A Supplement for Diabetes, Body Composition, Cardiovascular Health & Antioxidant Protection

Don't you just love the smell and taste of cinnamon in a warm, gooey cinnamon bun? As it turns out, the cinnamon may actually provide you with some significant health benefits (although the same can't be said of the gooey bun; sorry). So let's take a closer look at cinnamon.

Background
The use of cinnamon for health is not new. In fact, cinnamon bark has been used for several thousand years in traditional Eastern and Western systems of medicine, for such purposes as anorexia, bloating, dyspepsia with nausea, flatulent colic, and spastic conditions of the GI tract.¹ Cinnamon also has a history of traditional use in Korea, China and Russia for treating people with diabetes.²

So what is it about cinnamon that gives it these medicinal properties? The answer is its natural constituents. Specifically, it is the volatile oils (such as eugenol and cinnamaldehyde) as well as the phenolic compounds (such as polyphenol type-A polymers).^3,4

Modern research
In addition to traditional use, modern research has demonstrated a number of benefits resulting from cinnamon supplementation. These include improvements in blood sugar for type 2 diabetics, improvements in body composition (e.g., increased lean mass), improvements in cardiovascular parameters, and substantial antioxidant properties. Following is a brief overview of this research.

Improvements in blood sugar
In research by Khan et al⁵, subjects with type 2 diabetes who took 1, 3 or 6 grams of cinnamon per day for 40 days lowered fasting blood sugar by 18 to 29 percent. The highest dose produced the most rapid response, although the lowest dose produced the most sustained response over the course of the study.

A more recent placebo-controlled, double-blind study⁶ was conducted on 79 patients with type 2 diabetes mellitus. Subjects were given 336 mg daily of a water-soluble cinnamon extract (corresponding to 3g of cinnamon powder) or a placebo for four months. Those using the cinnamon experienced a significant 10.3 percent reduction in fasting blood sugar, compared to a non-significant 3.4 percent reduction in the placebo group.

In a placebo-controlled, double-blind study by Ziegenfuss et al⁷, 21 adults with metabolic syndrome (i.e., prediabetes) were given a water-soluble cinnamon extract (500 mg per day) or a placebo for 12 weeks. The results were that 83 percent of those given the extract experienced a significant decrease (about eight percent) in fasting blood sugar, compared to only 33 percent in the placebo group who experienced a decrease.

Improvements in body composition
In the aforementioned study by Ziegenfuss et al⁸, the subjects also experienced a significant alteration in body composition. Their body fat decreased by 0.7 percent, and their muscle mass increased by 1.1 percent. These changes took place without alterations in the diet or physical activity of the subjects.

Improvements in cardiovascular parameters
In the previously cited study by Khan et al⁹, type 2 diabetics who were given 1, 3 or 6 grams of cinnamon a day for 60 days experienced significant drops in triglycerides (23 to 30 percent), low-density lipoprotein (LDL) cholesterol (7 to 27 percent), and total cholesterol (12 to 26 percent).

In the Ziegenfuss et al¹⁰ study, cinnamon resulted in a 3.8 percent reduction in systolic blood pressure. Likewise, other research¹¹ demonstrated that cinnamon was able to reduce systolic blood pressure in spontaneously hypertensive rats.

Substantial antioxidant properties
As stated previously, cinnamon contains polyphenols. This is important since polyphenols are potent antioxidant compounds, which can help to reduce the oxidative damage caused by free radicals.¹² According to Webb¹³, a recent study assessed antioxidant status and oxidative damage in 11 obese, prediabetic subjects given a water-soluble cinnamon extract, compared to10 obese, prediabetic subjects given a placebo. Those who received the cinnamon experienced a 14 percent reduction in markers of oxidative damage, as well as an increase in markers of total antioxidant capacity.

Cinnamon Safety
When used orally and appropriately, cinnamon is a safe supplement.¹⁴ As a matter of fact, cinnamon has Generally Recognized as Safe (GRAS) status in the United States.¹⁵ In pregnancy, cinnamon is likely safe when consumed in amounts commonly found in foods¹⁶, but may not be safe when used orally in amounts greater than those found in foods.¹⁷

References

1. Blumenthal M, Goldberg A, Brinckmann J (eds). Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications; 2000.
2. Kim SH, Hyun SH, Choung SY. Anti-diabetic effect of cinnamon extract on blood glucose in db/db mice. Journal of Ethnopharmacology 2006 104:119-123.
3. Blumenthal M, Goldberg A, Brinckmann J (eds). Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications; 2000.
4. Webb D. A scientific review: Cinnamon and its role in diabetes. Sarasota, FL: Integrity Nutraceuticals International; n.d.
5. Khan A, Safdar M, Ali Khan M, et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care 2003; 26:3215-8.
6. Mang B, Wolters M, Schmitt B, Kelb K, Lichtinghagen R, Stichtenoth DO, Hahn A. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipids in diabetes mellitus type 2. European Journal of Clinical Investigation 2006; 36:340-344
7. Ziegenfguss TN, Hofheins JE, Mendel RW, Landis J, Anderson RA. Effects of a Water-Soluble Cinnamon Extract on Body Composition and Features of the Metabolic Syndrome in Pre-Diabetic Men and Women. Journal of the International Society of Sports Nutrition 2006; 3(2):45-53.
8. Ziegenfguss TN, Hofheins JE, Mendel RW, Landis J, Anderson RA. Effects of a Water-Soluble Cinnamon Extract on Body Composition and Features of the Metabolic Syndrome in Pre-Diabetic Men and Women. Journal of the International Society of Sports Nutrition 2006; 3(2):45-53.
9. Khan A, Safdar M, Ali Khan M, et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care 2003; 26:3215-8.
10. Ziegenfguss TN, Hofheins JE, Mendel RW, Landis J, Anderson RA. Effects of a Water-Soluble Cinnamon Extract on Body Composition and Features of the Metabolic Syndrome in Pre-Diabetic Men and Women. Journal of the International Society of Sports Nutrition 2006; 3(2):45-53.
11. Preuss HG, Echard B, Polansky MM, Anderson R. Whole Cinnamon and Aqueous Extracts Ameliorate Sucrose-Induced Blood Pressure Elevations in Spontaneously Hypertensive Rats. Journal of the American College of Nutrition 2006; 25(2):144-150.
12. Shobana S, Naidu KA. Antioxidant activity of selected Indian spices. Prostaglandins Leukot Essent Fatty Acids 2000; 62(2):107-110.
13. Webb D. A scientific review: Cinnamon and its role in diabetes. Sarasota, FL: Integrity Nutraceuticals International; n.d.
14. McGuffin M, Hobbs C, Upton R, Goldberg A, eds. American Herbal Products Association's Botanical Safety Handbook. Boca Raton, FL: CRC Press, LLC 1997.
15. FDA. Center for Food Safety and Applied Nutrition, Office of Premarket Approval, EAFUS: A food additive database. Available at: vm.cfsan.fda.gov/~dms/eafus.html.
16. FDA. Center for Food Safety and Applied Nutrition, Office of Premarket Approval, EAFUS: A food additive database. Available at: vm.cfsan.fda.gov/~dms/eafus.html.
17. McGuffin M, Hobbs C, Upton R, Goldberg A, eds. American Herbal Products Association's Botanical Safety Handbook. Boca Raton, FL: CRC Press, LLC 1997.

In Part 1 of this series, we reviewed the discovery of coenzyme Q10 and the initial studies that established CoQ10 as a very effective natural therapy for the prevention and treatment of cardiovascular disease. In addition to being a powerful antioxidant, early studies also revealed that CoQ10 is an essential for the generation of cellular energy (ATP) within the mitochondria of every cell in the body with the exception of red blood cells.

Coenzyme Q10's dual functions (antioxidant and energy production) make it essential for the health of virtually all human tissues and organs. As a fat-soluble antioxidant, it protects proteins (like LDL-cholesterol), enzymes, fats (all cell walls/ membranes) and especially DNA from free radical damage. In terms of energy production, areas of the body with high rates of metabolic activity (high energy demands) such as the heart, lungs, kidneys, brain and immune system are especially sensitive to low levels of CoQ10.¹

Coenzyme Q10 and Cancer/History

Early CoQ10-cell culture studies revealed that coenzyme Q10 resulted in an 80 percent reduction in the growth of cancer cells within 90 days.² Animal studies published in the late 1990s reported that treatment with coenzyme Q10 resulted in suppression of tumor growth, reduced size and/or shrinkage of tumors and increased survival time.^3,4,5

In the late 1980s, Dr. K. Folkers began analyzing coenzyme Q10 levels in cancer patients. His testing revealed that virtually all cancer patients have CoQ10 levels that are extremely low. In 1994, Drs. K. Lockwood and K. Folkers reported treating 32 "high-risk" breast cancer patients with antioxidants, fatty acids, and 90 mg. of CoQ10.

Six of the 32 women showed partial tumor regression. In one woman, the dosage of CoQ10 was increased to 390 mg. In one month, her tumor was no longer palpable and in another month, mammography confirmed the absence of tumor. Encouraged, another case having a verified breast tumor, after non-radical surgery and with verified residual tumor in the tumor bed was then treated with 300 mg. CoQ10. After three months, the patient was in excellent clinical condition and there was no residual tumor tissue.⁶

In 1996, William Judy and Dr. Folkers reported the results of a CoQ10-prostate cancer study. Their results revealed that men with prostate cancer who were treated with 600 mg of CoQ10 daily achieved dramatic reductions in both PSA and tumor size.⁷ An interesting aspect of this study is that the men did not begin to show any signs of response until about 90 days into the trial.

Several clinical trials have also reported that coenzyme Q10 substantially protects against and/or reduces side effects in patients undergoing various forms of chemotherapy.

A New Understanding of Cancer: In healthy cells, mitochondria utilize oxygen to produce energy. In cancer cells, energy production switches from away from oxygen and instead begins to utilize glucose/sugar for energy production. This was first discovered and explained by Otto Warburg, MD. Warburg was awarded the Nobel Prize in 1931 for discovering that cancer cells are low in oxygen because cellular respiration has switched from using oxygen to the fermentation of sugar. To summarize, healthy cells utilize oxygen to produce energy whereas cancer cells begin to utilize sugar for energy production. It is damage to mitochondria that causes this change in energy production.⁹

"Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer" is the title of a very important book written by Thomas N. Seyfried, MD. Dr. Seyfried advances Otto Warburg's theory of cancer in a way that revolutionizes our understanding of cancer. Up until now, most scientists have assumed that cancer is a genetic disease resulting from DNA mutations/damage.

Instead, Seyfried teaches us that cancer is a metabolic disease due to mitochondrial damage, which hinders the ability of cells to produce adequate energy. This causes the metabolic shift from oxygen to glucose for energy production, which is the hallmark of cancer cell metabolism.

Coenzyme Q10/Cancer Answer: Drs. Warburg and Seyfried did not explain coenzyme Q10's role in protecting mitochondria from free radical damage and in mitochondrial energy production. In this article, we will explain how CoQ10 deficiency results in mitochondrial damage that progresses to metabolic changes in energy production, which results in the origin and progression of cancer.

The Miracle Nutrient: Coenzyme Q10. Coenzyme Q10 plays two critical roles in this scenario. First, CoQ10 is required in several steps for energy production within mitochondria. Thus, coenzyme Q10 deficiency impairs mitochondria's ability to use oxygen for energy production. This causes a shift to using sugar, which characterizes cancer cell metabolism.

Secondly, CoQ10 is a powerful antioxidant that neutralizes free radicals. This is especially important in mitochondria, because more free radicals are generated in mitochondria during the process of energy production than anywhere else in the body. Thus, coenzyme Q10 deficiency is a "double whammy" in that it weakens mitochondria's ability to produce energy (like an engine running out of gas) while also accelerating free radical damage to mitochondrial DNA (causing damage to the engine so it cannot function).

Causes of Coenzyme Q10 Deficiency: The synthesis of coenzyme Q10 in the body is a complex process that requires multiple nutrients as cofactors. Over the past 80 years there has been a dramatic and continual decline in the nutritional content of our commercial/agricultural food supply. Reasons for this decline include:

a) Rising levels of atmospheric CO2 is causing reductions in the mineral content of plants.¹⁰

b) Massive use of pesticides and herbicides on agricultural crops, which kills the microbiome (bacteria) in the soil. Bacteria in the soil are necessary for the breakdown of organic matter and the delivery of nutrients into the plant.¹¹

c) A high percentage of the food that Americans consume are highly processes. Food processing results in substantial losses of nutritional content of the foods.¹²

d) In "The Drug-Induced Nutrient Depletion Handbook," Ross Pelton lists multiple reports following classes of commonly prescribed drugs that cause depletion of coenzyme Q10: statin cholesterol-lowering drugs, oral contraceptives, hormone replacement therapy (HRT), drugs for diabetes, tricyclic antidepressants, major tranquilizers, beta-blockers, thiazide diuretics and vasodilators.¹³ Many more drugs probably deplete CoQ10, but just haven't been tested yet for their effect on CoQ10 biosynthesis.

e) Increasing age, after 20 years of age, reduces CoQ10 synthesis in man (International CoQ10 Association).

Other Therapeutic Applications: In addition to cardiovascular disease and cancer, studies have also been published showing that CoQ10 can provide therapeutic benefits in the following conditions: diabetes, radiation injury, periodontal disease, gastric ulcers, mitochondrial disorders, migraine headaches, obesity, kidney failure, acquired immune deficiency (AIDS), Parkinson's disease and Alzheimer's disease.

CoQ10 and Life Extension: In addition to the many ways CoQ10 can help prevent and treat many disease conditions, it is also one of the most important nutrients for life extension and healthy longevity.

When you understand CoQ10's critical roles in protecting mitochondria and producing energy, it seems obvious that it would slow down the onset of chronic degenerative diseases and increase longevity with healthy additional years. Imagine a growing number of vibrant, energetic centenarians.

Coenzyme Q10 Doubles Lifespan in Mice: Emile Bliznakov, MD, who wrote "The Miracle Nutrient: Coenzyme Q10," conducted the following experiment. Dr. Bliznakov started his experiment with 100 "old" female white mice that were 16 to 18 months of age. One week for mice is roughly equivalent to one year of human life. Thus, the mice were in their 60s to 70s in human terms and already beginning to show some signs of decreased immunity and aging bodily functions.¹⁴

These old mice were divided into two groups of 50 and maintained on optimally nutritious diets. One group were controls while the second group were regularly given doses of CoQ10.

• At 28 weeks after the beginning of the study, 70 percent of the control mice had died compared to only 40 percent of the CoQ10-treated mice.
• At 36 weeks, 100 percent of the control mice were dead while about 40 percent of the CoQ10-treated mice were still alive and active with most not showing the normal signs of physical deterioration that are commonly associated with advanced age.
• At week 56, 10 percent of the CoQ10-treated mice were still thriving (2X longer than these mice would normally be expected to survive beyond the beginning of the experiment).
• At the 80th week (remember the last control mouse died at week 36), four mice were still alive; at the 82nd week, the last mouse died. In human terms, this is a life span of roughly 130 years of age!

Dr. Bliznakov explained the following remarkable visual differences between the two groups of mice towards the end when some of the control mice were still alive. The fur on the control mice that had not received CoQ10 had lost its sheen, became dull, coarse, matted and on some mice, clumps of hair had fallen out, leaving bald patchy spots and they were also very listless and spent most of their time lying around and not socializing. On the other hand, the fur in the coats of the CoQ10-treated mice remained smooth and soft, and they maintained a much greater level of activity and socialization. Another interesting feature was the fact that the CoQ10-treated mice still engaged in sexual activity whereas sexual activity had stopped among the control mice months earlier.

Human clinical life extension trials will be conducted in our lifetime. Several studies have reported CoQ10's therapeutic benefits in a wide range of disease states. This certainly suggests that CoQ10 enhances and extends life and improves quality of life. Three rather large clinical studies support the influence of CoQ10 on longevity. The first was a 30-year study that was completed by Dr. Folkers and Judy. In this study 500 congestive heart failure patients were divided into two groups. One group was treated with 200 mg CoQ10 daily and conventional therapy. The other group was treated with conventional therapy only. The conventional therapy group were all deceased in seven years. In the CoQ10 group 42 percent were still living at seven years. At 15 years, 24 percent were still living. At 30 years two individuals were still living. Both were in their late 90's and in good health. Both had been on CoQ10 for over 35 years and were only on a diuretic and CoQ10.

Other long-term studies have been conducted by Dr. Alihanen and his group in Sweden. In this study thousands of elderly patients were supplemented with CoQ10 for 10 years. The 10- year survival rate was 45 percent. In another study in Class III and IV congestive heart failure conducted by Dr. Sven Mortensen and his group showed a two-year survival compared to the control group of 48 percent. The morbidity was reduced by 52 percent and the classification of heart failure was reduced to Class II or I. The acute hospitalizations were reduced by 52 percent (Q-Symbio multicenter clinical trial 2014. A.J. Clinical Cardiology, 2014.

Ubiquinone/Ubiquinol: After the discovery of coenzyme Q10 (ubiquinone) in 1956, clinical trials began in the mid-1960s. In the ensuing half-century, the vast majority of clinical trials have been conducted with the ubiquinone, which is the oxidized form of CoQ10.

In 2006, the Kaneka Corporation in Japan began producing and marketing the ubiquinol (reduced) form of CoQ10 after learning how to stabilize the compound and keep it from oxidizing back to ubiquinone. Kaneka claims that the ubiquinol/ reduced form of CoQ10 is more active and better absorbed than ubiquinone. This has been a very successful marketing strategy for Kaneka, but actually, the claims are not scientifically correct.

There are several issues to discuss when confronting Kaneka's claims that ubiquinol is superior to ubiquinone. Many companies are private labeling Kaneka's ubiquinol CoQ10, which are substantially more expensive. However, studies reveal that when Kaneka's reduced CoQ10 is taken orally, it rapidly gets converted into ubiquinone in the stomach. Hence, people are paying more for ubiquinol, which actually gets converted back into ubiquinone when taken orally.

For a full explanation of the issues and controversies between ubiquinone and ubiquinol, read a report titled Coenzyme Q10 Facts or Fabrications by William Judy, Ph.D. Dr. Judy has been educating people around the world about the importance and benefits of coenzyme Q10 for over 40 years. He has also conducted CoQ10 clinical trials and served as a consultant for many companies on CoQ10 product formulations. Hence, he is well qualified to address both the scientific and the marketing issues related to the ubiquinone/ubiquinol controversy.

The Recrystallization Problem: Many CoQ10 products on the market have abysmally low rates of absorption. Here's the problem. The melting point of CoQ10 is about ten degrees higher than human body temperature, which is 98.60F. Hence, most coenzyme Q10 products crystallize in the softgel capsule after cooling to room temperature. Even CoQ10 products that are dissolved in oil by heating to 50 degrees centigrade recrystallize in the softgel capsule when cooled to room temperature. Crystals consist of many millions of single CoQ10 molecules. Humans can't absorb crystals. We can only absorb single molecules of any substance. This explains why CoQ10 products on the market do not achieve significant increases in plasma CoQ10 levels compared to that of the pure crystal free CoQ10 products.

^{Crystal Free Coenzyme Q10:}
Crystal free CoQ10 is the new era in the CoQ10 industry. The dry powder CoQ10 entered the marketplace in 1974 as a comp softgel product. These were crystalline CoQ10 in an oil and water base. When CoQ10 was deregulated from a drug to a natural product in Japan the consumer market in Japan increased so significantly that the CoQ10 producers in Japan could not meet the world demand. The price of CoQ10 increased from $800 to $4500 a kilogram. In the USA almost no one could afford the CoQ10. Thus, the need for a more highly absorbable CoQ10 that could offset the poorly absorbed CoQ10 and its high price.

Three companies in the USA took the challenge and started developing a crystal free CoQ10 product between 2002 and 2006. All three products had different solvents and were crystal free at an encapsulation temperature of 50 degrees centigrade. Their single dose absorption was between six and eight percent of a 100 mg dose. However, when the capsules cooled to room temperature, two of these products recrystallized and the absorption and steady state bioavailability was no better than a crystalline CoQ10 in a lipid based softgel.

The higher absorbable CoQ10 and steady state bioavailable allows the consumer to attain the health benefits for the clinical conditions describes in Part I of this series. Two of the developed products were unstable and recrystallized in the softgel capsule. One remained viable as a pure crystal free product.

A crystal free product at body temperature manufactured in Scandinavia was used in a major long-term clinical trial in Sweden. This trial has continued for over 10 years in thousands of patients (Ailhagen Sweden). In this study, the 10-year survival was 50 percent. In a multi-center study in 500 class III and IV congestive heart failure patients the 250 in patients on CoQ10 and conventional therapy has a heart failure mortality rate 56 percent less than the control group on conventional therapy only. In this study, the morbidity was 48 percent less and the degree of failure was 58 percent less than the control group. The CoQ10 treated patients admitted to the hospital was 43 percent less than the conventionally treated patients (Q-symbio trial, Mortensen. Am J Clinical Cardiology. 2014). The new era of crystal free CoQ10 has proven that it has the potential to be effective in the management of congestive heart failure, age related degenerative diseases such as cancers, chronic fatigue, Parkinson's disease and high blood pressure.

The newest and most stable of the crystal free products, and the new therapeutic era for CoQ10 in the USA is marketed by the Cyto Health Company. It will soon be in the USA marketplace. For more information please call 941-920-2824.

1. Saini R. Coenzyme Q10: The essential nutrient. J Pharm Bioallied Sci. 2011 Jul-Sep;3(3):466-467.
2. Bliznakov E. (1986) "The Miracle Nutrient: Coenzyme Q10." New York. Bantam Books.
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9. John AP. Dysfunctional mitochondria, not oxygen insufficiency, cause cancer cells to produce inordinate amounts of lactic acid: the impact of this on the treatment of cancer. Med Hypotheses. 2001;57:429–31
10. Weigel, H. Plant quality declines as CO2 levels rise. eLife 2014;3:e03233.
11. Aktar, W, et al. Impact of pesticides use in agriculture: their benefits and hazards. Interdiscip Toxicol. 2009 Mar;2(1):1–12.
12. Karmas E, Harris RS. (Dec. 2012) Nutritional Evaluation of Food Processing. Springer Science & Business Media
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14. Bliznakov E. (1986) "The Miracle Nutrient: Coenzyme Q10." New York. Bantam Books.

It wasn’t so long ago that cocoa and chocolate were considered unhealthy. In fact, back in the late 70s and early 80s carob was being touted as a chocolate substitute—albeit a very sad and far less delicious excuse for a substitute. Since then, study after study has been published extolling the health-promoting properties of cocoa and chocolate. Of course chocolate bars also contain sugars, fats and other dietary components whose intake we’re trying to limit, but the cocoa itself still offers several healthy benefits such as its effects on energy, digestion, cardiovascular health, lung health, antioxidant protection and mood.

ENERGY
People have often noticed that they feel more energetic after consuming cocoa or chocolate, and tend to attribute this to the sugar and calories, but there is more to the story. It turns out that cocoa contains a methylxanthine (the family of compounds to which caffeine belongs) known as theobromine (3.7 percent on a fat-free basis).¹ This is significant since theobromine tends to have a mild stimulatory effect.² In fact, a study3 examined the effects of a chocolate bar, an apple or nothing in 37 healthy, normal-weight women who ate these foods and rated their subjective state 5, 30, 60 and 90 min after eating. Both chocolate and the apple reduced hunger, elevated mood and increased activation, but the effects of the chocolate were greater. The increased activity (induced by the stimulating ingredients of cocoa) was statistically significant (p<0.002).³

DIGESTION
The friendly bacteria in our gut play a role in the digestion of foodstuffs. Research⁴ suggests that cocoa has beneficial effects on the metabolism of our friendly bacteria. Furthermore, research⁵ also shows that compounds in cocoa can actually help promote the growth of friendly bacteria. In addition, a historical review⁶ of the medicinal uses of chocolate indicated that it was used to improve digestion and elimination, where cocoa/chocolate was said to counter the effects of stagnant or weak stomachs, stimulate kidney and improve bowel function. Not surprisingly, human research has shown that salivation was triggered after tasting a very small amount of chocolate.⁷ This effect has benefits for digestion since saliva contains the enzyme ptyalin amylase that breaks down starch into sugar. Salivary glands also secrete salivary lipase (a more potent form of lipase) to start fat digestion.

CARDIOVASCULAR HEALTH
An 18 week, randomized, controlled, investigator-blinded, parallel study⁸ examined the effect of 30 mg of polyphenols/ day from dark chocolate or the same amount of white chocolate without polyphenols in 44 adults with untreated prehypertension or stage 1 hypertension. The results were that the group eating the polyphenols from dark chocolate experienced decreased systolic blood pressure by 2.9 points and diastolic blood pressure by 1.9 points. Hypertension prevalence also declined from 86 to 68 percent. Since cocoa powder provides an average of 40.20 mg polyphenols/ gram⁹, relatively small amounts of cocoa would be needed to offer a similar benefit. Other research¹⁰ has also shown that healthy elderly men who consumed a median intake of 2.11 grams cocoa daily had a statistically significant (P=0.03) lower average blood pressure compared to those consuming lower amounts. They also have a lower risk of cardiovascular (P=0.004) and all-cause mortality (P=0.001).

LUNG HEALTH
A historical review¹¹ of the medicinal uses of chocolate recounts 17th and 18th century writers’ discussions on the use of chocolate, including statements such as, "...it cures consumption, and the cough of the lungs," and "has an effect equally... to suspend the violent cause of rheumatoids and inflammation of the lungs, and to dull the irritation and ferocity which incites cough [and] to put out the inflammations of the throat and lungs [pleure]," and "[an] easer of pain, it is excellent, taken inwardly, to cure hoarseness, and to blunt the sharpness of the salts that irritate the lungs..." A more recent randomized, double-blind, placebo-controlled, human study¹² suggests a mechanism by which chocolate may have offered its beneficial effects. The study indicated that theobromine (the compound found in chocolate as discussed earlier) was found to suppress capsaicin-induced cough with no adverse effects. The study also demonstrated that theobromine directly inhibits a sensory suggestive of an inhibitory effect on afferent nerve activation. The authors concluded that theobromine is a novel and promising treatment that may form the basis for a new class of antitussive drugs.

ANTIOXIDANT PROTECTION
Research¹³ has shown that cocoa has potent antioxidant capacity as compared with other products. This can be quantified by a method of measuring antioxidant capacities of various foods: Oxygen Radical Absorbance Capacity (ORAC). According to the USDA,¹⁴ 100 grams of unsweetened cocoa powder has a total ORAC value of 55,653. Furthermore, a double-blind, randomized study¹⁵ reported that markers of antioxidant status increased after dark chocolate consumption, and a reduction of serum oxidative stress was seen.

IMMUNE HEALTH
An interesting study¹⁶ reviewed research suggesting a regulatory effect of cocoa on the immune cells implicated in innate and acquired immunity. Cocoa exerts regulatory activity on the secretion of inflammatory mediators. In addition, emerging data from animal studies support an immunomodulating effect. Long-term cocoa intake in rats affects both intestinal and systemic immune function. Other research¹⁷ has shown that cocoa extract down-modulated T lymphocyte activation and therefore the acquired immune response, suggesting that it could be important in some states of the immune system hyperactivity such as autoimmune or chronic inflammatory diseases.

MOOD
A British journal¹⁸ reported on a study examining chocolate craving in people who were depressed. Nearly 3000 clinically depressed individuals completed a web-based questionnaire, the results of which revealed that chocolate was craved by half of the respondents (more so by women), judged as beneficial for depression, anxiety and irritability, and associated specifically with personality facets encompassed by the higher-order construct of neuroticism. Another study¹⁹ argued that the food with the greatest impact on mood is chocolate. Those who crave chocolate tend to do so when they feel emotionally low. There have been a series of suggestions that chocolate’s mood-elevating properties reflect ‘drug-like’ constituents including anandamines, caffeine, phenylethylamine and magnesium. However, the levels of these substances are so low as to preclude such influences. As all palatable foods stimulate endorphin release in the brain this is the most likely mechanism to account for the elevation of mood.

CONCLUSION
Cocoa offers a range of potential health benefits. Not only that, but it tastes good! The consumption of some cocoa daily may make sense—but try to avoid excessive sugar intake when doing so. The use of sweeteners such as stevia would be a good alternative.

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11. Dillinger
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16. Ramiro-Puig
17. Ramiro E, Franch A, Castellote A, et al. Effect of Theobroma cacao flavonoids on immune activation of a lymphoid cell line. British Journal of Nutrition 2005; 93:859.66.
18. Parker G, Crawford J. Chocolate craving when depressed: a personality marker. Br J Psychiatry 2007;191:351.2.
19. Benton D, Donohoe RT. The effects of nutrients on mood. Public Health Nutrition: 2(3a), 403.9.

The nutrients L-carnitine and choline are two of the most important for heart and liver health. Large bodies of literature support the benefits of these compounds and that of related items, such as phosphatidylcholine. Despite this history, recently news media articles have appeared suggesting that these nutrients actually cause heart disease. Similarly, in the medical professional research literature, there is a groundswell of publications that attempt to associate L-carnitine and choline with cardiovascular disease through entirely indirect arguments involving primarily the compound trimethylamine-N-oxide.

In a nutshell, these publications cast aside direct clinical evidence that supplementing with L-carnitine and choline improves heart and liver health by focusing, instead, on marker compounds in the blood and correlations between these and illness without establishing causation. The presence of a biochemical marker is used to overturn clinical evidence such that compounds proven in practice to be good for health suddenly are associated with disease. As argued in the following paragraphs, this guilt by association does not withstand close scrutiny.

L-Carnitine and Choline

Although the L-carnitine is usually referred to as an amino acid, this is technically incorrect inasmuch as there is no amino (NH2) group present in the molecule. The primary role of L-carnitine in the body is as a biocatalyst or coenzyme. One of the most important functions of L-carnitine is in the oxidation of long chain fatty acids, a process which takes place inside of mitochondria, the “energy factories” of the cells. This process is known as beta-oxidation. L-Carnitine acts as a shuttle for bringing fatty acids into the mitochondria and then removing waste afterwards. Fats are the preferred source of fuel for the kidneys, the skeletal muscles, and even more so for the heart muscle. As much as 70 percent of the energy generated in muscle tissue comes from the oxidation of fats!

L-Carnitine also increases the rate of oxidation of fats in the liver, and this suggests that it plays a role in energy generation from this angle as well.¹ Some authors argue that in the proper amounts, L-carnitine supplementation during dieting can help to control the negative effects of ketosis (the accumulation of waste products of fat metabolism) in those who are susceptible to this problem.² Similarly, there is evidence that some forms of obesity may be related to a genetic propensity to produce less L-carnitine, and liver and kidney problems will reduce the body’s production since some four fifth’s of our total L-carnitine is produced internally by these organs.^3,4

L-Carnitine has been shown to have positive benefits upon the myocardium of the heart and upon peripheral circulation. The effects upon the heart include improvements in energy production and other parameters. Supplemental L-carnitine is associated with significantly higher concentrations of pyruvate, ATP and creatine phosphate in portions of the heart muscle during conditions of extreme stress.⁵ Similarly, in tests upon peripheral circulation, L-carnitine has been found to be quite useful for improving blood flow.⁶ Of course, the true test of the benefits of L-carnitine is survival: In a randomized controlled trial, there was a 90 percent decrease in mortality over the next 12 months compared with people who did not receive L-carnitine when patients started supplementing shortly after suffering a heart attack.⁷ Another study analyzing 13 controlled trials (involving a variety of settings) found that L-carnitine led to a 27 percent reduction in all-cause mortality.⁸ Choline, phosphatidylcholine and related compounds are especially protective of liver health, including in both nonalcoholic and alcoholic fatty liver disease.^9,10 Liver dysfunction is extremely common in those who carry excessive weight and is viewed as causative in diabetes type 2. L-Carnitine and choline reduce overall oxidative stress in individuals and lower lipid peroxidation, recognized factors in promoting cardiovascular and liver health.¹¹

L-Carnitine Slows Plaque Formation in Arteries Despite TMAO
A paper published in the journal Atherosclerosis (2016) reconfirms some of the health benefits of L-carnitine and, by implication, those of choline, phosphatidylcholine and related nutrients. In a nutshell, researchers fed supplemental L-carnitine to mice for 12 weeks and then observed aortic lesion development and blood lipid profiles. These scientists wanted to test the truth of a vast body of older science that demonstrated the cardioprotective properties of L-carnitine versus new theories that gut microbes transform L-carnitine into trimethylamine (TMA) that the liver further transforms into trimethylamine-N-oxide (TMAO) that promotes atherosclerosis. The researchers found that L-carnitine supplementation slows aortic lesion formation in their mouse model. L-Carnitine was heart protective just as indicated in previous research based on examining clinical results rather than looking only at short term markers purported to indicate future results (endpoints versus markers). Moreover, TMAO, the supposedly toxic metabolite of L-carnitine, actually appeared to protect the arteries. One implication of this study is that L-carnitine, including its metabolite TMAO, may be similarly protective against atherosclerosis development in humans.

Study Summary
The current study was designed to test the hypothesis of an article published in Nature Medicine (2013) that suggested that the nutrient L-carnitine, found in red meat and nutritional supplements, promotes atherosclerosis as a result of bacteria in the gut forming a toxin called trimethylamine (TMA), which is further metabolized in the liver to trimethylamine-Noxide (TMAO).¹³ Two follow-up articles by many of the same Nature Medicine authors argue that gut bacteria similarly transform dietary betaine, choline and phosphatidylcholine (and presumably other choline-related nutrients) to yield TMA followed by TMAO with negative cardiovascular consequences. Since the initial publications, there has been a flood of research putatively supporting the original findings. Inasmuch as TMAO plasma levels have been associated with atherosclerosis development in the particular mouse model used in the initial research, the goal was to better understand the mechanisms behind the TMAO/CVD association. The Atherosclerosis (2016) research was designed to investigate both in vitro (isolated cell or tissue) mechanisms—does TMAO promote foam cells formation—and in vivo (live animal) endpoints—does TMAO promote or inhibit lesion development in the arteries.

The in vitro part of the study demonstrated that TMAO at concentrations up to ten times the maximum reported in humans did not affect foam cell formation. In other words, there was no indication that a mechanism exists through which TMAO causes damage to the lining of the arteries. However, there still were outstanding issues, such as why TMAO was both elevated in the usual mouse model and linked to increased levels of atherosclerosis.

The in vivo part of the study provides important answers to these issues. First, it must be understood that rodents in general process lipids, including cholesterol, differently than do humans. For instance, the usual mouse model for atherosclerosis lacks cholesteryl ester transfer protein (hCETP), which in humans is involved in the movement of cholesterol between high density lipoprotein (HDL) and low density lipoprotein cholesterol (LDL). Using a model that more properly matches human lipid metabolism, high doses of L-carnitine resulted in a significant increase in plasma TMAO levels, yet—and regardless of treatment—TMAO levels were inversely correlated with aortic lesion size. Indeed, as the blood levels of TMAO went up, the size of the aortic lesion area went down and this bore no relation to changes in blood lipids. One clear implication of these findings is just the opposite of that commonly being suggested regarding TMAO, to wit, TMAO is protective of arterial health rather than being a toxin.

So What Goes Wrong in Humans to Elevate TMAO?
There is little doubt that ingestion of L-carnitine, betaine, choline and related nutrients can increase TMAO levels in many individuals and that increased TMAO also can be associated in many cases with increased cardiovascular disease. However, it is becoming increasingly clear that TMAO is not a cause of atherosclerosis.

Study after study after study that has looked at clinical endpoints, meaning the actual outcomes of the use of L-carnitine with human beings, has shown significant benefits across a wide array of heart and circulatory issues.¹⁴ Benefits are found with choline, phosphatidylcholine and related nutrients along with eating oily fish, a practice that necessarily dramatically increases TMAO, yet supports good health.

This is a classic case of blaming a messenger for the message. Just as with TMAO, elevated blood levels of choline sometimes are seen in patients with artery plaque instability, but this is a result of the instability itself and is unrelated to supplements just as an analogously disturbed L-carnitine regulation arguably is a result of cardiovascular problems and not due to dietary intake.^15,16 In a clinical trial, oral L-carnitine supplementation increased trimethylamine-N-oxide, but reduced indications of vascular injury in hemodialysis patients.¹⁷ Elevated TMAO blood levels are associated with low HDL and related disturbances just as elevated TMAO levels appear to be linked to impaired kidney function and poor metabolic control.^18,19 The clear implication is that TMAO levels may reveal problems that originate elsewhere in the body and that artificially lowering TMAO blood levels will not improve health because TMAO is not the cause of these issues. The key concept here is to look at "endpoints," not "markers."

Food Sources
Meat, poultry, fish, and dairy products are the richest food sources of L-carnitine, although L-carnitine intake probably is increased best via supplements. This route is not so necessary for betaine, choline and a number of related nutrients. According to the Linus Pauling Institute, the consumption of choline is far below the recommended intake in the United States. Rich sources of choline include eggs, liver, wheat germ, many types of seafood and even peanuts. According to Whole Foods, vegetable options include collard greens, Brussels sprouts, broccoli, Swiss chard, cauliflower, and asparagus. A large listing of food sources can be found at http://nutritiondata.self.com/. Many choline sources also are good sources of phosphatidylcholine (liver, egg yolk, peanuts). Choline's metabolite betaine can be found in spinach, beets and shellfish.

Endnotes

1. Preuss HG, Mrvichin N, Clouatre D, et al. Importance of Fasting Blood Glucose in Screening/Tracking Overall Health. The Original Internist. 2016, March:13¡V15,17¡V18.
2. Bjornholt JV, Erikssen G, Aaser E, et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care. 1999 Jan;22(1):45¡V9.
3. Sears B. Anti-inflammatory Diets. J Am Coll Nutr. 2015;34 Suppl 1:14¡V21.
4. Mauro DiPasquale, M.D., "Let the Fat be with You: The Ultimate High-Fat Diet," Muscle Magazine International (July and September 1992); "High Fat, High Protein, Low Carbohydrate Diet: Part I," Drugs in Sports 1, 4 (December 1992) 8¡V9.
5. https://bengreenfieldfitness.com/2015/12/how-to-get-into-ketosis/
6. Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. 2000 Dec;130(12):2990¡V5.
7. Lim K, Ryu S, Suh H, Ishihara K, Fushiki T. (-)-Hydroxycitrate ingestion and endurance exercise performance. J Nutr Sci Vitaminol (Tokyo). 2005 Feb;51(1):1¡V7.
8. Cheng IS, Huang SW, Lu HC, Wu CL, Chu YC, Lee SD, Huang CY, Kuo CH. Oral hydroxycitrate supplementation enhances glycogen synthesis in exercised human skeletal muscle. Br J Nutr. 2012 Apr;107(7):1048¡V55.
9. Louter-van de Haar J, Wielinga PY, Scheurink AJ, Nieuwenhuizen AG. Comparison of the effects of three different (¡V)-hydroxycitric acid preparations on food intake in rats. Nutr Metab (Lond). 2005 Sep 13;2(1):23. See also notes 18 and 19.
10. Clouatre D, Talpur N, Talpur F, Echard B, Preuss H. Comparing metabolic and inflammatory parameters among rats consuming different forms of hydroxycitrate. Journal of the American College of Nutrition 2005;24:429 Abstract.
11. Clouatre D, Preuss HG. Potassium Magnesium Hydroxycitrate at Physiologic Levels Influences Various Metabolic Parameters and Inflammation in Rats. Current Topics in Nutraceutical Research 2008;6(4): 201¡V10.
12. Han N, Li L, Peng M, Ma H. (-)-Hydroxycitric Acid Nourishes Protein Synthesis via Altering Metabolic Directions of Amino Acids in Male Rats. Phytother Res. 2016 May 4. doi: 10.1002/ptr.5630. [Epub ahead of print]
13. http://www.totalhealthmagazine.com/Vitamins-and-Supplements/Going-WILD-with-Bitter-Melon-for-Blood-Sugar-Support.html
14. Lim JS, Adachi Y, Takahashi Y, Ide T. Comparative analysis of sesame lignans (sesamin and sesamolin) in affecting hepatic fatty acid metabolism in rats. Br J Nutr. 2007 Jan;97(1):85¡V95.
15. Ide T, Lim JS, Odbayar TO, Nakashima Y. Comparative study of sesame lignans (sesamin, episesamin and sesamolin) affecting gene expression profile and fatty acid oxidation in rat liver. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):31¡V43.
16. Henry-Vitrac C, Ibarra A, Roller M, Merillon JM, Vitrac X. Contribution of chlorogenic acids to the inhibition of human hepatic glucose-6-phosphatase activity in vitro by Svetol, a standardized decaffeinated green coffee extract. J Agric Food Chem. 2010 Apr 14;58(7):4141¡V4.
17. Bassoli BK, Cassolla P, Borba-Murad GR, et al. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochem Funct. 2008 Apr;26(3):320 ¡V8.
18. Malmsten C, Lignell A. Dietary Supplementation with Astaxanthin- Rich Algal Meal Improves Strength Endurance; A Double Blind Placebo Controlled Study on Male Students. Carotenoid Science. 2008;13:20 ¡V22.
19. Aoi W, Naito Y, Takanami Y, Ishii T, Kawai Y, Akagiri S, Kato Y, Osawa T, Yoshikawa T. Astaxanthin improves muscle lipid metabolism in exercise via inhibitory effect of oxidative CPT I modification. Biochem Biophys Res Commun. 2008 Feb 22;366(4):892¡V7.

Nattokinase is a fibrinolytic (i.e., fibrin degrading) enzyme derived from a Japanese food called natto. Nattokinase is produced during the very fermentation process which creates natto, involving boiled soybeans fermented with the bacteria Bacillus natto.^1,2 Nattokinase has fibrinolytic activity that is 4-times more potent than plasmin³ (a blood enzyme that degrades many blood plasma proteins, most notable, fibrin clots).⁴ Nattokinase works by inactivating plasminogen activator inhibitor 1 (PAI-1).^5,6 PAI-1 would otherwise inactivate plasminogen and hence fibrinolysis (the breakdown of fibrin clots). Its average activity is about 40 CU (plasmin units)/gram.⁷ Also, Nattokinase is orally available as a dietary supplement. This has been demonstrated in both human and animal research.^8,9

Nattokinase And Blood Clotting Factors
Accumulation of fibrin in the blood vessels usually results in thrombosis (the formation of blood clots), leading to myocardial infarction (heart attack) and other cardiovascular diseases. For thrombolytic therapy, microbial fibrinolytic enzymes have now attracted much more attention than typical thrombolytic agents because of the expensive prices and the undesirable side effects of the latter. The fibrinolytic enzymes were successively discovered from different microorganisms, the most important among which is the genus Bacillus from traditional fermented foods. Perhaps the most significant of the enzymes is nattokinase, which has been shown thrombolysis (the breakdown of blood clots).¹⁰

In an open-label, self-controlled clinical trial¹¹, researchers hypothesized that nattokinase could reduce certain blood clotting factors that are associated with an increased risk for cardiovascular disease. The subjects in the study were divided into the following groups: healthy volunteers (Healthy Group), patients with cardiovascular risk factors (Cardiovascular Group), and patients undergoing dialysis (Dialysis Group). All subjects ingested two capsules of nattokinase (2000 fibrinolysis units per capsule) daily orally for two months. The laboratory measurements were performed on the screening visit and, subsequently, regularly after the initiation of the study. After two months, the results were a significant time effect was observed in the change from baseline of fibrinogen, factor VII, and factor VIII, suggesting that the plasma levels of the three coagulation factors continuously declined during intake: No significant changes of uric acid or notable adverse events were observed in any of the subjects. In summary, this study showed that oral administration of nattokinase could be considered as a cardiovascular disease nutraceutical by decreasing plasma levels of the blood clotting factors: fibrinogen, factor VII, and factor VIII.

The development of edema, and superficial and deep vein thrombosis (DVT) is not uncommon in long-haul flights (seven to eight hours), particularly in high-risk subjects. In a randomized, controlled trial¹², high-risk subjects on longhaul flights were supplemented with a combination product containing nattokinase plus pycnogenol. Two capsules were taken two hours before the flight and then again six hours later. The results were that the nattokinase combination product was effective in reducing thrombotic events and in controlling edema in high-risk subjects in long flights. Furthermore, the difference between the control group and the nattokinase group was statistically significant.

In addition to human research, nattokinase has also been investigated in animal studies. In one such study, nattokinase was administered to rats with a thrombus in the common carotid artery. The results were that the thrombolytic properties of nattokinase were stronger than that of plasmin or elastase.¹³ Likewise, other animal research has also demonstrated the fibrinolytic effect of nattokinase.^14,15

In-vitro and in-vivo studies have consistently demonstrated the potent fibrinolytic effect of nattokinase. Additional invitro research¹⁶ has also shown a significant, dose-dependent decrease of red blood cell aggregation, with these beneficial effects evident at concentrations similar to those achieved in previous in-vivo animal trials. This additional research data also suggests value for nattokinase as a therapeutic blood-thinning agent.

Nattokinase And Hydrolyzing Amyloid Fibrils
More than 20 unrelated proteins can form amyloid fibrils, which are related to various diseases, such as Alzheimer’s disease, prion disease (e.g. “mad cow” disease), and systematic amyloidosis. Amyloid fibrils are an insoluble fibrous protein aggregates. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In one study¹⁷, researchers explored the amyloid-degrading ability of nattokinase. Results demonstrated that nattokinase was effective in hydrolyzing amyloid fibrils. In fact, it was effective in hydrolyzing three different amyloid fibrils. These included Aβ40 fibrils (found in Alzheimer’s disease), insulin fibrils (caused by repeated insulin injection of diabetes patients) and prion peptide fibrils. The researchers concluded that this, “amyloid-degrading ability of nattokinase suggests that it may be useful in the treatment of amyloid-related diseases.”

Nattokinase And Hypertension
In a randomized, double-blind, placebo-controlled trial¹⁸, 86 participants ranging from 20 to 80 years of age with an initial untreated systolic blood pressure (SBP) of 130 to 159 mmHg received nattokinase (2,000 FU/capsule) or a placebo capsule for eight weeks. The objective of this study was to examine the effects of nattokinase supplementation on blood pressure in subjects with pre-hypertension or stage 1 hypertension. Seventy-three subjects completed the protocol. Compared with the control group, the statistically significant changes in SBP and diastolic blood pressure (DBP) were -5.55 mmHg and -2.84 mmHg, respectively, after the 8-week intervention. The corresponding net change in renin activity was -1.17 ng/mL/h for the nattokinase group compared with the control group. In conclusion, nattokinase supplementation resulted in a reduction in SBP and DBP. These findings suggest that increased intake of nattokinase may play an important role in preventing and treating hypertension.

Nattokinase And Artery Intimal Thickening
As the internal diameter of an artery, or intima, thickens, so does the risk for atherosclerosis and stroke. The thickening process is characterized by a remodeling of arteries involving the concomitant accumulation of fatty plaque formations. This is then complicated by the formation of blood clots involving fibrin. As the blood clots accumulate around the plaque, blood flow is cut off and a heart attack or stroke can result. It was previously noted how nattokinase can help reduce blood lotting factors. In addition, this enzyme can also help reduce the thickening of the arterial intima.

In animal research, intimal thickening occurs following endothelial injury to the artery. However, the administration of nattokinase was successful at inhibiting intimal thickening.¹⁹ In other animal research nattokinase also suppressed intimal thickening produced by endothelial injury in the artery. Apparently, nattokinase causes lysis (breakdown) of thrombi (blood clots) that form at the vessel wall.^20,21

Conclusion
Nattokinase is a fibrinolytic enzyme with demonstrated efficacy in reducing blood clotting factors. It has also demonstrated effectiveness in hydrolyzing amyloid fibrils, reducing hypertension and reducing artery intimal thickening. Collectively, these functions have benefits for cardiovascular health and more.

References:

1. Sumi H, Hamada H, Tsushima H, et al. A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet. Experientia 1987;43:1110–1.
2. Fujita M, Nomura K, Hong K, et al. Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the vegetable cheese natto, a popular soybean fermented food in Japan. Biochem Biophys Res Commun 1993;197:1340–7.
3. Fujita M, Hong K, Ito Y, et al. Thrombolytic effect of nattokinase on a chemically induced thrombosis model in a rat. Biol Pharm Bull. 1995;18:1387–91.
4. Sumi H, Hamada H, Tsushima H, et al. A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet. Experientia 1987;43:1110–1.
5. Suzuki Y, Kondo K, Matsumoto Y, et al. Dietary supplementation of fermented soybean, natto, suppresses intimal thickening and modulates the lysis of mural thrombi after endothelial injury in rat femoral artery. Life Sci2003;73:1289–98.
6. Urano T, Ihara H, Umemura K, Suzuki Y, Oike M, Akita S, Tsukamoto Y, Suzuki I, Takada A. The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis Cleaves and inactivates plasminogen activator inhibitor type 1. J Biol Chem 2001;276(27):24690–6.
7. Cesarone MR, Belcaro G, Nicolaides AN, et al. Prevention of venous thrombosis in long-haul flights with Flite Tabs: The LONFLIT-FLITE randomized, controlled trial. Angiology 2003;54:531–9.
8. Fujita M, Hong K, Ito Y, Misawa S, Takeuchi N, Kariya K, Nishimuro S. Transport of nattokinase across the rat intestinal tract. Biol Pharm Bull. 1995;18(9):1194–6.
9. Sumi H, Hamada H, Nakanishi K, Hiratani H. Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase. Acta Haematol 1990;84(3):139–43.
10. Peng Y, Yang X, Zhang Y. Microbial fibrinolytic enzymes: an overview of source, production, properties, and thrombolytic activity in vivo. Appl Microbiol Biotechnol 2005;69(2):126–32.
11. Hsia CH, Shen MC, Lin JS, Wen YK, Hwang KL, Cham TM, Yang NC. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutr Res 2009;29(3):190–6.
12. Cesarone MR, Belcaro G, Nicolaides AN, et al. Prevention of venous thrombosis in long-haul flights with Flite Tabs: The LONFLIT-FLITE randomized, controlled trial. Angiology 2003;54:531–9.
13. Fujita M, Hong K, Ito Y, Fujii R, Kariya K, Nishimuro S. Thrombolytic effect of nattokinase on a chemically induced thrombosis model in rat. Biol Pharm Bull. 1995;18(10):1387–91.
14. Fujita M, Hong K, Ito Y, Misawa S, Takeuchi N, Kariya K, Nishimuro S. Transport of nattokinase across the rat intestinal tract. Biol Pharm Bull. 1995;18(9):1194–6.
15. Sumi H, Hamada H, Nakanishi K, Hiratani H. Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase. Acta Haematol 1990;84(3):139–43.
16. Pais E, Alexy T, Holsworth RE Jr, Meiselman HJ. Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity. Clin Hemorheol Microcirc 2006;35(1-2):139–42.
17. Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP. Amyloid-degrading ability of nattokinase from Bacillus subtilis natto. J Agric Food Chem 2009;57(2):503–8.
18. Kim JY, Gum SN, Paik JK, Lim HH, Kim KC, Ogasawara K, Inoue K, Park S, Jang Y, Lee JH. Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertens Res 2008;31(8):1583–8.
19. Gong M, Lin HB, Wang Q, Xu JP. [Effect of nattokinase on restenosis after percutaneous transluminal angioplasty of the abdominal artery in rabbits] Nan Fang Yi Ke Da Xue Xue Bao 2008;28(9):1538–41.
20. Suzuki Y, Kondo K, Matsumoto Y, et al. Dietary supplementation of fermented soybean, natto, suppresses intimal thickening and modulates the lysis of mural thrombi after endothelial injury in rat femoral artery. Life Sci 2003;73:1289–98.
21. Suzuki Y, Kondo K, Ichise, H, et al. Dietary supplementation with fermented soybeans suppresses intimal thickening. Nutrition 2003;19:261–4.

Feel Like You Could Use More Energy?
One of the consequences of our stressful modern life is an increased need for energy. With less sleep and the depletion of nutrients in our food supply, however, it is getting harder and harder for our bodies to keep up.

There is a lot out there about how competitive athletes can up their energy. Although the approach we’ll discuss below is also excellent for athletes, it was developed, and is outstanding, for the rest of us. Whether you are a mom trying to juggle a fast paced hectic life, a student on a fast food diet, or just trying to optimize your day to day energy, here’s how to get from being fatigued to feeling fantastic!

Having spent the last 30 plus years specializing in treating chronic fatigue and chronic pain, we have learned about the keys to energy production. As an unexpected fringe benefit, these treatments have also offered enormous benefits to those suffering from heart disease.

Optimize energy production with the “SHINE Protocol” Ribose (and our overall approach to treating fatigue) has been highlighted by Dr. Oz, “America’s Doctor” on Oprah, in his wonderful new book YOU: Being Beautiful—The Owner’s Manual to Inner and Outer Beauty.

In addition, our research has shown that severely fatigued people with Chronic Fatigue Syndrome (CFS) and Fibromyalgia can increase their energy by an average of 90 percent (see the published study at www.Vitality101.com) by treating with “SHINE”: Sleep, Hormonal support, Infections, Nutrition and Exercise. For mild fatigue, the physical keys to optimizing energy are Nutrition, Sleep and Exercise, while the emotional key is to start paying attention to what feels good—while letting go of things that don’t.

How Do I Start?
Given my hectic schedule as an educator and physician, people often ask me what I do to keep my energy turbo charged. I like to keep it simple, so here is what I do personally. All of the vitamins, minerals and other essential nutrients are important to health, and the American diet is so highly processed that people have widespread deficiencies. Because of this, I like to use vitamins that make supplementation simple.

Why Ribose—And What Is Ribose?
Ribose, also called D-Ribose, is the key to your body’s energy production. Ribose is a special, five-carbon sugar (known as a pentose by biochemists) that is found naturally in our bodies. But ribose is not like any other sugar. Sugars we are all familiar with, such as table sugar (sucrose), corn sugar (glucose), milk sugar (lactose), honey (predominantly fructose), and others are used by the body as fuel. These sugars are consumed and, with the help of the oxygen we breathe, are “burned” by the body to recycle energy. Because they are used excessively, they become toxic— acting as energy loan sharks.

Ribose, on the other hand, is special. When we consume ribose, the body recognizes it is different from other sugars and preserves it for the vital work of actually making the special “energy molecules” (called ATP, NADH, and FADH) that power our hearts, muscles, brains, and every other tissue in the body. These represent the energy currency in your body, and are like the paper that money is printed on. You can have all the fuel you want, but if it cannot be converted to these molecules, it is useless. For years, I talked about the importance of B vitamins, which are a key component of these molecules. These helped improve energy to a degree, but it was clear that a key component was missing. In looking at the biochemistry of these energy molecules, they are also made of two other key components-adenine and ribose. Adenine is plentiful in the body and supplementing with adenine did not help energy production. We then turned our attention to Ribose.

Ribose is made in your body in a slow, laborious process and cannot be found in food. We knew that severe fatigue and stress causes your body to dump other key energy molecules like acetyl-L-carnitine. We then found that the body did the same with Ribose, making it hard to get your energy furnaces working again even after the other problems were treated.

This was one of those “Eureka!” moments where things came together. Not having Ribose would be like trying to build a fire without kindling—nothing would happen. We wondered if giving Ribose to people with fatigue and even CFS would jumpstart their energy furnaces. The answer was a resounding yes! Our recently published study (see the study abstract at www. Vitality101.com) showed an average 44.7 percent increase in energy after only three weeks (improvement began at 12 days) and an average overall improvement in quality of life of 30 percent. Two-thirds of the study patients felt they had improved. Usually a 10 percent improvement for a single nutrient is considered excellent. A 44.7 percent increase left us amazed, and I am now recommending Ribose for all of my chronic fatigue, chronic pain and fibromyalgia patients, for athletes, and for any one with fatigue or heart problems. Ribose recently became available (over the counter) to physicians, and is one of the few natural products actually starting with physicians and then moving out into supplement companies and health food stores. It is critical to use the proper dose for the first three weeks, which is five grams (5000 mg) three times a day. It can then be dropped to twice a day (and often even once a day in the morning with the vitamin powder to maintain optimized energy for those that are otherwise healthy).

Normal, healthy heart and muscle tissue has the capacity to make the ribose it needs. But when we are chronically stressed by life or illness, it helps to have extra ribose to help boost energy production.

The Scientific Link Between Ribose, Energy, And Fatigue
Clinical and scientific research has repeatedly shown giving ribose to energy deficient hearts and muscles stimulates energy recovery. Research in Ribose and fatigue began with a case study that was published in the prestigious journal Pharmacotherapy in 2004. This case study told the story of a veterinary surgeon diagnosed with fibromyalgia. For months, this dedicated doctor found herself becoming more and more fatigued, with pain becoming so profound she was finally unable to stand during surgery. As a result, she was forced to all but give up the practice she loved.Upon hearing that a clinical study on ribose in congestive heart failure was underway in the university where she worked, she asked if she could try the ribose to see if it might help her overcome the mind-numbing fatigue she experienced from her disease. After three weeks of ribose therapy she was back in the operating room, practicing normally with no muscle pain or stiffness, and without the fatigue that had kept her bedridden for many months. Being a doctor, she was skeptical, not believing that a simple sugar could have such a dramatic effect on her condition. Within two weeks of stopping the ribose therapy, however, she was out of the operating room and back in bed. So, to again test the theory, she began ribose therapy a second time. The result was similar to her first experience, and she was back doing surgery in days. After yet

a third round of stopping (with the return of symptoms) and starting (with the reduction of symptoms) the ribose therapy, she was convinced, and has been on ribose therapy since that time. I found this report intriguing and decided to design a larger study in patients with fibromyalgia or chronic fatigue syndrome which I began to discuss earlier. Our study included 41 patients with a diagnosis of fibromyalgia or chronic fatigue syndrome who were given ribose at a dose of five grams three times per day for three weeks. We found the ribose treatment led to significant improvement in energy levels, sleep patterns, mental clarity, pain intensity, and well being. Of the patients participating in the study, 65.7 percent experienced significant improvement while on ribose, with an average increase in energy of 44.7 percent and overall well being of 30 percent- remarkable results from a single nutrient! The only significant side effects were two people felt too energized and hyper/anxious on the ribose. This is simply dealt with by lowering the dose and/or taking it with food.

The good news is that we now have a wonderful tool to increase energy naturally. Take five grams of ribose three times per day for three weeks, then twice a day (can be mixed with any liquid or food) for two to three weeks, and then one to two times per day to see what it will do for you. You’ll be amazed!

According to the American Heart Association, approximately every 40 seconds an American will have a heart attack. The estimated annual incidence of heart attacks in the United States is 720,000 new attacks and 335,000 recurrent attacks.

Here at TotalHealth we recognize the dire need to improve diets, increase exercise, change lifestyle etc. in order to improve your cardiovascular health. Diet and exercise are probably the two most important lifestyle changes you have complete control over. However, it is difficult to get the quality of nutrients and supplements we really need in our diets due to processed foods, fast foods, and pesticides. A big part of the solution is proper supplementation with high quality and efficacious products. Reb'Active Cardio Wellness is one such product that we highly recommend as part of your cardio health supplementation regimen. As we get older our bodies produce less and less of the vital nutrients we need like CoQ10. The answer to aging is a proper diet, supplementation, and regular exercise.

Reg'Active CARDIO WELLNESS™ is a probiotic that supports heart health with a paradigm-changing probiotic that produces a cardio health antioxidant.

It contains the revolutionary probiotic strain Lactobacillus fermentum ME-3. Studied for over 20 years, ME-3 has been found to support healthy glutathione levels in the cardiovascular system.

Glutathione is the body’s “Master Antioxidant.” It is used by every cell in the human body, and it’s absolutely vital for heart health. In the cardiovascular system, glutathione affects how the body processes LDL cholesterol in a healthy fashion. Glutathione’s effects ultimately support the health of the endothelium (vascular lining).

Reg´Activ CARDIO WELLNESS™* pairs this powerhouse probiotic strain with additional heart health nutrients:

• B vitamins, including Pantethine (B5) – Helps maintain healthy cholesterol levels already in the normal range
• Coenzyme Q10 (active form, Ubiquinol) – Supports healthy energy production in heart muscle tissue

Reg´Activ™ formulas utilize breakthrough probiotic research to create proven products that support your well-being.

Read about the compatibility of Reg'Activ Cardio Wellness with Dr. Ohhira's Priobiotics here.

Which supplements should people take to help promote good health, and at what doses? Vitamins? Minerals? Herbs? Nutraceuticals? Perhaps the best answer is before experimenting with exotic dietary supplement ingredients, it first makes sense to start out with the three dietary supplements that everyone should be taking. This includes a multivitamin, vitamin D and omega- fatty acids.

MULTIVITAMINS

There is a good case for the daily use of a multivitamin, as a nutrition insurance policy that helps to fill in the gaps for those nutrients people may not be getting in their diet. Furthermore, in a study¹ of 90,771 men and women, the regular use of a multivitamin was found to significantly improve adequate intake of nutrients compared to non-users. Also, research² found that multivitamin supplements are generally well tolerated, do not increase the risk of mortality, cerebrovascular disease, or heart failure, and their use likely outweighs any risk in the general population (and may be particularly beneficial for older people). So, the bottom line is that multivitamins really do work as a nutrition insurance policy.

Other multivitamin benefits
In addition to functioning as a nutrition insurance policy, the daily use of a multivitamin may offer other benefits as well.

Cardiovascular Disease
A 12-week, randomized, placebo-controlled study³ of 182 men and women (24 to 79 years) found that a multivitamin was able to lower homocysteine levels and the oxidation of LDLcholesterol—both of which are highly beneficial in reducing the risk for cardiovascular disease. Other multivitamin research⁴ has also demonstrated effectiveness in lowering homocysteine levels.

A 6-month, randomized, double-blind, placebo-controlled study⁵ of 87 men and women (30 to 70 years) found that multivitamin use was associated with lower levels of C-reactive protein, a measurement of inflammation associated with cardiovascular disease and other degenerative diseases. Other multivitamin research⁶ in women has shown similar results.

A Swedish, population-based, case-control study⁷ of 1296 men and women (45 to 70 years) who previously had a heart attack and 1685 healthy men and women as controls, found those using a multivitamin were less likely to have a heart attack. Other multivitamin research⁸ in Swedish women has shown similar results.

Cancer:
A large-scale, randomized, double-blind, placebo-controlled study⁹ was conducted with 14,641 male U.S. physicians initially 50 years or older, including 1312 men with a history of cancer, to determine the long-term effects of multivitamin supplementation on the incidence of various types of cancers. Results showed that during a median follow-up of 11.2 years, men with a history of cancer who took a daily multivitamin had a statistically significant reduction in the incidence of total cancer compared to those taking a placebo.

Stress/Energy:
A human clinical study¹⁰ with 96 healthy men (18 to 46 years) examined the effect of multivitamin supplementation in relation to plasma interleukin-6 (IL-6, a pro-inflammatory chemical produced by the body) and anger, hostility, and severity of depressive symptoms. The results showed that plasma IL-6 was associated with anger, hostility, and severity of depressive symptoms, and that multivitamin use was associated with lower plasma IL-6 levels.

A review¹¹ of the scientific literature indicated that patients complaining of fatigue, tiredness, and low energy levels may have low levels of vitamins and minerals. Certain risk groups like the elderly and pregnant women were identified, as was the role of B-vitamins in energy metabolism. Results found that supplementation with nutrients including B-vitamins (e.g., a multivitamin) can alleviate deficiencies, but supplements must be taken for an adequate period of time.

A meta-analysis¹² of eight randomized and placebo-controlled studies evaluated the influence of diet supplementation on stress and mood. Results showed that supplementation reduced the levels of perceived stress, mild psychiatric symptoms, anxiety, fatigue, and confusion. Supplements containing high doses of B-vitamins (e.g., multivitamins) may be more effective in improving mood states.

Aging:
At the ends of our chromosomes are stretches of DNA called telomeres. These telomeres protect our genetic data, making it possible for cells to divide. Each time a cell divides, telomeres get shorter. When they get too short, the cell can no longer divide and becomes inactive or "senescent" or dies. This process is associated with aging. In a cross-sectional analysis of data from 586 women (35 to 74 years), multivitamin use was assessed, and relative telomere length was measured. The results were that multivitamin use was significantly associated with longer telomeres. Compared with nonusers, the relative telomere length was on average 5.1 percent longer among daily multivitamin users. It is possible, therefore, that multivitamins may help us live longer.

VITAMIN D

Vitamin D is the "sunshine vitamin," so coined because exposure to the sun's ultraviolet light will convert a form of cholesterol under the skin into vitamin D. This nutrient is best known for its role in helping to facilitate the absorption of calcium and phosphorus (as well as magnesium), and so helping to promote bone health.¹³ Over the past decade, however, research on vitamin D has identified numerous other roles it plays in human health and wellness, which includes:

• Inhibiting the uncontrolled proliferation of cells (as in the case of cancer) and stimulating the differentiation of cells (specialization of cells for specific functions).¹⁴
• Helping prevent cancers of the prostate and colon.^15,16
• Functioning as a potent immune system modulator.^17,18
• Helping prevent autoimmune reactions.^19,20,21
• Helping improve insulin secretion.^22,23,24
• Decreasing the risk of high blood pressure via the reninangiotensin system's regulation of blood pressure.²⁵
• Reducing osteoporotic fractures.^26,27,28
• Reducing the incidence of falls in older adults.^29,30
• Reducing the risk of developing premenstrual syndrome (PMS).³¹
• Reducing the prevalence of depression, especially in the elderly.³²
• Reducing the prevalence of urinary infections and lower urinary tract symptoms (e.g., benign prostatic hyperplasia or BPH).³³

Vitamin D deficiency and insufficiency
Outright vitamin D deficiency is present in 41.6 percent of the U.S. population,³⁴ while vitamin D insufficiency (i.e., lacking sufficient vitamin D) is present in 77 percent of the world's population.³⁵ If you are deficient in vitamin D you will not be able to absorb enough calcium to satisfy your body's calcium needs.³⁶ It has long been known that severe vitamin D deficiency has serious consequences for bone health, but other research indicates that lesser degrees of vitamin D deficiency are common and increase the risk of osteoporosis and other health problems.^37,38

Vitamin D sufficiency is measured by serum 25-hydroxyvitamin D levels in the body.³⁹ Laboratory reference ranges for serum 25-hydroxyvitamin D levels are based upon average values from healthy populations. However, recent research examining the prevention of secondary hyperparathyroidism and bone loss suggest that the range for healthy 25-hydroxyvitamin D levels should be considerably higher. Based upon the most current research, here are the ranges for serum 25-hydroxyvitamin D values:

• Less than 20–25 nmol/L: Indicates severe deficiency associated with rickets and osteomalacia.^40,41
• 50–80 nmol/L: Previously suggested as normal range.⁴²
• 75–125 nmol/L: More recent research suggests that parathyroid hormone^43,44 and calcium absorption⁴⁵ are optimized at this level; this is a healthy range.⁴⁶

Based upon the 75–125 nmol/L range, it is estimated that one billion people in the world are currently vitamin D deficient.⁴⁷ Furthermore, research indicates that supplementation with at least 800–1,000 IU daily are required to achieve serum 25-hydroxyvitamin D levels of at least 80 nmol/L.^48,49 Furthermore, there are many groups of individuals who currently are at risk for vitamin D deficiency. These include:

• Exclusively breast-fed infants: Especially if they do not receive vitamin D supplementation and if they have dark skin and/or receive little sun exposure.⁵⁰
• Dark skin: People with dark-colored skin synthesize less vitamin D from sunlight than those with light-colored skin.⁵¹ In a U.S. study, 42 percent of African American women were vitamin D deficient compared to four percent of white women.⁵²
• The Elderly: When exposed to sunlight have reduced capacity to synthesize vitamin D.⁵³
• Those using sunscreen: Applying sunscreen with an SPF factor of eight reduces production of vitamin D by 95 percent.⁵⁴
• Those with fat malabsorption syndromes: The absorption of dietary vitamin D is reduced in Cystic fibrosis and cholestatic liver disease.⁵⁵
• Those with inflammatory bowel disease: An increased risk of vitamin D deficiency occurs in those with inflammatory bowel disease like Crohn's disease.⁵⁶
• Obese individuals: Obesity increases the risk of vitamin D deficiency.⁵⁷

Vitamin D2 and D3
There are two forms of vitamin D available as a dietary supplement: cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Cholecalciferol is the form made in the human body, and it is more active than ergocalciferol. In fact, Vitamin D2 potency is less than one third that of vitamin D3.⁵⁸

Commercially, ergocalciferol is derived from yeast, and so is considered vegetarian, while cholecalciferol is commonly derived from lanolin (from sheep) or fish oil—although a vegetarian D3 derived from lichen is available.

Ideal dosing for vitamin D
The Linus Pauling Institute recommends that generally healthy adults take 2,000 IU of supplemental vitamin D daily.⁵⁹ The Vitamin D Council states that if well adults and adolescents regularly avoid sunlight exposure, then it is necessary to supplement with at least 5,000 IU of vitamin D daily.⁶⁰ The Council for Responsible Nutrition recommends 2,000 IU daily for adults.⁶¹ Taking a conservative position, at least 2,000 IU of vitamin makes sense for adults.

OMEGA-3 FATTY ACIDS
Chemically, a fatty acid is an organic acid that has an acid group at one end of its molecule, and a methyl group at the other end.⁶² Fatty acids are typically categorized in the omega groups 3, 6 and 9 according to the location of their first double bond (there's also an omega 7 group, but these are less important to human health).⁶³ The body uses fatty acids for the formation of healthy cell membranes, the proper development and functioning of the brain and nervous system, and for the production of hormone-like substances called eicosanoids (thromboxanes, leukotrienes, and prostaglandins). These chemicals regulate numerous body functions including blood pressure, blood viscosity, vasoconstriction, immune and inflammatory responses.⁶⁴

Deficiency of omega-3 fatty acids
While omega-3, 6 and 9 fatty acids are all important for different reasons, it is the omega-3 fatty acids (O3FA) that are currently particularly critical—and specifically the O3FA known as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The reason for this current importance is that Western diets are deficient in O3FA, and have excessive amounts of omega-6 fatty acids. While human beings evolved on a diet with approximately a 1:1 ratio of omega-6 to omega-3 fatty acids (EFA), the current Western diet provides about a 16:1 ratio.⁶⁵ As a matter of fact, a recent Harvard School of Public Health study indicates that Omega-3 deficiency causes 96,000 U.S. deaths per year.⁶⁶ Other research has clearly shown that excessive amounts of omega-6 fatty acids and a very high omega-6 to omega-3 ratio, as is found in today's Western diets, promote many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 (a low omega-6 to omega-3 ratio) exert protective effects.⁶⁷

Benefits of omega-3 fatty acids

O3FA offer a broad range of benefits in human health. These benefits are listed below categorically:

Cardiovascular Health
In several studies O3FA have been shown to help lower triglyceride levels.⁶⁸ In fact, the FDA has even approved an O3FA product for this purpose.⁶⁹ Individually, EPA and DHA also have triglyceride-lowering properties. Consuming 1 gram/day of fish oils from fish (about 3 ounces of fatty fish such as salmon) or fish oil supplements has a cardioprotective effect.⁷⁰

Evidence suggests increased consumption of O3FA from fish or fish-oil supplements, but not of alpha-linolenic acid, reduces the rates of all-cause mortality, cardiac and sudden death, and possibly stroke.⁷¹ Higher consumption of fish and O3FA has been associated with a lower risk of coronary heart disease.^72,73 Clinical research shows that DHA supplementation helps increase HDL cholesterol levels (the "good cholesterol").^74,75 Supplementation with fish oil produces modest, but significant reductions in systolic and diastolic blood pressure in patients with mild hypertension.^76,77,78

Inflammation
O3FA have been shown to help relieve inflammation caused by a variety of factors.^79,80

Research⁸¹ has demonstrated that fish oil supplementation is effective in the treatment of rheumatoid arthritis.

Menopause
Clinical research shows that taking supplements with 500 mg EPA, three times daily, modestly but significantly reduces the frequency of hot flashes compared to placebo in menopausal women.⁸²

ADHD
Research has shown children with attention deficit/hyperactive disorder (ADHD) may have low plasma levels of EPA and DHA.^83,84 Clinical research suggests that supplementation with DHA might improve aggression and social relationships in ADHD children.⁸⁵

Macular degeneration
Increased dietary consumption of DHA is associated with reducing the risk of macular degeneration.⁸⁶

Alzheimer's Disease
Participants who consumed fish once per week or more had 60 percent less risk of Alzheimer's disease compared with those who rarely or never ate fish, and this was attributed to the DHA content of the fish.⁸⁷

The sources of omega-3 fatty acids

To begin with, the overwhelming majority of research on the health benefits of supplementation with O3FA has been conducted using fish oil products. Consequently, a strong argument can be made that fish oil supplements are the preferred source of O3FA. Amongst these, the primary fish used commercially as the source from which O3FA are derived include mackerel, herring, tuna, halibut, salmon and cod liver.⁸⁸ Although some fish are touted as superior over others as sources for supplemental fish oil, it is the opinion of this author that they all provide acceptable sources of omega-3s. Still, there are other sources of O3FA besides fish oil. This includes squid, krill, flax seed oil and algae oil.

Squid
Squid-derived O3FA are derived from by-products of squid that are usually discarded when squid are commercially fished, and provides a much higher concentration of DHA (up to 50 percent) than do fish oil. However, there is a lack of human clinical data on squid-source O3FA, although they likely will have similar effects as fish oil.

Krill
Krill oil derived from the shrimp-like crustacean know as krill contain significant amounts of the EPA and DHA omega-3 fatty acids, as well as phospholipids (e.g., phosphatidylcholine),⁸⁹ vitamin A, vitamin E and astaxanthin, a powerful carotenoid antioxidant.^90,91 Human clinical research⁹² has shown that krill oil has greater absorption than fish oil—although krill provides significantly less EPA/DHA per gram than fish oil.

Flaxseed
Flaxseed oil contains about 52–55 percent omega-3s, but as alpha-linolenic acid (ALA), not EPA/DHA.⁹³ This is significant since ALA has to be converted to EPA and DHA before it will provide the much-touted health benefits attributed to O3FA. This is problematic since studies indicate that in men approximately eight percent of ALA is converted to EPA and 0–4 percent is converted to DHA.⁹⁴ In women, approximately 21 percent of dietary ALA is converted to EPA and nine percent is converted to DHA.⁹⁵ This is not to say that flaxseed oil has no value. It does, but just not as significant a value as fish oil.

Algae oil
Certain algae extracts provide a vegetarian source of O3FA—but in this case the O3FA are EPA and DHA, not ALA. Consequently, for vegetarians, algae oil is a viable substitute for fish oil. That being said, human clinical research on algae oil sources of O3FA is limited, and the cost is far more than fish oil.

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65. Danaei G, Ding EL, Mozaffarian D, et al. The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors. PLoS Med. 2009 Apr 28;6(4):e1000058.
66. Ibid. 105
67. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(5 Suppl):1645S–54S.
68. Lovaza: Omega-3 Acid Ethyl Esters. Retrieved August 6, 2009 from http://www.lovaza.com/index.html?banner_s=208381923&rotation_s=30492788.
69. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106(21):2747–57.
70. Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84(1):5–17.
71. Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002;287(14):1815–21.
72. Jarvinen R, Knekt P, Rissanen H, Reunanen A. Intake of fish and long-chain n-3 fatty acids and the risk of coronary heart mortality in men and women. Br J Nutr. 2006;95(4):824–9.
73. Agren JJ, Hanninen O, Julkunen A, et al. Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels. Eur J Clin Nutr 1996;50:765–71.
74. Mori TA, Burke V, Puddey IB, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr 2000;71:1085–94.
75. Prisco D, Paniccia R, Bandinelli B, et al. Effect of medium-term supplementation with a moderate dose of n-3 polyunsaturated fatty acids on blood pressure in mild hypertensive patients. Thromb Res 1998;1:105–12.
76. Toft I, Bonaa KH, Ingebretsen OC, et al. Effects of n-3 polyunsaturated fatty acids on glucose homeostasis and blood pressure in essential hypertension. A randomized, controlled trial. Ann Intern Med 1995;123:911–8.
77. Yosefy C, Viskoper JR, Laszt A, et al. The effect of fish oil on hypertension, plasma lipids and hemostasis in hypertensive, obese, dyslipidemic patients with and without diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids 1999;61:83–7.
78. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68(5):280–9.
79. Calder PC. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83:1505S–19S.
80. Fortin PR, Lew RA, Liang MH, et al. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol. 1995;48(11):1379–90.
81. Lucas M, Asselin G, Merette C, et al. Effects of ethyl-eicosapentaenoic acid omega-3 fatty acid supplementation on hot flashes and quality of life among middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Menopause. 2009;16:357–66.
82. Stevens LJ, Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr. 1995;62:761–8.
83. Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr. 2001;139:189–6.
84. Hamazaki T, Hirayama S. The effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder-a placebo-controlled double-blind study. Eur J Clin Nutr. 2004;58:838.
85. Cho E, Hung S, Willet W, et al. Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr. 2001;73:209–18.
86. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60:940–6.
87. MedlinePlus. Fish Oil. U.S. National Library of Medicine. Last reviewed–12/10/2011.
88. Bottino NR. Lipid composition of two species of Antarctic krill: Euphausia superba and E. crystallorophias. Comp Biochem Physiol B 1975;50:479–84.
89. Ibid.
90. Dunlap WC, Fujisawa A, Yamamoto Y, et al. Notothenioid fish, krill and phytoplankton from Antarctica contain a vitamin E constituent (alphatocomonoenol) functionally associated with cold-water adaptation. Comp Biochem Physiol B Biochem Mol Biol 2002;133:299–305.
91. Ulven SM, Kirkhus B, Lamglait A, Basu S, Elind E, Haider T, Berge K, Vik H, Pedersen JI. Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of EPA and DHA, in healthy volunteers. Lipids 2011;46(1):37–46.
92. Vereshagin AG and Novitskaya GV. The triglyceride composition of linseed oil. Journal of the American Oil Chemists' Society 1965;42:970–4.
93. Burdge GC, Jones AE, Wootton SA. Eicosapentaenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men. Br J Nutr. 2002;88(4):355–64.
94. Burdge GC, Wootton SA. Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr. 2002;88(4):411–20.

Today, most people know that the omega-3 fatty acids, such as are found in cold-water fish, are good for us. In fact, these are among the “stars players” of health supplements. The omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) have been widely studied in connection with cardiovascular, joint, immune and brain health. Numerous scientific findings have demonstrated that omega-3 fatty acids are important for a healthy inflammatory response. In fact, research on omega-3s is so compelling that the FDA has granted a qualified health claim to the effect that consuming omega-3s reduces the risk of heart disease. For more than a decade, many of the benefits of omega-3 fatty acids have been largely beyond reasonable doubt. This year, that certainty has been called into question.

Publications from early 2015 challenge, or at least appear to challenge, two of the most important assertions often made for omega-3 fatty acid supplementation. These are the assertion that fish oils are valuable assets in reducing key components of cardiovascular disease and the assertion that these oils are useful supplements for preventing cognitive decline. The first shoe fell on March 31 with the publication in the New York Times of the essay, “Fading claims on fish oils.” This article was quite direct in judging that “no evidence that fish oil lowers risk for heart attack or stroke” has been found according to the majority of clinical trials that have been conducted on the topic.

The second shoe fell on August 26 in the form of a Newsweek article entitled “Omega-3 Supplements Are a Waste of Money.” The basis of this judgment was a medical study published in August 2015 in which the authors Chew et al. concluded, “oral supplementation with LCPUFAs (long-chain polyunsaturated fatty acids) … had no statistically significant effect on cognitive function.” 1 The same research group the previous year, based on the same trial design and data, had concluded that omega-3 supplementation “did not reduce the risk of CVD in elderly participants with age-related macular degeneration.” 2 This study, dubbed AREDS2, was a large double-blinded randomized study involving more than 4,000 subjects in its overall design and lasting approximately five years. On the surface, the results appear to be definitive. As often is the case, however, appearances can be deceiving.

The latest studies are not always the best or the most definitive studies despite the breathless hype so often found in the popular press. As usual, the devil is in the details with both of the negative judgments in the above paragraphs. The following sections provide a bit of guidance for the perplexed.

Omega-3s versus Cardiovascular Disease

In evaluating the findings of clinical trials, it is necessary to consider a range of questions regarding the basis and the aims of the trials in question. For instance, was a given trial performed in the right subject population to support its conclusions? The AREDS2 study mentioned above for its CVD conclusions used a population of participants who were “primarily white, married, and highly educated, with a median age at baseline of 74 years” that included “participants with stable, existing CVD (>12 months since initial event)” to determine a “composite outcome of myocardial infarction, stroke, and cardiovascular death…” “Approximately 19% had a history of CVD; 44% reported taking a statin medication; and 14% reported taking any type of medication for congestive heart failure, CVD, or cerebrovascular disease.” Several issues should be flagged immediately with this study population.

First, it was a group that might be expected to already have adopted dietary changes, such as eating fish two or more times per week and preferring olive oil for cooking and salads, that would have reduced the impact of supplementation with additional omega-3 oils. The average American may eat a diet highly unbalanced in the ratio of omega-3 to omega-6 fatty acids, high in saturated fats and low in magnesium, low in vegetables and fiber, etc., but the study population would have been much less likely to be following the standard American diet. Did the researchers check? Not as far as I could tell from reading the methods section. My suspicion is that a substantial percentage of the subjects already were consuming considerable omega-3 fatty acids in their diets and already had adopted a more healthful ratio of omega-3 to omega-6 fatty acids than is true of most Americans.

Second, 44 percent of the study group already was taking a statin medication and 14 percent (whether overlapping the statin takers is not indicated, but the implication is “not”) were taking other CVD medications. In other words, this was not a medically “naïve,” i.e., pharmaceutically untreated, starting population. The researchers in AREDS2 did try to control for some of these issues (see Figure 3 in the study), yet their data in this regard are a bit odd. Despite the non-significance of the statistics regarding the number of cardiac events between omega-3 and non-omega-3 arms with regard to, say, statin use, there were statistically significant differences between the arms involving hypertension history (a proven benefit of omega-3 supplementation, P = 0.02) and cardiovascular disease history (P = 0.04) implying a medical treatment effect not captured in the write-up. The authors, by the way, do admit the data that I mention imply potential benefit from omega-3 supplementation, but then try to explain this away without pursuing the implications regarding their collected data and its reliability regarding the impact of medications and lifestyle changes.

Another issue involves the endpoints selected for evaluating the outcome of a study. Surely, the meta-analyses have been conducted to evaluate the quite massive volume of clinical research, which has been performed with omega-3 fatty acids. This research consistently has found that fish oil consumption reduces cardiac death risk between approximately 10 and 30 percent with a low of nine percent and a high of 35 percent.³ These figures surely are not bad for a simple and safe dietary supplement!

With regard to other important CVD risk factors, omega- 3s have been found to consistently perform well. Omega-3 supplementation reduced blood pressure in studies in the general population approximately 4.5 mm Hg, which similar to lifestyle changes, including reduced intake of dietary sodium, increased physical activity and a reduction in excessive alcohol consumption. High fasting triglycerides were reduced by 30– 40 percent, yet another healthful change.⁴

Again, it must be remembered that study populations are important for outcomes. If one focuses on populations with advanced cardiovascular disease, this will be quite misleading with regard to the benefits of taking a nutrient, in this case, omega-3 fatty acids, over a significant period of time starting before the disease has manifested. This, of course, is precisely the role of supplements as opposed to drugs. The New York Times article applied the wrong model and created a controversy by doing so.

Omega-3s and Cognition

Let’s return to the citation above in which Chew et al. concluded, “oral supplementation with LCPUFAs (long-chain polyunsaturated fatty acids) … had no statistically significant effect on cognitive function.” The authors actually state in another spot, “Contrary to popular belief, we didn’t see any benefit of omega-3 supplements for stopping cognitive decline.”

The study by Chew et al. refers to its experimental supplementation as a “high dose,” yet the truth is that only 350 mg of the dose was DHA and the other 650 mg was EPA. This matters because these two omega-3 fatty acids do different things. To combat depression, which the AREDS2 study did not examine, EPA is the more significant nutrient. Trials using a mixture of the two mostly have been successful.⁵ Nevertheless, in a face-off of the two omega-3 fatty acids, EPA is the stronger anti-inflammatory in the brain and may deliver better results against depression.⁶

For cognition, the reverse is true: DHA outperforms EPA. This should not come as a surprise given that DHA plays a major structural role in brain cellular membranes and in the neurologic system more generally. In a study of 22 healthy adults, 12 weeks of daily dietary supplementation with either 1 g DHA-rich or 1 g EPA-rich fish oil (FO) or placebo (1 g olive oil) were assessed with the result being that DHA consumption leads to greater blood flow and activity in the prefrontal cortex during cognitive tests than does EPA.⁷ In older adults, episodic memory outcomes in adults with mild memory complaints are improved with the intake of greater than 1 gram DHA/EPA per day.⁸ In other words, the study by Chew et al., focused on the wrong omega-3 fatty acid to better influence cognition and was below an accepted threshold for the dosage for some aspects of cognition and memory.

To be fair to Chew et al., their trial was designed before papers became available that demonstrated that higher dosages of DHA and/or DHA/EPA improved cognition and memory, whereas lower dosages did not. A clarifying discussion of the issues involved has been published under the title “Omega-3s and Cognition: Dosage Matters.”⁹ For those interested in pursuing this issue further, a table of relevant papers can be downloaded from http://goedomega3.com/files/download/334/memory-and-cognitive-functionpapers-table.pdf.

Conclusion
The misleading conclusions of the New York Times article on fish oils and cardiovascular disease and the Newsweek article on DHA and cognition are cautionary tales regarding the interpretation of studies. In reality, adequate intakes of omega-3 fatty acids reduce CVD mortality by 10 to 30 percent, although supplementation may not deliver this same degree of benefit in populations already suffering from active CVD, already taking numerous medications or already having adopted appropriate diet and lifestyle modifications. Similarly, DHA supplementation significantly improves some aspects of cognition and memory, but only at intake levels above 1 gram per day in older individuals. Younger adults may benefit from 1 gram mixed DHA/EPA with the proviso still in place that for this purpose DHA is more active than is EPA whereas for depression, the opposite is true.

Endnotes:

1. 1. Chew EY, Clemons TE, Agron E, Launer LJ, Grodstein F, Bernstein PS; Age-Related Eye Disease Study 2 (AREDS2) Research Group. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA. 2015 Aug 25;314(8):791.801.
2. 2. Writing Group for the AREDS2 Research Group, Bonds DE, Harrington M, Worrall BB, Bertoni AG, Eaton CB, Hsia J, Robinson J, Clemons TE, Fine LJ, Chew EY. Effect of long-chain ƒÖ-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA Intern Med. 2014 May;174(5):763.71.
3. 3. Ismail A. The real story of omega-3s in heart health. April 3, 2015. http://goedomega3.com/index.php/blog/2015/04/the-realstory-of-omega-3s-in-heart-health
4. 4. Ibid.
5. 5. Yang JR, Han D, Qiao ZX, Tian X, Qi D, Qiu XH. Combined application of eicosapentaenoic acid and docosahexaenoic acid on depression in women: a meta-analysis of double-blind randomized controlled trials. Neuropsychiatr Dis Treat. 2015 Aug 10;11:2055.61.
6. 6. Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr. 2009 Oct;28(5):525.42.
7. 7. Jackson PA, Reay JL, Scholey AB, Kennedy DO. DHA-rich oil modulates the cerebral haemodynamic response to cognitive tasks in healthy young adults: a near IR spectroscopy pilot study. Br J Nutr. 2012 Apr;107(8):1093.8.
8. 8. Yurko-Mauro K, Alexander DD, Van Elswyk ME. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One. 2015 Mar 18;10(3):e0120391.
9. 9. Ismail A. Omega-3s and Cognition: Dosage Matters. August 31, 2015. http://goedomega3.com/index.php/blog/2015/08/omega-3s-and-cognition-dosage-matter

This article is the fourth in the series that began with “Solving the Mystery of the Multivitamin.” The focus now shifts to reasons for taking a multivitamin/mineral as we enter the second half of life and, more importantly, the overall approach to nutrition that should inform any anti-aging program. Readers will discover that some, but not all of the gender-specific nutritionaln needs covered in earlier articles become less meaningful in later life. As individuals approach 60, overall physiology changes in ways that tend to lead to a convergence of nutritional requirements.