Practical hints for helping to manage brain trauma

Since the recent story on CNN (“He’s going to be better than he was before,” Jan. 18, 2014,) about the extraordinary recovery of Grant Virgin from severe brain trauma, I have gotten a lot of requests for information. Since I have been doing this protocol for more than seven years after first working with Dr. Julian Bailes on the equally remarkable recovery of Randal McCloy Jr. (the sole survivor of the Sago mine disaster in 2006) and others (1,2), I can offer some broad guidelines. Make no mistake, each case is different, but these guidelines will considerably help your decision-making process.

What Type of Fish Oil to Use

Purity

When is comes to treating brain trauma, purity and potency of the omega-3 product count. All fish and all fish-oil products are contaminated with various toxins. The most important is polychlorinated biphenyls or PCBs. These are known neurotoxins. It makes little sense giving someone a fish-oil product that is rich in PCBs. One of the dirty secrets of the fish-oil manufacturing industry is that it is extremely difficult to remove PCBs from a final product. In fact, it is so difficult, the industry tries to ignore it. Making a statement that a fish-oil product is free from PCBs is an outright lie. It is equally ridiculous to state that the PCBs levels in its products are lower than the international standards. Those international PCB standards (90 parts per billion or ppb) are so lax that virtually any fish-oil product in the supermarket is going to exceed them. Of course, if you want to heal the brain, then I would recommend looking for the purest fish oil you can find. If you are even considering using fish oil, make sure that the levels of total PCBs are less than 5 ppb. This is 18 times lower than the international standard. Using this more rigorous criterion of purity, your choices become very limited. Furthermore, PCB levels will vary from lot to lot. So you want to make sure that the lot you are actually using contains less than 5 ppb. Go to the product’s website or call the manufacturer. If the manufacturers can’t supply that data, it means they don’t know. If they said it is pure, then they mean it might pass the very lax international standards. Here’s a good rule about fish oils: Trust but always verify. PCB testing is expensive but so is saving a brain. Of course, if you don’t care about potential PCB accumulation in the brain, then use the cheapest fish-oil product you can find.

Potency

You are going to have to use a lot of fish oil to put out the inflammation in the brain and to rebuild it. Therefore, the potency of the fish oil counts. I would never recommend any fish-oil product containing any less than 60% EPA and DHA. Usually the higher the potency of the fish oil, the higher the purity, but not always. Removal of PCBs is very different than increasing omega-3 fatty acid potency. I have tested many high-potency fish oils that also have high PCB levels. Likewise, the omega-3 fatty acids levels will vary from lot to lot. Before you use any omega-3 fatty-acid product, ask for the potency of that particular lot. If company representatives can’t provide it or say it meets their standards, then it means they don’t really know.

The fish oil needs to contain both EPA and DHA. EPA puts out the inflammation in the brain, and DHA helps rebuild the brain. You need both. I usually recommend a 2:1 ratio of EPA to DHA as that is the ratio I have used for several years with great success.

Omega-3 fatty acids are prone to oxidation, which leads to rancidity. The rancidity comes from breakdown products of the fatty acids into aldehydes and ketones that can cause damage to the DNA. That’s why there is an international rancidity standard (called total oxidation or TOTOX) that governs all edible oil trading in the world. Before you use any fish oil product, ask for the TOTOX levels of the finished product (not the raw materials). If it is less than 26 meq/kg (the upper limit for an edible oil), then it is OK to use. If not, don’t even consider it.

Amounts

Even if you if you have a high-quality fish-oil product, you are going to need a lot for brain injuries. This will usually be in the range of 10-15 grams of EPA and DHA per day. That’s why you need the high-purity and high-potency fish oil. Because of the high amounts, it will have to be given in a liquid format. Why the high doses? Because you have to put out the fire in the brain before you can rebuild it.

The levels of fish oil needed are based on testing, not guessing. The best test for the levels of fish oil required is the ratio of two fatty acids in the blood. One is arachidonic acid (AA), and the other is EPA. Why this is important is because AA causes inflammation, and EPA reverses inflammation. You measure the levels of AA and EPA using a simple finger-stick blood test. The AA/EPA ratio is not a standard clinical test, but it has been in medical research for nearly 30 years, starting first at Harvard Medical School (3). The AA/EPA ratio will tell you how much a pure fish oil product you need as you want the AA/EPA ratio to be in the range of 1.5 to 3. If the AA/EPA ratio is higher than 3, you will need more fish oil. If AA/EPA is less than 1.5, you will need less fish oil. Maintaining the AA/EPA between 1.5 and 3 addresses the largest concern of using high-dose fish oil, which is potential bleeding. I chose an AA/EPA ratio of 1.5 as my lower limit since that is what it is in the Japanese population, and they don’t bleed to death (4-11).

The most inexpensive test for the AA/EPA ratio can be found at www.zonediagnostics.com.

Why drugs don’t work, and fish oil does

With severe brain trauma, the usual response of the physician is “we just have to wait”. The reason why is because there are no drugs that can cross the blood-brain barrier to put out the inflammation in the brain. That is not true with omega-3 fatty acids. They can easily enter the brain if there are high enough levels in the blood. What is the correct level in the blood? The AA/EPA ratio will tell you. Not only should the AA/EPA ratio be between 1.5 and 3, but also the EPA levels should be greater than 4% of the total fatty acids in the blood.

What Else?

When using high levels of fish oil even if it is pure and potent, you still have to emulsify it to reduce the size of oil droplets for better absorption. One of the best methods to emulsify liquid fish oil is to mix it with either a seaweed or an aloe vera product to reduce the size of the oil droplets to increase the absorption into the blood.

You also have to provide extra anti-oxidant protection to protect the omega-3 fatty acids from oxidation. The best way is using polyphenols to be mixed with the fish oil before administration. Adding extra virgin olive oil is a good choice. Adding highly purified polyphenol extracts to the liquid fish oil is a better choice.

What to expect

Each case is different. Based on my experience if you are using the correct amount of omega-3 fatty acids, you should see the beginnings of a response within 60 days. In Grant’s case, it was two days. If you do, then continue the same level of fish oil since putting out the inflammatory fire is only the first step of the process. The next step is rebuilding the brain. I would suggest monitoring the AA/EPA ratio every 30 days for the first 60 days and then every 60 days thereafter to make sure you are giving the right amount of fish oil.

Most importantly, this is not a Mr. Wizard home experiment. You should always be working with your physicians, not against them. They will also need education in the use and safety of high-dose fish oil, but this short summary is a good start.

Don’t expect any reimbursement from your insurance company for the use of the fish oil or AA/EPA testing. It may seem expensive, but compared to the human suffering of not trying to rebuild the brain, the costs of both the fish oil and AA/EPA testing are minor. I would also consider using flexible- spending health-care accounts if you have access to them to lower the overall cost, since they are based on pre-tax income.

Taking fish oil and following an anti-inflammatory diet is key

One of the reasons for Grant Virgin’s rapid progress was the fact that he was already taking moderate doses of fish oil for a medical condition. This meant he already had some reserve capacity in the body and the brain to reduce the inflammatory burden caused by a hit-and-run accident. You never know when brain trauma will occur. Maintaining a relatively low AA/EPA ratio in the blood is your best insurance policy for protection against future brain trauma if it does strike. You don’t have to be as aggressive as in the treatment phase, but aim for keeping the AA/EPA ratio between 5 and 10 in the blood. For comparison, the average American has an AA/EPA ratio of 20 (12). When dealing with brain trauma, an ounce of prevention is worth pounds of cure.

Finally, to accelerate the healing and rebuilding of the brain, you want to be following an anti-inflammatory diet (13-15). An anti-inflammatory diet is one that reduces the production of AA that drives inflammation in the brain. The less AA you have in the blood, the less AA gets into the brain. Try to keep the AA level in the blood to less than 9% of the total fatty acids. This takes more work than simply giving fish oil, but the more you reduce the levels of AA in the blood, the less high-dose fish you will need to maintain the AA/EPA ratio required to accelerate the healing and rebuilding process in the brain.

References

  1. Roberts L, Bailes J, Dedhia H, Zikos A, Singh A, McDowell D, Failinger C, Biundo R, Petrick J, and Carpenter J. “Surviving a mine explosion.” J Am Coll Surg 207:276-283 (2008)
  2. Sears B, Bailes J, and Asselin B. “Therapeutic use of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury.” PhamaNutrition 1: 86-89 (2013)
  3. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaefer 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 320:265-271 (1989)
  4. Swails WS, Bell SJ, Bistrian BR, Lewis EJ, Pfister D, Forse RA, Kelly S, Blackburn GL. “Fish-oil-containing diet and platelet aggregation.” Nutrition 9:211-217 (1993)
  5. Parkinson AJ, Cruz AL, Heyward WL, Bulkow LR, Hall D, Barstaed L, and Connor WE. “Elevated concentrations of plasma omega-3 polyunsaturated fatty acids among Alaskan Eskimos”. Am J Clin Nutr 59:384-388 (1994)
  6. Eritsland J, Arnesen H, Seljeflot I, andKierulf P. “Long-term effects of n-3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease.” Blood Coagul Fibrinolysis 6:17-22 (1995)
  7. Watson PD, Joy PS, Nkonde C, Hessen SE, and Karalis DG.
    Comparison of bleeding complications with omega-3 fatty acids + aspirin + clopidogrel–versus–aspirin + clopidogrel in patients with cardiovascular disease. Am J Cardiol 104:1052-1054 (2009)
  8. Salisbury AC, Harris WS, Amin AP, Reid KJ, O’Keefe JH, and Spertus JA.
    “Relation between red blood cell omega-3 fatty acid index and bleeding during acute myocardial infarction.” Am J Cardiol 109:13-18 (2012)
  9. Larson MK, Ashmore JH, Harris KA, Vogelaar JL, Pottala JV, Sprehe M, and Harris WS. “Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects.” Thromb Haemost 100:634-641 (2008)
  10. Harris WS. “Expert opinion: omega-3 fatty acids and bleeding-cause for concern?” Am J Cardiol 99:44C-46C (2007)
  11. 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)
  12. Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, and McConnell JP. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257-263 (2013)
  13. Sears B. The Zone. Regan Books. New York, NY (1995)
  14. Sears B. The OmegaRx Zone. Regan Books. New York, NY (2002)
  15. Sears B. The Anti-inflammation Zone. Regan Books. New York, NY (2005)

Omega-3 fatty acids and prostate cancer? Oh, really?

There was a recent publication suggesting that higher levels of omega-3 fatty acids are associated with a greater risk of prostate cancer 1. Of course, the immediate media response was to indicate that taking fish oil supplements is dangerous. Of course, let’s not forget, then, that eating fish must also be dangerous.

Before letting the media focus on sound bites, a realistic first step might be to analyze the data and use some common sense to see if it justifies the headlines.

Everyone in the cancer field agrees that inflammation drives cancers. I believe the best marker for inflammation is the AA/EPA ratio as I have outlined in my various books for more than a decade. The reason is simple: As the AA/EPA ratio decreases, you make fewer inflammatory hormones (i.e. eicosanoids coming from AA) and more anti-inflammatory hormones (i.e. resolvins coming from EPA). Bottom line, this means less inflammation in the body. So let’s look at the fatty acid data as percent of the total fatty acids that was presented in this article that were associated with no development of prostate cancer, total prostate cancer incidence, and breaking of the total cancer group into either low-grade or high-grade cancer 1.

Non-cancer Cancer Low-grade cancer High-grade cancer
EPA 0.6% 0.7% 0.7% 0.7%
AA 11.4% 11.2%   11.2%   11.3%  
AA/EPA 19 16 16 16

Having decades of experience of doing fatty acid analyses, I can tell that these numbers are clinically insignificant. What does that mean? The numbers are basically the same. They might be statistically significant, but the differences definitely are not clinically relevant.

I have been very consistent over the years in stating that to have an impact on reducing inflammation, you have to have EPA levels greater than 4% of the total fatty acids, AA levels less than 9% of the total fatty acids and an AA/EPA ratio between 1.5 and 3. As you can see, the subjects in this article were nowhere close to those parameters. In fact, I would say all the subjects in this trial were identical relative to AA, EPA and the AA/EPA ratio. In other words, the analysis is meaningless.

Is there any population in the world that may have the ranges that I recommend? The answer is the Japanese population. Their levels of EPA are about 3% of total fatty acids, and they have an AA/EPA ratio of about 1.6 2. The JELIS study was a long-term study (3 ½ years) of 18,000 Japanese with high cholesterol levels given extra omega-3 fatty acids to lower their AA/EPA an even lower ratio. With this lower AA/EPA ratio (now 0.8), their cardiovascular events were reduced by 20% with no increase in any type of cancer. Likewise, high levels of omega-3 fatty acids have been used as prescription drugs for the treatment of elevated triglyceride levels with absolutely no reports of any increase in any type of cancer.

This is where common sense hopefully comes into play. If the conclusion of the article was correct that higher levels of omega-3 fatty acids increase prostate cancer, then the Japanese male population should be decimated with prostate cancer. So what are the facts? The Japanese have one of lowest rates of prostate cancer incidence in the world. In fact, their rate of prostate cancer incidence is 10 times lower than the United States 3. More importantly, the mortality from prostate cancer is also about 5 times less in Japan than in the United States 4. I emphasize the word mortality since prostate cancer is usually very slow growing so that males usually die with prostate cancer, not because of it. This is why the recent recommendation is to dramatically reduce the screening for prostate cancer because the harm of treatment usually outweighs the benefits of detection.

Common sense (and a little understanding of the biochemistry of inflammation) says that if you reduce inflammation (determined by your AA/EPA ratio), then your likelihood of living longer is greatly increased. The best way to reduce AA is to follow a strict Zone Diet. The best way to increase EPA is to take adequate levels of purified omega-3 fatty acids rich in EPA. It is obvious the subjects of this study were doing neither.

References

  1. Brasky TM, Darke AK, Song X, Tangen CM, Goodma PJ, Thompson IM, Meyskens FL, Goodman GE, Minasian LM, Parnes HL, Klein EA, and Kristal AR. “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial.” J Nat Cancer Inst DOIL10.109393 (2013)
  2. 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 367:1090-1098 (2007)
  3. Haas GP, Delongchamps N, Brawley OW, Wang CY, and de la Roza G. “The worldwide epidemiology of prostate cancer: perspectives from autopsy studies.” Can J Urol 15: 3866-3871 (2008)
  4. Marugame T and Mizuno S. “Comparison of Prostate Cancer Mortality in Five Countries: France, Italy, Japan, UK and USA from the WHO Mortality Database (1960–2000).” Jpn J Clin Oncol 35: 690–691 (2005)

Good Diet, Bad Study

As the creator of the Zone Diet, I am a strong believer in the Mediterranean diet as a lifetime dietary program for good health. In fact, the Zone Diet can be considered to be the evolution of the Mediterranean diet as it provides even greater anti-inflammatory benefits. That being said, this week’s New England Journal of Medicine contained an article on using the Mediterranean diet with high-risk cardiovascular patients that got great press based on some really poor science1. Let’s get to the bad science first.

The researchers compared two “Mediterranean” diets (one with extra nuts and the other with extra olive oil) to a low-fat diet. Unfortunately, they were unable to get the subjects to follow a low-fat diet. If you are a follower of Dean Ornish, then a low-fat diet means less than 10% of your calories coming from fat. Using that definition of a low-fat diet, you have to throw out one-third of the subjects because they couldn’t reduce their fat intake below 37% of total calories. In fact, at the end of this five-year study, the percentages of protein, carbohydrate, and fat in the diets of all three groups were approximately the same. As a result, you are left with a study with two groups of subjects being compared to another group of subjects who really didn’t change their diet that much.

Even Dean Ornish pointed this out in his rebuttal blog in the Huffington Post to this study2. He wrote that if people had followed his low-fat diet, then the results would have been much different. Well, actually when high-risk cardiovascular patients did follow his diet in a study done 15 years ago, those on his low-fat diet had twice the deaths compared to those in the control group3. So maybe it’s a good thing that the low-fat group couldn’t follow the prescribed low-fat diet.

The reason for adverse effects of a low-fat, low-protein, very high-carbohydrate diet for cardiovascular patients is quite clear. Those subjects following his high-carbohydrate, low-fat, and low-protein diet developed insulin resistance as evidenced by a significant increase in their triglyceride-to-HDL ratio3. If you already have had a heart attack, then an increase in insulin resistance and the accompanying increase in inflammation are almost certain to push you over the edge.

If you really dig deeper into the supplemental material (Table S7 to be exact) of this article (as most journalists neglected to do), you are remarkably unimpressed by the changes in the diet over a five-year period except that the people who got free olive oil and free nuts were consuming more free olive oil and free nuts than those who were not getting free food.

Now, back to the clinical results — a strange brew of stroke, heart attack, and death. Usually when you include a lot of different clinical end points as your primary goal, it means you are not very confident about seeing any real striking clinical benefit. Stroke is primarily associated with high blood pressure, whereas heart attack is associated with the rupture of small vulnerable plaques leading to blockage of the coronary arteries. I personally like death as a clinical end point since you can’t cheat on its definition, thus making it harder to manipulate your statistics to prove your point.

So let’s look at the individual clinical endpoints. There was a reduction in strokes that was statistically significant. Unfortunately, there was no statistically significant reduction in either heart attacks or death. For such a large study, these clinical results are not too impressive. Maybe if the researchers had actually gotten the low-fat group to reduce their fat intake to less than 10% of calories (instead of going from 39% to 37% of calories), there might have been more deaths in that group, which would have made the other two Mediterranean diet groups look better.

Virtually every cardiovascular researcher knows that fatty acid composition of the plasma is an important factor in the prediction of future cardiovascular events. Unfortunately, the authors of the New England Journal of Medicine article apparently didn’t think so. Obviously, they measured one fatty acid (alpha linolenic acid) in Figure 5S (again buried deep in the supplemental material), but somehow forgot to report the other 34 fatty acids also found in the plasma. Two of the most important of these unreported fatty acids would have included arachidonic acid (AA) and eicosapentaenoic (EPA). The AA/EPA ratio in the blood is the best marker of cellular inflammation that drives heart disease4. You would think inclusion of information on this ratio (or at least providing the fatty acid levels) would be important since a far larger JELIS study demonstrated that the lowering of the AA/EPA ratio resulted in a significant reduction of cardiovascular events5.

In contrast to this poorly executed study, there exists a far more powerful study conducted nearly 20 years ago on the benefits of a stricter Mediterranean diet. This is was the Lyon Diet Heart Study6. The primary clinical difference between this new study and older Lyon Diet Heart Study is that the Lyon Diet Heart Study generated a 65% reduction in overall cardiovascular mortality, a complete reduction in cardiac sudden death, and 44% reduction in all-cause mortality6,7. Those are clinical end points to get excited about. On the other hand, this New England Journal of Medicine article showed no impact on mortality. The only striking difference between the two groups in the Lyon Diet Heart Study was the restriction of omega-6 fatty acids in the experimental group. You find omega-6 fatty acids in vegetable oils like corn, safflower, and sunflower oils. They accomplished this dietary change by giving the subjects in the experimental groups margarines rich in omega-3 fats and trans fats. Although there was a dramatic decrease in death between the two groups in the Lyon Diet Heart Study, there were no differences in weight, BMI, blood pressure, cholesterol (good and bad), and blood lipids between the two groups. In other words, all the usual suspects in heart disease were eliminated. The only differences between the two groups were in the fatty acids, both linoleic acid and the AA/EPA ratio. If you again go back to bowels of the recent New England Journal article (in supplemental Table S7), you find out that the levels of linoleic acid (an omega-6 fatty acid) as analyzed from dietary records of the subjects was between 5 and 6% in both of the Mediterranean diets. In the Lyon Diet Heart Study, the investigators were able to reduce to the linoleic levels to 3.6%, which is similar to levels found in the Japanese (actually Okinawans), who have the lowest cardiovascular mortality in the developed world (8). The subjects in the control group of the Lyon Diet Heart Study had a nearly 50% higher level of linoleic acid in their blood compared to the experimental group8. However, those subjects following the “Mediterranean” diets in the new study had even higher levels of linoleic acid than those in the control group of the Lyon Diet Heart Study. That is the most likely reason there wasn’t any change in cardiovascular mortality or overall mortality in the New England Journal of Medicine study. Unlike this more “modern” study, the Lyon researchers further demonstrated that the AA/EPA ratio was reduced by some 30% (from 9 to 6.2) in the active group compared to the control group, and this resulted in a 65% reduction of cardiovascular death.

Bottom line, unless you dramatically reduce omega-6 intake by reducing your consumption of vegetable oils (such as corn, soy and safflower oils), you will not get clear-cut clinical results (like reduction in death) no matter how much hype the media give to the research.

As I said earlier, the Zone Diet can be considered to be the evolution of the Mediterranean diet because it represents a superior dietary program to control inflammation, the true underlying cause of heart disease. This is because the Zone Diet dramatically reduces white carbohydrates (pasta, bread, rice, and potatoes) and replaces them with increased amounts of colorful carbohydrates (vegetables and fruits). Unlike the New England Journal of Medicine article where the subjects were consuming about 5 servings a day of vegetables and fruits, the Zone Diet recommends 10 servings per day. Rather than keeping the linoleic acid content at 6% of the calories (the American Heart Association recommends 10-15%) or even at the 3.6% level as in the Lyon Diet Heart Study, the Zone Diet recommends fewer than 2% of total calories should consist of linoleic acid. Like the JELIS study, the Zone Diet recommends extra supplemental of omega-3 fatty acids to reduce the AA/EPA ratio to 1.5 or less.

Although the jury may still be out on the Mediterranean diet (especially after this poorly executed study) for the primary prevention of heart disease, the data from secondary prevention studies (5-7) strongly suggest that the Zone Diet may be the dietary approach you want to follow if reducing mortality is your personal clinical end point.

References

  1. Estuch R et al. “Primary prevention of cardiovascular disease with a Mediterranean diet.” N Engl J Med 368: doi10.1056/NEJMoa1200303 (2013)
  2. Ornish D. “Does a Mediterranean diet really beat a low-fat for health?” HuffPost Healthy Living Feb 25 (2013)
  3. Ornish D et al. “Intensive lifestyle changes for reversal of coronary heart disease.” JAMA 280: 2001-2007 (1998)
  4. Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005)
  5. Yokoyama M et al. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis.” Lancet 369: 1090-1098 (2007)
  6. de Lorgeril et al. “Mediterranean alpha-linolenic-rich diet in secondary prevention of coronary heart disease.” Lancet 343: 1454-1459 (1994)
  7. de Lorgeril et al. “Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction.” Circulation 99: 779-785 (1999)
  8. Kagawa Y et al. “Eicosapolyenoic acids of serum lipids of Japanese islanders with low incidence of cardiovascular disease.” J Nutr Sci Vitaminol 28: 441-453 (1982)

Put Statins in the Drinking Water? I Think Not.

Put Statins in the Drinking Water?  I Think Not.

It is amazing that only after the patent expiration of the best-selling statin drug of all time (i.e. Lipitor) that the FDA finally admitted that maybe the drug class that many physicians wanted to put into the drinking water might have some problems after all (1). In particular, the FDA issued a warning that use of statins increases the risk of memory loss and diabetes. The FDA said the risk of diabetes is “small;” however, they were playing fast and loose with the data. This is because the weaker the statin, the less the side-effect profile. The stronger (and better selling) the statin, the greater the side effects are (like diabetes and memory loss). You would think that after having Americans spend more than $50 billion in statin sales that the FDA would have asked these safety questions earlier.

How could statins cause memory loss and diabetes? It has been known for nearly 20 years that statins are the only drug that increase the levels of arachidonic acid (AA) by stimulating the enzyme delta 5-desaturase (2-4). This means greater cellular inflammation that leads to insulin resistance (thus increasing diabetes) and disturbances in signaling mechanisms in nerve cells (thus decreasing memory). I guarantee that no physician knows these facts because the drug companies had no reason to lose a potential sale to disclose that information. Apparently the FDA agreed with the drug companies, since that relevant information was never mentioned in any of the side-effect profiles until now.

The drug industry developed a great marketing pitch for statins: “If your cholesterol is high, you are going to die”. Unfortunately, the data never supported that spiffy slogan. Epidemiological studies do indicate that if your cholesterol levels are high and you are less than 50 years of age, then there is an increased risk for mortality. After age 50, that risk of increased mortality with high cholesterol disappears (5).

Furthermore, keep in mind that statins were not the first drugs to lower cholesterol. There were many other drugs before the statins, but they had the unfortunate side-effect of increasing mortality. It was only with use of the first statin drugs that decreased mortality was finally shown in those having had a prior heart attack. This is called secondary prevention trial. Aspirin and fish oil are also effective in secondary prevention trials, but neither of those interventions reduces cholesterol (6). However, in primary prevention trials (done with people with no history of heart attacks), statins aren’t very good. This is estimated by looking at a number known as “number needed to treat” or NNT. This number indicates how many people have to take a drug to prevent a single heart attack. With the newest statins, the NNT is usually 2 percent. That means you have to treat 100 people to prevent two heart attacks. Unfortunately you have no idea who those two people are, which means the other 98 people will have a lifetime of side effects. One of those side effects is developing diabetes, which occurs in about 1 percent of the patients (forget the other side effects, such as memory loss, muscle fatigue, etc). Who that one person is out of 100 who will develop diabetes is also unknown. Therefore your chances of reducing a heart attack are significantly cut by the likelihood of increasing your chances of developing diabetes. Some wonder drug!

Finally, defenders of statins for the primary prevention of heart disease point to the recent JUPITER trial (7). This clinical trial used people that had normal levels of LDL cholesterol, but very high levels of C-reactive protein (CRP). These people were already inflamed. It should be noted that the drug company that markets the statin drug used in the study funded this particular study. In fact, the government had no interest in the trial. Maybe government officials knew from previous statin trials that in people with normal LDL cholesterol levels and normal levels of CRP that statins had absolutely no benefit in reducing future heart attacks (8). Nonetheless in this small subsection of the population (more than 80 percent of the screened patients were rejected), there was a reduction in first-time heart attacks. But since the patients were highly inflamed to begin with, this means that aspirin or fish oil would probably have given the same result had the same population been tested (9,10). In fact, the JELIS study in Japan confirmed this hypothesis (11). Using the same number of patients, with high cholesterol and lows levels of inflammation (as measured by the AA/EPA ratio), it was demonstrated that those patients given more EPA to lower the AA/EPA ratio had significant reduction in future cardiovascular events. I will make a leap of faith that if the population in the JELIS study was as inflamed as that in the JUPITER study, the results with omega-3 fatty acids would have been even more dramatic.

Lost in all this marketing hype is what actually causes LDL cholesterol to increase in the first place. The answer was known in the 1970s. It’s high levels of insulin (12). This is because insulin activates the same enzyme that statins inhibit. Call me crazy, but it seems to make more sense to lower insulin by the diet rather than taking statins for a lifetime if your goal is to live longer. The best way to lower insulin is the anti-inflammatory Zone Diet coupled with enough fish oil to reduce the AA/EPA ratio to the in the Japanese population range. That’s just good science, not good marketing.

References

  1. Harris G. “Safety alerts cite cholesterol drugs’ side effects.” New York Times, Feb 28. (2012)
  2. Hrboticky N, Tang L, Zimmer B, Lux I, Weber PC. “Lovastatin increases arachidonic acid levels and stimulates thromboxane synthesis in human liver and monocytic cell lines. J Clin Invest 93: 195-203 (1994)
  3. Rise P, Pazzucconi F, Sirtori CR, and Galli C. “Statins enhance arachidonic acid synthesis in hypercholesterolemic patients.”
  4. Nutr Metab Cardiovasc Dis 11:88-94 (2001)
  5. Rise P, Ghezzi S, and Galli C. “Relative potencies of statins in reducing cholesterol synthesis and enhancing linoleic acid metabolism.” Eur J Pharmacol 467:73-75 (2003)
  6. Anderson KM, Castelli WP, and Levy D. “Cholesterol and mortality. 30 years of follow-up from the Framingham study.” JAMA 1987 257:2176-2180 (1987)
  7. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, and Zanchetti A. “Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.” Lancet 373:1849-1860 (2009)
  8. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. “Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.” Lancet 354:447-455 (1999)
  9. Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, and Lau J. “n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.” Am J Clin Nutr 84:5-17 (2006)
  10. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, and Glynn RJ. “Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.” N Engl J Med 359:2195-2207 (2008)
  11. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, and Gotto AM. “Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.” N Engl J Med 344:1959-1965 (2001)
  12. 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)
  13. Lakshmanan MR, Nepokroeff CM, Ness GC, Dugan RE, and; Porter JW. “Stimulation by insulin of rat liver hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activities.” Biochem Biophys Res Commun 50:704-710 (1973)

What are the real differences between EPA and DHA?

The first casualty of marketing is usually the truth. The reality is that the two key omega-3 fatty acids (EPA and DHA) do a lot of different things, and as a result the benefits of EPA and DHA are often very different. That’s why you need them both. But as to why, let me go into more detail.

Benefits of EPA

The ultimate goal of using omega-3 fatty acids is the reduction of cellular inflammation. Since eicosanoids derived from arachidonic acid (AA), an omega-6 fatty acid, are the primary mediators of cellular inflammation, EPA is the most important of the omega-3 fatty acids to reduce cellular inflammation for a number of reasons. First, EPA is an inhibitor of the enzyme delta-5-desaturase (D5D) that produces AA (1). The more EPA you have in the diet, the less AA you produce. This essentially chokes off the supply of AA necessary for the production of pro-inflammatory eicosanoids (prostaglandins, thromboxanes, leukotrienes, etc.)

DHA is not an inhibitor of this enzyme because it can’t fit into the active catalytic site of the enzyme due to its larger spatial size. As an additional insurance policy, EPA also competes with AA for the enzyme phospholipase A2 necessary to release AA from the membrane phospholipids (where it is stored). Inhibition of this enzyme is the mechanism of action used by corticosteroids. If you have adequate levels of EPA to compete with AA (i.e. a low AA/EPA ratio), you can realize many of the benefits of corticosteroids but without their side effects. That’s because if you don’t release AA from the cell membrane, you can’t make inflammatory eicosanoids. Because of its increased spatial dimensions, DHA is not a good competitor of phospholipase A2 relative to EPA. On the other hand, EPA and AA are very similar spatially so they are in constant competition for the phospholipase A2 enzyme, just as both fatty acids are in constant competition for the delta-5 desaturase enzyme. This is why measuring the AA/EPA ratio is such a powerful predictor of the state of cellular inflammation in your body.

The various enzymes (COX and LOX) that make inflammatory eicosanoids can accommodate both AA and EPA, but again due to the greater spatial size of DHA, these enzymes will have difficulty-converting DHA into eicosanoids. This makes DHA a poor substrate for these key inflammatory enzymes. Thus DHA again has little effect on cellular inflammation, whereas EPA can have a powerful impact.

Finally, it is often assumed since there are not high levels of EPA in the brain, that it is not important for neurological function. Actually, it is key for reducing neuro-inflammation by competing against AA for access to the same enzymes needed to produce inflammatory eicosanoids. However, once EPA enters into the brain, it is rapidly oxidized (2,3). This is not the case with DHA (4). The only way to control cellular inflammation in the brain is to maintain high levels of EPA in the blood. This is why all the work on depression, ADHD, brain trauma, etc., has demonstrated that EPA is superior to DHA (5).

Benefits of DHA

At this point, you might think that DHA is useless. Just the opposite, because DHA can do a lot of different things than EPA and some of them even better.

First is in the area of omega-6 fatty acid metabolism. Whereas EPA is the inhibitor of the enzyme (D5D) that directly produces AA, DHA is an inhibitor of another key enzyme, delta-6-desaturase (D6D), that produces the first metabolite from linoleic acid known as gamma linolenic acid or GLA (6). However, this is not exactly an advantage. Even though reduction of GLA will eventually decrease AA production, it also has the more immediate effect of reducing the production of the next metabolite known as dihomo gamma linolenic acid or DGLA. This can be a disaster as a great number of powerful anti-inflammatory eicosanoids are derived from DGLA. This is why if you use high-dose DHA, it is essential to add back trace amounts of GLA to maintain sufficient levels of DGLA to continue to make anti-inflammatory eicosanoids.

In my opinion, the key benefit of DHA lies in its unique spatial characteristics. As mentioned earlier, the extra double bonds and length of DHA compared to EPA means it takes up a lot more space in the membrane. Although this increase in spatial volume makes DHA a poor substrate for phospholipase A2 as well as the COX and LOX enzymes, it does a great job of making membranes (especially those in the brain) a lot more fluid as the DHA sweeps out a much greater volume in the membrane than EPA. This increase in membrane fluidity is critical for synaptic vesicles and the retina of the eye because it allows receptors to rotate more effectively, thus increasing the transmission of signals from the surface of the membrane to the interior of the nerve cells. This is why DHA is a critical component of these parts of the nerves (7). On the other hand, the myelin membrane is essentially an insulator so that relatively little DHA is found in that part of the membrane.

This constant sweeping motion of DHA also causes the breakup of lipid rafts in membranes (8). Disruption of these islands of relatively solid lipids makes it more difficult for cancer cells to continue to survive and more difficult for inflammatory cytokines to initiate the signaling responses to turn on inflammatory genes (9). In addition, these greater spatial characteristics of DHA increase the size of LDL particles to a greater extent compared to EPA. As a result DHA helps reduce the entry of these enlarged LDL particles into the muscle cells that line the artery, thus reducing the likelihood of developing atherosclerotic lesions (10). Thus the increased spatial territory swept out by DHA is good news for making certain areas of membranes more fluid or lipoprotein particles larger, even though it reduces the benefits of DHA in competing with AA for key enzymes important in the development of cellular inflammation.

Common Effects for Both EPA and DHA

Not surprisingly, there are some areas in which both EPA and DHA appear to be equally beneficial. For example, both are equally effective in reducing triglyceride levels (10). This is probably due to the relatively equivalent activation of the gene transcription factor (PPAR alpha) that causes the enhanced synthesis of the enzymes that oxidize fats in lipoprotein particles. There is also apparently equal activation of the anti-inflammatory gene transcription factor PPAR-gamma (11). Both seem to be equally effective in making powerful anti-inflammatory eicosanoids known as resolvins (12). Finally, although both have no effect on total cholesterol levels, DHA can increase the size of LDL particle to a greater extent than EPA can (10).

Summary

EPA and DHA do different things, so you need them both. If your goal is reducing cellular inflammation, then you probably need more EPA than DHA. How much more? Probably twice the levels, but you always cover your bets with omega-3 fatty acids by using both at the same time.

References

  1. Sears B. “The Zone.” Regan Books. New York, NY (1995)
  2. Chen CT, Liu Z, Ouellet M, Calon F, and Bazinet RP. “Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study.” Prostaglandins Leukot Essent Fatty Acids 80:157-163 (2009)
  3. Chen CT, Liu Z, and Bazinet RP. “Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: an intracerebroventricular study. J Neurochem 116:363-373 (2011)
  4. Umhau JC, Zhou W, Carson RE, Rapoport SI, Polozova A, Demar J, Hussein N, Bhattacharjee AK, Ma K, Esposito G, Majchrzak S, Herscovitch P, Eckelman WC, Kurdziel KA, and Salem N. “Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography.” J Lipid Res 50:1259-1268 (2009)
  5. Martins JG. “EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials.” J Am Coll Nutr 28:525-542 (2009)
  6. Sato M, Adan Y, Shibata K, Shoji Y, Sato H, and Imaizumi K. “Cloning of rat delta 6-desaturase and its regulation by dietary eicosapentaenoic or docosahexaenoic acid.” World Rev Nutr Diet 88:196-199 (2001)
  7. Stillwell W and Wassall SR. “Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids 126:1-27 (2003)
  8. Chapkin RS, McMurray DN, Davidson LA, Patil BS, Fan YY, and Lupton JR. “Bioactive dietary long-chain fatty acids: emerging mechanisms of action.” Br J Nutr 100:1152-1157 (2008)
  9. Li Q, Wang M, Tan L, Wang C, Ma J, Li N, Li Y, Xu G, and Li J. “Docosahexaenoic acid changes lipid composition and interleukin-2 receptor signaling in membrane rafts.” J Lipid Res 46:1904-1913 (2005)
  10. Mori TA, Burke V, Puddey IB, Watts GF, O’Neal DN, Best JD, and Beilin LJ. “Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.” Am J Clin Nutr 71:1085-1094 (2000)
  11. 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)
  12. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, and Moussignac RL. “Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.” J Exp Med 1996:1025-1037

Anxiety and Omega-3 Fatty Acids

Anxiety is one of most the common neurological disorders, but it also is one of the most difficult to understand. Simply stated, anxiety is an apprehension of the future, especially about an upcoming challenging task. This is normal. What is not normal is when the reaction is significantly out of proportion to what might be expected. Over the years, a number of specific terms, such as generalized anxiety disorder, panic disorder, phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and separation anxiety disorder have emerged in an attempt to better categorize general anxiety. Any way you describe anxiety, it is a big problem with nearly 20% of Americans suffering from it, thus making anxiety the largest neurological disorder in the United States (1).

If anxiety is worrying about the future, then it has a fellow traveler, depression. Depression can be viewed as an over-reaction about regret associated with past events. Not surprisingly, almost an equal number of Americans suffer from this condition. This leads to the question: Is there a linkage between the two conditions? I believe the answer is yes and it may be caused by radical changes in the American diet in the past 40 years. These changes have resulted in what I term the Perfect Nutritional Storm (2). The result is an increase in the levels of inflammation throughout the body and particularly in the brain.

The brain is incredibly sensitive to inflammation, not the type you can feel but the type of inflammation that is below the perception of pain. I term this cellular inflammation. What makes this type of inflammation so disruptive is that it causes a breakdown in signaling between cells. What causes cellular inflammation is an increase in the omega-6 fatty acid known as arachidonic acid (AA). From this fatty acid comes a wide range of inflammatory hormones known as eicosanoids that are the usual suspects when it comes to inflammation. This is why anti-inflammatory drugs (aspirin, non-steroid anti-inflammatories, COX-2 inhibitions and corticosteroids) all have a single mode of action—to inhibit the formation of these inflammatory eicosanoids. These drugs, however, can’t cross the blood-brain barrier that isolates the brain from a lot of noxious materials in the blood stream. So when the brain becomes inflamed, its only protection is adequate levels of anti-inflammatory omega-3 fatty acids. But what happens when the levels of omega-3 fatty acids are low in the brain? The answer is increased neuro-inflammation and continual disruption of signaling between nerves.

There are two omega-3 fatty acids in the brain. The first is called docosahexaenoic acid or DHA. This is primarily a structural component for the brain. The other is called eicosapentaenoic acid or EPA. This is the primary anti-inflammatory omega-3 fatty acid for the brain. So if the levels of EPA are low in the blood, they are going to be low in the brain. To further complicate the matter, the lifetime of EPA in the brain is very limited (3,4). This means you have to have a constant supply in the blood stream to keep neuro-inflammation under control.

It is known from work with uni-polar and bi-polar depressed patients, that high-dose fish oil rich in EPA has remarkable benefits (5,6). On the other hand, supplementing the diet with oils rich in DHA have virtually no effects (7).

Since anxiety has a significant co-morbidity with depression, the obvious question becomes is it possible that high levels of EPA can reduce anxiety? The answer appears to be yes (8), according to a study conducted in 2008 using substance abusers. It is known that increased anxiety is one of the primary reasons why substance abusers and alcoholics tend to relapse (9,10). When these patients were given a high dose of EPA (greater than 2 grams of EPA per day), there was a statistically significant reduction in anxiety compared to those receiving a placebo. More importantly, the degree of anxiety reduced was highly correlated to the decrease of the ratio of AA to EPA in the blood (8). In other studies with normal individuals without clinical depression or anxiety, increased intake of EPA improved their ability to handle stress and generated significant improvements in mood (11-13). It may be that depression and anxiety are simply two sides of the same coin of increased cellular inflammation in the brain. Even for “normal” individuals, high dose EPA seems to make them happier and better able to handle stress.

So let’s go back to an earlier question and ask about the dietary changes in the American diet that may be factors in the growing prevalence of both depression and anxiety. As I outline in my book Toxic Fat, it is probably due to a growing imbalance of AA and EPA in our diets (2). What causes AA to increase is a combination of increased consumption of vegetable oils rich in omega-6 fatty acids coupled with an increase in the consumption of refined carbohydrates that generate insulin. When excess omega-6 fatty acids interact with increased insulin, you get a surge of AA production. At the same time, our consumption of fish rich in EPA has decreased. The end result is an increasing AA/EPA ratio in the blood, which means a corresponding increase in the same AA/EPA ratio in the brain creating more cellular inflammation.

Cutting back vegetable oil and refined carbohydrate intake is difficult since they are now the most inexpensive source of calories. Not surprisingly, they are key ingredients for virtually every processed food product. So if changing your diet is too hard, then consider eating more fish to get adequate levels of EPA. Of course, the question is how much fish? If we use a daily intake level of 2 grams of EPA per day that was used the successful trials of using omega-3 fatty acids reduce anxiety, then this would translate into consuming 14 pounds of cod per day. If you prefer a more fatty fish like salmon, then you would only need about 2 pounds per day to get 2 grams of EPA. The Japanese are able to reach that level because they are the largest consumers of fish in the world. These are highly unlikely dietary changes for most Americans. However, it has been demonstrated that following a strict anti-inflammatory diet coupled with purified fish oil supplements can generate an AA/EPA ratio similar to that found in the Japanese population (11).

There is simply no easy way out of this problem created by the Perfect Nutritional Storm, which will only intensify with each succeeding generation due to the insidious effect of cellular inflammation on fetal programming in the womb. Unfortunately for most Americans this will require a dietary change of immense proportions. This probably means that Valium and other anti-anxiety medications are here to stay.

References

  1. Kessler RC, Chiu WT, Demler O, Merikangas KR, and Walters EE. “Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication”. Arch Gen Psychiatry 62:617–627 (2005)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Chen CT, Liu Z, Ouellet M, Calon F, and Bazinet RP. “Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study.” Prostaglandins Leukot Essent Fatty Acids 80:157-163 (2009)
  4. Chen CT, Liu Z, and Bazinet RP. “Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: an intracerebroventricular study.” J Neurochem 116:363-373 (2011)
  5. Nemets B, Stahl Z, and Belmaker RH. “Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.” Am J Psychiatry 159:477-479 (2002)
  6. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, and Marangell LB. “Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.” Arch Gen Psychiatry 56:407-412 (1999)
  7. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, and Puryear LJ. “A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.” Am J Psychiatry 160:996-998 (2003)
  8. Buydens-Branchey L, Branchey M, and Hibbeln JR. “Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers.” Prog Neuropsychopharmacol Biol Psychiatry 32:568-575 (2008)
  9. Willinger U, Lenzinger E, Hornik K, Fischer G, Schonbeck G, Aschauer HN, and Meszaros K. “Anxiety as a predictor of relapse in detoxified alcohol-dependent patients.” Alcohol and Alcoholism 37:609-612 (2002)
  10. Kushner MG, Abrams K, Thuras P, Hanson KL, Brekke M, and Sletten S. “Follow-up study of anxiety disorder and alcohol dependence in comorbid alcoholism treatment patients.” Alcohol Clin Exp Res 29:1432-1443 (2005)
  11. Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with Omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35:499-507 (2005)
  12. Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, and Lodi L. “Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. “Eur J Clin Invest 35:691-699 (2005)
  13. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, and Glaser R. “Omega-3 supplementation lowers inflammation and anxiety in medical students: A randomized controlled trial.” Brain Behav Immun 25:1725-1734 (2011)

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.

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.

References

  1. Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Sears B and Riccordi C. “Anti-inflammatory nutrition as a pharmacological approach to treat obesity.” J Obesity doi:10.1155/2011/431985 (2011)
  4. 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)
  5. 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)
  6. 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)
  7. 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)
  8. Kim JJ and Sears DD. “TLR4 and Insulin Resistance.” Gastroenterol Res Pract doi:10./2010/212563 (2010)
  9. 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)
  10. 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)
  11. 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)
  12. 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)
  13. 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)
  14. 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)
  15. 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)
  16. 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)
  17. 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)

Hard times are ahead

Last month was a red-letter month for the future of mankind as the world population passed 7 billion. Unfortunately, this fact dovetails with recent research that indicates it is likely that one-half of all Americans will be diabetic by 2050 (1).

The combination of these two trends does not bode well for the future. To begin with, how are we going to feed all these people? Most of the arable land on the planet is already under cultivation. Furthermore, urbanization is destroying prime cropland at a rapid pace.

Added to these facts is that the diversity of most of the world’s calories is rapidly decreasing. Currently the five top sources of calories in the world are corn, soybeans, wheat, rice and potatoes (as well as its kissin’ cousin cassava, which is incredibly poor in protein and nutrients). The first two crops (corn and soy) are rich sources of omega-6 fatty acids. In addition, corn, wheat, and rice provide extremely high-glycemic carbohydrates that can be easily refined to last forever and make thus a wide variety of processed foods. (Potatoes and cassava tend to decompose rapidly and can’t be easily refined, except perhaps as potato chips). As a consequence, omega-6 fatty acids and refined carbohydrates are now the cheapest form of calories in the world. In fact, it is estimated that they are 400 times less expensive per calorie than fresh fruits and vegetables.

So how can you feed this growing population of more than 7 billion people? The answer is easy—produce even more refined carbohydrates and omega-6 fatty acids.

Unfortunately, feeding the growing population of the world with cheap omega-6 fatty acids and refined carbohydrates is exactly the best way to increase cellular inflammation and drive the development of diabetes (2). It is estimated that by 2050 diabetes will be the primary non-infectious disease on the planet. This is equally bad news as it is also the most expensive chronic disease to treat on a long-term basis.

Today, more than 26 percent of all Americans older than 65 has diabetes. If the estimates of increased diabetes are correct (1), then it is likely that the number of Americans older than 65 in 2050 with diabetes may be greater than 50 percent. The current level of diabetes is the primary reason why our health-care expenses are spiraling out of control. If you double number of older Americans with diabetes by 2050, there is no way the current health-care system, as we know it can possibly survive. Add to the fact that once you have diabetes, you are 2-4 times more likely to develop heart disease and Alzheimer’s. It is not a very pleasant picture of the future of health care in America.

What can you do about it? On a global basis, not much unless you would like to see an apocalyptic event that reduces the population from 7 billion to a more manageable 1-2 billion individuals. Of course, this is highly unlikely. However, on the individual basis there is a lot you can do to protect yourself in the future. Simply take control of your future by focusing on managing cellular inflammation for a lifetime by following an anti-inflammatory diet. This may be your only real health security in times of increasing demands on the planet’s resources to produce food. There is no question that we have other troubles brewing like climate change, decreasing water supplies, and decreasing cheap energy, all of which will also impact the cost of food, driving more individuals toward inexpensive sources of calories no matter what the health consequences. But the rise of diabetes will occur first.

Old folks like myself will probably be OK, but the future generations will take the brunt of trouble brewing ahead.

References

  1. Boyle JP , Thompson TJ, Gregg EW, Barker LE, and Williamson DF. “Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence.” Population Health Metrics 8:29 (2010)
  2. Sears B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)

Changing gene expression

I have often stated that the real power of the Zone Diet is to change gene expression, especially the expression of anti-inflammatory genes. What I never realized is how rapid gene expression could occur. Now, new research from Norway gives me the answer (1). It takes about 24 hours!

This pilot study is on the effect of diet on gene expression in healthy obese individuals. Interestingly, when the researchers calculated the estimated daily calorie requirements for these subjects necessary to maintain their weight, they were surprised that they were already eating 250 fewer calories per day than predicted to maintain their current weight. So much for the “fact” that obese individuals are fat because they eat more calories than they need to maintain their weight. In fact, this observation was confirmed in an earlier study in which the number of calories consumed by obese and lean individuals did not vary, but the obese individuals consumed fewer meals consisting of larger servings (2).

So what the Norwegian researchers did was simply maintain the same number of calories the subjects were already eating and change the macronutrient balance to be very close to the Zone Diet (30 percent carbohydrates, 30 percent protein, and 40 percent fat). Then the subjects consumed six meals containing about 460 calories evenly spaced throughout the day so that the total calories consumed at any one time was moderate. Just making those two simple dietary changes resulted in more than an eight-pound weight loss in 28 days. The levels of body fat didn’t change since the number of calories consumed was exactly the same as they were previously consuming. However, it appears that evenly spacing the meals and reducing the calorie size of the meals resulted in less insulin production and therefore less retained water.

Then they looked to see if they could find any changes in gene expression in both the fat cells and the blood with the dietary changes. Amazingly they found dramatic changes in only 24 hours. Of the 16,000 genes they could identify, about 60 percent remained unchanged in their expression, but 40 percent were either turned on (i.e., up-regulated) or turned down (i.e., down-regulated). Interestingly, the changes seen in the first 24 hours were held constant throughout the 28 days of the experiment.

Upon further analysis, the up-regulated genes corresponded to those that had anti-inflammatory properties, and the down-regulated genes were those associated with chronic disease conditions, such as diabetes and heart disease. Furthermore, since these changes in gene expression occurred within 24 hours of the dietary change, they could not be attributed to any change in body weight and fat loss.

Fortunately, I had the opportunity to have dinner with the lead author of the study to discuss her work while I was in Europe last week. She told me that she has expanded the number of subjects in several new trials, and the results remain the same. I also found out that she has been following my work for many years.

This type of study only confirms the power of genetic analysis to demonstrate how a highly structured diet with the correct macronutrient content can rapidly alter genetic expression and hence controls your future health. But the door swings both ways. An unbalanced diet will have just the opposite genetic effects. While I have always been impressed by the power of the Zone Diet, this new experimental data takes my respect for the Zone Diet to a new level of awe, even by me.

References

  1. Brattbakk H-R, Arbo I, Aagaard S, Lindseth I, de Soysa AK, Langaas M, Kulseng B, Lindberg, and Johansen B. “Balanced caloric macronutrient composition down regulates immunological gene expression in human blood cells-adipose tissue diverges.” OMICS 15: doi:1089/omi.2010.0124 (2011)
  2. Berg C, Lappas G, Wolk A, Strandhagen E, Toren K, Rosengren A, Rosengren A, Thelle D, and Lissner L. “Eating patterns and portion size associated with obesity in a Swedish population.” Appetite 52: 21-26 (2009)

Eat Less, Get Hungry

Telling an obese person simply to eat less rarely succeeds. Is it because they are weak-willed individuals or is there something more complex going on? New research indicates the latter. A new article in Cell Metabolism showed that during extreme calorie restriction, the levels of fatty acids begin to rapidly rise in the blood as the body begins breaking down stored fat for energy. These newly released fatty acids from the fat cells can then enter into the brain (the hypothalamus to be exact) and cause the self-digestion of cells in the hunger neurons (1). This self-digestion of the cells in the hunger neurons produces a rise in the very powerful hunger hormone (AgRP) from the same bundle of neurons. Not surprisingly, the urge to eat becomes almost overpowering. This begins to explain why very low calorie diets can cause rapid weight loss, but are rarely successful in keeping the weight off.

This is why very low calorie diets that promise quick weight loss invariably cause the rapid release of stored fatty acids that promotes constant hunger. This is clearly not a sustainable way to maintain long-term weight management.

Of course the question might be whether it is all fatty acids or just one that causes the problem of cellular death in the hunger neurons? I believe the answer comes back to the usual suspect, arachidonic acid (2). It has been known for 20 years that when you put obese individuals on a very low calorie diet there is a rapid increase in the levels of arachidonic acid levels in the blood (3). Arachidonic acid can easily cross the blood brain barrier and enter into the hypothalamus. Since arachidonic acid is a powerful promoter of cell death (4), increased concentrations inside the hypothalamus may be the primary accelerator of the death of the hunger neurons. Increased levels of arachidionic acid in the blood are also the underlying cause of insulin resistance because of its effect on the generation of cellular inflammation (2). So as you build up the levels of stored arachidonic acid in the fat cells, caused by the Perfect Nutritional Storm (2), you are almost ensuring constant hunger when you try to lose weight quickly by following very low calorie diets. To make matters even worse, as arachidonic acid levels also build up in the brain increasing the production of endocannabinoids (5). These are the hormones that give you the continual munchies (they are related to the active ingredient in marijuana).

So is there any good news in all of this research? Yes as long as you develop a lifetime dietary strategy for reducing arachidonic acid and the cellular inflammation it causes as well as following a reasonable low calorie diet that supplies adequate levels of fat to moderate the release of stored fatty acids from the fat cells. It means following an anti-inflammatory diet with adequate protein using low-glycemic load carbohydrates and fats very low in omega-6 fatty acids, but adequate in monounsaturated and omega-3 fats.

That’s why you never want to start any type of weight loss program without adding omega-3 fatty acids to counteract the released of stored arachidonic acid from the fat cells. Not only will these omega-3 fatty acids reduce the degradation of the hunger neurons thereby reducing the release of powerful hunger hormones during calorie restriction, but they will also inhibit the release of endocannabinoids in the brain (6). The combination of the two events will ensure weight loss without hunger and that’s sustainable.

References

  1. Kaushik S,Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, Cuervo AM, and Singh R. “Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance.” Cell Metabolism 14: 173-183 (2011)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Phinney SD, Davis PG, Johnson SB, and Holman RT. “Obesity and weight loss alter serum polyunsaturated lipids in humans.” Amer J Clin Nutr 53: 831-838 (1991)
  4. Pompeia C, Lima T, and Curi R. “Arachidonic acid cytotoxicity: can arachidonic acid be a physiological mediator of cell death?” Cell Biochemistry and Function 21:97-104 (2003)
  5. Kim J, Li Y, and Watkins BA. “Endocannabinoid signaling and energy metabolism: A target for dietary intervention.” Nutrition 27: 624-632 (2011)
  6. Oda E. “n-3 Fatty acids and the endocannabinoid system.” Am J Clin Nutr 85: 919 (2007)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.