcobalamin II. If there are deficiencies in any of these factors absorption of Vitamin B12 can be seriously decreased.
When vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and, thus, does not require the separation from food protein step. Free vitamin B12 then combines with intrinsic factor, a glycoprotein secreted by the stomach’s parietal cells, and the resulting complex undergoes absorption within the distal ileum by receptor-mediated endocytosis.
Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of vitamin B12).
Vitamin B12 deficiency can be difficult to detect, especially since the symptoms of a vitamin B12 deficiency can be similar to many common symptoms, such as feeling tired or unfocused, experienced by people for a variety of reasons.
Vitamin B12 deficiency is commonly associated with chronic stomach inflammation, which may contribute to an autoimmune vitamin B12 malabsorption syndrome called pernicious anemia and to a food-bound vitamin B12 malabsorption syndrome. Poor absorption of vitamin B may be related to coeliac disease. Impairment of vitamin B12 absorption can cause megaloblastic anemia and neurologic disorders in deficient subjects. In some cases, permanent damage can be caused to the body when B12 amounts are deficient.
It is noteworthy that normal function of the digestive system required for food-bound vitamin B12 absorption is commonly impaired in individuals over 60 years of age, placing them at risk for vitamin B12 deficiency.
A diagnosis of vitamin B12 deficiency is typically based on the measurement of serum vitamin B12 levels within the blood. However, studies show that about 50 percent of patients with diseases related to vitamin B12 deficiency have normal B12 levels when tested. This can cause individuals to ignore taking in adequate levels of vitamin B12 with potential serious consequences.
FUNCTIONS AND ISSUES ASSOCIATED WITH VITAMIN B12 STATUS IN THE BODY
Vitamin B12 or cobalamin plays essential roles in folate metabolism and in the synthesis of the citric acid cycle intermediate, succinyl-CoA.
Vitamin B12 deficiency is commonly associated with chronic stomach inflammation, which may contribute to an autoimmune vitamin B12 malabsorption syndrome called pernicious anemia and to a food-bound vitamin B12 malabsorption syndrome. Impairment of vitamin B12 absorption can cause megaloblastic anemia and neurologic disorders in deficient subjects.
Normal function of the digestive system required for food-bound vitamin B12 absorption is commonly impaired in individuals over 60 years of age, placing them at risk for vitamin B12 deficiency.
Vitamin B12 and folate are important for homocysteine metabolism. Elevated homocysteine levels in blood are a risk factor for cardiovascular disease (CVD). B vitamin supplementation has been proven effective to control homocysteine levels.
The preservation of DNA integrity is dependent on folate and vitamin B12 availability. Poor vitamin B12 status has been linked to increased risk of breast cancer in some, but not all, observational studies.
Low maternal vitamin B12 status has been associated with an increased risk of neural tube defects (NTD), but it is not known whether vitamin B12 supplementation could help reduce the risk of NTD.
Vitamin B12 is essential for the preservation of the myelin sheath around neurons and for the synthesis of neurotransmitters. A severe vitamin B12 deficiency may damage nerves, causing tingling or loss of sensation in the hands and feet, muscle weakness, loss of reflexes, difficulty walking, confusion, and dementia.
While hyperhomocysteinemia may increase the risk of cognitive impairment, it is not clear whether vitamin B12 deficiency contributes to the risk of dementia in the elderly. Although B-vitamin supplementation lowers homocysteine levels in older subjects, the long-term benefit is not yet known.
Both depression and osteoporosis have been linked to diminished vitamin B12 status and high homocysteine levels.
The long-term use of certain medications, such as inhibitors of stomach acid secretion, can adversely affect vitamin B12 absorption.
Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis.
MORE DETAILS ASSOCIATED WITH VITAMIN B12 STATUS IN THE BODY
1. Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis. Vitamin B12 as methylcobalamin functions as a cofactor for methionine synthase. Methionine synthase (MS) catalyzes the conversion of homocysteine to methionine. Methionine along with ATP is required for the formation of S-adenosylmethionine (SAMe), a universal methyl donor for almost 100 different substrates, including DNA, RNA, hormones, proteins, and lipids.
2. Vitamin B12 as 5-deoxyadenosylcobalamin functions as a cofactor along with L-methylmalonyl-CoA mutase (MUT) to convert L-methylmalonyl-CoA to succinyl-CoA in the degradation of propionate, an essential biochemical reaction in fat and protein metabolism. Succinyl-CoA is also required for hemoglobin synthesis.
3. Vitamin B12, bound to protein in food, is released by the activity of hydrochloric acid and gastric protease in the stomach. When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and, thus, does not require this separation step. Free vitamin B12 then combines with intrinsic factor, a glycoprotein secreted by the stomach’s parietal cells, and the resulting complex undergoes absorption within the distal ileum by receptor-mediated endocytosis. Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of vitamin B12).
4. Pernicious anemia is an autoimmune disease that affects the gastric mucosa and results in gastric atrophy. This leads to the destruction of parietal cells, achlorhydria, and failure to produce intrinsic factor, resulting in vitamin B12 malabsorption. If pernicious anemia is left untreated, it causes vitamin B12 deficiency, leading to megaloblastic anemia and neurological disorders, even in the presence of adequate dietary intake of vitamin B12.
5. Vitamin B12 status is typically assessed via serum or plasma vitamin B12 levels. Values below approximately 170–250 pg/mL (120–180 picomol/L) for adults indicate a vitamin B12 deficiency. However, evidence suggests that serum vitamin B12 concentrations might not accurately reflect intracellular concentrations. An elevated serum homocysteine level (values >13 micromol/L) might also suggest a vitamin B12 deficiency. However, this indicator has poor specificity because it is influenced by other factors, such as low vitamin B6 or folate levels. Elevated methylmalonic acid levels (values >0.4 micromol/L) might be a more reliable indicator of vitamin B12 status because they indicate a metabolic change that is highly specific to vitamin B12 deficiency.
6. Vitamin B12 deficiency is characterized by megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, and weight loss. Neurological changes, such as numbness and tingling in the hands and feet, can also occur . Additional symptoms of vitamin B12 deficiency include difficulty maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue. The neurological symptoms of vitamin B12 deficiency can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage. During infancy, signs of a vitamin B12 deficiency include failure to thrive, movement disorders, developmental delays, and megaloblastic anemia. Many of these symptoms are general and can result from a variety of medical conditions other than vitamin B12 deficiency.
7. Typically, vitamin B12 deficiency is treated with vitamin B12 injections, since this method bypasses potential barriers to absorption. However, high doses of oral vitamin B12 can also be effective. The authors of a review of randomized controlled trials comparing oral with intramuscular vitamin B12 concluded that 2,000 mcg (I like 5,000 mcg) of oral vitamin B12 daily, followed by a decreased daily dose of 1,000 mcg and then 1,000 mcg weekly and finally, monthly might be as effective as intramuscular administration. Overall, an individual patient’s ability to absorb vitamin B12 is the most important factor in determining whether vitamin B12 should be administered orally or via injection. In most countries, the practice of using intramuscular vitamin B12 to treat vitamin B12 deficiency has remained unchanged.
8. Large amounts of folate can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological damage that also occurs. Moreover, preliminary evidence suggests that high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency. Permanent nerve damage can occur if vitamin B12 deficiency is not treated. For these reasons, folate intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults.
Groups at Risk of Vitamin B12 Deficiency
The main causes of vitamin B12 deficiency include vitamin B12 malabsorption from food, pernicious anemia, postsurgical malabsorption, and dietary deficiency. However, in many cases, the cause of vitamin B12 deficiency is unknown. The following groups are among those most likely to be vitamin B12 deficient.
Older adults: Atrophic gastritis, a condition affecting 10%–30% of older adults, decreases secretion of hydrochloric acid in the stomach, resulting in decreased absorption of vitamin B12. Decreased hydrochloric acid levels might also increase the growth of normal intestinal bacteria that use vitamin B12, further reducing the amount of vitamin B12 available to the bodY.
Individuals with atrophic gastritis are unable to absorb the vitamin B12 that is naturally present in food. Most, however, can absorb the synthetic vitamin B12 added to fortified foods and dietary supplements. As a result, the IOM recommends that adults older than 50 years obtain most of their vitamin B12 from vitamin supplements or fortified foods. However, some elderly patients with atrophic gastritis require doses much higher than the RDA to avoid subclinical deficiency.
Individuals with pernicious anemia: Pernicious anemia, a condition that affects 1%–2% of older adults, is characterized by a lack of intrinsic factor. Individuals with pernicious anemia cannot properly absorb vitamin B12 in the gastrointestinal tract. Pernicious anemia is usually treated with intramuscular vitamin B12. However, approximately 1% of oral vitamin B12 can be absorbed passively in the absence of intrinsic factor, suggesting that high oral doses of vitamin B12 might also be an effective treatment.
Individuals with gastrointestinal disorders: Individuals with stomach and small intestine disorders, such as celiac disease and Crohn’s disease, may be unable to absorb enough vitamin B12 from food to maintain healthy body stores. Subtly reduced cognitive function resulting from early vitamin B12 deficiency might be the only initial symptom of these intestinal disorders, followed by megaloblastic anemia and dementia.
Individuals who have had gastrointestinal surgery: Surgical procedures in the gastrointestinal tract, such as weight loss surgery or surgery to remove all or part of the stomach, often result in a loss of cells that secrete hydrochloric acid and intrinsic factor. This reduces the amount of vitamin B12, particularly food-bound vitamin B12, that the body releases and absorbs. Surgical removal of the distal ileum also can result in the inability to absorb vitamin B12. Individuals undergoing these surgical procedures should be monitored preoperatively and postoperatively for several nutrient deficiencies, including vitamin B12 deficiency.
Vegetarians: Strict vegetarians and vegans are at greater risk than lacto-ovo vegetarians and non-vegetarians of developing vitamin B12 deficiency because natural food sources of vitamin B12 are limited to animal foods. Fortified breakfast cereals and fortified nutritional yeasts are some of the only sources of vitamin B12 from plants and can be used as dietary sources of vitamin B12 for strict vegetarians and vegans. Fortified foods vary in formulation, so it is important to read the Nutrition Facts labels on food products to determine the types and amounts of added nutrients they contain.
Pregnant and lactating women who follow strict vegetarian diets and their infants: Vitamin B12 crosses the placenta during pregnancy and is present in breast milk. Exclusively breastfed infants of women who consume no animal products may have very limited reserves of vitamin B12 and can develop vitamin B12 deficiency within months of birth. Undetected and untreated vitamin B12 deficiency in infants can result in severe and permanent neurological damage.
The American Dietetic Association recommends supplemental vitamin B12 for vegans and lacto-ovo vegetarians during both pregnancy and lactation to ensure that enough vitamin B12 is transferred to the fetus and infant. Pregnant and lactating women who follow strict vegetarian or vegan diets should consult with a pediatrician regarding vitamin B12 supplements for their infants and children.
Health Risks from Excessive Vitamin B12
The IOM did not establish a UL for vitamin B12 because of its low potential for toxicity. In Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, the IOM states that “no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy individuals”.
Findings from intervention trials support these conclusions. In the NORVIT and HOPE 2 trials, vitamin B12 supplementation (in combination with folic acid and vitamin B6) did not cause any serious adverse events when administered at doses of 0.4 mg for 40 months (NORVIT trial) and 1.0 mg for 5 years (HOPE 2 trial).
Interactions with Medications
Vitamin B12 has the potential to interact with certain medications. In addition, several types of medications might adversely affect vitamin B12 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B12 status with their healthcare providers.
Chloramphenicol: Chloramphenicol (Chloromycetin®) is a bacteriostatic antibiotic. Limited evidence from case reports indicates that chloramphenicol can interfere with the red blood cell response to supplemental vitamin B12 in some patients.
Proton pump inhibitors: Proton pump inhibitors, such as omeprazole (Prilosec®) and lansoprazole (Prevacid®), are used to treat gastroesophageal reflux disease and peptic ulcer disease. These drugs can interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach. However, the evidence is conflicting on whether proton pump inhibitor use affects vitamin B12 status. As a precaution, healthcare providers should monitor vitamin B12 status in patients taking proton pump inhibitors for prolonged periods.
H2 receptor antagonists: Histamine H2 receptor antagonists, used to treat peptic ulcer disease, include cimetidine (Tagamet®), famotidine (Pepcid®), and ranitidine (Zantac®). These medications can interfere with the absorption of vitamin B12 from food by slowing the release of hydrochloric acid into the stomach. Although H2 receptor antagonists have the potential to cause vitamin B12 deficiency, no evidence indicates that they promote vitamin B12 deficiency, even after long-term use. Clinically significant effects may be more likely in patients with inadequate vitamin B12 stores, especially those using H2 receptor antagonists continuously for more than 2 years.
Metformin: Metformin, a hypoglycemic agent used to treat diabetes, might reduce the absorption of vitamin B12, possibly through alterations in intestinal mobility, increased bacterial overgrowth, or alterations in the calcium-dependent uptake by ileal cells of the vitamin B12-intrinsic factor complex. Small studies and case reports suggest that 10%–30% of patients who take metformin have reduced vitamin B12 absorption. In a randomized, placebo controlled trial in patients with type 2 diabetes, metformin treatment for 4.3 years significantly decreased vitamin B12 levels by 19% and raised the risk of vitamin B12 deficiency by 7.2% compared with placebo. Some studies suggest that supplemental calcium might help improve the vitamin B12 malabsorption caused by metformin, but not all researchers agree.
Background: Low vitamin B-12 status is prevalent among the elderly, but few studies have examined the association between vitamin B-12 status and intake.Objective: We hypothesized that vitamin B-12 concentrations vary according to intake source.Design: Plasma concentrations and dietary intakes were assessed cross-sectionally for 2999 subjects in the Framingham Offspring Study. The prevalence of vitamin B-12 concentrations <148, 185, and 258 pmol/L was examined by age group (26–49, 50–64, and 65–83 y), supplement use, and the following food intake sources: fortified breakfast cereal, dairy products, and meat.Results: Thirty-nine percent of subjects had plasma vitamin B-12 concentrations <258 pmol/L, 17% had concentrations <185 pmol/L, and 9% had concentrations <148 pmol/L, with little difference between age groups. Supplement users were significantly less likely than non-supplement-users to have concentrations <185 pmol/L (8% compared with 20%, respectively). Among non-supplement-users, there were significant differences between those who consumed fortified cereal >4 times/wk (12%) and those who consumed no fortified cereal (23%) and between those in the highest and those in the lowest tertile of dairy intake (13% compared with 24%, respectively), but no significant differences by meat tertile. Regression of plasma vitamin B-12 on log of intake, by source, yielded significant slopes for each contributor adjusted for the others. For the total group, b = 40.6 for vitamin B-12 from vitamin supplements. Among non-supplement-users, b = 56.4 for dairy products, 35.2 for cereal, and 16.7 for meat. Only the meat slope differed significantly from the others.Conclusions: In contrast with previous reports, plasma vitamin B-12 concentrations were associated with vitamin B-12 intake. Use of supplements, fortified cereal, and milk appears to protect against lower concentrations. Further research is needed to investigate possible differences in bioavailability.
Almost daily articles, reports, or studies appear claiming nutritional supplements are not effective. The claims vary, but the verdict is always there is little or no scientific evidence proving supplements (or the nutrients in supplements) work. Others assert that people who take supplements have the world’s most expensive urine. This is nonsense! The scientific evidence is clear, available, and it has been for a long time.
Among the many problems with these reports is bashing supplements based on studies using low dose or non-therapeutic levels of nutrients. There is frequently failure to consider the importance of synergy among nutrients. Often there is data manipulation via statistical methods (often in meta-analyses).
Well beyond the question of whether supplements support health are the factors in modern life that create a greater needs for supplementing with important vitamins, minerals, cofactors, and other nutrients.
This month we present “Seven Arguments for Nutritional Supplements.” As the title implies, there are at least seven solid arguments for nutritional supplementation. There are actually a lot more.
To preview these arguments in favor of taking supplements, they are: 1) reduced food quality, 2) nutrient density varies by location, 3) modern lifestyles and stress, 4) environmental pollution, 5) too low RDAs, and 6) promotion of health and delaying of aging, and 7) the human right to correct information.
Essential Fatty Acids (EFA) are one type of essential nutrient required for health.
We at HPDI re-publish articles from the Orthomolecular News Service (OMNS) because the authors provide much needed truth. Truth the form of correcting the false assumptions of anti-supplement propagandists to clarify the benefits of nutritional supplements. This information can help people be healthier easily and at relatively low cost.
HPDI offers a full line of foundational nutritional supplements, including multivitamins, vitamin C and antioxidant formulas, essential fats, and high-RNA Rejuvenate! superfoods. We also offer nearly 100 other nutritional supplements from single nutrients to condition specific formulas. See our full product overview.
Enjoy this article from the Orthomolecular News Service (OMNS). ~
Seven Arguments for Taking Nutritional Supplements
by Dag Viljen Poleszynski, PhD
(OMNS Sept 12 2018)
One of the most vitamin-restrictive countries in the world is Norway. There, authorities limit potencies to only slightly higher than RDA (Recommended Dietary Allowance) levels for dietary supplements sold outside of pharmacies. The traditional reasoning is that most people receive the nutrients they need from a “balanced diet.” 
The authorities are also obsessively concerned that some vitamins and minerals are harmful in high doses. And, since an intake of water-soluble vitamins in excess of needs is excreted in the urine, Norwegian “experts” advise that taking supplements is a waste of money.
Accordingly, the argument goes, the public should be protected not only from possible harm, but also from wasting money on unnecessary nutrients. The official policies on nutritional supplements vary within OECD (Organization for Economic Cooperation and Development) countries. Some are more liberal, while others are even more restrictive.
The official view on the connection between nutrient intake and possible toxicity is illustrated by the Norwegian Food Authority in a graph. 
Perceived risk from intake of nutrients. (Source: Expert Group on Vitamins and Minerals. Safe upper limits for Vitamins and Minerals. May 2003: Food Standards Agency, UK.)
The graph illustrates the official view on nutrients, assuming that nutrients function in the same way as pharmaceuticals, which they do not. Supplements of most vitamins, but also minerals and other nutrients, do not have very serious side effects even when taken at very high levels – in contrast with most drugs. [3,4] The fact that most of the chemotherapeutic drugs used against cancer have none or even just marginal effects against most cancers , while at the same time cause a lot of serious side effects, is rarely up for discussion.
The idea that nutritional supplements are not safe has a legal underpinning in Norwegian Food Law, which in section 16 prohibits sale of any food which is not safe: “Any food shall be considered not to be safe if it is seen as detrimental to health or not fit for consumption.” 
However, the Norwegian authorities do admit that vitamin D supplements are needed during part of the year.  Only part of the year? One third of Norway is within the Arctic Circle. Norway has far too little sunshine (especially during winter months) to get adequate levels of vitamin D from UVB radiation on the skin.
The authorities also recommend that pregnant women take folic acid to prevent birth defects, and omega-3-fatty acids may be advisable for those who do not eat fish regularly. Norwegians have a long tradition of giving children cod liver oil, which in a daily tablespoon provides enough vitamin A and D and essential fatty acids to cover basic needs.
Essential and conditionally essential nutrients
There are thousands of dietary supplements on the market, including 40+ essential nutrients alone and in various combinations, i.e. vitamins, minerals, trace elements and fatty acids. However, a number of other nutrients are “conditionally essential”, meaning that the body normally can make these molecules, but some people do not make optimal amounts. Examples are L-carnitine, alpha-lipoic acid, the methyl donor betaine,  chondroitin sulfate, coenzyme Q10, choline, amino acids such as tyrosine or arginine, and “essential” sugars normally formed in the body. 
Healthy young people normally make sufficient amounts of conditionally essential molecules in the body, although the levels are not always optimal. With inadequate levels of minerals or vitamins, key enzymes in biochemical pathways may not function optimally.
Due to genetic mutations, some enzymes may have increased needs for certain cofactors (vitamins), which can prevent them from functioning optimally. Some enzymes only function normally when supplied with cofactors in greater amounts than normally required.
If supplements of essential nutrients prove insufficient for optimal enzyme function, “conditionally essential” nutrients may be added as part of a comprehensive, therapeutic program.
Parents are advised to become familiar with the literature on essential nutrients, for instance by consulting the Orthomolecular News Service. Children should be given supplements in appropriate doses and in a suitable form. Pills should not be given before children can control the swallowing reflex. Multivitamin powder can be given dissolved in water or juice. Parents should not dose vitamin C so high that a child comes to school or kindergarten with loose bowels or diarrhea.
In high doses, niacin may cause unpleasant side effects such as flushing and itching lasting up to several hours.  Although this is not dangerous, it may cause a child to feel unwell and anxious. Starting niacin supplementation with a low dose and gradually increasing it will allow the body to adapt and avoid the niacin flush.
A multivitamin supplement containing moderate amounts of niacin is often adequate until a child is 8-10 years old. For younger children, the dosage should start with only a few tens of milligrams, and not increased to more than 50-100 mg/day. Adults may gradually get used to taking 1,000-1,500 mg/d divided into 3 doses per day.
When it comes to omega-3 fatty acids (omega = ω) such as EPA and DHA, children may be given cod liver oil and served fish and/or other seafood 2-3 times a week. It is important to check the dose of vitamin A supplied, as it can be toxic in high doses, especially for children. One problem with cod liver oil today is that vitamin D has been removed during processing, thus changing the natural ratio of the two vitamins so that we ingest relatively too much of vitamin A. 
Higher dosages may be given after having consulted a therapist who has measured the ratio of omega-6 to omega-3 fatty acids in relevant cell membranes (red blood cells). In most industrialized countries, many people get too much of the omega-6 fatty acids, and would therefore benefit from eating more seafood or taking supplements with omega-3 fatty acids derived from organisms low in the food chain (algae, krill).
Flax seeds contain a high level of the essential omega-3 fatty acid alpha-linolenic acid, and freshly ground flaxseed meal or flax oil can be mixed with breakfast cereals or smoothies. Note that it may be advisable to limit eating farmed fish to once per week, since their fodder contains less omega-3 fatty acids than the food eaten by wild fish, and possibly also contains more contaminants.  Some researchers even warn against letting children eat too much fish because of the content of environmental toxins. [13,14]
Reasons for high-dose supplements of micronutrients
I have identified a number of arguments in favor of supplementing the modern diet with essential nutrients, here summarized with seven headlines. Most people should consider taking a multivitamin supplement containing vitamins and minerals even if they eat a nutritionally balanced diet.
Additional nutrients may contribute to better health and, in some cases, can be of vital importance in our modern world. The arguments are presented in random order, i.e. the order does not reflect priority.
1. The agricultural revolution has reduced food quality
The transition from an existence as hunter and gatherers to urban agriculture around 10,000 years ago began an epoch when foods were mass-produced but had lower nutritional density, compared with the previous food eaten by our ancestors. The nutritional density in many foods has fallen significantly since human societies transformed from hunter-gatherers into resident farmers. This is especially true in the last 60-70 years after agriculture was changed from small, versatile ecologically driven family farms to large, chemical-based, industrial agriculture. 
The reduction of nutritional content in modern crops, compared with older varieties, is well documented.  It is a consequence of soil erosion, loss of essential minerals from continual heavy use, combined with breeding of new varieties, which has increased the size and growth rate of plants by increasing the content of sugar and water and decreasing their mineral content compared to ancient species. At the same time, the relative content of other macronutrients (fat, protein/amino acids) and antioxidants may have been reduced.
Reduced nutritional density in many foods, combined with the use of refined “foods” like sugar, white flour and refined oils, places a greater priority on eating the most nutritious foods.
Farm produce grown organically generally has higher levels of essential nutrients such as trace minerals because the soil contains higher levels of trace minerals and the produce grows slower and thus has more time to absorb nutrients from the soil. Examples of nutrient dense foods are sardines, wild salmon, shellfish, eggs, liver, kale, collards and spinach, sea plants (seaweed), garlic, blueberries, and dark chocolate. 
2. Nutritional content of food varies with geographical location
Nutritional density varies considerably geographically between different regions, even with the same agricultural methods. This was documented in the United States in 1948 by a researcher at Rutgers University in the so-called Firman Bear report.  At that time agriculture was little mechanized, and artificial fertilizers and pesticides were hardly used.
The analysis found large differences in the content of minerals in the same food. The largest variations were found for potassium, sodium, boron and iron in spinach, while the greatest differences in calcium, magnesium and copper content were found in tomatoes.
The soil in areas with relatively low rainfall may in some cases contain an extremely high concentration of minerals, which is reflected in the plants growing there. This was well documented 70 years ago in the book Tomorrow’s Food.  The dentist George W. Heard found that the soil in Hereford, Texas, was exceptionally rich in minerals.
Hereford became known as the “town without a toothache” after a newspaper article from January 29, 1942, reported that Hereford had the lowest incidence of tooth decay of any city in the United States.  Dr. Heard found that people in Hereford had exceptionally few dental cavities and also that the soil locally was especially rich in minerals. He emphasized that the population in the county ate unprocessed food and was drinking raw milk. 
Recent research shows that differences in the content of the selenium in the soil can cause major differences in the concentration of selenium in meat.  For instance, since the soil in Finland is poor in selenium, the authorities decided in the early 1980s to add selenate to commercial fertilizers. A survey of selenium status among 108 healthy young people showed an increase in the blood selenium level of about 50 percent after four years. 
A similar problem with the level of minerals in the soil exists for the content of magnesium. Often when the soil gets depleted of magnesium from heavy use, this essential mineral is not included in soil amendment with fertilizers. Produce grown in soil with an adequate level of magnesium will contain more magnesium than produce grown in soil deficient in magnesium.
Perhaps as many as 70-80% of the US population is magnesium-deficient, which causes many health problems.  Magnesium supplements (chloride, malate or citrate) can provide an adequate level when vegetables grown in soil with adequate magnesium are not available.
3. Stress and the modern lifestyle increase the need for nutrients
Mental stress increases the excretion and hence the need for many nutrients. Among the most important are magnesium and vitamin C, both of which are used by the body in larger quantities during periods of physical and mental stress. [24,25] Compared with our past as hunters and gatherers, today´s stress is often of a more permanent nature. Instead of experiencing occasional situations where we had to fight or flee, many of us live with recurring stress day in and out.
Vitamin C protects the brain and nervous system from damage caused by stress because the synthesis and maintenance of chemical neurotransmitters such as adrenaline and noradrenaline requires adequate levels of vitamin C. 
Vitamin C is also needed to repair collagen which is essential for skin, blood vessels, bones and joints, and muscles. When these are damaged by physical stress, extra vitamin C is necessary.
A controlled trial of 91 adults who experienced increased anxiety and stress 2-3 months after an earthquake in New Zealand in 2011 was divided into three groups, two were given a broad spectrum supplement of micronutrients in low or higher doses.  The supplements were found to alleviate the experience of stress, with the biggest dose having the biggest effect.
Our sedate, modern lifestyle reduces the need for energy from food, which implies a lower food intake or obesity. Loren Cordain, PhD, and coworkers have estimated that hunter-gatherers had significantly higher energy needs than the typical modern office worker. 
A lower energy intake generally reduces the absolute intake of all nutrients, while the need for some nutrients is not always reduced proportionally with energy intake. Overall this suggests that more exercise along with a more nutritious diet, including supplements of essential nutrients and less carbohydrates, will help to prevent obesity and maintain health.
Processing of food reduces its nutritional content, and the finished products are often based on fractions of the original foods. One example is milling grain to make white flour,  which has a lower nutritional density than whole grain flour.
The reduction in nutritional value has accelerated since whole foods are now divided into pieces, for example, boneless chicken breast. When meat is injected with saline to increase the volume, the relative level of essential nutrients is reduced. In the United States, many supermarkets in low-income rural and inner city areas have a limited selection of nutrient-dense foods, compared with high-income areas. 
4. Environmental pollutants increase the need for nutrients
The need for efficient detoxification and excretion is greatly increased by environmental pollution from the chemical industry, herbicides and pesticides used by industrial agriculture, antibiotic treatment of animals, transport, and plastic packaging. 
In our polluted world, the increased toxic load may be compensated for by an increase in nutrients to promote detoxification. One can respond by taking large doses of supplements of essential nutrients, for example, antioxidants vitamin C and E, and an adequate dose of selenium, which help the body detoxify harmful chemicals. Also helpful is regularly taking sauna baths, fasting periodically, and eating an excellent diet that includes generous portions of dark green leafy vegetables and colorful vegetables and fruits. 
A recent study predicts that global warming may reduce the nutrient density in many foods worldwide.  Atmospheric CO2 is estimated to surpass 550 ppm in the next 30-80 years, leading to larger crops with lower content of protein, iron and zinc per energy unit.
Assuming that diets remain constant, while excluding other climate impacts on food production, the researchers estimated that elevated CO2 could cause an additional 175 million people to be zinc deficient and an additional 122 million people to be protein deficient in 2050. Anemia would increase significantly if crops lose even a small amount of iron. The highest risk regions – South and Southeast Asia, Africa, and the Middle East – are especially vulnerable, since they do not have the means and access to compensate using nutritional supplements.
5. The RDA for essential nutrients is too low
The recommended nutrient reference intake (NRI) has been defined by UK authorities and the EU Food Safety Agency as the dose that is adequate for 95 percent of the population.  These authorities have given recommendations for a total of 41 chemical substances,  including 13 vitamins, 17 minerals/trace elements, 9 amino acids and two fatty acids. The problem with such guidelines is that when using the same 0.95 fraction for just 16 of the essential nutrients, the fraction of the overall population that has their needs met with the RDA is less than half (0.9516 = 0.44).
Given the above assumption, the proportion of the population having all nutrient needs met falls below 25 percent for 30 nutrients (0.9530 = 0.21). These 25 percent will not necessarily get optimal amounts, just enough so that they probably will have no deficiencies in accordance with established standards. Each individual is different and has different biochemical needs, so we all need different doses of essential nutrients. Many vitamins and minerals can give additional benefit when taken at higher doses.
The need for several essential nutrients increases with age and sickness. This applies, for example, to vitamin C, vitamin D, magnesium, and iron. In 2017 the Norwegian Food Safety Authority proposed to revise the official maximum levels for vitamins and minerals in dietary supplements. 
Their proposal introduced four different age categories with separate maximum intakes. Initially, the agencies proposed to revise the daily doses allowed in dietary supplements for folic acid, magnesium, calcium, vitamin C and D. At the same time, maximum rates were temporarily suspended for vitamins A, E, K, thiamine (B1), riboflavin (B2), niacin (B3), pantothenate (B5), pyridoxine (B6), cobalamine (B12), biotin, and for phosphorus, iron, copper, iodine, zinc, manganese, selenium, chromium, molybdenum, sodium, potassium, fluoride, chloride, boron and silicon.
The upper limits for some nutrients may be changed in the future. Unfortunately, Norwegian nutrition “experts” will likely continue to limit allowable doses below those freely available in the US and even Sweden.
6. An optimal nutrient intake promotes health and delays aging
A spokesperson for optimal nutritional intake is the well-known biochemist Bruce Ames, who proposed the “triage theory of nutrients,” in which enzymes responsible for cell maintenance functions evolved to have lower affinity for the essential vitamin and mineral cofactors than the enzymes responsible for short-term survival, to preserve life during times of famine. 
Thus, higher levels of vitamins and minerals may delay mitochondrial aging, speed up the repair of large molecules such as DNA and collagen, and generally improve other cellular functions. This is an important rationale for taking higher doses of vitamins and minerals than recommended reference intakes.
Dietary supplements can slow the aging process, in part by reducing the harmful effects of free radicals, known to be involved in many diseases such as cardiovascular disease and cancer. 
Naturally occurring hormones and/or supplements of cofactors needed for optimal hormone production in the body can have a significant life-prolonging effect if the body produces less than optimal amounts.  This is especially relevant for those with a genetic predisposition for disease.
An optimum intake of all nutrients is difficult to achieve even for those who eat almost exclusively an excellent diet of nutrient dense foods, such as meat and innards, fish, shellfish, fowl, eggs, nuts, mushrooms, and vegetables, berries and nutritious fruits. Some nutrients such as folic acid or carotenoids in vegetables are absorbed better from processed than unprocessed foods.
Although vegetables are often considered to be a good source of vitamins, for example vitamin A from carrots, vitamin A is only found in animal products such as liver, egg yolk, fish cod and cod liver oil. Although eating raw vegetables is helpful for several reasons (vitamin C, fiber, microbiota), carotenoids (alpha/beta-carotene, lutein, lycopene) in vegetables are less well absorbed from raw than cooked food and better absorbed in the presence of added fat. [38,39].
Nutrients in vegetables are better absorbed when finely chewed, graded, or mashed , and cooking and grinding meat reduces the energy required to digest it  and increases nutrient absorption .
Orthomolecular pioneer Abram Hoffer and Orthomolecular News Service Editor Andrew W. Saul suggested this list of daily intakes of vitamins and minerals.  The Norwegian 2017 recommendations for adult men and women  are given in comparison. Individual needs may vary substantially from person to person and also with health status.
The figures for optimal intake are obtained from the Independent Vitamin Safety Review Panel of physicians, researchers and academics, who concluded:
“People are deceived in believing that they can get all the nutrients they need from a ‘balanced diet’ consisting of processed foods. To achieve an adequate intake of vitamins and minerals, a diet of unprocessed whole foods, along with intelligent use of dietary supplements is more than just a good idea: it is vital.” [44: 55]
A well-known example is vitamin C, which can effectively fight viral infections, prevent or reverse disease caused by bacteria, and help the body detoxify organic and inorganic toxins.  Vitamin C also reduces the risk for cancer, strengthens connective tissues (collagen), and counteracts stress by increasing the adrenal´s production of cortisol. The dose required is set according to the body’s need.
Nobel Price Laureate Linus Pauling suggested that an optimal daily intake of vitamin C could vary from at least 250 mg up to 20 grams per day.  Because unabsorbed vitamin C attracts water into the gut, some people may experience loose stools, gas and/or diarrhea by ingesting only 1-2 grams at a time, while others with a higher level of stress may tolerate 5-6 grams or more. The dose that causes loose stools is called the “bowel tolerance” for vitamin C.  To avoid the laxative effect of high doses, it is best to take vitamin C throughout the day in smaller divided doses.
When the body is stressed by disease, the gut will naturally absorb more vitamin C because the body needs more. To find the optimal dose, the intake should be increased until bowel tolerance is reached. Some people can tolerate more than 100,000 mg/d of vitamin C in divided doses during serious illness without having loose stool.
Liposomal vitamin C bypasses the normal bowel tolerance because it is absorbed directly through cell membranes, so higher doses can be tolerated without diarrhea.
7. A human right to receive correct information
Access to correct information about food and essential nutrients, including knowledge about the importance of food for health is a fundamental human right. Such information should not only provide a summary of the nutrient content of food, but in our opinion should also explain how dietary supplements can counteract deficiencies and prevent and reverse disease caused by nutrient deficiencies.
We should be free to purchase quality-controlled supplements of essential nutrients and to use them to counteract aging and damage from stress as part of a long-term health plan. The right to reject recommendations by doctors for symptomatic treatment with synthetic, some times life-threatening, drugs to alleviate symptoms should be included. [48,49]
I have not found any formulation of such rights from the Norwegian authorities. The role of parents and their right to receive correct health information is addressed in a book by lawyer Anne Kjersti C. Befring, a fellow at the University of Oslo since 2014. 
The use of dietary supplements is widespread. High doses of vitamins are thought to be helpful because they help the body recover from damage and maintain itself long-term. Many vitamins are not harmful in doses even 10 to 100-fold higher than officially recommended.
Some governments warn about possible negative side effects, even including increased mortality from “excessive” intake of certain supplements. However, supplements of essential nutrients have been available for more than 80 years. They are known to be safe, and the observed side effects are generally mild with few exceptions.
It is possible to ingest too much of certain vitamins and minerals (vitamin A, calcium, iron, copper, selenium) which may exacerbate an existing imbalance or lack of another mineral (magnesium, zinc). It is also important to balance intake of fatty acids in the omega-6 and omega-3 series, as most people get too much omega-6 and not enough omega-3.
Small children can be overdosed with adult doses of for example vitamin A or iron, and pills may be dangerous for babies or young children because they can get stuck in the throat. Therefore, I recommend consulting a doctor or nutritionist educated in orthomolecular medicine. Most people are likely to benefit from taking a broad-spectrum multivitamin/mineral supplement as a basic insurance against deficiencies.
Compared to pharmaceutical drugs, supplements of most essential nutrients are quite harmless. However, some supplements may have poor quality, or contain toxic metals such as lead or cadmium. Therefore, it is the duty of our authorities to ensure that potentially hazardous products or supplements of poor quality are not sold, and that consumers are offered fair prices in a free market.
An example where the Norwegian authorities do not follow up such basic duties is that pharmacies demand more than 1,600 Norwegian Kroner (about $190) per kg of vitamin C in powder form, which would cost less than $20 with free competition and no restrictions in permitted doses or outlets.
Those who want to use natural healing methods, such as the use of food and supplements of essential nutrients to prevent or reverse illness, should consult therapists who are qualified to give advice on how natural therapies can help.
I recommend that anyone interested in supplements read the references for this article as well as the archives of the Journal of Orthomolecular Medicine http://orthomolecular.org/library/jom/ and the Orthomolecular Medicine News Service http://orthomolecular.org/resources/omns/index.shtml . Both are free access online.
(Dag Viljen Poleszynski, PhD, is the editor of Helsemagasinet [Health Magazine] https://vof.no/arkiv/ . He has translated and published a large number of OMNS releases in Norwegian.)
1. National Nutrition Council. Dietary advice to promote public health and prevent chronic disease. Directorate of Health, Oslo January 2011.
22. Hintze KJ, Lardy GP, Marchello MJ, et al. Areas with high concentration of selenium in the soil and forage produce beef with enhanced concentrations of selenium. Journal of Agricultural and Food Chemistry 2001; 49: 1062-7. https://pubs.acs.org/doi/abs/10.1021/jf000699s
23. Mäkelä AL, Näntö V, Mäkela P, et al. The effect of nationwide selenium enrichment of fertilizers on selenium status of healthy Finnish medical students living in South Western Finland. Biological Trace Element Research 1993; 36: 151-7. https://link.springer.com/article/10.1007/BF02783174
24. Dean C. The Magnesium Miracle. Second Edition. New York: Ballantine Books, 2017. ISBN-13: 978-0399594441
25. Hickey S, Saul AW. Vitamin C: the real story. Laguna Beach, CA: Basic Health Publications, Inc., 2008. ISBN-13: 978-1591202233
26. Rucklidge JJ, Andridge R, Gorman B, et al. Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses. Human Psychopharmacology and Clinical Experience 2012; 27: 440-54. https://onlinelibrary.wiley.com/doi/abs/10.1002/hup.2246
27. Cordain L, Gotshall RW, Eaton SB. Evolutionary aspects of exercise. In: Simopoulos AP, ed.: Nutrition and fitness: Evolutionary aspects. World Review of Nutrition and Diet 1997; 81: 49-60. https://www.ncbi.nlm.nih.gov/pubmed/9287503
28. Zenk SN, Powell LM, Rimkus L, et al. Relative and absolute availability of healthier food and beverage alternatives across communities in the United States. American Journal of Public Health 2014; 104: 2170-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202991/
29. Waldbott GL. Health effects of environmental pollutants. Second edition. St. Louis, MI: The C. V. Mosby Company, 1978. ISBN-13: 978-0801653308
36. Halliwell B, Gutteridge HMC. Free radicals in biology and medicine. 5th edition. Oxford, NY: Clarendon Press, 2015. ISBN-13: 978-0198717485
37. Hertoghe T. The hormone handbook. Copyright (c) 2006 Thierry Hertoghe. Surrey, UK: International Medical Publications, 2006.
38. Edwards AJ, Nguyen CH, You CS, et al. a- og ß-carotene from a commercial carrot puree are more bioavailable to humans than from boiled-mashed carrots, as determined using an extrinsic stable isotope reference method. Journal of Nutrition 2002; 132: 159-67. https://academic.oup.com/jn/article/132/2/159/4687130
39. Unlu NZ, Bohn T, Clinton SK et al. Carotenoid absorption from salad and salsa by humans is enhanced by the addition of avocado or avocado oil. The Journal of Nutrition 2005; 135: 431-6. https://www.ncbi.nlm.nih.gov/pubmed/15735074
40. Boback SM, Cox CL, Ott BD et al. Cooking and grinding reduces the cost of meat digestion. Comparative biochemistry and physiology. Part A, molecular & integrative physiology 2007; 148: 651-6. https://www.ncbi.nlm.nih.gov/pubmed/17827047
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