Two years ago in this space the topic was the entourage effect and how it differed from nutritional and medical findings involving synergy: "Whereas synergism involves components each of which is active on its own and which in combination yield effects greater than the sum of the individual contributions, the entourage effect may involve components most of which on their own may exhibit little or no benefit or may yield benefits that are otherwise unrelated."1 In practice, of course, there is more than a little overlap and one finds this all the time with foods and supplements. A good example is the so-called French paradox, generally presented as the supposed paradox between the French consumption of comparatively large percentage of calories as fat, especially as animal fat, and the Gallic low rate of heart disease.
Is the French Paradox Explained by Nutrient Synergies?
Sardonic observers sometimes remark that Americans count calories with neat little categories for carbohydrates, fat and protein whereas the French are only concerned with how food tastes and how the meal looks, its "presentation." Assuming that the consumption of animal fat matters, a point increasingly in question, the French classically have not cared while enjoying enviable levels of health, hence, by Anglo- American lights, the paradox. The traditional French diet is >42 percent fat, much of it either saturated or monounsaturated. The French (traditionally, at least, maybe still) drink red wine daily, yet outlive Americans (81.6 years versus 78.8 years, as of 2015, other statistical bases giving similar results).2 The French also suffer from fewer cases of coronary heart disease and, in actuality, remain ambulatory and self-sufficient much longer than do Americans, meaning that statistics of relative life expectancy should be balanced by a close look at morbidity statistics. According to the 2014 World Health Organization data set, the French rank second in the world, behind South Korea, for having the lowest mortality rates from coronary heart disease. America? We rank 44th.3 Significantly, in France they consume almost no sugary drinks and eat very little sugar in any form. These dietary practices should be contrasted with those in the States.4
A new report from the USDA says Americans are eating less fat than we did 30 years ago. Here's the opening from an online article about the report:5 On average, Americans are eating 10g less fat per day today than they were in the late 1970s, according to new research. In a report comparing food consumption patterns in 1977–78 versus 2005–2008, Biing-Hwan Lin and Joanne Guthrie from USDA's Economic Research Service found that on average, Americans consumed 75.2g of fat in 2005–08 compared with 85.6g in 1977–78. Meanwhile, the percentage of total calories derived from fat also declined substantially from 39.7% to 33.4% between 1977 and 2008, said the authors.
Of course, there is no paradox if the long-standing condemnation of the role of fat and saturated fats in cardiovascular disease is mistaken, as discussed in last month's column and previously in Heart Matters Do Statin Drugs. However, let's assume that there is a connection and that the paradox, as often suggested, is a result of the French love of red wine. Is wine's protection from a single magic phytonutrient, resveratrol, or is the combination of ingredients the key?
Many who argue that there is a paradox suggest that the phytochemical known as resveratrol is responsible for the low rates of cardiovascular disease. Critics argue that this is nonsense because there simply is not enough of the compound present to exert any effect. In fact, just this point was the focus of an exchange back in 2008 in which a colleague, Joseph Evans, and I were participants.6 Subsequent findings decisively have proven that Evans and I were correct and our interlocutor mistaken in both his evidence and his arguments.
The skeptic's argument went like this: "The potency of most of the nutritional supplements labeled as resveratrol is in the range of 30 mg to 100 mg. This is 30 to 100 times lower than doses thought to be in the range for therapeutic effects in humans." Our response was that red wine is a widely studied source of the combination of resveratrol and quercetin and that significant health benefits are associated with men it was demonstrated that "the platelet antiaggregatory effect of de-alcoholized red wines could be computed...from its concentrations of resveratrol and quercetin."7 Similarly, the combination of resveratrol and quercetin exerts a powerful synergy in the inhibition of inducible nitric oxide (the form linked to inflammation).8 In animals fed a high-cholesterol diet, the human equivalent of 210 mg resveratrol per day improved endothelial function.9 However, more was not better, with animal experiments demonstrating that, in human equivalent amounts, approximately 360 mg per day led to greater life expectancy than approximately 1,565 mg per day.10 Finally, there is experimental evidence that the combination of nutrients such as pterostilbene, quercetin, and resveratrol might be more active than any one of these alone at much higher dosages with research showing that subeffective doses of combinations of anti-inflammatory compounds can inhibit, for instance, carcinogenesis.11
In contention was whether relatively modest amounts of resveratrol in combination yield significant health benefits for humans despite the amounts being ineffective on their own. A recent clinical study provides an instance of proof that is in line with other studies published since 2008.12 In a randomized, placebo-controlled crossover clinical trial with 29 overweight and obese subjects, trans-resveratrol and hesperetin taken together were effective in altering a marker related to insulin resistance and improving metabolic and vascular health. (Hesperetin is a flavanone, a particular type of flavonoid.) Treatment was one capsule daily for eight weeks and a washout period of six weeks with 90 mg resveratrol and 120 mg hesperetin and placebo. Neither resveratrol nor hesperetin was efficacious by itself, whereas together they significantly decreased fasting and postprandial plasma glucose, increased the oral glucose insulin sensitivity index and improved arterial dilatation.13 In other words, combining these nutrients is pivotal in promoting their benefits.
Underappreciated Nutrient Combinations
Magnesium and Potassium
Not usually considered as an aspect of the French diet that separates it from American nutrient intake is the ingestion of minerals important for blood pressure and blood sugar regulation, such as magnesium and potassium. Americans notoriously do not consume green vegetables, primary dietary sources of both minerals. This is a shame because dietary potassium regulates vascular calcification and arterial stiffness, which is to say, two major factors determining cardiovascular health.14 There is much noise made about lowering sodium intake, but it is the ratio of sodium to potassium in the diet that determines blood pressure, not the simple amount of sodium.15
The combination of magnesium and potassium arguably is particularly efficacious for a number of reasons. For one, the development of insulin resistance impedes the proper uptake of potassium.16 Magnesium deficiency inclines subjects toward insulin resistance. There is considerable evidence that inadequate magnesium predisposes individuals to potassium deficiency and makes this deficiency difficult to treat with potassium alone. Magnesium, which is a natural calcium channel blocker, controls the flow of sodium and potassium across the cell membrane and therefore potentiates cellular replenishment of potassium.17 Significantly, Mildred Seelig, the great magnesium researcher, pioneered an approach in which the ingestion of a potassium and magnesium salt with fixed ratios of the two minerals and a certain minimum per day proved to be adequate to reverse and control moderate hypertension.18,19
Improvement in bone health is another benefit that long-time readers of these TotalHealth articles may recall is associated with an adequate consumption of magnesium and potassium. In older individuals an increased intake of animal protein (but not plant) in conjunction with a significant intake of green vegetables, i.e., sources of magnesium and potassium, is associated with better bone health.
How About Food/Nutrient Combinations?
Some quite simple food combinations easily improve nutrient uptake. For instance, today there is much hype about the development of "golden rice" via genetic modification as a means of overcoming vitamin A deficiencies in poorer regions of the world. Not mentioned in this hype is that these areas are so poor that they have no fats or oils available with which to cook food and that the mere cooking of vegetables in oil largely resolves the vitamin A issue. In fact, the same approach is true for improved nutrient bioavailability in developed countries. In one trial, merely adding soybean oil in salad dressing improved carotenoid and fat-soluble vitamin bioavailability in salad vegetables.20 Similarly, co-consuming cooked whole eggs is an effective way to enhance carotenoid absorption from other carotenoid-rich foods, such as a raw mixed-vegetable salad.21
A word of caution on oils: Recent research strongly suggests that olive oil and coconut oil are preferable to soybean oil. "Rich in unsaturated fats, especially linoleic acid, soybean oil is assumed to be healthy, and yet it induces obesity, diabetes, insulin resistance, and fatty liver in mice."22,23 Moreover, in general the US diet exhibits an excessive and unhealthful ratio of omega-6 to omega-3 fatty acids.24 Butter, by the way, after years of condemnation, appears to be neutral as a fat for most purposes. A recent systematic review and meta-analysis suggests relatively small or neutral overall associations of butter with mortality, CVD, and diabetes.25,26 Any worries would appear to be easily overcome by simply eating more leafy green vegetables to increase daily magnesium intake!27
HCA and a Largely Unknown Positive Combination
One of the more interesting compounds available in the American health food market, albeit of highly variable and often suspect quality, is (–)-hydroxycitric acid (HCA, always sold as a salt) (extracted from Garcinia cambogia, G. atroviridis, G. indica and other G. species).28 Medically, HCA has been shown to exhibit potential additive effects of with, for instance, atorvastatin treated hyperlipidemic patients.29 Almost never pointed out by the marketers of HCA is that the compound's mechanism of action is inhibited by diets that are very high in fats and/or alcohol just as the mechanism is not operational under fasting conditions. Just as an inadequate level of intake or the intake of poor quality salts leads to a failure to achieve benefits, so does intake under improper conditions.30,31,32 One approach to preserving benefits even in the face of high fat and/or high alcohol intake is to ingest HCA along with the phytonutrient known as caffeic acid. Caffeic acid is found in quite small amounts in some, but not all green coffee bean extracts; it should not be confused with chlorgenic or caffeoquinic acids.33,34 Effectively using HCA with a coffee extract to reduce the reverse effects of fat and alcohol is patented.35
Two Bad Combinations Typical of the American Diet
Just as there are "good" nutrient combinations, such as examined above, there are "bad" nutrient combinations. Sugars and refined carbohydrates increase the absorption of fats from meals while reducing the oxidation of fats for energy. The evidence against coupling refined carbohydrates and fats is clear and unambiguous. Similarly, there is an unfortunate interplay between the consumption of sugars/ refined carbohydrates and table salt leading to impaired blood pressure regulation.36
- Low glycemic index diets improve glycemic (blood sugar) response and variability as well as promote the metabolism of fat for energy; they may promote long-term health.37,38
- Taken in a milkshake, fructose (30 g) increased postprandial lipemia by 37 percent compared with control; glucose (17.5 g) increased postprandial lipemia by 59 percent.39 (Lipemia is the presence in the blood of an abnormally high concentration of emulsified fat, meaning primarily triglycerides, not cholesterol.)
- In Syndrome X/insulin resistant subjects (BMI of 30), glucose consumption (50 g) led to a 15.9 percent greater glycemic response and a 30.9 percent greater insulin response than did fructose (50 g). This is true in part because fructose is processed in the liver and then released later as glucose and/or converted into fat.
- On an energy balanced diet in these same subjects, fructose compared with glucose increased carbohydrate oxidation 31 percent, but decreased fat oxidation by 39 percent.40
- Low-fat/high-carbohydrate diets in Syndrome X individuals reduce levels of HDL cholesterol and increase triacylglycerol concentrations.41
- Sucrose is glucose + fructose; lactose is glucose + galactose; grape sugar (dextrose) is glucose.
The benefits of foods and the nutrients that they supply, as also is true of supplements, is highly dependent on food and nutrient combinations. Many nutrients that clinically are inactive on their own, including even at large levels of intake, are beneficial when consumed with appropriate partners. Resveratrol, so often associated with red wine and the French paradox, is but one example of this phenomenon. Many other everyday combinations, such as magnesium and potassium, similarly exhibit positive dose relations. Contrarily, certain combinations are not good if habitually practiced. The combination of sugars/refined carbohydrates with fats, such as the far too widely consumed omega-6 fatty acids found in, for instance, soybean oil, is one example of a pairing that, if consumed regularly, tends to impair aspects of metabolism, including the oxidation of fats for energy. Likewise, consumption patterns that couple sugars with salt can lead to health consequences, such as blood pressure dysregulation, not typical of either nutrient consumed by itself.
- Beyond Synergy-the Entourage Effect in Nutrition and Herbalism TotalHealth Sep 2015
- Bland J. Resveratrol opportunism: what is the science behind the claims? Integr Med Clin J. 2009;7(6):50–1 and the response by Evans JL, Clouatre DL. Reservations about the Resveratrol Article. Integr Med Clin J. 2009;8(3):16–8.
- Soleas GJ, Diamandis EP, Goldberg DM. Wine as a biological fluid: history, production, and role in disease prevention. J Clin Lab Anal. 1997;11(5):287–313.
- Chan MM, Mattiacci JA, Hwang HS, Shah A, Fong D. Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. Biochem Pharmacol. 2000;60(10):1539–548.
- Zou JG, Wang ZR, Huang YZ, Cao KJ, Wu JM. Effect of red wine and wine polyphenol resveratrol on endothelial function in hypercholesterolemic rabbits. Int J Mol Med. 2003;11(3):317–20.
- Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008;8(2):157–68.
- Khor TO, Yu S, Kong AN. Dietary cancer chemopreventive agents—targeting inflammation and Nrf2 signaling pathway. Planta Med. 2008;74(13):1540–47.
- Biesinger S, Michaels HA, Quadros AS, Qian Y, Rabovsky AB, Badger RS, Jalili T. A combination of isolated phytochemicals and botanical extracts lowers diastolic blood pressure in a randomized controlled trial of hypertensive subjects. Eur J Clin Nutr. 2016 Jan;70(1):10-6.
- Xue M, Weickert MO, Qureshi S, Kandala NB, Anwar A, Waldron M, Shafie A, Messenger D, Fowler M, Jenkins G, Rabbani N, Thornalley PJ. Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation. Diabetes. 2016 Aug;65(8):2282-94.
- Sun Y, Byon CH, Yang Y, Bradley WE, Dell'Italia LJ, Sanders PW, Agarwal A, Wu H, Chen Y. Dietary potassium regulates vascular calcification and arterial stiffness. JCI Insight. 2017 Oct 5;2(19). pii: 94920.
- Linder, Maria C, ed., "Nutritional Biochemistry and Metabolism" (1991) 197–202.
- DeFronzo RA, Felig P, Ferrannini E, Wahren J. Effect of graded doses of insulin on splanchnic and peripheral potassium metabolism in man. Am J Physiol. 1980 May;238(5):E421–7.
- Altura BM, Altura BT. New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. II. Experimental aspects. Magnesium. 1985;4(5-6):245–71.
- Karppanen H. An antihypertensive salt: crucial role of Mildred Seelig in its development. J Am Coll Nutr. 1994 Oct;13(5):493–5.
- Sarkkinen ES, Kastarinen MJ, Niskanen TH, Karjalainen PH, Venäläinen TM, Udani JK, Niskanen LK. Feasibility and antihypertensive effect of replacing regular salt with mineral salt -rich in magnesium and potassium- in subjects with mildly elevated blood pressure. Nutr J. 2011 Sep 2;10:88.
- White WS, Zhou Y, Crane A, Dixon P, Quadt F, Flendrig LM. Modeling the dose effects of soybean oil in salad dressing on carotenoid and fat-soluble vitamin bioavailability in salad vegetables. Am J Clin Nutr. 2017 Oct;106(4):1041–51.
- Kim JE, Gordon SL, Ferruzzi MG, Campbell WW. Effects of egg consumption on carotenoid absorption from co-consumed, raw vegetables. Am J Clin Nutr. 2015 Jul;102(1):75–83.
- Deol P, Fahrmann J, Yang J, Evans JR, Rizo A, Grapov D, Salemi M, Wanichthanarak K, Fiehn O, Phinney B, Hammock BD, Sladek FM. Omega-6 and omega-3 oxylipins are implicated in soybean oil-induced obesity in mice. Sci Rep. 2017 Oct 2;7(1):12488.
- Deol P, Evans JR, Dhahbi J, Chellappa K, Han DS, Spindler S, Sladek FM. Soybean Oil Is More Obesogenic and Diabetogenic than Coconut Oil and Fructose in Mouse: Potential Role for the Liver. PLoS One. 2015 Jul 22;10(7):e0132672.
- Lazic M, Inzaugarat ME, Povero D, Zhao IC, Chen M, Nalbandian M, Miller YI, Cherñavsky AC, Feldstein AE, Sears DD. Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis. PLoS One. 2014 Sep 24;9(9):e107658.
- Brassard D, Tessier-Grenier M, Allaire J, Rajendiran E, She Y, Ramprasath V, Gigleux I, Talbot D, Levy E, Tremblay A, Jones PJ, Couture P, L marche B. Comparison of the impact of SFAs from cheese and butter on cardiometabolic risk factors: a randomized controlled trial. Am J Clin Nutr. 2017 Apr;105(4):800–9.
- Pimpin L, Wu JH, Haskelberg H, Del Gobbo L, Mozaffarian D. Is Butter Back? A Systematic Review and Meta-Analysis of Butter Consumption and Risk of Cardiovascular Disease, Diabetes, and Total Mortality. PLoS One. 2016 Jun 29;11(6):e0158118.
- Kummerow FA, Wasowicz E, Smith T, Yoss NL, Thiel J. Plasma lipid physical properties in swine fed margarine or butter in relation to dietary magnesium intake. J Am Coll Nutr. 1993 Apr;12(2):125–32.
- Optimizing the Benefits of Garcinia Cambogia. TotalHealth April 2014.
- Alkuraishy Hayder M, Algareeb Ali I, Albuhadilly Ali K, ALmgoter Basim M. Potential additive effects of garcinia cambogia on atorvastatin treated hyperlipidemic patients: randomized crossover clinical study. International Journal of Advances in Medicine. 2014 Nov 1 (3):189–95.
- Clouatre DL, Preuss HG. The evidence of hydroxycitric acid (HCA) health risks to the testes points to manufacturing failings, not to properly made HCA salts. Mol Nutr Food Res. 2017 Sep;61(9).
- Louter-van de Haar J, Wielinga PY, Scheurink AJ, Nieuwenhuizen AG. Comparison of the effects of three different (-)-hydroxycitric acid preparations on food intake in rats. Nutr Metab (Lond). 2005 Sep 13;2:23.
- 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): 201–10.
- Tsuda S, Egawa T, Ma X, Oshima R, Kurogi E, Hayashi T. Coffee polyphenol caffeic acid but not chlorogenic acid increases 5'AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscle. J Nutr Biochem. 2012 Nov;23(11):1403–9.
- Liao CC, Ou TT, Huang HP, Wang CJ. The inhibition of oleic acid induced hepatic lipogenesis and the promotion of lipolysis by caffeic acid via up regulation of AMP-activated kinase. J Sci Food Agric. 2014 Apr;94(6):1154–62.
- United States Patent 9,789,076 –– Bolus dose of hydroxycitric acid with glycerol.
- Preuss HG, Clouatre D, Swaroop A, Bagchi M, Bagchi D, Kaats GR. Blood Pressure Regulation: Reviewing Evidence for Interplay Between Common Dietary Sugars and Table Salt. J Am Coll Nutr. 2017 Sep 29:1–8.
- Henry CJ, Kaur B, Quek RYC, Camps SG. A Low Glycaemic Index Diet Incorporating Isomaltulose Is Associated with Lower Glycaemic Response and Variability, and Promotes Fat Oxidation in Asians. Nutrients. 2017 May 9;9(5).
- Bennett CB, Chilibeck PD, Barss T, Vatanparast H, Vandenberg A, Zello GA. Metabolism and performance during extended high-intensity intermittent exercise after consumption of low- and high-glycaemic index pre-exercise meals. Br J Nutr. 2012 Aug;108 Suppl 1:S81–90.
- Singleton MJ, Heiser C, Jamesen K, Mattes RD. Sweetener augmentation of serum triacylglycerol during a fat challenge test in humans. J Am Coll Nutr 1999 Apr;18(2):179–85.
- Tittelbach TJ, Mattes RD, Gretebeck RJ. Post-exercise substrate utilization after a high glucose vs. high fructose meal during negative energy balance in the obese. Obes Res 2000 Oct;8(7):496–505.
- Poppitt SD, Keogh GF, Prentice AM, Williams DE, Sonnemans HM, Valk EE, Robinson E, Wareham NJ. Long-term effects of ad libitum
- low-fat, high-carbohydrate diets on body weight and serum lipids in overweight subjects with metabolic syndrome. Am J Clin Nutr. 2002 Jan;75(1):11–20.
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Dallas Clouatre, PhD
Dallas Clouatre, Ph.D. earned his A.B. from Stanford and his Ph.D. from the University of California at Berkeley. A Fellow of the American College of Nutrition, he is a prominent industry consultant in the US, Europe, and Asia, and is a sought-after speaker and spokesperson. He is the author of numerous books. Recent publications include "Tocotrienols in Vitamin E: Hype or Science?" and "Vitamin E – Natural vs. Synthetic" in Tocotrienols: Vitamin E Beyond Tocopherols (2008), "Grape Seed Extract" in the Encyclopedia Of Dietary Supplements (2005), "Kava Kava: Examining New Reports of Toxicity" in Toxicology Letters (2004) and Anti-Fat Nutrients (4th edition).