Tag Archives: omega-3

Good Diet, Bad Study

Posted on by
Reply

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)

Meta-analysis study on fish oil effectiveness is fatally flawed

Posted on by
Reply

One of the events in the food industry you never want to see is the making of sausage where sometimes good cuts of meat are combined with items you would never want to eat. 

The same is true of meta-analysis studies in medical research.  Meta-analysis means that you take a lot of different studies (some good, some not so good) using different patient populations, different inclusion criteria, different protocols, and different outcome criteria and mix them together to get a conclusion that often demonstrates a non-result.  The best example of this is the recent study in the Journal of the American Medical Association that combined a wide number of studies using fish oil supplements to come up with the conclusion that omega-3 fatty acids have no benefit (1).  So let’s take a look at this study in a little more detail.

First, it is always useful to look at the investigators.  In this case, the authors are from Greece (not exactly a hotspot of high-quality clinical research since Aristotle), and to my knowledge none of them has been involved in any actual cardiovascular intervention studies in the past, let alone any work with omega-3 fatty acids. (I believe a little background is a good foundation to build from, but then call me crazy.)

Second, the average dose used in these studies was 1.5 grams of omega-3 fatty acids per day.  Surprisingly, the American Heart Association recommends more than double this dose to reduce triglycerides, a known risk factor for heart disease (apparently not in Greece since the authors ignored this fact).  This would indicate the authors were making conclusions based on placebo doses of omega-3 fatty acids.  Usually a placebo dose gives placebo effects, which was confirmed in their meta-analysis.  Furthermore, just giving a dose of anything is meaningless unless it is reducing a measureable clinical parameter in the blood that has a relationship to the disease condition being studied.  For example, if I gave a statin dose that reduced LDL cholesterol levels from 250 mg/dl to 245 mg/dl, I wouldn’t expect any therapeutic benefits unless I gave enough statin drug to reduce the LDL cholesterol level to less than 130 mg/dl, if not much lower. 

So what is a good dose of omega-3 fatty acids?  As I have already mentioned, the American Heart Association recommends 3.4 grams of EPA and DHA per day to lower triglyceride levels.  However, I believe a better marker is the amount of omega-3 fatty acids needed to reduce the AA/EPA ratio to the levels found in the Japanese population, which has the lowest levels of cardiovascular events in the world.  Recent studies with healthy Americans indicate that would take between 5 and 7.5 grams of EPA and DHA per day (2).  Again, this indicates that the dose of omega-3 fatty acids in this meta-analysis was providing a placebo dose. 

Third, another problem with meta-analysis is conflicting protocols.  In this study, almost half the patients came from two just studies: The GISSI study and the JELIS study.  The GISSI study (more than 11,000 patients) indicated that omega-3 fatty acid supplementation on the foundation of a Mediterranean diet could reduce sudden cardiovascular death rate by 45% versus a placebo and reduced overall cardiovascular death by 20% (3).  This study was criticized because the care that all groups were receiving didn’t include statins (since they were not yet approved).  After all, the thinking for a typical cardiologist is that there is no reason to use omega-3 fatty acids if you can simply give a statin drug instead.

That faulty thinking was addressed by the JELIS study in which all the patients (about 18,000) were getting statins (4).  Unlike the GISSI study, the AA/EPA ratio was measured in these patients.  The initial AA/EPA ratio was 1.6 (a level requiring Americans to take about 5 to 7.5 grams of omega-3 fatty acids per day just to reach that starting point), and then even more EPA was added to the active group.  After 4 ½ years, those Japanese patients getting the statins and extra fish oil had another 20% reduction in cardiovascular events over and above those getting the statins and an equivalent amount of supplemented olive oil.  The take-home lesson from the JELIS study was that any physician who didn’t prescribe supplemental omega-3 fatty acids along with statins was simply practicing bad medicine. 

Meta-analysis studies are supposed to make up for potential shortcomings in small clinical trials (like the ones used to approve virtually all pharmaceutical drugs).  In the hands of unqualified researchers who have little understanding of the field or compound being studied, a meta-analysis can become an instrument for the mass confusion generated by this recent article in the Journal of American Medical Association. 

The bottom line is that you need adequate doses of natural compounds to generate a therapeutic effect.  The levels of these doses of natural compounds will always be far greater than with drugs, but also with far fewer side-effects.  If you give a placebo dose of a natural compound, then expect a placebo result.  But please don’t try to pass off such an obvious result as “science”.

References

  1. Rizos EC et al.  “Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events.”  JAMA 308: 1024-1038 (2012)
  2. Yee LD et al. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.”  Amer J Clin Nutr 91: 1185-1194 (2010)
  3. GISSI-Prevenzione Investigators. “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)
  4. 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)   

Put Statins in the Drinking Water? I Think Not.

Posted on by
Reply

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?

Posted on by
2

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

Posted on by
9

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?

Posted on by
19

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)

Meditation: Push-ups for the brain?

Posted on by
12

Meditation has always been considered a “fringe” area of medicine. Although it has been around for thousands of years, it was never considered “high-tech”.

However, the development of new imaging technologies has finally given researchers the ability to ask some interesting questions about meditation and its effect on brain structure and cognitive performance.

When comparing brain wave patterns using old technologies like an EEG, it has been demonstrated that experienced meditators have higher levels of alpha waves (indicative of a relaxed brain) and lower levels of beta waves (indicative of focusing on intentional tasks or anxiety) during mediation (1). More recent imaging technology like the SPECT scan indicates that experienced meditators have improved cerebral blood flow (2). MRI technology has shown that experienced meditators have a greater density of grey matter in the brain (3), improved neural connections (4), and lower sensitivity to induced pain (5) when compared to matched control groups.

One of the problems with these types of studies has always been subject recruitment. The studies described above are simply various examples of case-control epidemiological studies. This type of study is often done in cancer epidemiology and is used to compare someone with cancer to a control without cancer to see if any differences are apparent (like if smoking is associated with lung cancer). The problem is that experienced meditators may already have different brain structures or improved neural networks and corresponding improved attention spans that attracted them to meditation in the first place. This is like comparing professional athletes to their fans watching them on TV and then looking for differences in fitness between the two groups.

Aware of these shortcomings, more recent, better controlled, shorter-term studies have taken either non-meditators or experienced meditators and put them into an intensive meditation program to be compared to equally matched subjects waiting to enter the same a program. Using a more tightly controlled group of subjects, it has been found that meditation does indeed have benefits in reducing sensitivity to pain (6), improving ability to modulate alpha waves that help reduce distractions (7), increasing brain grey matter (8), and increasing telomerase activity (9). The increased telomerase activity is usually associated with increased lifespan because when telomeres on the DNA become too short, the cell dies.

There are a lot of health benefits that stem from sitting in a comfortable chair thinking of nothing for at least 20 minutes a day. In fact, it is so easy that most people never get around to doing it.

So if you don’t have time to take at least 20 minutes a day to meditate, then consider taking high-dose fish oil. In as little as 35 days, you will see it also generates significant increases in the intensity of alpha waves, increased attention span, and improved mood (10) just like experienced meditators, who have spent years trying to reach the same goals. And if you maintain high levels of omega-3 fatty acids in your blood for a longer period of time, it appears that you get decreased telomere shortening that should help you live longer (11). And if you are worried about time, taking adequate levels of fish oil to get these benefits only takes 15 seconds a day.

Of course, if you were really smart, you would do both every day.

References

  1. Lagopoulos J, Xu J, Rasmussen I, Vik A, Malhi GS, Eliassen CF, Arntsen IE, Saether JG, Hollup S, Holen A, Davanger S, and Ellingsen O. “Increased theta and alpha EEG activity during nondirective meditation.” J Alt Complementary Medicine 15: 1187-1192 (2009)
  2. Newberg A, Alavi A, Baime M, Pourdehnad M, Santanna J, and d’Aquili E. “The measurement of regional cerebral blood flow during the complex cognitive task of meditation: a preliminary SPECT study.” Psychiatry Res 106: 113-122 (2001)
  3. Toga AW, Lepore N., Gaser C. The underlying anatomical correlates of long-term meditation: larger hippocampal and frontal volumes of gray matter. Neuroimage 45: 672-678 (2009)
  5. Luders E, Clark K, Narr KL, Toga AW. “Enhanced brain connectivity in long-term meditation practitioners [In Process Citation] Neuroimage 57: 1308-1316 (2011)
  7. Grant JA, Courtemanche J, Duerden EG, Duncan GH, and Rainville P. “Cortical thickness and pain sensitivity in zen meditators.” Emotion 10: 43-53 (2010)
  8. Zeidan F, Martucci KT, Kraft RA, Gordon NS, McHaffie JG, and Coghill RC. “Brain mechanisms supporting the modulation of pain by mindfulness meditation.” J Neuroscience 31: 5540-5548 (2011)
  9. Kerr CE, Jones SR, Wan Q, Pritchett DL, Wasserman RH, Wexler A, Villanueva JJ, Shaw JR, Lazar SW, Kaptchuk TJ, Littenberg R, Hamalainen MS, and Moore CI. “Effects of mindfulness meditation training on anticipatory alpha modulation in primary somatosensory cortex.” Brain Research Bulletin 85: 96-103 (2011)
  10. Holzel BK, Carmody J, Vangel M, Congleton C, Yerramsetti SM, Gard T, and Lazar SW. “Mindfulness practice leads to increases in regional brain gray matter density.” Psychiatry Research 191: 36-43 (2011)
  11. Jacobs TL, Epel ES, Lin J, Blackburn EH, Wolkowitz OM, Bridwell DA, Zanesco AP, Aichele SR, Sahdra BK, Maclean KA, King BG, Shaver PR, Rosenberg EL, Ferrer E,; Wallace BA, and Saron CD. “Intensive meditation training, immune cell telomerase activity, and psychological mediators.” Psychoneuroendocrinology 36: 664-681 (2011)
  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-
  13. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, and Whooley MA. “Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease.” JAMA 303: 250-257 (2010)

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.

Eat Less, Get Hungry

Posted on by
51

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.

Preventing obesity through prenatal nutrition

Posted on by
64

It is obvious that pediatric obesity is a growing problem. However, compared to adult obesity, it is a relatively new problem. In a new article to be published in the Journal of Adolescent Health, it is pointed out that while childhood obesity has increased some 300 percent since 1960, most of that increase only began in the mid 1990s (1). This is well after the beginning of the climb of adult obesity, which started in the 1980s. Why the lag time? I believe it may have been caused by the amplification of any genetic predisposition to obesity by prenatal programming in the womb. That means you had to have obese mothers whose own hormonal changes and diet were altering the fetal programming of their children, thus amplifying their likelihood for obesity after birth.

This possibility makes sense based on results from another recent article that demonstrates that the lower the omega-3 fatty acid status in the mother, the more likely the child would be obese by the age of 3 (2). In this particular study, researchers found that by age 3 about 10 percent of the children were already obese. What they also analyzed was even though virtually all the women were consuming very low levels of omega-3 fatty acids during pregnancy, the higher the levels of the omega-3 fatty acids in mother’s diet, or her blood, and especially in the blood from the umbilical cord to the fetus, the lower the levels of obesity in the child three years later after birth.

Of course, lower levels of omega-3 fatty acids usually indicate higher levels of omega-6 fatty acids, giving rise to an unbalanced ratio of omega-3 to omega-6 fatty acids. This is why the highest correlation with increased childhood obesity was found with an increasing ratio of arachidonic acid to EPA and DHA in the blood of the mother and also in the umbilical cord of the fetus. This makes perfect sense since it is known from animal studies that the higher the omega-6 to omega-3 ratio in the diet of the mother, the greater the obesity in the offspring (3-5).

So if you want to begin to decrease childhood obesity, it is probably best to start in the womb of the mother with appropriate prenatal nutrition using appropriate levels of omega-3 fatty acids. This would prevent the fetal programming of the unborn child that would lead to rapid accumulation of excess body fat after birth. I think this makes a lot more sense than telling obese children to “eat less and exercise more” after their genetic expression has been altered in the womb. And if this makes sense, then doesn’t it also strongly suggest that feeding children more omega-3 and less omega-6 fatty acids after birth will silence the activation of ancient genes that make them fat and keep them fat (6).

References

  1. Lee H, Lee D, Guo G, and Harris KM. “Trends in body mass index in adolescence and young adulthood in the United States: 1959-2002.” J Adolescent Heath DOI:10.1016/jadolheath2011.04.019 (2011)
  2. Donahue SMA, Rifas-Shiman SL, Gold DR, Jouni ZE, Gilman MW, and Oken E. “Prenatal fatty acid status and child adiposity at age 3.” Am J Clin Nutr 93: 780-788 (2011)
  3. Korotkova M, Gabrielsson BG, Holmang, A, Larrson BM, Hanson LA, and Strandvik B. “Gender-related long-term effects in adult rats by perinatal dietary ratio of n-6/n-3 fatty acids.” Am J Physiol Regul Integr Comp Physiol 288: R575-579 (2005)
  4. Ailhaud G, Guesnet P, and Cannane SC. “An emerging risk factor for obesity: does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development?” Br J Nutr 100: 461-470 (2008)
  5. Massiera L, Barbry P, Guesnet P, Joly A, Luquet S, Moreihon-Brest C, Moshen-Kanson T, Amri E-Z, and Ailhaud G. “A western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations.” J Lipid Res 51: 2352-2361 (2010)
  6. Massiera Saint-Marc P, Seydoux J, Murata T, Kobayshi T, Narumiya S, Guesnet P, Amri E-Z, Negrel R, and Alhaud G. “Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern?’ J Lipid Res 44: 271-279 (2003)

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.

How to eliminate 50 percent of all coronary events

Posted on by
20

The European Society of Cardiology estimates a 50 percent reduction of coronary events if you can stabilize soft, vulnerable plaques (1). We are often led to believe that plaques you can see on an angiogram are “killer” plaques. It’s true that if they are large enough to obstruct blood flow, they will decrease oxygen transfer to the heart muscle cells making them more tired with less effort.

This is the definition of stable angina. It simply means it takes less effort to over-exert the heart muscles before they fatigue. However, you need approximately a 90 percent total obstruction of the blood vessel to develop stable angina. These plaques account for most of the plaques you might find in an angiogram. This is why if you take an angiogram, you are often immediately wheeled into the operating room to have a stent put into the artery with the belief you are only seconds away from an immediate heart attack and death.

However, the same angiogram can’t see a few plaques (because they are so small), known as the soft, vulnerable ones. When soft, vulnerable plaques rupture (like a pimple), then you have the death and disability (i.e., damaged heart tissue) that truly characterize heart disease. Technically, this is called an acute coronary event, and it has very little to do with the stable plaques that can cause angina. It is this small number of “rogue” soft, vulnerable plaques that are the true killers in heart disease (2,3).

The ultimate cause of plaque rupture is cellular inflammation inside the plaque. Cellular inflammation degrades the fibrous external coating of the plaque. Usually inside these soft, vulnerable plaques are also a lot of macrophages engorged with lipids. This is called the “necrotic core”. When the plaque bursts, these lipid pools are released into the bloodstream causing platelet aggregation and the rapid blockage of the artery resulting in a complete restriction of blood flow (as opposed to a limited restriction of blood flow with a typical stable plaque that will never rupture). It is estimated that about 75 percent of all coronary events are caused by ruptures of the soft, vulnerable plaques (2).

As I mentioned above, the really scary part of this story is that there is no type of imaging technology that can detect dangerous soft, vulnerable plaques. In essence, you don’t know if you have them or not. This is why the prediction of impeding cardiovascular events remains a guessing game. Even more interesting is that these soft, vulnerable plaques seem to form rather quickly (in about 10 years) as opposed to growing slowly over a lifetime (4). Moreover, the rate of growth of these soft, vulnerable plaques is strongly correlated with increasing insulin levels in the blood (4).

So what does this mean for people who don’t want to die from a sudden rupture of soft, vulnerable plaques that can’t be detected? The first thing is to reduce the inflammation within the plaque. Surprisingly, there is only one clinical study that has ever been published that addressed this question, and it used fish oil (5). This study indicated that if you give patients relatively high doses of fish oil, you could see a definite remodeling of the soft, vulnerable plaques in about 40 days compared to subjects taking a placebo composed of safflower oil. The plaques in the subjects taking the fish oil became less inflamed, had higher levels of omega-3 fatty acids, fewer macrophages and more well-formed fibrous caps compared to those taking the placebo. So taking a therapeutic level of fish oil for a lifetime seems to be a good way to reduce the rupture of these plaques.

Another way to potentially reduce their formation in the first place is lower insulin levels. The reason insulin levels are elevated is because organs, such as the adipose tissue, the liver and the muscles, are also inflamed (6). The best way to reduce that systemic inflammation is to follow the anti-inflammatory diet and take therapeutic levels of fish oil for a lifetime. Your success is best measured by the AA/EPA ratio in the blood. Call me crazy, but I think that’s what I have been recommending for the past 16 years (7).

References

  1. Yia-Herttulala S, Bentzon JF, Daemen M, Falk E, Garcia-Garcia HM, Merrmann J, Hoefer IM, Juekma JW, Krams R, Kwak BR, Marx N, Maruszeqica M, Newby A, Pasterkamp G, Serruys PWJC, Waltenberger J, Weber C, and Tokgozoglu L. “Stabilization of atherosclerotic plaques.” Thomobosis and Haemostasis 106: 1-19 (2011)
  2. Schaar JA, Muller JE, Falk E, Virmani R, Fuster V, Serruys PW, Colombo A, Stefanadis C, Ward Casscells S, Moreno PR, Maseri A, and van der Steen AF. “Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque.” Eur Heart J 25: 1077-1082 (2004)
  3. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, and Hong Y. “Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.” Circulation 119:480-486 (2009)
  4. Hagg S, Salehpour M, Noori P, Lundstrom J, Possnert G, Takolander R, Konrad P, Rosfors S, Ruusalepp A, Skogsberg J, Tegner J, and Bjorkegren J. “Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin.” PLoS One 6: e1824 (2011)
  5. Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, Gallagher PJ, Calder PC, and Grimble RF. “Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomized controlled trial.” Lancet 2003 361: 477-485 (2003)
  6. Sears, B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)
  7. Sears B. “The Zone.” Regan Books. New York, NY (1995)

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.