• Aging and the Mitochondria

    Aging and the Mitochondria Dallas Clouatre

    In aging and many disease states, the energy production capacity of the body’s cells is diminished. The mitochondria are the structures within the cell responsible for generating energy from oxygen and nutrients. If their number is reduced or their function is impaired, free radicals are produced and damaging toxins accumulate in the cells. These toxins further damage the mitochondria and impair other aspects of cellular function. Many of the most common health problems, such as obesity, diabetes, and many problems associated with aging, arise from problems in cellular energy production. As one group of researchers has put this, "[a]ging is associated with an overall loss of function at the level of the whole organism that has origins in cellular deterioration. Most cellular components, including mitochondria, require continuous recycling and regeneration throughout the lifespan."1 Another has observed, "[m]itochondrial biogenesis [the creation of new mitochondria] is a key physiological process that is required for normal growth and development and for maintenance of ongoing cellular energy requirements during aging."2 These observations link two key aspects of mitochondrial health, preventing and removing damaged mitochondria (mitophagy) and creating new mitochondria (mitogenesis).

    Although the importance of the mitochondria as a central point of health has been accepted for decades, over the last few years the understanding of the mechanisms involved has changed significantly. Twenty or ten years ago, antioxidants and the free radical theory of aging largely dominated thinking. Today, the importance of mitochondrial biology linking basic aspects of aging and the pathogenesis of age-related diseases remains strong, yet the emphasis has changed. The focus has moved to mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics.3

    What Promotes Mitochondrial Biogenesis?
    The body maintains a complex network of sensors and signaling functions to maintain stability despite a constantly changing environment and numerous challenges. Of special note is the concept of hormesis, meaning a state in which mild stress leads to compensation that improves the ability of the body to respond in the future to similar challenges. It turns out that many of the approaches that are associated with longevity and healthy aging promote hormesis. In terms of mitochondria biogenesis, these include caloric restriction, certain nutrient restrictions or shortages, caloric restriction mimetics, and exercise.

    Many of the mechanisms that activate mitochondrial biogenesis in the face of hormesis have been elucidated. Keeping in mind that there always must be a balance between the elimination of worn-out and defective mitochondria and the generation of new ones, the activators of both actions can overlap. For instance, low energy levels (caloric restriction) and increased reactive oxygen species/free radicals can promote the activity of special cellular control points. These include activating metabolic sensors such as AMP kinase/ AMPK (adenosine monophosphate kinase) and the protein known as SIRT1 (sirtuin 1, i.e., silent mating type information regulation 2 homolog 1). Activated AMPK is an indicator that cellular energy is low and serves as a trigger to increase energy production. It inhibits insulin/IGF-1/mTOR signaling, all of which are anabolic and can lead not just to tissue production, such as muscle growth, but also to fat storage. Along with SIRT1, AMPK activates the biogenesis of new mitochondria to enable the cell to generate more energy. At the same time, activated AMPK and SIRT1 increase the activity of a tumor suppressor that induces mitophagy. The balance of the dual activations replaces defective mitochondria with newly formed functionally competent mitochondria.

    A key to health and healthy aging is to regulate the catabolic processes via controlled amounts and types of stressors such that worn out mitochondria are removed without overshooting the mark and reducing overall cellular and tissue functionality. The most successful way to maintain this balance is to follow the body’s own natural metabolic signals rather than to attempt to override the body’s checkpoints. AMPK and SIRT1 ultimately are energy/nutrient sensors or control points. Hence rather than attempting to manipulate these directly, it likely is safer and ultimately more effective to address the factors in the cell that these sensors sense. The recent attention in the issue of aging to the role of NAD+ (the oxidized form of nicotinamide adenine dinucleotide) is a good example of this principle. Directions coming from the nucleus of the cell that help to regulate the normal production of NAD+ and the ratio between distinct pools found in the cytoplasm and in the mitochondria decline with age. The changes in the NAD+ from the nucleus lead to a disruption on the mitochondrial side. In terms of energy production, it is a bit like losing a link or two in the timing chain on your car engine with a resultant reduction in engine efficiency. To date, attempts to increase NAD+ in cells via supplementation with precursors have not proven particularly successful. Major benefits have been demonstrated in animal models only in the already seriously metabolically impaired or the relatively old. Recent research on oral supplementation has led to at least one extremely difficult article which, at least in this author’s opinion, delivers more smoke than heat.4,5 There is, however, an argument to the effect that supplementing together both nicotinamide riboside (a NAD+ precursor) and a sirtuin activator, such as pterostilbene, may prove to be more successful.

    It turns out that there are key points in normal cellular energy generation processes that strongly influence the NAD+ pools available for the cell to draw upon and the rate at which NAD+ can be replaced in these pools. Aging has been shown to promote the decline of nuclear and mitochondrial NAD+ levels and to increase the risk of cancer along with components of the metabolic syndrome. It is significant that the risks of these conditions can be reduced in tandem. Three places to start are 1) the pyruvate dehydrogenase complex, 2) the tricarboxylic acid cycle (TCA cycle) also known as the Krebs Cycle, and 3) the malate shuttle. A fourth junction is Complex I of the electron transport system, again, in the mitochondria.6 Manipulation of steps (1) and (2) already is being used in cancer treatment.7 Readily available dietary supplements can influence all four of these metabolic bottlenecks.

    Supplements for Promoting Mitochondrial Biogenesis
    Medicine has started to pay a great deal of attention to effecting mitochondrial biogenesis through not just drugs, but also dietary supplements. Those interested should go online and look up "Mitochondrial Biogenesis: Pharmacological Approaches" in Current Pharmaceutical Design, 2014, Vol. 20, No. 35. Quite a few options are mentioned, including well known compounds, such as R-lipoic acid (including with L-carnitine), quercetin and resveratrol, along with still obscure supplements, including various triterpenoids and the Indian herb Bacopa monnieri.

    Pomegranate, French White Oak and Walnuts
    The pomegranate, with its distinctive scarlet rind (pericarp) and vibrantly colored seed cases (arils), is one of the oldest cultivated fruits in the world. This exotic fruit features prominently in religious texts and mythological tales and has been revered through the ages for its medicinal properties. An image of a pomegranate even can be found on the shield of the British Royal College of Medicine. Numerous studies have demonstrated the benefits of the fruit for cardiovascular health with other benefits suggested in areas ranging from arthritis to stability of cell replication to bone health. Now a study in Nature Medicine (July 2016) has uncovered perhaps the most important benefit of all, the ability of pomegranate compounds (ellagitannins) transformed by gut bacteria to protect the mitochondria of the muscles and perhaps other tissues against the ravages of aging. The mitochondria are the energy generators of the cells and the weakening of this energy generating function in an increasing percentage of mitochondria as we age is a primary source of physical decline over the years. Urolithin A, a byproduct of gut bacterial action on pomegranate compounds, allows the body to recycle defective mitochondria and thereby slow or even reverse for a time some of the major aspects of aging. The lifespan in a nematode model of aging was increased by more than 45 percent. Older mice in a rodent model of aging exhibited 42 percent better exercise endurance. Younger mice also realized several significant benefits.8

    Beginning almost three decades ago, there were numerous speculations in the research world regarding the so-called "French Paradox" in which the French consumed quite large amounts of saturated fat in the form of butter and cheese, yet consistently experienced much lower rates of cardiovascular disease than did Americans. Not only that, the French, especially in the southwest of the country, typically led longer lives even in the areas noted for consuming large amounts of goose fat and pate de foie gras, which is to say, not just the Mediterranean diet based on olive oil, etc. One hypothesis put forth very early on was that it was the French consumption of red wine that protected them. It was thought that red wine components, including anthocyanidins, proanthocyanidins and resveratrol, are the protective compounds. Not considered until recently is that French red wines traditionally have been aged in casks made from white oak (Quercus robur). White oak contains roburin A, a dimeric ellagitannin related chemically to punicalagin. Human data show relatively good absorption and conversion of roburins into substances including urolithin A and ellagic acid—as compared with ellagitannins in general, which evidence only poor absorption. Hence, the benefits of good red wine traditionally produced and good cognac (also aged in oak barrels) involve urolithin A. Notably, the benefits of roburins, most likely derived from the conversion to urolithin A, go beyond mitophagy to include ribosomes, referring to cell components that translate DNA instructions into specific cellular proteins.9,10,11,12

    Other sources of ellagitannins have been shown to lead to the production of urolithin A by bacteria in the human gut. Not surprisingly, sources of ellagitannins are foods long associated with good health longevity, including not just pomegranate and oak-aged red wine, but also walnuts (and a smattering of other nuts), strawberries, raspberries, blackberries, cloudberries and even black tea in small amounts.

    Exercise and Pyrroloquinoline Quinone (PQQ)
    Peroxisome proliferator-activated receptor gamma coactivator (PGC-1á) is the master regulator of mitochondrial biogenesis.13 Exercise is perhaps the most significant activator of PGC-1á that most individuals can access. Exercise, furthermore promotes mitochondrial biogenesis through a number of other pathways, especially endurance and interval training.14

    There are non-exercise options. You can’t take PGC-1á orally because it is a large protein molecule which does not survive digestion. PQQ is a small molecule that is available when ingested and that increases circulating PGC-1á. PQQ supplementation leads to more mitochondria and more functional mitochondria.15

    Fasting, Ketogenic Diets and Fasting-Mimicking Supplements As already discussed, fasting promotes mitochondrial biogenesis by AMPK activation.16 AMPK senses the energy status of the cell and responds both to acute shortages, such as that induced by exercise, and to chronic shortages, such as from fasting. Probably due to an overall reduction in metabolic rate, chronic caloric restriction (as opposed to intermittent fasting) contributes to the health of mitochondria rather than biogenesis.17 The robustness of AMPK response decreases with age.18

    Ketogenic diets (very low carbohydrate diets) also promote increases in mitochondria.19 Few individuals are willing or able to follow ketogenic diets chronically just as few individuals are willing to undergo routine fasts. Fasting-mimicking supplements offer an alternative approach. The dietary supplement (-)–hydroxycitric acid (HCA) is the best researched of these compounds. (Keep in mind that there is a vast difference in the efficacy of commercially available forms.20) Researchers have proposed that HCA used properly can activate mitochondrial uncoupling proteins and related effects.21

    Furthermore, according to a study published in the journal Free Radical Research in 2014, HCA improves antioxidant status and mitochondrial function plus reduces inflammation in fat cells.22 Inflammation is linked to the metabolic syndrome at the cellular level by way of damage to the antioxidant enzyme system (e.g., superoxide dismutase, glutathione peroxidase, glutathione reductase) and mitochondria. This damage, in turn, propagates further production of pro-inflammatory mediators (e.g., TNF-á, MCP-1, IFN-ã, IL-10, IL-6, IL-1â). HCA protected fat cells from ER stress by improving the antioxidant status to reduce oxidative stress (i.e., reduce ROS) and improve the function of the mitochondria to short circuit an ER stress—inflammation loop in these cells. Reducing TNF-á is important in that doing so removes a major impediment to mitochondrial biogenesis.23

    Other Supplements to Promote Mitochondrial Biogenesis

    Scholarly reviews looking at natural compounds such as those that are found in anti-aging diets suggest yet other supplements to promote mitobiogenesis. For instance, it turns out that hydroxytyrosol, the most potent and abundant antioxidant polyphenol in olives and virgin olive oil, is a potent activator of AMPK and an effective nutrient for stimulating mitochondrial biogenesis and function via what is known as the PGC-1á pathway.24 Another herb with anti-aging effect, this time by activating the malate shuttle mechanism mentioned above, is rock lotus (Shi Lian Hua). This herb has been described in detail in this magazine in the article, "Uncovering the Longevity Secrets of the ROCK LOTUS."25

    It is possible to improve the functional capacity of the mitochondria through dietary practices, exercise and supplements. Indeed, a number of compounds have been identified by researchers as mitochondrial nutrients. These compounds work together to increase the efficiency of energy production, to reduce the generation of free radicals, and so forth and so on. Likewise, these nutrients have been shown to improve the age-associated decline of memory, improve mitochondrial structure and function, inhibit the ageassociated increase of oxidative damage, elevate the levels of antioxidants, and restore the activity of key enzymes. Perhaps best of all, the body can be encouraged both to remove damaged mitochondria (mitophagy) and to create new ones, which is to say, mitochondrial biogenesis.


    1. López-Lluch G, Irusta PM, Navas P, de Cabo R. Mitochondrial biogenesis and healthy aging. Exp Gerontol. 2008 Sep;43(9):813–9.
    2. Stefano GB, Kim C, Mantione K, Casares F, Kream RM. Targeting mitochondrial biogenesis for promoting health. Med Sci Monit. 2012 Mar;18(3):SC1-
    3. Gonzalez-Freire M, de Cabo R, Bernier M, Sollott SJ, Fabbri E, Navas P, Ferrucci L. Reconsidering the Role of Mitochondria in Aging. J Gerontol A Biol Sci Med Sci. 2015 Nov;70(11):1334-42.
    4. Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016 Oct 10;7:12948.
    5. Mitteldorf J. Nicotinamide Riboside —Where’s the Beef? http://joshmitteldorf.scienceblog.com/2014/11/17/nicotinamide-riboside-wheres-thebeef/.
    6. Yang Y, Sauve AA. NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta. 2016 Dec;1864(12):1787– 1800.
    7. Schwartz L, Buhler L, Icard P, Lincet H, Steyaert JM. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res.2014 Feb;34(2):973–80.
    8. Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med.2016 Aug;22(8):879-88.
    9. Pellegrini L, Belcaro G, Dugall M, Corsi M, Luzzi R, Hosoi M. Supplementary management of functional, temporary alcoholic hepatic damage with Robuvit® (French oak wood extract). Minerva Gastroenterol Dietol. 2016 Sep;62(3):245–52.
    10. Vinciguerra MG, Belcaro G, Cacchio M. Robuvit® and endurance in triathlon: improvements in training performance, recovery and oxidative stress. Minerva Cardioangiol. 2015 Oct;63(5):403–9.
    11. Országhová Z, Waczulíková I, Burki C, Rohdewald P, Ïuraèková Z. An Effect of Oak-Wood Extract (Robuvit®) on Energy State of Healthy Adults-A Pilot Study. Phytother Res. 2015 Aug;29(8):1219–24.
    12. Natella F, Leoni G, Maldini M, Natarelli L, Comitato R, Schonlau F, Virgili F, Canali R. Absorption, metabolism, and effects at transcriptome level of a standardized French oak wood extract, Robuvit, in healthy volunteers: pilot study. J Agric Food Chem. 2014 Jan 15;62(2):443–53.
    13. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008 Jul 15;79(2):208–17.
    14. Wright DC, Han DH, Garcia-Roves PM, Geiger PC, Jones TE, Holloszy JO. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J Biol Chem. 2007 Jan 5;282(1):194–9.
    15. Bauerly K, Harris C, Chowanadisai W, Graham J, Havel PJ, Tchaparian E, Satre M, Karliner JS, Rucker RB. Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One.2011;6(7):e21779.
    16. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15983–7.
    17. Lee CM, Aspnes LE, Chung SS, Weindruch R, Aiken JM. Influences of caloric restriction on age-associated skeletal muscle fiber characteristics and mitochondrial changes in rats and mice. Ann N Y Acad Sci. 1998 Nov 20;854:182–91.
    18. Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010;47:69–84.
    19. Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007 Jan;48(1):43–58.
    20. 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.
    21. McCarty MF. High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy. Med Hypotheses.2005;64(6):1216–9.
    22. Nisha VM, Priyanka A, Anusree SS, Raghu KG. (-)–Hydroxycitric acid attenuates endoplasmic reticulum stress-mediated alterations in 3T3-L1 adipocytes by protecting mitochondria and downregulating inflammatory markers. Free Radic Res.2014 Nov;48(11):1386-96.
    23. Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S, Carruba MO, Nisoli E. TNFalpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Invest. 2006 Oct;116(10):2791–8.
    24. Liu J, Shen W, Zhao B, Wang Y, Wertz K, Weber P, Zhang P. Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients. Adv Drug Deliv Rev. 2009 Nov 30;61(14):1343–52.
    25. http://www.totalhealthmagazine.com/Anti-Aging/Uncovering-the-Longevity-Secrets-of-the-ROCK-LOTUS.html.
  • Nutrient Combining

    Nutrient Combining Dallas Clouatre

    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.


    1. Beyond Synergy-the Entourage Effect in Nutrition and Herbalism TotalHealth Sep 2015
    2. http://www.geoba.se/population.php?pc=world&page=1&type=15&st=rank&asde=&year=2015
    3. http://www.worldlifeexpectancy.com/cause-of-death/coronary-heart-disease/by-country/
    4. http://www.fathead-movie.com/index.php/2013/01/14/usda-report-we-eat-less-fat-but-fat-is-killing-us
    5. http://www.foodnavigator-usa.com/Science/Americans-are-eating-10g-less-fat-per-day-than-they-did-in-the-late-1970s
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    11. Khor TO, Yu S, Kong AN. Dietary cancer chemopreventive agents—targeting inflammation and Nrf2 signaling pathway. Planta Med. 2008;74(13):1540–47.
    12. 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.
    13. 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.
    14. 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.
    15. Linder, Maria C, ed., "Nutritional Biochemistry and Metabolism" (1991) 197–202.
    16. 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.
    17. 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.
    18. Karppanen H. An antihypertensive salt: crucial role of Mildred Seelig in its development. J Am Coll Nutr. 1994 Oct;13(5):493–5.
    19. 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.
    20. 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.
    21. 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.
    22. 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.
    23. 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.
    24. 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.
    25. 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.
    26. 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.
    27. 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.
    28. Optimizing the Benefits of Garcinia Cambogia. TotalHealth April 2014.
    29. 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.
    30. 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).
    31. 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.
    32. 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.
    33. 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.
    34. 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.
    35. United States Patent 9,789,076 –– Bolus dose of hydroxycitric acid with glycerol.
    36. 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.
    37. 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).
    38. 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.
    39. 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.
    40. 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.
    41. Poppitt SD, Keogh GF, Prentice AM, Williams DE, Sonnemans HM, Valk EE, Robinson E, Wareham NJ. Long-term effects of ad libitum
    42. 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.
  • Sports Supplements For Better Metabolic Flexibility and Performance

    Sports Supplements For Better Metabolic Flexibility and Performance Dallas Clouatre Almost two years ago, this magazine ran an article entitled

    "Supplements Target Ketogenesis and Metabolic Flexibility for Sports and Health."1 (June 2016) Last month there was a review of the state of caloric restriction / fasting and ketogenic diets today. However, many readers have little interest in either caloric restriction or ketogenic diets as lifestyle choices. Both of these approaches are difficult to follow even if being utilized for specific health purposes. Nevertheless, their basic principles have application to general health and to athletics. The foremost impediment to taking advantage of these approaches was laid out in the 2016 article.

    A major problem in achieving keto-adaptation by diet alone is that most individuals who have been raised on Western-style diets can take six months or more to make the shift and this shift becomes ever more difficult as we age. Studies examining the role of carbohydrates in the metabolism with roughly 30 year old males in good physical condition have revealed, for instance, that even transitioning from a high glycemic index diet to a low glycemic index diet while maintaining the same ratio of carbohydrate, fat and protein can take more than four weeks. Shifting to fatty acid metabolism for energy can be difficult.

    For most of us, the issue is whether a moderate change in diet accompanied by a judicious utilization of special foods and dietary supplements can achieve the goals usually associated with caloric restriction, fasting and ketogenic diets. Fortunately, the answer for the preponderance of readers is "yes." Both for anti-aging purposes and for athletics, metabolic flexibility likely can be achieved through approaches within the reach of almost everyone. The goal is not to be ketogenic all the time, but to be able to metabolize ketones and free fatty acids routinely and easily. For a nice introduction to the distinction, readers might visit the blog entitled "Ketogenesis, Measuring Ketones, and Burning Fat vs Being in Ketosis."2

    The Diet

    Previously in these pages, it was noted that consuming too little protein presents issues, but, likewise, too much protein in the diet, meaning above roughly 30 percent of calories, defeats a major goal of caloric restriction, which is to not just reduce circulating insulin, but also to avoid elevating insulin-like growth factor-1 (IGF-1). Although those not trained in nutrition seldom realize this, protein sources can be used for gluconeogenesis, which is to say, to produce glucose from, non-carbohydrate sources. It is not just consuming too little fat and too much carbohydrate or too much of these two together with too little protein that defeat the aims of an anti-aging diet.

    The recent Prospective Urban Rural Epidemiology (PURE) study followed 135,335 adults in eighteen countries for over seven years with respect to morbidity and mortality in terms of cardiovascular disease, strokes and non-cardiovascular disease mortality as correlated with the effects of nutrients.3 In an interview, Dr. Mashid Dehghan, the lead author, reported that Participants were categorized into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality.

    As noted by the researchers, their results flatly contradict decades of nutritional advice: High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings.

    In the PURE study, those who consumed at least 35 percent of their calories from fat were 23 percent less likely to die than those who consumed only 10 percent or less as fat. According to PURE findings, the higher the fat intake, the less the chance of stroke. Those who consumed 77 percent of their calories as carbohydrates were 28 percent more likely to die than those who consumed less than 46 percent as carbohydrates. The conclusion of the study? "In a nutshell, a healthy diet based on the PURE results would be rich in fruits, beans, seeds, vegetables, and fats, include dollops of whole grains, and be low in refined carbohydrates and sugars."

    The observant reader who takes the time to look at the PURE study's findings will quickly realize that the traditional reliance on "markers" such as blood LDL-cholesterol levels—markers long used to argue against the inclusion saturated fats any large amount of fats in general in the diet as well to promote carbohydrate consumption— does not correspond well with the actual endpoints of morbidity and mortality. This does not mean that the PURE diet needs to be ketogenic. To quote from the TotalHealth 2016 article, As admitted by Ben Greenfield, a serious triathlete who was tested with regard to the ergogenic benefits of a ketogenic diet, "after the study at University of Connecticut, I personally quit messing around with ketosis and returned to what I considered to be a more sane macronutrient intake of 50-60% fat, 20- 30% protein, 10-30% carbohydrate."4

    As a practical matter, a more normal diet with supplements might look like this:
    The diet should not be high in simple sugars, fructose or refined carbohydrates. For non-athletes and those looking primarily to increase metabolic flexibility, the diet should resemble a modified Sears Diet, meaning approximately 20 - 30 percent protein, 30 - 40 percent carbohydrate and 30 - 40 percent fat. For athletes and individuals who seriously want to initiate and maintain a fat-adapted diet, Ben Greenfield's suggestion is more in order: "50-60% fat, 20-30% protein, 10-30% carbohydrate."

    Those who want to achieve most of the benefits of a ketogenic diet without undergoing the grueling restrictions normally involved (limitations not just on carbohydrate intake, which are extreme, but also on protein intake) should consider the fact that ketone bodies supply 2–6 percent of the body's energy requirements after an overnight fast (no eating at bedtime) with the higher figure reflecting a longer period without eating. After three days of fasting, 30–40 percent of energy needs are met by endogenously produced ketones. Such facts, again, lead to at least two possibilities aside from caloric restricted and ketogenic diets. First, will consuming exogenous ketones as esters or salts provide the same benefits as special diets? Second, is there a role for dietary supplements in delivering these benefits?

    Ketones (Acetoacetate and β-hydroxybutyrate) Esters and Salts?

    The new kid on the block in anti-aging and sports supplements is oral ketones, including a ketone ester (D-beta-hydroxybutyrate and D 1,3-butanediol) sports drink and ketone salts, typically beta-hydroxybutyrate bound to calcium, magnesium, potassium or sodium. A limited body of research indicates that such supplements may improve very long-duration endurance performance, but relatively little is known about their impact on short-duration and high-intensity workouts. Likewise, it is unclear that supplementation with ketones delivers the same benefits as adaptation to a ketogenic diet.

    As one can learn from a variety of sources, "ketone bodies are three water-soluble molecules that are produced by the liver from fatty acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation and prolonged intense exercise… These ketone bodies are readily picked up by the extra-hepatic [outside the liver] tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy. In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids."5

    In the liver, metabolism of fatty acids for energy, as opposed to ketone bodies, works in conjunction with a normal pattern of activity in the mitochondria, including the citric acid cycle. Ketone bodies are formed when there is not enough glucose from either carbohydrates, including glycogen, or the breakdown of protein to fuel the cycle. Technically, the supply of oxaloacetate is exhausted, at which point the liver produces and exports ketone bodies to tissues that can metabolize ketones fully. In starvation and under very low carbohydrate intake accompanied by restrained protein intake, ketone bodies supply up to 50 percent of the energy requirements for most body tissues and up to 70 percent of the energy required by the brain. The blog mentioned above provides a nice diagram of the cellular steps involved in ketone formation. The author also helpfully points out:

    As I have written about eight hundred times in other posts, you do not need to be generating high levels of ketones to be metabolizing fat. The body does not operate in a binary system where the two choices are:

    (1) Maintain deep ketosis …or…
    (2) Become obese

    Just because you're not in ketosis doesn't mean you're somehow not metabolizing fat so that the only other possible destination for it is to be stored.6

    Ketone esters and salts can be ingested in an attempt to mimic a ketogenic state and work by elevating blood ketone levels to force the burning fat as fuel while interfering with certain other glycogen-related metabolic pathways. Whether supplements are the equivalent of a ketogenic diet in terms of benefits has been tested in humans only to a limited extent. In animal trials, they are not entirely equivalent and this appears also to be the case in humans. Let's start first with the animal experiments. The positive finding is that a 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague– Dawley rats caused a rapid and sustained elevation of beta-hydroxybutyrate and a reduction of blood glucose.7 No doubt, this represented a shift in the energy source to make use of the ingested ketones.

    However, in a comparative trial of a ketogenic diet, ketone supplementation and control diet examining both control and chronic stress conditions, results differed with the intervention. Chronic experiments showed that under control conditions, only the ketogenic diet resulted in pronounced metabolic alterations and improved performance in the novel object recognition test and only the ketogenic diet prevented stress-induced deficits at the end of the trial and improved certain other aspects of performance. The advantage was to the ketogenic diet rather than supplementation in the areas of blood glucose, insulin and overall fat metabolism.8 Ketone supplements in animal models do indeed provide benefits, but not at the level of diet-induced endogenous production.

    Thanks to recently published clinical trials, in the area of human athletic performance there now is evidence as to the limitations of ketone supplements. In one study, ten healthy adult males with similar athletic abilities and body mass indices fasted and then consumed either beta-hydroxybutyrate ketone salts or a matched placebo in a randomized order followed by a cycling time trial. Power output on the day participants consumed ketone salts was seven percent lower than on the day they consumed the placebo. As observed by study co-author Jonathan Little, assistant professor in University of British Columbia's (UBC) Okanagan's School of Health and Exercise Sciences, "Elevated blood ketones seem to inhibit the body's use of glycogen, the stored form of glucose, and favours burning fat instead."9,10 A previous study utilizing ketone esters (573 mg/kg athlete body weight) in conjunction with carbohydrate consumption had positive findings of better performance in cycling to exhaustion trials.11

    The authors of both studies seem to agree that the ingestion of ketones leads to nutritional ketosis that alters the hierarchy of fuel substrate usage during exercise and it is clear that as the intensity of exercise increases, the demand for carbohydrate as an energy source increases. The ketone salt trial tested shorter and higher intensity training versus the longer period tested in the ketone ester trial, hence these were not entirely apple-to-apple trials. In addition, the ketone ester trial tested roughly 30 grams of ketone ester taken in conjunction with carbohydrate leading to significant benefit versus carbohydrate alone. However, bicycle ergometer time trial performance was only approximately two percent greater using the ketone ester plus carbohydrate versus carbohydrate alone "representing a modest increase in physical capacity in these highly trained athletes, despite significant changes in muscular metabolism." This finding, once again, indicates the difficulty of fully substituting ketones for glycogen-dependent aspects of muscle performance.

    The latest studies continue the trend from above. Ingested ketones, for instance, as esters, impaired performance in elite cyclists in ˜31 kilometer laboratory-based time trials on a cycling ergometer programmed to simulate the 2017 World Road Cycling Championships course.12 Achieving overall fat / keto adaptation via dietary means is more successful. Nevertheless, aside from the difficulty in following such diets, keto adaptation to a low carbohydrate, high fat diet requires time. Three weeks clearly is not sufficient even in highly trained athletes such as elite endurance walkers.13 Ten weeks in trained athletes appears to be on the margin, improving feelings of wellbeing, but not performance.14 At least insofar as attested in published trials, a full 12 weeks or more of adaptation is required even in the relatively young (20 subjects, 33 ± 11 years) and vigorous to achieve superior endurance results in comparison to a high carbohydrate diet.15

    The above findings lead this author to the observation that although ketone ester-induced ketosis may increase metabolic flexibility during exercise by reducing glycolysis and increasing muscle fat oxidation, the benefits during shorter time periods and/or higher VO2/max demands are either not great or actually negative. Metabolic flexibility in the ester trial, such as it was, required the coingestion of carbohydrate. Without the co-ingestion of carbohydrate, as demonstrated in the other ketone trials (both salt and ester), there was a significant inhibition of the ability to access glycogen stores for energy upon demand.

    Metabolic Fitness Supplements

    Before looking at individual supplements, it is important

    to understand that nutrients that aid metabolic fitness generally fulfill a number of requirements, among them the following:

    • It is helpful to support fat metabolism directly such as through improved transport of fatty acids into the mitochondria for oxidation.
    • Insulin sensitivity must be improved and maintained and insulin levels kept low.
    • The release of fatty acids from fat cells likely is less important than is dis-inhibiting fatty acid metabolism. The first is accomplished with caffeine, yet often with a downside such as increased cortisol levels, hence alternatives to caffeine and other similar stimulants are needed.
    • Inclusion of substances that actively promote fatty acid oxidation is important to help kick-start the body's ability to metabolize fats.
    • Excessive gluconeogenesis by the liver (creation of glucose from glycogen in response to the release of glucagon) should be inhibited to promote fatty acid oxidation as the alternative.
    • With diets that are heavy in alcohol and fat, potential "reverse" effects must be prevented.

    The sources of useful supplements are not generic and this should be kept in mind because different production methods lead to different products with different results. The following discussion reviews key nutrients that fulfill one or more of the above requirements.

    Potassium-Magnesium Hydroxycitrate
    Very few athletes are aware of the benefits of (–)-hydroxycitric acid (HCA) for sports despite some impressive findings in terms of greater endurance and faster recovery plus reduced inflammation. This is because early trials—there were several large ones—failed to produce benefits for reasons that, in retrospect, are obvious. First, calcium HCA and calcium-containing HCA salts exhibit very poor uptake and poor results in comparative trials.16,17,18 To this should be added the "food effect," meaning the finding that consuming food within 30 minutes of ingesting HCA typically reduces uptake by approximately 60 percent. HCA salts under normal delivery never exhibit more than lackluster bioavailability, hence any reduction of that already modest uptake into the system leads to extremely poor results. A third factor is that even seemingly nearly identical HCA salts (as tested by standard high performance liquid chromatography / HPLC) produced by slightly differing production techniques can exhibit up to 10-fold differences in bioavailability.19 Notably lacking in the research literature is any attempt to determine cellular uptake, an issue separate from bioavailability. Published research simply assumes that all uptake issues can be reduced to bioavailability, meaning blood levels, an assumption proven to be invalid with a number of nutritional substances, such as coenzyme Q10.

    One way around these uptake problems with HCA is by means of a special liquid delivery. HCA salts normally are not stable in ready-to-drink formats and break apart to yield what is known as a lactone. The HCA lactone leads to good uptake—bioavailability—but little or no benefits because the molecule exhibits the wrong shape.20 A recently issued US patent describes a method that not only stabilizes HCA salts in liquid, but also dramatically improves their bioavailability and physiologic efficacy.21

    Properly produced and delivered HCA can lead to striking improvements in early fat utilization for energy, glycogen sparing and increases in endurance. This is in part because HCA helps to control the muscle's selection of fuels, an experimental finding from twenty years ago.22 More recently, using mice as the model, HCA ingestion for 13 days was found to increase fat oxidation and improve endurance exercise time to fatigue by 43 percent compared to a placebo.23 Chronic HCA ingestion alters fuel selection rather than the simple release of fat from stores as is true of lipolysis per se, i.e., the mechanism for HCA is not the same as with caffeine, capsaicin, etc. Second, the combination of HCA plus L-carnitine improves glycogen status in liver and various muscle tissues versus placebo in exercised-trained rodents. Readers will recall that glycogen-related issues bulk large in the performance failings of ketogenic diets and ketone supplements.

    What about HCA ingestion in humans? Similar positive endurance results were found by the same laboratory both with untrained men and women and with trained athletes as found in the animal tests. The following trial was conducted in trained athletes leading to significant improvements in endurance:

    Subjects [n = 6] were administered … HCA or placebo as a control (CON) for 5 d, after each time performing cycle ergometer exercise at 60% VO2max for 60min followed by 80% VO2max until exhaustion.24

    Under the conditions of the trial, time to exhaustion at 80 percent VO2max went from approximately six minutes to approximately 8.5 minutes, which is a remarkable level of improvement. Lactate levels were lower. In evaluating the results, it must be observed that the earlier animal trials indicated that there is a greater shift in metabolism if the ingestion period lasts longer. But note clearly: the HCA salt used in these trials was a pure synthesized trisodium hydroxycitrate, not the usual HCA available as a dietary supplement.25

    Another benefit from HCA is as much as a 100 percent improvement in glycogen repletion in muscle after exercise when a post-workout snack is consumed.26

    Mango Leaf Extract and Caffeic Acid Enhance HCA's Ability to Improve Fat Metabolism

    An issue that almost always is ignored with HCA is that under conditions of accelerated use of fat for energy, such as during fasting or ketogenic diets, there is a cycle that can undermine the compoundfs effects on fat metabolism by activating inside cells the substance acetyl-CoA carboxylase.27 Two compounds that help to prevent this and actually improve fatty acid oxidation are caffeic acid and mangiferin (a constituent of mango leaf).

    Caffeic acid is interesting for a number of reasons. For current purposes, it has been shown to improve the ability to metabolize fats for energy and also to promote the ability of glucose to enter cells, i.e., it is insulin sensitizing. In terms of HCA, caffeic acid helps block the actions of acetyl-CoA carboxylase.28 This means that it helps to block the impact of high alcohol intake and high fat intake or fasting on HCA, thus allowing HCA to perform the function of disinhibiting fatty acid metabolism via β-oxidation as mentioned above.

    Mangiferin, the primary active component in mango leaf extract, is even more significant than is caffeic acid. With regard to HCA, mangiferin, like caffeic acid, inhibits acetyl- CoA carboxylase. However, matters do not stop there. In various in vitro and animal trials, mangiferin increased fatty acid oxidation. A major finding is that the compound does the same, and safely, in human beings. Overweight patients with hyperlipidemia (serum triglyceride ≥ 1.70 mmol/L, and total cholesterol ≥ 5.2 mmol/L) were included in a double-blind randomized controlled trial. Participants were randomly allocated to groups, either receiving mangiferin (150 mg/day) or an identical placebo for 12 weeks. As reported in the published study,29

    A total of 97 participants completed the trial. Compared with the placebo control, mangiferin supplementation significantly decreased the serum levels of triglycerides and FFAs, and insulin resistance index. Mangiferin supplementation also significantly increased the serum levels of mangiferin, high-density lipoprotein cholesterol, L-carnitine, β-hydroxybutyrate, and acetoacetate, and increased lipoprotein lipase activity.

    The increase in β-hydroxybutyrate and acetoacetate as well as lipoprotein lipase activity is a clear indication that mangiferin improves the availability of stored fats and promotes the oxidation of these fats for the production of energy as they became available.

    Asparagine, Malate and Aspartates for Energy and Endurance

    Some of the best supplements for health and sports have, as it were, slipped under the radar over the years. We tend to be attracted to whatever is "new" to the point of overlooking that these new items often are not actually novel, just older concepts dressed up in new terminology. A good example of this is the great fanfare given to the recent "discoveries" involving nicotinamide riboside. (Caloric Restriction, Fasting and Nicotinamide Riboside TotalHealth Feb 2015)30 Proffered benefits include anti-aging effects, better energy metabolism and endurance.31 Strikingly, both the mechanisms involved and the benefits, upon closer examination, look remarkably similar to the benefits associated with what is known as the malate-aspartate shuttle. The anti-aging benefits, for instance, are similar to those associated with the Chinese herb rock lotus, which activates the enzyme (malate dehydrogenase) linked with this shuttle. (Uncovering the Longevity Secrets of the ROCK LOTUS TotalHealth April 2010)32

    For the hard science minded, the malate/aspartate shuttle is a principal mechanism for the movement of reducing equivalents from the cytoplasm to the mitochondria. In other words, this mechanism keeps energy as electrons flowing from the cytoplasm of the cell into the mitochondria and supports the production of adenosine triphosphate (ATP), the basic energy unit of the body. Ketones can play a similar role. As expressed in a recent paper, "cellular energy production depends on the metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation... [a ketogenic diet] will increase the NAD+/NADH ratio."33 (NAD exists in oxidized and reduced forms, NAD+ and NADH.) This process is exactly what the recent discoveries regarding nicotinamide riboside are about. The shuttle also is involved in replenishing oxaloacetate, which was mentioned above with regard to ketogenesis and the Krebs/Citric Acid Cycle. Part of the role of oxaloacetate is shown in the diagram.

    Now it just so happens that malic and aspartic acid (the "salts" are termed malate and aspartate) are components of this movement of energy. Malate, aspartate and the compound asparagine are known as oxaloacetate precursors. Many athletes use citrulline malate to help promote performance and reduce fatigue thinking that it is the citrulline that is active although, in fact, it is the malate. For instance, in an animal trial a month of supplementation with L-malate increased swimming time endurance by between 26.1 and 28.5 percent.34 The researchers observed the activities of cytosolic and mitochondrial malate dehydrogenase were significantly elevated in the L-malate-treated group compared with the control group.

    As pointed out in the TotalHealth article on the rock lotus, the malate dehydrogenase enzyme takes a period of time to be increased in the cell. A number of acute trials of, for instance, aspartates in athletes, compounds that affect the same shuttle mechanism, failed, but this should have been expected due to basic physiology and one wonders why those researchers even bothered. Under conditions of moderate exertion, supplementation with asparagine and aspartate plus L-carnitine increased time to exhaustion by approximately 40 percent.35 In another animal trial, this time with intense exercise and only the two amino acids, the supplemented group showed higher exercise time, lower blood lactate concentration and a decreased the rate of glycogen degradation compared to control leading to the conclusion that "supplementation may increase the contribution of oxidative metabolism in energy production and delay fatigue during exercise performed above the AT [anaerobic threshold]."36

    To be sure, there are skeptics regarding magnesium—potassium aspartates for use as ergogenic aids.37 However, the proposed mechanisms of action until recently have been wrong, the time frame for supplementation (acute rather than chronic), the amounts supplemented, etc., typically have been quite wide of the mark. The key mechanism of action involves the shuttle and oxaloacetate. Interestingly, this mechanism also promotes the proper metabolism of that great enemy of athletes, lactic acid. Lactic acid actually can be converted back into an energy source during exercise. As Ben Greenfield explains things in a wonderful post,38 A significant rate limiting step of converting lactic acid into glucose is the conversion of the molecule Nicotinamide Adenine Dinucleotide (NAD) into Nicotinamide Adenine Dinucleotide Hydrogenase (NADH). So what does this have to do with oxaloacetate? In studies, acute oxaloacetate exposure enhances resistance to fatigue by increasing NAD to NADH conversion and allowing lactic acid to get recycled and converted to glucose at a much higher rate.39

    Oxaloacetate is notoriously unstable and difficult to supplement orally. A mixture of its precursors (aspartate salts, asparagine and a malate source) plus an activator of the malate dehydrogenase enzyme (rock lotus) supplemented over a period of time (three to four weeks) is a better way to achieve desired benefits. Finally, another benefit of a mixture of malate and aspartate is that the malate-aspartate shuttle plays a role in the regeneration of L-arginine and the production of nitric oxide.40

    Move over, NO (nitric oxide) supplements! Altering muscle fuel selection and increasing the anaerobic threshold are the hallmarks of metabolic flexibility in sports. Greater utilization of stored fatty acids for fuel, reduced lactate accumulation and better recycling, enhanced glycogen stores and an elevation of VO2max before the body's limited stores are called upon without an impairment of carbohydrate utilization is an ideal situation. It is not clear that fulfilling this goal demands artificially elevating blood ketone bodies, either through diet or supplements. Instead, maximizing the efficiency of energy pathways that make use of stored fatty acids and the malate-aspartate shuttle would seem to be not just sufficient, but preferred. Chronic HCA ingestion alters muscle fuel selection and improves glycogen stores, especially in conjunction with L-carnitine. Caffeic acid enhances these actions, as does mangiferin from mango leaf in ways that have been demonstrated in humans to augment the metabolism of both fatty acids and carbohydrates leading to elevated energy production. The malate-aspartate shuttle and the enzyme malate dehydrogenase support oxaloacetate recycling and the efficient operation of the citric acid cycle to sustain fatty acid oxidation and the reconversion of lactic acid to glucose for use as fuel by the muscles. Surely a clincher for this approach is that it promises health and anti-aging benefits, not just improvements in athletic performance.


    1. Supplements Target Ketogenisis and Metabolic Flexibility TotalHealth Magazine
    2. Measuring Ketones
    3. Dehghan M, Mente A, Zhang X, Swaminathan S, Li W, Mohan V, Iqbal R, Kumar R, Wentzel-Viljoen E, Rosengren A, Amma LI, Avezum A, Chifamba J, Diaz R, Khatib R, Lear S, Lopez-Jaramillo P, Liu X, Gupta R, Mohammadifard N, Gao N, Oguz A, Ramli AS, Seron P, Sun Y, Szuba A, Tsolekile L, Wielgosz A, Yusuf R, Hussein Yusufali A, Teo KK, Rangarajan S, Dagenais G, Bangdiwala SI, Islam S, Anand SS, Yusuf S; Prospective Urban Rural Epidemiology (PURE) study investigators. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017 Nov 4;390(10107):2050–62.
    4. How To Get Into Ketosis
    5. Ketone_Bodies
    6. Measuring Keytones
    7. Kesl SL, Poff AM, Ward NP, Fiorelli TN, Ari C, Van Putten AJ, Sherwood JW, Arnold P, D'Agostino DP. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Nutr Metab (Lond). 2016 Feb 4;13:9.
    8. Brownlow ML, Jung SH, Moore RJ, Bechmann N, Jankord R. Nutritional Ketosis Affects Metabolism and Behavior in Sprague-Dawley Rats in Both Control and Chronic Stress Environments. Front Mol Neurosci. 2017 May 15;10:129.
    9. Ketone sports supplements: Good for athletic performance or not?
    10. O'Malley T, Myette-Cote E, Durrer C, Little JP. Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males. Appl Physiol Nutr Metab. 2017 Oct;42(10):1031–5.
    11. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256–68.
    12. Leckey JJ, Ross ML, Quod M, Hawley JA, Burke LM. Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists. Front Physiol. 2017 Oct 23;8:806.
    13. Burke LM, Ross ML, Garvican-Lewis LA, Welvaert M, Heikura IA, Forbes SG, Mirtschin JG, Cato LE, Strobel N, Sharma AP, Hawley JA. Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers. J Physiol. 2017 May 1;595(9):2785–2807.
    14. Zinn C, Wood M, Williden M, Chatterton S, Maunder E. Ketogenic diet benefits body composition and well-being but not performance in a pilot case study of New Zealand endurance athletes. J Int Soc Sports Nutr. 2017 Jul 12;14:22.
    15. McSwiney FT, Wardrop B, Hyde PN, Lafountain RA, Volek JS, Doyle L. Keto-adaptation enhances exercise performance and body composition responses to training in endurance athletes. Metabolism. 2017 Dec 2. pii: S0026-0495(17)30328-1.
    16. 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(1):23.
    17. 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.
    18. Clouatre D, Preus 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.
    19. Analytical report, Chemical Analysis of HCA in Rabbit Serum Samples, Bálint Analitika, LTD., Budapest, Hungary (2005)
    20. Lowenstein JM, Brunengraber H. Hydroxycitrate. Methods Enzymol. 1981;72:486-97.
    21. United States Patent 9,789,076 Bolus Dose of Hydroxycitric Acid with Glycerol
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    23. 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):2990–5.
    24. Lim K, Ryu S, Ohishi Y, Watanabe I, Tomi H, Suh H, Lee WK, Kwon T. Short-term (-)-hydroxycitrate ingestion increases fat oxidation during exercise in athletes. J Nutr Sci Vitaminol (Tokyo). 2002 Apr;48(2):128-33.
    25. 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):1-7.
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    27. Triscari J, Sullivan AC. Comparative effects of (--)-hydroxycitrate and (+)-allo-hydroxycitrate on acetyl CoA carboxylase and fatty acid and cholesterol synthesis in vivo. Lipids. 1977 Apr;12(4):357-63.
    28. 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.
    29. Na L, Zhang Q, Jiang S, Du S, Zhang W, Li Y, Sun C, Niu Y. Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: a double-blind randomized controlled trial. Sci Rep. 2015 May 19;5:10344.
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    32. Uncovering the Longevity Secrets of the ROCK LOTUS TotalHealth Magazine
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    40. Hou E, Sun N, Zhang F, Zhao C, Usa K, Liang M, Tian Z. Malate and Aspartate Increase L-Arginine and Nitric Oxide and Attenuate Hypertension. Cell Rep. 2017 May 23;19(8):1631–39.
  • Weight Loss Supplements

    Weight Loss Supplements Dallas Clouatre

    Many of us start off the year with a determination—backed by a gym membership— to get into shape and lose weight. It now is February. How are those New Year's resolutions faring? Is it time for Plan B?

    If that means diets and weight loss aids, there is no one-size-fits- all. Choosing the right approach with realistic expectations as to how much can be lost and how quickly will help prevent frustration and disappointment, not to mention major weight regain later in the year. Research in advance is the key. The following are some major categories and rationales for weight loss supplements:

    • Appetite suppressants and mood enhancers
    • Calorie (carbohydrate and/or fat) absorption blockers
    • Diuretics and laxatives
    • Metabolism enhancers and thermogenic agents
    • Nutrient partitioning agents

    Of the above approaches, for many reasons, the most commonly adopted method remains that of metabolism enhancers and thermogenic agents. Typical ingredients for this tactic for weight loss are bitter orange, caffeine, country mallow, green tea, guarana, 7-keto DHEA, synephrine, yerba mate and yohimbe. Inasmuch as one or more of these ingredients can lead to side effects if used incorrectly or by individuals for whom they are inappropriate, the following observations start by examining thermogenic agents.

    How Do Thermogenic Agents Function Within the Body To Burn Fat?
    Thermogenesis literally means causing the production of heat. Aside from the shivering response to cold, body heat production is a side effect of exercise and or of increased basal metabolic rate. The thermic effect of food ideally should be on the order of 10 percent of calories consumed. Thermogenic products are designed to stimulate the metabolism to be above where it normally would be in order to burn additional calories and to access fatty acids for this purpose. The most common approach for achieving this is to manipulate one of the body's hormonal signals, usually norepinephrine. Green tea epigallocatechin gallate (EGCG) reduces norepinephrine degradation and thereby increases catecholamine-mediated stimulation of β-adrenergic receptors and activates the sympathetic side of the nervous system. Ingesting EGCG by itself and in conjunction with caffeine prolongs the actions of norepinephrine. This increases the metabolic rate, hence increases energy expenditure by increasing the oxidation of glucose and fat for energy and increasing calorie-consuming actions. As a rule, there is a significantly greater mobilization and utilization of fat for energy than glucose—in fact, most metabolic stimulants cause fat to be released from storage so that it is more readily available for energy generation. The stimulation involved may make a person more wide awake and even more inclined to exercise, but some of the stimulation may involve what are termed "futile cycles" that consume energy and create heat, but do not lead to physical exertion.

    How Can Those Who Want To Avoid the Negative Effects of Stimulants Benefit From Thermogenic Agents?
    There are at least three side effects that dieters should look to avoid: 1) increased heart rate, 2) increased blood pressure and 3) excessive central nervous system stimulation. One solution to the cardiovascular side of things is to improve the circulation, especially to the heart. Hawthorne extracts help to open the circulation of the coronary artery, that is, the main blood supply to the heart. Herbs such as specialized grape seed extract and wild bitter melon, similarly, are useful for supporting the body in blood pressure regulation. The mineral magnesium is another aid here in that it both helps to regulate blood pressure and is calming to the nervous system.

    Excessive stimulation that overly activates the central nervous system leading to agitation, emotional control issues and/or sleeplessness actually does not usually increase thermogenesis, a fact that emerged from the ephedra-caffeine trials at Harvard and elsewhere. The clearly thermogenic combination of ephedra-caffeine increased energy expenditure at low to moderate doses, but above a not particularly high level of intake the amount of extra calories burned went down rather than up. Moreover, excessive stimulation induces a release of cortisol, which tends to cause the loss of lean tissue rather than fat tissue.

    For Consumers Who Use Caffeine To Increase Their Metabolism, What Are the Concerns Surrounding Caffeine?

    Caffeine definitely is a mixed bag when it comes to metabolism.

    • Looking only at caffeine by itself, there is evidence for acute increases in resting metabolic rate and thermogenesis, but habituation nullifies such benefits with chronic intake.
    • Habitual caffeine use reduces the benefits of caffeine/EGCG mixtures compared to findings in test subjects who do not consume significant amounts of caffeine regularly.
    • Overall, there is little or no support for the claim that caffeine by itself induces or maintains weight loss over the long term.

    In short, caffeine is more useful for metabolic effect if consumed with something like EGCG, such as from green tea, but habituation is rapid. Caffeine-related compounds in green mate appear to have more benefits over the long term than does simple caffeine. The health benefits of coffee, such as they are, come from chlorogenic acid and related compounds, not mainly from the caffeine.

    Keep in mind, an intake of 700 mg or more caffeine per day (about five cups of coffee) is often associated with depression and mood swings. Some authorities draw the line at 600 mg per day. Caffeine causes short-term increases in blood sugar levels that can be followed by dramatic downward fluctuations. Consuming caffeine, in other words, is yet another path to the sugar "roller-coaster" of energy ups and downs and sugar cravings. Cutting out caffeine and refined sugars for as little as one week has been shown clinically to improve mood in many individuals complaining of depression.1

    What Are Some of the Concerns Surrounding Weight Loss Supplements, Such as Synephrine and Yohimbe?
    No doubt, the major concerns are elevated blood pressure and elevated heart rate. In addressing these concerns, the source of synephrine is important. ρ-synephrine is an alkaloid occurring naturally in some plants and animals. A related compound is found in approved drugs as the m-substituted analog known as neo-synephrine. Bitter orange (Citrus aurantium) is a source of ρ-synephrine, which does not seem to increase blood pressure significantly, although it may have an effect on heart rate. (http://www.medsci.org/v09p0527.htm) m-Synephrine, often confused in the literature with ρ-synephrine, exhibits cardiovascular effects, but reportedly is not a constituent of bitter orange. It remains controversial whether ρ-synephrine exerts effects on blood pressure and heart rate if consumed with large amounts of caffeine or other stimulants.

    ρ-Synephrine is used to increase energy expenditure and lipolysis; ρ-synephrine is a β-3 adrenergic receptor agonist, which is to say, a thermogenic compound. By itself, ρ-synephrine as found in bitter orange is not associated with significantly increased blood pressure or heart rate; no significant α-adrenergic effects have been demonstrated, unlike the case with, say, ephedrine.2 Again, synthetic synephrine is a slightly different compound and can lead to high blood pressure and other effects even at relatively modest doses.

    It is neither necessary nor useful to push an intake of ρ-synephrine above approximately 50 mg. Rather, greater energy expenditure is induced by adding 600 mg naringenin to the mixture and a further increase can be induced by adding 100 mg hesperidin. (https://www.ncbi.nlm.nih.gov/pubmed/21537493)

    Another widely promoted thermogenic herb is yohimbe (Pausinystalia yohimbe). It is claimed as a thermogenic agent due to its active component, yohimbine, an α-2 receptor antagonist. Three double-blind RCTs, which included patients who were > 15–20 percent over their ideal body weight or had a BMI ranging between 28 and 48 and lasted three weeks to six months, yielded weight loss only at three weeks on a restricted diet, the loss being 1.34 kg greater than with placebo.3 However, yohimbe exhibits erratic effects on blood pressure, heart rate and neurological parameters with a high risk of toxicity.4

    How Do the Satiety Supplements 5-HTP and Hydroxycitric Acid Work?
    Items that affect serotonin, such as 5-HTP (5-hydroxytryptophan) and St. John's Wort, may influence mostly carbohydrate consumption. 5-HTP activates serotogenic pathways and at 600 to 900 mg/day induces weight loss of 3.1–3.7 pounds in 5–6 weeks without dieting. At 900 mg, 70 percent of subjects experienced significant nausea, but adjusted after six weeks.5 Although anyone being treated with pharmaceutical psychoactive drugs should not use 5-HTP without their doctor's agreement, 5-HTP otherwise has been found to be safe at ordinary dosages.6

    (–)-Hydroxycitric Acid / HCA, always sold as a mineral salt, is unusually well studied with at least 12 randomized placebo-controlled trials, but studies have used different salts and widely differing dosages. Mechanisms of action remain controversial. HCA does not cross the blood-brain barrier, hence does not influence the central nervous system directly; neither does it depend on activating nerves involving the liver (vagal afferents). HCA delays gastric emptying, however, and it prolongs glucose absorption from the small intestine. The primary effects seem to be to reduce between-meal snacking and to increase the length of time that dieters feel satiated after meals. Potassium and potassium-magnesium HCA salts are insulin sensitizing at human acceptable dosages whereas calcium- and calcium-potassium HCA salts are not. Apparently no one has tested the socalled "triple" salts even in animals. Weight loss in randomized controlled trials (RCTs) ranges from none to approximately 1/2 to one pound per week for eight weeks at higher dosages (2.8 g HCA) of potassium-based salts. In other words, approximately 4.5 grams/day of a potassium-based salt can lead to as much as one pound per week weight loss if taken as directed. Weight loss normally starts after the first or second week of usage for reasons having to do with refilling glycogen stores in the liver and muscle as well as greater hydration of muscle tissue. No toxicity or significant side effects have been found with properly manufactured HCA salts in controlled trials and safety reviews. Despite extremely widespread usage for roughly 25 years, only a handful of adverse event reports have appeared, usually with combination products and/or in cases in which the report could not even name the HCA salt involved.7,8

    Do Chia Seeds and Similar Foods Promote Satiety?
    Good fiber sources, especially very viscous fibers, increase satiety by increasing stomach distention (the feeling that the stomach is extended and full) and reducing the rate of gastric emptying. They also tend to reduce the rate at which carbohydrates release glucose into the blood stream. Viscous soluble fibers include, but are not limited to pectins, β-glucans, psyllium, glucomannan and guar gum. Foods such as ground flax seed, baked acorn squash, artichoke hearts and most legumes are good fiber sources. Oats and barley are good items, but not if they have been "instantized" since this process causes them to act more like high-glycemic foods.

    Protein sources also are good for satiety, although one can over-consume calories from protein just like anything else. Plant protein sources are slower to be absorbed into the tissues and thus may be especially good for prolonging satiety. At the other end of the scale, fructose is a particularly bad sugar for dieters and for health in general. Indeed, it is significantly worse than glucose or sucrose according to recent research.

    How Do Fat and Carbohydrate Blockers Aid in Weight Management?
    White kidney bean extracts and a number of other products, including bitter melon, inhibit carbohydrate digestion by inhibiting the actions of alpha-amylase and/or related compounds. The drawback of these in the American diet is that more and more calories in our diet are from corn sugar and other simple sugars. Indeed, corn sugars often are the cheapest binders and fillers available for processed foods. Carb blockers may be helpful with traditional foodstuffs, but this is modern America. Corn is subsidized and processed corn components are everywhere.

    HCA reduces the rate at which carbohydrates are available, but it is not a traditional carbohydrate blocker. Its mechanism of action is different in that it slows and prolongs the passage of glucose across the gut membrane into the blood stream via its effects on the sodium pump in the gut. There likely are a small number of other supplements that work similarly.

    A well-known lipase inhibitor (blocker of fat digestion) is derived from Cassia Nomame Mimosoides. This item was created to mimic the actions of a pharmaceutical weight loss product that inhibits the absorption of 30 percent of fat found in the diet. Concerns are sometimes expressed as to the wisdom on preventing the proper digestion of fats in the small intestine. Unlike carbohydrates, which can be acted upon by various bacteria in the large intestine, the body is poorly equipped to chronically handle fats not digested in the normal fashion. At this point in time, even the pharmaceutical fat blockers have largely disappeared and no trials seem ever to have been undertaken to demonstrate the efficacy of "natural" fat blockers claimed to be natural alternatives to the drugs.

    Begin with Your Eating and Exercise Habits
    To repeat a point made in articles in the past, diets that are inadequate in terms of vitamins and minerals, and in many cases protein, often coincide not only with weight gain, but also with low energy levels and mood swings. The consumption of a diet based largely upon sugars, refined carbohydrates, soft drinks and "junk foods" in general is just not sufficient to maintain good bodily health. If the overall quality of health is poor, it is unlikely that mental functioning and emotional well-being will fare any better. A powerful incentive for binge eating and a source of sugar cravings is the effort to counter depression and mood swings.

    Remember, as well, the place of exercise. Exercise is less important for its role in directly burning calories than for increasing basal metabolic rate in the morning and helping the body to access fats for energy. As little as 20 to 30 minutes walking every day can help the body to relearn how to burn fat for fuel. Walking early in the day has the added benefit of speeding up the metabolism when this can do the most good and also providing a daily dose of mood-brightening sunshine. Before or after the evening meal are two other good times to take a walk.


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