Taking Supplementation Seriously Part IV

In past articles, we presented the case for insuring nutritional sufficiency of the essential vitamins and minerals through supplementation. There is little debate that these micronutrients are requisite for human survival, and that their supplementation may be an apt course for some. A healthy diet also provides several other nutritionally-beneficial elements which, like the vitamins and minerals, are not always present at optimal levels and thus can potentially benefit from supplementation.

Here is a list of five dietary supplements that are worth considering as additions to the multivitamin. They are not meant to represent the "best" or "most useful" of the supplement field (which has little meaning given the individuality of metabolism); rather, these choices represent common dietary constituents that primarily function to broadly improve health and well-being (as opposed to addressing a single aspect of it). Each has a defined, critical role in normal human metabolism, and all but one are only obtainable through the diet.

Omega-3 fatty acids and whey protein are sources of essential fatty and amino-acids, the two remaining classes of essential nutrients after the vitamins and minerals. Fiber supplements provide this oft-deficient dietary macronutrient, which along with probiotic bacteria are a major determinant in intestinal function and the maintenance of healthy gut microflora. Supplementing with the nutritionally non-essential Coenzyme Q10 can augment the levels of this general purpose fat-soluble antioxidant and critical component for cellular energy generation, which may be of particular significance for older consumers.

Note that this list is a starting point; there are many additional dietary supplements that truly "supplement" the diet with nutrients that are often missing or suboptimal (phytonutrients such as carotenoids, isothiocyanates, and polyphenolic antioxidants are notable examples), as well as several well-studied natural ingredients that address specific health concerns but may not be "normal" constituents of the diet (herbal supplements such as milk thistle or saw palmetto fall into this category).

Omega-3 fatty acids. Omega-3 fatty acids are long-chain polyunsaturated fatty acids from fish, shellfish, algae, or seed oils that have well-established roles in human nutrition, both as building blocks for the cell membranes of the brain, and as precursors to the human body's own natural anti-inflammatory system. Sufficient intake of omega-3s has been associated with reduced risk of heart disease, may facilitate healthy levels of circulating cholesterol and triglycerides, and may help maintain a healthy heartbeat and blood pressure. A balanced inflammatory response also relies on sufficient omega-3 fatty acids for the synthesis of endogenous anti-inflammatory factors.

Alpha-linolenic acid (ALA), a constituent of seed oils from flax, perilla, and chia, is an essential nutrient for humans. The principle omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from marine oils are not considered essential to human nutrition (we can make these from dietary ALA), but there is evidence some people may have trouble synthesizing sufficient levels of these fatty acids on their own, making them a good supplement choice. Omega-3 fatty acids from krill (a cold water crustacean) are in a potentially more bioavailable form (phospholipids) and contain high levels of the fat soluble antioxidant astaxanthin. Initial studies of krill oil suggest it may have a more potent lipid-lowering effect than other cold-water fish oils, meriting its choice as an omega-3 source.

Whey Protein. It's not a capsule, and might be better described as a food product, but whey deserves consideration for increasing the amount of high-quality protein and essential amino acids in the diet. Whey protein is the "soluble" protein fraction from milk, and is commonly sold as a concentrate (most often about 70 percent protein with very low amounts of milk sugar or fat) or isolate (>90 percent protein, usually fatand lactose-free ), as well as in flavored pre-mixes or ready to drink beverages. Diets which are higher in protein have been associated with better glycemic control, normalized blood lipids, and have been shown to promote greater fat reduction, thermogenesis, and energy expenditure than high carbohydrate or high fat diets. Protein can also be more satiating than other macronutrients. "Fast proteins," like whey, are quickly digested and absorbed, which results in large, rapid increases of amino acids in the bloodstream following a meal, signaling fullness. Compared to other common protein supplements (soy, casein), whey exhibits superior appetite suppression when taken with a meal as 25 percent of total calories.

Many of the health benefits of whey have been attributed to its high concentration of branched chain amino acids (BCAAs), a group of three nutritionally essential amino acids (leucine, isoleucine, valine). BCAAs serve as muscle fuel (which is why whey is often considered a “sports” supplement), but they may also stimulate the bodies basic satiety response. BCAAs also aid in fat loss, preserve lean body mass, and may help to lower insulin levels following a meal.

Probiotics: Probiotics are living microorganisms, which upon ingestion in sufficient numbers, exert health benefits beyond general nutrition. Probiotic bacteria and yeast can reside on the surfaces of mucosal tissues (such as the gastrointestinal or upper respiratory tract) and provide a living barrier to environmental insults. Probiotic bacteria function in a variety of ways; they can inhibit the growth or block the attachment of rival pathogenic bacteria, they can improve the barrier function of mucosal membranes (providing protection from pathogens or toxins), they bolster immune function, produce vitamins, and enhance mineral absorption. Probiotic bacteria can play significant roles in systemic detoxification by trapping and metabolizing harmful dietary compounds or heavy metals. The production of the short chain fatty acids by probiotic bacteria in the intestines (from the fermentation of dietary fiber) improves the detox function of the liver and skin; this may also contribute to some of the anti-carcinogenic properties of dietary fiber.

Probiotic supplements come in a myriad of forms and formulations, encompassing a wide variety of bacterial species and potency (probiotic potency is expressed in colony forming units—CFU—which is a measurement of the number of bacteria per serving.) A good starting point for general health maintenance would be a multi-strain product (having more than one type of bacteria) at a moderate potency (3–10 billion organisms); this is similar to the probiotic intake from a diet that contains fermented foods.

Fiber Supplements: Fibers are polysaccharides (complex carbohydrates) that are indigestible by humans, yet have some significant roles in general health maintenance. The bulk of fiber and its resistance to digestion lend it satiating properties in the stomach; these same properties also cause it to increase the bulk of stool and hasten the transit of digested food through the intestines. This increase in gastric motility helps to minimize exposure of colonic epithelial cells to potential carcinogenic compounds or other dietary toxins. Dietary fibers can bind up bile acids and cholesterol, and prevent them from being re-absorbed; this facilitates the body’s ability to rid itself of excess cholesterol. Some fibers can also be specifically digested (fermented) by beneficial colonic bacteria into short chain fatty acids (like lactate or butyrate), which have their own health benefits throughout the body. Fermentable or prebiotic fibers (such as inulin and fructooligosaccharides) are available as supplements as well and are an appropriate complement to probiotics.

There is convincing evidence that fiber intake reduces the risk of colon and breast cancers and cardiovascular disease; it has also been associated with healthy body weight, serum cholesterol levels, blood sugar control, and blood pressure. Unfortunately, the overwhelming majority of adults in the United States do not get the daily recommended intake of fiber, which is 38 grams/day for men 19–50 (30 grams/day for men over 50) and 25 grams/day for women 19–50 (21 grams/ day for women over 50). Even a modest increase to 20 grams a day from average current dietary levels has been estimated to reduce the rate of colorectal cancer by 40 percent. The fiber in our diets is heterogenous, containing several types of gums, pectins, lignans, cellulose, beta-glucans, fructans, and digestion-resistant starches. A good choice in fiber supplements would contain a mixture of multiple fiber types.

Coenzyme Q10. Despite being the only member of the list that isn’t a nutritionally essential nutrient or a major component of the diet (young, healthy people can make sufficient CoQ10 for their metabolic needs), the potential health benefits of CoQ10 merit its consideration as part of a supplement regimen, especially in older consumers. CoQ10 is a fat-soluble substance that is an essential component of the energy production system in cells. It is found in each cell in the body, but is particularly concentrated in tissues which have large energy requirements (like the heart). There are also substantial amounts of CoQ10 in the blood, protecting circulating lipids (LDL and HDL) from oxidative damage. Supplemental CoQ10 has been the subject of numerous studies, particularly in applications for improving cardiovascular health (as in subjects with chronic heart failure, exercise-induced angina, or hypertension); it may also be protective of the cardiovascular system in diabetics. CoQ10 continues to be the subject of academic research, and is beginning to find acceptance as a supplement amongst mainstream medical practitioners.

The average diet contains only a small amount of CoQ10, which is generally poorly absorbed (by some estimates, as little as two to three percent of dietary CoQ10 is absorbed). Variability in absorption also appears to be age-dependent; case reports suggest decreased fractional absorption in older patients. Several "enhanced absorption" strategies and products have been developed to overcome this hurdle, with improved uptakes verified by clinical data. Recently, the second naturallyoccurring form of CoQ10 (ubiquinol) has been introduced into the supplement market (CoQ10 supplements have typically been in the form of ubiquinone.) Ubiquinol is absorbed more efficiently than ubiquinone, especially in individuals who have difficulty absorbing CoQ10.

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