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

Conclusion
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.

References:

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.

Dear Readers,

Welcome to the April 2018 issue of TotalHealth Magazine Online.

Dallas Clouatre's, PhD, article, is "Caloric Restriction, Ketogenic Diet Or A Third Way?" Clouatre states, "His primary focus of this and related articles has been the concepts of metabolic fitness and metabolic flexibility. Human physiology and metabolism can adapt to a quite wide range of circumstances and can be "tweaked," likewise, with a broad number of approaches. Enhancing healthspan, even if perhaps not absolute lifespan, can be achieved through caloric restriction, fasting and dietary interventions involving properly balanced and selected foods combined with nutrients / dietary supplements. Some of these approaches are more easily sustainable under modern conditions and habits than are others."

Elson Haas, MD, "Food Reactions—The Sensitive Seven," is in reference to Wheat, Cow's milk, Sugar, Eggs, Corn, Soy, and Peanuts. There are many causes of indigestion including too much food, not chewing food thoroughly, and too much liquid while eating. Haas discusses toxins we are exposed to, their impact and the value of detox for us.

Gene Bruno, MS, MHS and Arthur Presser, PharmD present, "The Principles Of Homeopathy." A discussion on the history of homeopathy, how it is formulated and the benefits of use. If you have questions on homeopathy this is a great read on a subject that may appear complex but a natural medicine of value.

Sherrill Sellman, ND, "Helping Our Pets Stay Healthy With Hemp Extract," explains the value and use of Hemp Extract for use with your pets.

Ann Louise Gittleman, PhD, CNS, continues her Smart Fats Series with "Vitamin, Mineral and Amino Acid Deficiencies." The focus is on low thyroid along with all the other reasons behind a metabolic slowdown and the benefits of smart fats as coconut oil, GLA (gamma linolenic acid), CLA (conjugated linoleic acid), omega-7 and pastured butter in correcting problems with metabolism.

Gloria Gilbère, CDP, DAHom, PhD, presents "WAIT...Don't Toss that Pickle Juice!" You'll find dozens of uses for pickle juice. You can make more cucumber pickles, pickle soup, meat marinade, and more suggestions that you haven't thought of—limitless uses and you won't "toss that pickle juice" after reading this article.

Charles K. Bens, PhD, "The Early Detection of Chronic Disease," current blood tests are very inadequate and usually detect chronic disease five to ten years after it has already begun. Good examples are kidney disease, liver disease, heart disease, breast cancer, Alzheimer's, Parkinson's Disease and diabetes. Bens also includes a chart on the five stages of cell deterioration.

Shawn Messonnier, DVM, this month the second and final in the series on, "Rickettsial Diseases." A discussion that includes, fish oils, flaxseed oils Proanthocyanidins and antioxidants, along with other natural treatments and conventional treatments.

Best in health,

TWIP The Wellness Imperative People

Click here to read the full April 2018 issue.

• Caloric Restriction, Ketogenic Diet Or A Third Way?
  Dallas Clouatre, PhD
• Food Reactions—The Sensitive Seven
  Elson Haas, MD
• The Principles Of Homeopathy
  Gene Bruno, MS, MHS and Arthur Presser, PharmD
• Helping Our Pets Stay Healthy With Hemp Extract
  Sherrill Sellman, ND
• Smart Fats—Vitamin, Mineral And Amino Acid Deficiencies
  Ann Louise Gittleman, PhD, CNS
• Wait...Don't Toss That Pickle Juice
  Gloria Gilbère, CDP, DAHom, PhD
• The Early Detection Of Chronic Disease
  Charles Bens, PhD
• Rickettsial Diseases In Pets
  Shawn Messonnier, DVM

Click here to read the full April 2018 issue.

Taming the CR/Fasting Interventions
Caloric restriction (CR) / fasting and ketogenic dietary interventions exhibit both overlaps and differences. One major overlap arises from the fact that caloric restriction, just as does the ketogenic diet, encourages ketogenesis. Both diets, in their more pure forms, are quite hard to follow. Caloric restriction generally involves a 20 to 40 percent reduction in energy intake. Even at this level, caloric restriction can lead to undesirable consequences, such as general malnutrition, muscle weakness and wasting, a failure to adapt to environmental challenges, neurological deficits, dizziness, irritability, lethargy, and depression.⁶

Ketogenic diets have different adverse effects, several of which are linked to a tendency to avoid almost all fruits and vegetables, hence losing adequate access to most phytonutrients and even to many of the canonical vitamins and minerals, such as vitamin C and potassium. Adverse consequences can include unwanted weight loss, constipation, kidney stones, calcium deficiency and other vitamin and mineral deficiencies. At 20 to 50 grams of carbohydrates per day (80 to 200 calories), a medical-style ketogenic diet is difficult to follow. A common failing on ketogenic diets is eating too much protein and too little fat. This defeats at least one of the major goals of ketogenic dieting, which is to reduce insulin-like growth factor 1 (IGF-1).⁷

Fasting and reduced caloric intake are practices in many of the world's medical systems, whether for healing or for preserving health. As but one example, consuming most food only during a restricted time window, in practice an eight–ten hour window, and avoiding all solid food after approximately 4 or 5 p.m. is an ancient Buddhist recommendation for health. For most individuals, versions of caloric restriction and/or fasting are far easier to follow over the long term than is any version of the ketogenic diet. Furthermore, there are quite a few flexible eating plans that have been developed to achieve at least some of the benefits of classic calorie restriction and fasting without requiring that the adherent become an ascetic.

Approaches to Caloric Restriction and Fasting

Calorie Restriction
Reduction in calorie intake by 20 to 40 percent (1200 calories for women versus 1400 calories for men per day) over an extend period of time ranging from weeks to months

Intermittent Calorie Restriction
Reduction in calorie intake by 50 to 70 percent (600– 1000 calories per day) for short periods of time, for instance, once or twice per week

Fasting
Complete avoidance of calorie intake for anywhere from one day to several weeks

Intermittent Fasting
Alternating a fasting day with a normal energy intake day or fasting once or twice per week; typically, there are no food restrictions on eating days, although eating should be moderate rather than compensatory; there are many versions of this plan, such as eating five days a week and fasting for two

Daily Partial Fasting
Complete avoidance of calorie intake for 14–18 hours daily; meals are resumed at the start of each day, but all meals are eaten within a defined period of approximately eight to ten hours⁹

Alternate-Day Dieting
Alternating a normal eating day with a calorie restriction day of approximately 20 percent of typical calorie intake; some writers call this alternate-day fasting

What Diets Do the Researchers Themselves Follow?
The author of the article mentioned above, "Running on Empty," very helpfully queried caloric restriction and fasting researchers as to the eating plans they practice themselves. The following are some of the responses that he received. Researchers give their rationales for various practices in the body of the article.

• Valter Longo, University of Southern California: Eats twice per day (skipping lunch) and practices a periodic fast for five days every six months
• Mark Mattson, National Institute on Aging: Eats within a six-hour window every day and does trail running
• Satchidananda Panda, Salk Institute: Eats within a 12-hour window every day and practices an extended water-only fast of five days once per year
• Krista Varady, University of Illinois at Chicago: Practices alternate-day fasting one or two months per year, "usually after Christmas to shed the five pounds of holiday weight."

Back to Ketogenesis
Lean tissue loss with caloric restriction quite clearly is an issue, especially in anyone past middle age, at which point regaining lean muscle tissue becomes much more difficult. Fasting, of course, is ketogenic and some version of fasting would appear to be more practical over the long term, keeping mind, however, that those who are insulin resistant have difficulty in accessing fat stores for fuel and thus will, again, sacrifice lean tissues for access to protein in order to fuel the glucose requirements that are required even with a ketogenic diet. A nice point about a ketogenic diet is that there is greater freedom to consume essential nutrients than is true of more extreme forms of fasting.

Recent research in animals suggests that, at least in this model, a ketogenic diet extends longevity and healthspan even when begun in adult animals.¹⁰ Similarly, a ketogenic diet in this model promotes better memory in this model.¹¹ Interestingly, although rodents typically are quite poor choices for testing high-fat diets due to their inappropriate metabolism of high-fat diets compared to humans, nevertheless, after animals made obese on a high-fat diet had transitioned to a ketogenic diet, they lost all excess body weight, exhibited improved glucose tolerance and displayed increased energy expenditure.¹² Likewise, there is improved antioxidant and free radical protection under ketogenic diet conditions.¹³ Short- and long-term ketogenic dieting improves select markers of liver oxidative stress compared to standard rodent chow feeding, although long-term ketogenic diet feeding may negatively affect skeletal muscle mitochondrial physiology. The picture is not entirely unmixed in the animal model (there are contradictory outcomes regarding the impact on skeletal muscle mitochondria), yet overall conclusions seem positive.^14,15

Next month in these pages, it will be noted that even in elite athletes of approximately 30 years of age, it can take three months or more to adjust adequately to a ketogenic diet. (See "Sports Supplements For Better Metabolic Flexibility and Performance," May 2018 TotalHealth.) For those who are older and not so physically elite, the transition might well run six to twelve months, which is quite a long time for a diet that is, frankly, difficult to follow except for Eskimos and Tibetan nomads!

In light of these considerations, the question arises as to whether there are alternatives to following a ketogenic diet. Again, last month it was pointed out that many of the benefits of a ketogenic diet, including the ability to produce and metabolize ketones, likely can be achieved by means of a combination of diet and selected dietary supplements to achieve metabolic fitness / metabolic flexibility. The other alternative considered was the consumption of ketone salts and/or esters. Although this route in animal research and in actual human trials has been shown thus far to be inferior for both general and athletic purposes to a sustained ketogenic diet,16 evidence is accumulating, at least in an animal model, that consumed ketone bodies may mimic at least in part the lifespan-extending properties of caloric restriction. Indeed, the argument is being made that calorie restriction extends lifespan at least in part through increasing the levels of ketone bodies.¹⁷

Conclusion
[B]illions of dollars have been spent on research into the biological factors affecting body weight, but the near-universal remedy remains virtually the same, to eat less and move more. According to an alternative view, chronic overeating represents a manifestation rather than the primary cause of increasing adiposity. Attempts to lower body weight without addressing the biological drivers of weight gain, including the quality of the diet, will inevitably fail for most individuals.

"Increasing adiposity: consequence or cause of overeating?"¹⁸

The primary focus of this and related articles have been the concepts of metabolic fitness and metabolic flexibility. Human physiology and metabolism can adapt to a quite wide range of circumstances and can be "tweaked," likewise, with a broad number of approaches. Enhancing healthspan, even if perhaps not absolute lifespan, can be achieved through caloric restriction, fasting and dietary interventions involving properly balanced and selected foods combined with nutrients / dietary supplements. Some of these approaches are more easily sustainable under modern conditions and habits than are others. Regardless of the approach selected, basic physiology, not willpower, needs to be the guiding principle. For most individuals, no dietary program will succeed in the long run that does not address both biological drivers and the constraints of life (personality, work, family, social obligations, etc.) as it actually is lived.

Endnotes:

1. Totalhealth magazine: Caloric Restriction Fasting and Nicotinamide Riboside
2. Totalhealth magazine: Supplements Target Ketogenesis and Metabolic Flexibility
3. Weindruch RH, Kristie JA, Cheney KE, Walford RL. Influence of controlled dietary restriction on immunologic function and aging. Fed Proc. 1979 May;38(6):2007–16.
4. Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cance incidence. Science. 1982 Mar 12;215(4538):1415–8.
5. Clouatre, Dallas L. Anti-Fat Nutrients, 4th edition (Basic Health Publications, Spring 2004)
6. Keys A, Brozek J, Henschels A & Mickelsen O & Taylor H. The Biology of Human Starvation, 1950, Vol. 2, p. 1133. University of Minnesota Press, Minneapolis.
7. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends in pharmacological sciences 2010;31:89–98.
8. https://www.the-scientist.com/?articles.view/articleNo/49462/title/Running-on-Empty/
9. Gill S, Panda S. A Smartphone App Reveals Erratic Diurnal Eating Patterns in Humans that Can Be Modulated for Health Benefits. Cell Metab. 2015 Nov 3;22(5):789–98.
10. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, Haj FG, Baar K, Cortopassi GA, Ramsey JJ, Lopez-Dominguez JA. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab. 2017 Sep 5;26(3):539–46.e5.
11. Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, Huang Y, Haldar S, Verdin E. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metab. 2017 Sep 5;26(3):547–57.e8.
12. Kennedy AR, Pissios P, Otu H, Roberson R, Xue B, Asakura K, Furukawa N, Marino FE, Liu FF, Kahn BB, Libermann TA, Maratos-Flier E. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1724–39.
13. Salomón T, Sibbersen C, Hansen J, Britz D, Svart MV, Voss TS, Møller N, Gregersen N, Jørgensen KA, Palmfeldt J, Poulsen TB, Johannsen M. Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis. Cell Chem Biol. 2017 Aug 17;24(8):935–43.e7.
14. Kephart WC, Mumford PW, Mao X, Romero MA, Hyatt HW, Zhang Y, Mobley CB, Quindry JC, Young KC, Beck DT, Martin JS, McCullough DJ, D'Agostino DP, Lowery RP, Wilson JM, Kavazis AN, Roberts MD. The 1-Week and 8-Month Effects of a Ketogenic Diet or Ketone Salt Supplementation on Multi-Organ Markers of Oxidative Stress and Mitochondrial Function in Rats. Nutrients 2017 Sep 15;9(9). pii: E1019.
15. Hyatt HW, Kephart WC, Holland AM, Mumford P, Mobley CB, Lowery RP, Roberts MD, Wilson JM, Kavazis AN. A Ketogenic Dietin Rodents Elicits Improved MitochondrialAdaptationsin Response to Resistance Exercise Training Compared to an Isocaloric Western Diet. Front Physiol. 2016 Nov 8;7:533.
16. Op cit. note 14.
17. Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017 May;69(5):305–14.
18. Ludwig DS, Friedman MI. Increasing adiposity: consequence or cause of overeating? JAMA. 2014 Jun 4;311(21):2167–8.

The obvious answer to this question is yes; it probably could be killing you. It primarily depends on what you are eating. If you are eating according to the Mediterranean Diet your food is actually helping you to live a longer and a healthier life. However, if you are eating almost any other diet you could be at risk if you have not done your homework about the various diets that are being featured in articles, books and on the Internet. Here is a brief explanation about how these diets rank according to a recent report comparing them.

There are many diets available as people consider how to lose weight and keep it off. A panel of nutritional experts was asked by U.S. News and World Reports to evaluate each of the following diets to determine which ones offered the most scientific and sustainable weight management options.

1. THE MEDITERRANEAN DIET—This diet was the panel’s top choice, and the foods in this diet include vegetables, fruits, nuts, seeds, healthy oils (Olive Oil), fish and poultry. The science behind this diet includes the Framingham Heart Study and several peer-reviewed scientific studies. Approximately 150,000 people have been evaluated for over 30 years and those on the Mediterranean Diet lived longer and had less chronic illness than all other dietary programs used by other participants.

2. The DASH DIET—DASH stands for Dietary Approaches to Stop Hypertension. Foods in this diet are very similar to the Mediterranean Diet with some changes, such as the use of low-fat dairy products. Red meat, fats, and sweets are allowed in small amounts. Studies have verified that people on this diet were able to reduce their blood pressure and often reduce their need for prescription medications.

3. VEGETARIAN/VEGAN DIET—Vegans eat no animal products while vegetarians are less strict on this. Some vegetarians allow dairy and eggs in their diet. This is a very heart-healthy approach featured in books by Dean Ornish and Neal Barnard. However, there are some challenges to the vegan diet including possible deficiencies in amino acids, vitamin D, iron, zinc and B vitamins, especially vitamin B12. This can lead to brain-related issues, osteoporosis, higher risk of cancer and other chronic illnesses. Usually, these issues can be addressed with quality nutritional supplements.

4. FLEXITARIAN DIET—This is basically a vegetarian diet, which allows the occasional piece of meat or fish. The key word here is "occasional." For people who are used to eating meat every day, occasional could mean switching to eating meat every other day. Eating Omega 3 rich fish a few times a week and one helping of grass-fed beef per month is probably a healthier option for flexitarians. Certain red meats like pork or processed bacon should be avoided at all times.

5. WEIGHT WATCHERS—This popular diet program has changed over the years to reflect the needs of their customer base with more emphasis on healthier foods. Portion and calorie control are the main benefits; however nutritional quality is not very high. Their typical consumer still eats foods that are processed, cooked and mostly non-organic, which means enzyme and nutrient levels are low. There are no incentives to eat the healthiest vegetables or fruits, and they allow two helpings of dairy per day. People are often eating better than they previously were, but not nearly as well as they could be. This is why this diet is on the lower end of the list of the best diets with the most science behind them.

6. KETO DIET—In last place is the keto diet. It is designed to force the body into ketosis through the consumption of high levels of protein and fat, as well as low levels of carbohydrates and fiber. Our bodies, especially our brains, are designed to burn carbohydrate so this is not a good diet for most people. Even people in the Paleo period would not eat this diet if they could have found more vegetables, fruits, nuts, and seeds. Some cultures like the Eskimos have adapted to this diet over hundreds of years, but only out of necessity. The keto diet cannot provide a sufficient level of nutrients necessary to meet the needs of our bodies. People on the keto diet often experience the following health challenges: loss of muscle mass, kidney problems due to high levels of uric acid, dehydration, digestive disorders due to low fiber levels, liver disease due to high protein intake, hormone imbalance and chronic illness due to vitamin and mineral deficiencies.

When a diet does not include some or many key nutrients, this begins a process of cellular deterioration, which eventually leads to a chronic illness. Poor nutrition is one of the main reasons why chronic disease happens and now over 60 percent of the adult population in the United States has a chronic disease. This is not surprising because in one study by the National Cancer Institute of 16,000 people they could not find one person with a truly healthy diet. The CDC agrees and reports that over 95 percent of our population has one or more nutritional deficiencies.

Many people try to compensate for their poor nutritional behavior and the lack of nutrients in today's food by taking nutritional supplements. That can be very helpful in spite of a recent study by Tufts University that indicated that supplements do not extend the life of people who take them. Such a study lacks any credibility since it was an observational study with no evaluation of specific factors such as the beginning health of the participants or the number or quality of the supplements taken. There are over 40,000 scientific studies that clearly show that quality supplements help people to live longer and healthier by preventing, as well as reversing chronic illness.

However, even if you eat the healthiest diet, and take quality nutritional supplements, there are still potential health risks due to the interaction between certain foods and certain biochemicals that are consumed by many people. Here are some of the most significant examples of these interactions that everyone should be aware of.

SYNTHETIC FOODS AND OTHER CHEMICALS DEPLETE NUTRIENTS.

• Synthetic iron destroys vitamin E, vitamin C and beta carotene.
• Brominating agents (fumigated fruit and bleached flour) destroys vitamin C, vitamin E, beta-carotene, riboflavin, pantothenic acid, potassium and selenium.
• Sulfites oxidize vitamin C, molybdenum, riboflavin and folic acid.
• Food dyes inactivate vitamin B6, folic acid and vitamin C.
• The food additive, ethylene glycol, destroys vitamin C, vitamin A, vitamin E and selenium (it is used to make antifreeze).
• Preservatives BHT and BHA destroys vitamin C, vitamin A and vitamin E.
• EDTA (used in chelation) prevents the absorption of minerals zinc, calcium and magnesium.
• Pesticides inactivate vitamin C, vitamin E, vitamin B6, digestive enzymes and selenium.
• Chlorine inactivates thiamine and destroys vitamins A, C and E.
• Fluoride destroys vitamin B1, vitamin C, vitamin E, beta carotene and disrupts the function of virtually all human enzymes.
• Antibiotics create vitamin B deficiencies and destroy good bacteria in the intestines.
• Aspirin destroys vitamin C, vitamin E and folic acid. It also can cause internal bleeding, as well as lead to heart disease, stomach ulcers, intestinal cancer and Reye's syndrome.
• Statin drugs deplete Co-enzyme Q10, which is critical for the heart, and can eventually cause a heart attack.
• Most prescription medications deplete or destroy one or more important nutrients

Food grown on non-organic farms have been shown to have 40 - 80 percent fewer nutrients than food grown on organic farms. The following chemicals contribute to this reduced nutritional value:

• Lime—Binds zinc and manganese and impedes copper intake.
• Nitrogenous fertilizers—Impairs copper absorption into plants.
• Phosphates—Create excess absorption of molybdenum and impairs calcium uptake.
• Potash (potassium)—Causes boron deficiency in plants.
• Pesticides/herbicides—Impair the absorption of all essential minerals.

These potentially dangerous interactions do not influence everyone’s health, but they are very prevalent when you consider how many people consume tap water for drinking, preservatives in food processing, non-organic fruits, and vegetables or commonly used prescription medications.

This is not information that you will find on food labels or will be shared with your doctor or your grocery store manager. This is your personal responsibility and you are responsible for finding this information and using it to protect the health of you, your family members and anyone else that you care about. Hippocrates is supposed to have said, “let your food be your medicine,” but I’m very certain he did not imagine we would have so many challenges finding truly healthy food considering all of the dangerous chemicals that we must contend with every day. Consider the following important facts when you take the previously mentioned information into consideration as you go forward with your plan to eat a truly healthy diet.

• Reports from the Centers for Disease Control, and others, indicate that 95 – 99 percent of the population has one or more nutritional deficiencies.
• Nutritional deficiencies have been shown to be the number one cause of chronic disease.
• Only five percent of doctors have received adequate training in nutrition.
• About 70 – 80 percent of all disease is preventable, and nutrition is the number one scientifically-proven method of preventing, and even reversing, most disease.
• Poor nutrition is the number one cause of the high cost of health care.

For Sports and Health

Most readers who have heard of ketosis and ketogenesis likely associate the concepts with dieting and the works of Dr. Robert C. Atkins (Dr. Atkins’ Health Revolution, 1989; Dr. Atkins’ New Diet Revolution, 1992) that launched a bit of a movement in the 1990s. Much less well known is the role of ketosis in sports and the importance of being able to enter ketosis as an aspect of metabolic flexibility, meaning the ability to rapidly and easily shift between carbohydrates and fats as fuel substrates to match, on the one hand, dietary sources of calories and, on the other hand, particular physical demands for energy. In fact, the health implications of metabolic flexibility are significant and are related to the body’s degree of insulin sensitivity and thereby to the components of the metabolic syndrome. The latter condition often is defined as being based on insulin resistance and associated with abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low high-density lipoprotein (HDL) levels. This way of looking at matters makes ketogenesis and metabolic flexibility major determinants of health. One does not need to be diabetic or even pre-diabetic for these issues to be important, a point that Harry Preuss, MD and various coauthors, including myself, make in a recent article intended for practicing physicians, “Importance of Fasting Blood Glucose in Screening/Tracking Overall Health.”^1,2

Not only athletes for reasons having to do with competition, but also non-athletes for reasons of health likely would benefit from some form of supplement protocol or other approach that can achieve ketogenesis and maintain metabolic flexibility without depending entirely on the diet. Indeed, achieving ketosis via diet alone is hard to maintain over the long haul for a variety of reasons. Eating mostly protein and fat may sound like a treat at the beginning, but highly restricting all sources of carbohydrates quickly leads to a boring diet and even limited social interaction because few social events are built around ketogenic snacks! It also means avoiding many or most sources of phytonutrients, not eating adequate fiber for gut health and bowel regularity, probably inadequately eliminating toxins via the bile route in the stool, and even ramping up production of the hormone cortisol.³ Extreme ketosis leads to unpleasant breath (acetone breath) although this is not an issue with moderate and healthy ketogenesis.

Background on Ketosis and Ketogenic Diets
There are only two primary sources of energy, carbohydrates and fats. If needed for energy, protein can be broken down to yield a carbohydrate component, not a fatty acid component. Ketosis refers to the state in which the body meets its energy requirements largely through the oxidation of ketone bodies. These build up in the blood when glucose is not being used for energy and even the brain can run on ketone bodies. Glycolysis is the opposite number to ketosis in that it refers to the oxidation of glucose, for which all carbohydrates ultimately are a source, for energy. People sometimes associate ketosis with diabetes, but ketosis is a nutritional process whereas in diabetes the body either lacks sufficient insulin or cannot respond properly to insulin and therefore builds up ketone bodies due to a failure of metabolism while at the same time not properly harnessing fats for fuel. There is plenty of evidence to the effect that ketogenic diets can be healthful. Traditional Eskimo diets consisted almost entirely of raw meat and blubber (fat) and yet the Eskimos did not exhibit diabetes. Similarly, for certain neurologic conditions children are raised from early life into their thirties or later with completely normal physiologic and mental development without eating any carbohydrates at all.

Athletes and some "paleodieters" speak of keto-adaptation, which means simply moving the metabolism to preferentially accessing stored fats as fuel sources rather than depending on glucose. The body has quite limited stores of glycogen or "animal starch" stored primarily in the liver in contrast to virtually unlimited calories stored as fats. A quite standard assessment is that there may be 400 grams of glycogen in the liver and another 100 grams in the muscles. Glycogen is associated with water on a 1:3 to 1:4 ratio. 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.

High fat diets were employed at the turn of the century to treat Type I diabetes, the form that begins in childhood with the destruction of the insulin-producing cells of the pancreas. Since the body can and will produce its own blood sugar from protein in order to feed the brain, there is always some role for insulin in the body regardless of the diet followed. Needless to say, those with juvenile diabetes almost invariably died young until the discovery of insulin.

In adult-onset or Type II diabetes, which typically begins fairly late in life and with those already overweight, diet and exercise often can completely control the problem. This and other clues have led a number of researchers to suspect that excess weight gain is related to insulin production either directly or indirectly, as discussed briefly above. Dr. Robert C. Atkins was one of the first to popularize the notion of dieting by bypassing the insulin mechanism through eliminating most carbohydrates from the diet while continuing to consume both proteins and fats. Atkins' Diet is both high in protein and high in fat.

High protein, low fat/very low carbohydrate diets have been common for some time, but not with the particular justification that they bypass the insulin mechanism. Generally the justifications have had to do with energy production, or rather the lack of it on these diets. In the Stillman Diet, for instance, it was argued that protein molecules are so large that they use up extra energy as a food for the body. This diet calls for the drinking of at least eight glasses of water a day, which truly is necessary to remove the waste products of excess protein consumption and from the oxidation of the body's own fats.

Very similar is the famous Scarsdale Diet, designed for use for only two weeks at a time. Both strictly limit carbohydrates and, somewhat less strictly, fats. Both do reduce weight in the short term, but such large amounts of protein are hard on the body. In contrast to these, the Dr. Atkins' Diet allows for unlimited amounts of both proteins and fats, but for restricted amounts of carbohydrates according to the theory that a faulty insulin mechanism is the cause of excess weight. A more limited form of this ketone-based diet popularized at about the same time as the Atkins Diet is presented by Dr. Calvin Ezrin in The Endocrine Control Diet (1990).

Athletes long have experimented with ketogenic diets. For instance, during the 1990s a number of top bodybuilders in the World Bodybuilding Federation adopted a diet similar to the one Atkins uses (roughly 40 percent of calories from protein and 60 percent from fat) in order to cut body fat and build muscle. These individuals were all undertaking extremely hard physical labor, so the diet itself cannot be a source of fatigue, but must in fact supply considerable energy.⁴ Nevertheless, even major competition class athletes ultimately generally give up on strict ketogenic diets. 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."⁵

Ketogenesis with Supplements
Can ketogenesis be achieved using a more normal diet with the help of supplements? The answer appears to be "yes." Nevertheless, there are important considerations, among which are the following:

• 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¨C 30 percent protein, 30¨C40 percent carbohydrate and 30¨C40 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."
• 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 disinhibiting 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.

A small number of supplements, especially if taken together, may fulfill the above requirements and actually have been tested successfully in a pilot case. The subject in question was able to consume a normal diet, indeed one that included quite a bit of alcohol, by relying on only four supplements to remain in moderate ketosis during much of the day: hydroxycitric acid, wild bitter melon extract, sesame lignan extract and green coffee bean extract. The sources of these supplements were not generic and this should be kept in mind because different production methods lead to different products with different results. Published comparative trials, for example, with hydroxycitric acid have shown this definitively.

Potassium-Magnesium Hydroxycitrate
The key component in supplement-support ketogenesis is (-)¨Chydroxycitric acid (HCA). That some forms of properly manufactured HCA can be used to encourage ketogenesis has been known at least since 2000. In that year, Ishihara published that HCA ingestion for 13 days increased fat oxidation and improved endurance exercise time to fatigue by 43 percent compared to a placebo in mice.⁶ Over the following few years, three studies by Lim and others in trained athletes demonstrated that ingestion of HCA enhances endurance performance via increasing fat oxidation and sparing glycogen utilization during moderate intensity exercise. In fact, in trained athletes HCA ingestion for five days shifted fuel selection to fat oxidation at both 60 percent and 80 percent VO2max during exercise.⁷ Lim further demonstrated a number of significant findings. First, using mice as his model, he showed that chronic HCA ingestion alters fuel selection rather than the simple release of fat from stores as is true of lipolysis, i.e., mechanism for HCA is not the same as with caffeine, capsaicin, etc. Second, Lim's review data that showed that the combination of HCA plus L-carnitine improves glycogen status in liver and various muscle tissues versus placebo in exercised-trained rodents. Since the publication of Lim's papers, this finding has been repeated more than once with human athletes. Although L-carnitine improves the effect, it is not necessary.⁸ Third, Lim in his studies employed a pure synthesized trisodium hydroxycitrate salt rather than commercial calcium or calcium-potassium HCA salts, which did not yield his results. As is true of many herbal products, the benefits of HCA are highly dependent upon how the item is prepared. The acid must be stabilized by the addition of high pH ions (basic or alkali), such as those of potassium, magnesium or calcium. Using the wrong stabilizing counter-ions results in little or no activity. In the case of the acid derived from Garcinia cambogia and related sources, adding any calcium at all reduces some desired benefits and blocks other benefits entirely.⁹ This fact has been verified by more than one comparative trial.

Another benefit of HCA that supports ketogenesis is its impact on insulin sensitivity. At the 2005 Annual Meeting of the American College of Nutrition for the first time it was reported that the potassium-magnesium HCA salt in an animal model gave the same blood glucose regulation as found in the control arm of the test while almost literally cutting insulin levels in half.¹⁰ The same study demonstrated that this salt dramatically improved glucose clearance from the blood, lowered systolic blood pressure and also lowered several key indicators of inflammation, including C-reactive protein and tumor necrosis factor-alpha (TNF-alpha). In contrast, the potassium-calcium salt exerted no effect upon insulin and blood sugar regulation and only very poorly influenced blood pressure.¹¹ In the areas of insulin metabolism, glucose regulation and blood pressure, the proprietary potassium-magnesium salt was between five and seven times as active as the potassium-calcium salt of the fruit acid. A paper just published this year also indicates that HCA may help to regulate thyroid hormones and promote muscle protein synthesis.¹²

Wild Bitter Melon Extract and Sesame Lignan Extract
As indicated above, HCA appears to be extremely useful in freeing the body's metabolism regulators to allow a shift towards preferentially oxidizing fatty acids for energy. Increasing insulin sensitivity and reducing insulin levels removes one of the primary brakes on fatty acid metabolism. A complement to these actions is direct activation of fatty acid oxidation. Both wild bitter melon and sesame seed lignans help to do just this. Bitter melon previously has been discussed in these pages under the title, "Going WILD with Bitter Melon for Blood Sugar Support."¹³ As noted in that article, it has been found that extracts of bitter gourd activate cellular machinery to regulate energy production (technically, AMP-activated protein kinase or AMPK) and the way that fats are handled by the liver. These components can account for as much as 7.1 g/ kg of the dried wild material.

The sesamolin lignan found in sesame seeds (but not in most extracts) likewise increases fat metabolism. As pointed out in an important study, the "[e]ffects of sesamin and sesamolin (sesame lignans) on hepatic fatty acid metabolism were compared in rats. Sesamolin rather than sesamin can account for the potent physiological effect of sesame seeds in increasing hepatic fatty acid oxidation observed previously. Differences in bioavailability may contribute to the divergent effects of sesamin and sesamolin on hepatic fatty acid oxidation. Sesamin compared to sesamolin was more effective in reducing serum and liver lipid levels [with]sesamolin more strongly increasing hepatic fatty acid oxidation." "Sesamolin rather than sesamin can account for the potent physiological effect of sesame seeds in increasing hepatic fatty acid oxidation observed previously."¹⁴ "...gene expression of hepatic enzymes involved in fatty acid oxidation [was] much stronger with episesamin and sesamolin than with sesamin¡­[serum] half lives of 4.7±0.2, 6.1±0.3 and 7.1±0.4 h for sesamin, espisesamin and sesamolin, respectively...¹⁵

Green Coffee Bean Extract
After meals, up to 70 percent of the glucose from food is stored in muscle and other lean tissues. However, moment-to-moment regulation of blood glucose typically is handled by the liver. It does this via two processes, both of which are highly regulated. Gluconeogenesis generates glucose from certain noncarbohydrate carbon substrates, including certain amino acids and lipid components, such as triglycerides. Glycogenolysis is the freeing of glucose from glycogen stores. In the liver, but not the muscles, the hormone glucagon is involved. The liver also uses the enzyme glucose-6-phosphatase. With aging and as the metabolic syndrome develops, regulation of these two processes becomes impaired. Dysregulation is a particularly significant issue in diabetes.

Coffee, especially green coffee extracts, supply chlorogenic acid, which inhibits the glucose-6-phosphatase enzyme.^16,17 Chlorogenic acid also inhibits glucose absorption from the intestinal tract and thus reduces after meal blood glucose spikes.

Ketogenesis requires that the body preferentially use fatty acids for fuel. This cannot happen if either gluconeogenesis or glycogenolysis is not under proper control.

L-Carnitine and Astaxanthin
L-carnitine is a nutrient that, among other things, helps to shuttle fatty acids into the mitochondria for oxidation. In the discussion of HCA above it was noted that the combination of HCA and L-carnitine greatly improves the replenishment of glycogen stores after exercise. Unfortunately, tissue levels of L-carnitine are highly regulated and difficult to elevate to the extent necessary for ergogenic benefits in athletes. HCA improves L-carnitine metabolism by increasing uptake.HCA is an insulin memetic as well as an insulin sensitizer. HCA also shifts the body towards metabolizing fats, which makes L-carnitine's job easier. Another approach is to supplement with astaxanthin. Astaxanthin (≥4 mg/d) has been shown to reduce lactic acid accumulation during exercise, improve fatty acid oxidation and maintain better blood glucose levels while improving endurance. The mechanism may involve carnitine palmitoyltransferase I.^18,19

Conclusion
Studies have demonstrated the importance of metabolic flexibility for maintaining cardiovascular health and reducing the risk of developing metabolic syndrome components. Likewise, studies have shown that the related ability to enter ketosis as needed for athletic purposes can render rich ergogenic rewards. Nevertheless, enabling ketogenesis or keto-adaptation, however desirable this might be, through dietary measures alone under modern circumstances in Western countries is not only inconvenient, but downright difficult. Fortunately, it is possible to enable keto-adaptation through the use of appropriate supplements. These include properly manufacture HCA salts, wild bitter melon extract, sesame lignans and green coffee bean extracts. L-carnitine and astaxanthin are two more supplements that fit into this schema.

1. Preuss HG, Mrvichin N, Clouatre D, et al. Importance of Fasting Blood Glucose in Screening/Tracking Overall Health. The Original Internist. 2016, March:13-15,17.18.
2. Bjornholt JV, Erikssen G, Aaser E, et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care. 1999 Jan;22(1):45.9.
3. Sears B. Anti-inflammatory Diets. J Am Coll Nutr. 2015;34 Suppl 1:14.21.
4. Mauro DiPasquale, M.D., "Let the Fat be with You: The Ultimate High-Fat Diet," Muscle Magazine International (July and September 1992); "High Fat, High Protein, Low Carbohydrate Diet: Part I," Drugs in Sports 1, 4 (December 1992) 8.9.
5. https://bengreenfieldfitness.com/2015/12/how-to-get-into-ketosis/
6. Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. 2000 Dec;130(12):2990.5.
7. Lim K, Ryu S, Suh H, Ishihara K, Fushiki T. (-)-Hydroxycitrate ingestion and endurance exercise performance. J Nutr Sci Vitaminol (Tokyo). 2005 Feb;51(1):1.7.
8. Cheng IS, Huang SW, Lu HC, Wu CL, Chu YC, Lee SD, Huang CY, Kuo CH. Oral hydroxycitrate supplementation enhances glycogen synthesis in exercised human skeletal muscle. Br J Nutr. 2012 Apr;107(7):1048.55.
9. Louter-van de Haar J, Wielinga PY, Scheurink AJ, Nieuwenhuizen AG. Comparison of the effects of three different (.)-hydroxycitric acid preparations on food intake in rats. Nutr Metab (Lond). 2005 Sep 13;2(1):23. See also notes 18 and 19.
10. Clouatre, D., Talpur, N., Talpur, F., Echard, B., Preuss, H. Comparing metabolic and inflammatory parameters among rats consuming different forms of hydroxycitrate. Journal of the American College of Nutrition 2005;24:429 Abstract.
11. Clouatre D, Preuss HG. Potassium Magnesium Hydroxycitrate at Physiologic Levels Influences Various Metabolic Parameters and Inflammation in Rats. Current Topics in Nutraceutical Research 2008;6(4): 201.10.
12. Han N, Li L, Peng M, Ma H. (-)-Hydroxycitric Acid Nourishes Protein Synthesis via Altering Metabolic Directions of Amino Acids in Male Rats. Phytother Res.2016 May 4. doi: 10.1002/ptr.5630.
13. http://www.totalhealthmagazine.com/Vitamins-and-Supplements/Going-WILD-with-Bitter-Melon-for-Blood-Sugar-Support.html
14. Lim JS, Adachi Y, Takahashi Y, Ide T. Comparative analysis of sesame lignans (sesamin and sesamolin) in affecting hepatic fatty acid metabolism in rats. Br J Nutr. 2007 Jan;97(1):85.95.
15. Ide T, Lim JS, Odbayar TO, Nakashima Y. Comparative study of sesame lignans (sesamin, episesamin and sesamolin) affecting gene expression profile and fatty acid oxidation in rat liver. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):31.43.
16. Henry-Vitrac C, Ibarra A, Roller M, Merillon JM, Vitrac X. Contribution of chlorogenic acids to the inhibition of human hepatic glucose-6-phosphatase activity in vitro by Svetol, a standardized decaffeinated green coffee extract. J Agric Food Chem. 2010 Apr 14;58(7):4141.4.
17. Bassoli BK, Cassolla P, Borba-Murad GR, et al. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochem Funct. 2008 Apr;26(3):320.8.
18. Malmsten C, Lignell A. Dietary Supplementation with Astaxanthin-Rich Algal Meal Improves Strength Endurance; A Double Blind Placebo Controlled Study on Male Students. Carotenoid Science. 2008;13:20.22.
19. Aoi W, Naito Y, Takanami Y, Ishii T, Kawai Y, Akagiri S, Kato Y, Osawa T, Yoshikawa T. Astaxanthin improves muscle lipid metabolism in exercise via inhibitory effect of oxidative CPT I modification. Biochem Biophys Res Commun. 2008 Feb 22;366(4):892.7.