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What Is An Effective Dose of Omega-3 Fatty Acids?

The November 10, 2018 issue of the New England Journal of Medicine contained two articles on the use of omega-3 fatty acids to treat cardiovascular conditions (1,2). One study (the VITAL trial) used essentially a low dose of omega-3 fatty acids (0.84 grams of omega-3 fatty acids) and found no cardiovascular benefits (1). The other study (the REDUCE-IT trial) used a much higher dose of omega-3 fatty acids (3.8  grams of omega-3 fatty acids) and found significant cardiovascular benefits (2). 

The FindingsBoth studies used the same endpoint for determining cardiovascular benefits. The low-dose study found no benefits, while the high-dose study found highly significant benefits. This is probably because the omega-3 fatty acid dosage used in the REDUCE-IT trial was 4.6 times greater than that used in VITAL. However, this is far from breaking news. These findings from REDUCE-IT simply confirmed the 2007 JELIS Trial conducted with much larger group of patients (18,000) who were also all taking statins (3).

Are There Any Differences Between EPA and DHA?

Both studies demonstrated some basic misunderstandings on the mechanism of omega-3 fatty acids and its impact on cardiovascular disease. Both the products used in the studies are only approved to lower very high levels of triglycerides (greater than 500 mg/dL) and not approved for treating heart disease. In addition, one product contained a combination of EPA and DHA (Lovaza) and the other product only contained EPA (Vascepa).  Since the REDUCE-IT trial that used the EPA-only product worked, this might imply that DHA is dangerous. This is a story that starts with a statement that EPA lowers LDL cholesterol and DHA raises LDL cholesterol levels and therefore only EPA containing products are useful. That’s a marketing statement that is only partially true. A meta-analysis showed that EPA lowers LDL cholesterol levels by 0.7% and DHA raises LDL cholesterol levels by 2.6% (4). If you have a high LDL cholesterol level of 130 mg/dL, this means using EPA-rich omega-3 supplements will lower your LDL cholesterol by 1 mg/dL and using DHA-rich omega-3 fatty acid supplements will raise your LDL cholesterol by 3.5 mg/dL (4). These changes are clinically meaningless. Furthermore, the same meta-analysis study indicated that DHA-rich omega-3 fatty acid supplements are better than EPA-rich omega-3 fatty supplements in reducing triglycerides and increasing HDL cholesterol. These differential lipid effects between EPA-rich or DHA-rich omega-3 fatty acid products essentially balance themselves and suggest that there are no differences between EPA and DHA in lowering total lipid levels. Both are beneficial. Therefore, it is not the absence of DHA that is important, but the dose used. Lowering lipid levels, however, is not the reason that high-dose omega-3 fatty acids have the benefits in reducing cardiovascular events.

The Real Benefits of Omega-3 Fatty Acids

It is well established that heart disease is an inflammatory disease (5,6). Much of that inflammation is mediated by pro-inflammatory proteins called cytokines.  A recent Harvard study indicated that reducing one of these inflammatory cytokines (IL-1b) using a targeted monoclonal antibody could reduce heart attacks without lowering LDL levels (7). An even earlier trial in 1989 in normal subjects demonstrated that high-dose omega-3 fatty acids (5 grams per day) significantly lowered the levels of a variety of pro-inflammatory cytokines (8). This is why the AA/EPA ratio in the blood is the best marker for determining the reduction of pro-inflammatory cytokine production. But reducing cytokine levels to lower inflammation is dramatically enhanced by the simultaneous increase in a group hormones known as resolvins.

Resolvins to the Rescue

Omega-3 fatty acids can produce two  groups of hormones. One are pro-inflammatory hormones known as eicosanoids and the other is a group of pro-resolution hormones known as resolvins. When it comes to eicosanoids, DHA cannot produce eicosanoids and the eicosanoids produced from EPA are weakly inflammatory. Since the eicosanoids generated from EPA are 10-100 times less inflammatory compared to those generated from AA the end result is that as EPA is increased at the expense of AA in the body. This means the intensity of the inflammatory response is significantly reduced (9). What might appear to be an “anti-inflammatory” effect, is actually a significant reduction of the intensity of overall inflammation.

The real benefits of omega-3 fatty acids comes from their production of resolvins. This is why you need both EPA and DHA as each omega-3 fatty acid makes different types of resolvins that interact with different receptors. Furthermore, you need a much higher concentration of both EPA and DHA in the blood to generate the levels of resolvins that are necessary to resolve existing inflammation (10-12). Thus, the real benefits of high-dose omega-3 fatty acids may come from their ability to increase resolvin production as well as the reduction of pro-inflammatory cytokines. 

This would explain why the low-dose of omega-3 fatty acids used in the VITAL study generated essentially negative results.  Unless you generate adequate levels of resolvins and simultaneously reduce cytokines by sufficiently lowering the AA/EPA ratio with high-dose omega-3 fatty acid supplementation, it is unlikely you will have significant clinical benefits. This was demonstrated in the subsequent analysis of the JELIS study when it was demonstrated that only when the AA/EPA ratio had been reduced to a level of less than 1.3 that statistically significant differences in cardiovascular events between the active and control groups become apparent (13). It was also demonstrated in an earlier study that the level of EPA (3.8 grams per day) used in the REDUCE-IT study would lower the AA/EPA ratio to 1.2 (14). Using a lower dose of 1.9 grams of EPA per day, the AA/EPA ratio was only reduced to 2.3. Based on the clinical results of the JELIS and REDUCE-IT studies, it appears that you have to reduce the AA/EPA to less than 1.3 using high-dose omega-3 fatty acid supplementation to see a therapeutic effect in treating cardiovascular disease by a combination of two factors of increasing resolvins as well as lowering cytokine levels. 

Since you need both EPA and DHA for optimal clinical benefits, I happen to believe a 2:1 ratio of EPA and DHA provides the greatest overall benefits to omega-3 fatty acid supplementation. The REDUCE-IT trial indicates you probably need 4 grams of EPA per day to get a cardiovascular benefit, but that means to get an optimal cardiovascular result you would want another 2 grams of DHA per day or a total of 6 grams of EPA and DHA per day. 

How Do You Know How Much EPA and DHA to Take?

It is virtually impossible to measure either eicosanoids or resolvins in the blood and it is relatively difficult to measure cytokines, but you can easily measure the AA/EPA ratio. The published data from the JELIS and REDUCE-IT trials indicates that to have maximum cardiovascular benefits, the AA/EPA ratio should less than 1.3. This is why you should always test, not guess about your health. Furthermore, don’t believe statements that omega-3 fatty acids have no health benefits. They do, but only if you lower the AA/EPA ratio in the blood to an appropriate range, which requires higher amounts of omega-3 fatty acids to do so (15, 16).

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References

  1. Mason JE, Cook NR, Lee I-M, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D’Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, and Burning JE.  “Marine n-3 fatty acids  and prevention of  cardiovascular disease and cancer."  New Engl J Med doi: 10.1056/NEjMoa1811403 (2018)
  2. Bhatt DL, Steg G, Mill M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Juliano RA, Jiao L, Granowitz G, Tardif J-C, and Ballantyne CM. “Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.”  New Engl J Med  doi:  10.1056/NEJMoa 1812792 (2018)
  3. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet  369: 1090-1098 (2007)

  4. Jacobson TA, Glickstein SB, Rowe JD,  and Soni PN. “Effects of eicosapentaenoic acid and docosahexaenoic acid on low density lipoprotein cholesterol and the other lipids.”  J Clin Lipidol 6:5-18 (2012)

  5. Libby P, Ridker PM, and Maseri A. “Inflammation and atherosclerosis.” CirculationMar 105: 1135-1143 (2002)
  6. Geovanini GR and Libby P. “Atherosclerosis and inflammation: overview and updates.”  Clin Sci 132:1243-1252 (2018)
  7. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, and Glynn RJ. . “Antiinflammatory therapy with canakinumab for atherosclerotic disease.”  N Engl J Med 377: 1119-1131 (2017)
  8. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, and Weber PC, Schaeffer EJ, Wolff SM, and Dinarello CA. .  “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.”  N Engl J Med 320: 265-71 (1989)
  9. Calder PC. “Omega-3 fatty acids and inflammatory processes: from molecules to man.” Biochem Soc Trans. 2017 Oct 15;45(5):1105-1115.
  10. Spite M, Clària J, and Serhan CN. “Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases.” Cell Metab 19: 21-36 (2014)
  11. Elajami TK, Colas RA, Dalli J, Chiang N, Serhan CN, and Welty FK. “Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling.”  FASEB J 30: 2792-2801 (2016)
  12. See VHL, Mas E, Prescott SL, Beilin LJ, Burrows S, Barden AE, Huang RC, and Mori TA. “Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: a double-blind, randomised controlled clinical trial.”  Br J Nutr 118: 971-980 (2017)
  13. Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, and Matsuzawa Y. “Relationships between plasma fatty acid composition and coronary artery disease.”  J Atheroscler Thromb 18: 99-107 (2011)
  14. Braeckman RA, Manku MS, Bays HE, Stirtan WG, and Soni PN.. “Icosapent ethyl:  Effects on plasma and red blood cell fatty acids.”  Prostagl Leuko Essen Fatty Acid  89: 195-201 (2013)
  15. Sears B. “Omega-3 fatty acids and cardiovascular disease:  Do placebo doses give placebo results?”  CellR4 5:e2302 (2017)

  16.  Sears B. “Omega-3 fatty acids and cardiovascular disease: Dose and AA/EPA ratio determine the therapeutic outcome.”  CellR4 6:e2531 (2018 

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062524---Keto-Blog

Ketogenic Diets and Aging

Chances are, you or someone you know has tried the keto diet at some point in time. This high-fat, very low-carbohydrate eating plan appeals to many due to its promise of rapid weight loss. In this blog, Dr. Sears explores some of the latest scientific findings on ketogenic diets and provides caution before hopping on this trend. What is a Ketogenic Diet? The ketogenic diet is a high-fat, very low-carbohydrate eating plan. This significant reduction in carbohydrates to induce a metabolic state is called ketosis. This only occurs when there is not enough carbohydrates in your liver to completely convert fatty acids to carbon dioxide and water. The normal conversion generates the chemical energy (ATP) that keeps us alive. In the absence of ketosis, each fatty acid generates 108 molecules of ATP when oxidized in the mitochondria. Ketone bodies make less ATP when they are metabolized by mitochondria. How much less? About five times less. This is like switching the gasoline in your car from high-octane fuel to low octane fuel as ketone bodies increase in the blood. Furthermore, contrary to popular belief, ketones are not an ideal energy source for the brain, as glucose remains the preferred fuel for ATP production in brain cells. Lack of blood glucose is a highly stressful situation for the brain. This is why the body secretes the stress hormone cortisol from the adrenal glands during ketosis to breakdown protein and convert the amino acids into glucose for the brain. This explains why even under complete starvation for 38 days, the blood glucose levels never dropped below 68 mg/dL. This is still considered as a normal blood sugar level. Where did this blood glucose come from if there was none in the diet for 38 days? The answer is neo-glucogenesis primarily using lean body mass. Ketogenic Diets Pros and Cons Interest in ketogenic diets rises and falls about every 20 years. They’re very low-carbohydrate diets that claim that carbohydrates make you fat and keep you fat. This is simply not true. It is not carbohydrates per se but a disrupted metabolism that makes you fat. To be more specific, it is the inhibition of AMPK, the master regulator of your metabolism that makes you fat. Why? As AMPK activity increases, you burn stored fat faster. Frankly, I’ve always been amazed by the re-emergence of ketogenic diets. Eighteen years ago, I published the premier clinical study demonstrating that, under equal calorie intake in which all the food was provided to the subjects for six weeks, the Zone Diet was better than a ketogenic diet in reducing total weight, excess body fat, and inflammation. Now, a recent study revealed some more very concerning findings about the long-term effects of ketogenic diets. This new study indicated that following a keto diet causes a rise in senescent cells, popularly known as “zombie cells.” Zombie Cells are damaged cells that no longer divide but don't die. That’s bad enough, but zombie cells continue spreading inflammation throughout the body. As the number of zombie cells increases in your body, they become a living nightmare. Why? Zombie cells accelerate aging because they cause the earlier development of many chronic diseases. In this study they found that zombie cells in the animals began to appear while they were on a ketogenic diet. The zombie cells then disappeared when researchers changed the diet to a “non-ketogenic diet” (i.e., the Zone diet). And when the animals were given a Keto diet again, the zombie cells reappeared. Notice a trend? If you want to hear more about this study you can listen to our recent podcast at Dr.Sears.com. Based on earlier blogs, this adds to the list of downsides for following a ketogenic diet versus the Zone Diet. PROS Rapid initial weight loss: This is primarily due to the loss of retained water from the glycogen stores in the liver, which is rapidly used up to maintain blood sugar levels. Since these glycogen stores in the liver contain significant levels of retained water, much of the initial weight loss is water rather than stored body fat. If your main goal is loss retained water, this can be seen as a benefit. Of course, going to a sauna would also work. Reduced hunger: Ketogenic diets are rich in protein. Any increase in protein intake can help reduce hunger. CONS Production of acetone: One of the ketone bodies produced during ketosis is acetone, which is also the main chemical in nail polish. Increased calcium loss: A ketogenic diet can lead to higher calcium loss from bones. Limited fat utilization: High levels of dietary fat reduce the likelihood of using stored body fat for energy unless you also significantly restrict calories. Reduced energy levels: The lack of ATP production on a ketogenic diet can lead to easier fatigue during mild exercise. Damage from cheat meals: After seven days on a keto diet, a single high-carb cheat meal can damage blood vessels. Lack of polyphenols: This makes it difficult to activate genes that optimize metabolism by improving mitochondrial efficiency in converting fat into ATP. No long-term weight loss advantage: Long-term studies show no difference in weight loss between a ketogenic diet and a low-fat, high-carb diet. No short-term metabolic advantage: Careful studies demonstrate that fat loss on a ketogenic diet is the same as on a low-fat, high-carb diet with the same caloric intake. Compromised gut health: A lack of fermentable fiber from carbohydrates can lead to poor gut health and an increased risk of developing a leaky gut, which can cause significant inflammation. Furthermore, short-chain fatty acids (SCFA) are the metabolic product of fermentable fiber. These SCFA are powerful epigenetic signaling agents that enhance gene transcription. Ketosis generates a different type of hydroxylated short fatty acid (3-hydroxyl butyrate, that has no effect on gene transcription. In addition, the lack of SCFA has significant negative consequences on the gut-brain axis. Cortisol build-up: To produce glucose for the brain, cortisol levels increase to breakdown protein to make sufficient glucose via neoglucogenesis. Excess cortisol can lead to insulin resistance that cause regain of some of initially loss body fat. In addition, increased cortisol levels cause a depressed immune system as well as destruction of memory cells in the hippocampus. The initial benefits of following the ketogenic diet result in some initial weight loss (primarily water weight rather than fat loss), long-term studies show no significant differences in overall weight loss. Now new findings show a ketogenic diet may lead to significant adverse health consequences by accelerating the formation of zombie cells. Call me crazy, but I feel the key to longevity and wellness comes down to better metabolic control instead of living in a constant state of ketosis. Following Metabolic Engineering® for a lifetime provides that pathway of losing body fat without ketosis. References 1. Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, and Sears B. “Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets.” Am J Clin Nutr 2006 83:1055-61. 2. White AM, Johnston CS, Swan PD, Tjonn SL, and Sears B. “Blood ketones are directly related to fatigue and perceived effort during exercise in overweight adults adhering to low-carbohydrate diets for weight loss: a pilot study.” J Am Diet Assoc. 2007 107:1792-1796. 3. Sung-Jen Wei, Joseph R Schell, E Sandra Chocron, Mahboubeh Varmazyad, Guogang Xu, Wan Hsi Chen, Gloria M Martinez, Felix F Dong, Prethish Sreenivas, Rolando Trevino Jr , Haiyan Jiang, Yan Du, Afaf Saliba, Wei Qian, Brandon Lorenzana, Alia Nazarullah, Jenny Chang, Kumar Sharma, Erin Munkácsy, Nobuo Horikoshi, David Gius. Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Sci Adv. 2024 May 17;10(20):eado1463. doi: 10.1126/sciadv.ado1463. 4. Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF Jr. Liver and kidney metabolism during prolonged starvation. J Clin Invest. 1969 Mar;48(3):574-83. doi: 10.1172/JCI106016. 5. Chriett, S., Dąbek, A., Wojtala, M. et al. Prominent action of butyrate over β-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule. Sci Rep 9, 742 (2019). https://doi.org/10.1038/s41598-018-36941-9. 6. Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020 Jan 31;11:25. doi: 10.3389/fendo.2020.00025. 

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050824---Tofu-Blog

Tofu: Tips and Recipes Ideas

I have been eating tofu for a very long time, much longer than the 30 or so years I have been following the Zone Diet. Back then many of my favorite recipes came from the Tassajara cookbooks by Edward Espe Brown, the celebrated chef from the kitchen at California’s famous Zen Mountain Center, and cookbooks by Louise Hagler, a.k.a. Wendy Louise, a well-known authority on vegetarian cooking who is associated with a community in Tennessee known as The Farm. Those books are still among the best resources for tofu recipes. My mantra has always been if you don’t like something, don’t eat it. Keep this in mind if you’re new to tofu, start slowly by combining it with flavors and foods you like.    Tips and Suggestions    Firm-sprouted tofu is my preference for the Zone Diet. Unlike traditional tofu, which contains significant amounts of both protein and carbohydrate, sprouted has almost no carbohydrates. It’s lighter tasting, refreshing, and very filling.   Freezing tofu results in a chewy, sponge-like texture. I don’t recommend freezing, but some people prefer it when using tofu to substitute for meat in a recipe.    Baked tofu comes in a variety of flavors and makes an excellent quick meal with some vegetables and fruit added. It’s also great in salads.     Tofu made it into the book “The Top 100 Zone Foods” by Barry Sears.    Some recipes call for draining the tofu first. I find that usually isn’t necessary.   Tofu takes on the flavor of whatever is added to it.    Add nutritional yeast flakes to give a cheesy flavor to vegan tofu scrambles and dips. It’s also rich in protein and vitamin B12.   Cherry Vanilla Tofu “Ice Cream”   Tip: This doesn’t freeze or store well, so prepare only the amount you plan to serve immediately.   Using an immersion blender or a food processor blend equal parts of frozen dark cherries and firm tofu, plus some vanilla extract (preferably alcohol-free for best flavor). Serve immediately.  Tofu Scramble  This is great for breakfast, lunch, or dinner, and we’ve even brought it on long day hikes for a snack.   Crumble some firm tofu and stir in a generous amount of seasonings, taking care not to overdo it with the salt. Heat in a well-seasoned or nonstick skillet with a little Zone-friendly oil to the desired doneness.    Optional: If time allows, sauté some chopped onion in the skillet before adding the tofu and seasonings.    My favorite seasoning combination for this dish at my house is onion powder, garlic powder, turmeric, paprika, some oregano or thyme, nutritional yeast flakes, salt, and ground black pepper. The yellow color of the turmeric makes it somewhat like scrambled eggs.   Tofu Veggie Almond Pasta Salad   Dressing: Thin some smooth almond butter by stirring in some water, a little vinegar, and either soy sauce or Bragg’s Liquid Aminos (an unfermented soy sauce found in the health food section of most grocery stores).    Toss together cooked Dr. Sears’ Zone PastaRx Fusilli, tofu cut into cubes, matchstick cut red bell pepper, chopped green parts of scallions (a.k.a. green onions), and the almond butter dressing. Serve immediately or chill to serve later. It will keep well in the fridge for two or three days.   Use your imagination and see what you can come up with.  Experiment and have fun with it. Try using tofu to make cheesecakes, whipped desserts, tofu chocolate pudding, tofu “cream” based soups, tofu pot pie (think chicken pot pie), tofu burgers, tofu burritos, Buffalo tofu (like Buffalo wings), layered Mediterranean dips, tofu “meatballs”, grilled tofu, and more.    Enjoy! 

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