The Zone Diet versus the Mediterranean Diet
For the past six years, the Mediterranean diet has been voted the Best Diet in America as well as the best diet to manage diabetes. It’s remarkable since no one can define the Mediterranean diet. No one knows how many calories you should consume each day or how many grams of protein or fat should be consumed daily on the Mediterranean diet. There is also no distinction between low-glycemic or high-glycemic carbohydrates, protein-to-carbohydrate balance, etc. It certainly doesn’t give a strong feeling of robust science for the best diet in America as I pointed out in my book, The Mediterranean Zone (1). Furthermore, the initial results indicating the breakthrough of the Mediterranean diet published in 2013 had to be retracted and republished because of severe methodological problems in the study (2). Nonetheless, the lack of good science doesn’t prevent the Mediterranean diet from being consistently voted the top diet for general health and diabetes management for the past six years. A new study presents much more controlled research that can be used to compare the benefits of the Mediterranean diet to the Zone diet (3). The study was a direct head-on comparison to the Zone diet, so it was a “winner take all.” The study was conducted in a metabolic ward in an Italian hospital where all the food was provided to the subjects. The subjects also had significant insulin resistance (HOMA-IR > 4). Since the subjects were confined to the hospital, their dietary intake was tightly monitored. The control group received a calorie-restricted Mediterranean diet (500 calories less than needed to maintain their current weight) consisting of 55 percent carbohydrates, 20 percent protein, and 25 percent fat. The active group had the same level of calorie restriction but it was composed of 40 percent carbohydrates, 30 percent protein, and 30 percent fat. Although the authors cite this higher protein diet as a “high-protein Mediterranean diet,” it was identical to the Zone diet I described in 1995 (4). Furthermore, it was a crossover study since halfway through the study, the diets the subjects were consuming were switched after ten days to reduce any potential impact of individual metabolic characteristics of the subjects on the results. The Results The Zone diet demonstrated superior insulin resistance and hyperinsulinemia reductions compared to the Mediterranean diet. But there is more. The Zone diet also reduced the variability of blood glucose levels, indicating better hormonal stability between meals than the Mediterranean diet. This result was hardly new since Harvard investigators reported similar results after a single Zone meal compared to an isocaloric meal containing a higher level of carbohydrates and a lower level of protein in 1998 (5). In addition, the Zone diet is the primary dietary program used by the Joslin Diabetes Research Center at Harvard Medical School for treating type 2 diabetes. The reason is that the Zone diet is defined and, more importantly it works (6-9). So why don’t you hear more about the Zone diet in the medical research literature? I think the primary reason appears to be that the researchers wish to believe they came up with the idea of the macronutrient balance of the Zone diet all on their own, even though the Zone Diet was granted a U.S. patent for the treatment of hyperinsulinemia and insulin resistance in 2000 (10). Furthermore, since more than six million books on the Zone diet have been sold in the United States since the publication of The Zone in 1995, it is not that no one has ever heard of the Zone diet. Another problem is understanding the underlying metabolic problem that causes what is loosely termed “insulin resistance. “ It’s insulin resistance that causes weight gain and diabetes. However, insulin resistance can be best understood as a general term to describe the disruption of your metabolism. Furthermore, insulin resistance is associated with many other chronic disease conditions other than obesity and type 2 diabetes. These other chronic diseases include heart disease and Alzheimer’s. However, the most likely molecular cause of insulin resistance is the inhibition of the master regulator of metabolism known as AMPK (11). To optimally activate AMPK, you need a dietary triad consisting of the calorie-restricted Zone diet coupled with adequate intakes of omega-3 fatty acids and polyphenols. This is the Zone Nutritional System. Each of these nutritional interventions works synergistically with each other to increase AMPK activity. Any single intervention is good but using all three simultaneously is powerful. The molecular mechanisms of their interactions are complicated, but nutrition is always more complex than simple pharmacology. References Sears B. The Mediterranean Zone. Ballantine Books. New York, NY (2014) Estruch R et al. “Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90 Retraction of Publication.” N Engl J Med. 378:2441-2442. doi: 10.1056/NEJMc1806491. (2018) Tettamanzi F et al. “A high-protein diet is more effective in improving insulin resistance and glycemic variability compared to a Mediterranean diet: A cross-over controlled inpatient dietary study. Nutrients 13:4380. doi: 10.3390/nu13124380. (2021) Sears B. The Zone. Regan Books. New York, NY (1995) Ludwig DS et al. “High glycemic index foods, overeating, and obesity.” Pediatrics 103:E26. doi: 10.1097/00008480-199908000-00005. (1999) Giusti J and Rizzott J. “Interpreting the Joslin Diabetes Center and Joslin Clinic clinical guideline for overweight and obese adults with type 2 diabetes.” Curr Diab Report 6:405-408. doi: 10.1007/s11892-006-0014-y. (2006) Hamdy O. “Diabetes weight management in clinical practice—the Why Wait model,” US Endocrinology 4:49–54. doi.org/10.17925/USE.2008.04.2.49. (2008) Hamdy O. and Carver C. “The Why WAIT program: improving clinical outcomes through weight management in type 2 diabetes.” Curr Diab Rep 8:413-420. doi: doi: 10.1007/s11892-008-0071-5. (2008) Hamdy O. et al. “Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: a 5-year longitudinal study.” BMJ Open Diabetes Res Care 5:e000259. doi: 10.1136/bmjdrc-2016-000259. (2017) Sears, B. “Method of and nutritional and pharmaceutical compositions for reduction of hyperinsulinemia.” U.S. Patent No. 6,140,304 (2000) Sears B and Saha A. “Dietary activation of AMP-activated protein kinase (AMPK) to treat insulin resistance.” Evolving Concepts in Insulin Resistance doi: http://dx.doi.org/10.5772/intechopen.103787. (2022)
Q&A with Dr. Sears: Anti-Inflammatory Diets
Learning more about anti-inflammatory diets and AMPK can be a bit confusing. Luckily, Dr. Sears is here to provide valuable insights and answer your questions about these topics. In this blog, you'll get access to his Q&A session and learn more about how to achieve a healthier lifestyle through an anti-inflammatory diet and the importance of AMPK. So, let's jump right in and find out how these can help you create a healthier version of yourself!Q. What is an anti-inflammatory diet?A. The best definition of an anti-inflammatory diet is one that reduces insulin resistance. Insulin resistance is a general term for a disrupted metabolism caused by inflammation. Insulin resistance can be quantified by a blood test known as HOMA-IR. If the levels of HOMA-IR are less than one, then whatever diet you follow is an anti-inflammatory diet. Less than 1 percent of Americans have a HOMA-IR level of less than one. Q. What are the benefits of following an anti-inflammatory diet? A. Although an anti-inflammatory is defined as one that reduces insulin resistance, the real benefit is the activation of AMPK, which is the master regulator of metabolism in each of your nearly 40 trillion cells. It is inhibition of AMPK that is the driving force for the development of obesity, diabetes, heart disease, Alzheimer's, and many other chronic diseases. If you have no insulin resistance (your HOMA-IR is less than one), that is your surrogate marker that AMPK is optimized and your likelihood of developing many chronic diseases is dramatically reduced. Q. How can chronic inflammation affect your health?A. Chronic inflammation decreases the activity of AMPK which controls your metabolism. It is the efficiency of your metabolism that is required to supply energy to the cell, reduce the excess production of inflammatory mediators, like eicosanoids and cytokines, and repair damaged tissue. Q. How can you activate AMPK?A. There are three distinct dietary pathways to activate AMPK. These would include omega-3 fatty acids and polyphenols that are usually deficient in American diets, and the Zone Diet which is a highly defined anti-inflammatory calorie-restricted diet designed to activate AMPK. Anyone of the three is good, but they are highly synergistic when they are all working together. (You may also like: Everything you need to know about the Zone Diet)Q. What foods are pro-inflammatory?A. It is excess calories and too much glucose that will increase inflammation and inhibit AMPK activity. Consuming too many omega-6 fatty acids (e.g., corn oil, safflower oil, soybean oil) and palmitic acid (e.g., palm oil, meat, butter) will also induce inflammation and reduce AMPK activity.Q. Can you share some quick tips on how to adapt an anti-inflammatory diet to your specific needs/preferences? A. You need to consume omega-3 fatty acids, polyphenols and follow the Zone Diet, and simultaneously reduce your intake of foods known to promote inflammation like omega-6 fats. There are hundreds of recipes and helpful tips at www.ZoneLiving.com. The decrease in your HOMA-IR levels will be the clinical indication of your success. The subjective markers are reductions in excess body fat and greater physical and mental energy. Do this for lifetime, and you get healthy aging. Q. How Easy Is It To Measure AMPK activity and HOMA-IR?A. Measuring AMPK activity is incredibly difficult since it never leaves the cell. Therefore, you need a tissue sample to measure its activity. Fortunately, it is very easy to measure HOMA-IR. All you need is your fasting glucose and insulin levels and you put them into a simple equation. If your HOMA-IR is less than one, then your future is bright. If your HOMA-IR is greater than 2, your future is bleak. The average HOMA-IR of non-diabetic Americans is 2.7. However, it’s future you can rapidly change by following an anti-inflammatory diet. Have more questions for Dr. Sears? Drop them in the comments below!
Dr. Sears Answers Your Questions On Protein and Protein Powder
The global market for protein supplements is anticipated to rise 8.5% by 2030. This increased demand is widely due health-conscious individuals, fitness go-ers, and millennials looking to add more balance to their diets. In this blog, Dr. Sears covers some basic questions on protein and then gets into protein powders and what you need to know. Q. How much protein do you need each day? A. It depends on your lean body mass and your level of physical activity. The reason you need protein is to maintain and repair damaged muscle tissue. If you are an active athlete, you will have more muscle mass, and your training will damage your existing muscle. Therefore, these individuals are going to need more protein. On the other hand, the average American male needs about 110 grams of protein per day, and the average American female requires about 90 grams per day. That amount of protein should be spread out throughout the day. This means you should eat no more protein at a meal than can fit on the palm of your hand. That’s about 3 ounces of protein for a female and 4 ounces for a male. Q. What are the primary nutritional differences between animal protein versus plant protein? A. Of the 20 amino acids in any protein source, only nine are essential. This designation is because essential amino acids can’t be synthesized by the body and must be supplied by the diet. Animal protein has a complete range of amino acids, whereas plant protein is usually deficient in some essential amino acids. Q. Does protein build muscle mass? A. To help with muscle growth, you need adequate protein in the diet and weight-bearing exercise.Simply consuming more protein doesn’t build muscle. Exercise causes muscle damage and this stimulates new muscle formation to replace the muscle that has been damaged. The higher the intensity of exercise, the more protein you need. Q. Does protein increase satiety? A. A benefit of adequate protein consumption is that it increases satiety. It does this by releasing hormones from the gut that go directly to the brain to stop hunger and by increasing the release of the hormone glucagon from the pancreas to stabilize blood sugar levels. This lack of appetite is why you want to consume adequate protein at every meal, especially breakfast. Q. Can you consume too much protein? A. The answer is yes. Of the nine essential amino acids, three are branched-chain amino acids. These amino acids are leucine, isoleucine, and valine, and these have the most significant effect on stimulating muscle development by activating the gene transcription factor called mTOR. High levels of mTOR are associated with insulin resistance, eventually leading to many chronic diseases such as diabetes and cancer. Q. Is there a connection between mTOR and AMPK? A. The more you activate mTOR, the more you inhibit your master regulator of metabolism known as AMPK. Low levels of AMPK activity ultimately cause insulin resistance. As a result, you want to keep your protein consumption in a zone; not too high but not too low. With this as a background, let’s talk about using protein powder to ensure you get enough protein to maintain your muscle mass but not too much to inhibit AMPK. Q. What are the benefits of using protein powder? A. Many of our meals, especially breakfast, can fall short on protein. If you are over the age of 50, you are likely not getting enough protein in your day. Protein is vital as we age since older adults are prone to losing muscle mass, resulting in loss of strength and function. Protein powder can help fill in the gaps when intake falls short. Isolated protein powder can also help balance out excess carbohydrate intake to provide a better hormonal response at meals generating stable blood sugar levels and hence greater satiety between meals. Q. Can protein powder help with weight management? A. It can as it helps to create satiety and minimize cravings. Q. How should protein powder be used? A. It should be used as an additive to carbohydrate-rich meals. For example, adding protein powder to oatmeal provides a superior meal compared to oatmeal alone, or adding protein power to a fruit smoothie will give excellent appetite suppression. Q. Can you use protein powder daily and is there a better time of day to use it? A. Yes, you can use protein powder daily as long as you don't exceed your daily protein requirements. Breakfast is probably the best meal to use it since that meal is most likely to contain excess carbohydrates relative to protein. Q. Who should use protein powder? A. Anyone who does not feel they are getting enough protein in a meal. Q. How do you know if it’s right for you or working? A. Your best indicator is the increasing lack of hunger after a meal. Q. Are there any negatives to using protein powder? The key with protein powder is making sure you do not consume too much relative to the rest of your meal. I generally tell people to aim for a total of 25 grams of protein at each meal and about 7-14 grams at each snack. This takes into account all of the sources of protein at each meal and a good gauge to know how much to consume. You do want to pay attention to the quality of the amino acids in the protein powder you choose. Some sources such as collagen are very poor in essential amino acids and therefore would not be recommended. Q. What type of protein powder is best, and what ingredients should you look for? A. I think dairy protein powders are best, but recommend looking for ones that are lactose-free. Plant-based protein sources such a soy or pea don't have the taste of dairy-based protein powders, but can be used for those who avoid dairy. All protein powders are superior to collagen protein which is highly deficient in essential amino acids. Have more questions for Dr. Sears? Drop them in the comments below!
Burn Fat Faster
Now that the Covid-19 epidemic seems to be slowing down, we must contend with the other epidemic that shows no signs of abating. That is our obesity epidemic. If you have excess body fat, you are already inflamed. That excess adipose tissue is the staging area for ongoing inflammatory attacks on every organ in the body. It is also the first sign that your metabolism is becoming dysfunctional, thus reducing your ability to burn excess stored fat for energy. Metabolism is defined as those complex processes that take place in your body to keep you alive. Metabolism allows you to breathe, digest food, circulate blood, keep the brain working, fight infections, and so on. All these processes require massive amounts of ATP. The “traffic cop” that controls your ability to convert stored body fat into ATP is called AMPK. AMPK can be considered the “master switch” of metabolism. If AMPK is optimized, you can burn stored body fat faster to make greater amounts of ATP. Conversely, if AMPK is inhibited, you accumulate incoming calories as excess body fat. Losing excess body fat is a challenge but keeping the excess body fat from returning is even more difficult because your metabolism slows down after losing any bodyweight. The good news is that AMPK activity is under robust dietary control. The best way to optimize AMPK activity is following the Zone Pro-Resolution Nutrition program. By following the anti-inflammatory Zone diet, you can constantly activate your AMPK while reducing calorie intake without hunger or fatigue. Adding omega-3 fatty acids and polyphenols as dietary supplements will also increase AMPK activity through different pathways. Although any one of these three nutritional interventions is good, when you combine all three, they are synergistic, as I describe in my latest book, The Resolution Zone. On the other hand, AMPK activity is inhibited by consuming either excess dietary calories or excess glucose. If you inhibit AMPK, then incoming calories easily get converted and stored at excess body fat. Activating AMPK is the biological key that allows you to burn fat faster and prevent its return. It’s also totally under your dietary control. Once you master these basic dietary concepts of the Zone Pro-Resolution Nutrition program, burning fat faster becomes a lifetime reality that leads to a longer and better life. Additional benefits from activating AMPK will be slowing down your rate of aging and improving the efficiency of your immune system. This is the real reason why you want to be in the Zone.
Stress and Omega-3 Fatty Acids
It’s common knowledge that stress can be a killer. But what is not clear is why is it harmful and what you can do to reduce it? A new research article provides more insight into both questions (1). The subjects in this study were middle-aged, overweight healthy adults. Thirty days before the trial, the subjects were split into three groups consuming either placebo capsules, 1.25, or 2.5 grams of EPA and DHA daily. The stress they were exposed to was being given 10 minutes to prepare a 5-minute speech. This speech entailed telling why they were the best candidates for a job. Furthermore, the speech was delivered in front of two live judges wearing white lab coats who were told to keep neutral facial expressions during the speech. The subjects couldn’t use any notes for their job interview speech in front of the judges. If they didn’t use their allotted 5-minute time, they were told to continue speaking until their five minutes were up. If that wasn’t enough stress, they also had to immediately do an oral 5-minute serial subtraction test after their speech before the same judges. If they made a mistake, they would have to start over from the beginning. This test is known as the Trier Social Stress Test, which produces stress and inflammation (2). About one and half hours before this stress test, the subjects had their blood drawn for cytokine levels and saliva for cortisol levels. Then, they ate a standardized breakfast and then answered a questionnaire on their current state of anxiety. After the 20-minute stress test, the same parameters were measured several times over the next two hours. What happened? Quite a lot. Those taking the 2.5 grams of EPA and DHA per day had significantly lower cortisol levels during and for the next two hours after the test. They also had lower pro-inflammatory cytokine levels and less inhibition of the telomerase enzyme activity that repairs damage to your DNA caused by stress. Similar results of lowered cytokine levels were found in a study of elderly, obese healthy adults taking 2.5 grams of EPA and DHA per day (3). So, what are the implications? If you are in a high-stress occupation, then taking adequate daily levels of EPA and DHA can be your best defense against the inflammation and damage to your DNA that comes with that occupation-induced stress. This group would also include elite athletes who live in a world of constant stress due to training and competition. However, most of us live with chronic low-level stress. The impact of this type of stress on the immune system is the same. It is unlikely that stress will be eliminated in our lives. Still, you can significantly reduce the inflammatory and genetic consequences of that stress by taking adequate EPA and DHA levels on a lifetime basis. References Madison AA et al. Omega-3 supplementation and stress reactivity of cellular aging biomarkers. Mol Psychiatry doi:10.1038/s41380-021-01077-2 (2021) Allen AP et al. Biological and psychological markers of stress in humans: Focus on the Trier Social Stress Test. Neurosci Biobehav Rev 38: 94-124 (2014) Tan A et al. Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating pro-inflammatory cytokines in aging adults. Prostaglandins Leukot Essent Fatty Acids 132:23-29 (2018)
Hormone Replacement Therapy
Dr. Sears Hormone Replacement Therapy Lecture This week Dr. Sears dives into a lecture on Hormone Replacement Therapy. We often think of anti-aging as just replacing the hormones of youth, but we now know hormones such as estrogen and testosterone are multi-tasking. These hormones also have anti-inflammatory properties which is their secret to anti-aging. Learn more in the video below.
Protein Q&A with Dr. Sears
Protein is an essential nutrient meaning we have to get it through our diet. One of its primary functions is building and preserving muscle mass. Protein is critical for both young and old to support growth as we develop and to counteract the decrease in absorption and metabolism as we age. With athletic performance and popularity in diets such as keto, there are misconceptions on just how much protein we need and whether some of the products in the marketplace are worth using. This week Dr. Sears answers some of the top questions we receive about protein. Q: The Zone Diet has long been thought to be a high protein eating plan, can you put this myth to bed? A: The Zone diet is a protein adequate nutritional plan. The amount of protein one requires is individualized as it depends on the existing muscle mass and level of physical activity. Furthermore, once the total of amount of protein is determined, it is spread evenly throughout the day to be balanced with moderate amounts of low-glycemic carbohydrates. This helps to stabilize blood glucose levels while simultaneously increasing satiety through the release of gut hormones that instruct the brain to stop eating. Q: How much protein do you recommend people consume each day? Does this amount vary from what you’ve previously recommended with your Zone Food Blocks? A: It depends on the amount of protein required to maintain your muscle mass. Usually that is 90 grams of protein for females and about 110 grams for males. However, the amount at any one meal is on average about 25 grams. The Zone Food Blocks take into account that the protein density in a protein source is variable with meat being more dense in protein than fish. For example, 1 ounce of meat is 1 block of Zone Protein whereas 1.5 ounces of fish is 1 block of Zone Protein. Both equal approximately 7 grams of protein. Q: Numerous studies have shown the connection between consuming red and processed meats and the increased risk of heart disease and certain cancers. A recent study published in Annals of Internal Medicine suggests this may not be true and that data regarding the health benefits of consuming less meat is weak. What are your thoughts on this controversial study? A: There is a large body of research that suggests that red meat consumption, especially processed meats, is associated with the increased risk of cardiovascular disease, diabetes, certain cancers and early death. The data here is clear. So what protein sources should you use? Relative to red meat, if you are to consume it, aim for grass-fed beef instead. Better choices for animal protein are low-fat chicken or fish. For lacto-ovo vegetarians, egg whites and dairy products are excellent protein choices. Finally, for vegans, plant-based imitation meat products are a useful choice. With these options just be careful to watch the number of ingredients. Typically the more ingredients you see on the label the less desirable the product is going to be. Q: Is there a difference between the protein you get in vegetables compared to meat? A: Vegetable protein has a far lower protein density. This requires you to consume a lot of vegetables to get the average 25 grams of protein per meal as recommended on the Zone diet. However, some vegetables such as mushrooms and the ABCs (artichoke, asparagus, broccoli, cauliflower, and spinach) have higher protein contents than other vegetables. Vegetable protein is usually lower in essential amino acids than animal, egg, or dairy protein. However, if you consume 25 grams of vegetable-based protein at a meal, you will have adequate levels of all amino acids. New sources of plant-based meat imitation products make it easier to consume the necessary protein needed for hormonal balance and satiety. Q: Many people are trying the keto diet right now for its touted weight loss and health benefits. The keto diet is a high fat, high protein eating plan. Do you think the benefits of keto are supported in the literature? A: The short answer is no. I published a highly controlled study in the American Journal of Clinical Nutrition in 2006 demonstrating the Zone diet was superior in all aspects compared to a ketogenic diet. Furthermore, follow-up studies indicated the ketogenic diet caused fatigue upon mild exercise and calcium loss. Since a ketogenic diet is deficient in glucose, there is also a corresponding increase in cortisol secretion with its continued use. Finally, a ketogenic diet is deficient in fermentable fiber and polyphenols that are essential for gut health. Q: Collagen levels decline with age. Supplementation has been promoted to help boost levels as we age while helping to improve muscle mass, joint health, and skin elasticity. What are your thoughts on collagen and do you think its supplementation can help with anti-aging? A: The short answer again is no. All the consequences of aging are due to increased unresolved inflammation. Collagen supplementation is fine for fingernails, hair, and structural components of the skin, but it is a very poor-quality protein and will have no effect on reducing inflammation. Since absorption and metabolism of protein declines with age its also critical to ensure that you are getting enough high quality protein in your diet to help preserve muscle mass and minimize frailty.
Omega-3 Fatty Acids and Blood Pressure
The FDA recently announced limited health claims for the use of omega-3 fatty acids in the treatment of hypertension and heart disease. These are qualified health claims since each of the allowed claims must carry the following language, “FDA has concluded that the evidence is inconsistent and inconclusive”. Nonetheless this indicates the FDA is beginning to acknowledge that omega-3 fatty acids have potential in the treatment of hypertension and cardiovascular disease. These health claims can only be used if a single-serving size contains at least 0.8 g of EPA and DHA. It took more than five years of study by the FDA to even allow these limited health claims as the petition for them was launched in 2014. The primary scientific document that used was a meta-analysis of various clinical trials published in the American Journal of Hypertension (1). More than 70 clinical trials were included in the analysis. Although the average reduction in systolic blood pressure by 1.5 mm Hg and diastolic blood pressure by 1 mm Hg was seemingly small, the effects in untreated hypertensive subjects was far greater (4.5 mm Hg reduction in systolic pressure and 3.1 mm Hg reduction in diastolic pressure). Furthermore, the reduction in the diastolic pressure was only observed if the daily dose of EPA and DHA was greater than 2 grams per day. Ironically, a lower dose of EPA and DHA between 1 and 2 grams per day had no effect on diastolic blood pressure. Therefore, it seems that the FDA qualified health claim would be far stronger if the minimum omega-3 dosage was greater than 2 grams per day as opposed to the stated 0.8 grams per day. Of course, there might be a problem since at those levels of daily EPA and DHA, intake of commercially available omega3s may contain too many toxins such as PCBs. The benefits of a higher dose of EPA and DHA for treating hypertension has been confirmed in more recent studies (2,3). In these studies, there were equivalent drops in systolic blood pressure at 0.7 and 1.8 grams of EPA and DHA per day, but the higher dose (1.8 grams per day) had a drop in diastolic pressure, but not with the lower dose (0.7 grams per day) (4). This differential effect of omega-3 fatty acids on risk of heart disease was illustrated in two recent trials (5,6). At a low dose of 0.8 grams of omega-3 fatty acids per day, there was no clinical benefits. At a higher dose of 3.9 grams of omega-3 fatty acids, there was a strong cardiovascular benefit. Further analysis of the high-dose omega-3 data indicated that among statin-treated individuals, the addition of the high-dose omega-3 fatty acids reduced the occurrence of a first heart attack, secondary heart attack, and total ischemic events by approximately 30 percent compared to statins alone (7). As pointed out in a recent commentary by me, the appropriate dose of omega-3 fatty acids are best measured by the reduction in the arachidonic acid (AA) to eicosapentaenoic acid (EPA) ratio in the blood (8). Unfortunately, the AA/EPA ratio was not reported in any of the hypertension or cardiovascular trials. Hopefully future clinical investigators will use the levels of omega-3 fatty acids required to reach an appropriate AA/EPA ratio (1.5 to 3) to obtain much stronger research findings so that the health claim for omega-3 fatty acids in hypertension and cardiovascular disease is not followed by the qualifier, “FDA has concluded that the evidence is inconsistent and inconclusive” . Miller PE et al. “Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: A meta-analysis of randomized controlled trials.” American Journal of Hypertension 27:885-896 (2014) Yang B et al. “Lowering effect of n-3 fatty acid supplements on blood pressure in Inner Mongolia hypertensive patients.” J Agric Food Chem 67: 184-192 (2019) Casanova MA et al. “Omega-3 fatty acids supplementation improves endothelial function and arterial stiffness in hypertensive patients with hypertriglyceridemia and high cardiovascular risk.” J Am Soc Hypertension 11; 10-19 (2017). Minihane AM et al. “Consumption of fish oil provide eicosapentaenoic acid and docosahexaenoic acid reduces blood pressure in adults with systolic hypertension.” J Nutr 146: 516-523 (2016) Manson JE et al. “Marine n-3 fatty acids and prevention of cardiovascular disease and cancer.” N Engl J Med 380: 23-32 (2019) Bhatt DL et al. “Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.” N Engl J Med 380: 11-22 (2019) Bhatt DL et al. “Effects of icosapent ethyl on total ischemic events.” Am Coll Cardiol 73: 2791-2802 (2019) Sears B. “Appropriate doses of omega-3 fatty acids for therapeutic results.” CellR4 6: e2578 (2018)
Beyond Cholesterol: The Real Link Between Diet and Heart Disease
One of the best ways to live longer is to reduce your likelihood of dying from a heart attack since it continues to be the #1 killer in America. If we could prevent heart disease tomorrow, it is estimated that the average life expectancy of every American would increase by ten years. We are led to believe by extensive drug marketing that elevated cholesterol is the cause of heart disease. Unfortunately, about 50 percent of the people who are hospitalized with heart attacks have normal cholesterol levels. What’s more, 25 percent of people who develop premature heart attacks have no traditional cardiovascular risk factors at all. So what if cholesterol was only a minor, secondary player in developing heart disease? The Cholesterol Hype Cholesterol does have a role in heart disease, but it is a secondary factor that plays a far lesser role in fatal heart attacks than the marketing of drug companies leads you to believe. It has been known since 2001 that oxidized LDL is a far better predictor for the development of atherosclerotic lesions than the traditional measurement of LDL (1). But it was also at this time that the first statin studies began to appear. This gave the pharmaceutical industry a patented drug to “prevent” heart disease but unfortunately statins could not specifically lower oxidized LDL. Furthermore, the LDL story was such an easy story to tell because it could be summarized “if your cholesterol levels are high, you are going to die”. That marketing statement ignored the fact that the most common drug (i.e. aspirin) to prevent heart attacks had no effect on reducing cholesterol. Today lowering LDL cholesterol (but not necessarily lowering oxidized LDL) is the number-one priority of every cardiologist in America. Various epidemiological studies have found that increased serum cholesterol levels occur more often in heart disease patients. But that increase is only 5 to 10 percent higher in those who develop heart disease than those who don’t. This doesn’t help explain why about half the people who die from heart disease don’t have elevated LDL cholesterol levels (less than 130 mg/dl). It also means that high LDL cholesterol is not a very good predictor of heart disease. On the other hand, a very different picture emerges if you look at the levels of oxidized LDL levels. You can see a very striking relationship in the prediction of heart disease with increasing levels of oxidized LDL levels (1). Even so the best way to lower oxidized LDL is not a statin, but high-dose polyphenol extracts (2), since they have anti-oxidant properties to help combat oxidation. Unresolved Cellular Inflammation: The Reason Heart Disease Kills A heart attack is simply the death of the muscle cells in the heart due to lack of oxygen caused by a constriction in blood flow. If this lack of oxygen is prolonged, and enough heart muscle cells die, your heart attack becomes a fatal one. What causes that constriction in blood flow is the rupture of soft vulnerable plaques that line the artery. Although you can’t see them, when they rupture they release a mass of cellular debris that accelerates the clotting process to stop blood flow and therefore stop oxygen from being delivered to the heart. The reason heart disease remains the primary killer of Americans is not due to cholesterol, but unresolved chronic inflammation in the arteries that causes these soft vulnerable plaques to rupture. You may be asking yourself, “What on earth is unresolved cellular inflammation?” This is simply inflammation that falls below the threshold of perceived pain. That’s what makes it so dangerous. You have no indication it is present and therefore you make no effort to reduce it. This inflammation results from an increased production of inflammatory mediators such as eicosanoids. Statins have no effect on reducing eicosanoid levels in the body. Eicosanoids, Resolvins, and Heart Disease Eicosanoids are the hormones that intensify inflammation. You need some to activate the immune system, but in excess they promote cellular inflammation. These hormones are generated by the combination of high levels of insulin and omega-6 fatty acids in your blood. On the other hand, resolvins are the hormones that resolve inflammation. These hormones are generated by the levels of omega-3 fatty acids in your blood. You need to have both eicosanoids and resolvins in the proper balance in order to be in a state of wellness because you have to turn on inflammation as well as turn it off. Unfortunately, most of us produce too many eicosanoids, which leads to increasing levels of unresolved cellular inflammation and eventually to chronic diseases like heart disease. Managing Unresolved Cellular Inflammation The Zone Diet was developed primarily to reduce the overproduction of eicosanoids. Adequate levels of omega-3 fatty acids in the diet (usually requiring supplementation) will ensure adequate levels to promote the formation of resolvins. A variety of factors forge the linkage between unresolved cellular inflammation and fatal heart attacks. First of all, eicosanoids make soft vulnerable plaque more likely to rupture. Eicosanoids act as powerful constrictors of your arteries and can lead to a vasospasm, a potentially fatal cramp or “charley horse” that prevents blood flow to the heart. Vasospasm is the second cause of fatal heart attacks. In addition, lack of sufficient levels of omega-3 fatty acids in the heart muscle can also lead to a fatal heart attack caused by chaotic electric rhythms in the heart. This condition, called sudden death, accounts for more than 50 percent of all fatal heart attacks. How can you tell if you have the right balance of eicosanoids to resolvins for heart health? That knowledge comes from the AA/EPA ratio in the blood. Arachidonic acid (AA) is the building block of eicosanoids and eicosapentaenoic acid (EPA) is the building block of resolvins. You want to maintain that AA/EPA ratio close to 1.5, and ideally have about 4 percent of your total fatty acids in the blood consisting of EPA (3-5) How The Zone Can Help Promote A Healthy Heart For optimal heart health you need the appropriate balance of eicosanoids to resolvins. This is why I recommend a multi-factorial dietary approach. This entails the Zone Diet, omega-3 fatty acids, and polyphenol extracts. The Zone Diet can help reduce the overproduction of eicosanoids. Consuming adequate levels of omega-3 fatty acids can help increase the production of resolvins and the use of maqui polyphenol extracts can help minimize oxidized LDL (2). This three-part dietary system or what I call the Zone Pro-Resolution Nutrition system will all be described in greater detail in my upcoming book, The Resolution Zone.{{cta('14dee37e-1816-403a-a6e8-a67c8b9cf45b')}} References Holvoet P, Mertens A, Verhamme P, Bogaerts K, Beyens G, Verhaeghe R, Collen D, Muls E, and Van de Werf F. “Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease.” Arterioscler Thromb Vasc Biol 21:844-848 (2001) Davinelli S, Bertoglio JC, Zarrelli A, Pina R, and Scapagnini G. “A Randomized Clinical Trial Evaluating the Efficacy of an Anthocyanin-Maqui Berry Extract on Oxidative Stress Biomarkers.” J Am Coll Nutr 34 Suppl 1:28-33 (2015) Sears B. “Omega-3 fatty acids and cardiovascular disease: Do placebo doses give placebo results?” CellR4 5:e2302 (2017) Sears B. “Omega-3 fatty acids and cardiovascular disease: Dose and AA/EPA ratio determine the therapeutic outcome.” CellR4 6:e2531 (2018) Sears B. “Appropriate doses of omega-3 fatty acids for therapeutic results.” CellR4 6: e2578 (2018)
Dr. Barry Sears Answers Your Questions on Omega-3 Fish Oil
Dr. Sears answers some of the top questions we receive about fish oil and omega-3 fatty acids and what makes OmegaRx 2 unique. What are EPA and DHA?EPA is an abbreviation for the omega-3 fatty acid Eicosapentaenoic Acid. DHA is short for Docosahexaenoic Acid. The anti-inflammatory properties of fish and fish oil are mainly due to these two omega-3 fatty acids. The benefit of EPA and DHA comes from reducing cellular inflammation by inhibiting the formation of inflammatory hormones (e.g. eicosanoids) derived from the omega-6 fat, Arachidonic Acid (AA). However, their greatest benefits come from the generation of pro-resolution hormones (i.e. resolvins) that turn off the inflammatory process. If someone considers themselves healthy, why would they need to take omega-3 fatty acids?Omega-3 fatty acids are considered essential fatty acids meaning they must be supplied in our diets. They are the building blocks for hormones that resolve existing inflammation. Unresolved inflammation is the primary reason we gain weight, develop chronic disease, and age at a faster rate. The typical American diet is very low in omega-3 fatty acids and rich in omega-6 fatty acids (the building blocks for pro-inflammatory hormones). This is why you need a high concentration of purified omega-3 fatty acids to make a difference in addition to lowering the levels of omega-6 fatty acids in the diet. Why is fish oil superior to krill oil, flaxseed or other omega-3 products on the market?Fish oil is made by heating fish to release the stored fats. From this crude fish oil, the omega-3 fatty acids can be further refined/purified into omega-3 concentrates. Krill oil is actually made of small shrimp that have been harvested and extracted using harsh chemicals (hexane and acetone). Furthermore, the omega-3 fatty acid content in krill oil is much lower than in omega-3 concentrates derived from fish oil. Flax seed oil is rich in alpha-linolenic acid (ALA). Although ALA is an omega-3 fatty acid, it has no health benefits unless converted into EPA and DHA. This conversion is very inefficient (about 1-10%) so you would have to consume large quantities to get the same benefits of a much smaller amount of omega-fatty acid concentrates. What is it about OmegaRx2 that makes it different from other brands?The answer is purity and potency. OmegaRx 2 is highly purified to remove as many PCBs as possible and our standards are eighteen times more rigid than the industry standards. In addition, Zone Labs publishes the purity data for every lot of OmegaRx 2 on our website to give our customers total transparency. All omega-3 fatty acids are prone to oxidation which is why we publish the levels of stability (defined by the TOTOX level or rancidity in layman terms) on every lot of OmegaRx2 as well. Our post production levels of rancidity are among the lowest on the market. Finally, the concentration of OmegaRx 2 is among the highest concentration of any non-prescription omega-3 fatty acid product on the market. How much fish oil do you recommend people take?I recommend taking a daily minimum of 3 grams of EPA and DHA. That said, we use our Cellular Inflammation test to determine the ideal amount an individual requires. This test looks at the ratio of two key fatty acids in the blood: Arachidonic Acid (AA), an omega-6 fatty acid which is the building block for pro-inflammatory hormones, and EPA which is the building block for pro-resolution hormones. The AA/EPA ratio or Cellular inflammation Score will tell you with the most precision how much you need to take on a daily basis to optimize your overall wellness. It has been demonstrated that decreasing the AA/EPA ratio is strongly associated with a longer life. If my cellular inflammation score is ideal, do I need the heightened concentration? If your Cellular Inflammation Score is between 1.5 to 3 you are in the ideal range to promote future wellness. The higher the Cellular Inflammation Score, the more inflamed you are. The average American has a Cellular Inflammation Score of 20. Resolution of inflammation is key to maintaining wellness, and this can only be achieved with a lower score. It is possible to achieve an ideal AA/ EPA ratio or Cellular Inflammation Score within 30 days with the correct dosage of OmegaRx 2. When will people start seeing the benefits after they begin to supplement and what will they be?I generally tell people that it takes about 30 days to truly see the impact of supplementation in the blood, but it's only a matter of days that their benefits subside once you stop taking them. This means you have to be consistent with your intake of purified fish oils and take it daily. Omega-3 fatty acids have been shown to help support a healthy heart, brain function, behavior and mood regulation, cellular rejuvenation, athletic performance and recovery, and improved vision. Their benefits are due to their role in resolving excess cellular inflammation. Do you have tips for how to take it? Most people do just fine taking our recommended dose of 4 capsules or 1 teaspoon of OmegaRx 2 daily. I always suggest taking it with food and if you want to split up your dose between morning and night to see how you do that is fine too. How long do you have to take it?For a lifetime if you want to maintain wellness. Once you stop taking omega-3 fatty acids your levels of omega-3s will soon return to baseline within a few days. What are the benefits of omega-3 fatty acids across the lifespan? Fish oil or omega-3 fatty acids are critical across the lifespan. This is why they are essential nutrients. It starts in the womb as they support brain development in utero in addition to minimizing post-partum depression for the mother. We now know that the dietary and metabolic environment the fetus is exposed to in the womb can echo through the rest of his or her so it’s critical to have good nutrition and adequate levels of omega-3s throughout pregnancy and after. The rise in conditions such as autism, ADHD, diabetes and heart disease in early childhood and young adulthood may have a connection with the high levels of omega-6 fatty acids in our diet and low amounts of omega-3s. I strongly believe that chronic conditions associated with aging such as heart disease, diabetes, cancer, and dementia start with the failure to resolve inflammation so by getting adequate levels of omega-3s early on you can help to promote a lifetime of wellness. {{cta('70a4b644-a93c-4f8b-83ec-5be1500ed236')}}
What Is the Ketogenic Diet and How Does It Compare to the Zone Diet?
Over the past few months we’ve received a number of inquiries regarding Dr. Sears’ stance on the Ketogenic Diet and how it relates to the Zone in terms of health and weight loss. Is this just the next diet craze or is it as good for weight loss and health as it’s touted to be? What Is the Ketogenic Diet? The ketogenic diet is a high-fat, low carbohydrate diet consisting of approximately 75% fat, 20% protein and 5% carbohydrate. Compare this to the Zone which is moderate in these macronutrients and supplies 30% fat, 30% protein and 40% carbohydrate as total dietary calories. The Ketogenic Diet is based on getting the body into a state of ketosis (hence “keto”). Ketosis is a back-up metabolic system used to provide the brain with an energy source, called ketones, if glucose isn’t available or if blood levels fall too low. What’s the Buzz About? The popularity in the Ketogenic Diet stems from the quick weight loss it produces and its perceived health benefits. The diet is thought to increase the body’s ability to burn stored body fat and lower insulin levels. It’s important to note that the weight loss that stems from this diet isn’t necessarily fat loss, despite fat being the preferred/primary fuel on this eating plan. Weight Loss from the Ketogenic Is Not From Stored Body Fat In general, when we lose weight, it results from one of three factors: the loss of retained water, loss of muscle mass or loss of stored body fat. The ideal scenario would be to lose stored body fat. Ketogenic diets can promote an initial loss of retained water that comes with the depletion of glycogen (storage form of glucose). This is because stored glycogen retains significant levels of water. As the glycogen levels are reduced (due to limited carbohydrates in the diet), the retained water associated with that stored glycogen is also rapidly lost through increased urination. Although the loss of weight on a scale can be considerable in the first few days of a ketogenic diet, it will result in little loss of stored body fat. The loss of stored body fat only comes with significant calorie restriction as the body has many biological processes that help us to preserve it. Why You Don’t Lose Fat on the Ketogenic Diet Ketogenic diets are high in fat, which means the blood levels of fat will also be increased. As the availability of glucose in the blood decreases and the availability of fat increases, the metabolic flexibility (inherent in muscle cells) switches to using circulating fat as the preferred source of fuel for energy production (a.k.a. ATP), instead of glucose. This leads to the misconception that by getting into a state of ketosis you burn stored body fat. Instead, it is that the higher levels of dietary fat entering the blood stream are now becoming the preferred source of energy. Furthermore, a ketogenic diet being low in carbohydrates lowers insulin levels so less of that circulating fat can be stored in adipose tissue for long-term storage. Protein can also increase insulin levels resulting in circulating fat being transported into the adipose tissue for storage. This is why eating a high-fat diet containing excess calories, but with adequate levels of protein would not result in any fat loss, even though the carbohydrate content of such a diet can be very low. Hormonal and Physiological Changes that Take Place on Long-term Ketogenic Diets What is known from clinical studies is that significant hormonal changes take place on ketogenic diets and it’s not necessarily for the better. Here is a snap shot of the hormones impacted when following the diet long-term. Hormonal Changes Insulin1 Thyroid 2 Cortisol 2 Testosterone 3,4 Physiological Changes Immune Function 5 Mental and Physical Fatigue Due to Low Blood Sugar 6 Gut Dysbiosis 7,8 Since the ketogenic diet is limited in carbohydrates, it will not supply enough fermentable fiber for gut health. This lack of fermentable fiber will reduce the production of short-chain fatty acids (SCFA) that are required for maintaining the integrity of the mucus barrier and tight junction of the mucosa as well as increasing the production of T-regulatory cells. The end result is a greater likelihood of metabolic endotoxemia which can lead to weight regain. Loss of Muscle Mass 9 Stimulation of protein synthesis requires the combination of insulin (to drive amino acids into the muscle cell) and testosterone (to activate the receptors that signal for the stimulation of new muscle formation. Both hormones are decreased in ketogenic diets thus making it difficult to maintain muscle mass. Why the Zone Diet Is Preferable to the Ketogenic Diet A few years back, we set out to test how the Zone Diet compared to a Ketogenic Diet. This study kept both the protein and total calorie intake constant between a ketogenic diet and the non-ketogenic Zone Diet10. It controlled the diet for the first six weeks by supplying all the food to the subjects. These were calorie restricted diets (1,500 calories per day) to ensure that there was a sufficient calorie deficit to determine the effect of the two diets on loss of stored body fat, which can be only be achieved if a calorie deficient is maintained for long enough period of time. In the first three weeks of the study, the weight loss of the non-ketogenic Zone Diet and the ketogenic were essentially the same. However, in the second three-week period, the weight loss on the non-ketogenic Zone diet was greater than compared to the ketogenic diet. The same was true for fat loss. Even though it was a calorie restricted diet, there was no change in the fat-free (i.e. muscle mass) mass of either group during the six-week period indicating that the protein intake (which was equal in both diets) was sufficient to spare the loss of muscle mass. The AA/EPA ratio in the blood is indicative of inflammation. On the ketogenic diet, this inflammatory marker doubled during the six-week period of the study, whereas there was slight lowering on the non-ketogenic Zone Diet. Furthermore, mental state and exercise capacity of the subjects following the non-ketogenic Zone Diet improved during the study when compared to the subjects following the ketogenic diet. This study presented evidence that there were no advantages of a ketogenic diet compared to one with equal protein, calories, and higher carbohydrate and lower fat content such as the Zone Diet. In addition, the study suggested that a ketogenic diet significantly increases inflammation in a relatively short period of time compared to non-ketogenic Zone Diet. Summary Although initial weight loss (but not necessarily fat loss) on a ketogenic diet may be higher compared to a non-ketogenic diet, there are no long-term differences in overall weight loss. This may be due to the changes in hormonal responses induced by a ketogenic diet. Furthermore, the hormonal and inflammatory changes induced by a ketogenic diet may have significant adverse health consequences as suggested in epidemiological studies. Fat loss is only achieved by calorie restriction and can be maintained only if the diet used is one that is without hunger or fatigue so that the fat loss can be maintained for a lifetime. This can be achieved by a calorie-restricted diet that is adequate in protein to prevent the loss of lean muscle mass, supplies adequate levels of carbohydrates to reduce the generation of ketone bodies and promote gut health, maintains adequate levels of blood glucose for the brain, and finally contains a low level of dietary fat to encourage the use of stored fat for energy by the rest of the body. That’s the promise of the Zone Diet.{{cta('cd305230-6e34-42f6-9e2c-c2beda556f50')}}References: Foster GD, Wyatt HR, Hill JO, Makris AP, Rosenbaum DL, Brill C, Stein RI, Mohammed BS, Miller B, Rader DJ, Zemel B, Wadden TA, Tenhave T, Newcomb CW, and Klein S. “Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial.” Ann Intern Med 2010 153:147-57 Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, and Ludwig DS. “Effects of dietary composition on energy expenditure during weight-loss maintenance.” JAMA 2012 307:2627-2634 Anderson KE, Rosner W, Khan MS, New MI, Pang SY, Wissel PS, and Kappas A. “Diet-hormone interactions: protein/carbohydrate ratio alters reciprocally the plasma levels of testosterone and cortisol and their respective binding globulins in man.” Life Sci. 1987 40:1761-1788. Lane AR, Duke JW, and Hackney AC. “Influence of dietary carbohydrate intake on the free testosterone: cortisol ratio responses to short-term intensive exercise training.” Eur J Appl Physiol 2010 108:1125-1131. Sephton SE, Dhabhar FS, Keuroghlian AS, Giese-Davis J, McEwen BS, Ionan AC, and Spiegel D. “Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer.” Brain Behav Immun 2009 23:1148-1155. 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. Duncan SH, Belenguer A, Holtrop G, Johnstone AM, Flint HJ, and Lobley GE. “Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces.” Appl Environ Microbiol 2007 73:1073-1078. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, and Burcelin R. “Metabolic endotoxemia initiates obesity and insulin resistance.” Diabetes. 2007 56:1761-1772. Fujita S, Rasmussen BB, Cadenas JG, Grady JJ, and Volpi E. “Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability.” Am J Physiol Endocrinol Metab 2006 291: E745–E754. 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.
What is Cellular Inflammation?
People (including virtually all physicians) are constantly confused what cellular inflammation is. So I decided to take the opportunity to explain the concept in more detail. There are two types of inflammation. The first type is classical inflammation, which generates the inflammatory response we associate with pain such as, heat, redness, swelling, pain, and eventually loss of organ function. The other type is cellular inflammation, which is below the perception of pain. Cellular inflammation is the initiating cause of chronic disease because it disrupts hormonal signaling networks throughout the body. Definition of Cellular Inflammation The definition of cellular inflammation is increased activity of the gene transcription factor know as Nuclear Factor-kappaB (NF-κB). This is the gene transcription factor found in every cell, and it activates the inflammatory response of the innate immune system. Although the innate immune system is the most primitive part of our immune response, it has been resistant to study without recent breakthroughs in molecular biology. In fact, the 2011 Nobel Prize in Medicine was awarded for the earliest studies on the innate immune system and its implications in the development of chronic disease. There are several extracellular events through which NF-κB can be activated by distinct mechanisms. These include microbial invasion recognized by toll-like receptors (TLR), generation of reactive oxygen species (ROS), cellular generation of inflammatory eicosanoids, and interaction with inflammatory cytokines via defined cell surface receptors. We also know that several of these initiating events are modulated by dietary factors. This also means that appropriate use of the diet can either turn on or turn off the activation of NF-κB. This new knowledge is the foundation of anti-inflammatory nutrition (1-3). Understanding Cellular Inflammation Although the innate immune system is exceptionally complex, it can be illustrated in a relatively simple diagram as shown below in Figure 1. Figure 1. Simplified View of the Innate Immune System Essential fatty acids are the most powerful modulators of NF-κB. In particular, the omega-6 fatty acid arachidonic acid (AA) activates NF-κB, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) does not (4). Recent work suggests that a subgroup of eicosanoids known as leukotrienes that are derived from AA may play a significant factor in NF-κB activation (5,6) Extracellular inflammatory cytokines can also activate NF-κB by their interaction with specific receptors on the cell surface. The primary cytokine that activates NF-κB is tumor necrosis factor (TNF) (7). Toll-like receptors (TLR) are another starting point for the activation of NF-κB. In particular, TLR-4 is sensitive to dietary saturated fatty acids (8). The binding of saturated fatty acids to TLR-4 can be inhibited by omega-3 fatty acids such as EPA. Finally ROS either induced by ionizing radiation or by excess free radical formation are additional activators of NF-κB (9). Anti-inflammatory Nutrition To Inhibit Cellular Inflammation Anti-inflammatory nutrition is based on the ability of certain nutrients to reduce the activation of NF-κB. The most effective way to lower the activation of NF-κB is to reduce the levels of AA in the target cell membrane thus reducing the formation of leukotrienes that can activate NF-κB. Having the patient follow an anti-inflammatory diet, such as the Zone Diet coupled with the simultaneous lowering omega-6 fatty acid intake are the primary dietary strategies to accomplish this goal (1-3). Another effective dietary approach (and often easier for the patient to comply with) is the dietary supplementation with adequate levels of high-dose fish oil rich in omega-3 fatty acids, such as EPA and DHA. These omega-3 fatty acids taken at high enough levels will lower AA levels and increase EPA levels. This change of the AA/EPA ratio in the cell membrane will reduce the likelihood of the formation of inflammatory leukotrienes that can activate NF-κB. This is because leukotrienes derived from AA are pro-inflammatory, whereas those from EPA are non-inflammatory. The increased intake of omega-3 fatty acids is also a dietary approach that can activate the anti-inflammatory gene transcription factor PPAR-γ (10-12), decrease the formation of ROS (13) and decrease the binding of saturated fatty acids to TLR-4 (14). This illustrates the multi-functional roles that omega-3 fatty acids have in controlling cellular inflammation. A third dietary approach is the adequate intake of dietary polyphenols. These are compounds that give fruits and vegetables their color. At high levels they are powerful anti-oxidants to reduce the generation of ROS (15). They can also inhibit the activation of NF-κB (16). Finally, the least effective dietary strategy (but still useful) is the reduction of dietary saturated fat intake. This is because saturated fatty acids will cause the activation of the TLR-4 receptor in the cell membrane (8,14). Obviously, the greater the number of these dietary strategies implemented by the patient, the greater the overall effect on reducing cellular inflammation. Clinical Measurement of Cellular Inflammation Since cellular inflammation is confined to the cell itself, there are few blood markers that can be used to directly measure the levels of systemic cellular inflammation in a cell. However, the AA/EPA ratio in the blood appears to be a precise and reproducible marker of the levels of the same ratio of these essential fatty acids in the cell membrane. As described above, the leukotrienes derived from AA are powerful modulators of NF-κB. Thus a reduction in the AA/EPA ratio in the target cell membrane will lead to a reduced activation of NF-κB by decreased formation of inflammatory leukotrienes. The cell membrane is constantly being supplied by AA and EPA from the blood. Therefore the AA/EPA ratio in the blood becomes an excellent marker of the same ratio in the cell membrane (17). Currently the best and most reproducible marker of cellular inflammation is the AA/EPA ratio in the blood as it represents an upstream control point for the control of NF-κB activation. The most commonly used diagnostic marker of inflammation is C-reactive protein (CRP). Unlike the AA/EPA ratio, CRP is a very distant downstream marker of past NF-κB activation. This is because one of inflammatory mediators expressed in the target cell is IL-6. It must eventually reach a high enough level in the blood to eventually interact with the liver or the fat cells to produce CRP. This makes CRP a more long-lived marker in the blood stream compared to the primary inflammatory gene products (IL-1, IL-6, TNF, and COX-2) released after the activation of NF-κB. As a consequence, CRP is easier to measure than the most immediate inflammatory products generated by NF-κB activation. However, easier doesn’t necessarily translate into better. In fact, an increase AA/EPA ratio in the target cell membrane often precedes any increase of C-reactive protein by several years. An elevated AA/EPA ratio indicates that NF-κB is at the tipping point and the cell is primed for increased genetic expression of a wide variety of inflammatory mediators. The measurement of CRP indicates that NF-κB has been activated for a considerable period of time and that cellular inflammation is now causing systemic damage. In Summary I believe the future of medicine lies in the control of cellular inflammation. This is most effectively accomplished by the constant application of anti-inflammatory nutrition. The success of such dietary interventions can be measured clinically by the reduction of the AA/EPA ratio in the blood. {{cta('4f5c5df9-024e-4218-ab5e-8490f8243f6f')}} References: Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005). Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008). Sears B and Riccordi C. “Anti-inflammatory nutrition as a pharmacological approach to treat obesity.” J Obesity doi:10.1155/2011/431985 (2011). Camandola S, Leonarduzzi G,Musso T, Varesio L, Carini R, Scavazza A, Chiarpotto E, Baeuerle PA, and Poli G. “Nuclear factor kB is activated by arachidonic acid but not by eicosapentaenoic acid.” Biochem Biophys Res Commun 229:643-647 (1996). Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, and Miller YI. “12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice.” PLoS One 4:e7250 (2009). Chakrabarti SK, Cole BK, Wen Y, Keller SR, and Nadler JL. “12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes.” Obesity 17:1657-1663 (2009). Min JK, Kim YM, Kim SW, Kwon MC, Kong YY, Hwang IK, Won MH, Rho J, and Kwon YG. “TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells.” J Immunol 175: 531-540 (2005). Kim JJ and Sears DD. “TLR4 and Insulin Resistance.” Gastroenterol Res Pract doi:10./2010/212563 (2010). Bubici C, Papa S, Dean K, and Franzoso G. “Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance.” Oncogene 25: 6731-6748 (2006). Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, and Varghese Z. “EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-gamma-dependent mechanism.” Kidney Int 67: 867-874 (2005). Kawashima A, Harada T, Imada K, Yano T, and Mizuguchi K. “Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma.” Prostaglandins LeukotEssent Fatty Acids 79: 59-65 (2008). Chambrier C, Bastard JP, Rieusset J, Chevillotte E, Bonnefont-Rousselot D, Therond P, Hainque B, Riou JP, Laville M, and Vidal H. “Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor gamma.” Obes Res 10: 518-525 (2002). Mas E, Woodman RJ, Burke V, Puddey IB, Beilin LJ, Durand T, and Mori TA. “The omega-3 fatty acids EPA and DHA decrease plasma F(2)-isoprostanes.” Free Radic Res 44: 983-990 (2010). Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, and Hwang DH. “Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids.” J Lipid Res 44: 479-486 (2003). Crispo JA, Ansell DR, Piche M, Eibl JK, Khaper N, Ross GM, and Tai TC. “Protective effects of polyphenolic compounds on oxidative stress-induced cytotoxicity in PC12 cells.” Can J Physiol Pharmacol 88: 429-438 (2010). Romier B, Van De Walle J, During A, Larondelle Y, and Schneider YJ. “Modulation of signaling nuclear factor-kappaB activation pathway by polyphenols in human intestinal Caco-2 cells.” Br J Nutr 100: 542-551 (2008). Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, and Clinton SK. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91: 1185-1194 (2010).
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