Trying to Make Science Out of Sausage

Epidemiology is the study of associations and not causality. It essentially began in 1854 when John Snow noticed that there seemed to be a higher concentration of cholera patients in a certain area in London during one of its many cholera epidemics in the 19th century. That’s an association. The real breakthrough for John Snow was to remove the pump handle on the suspected water source and then observe a significant reduction in the cases of cholera in that area. That’s called an intervention study based on epidemiology. Now in the 21st century we seem very reticent to do any type of intervention studies and rely more on epidemiology to guide our medical decisions. This is made even more confusing with the introduction of meta-analysis into the picture. Meta-analysis is taking a large number of studies (often done under very different conditions), pretending they are all valid and then coming up with a conclusion. When you do a meta-analysis on epidemiology studies, it’s like trying to separate a piece of filet mignon from intestines used to make sausage.

This month an article from the Annals of Internal Medicine suggested that there is no relationship of any type of fatty acid with heart disease (1). Well, if there is no association of any type of fatty acid with heart disease, why not just eat lard instead of salmon? If this sounds a little fishy to you (pardon the pun), it does to me too. As I stated earlier, the problem with meta-analysis is that good studies are added to bad ones. Here’s a dirty secret about medical research. There are a lot of bad studies that get published. Usually if you can’t get the funds to do original research, then you write a review paper, and if you can’t write a review paper, then you do a meta-analysis of all published studies and pretend it’s original research. The media might buy that, but I don’t.

The irony of this study is that one of the authors had actually published a good article using good controls in the same journal a year earlier indicating that the higher the levels of omega-3 fatty acids in the blood, the less heart disease death and the greater the longevity of the individuals (2). Maybe he forgot that article when publishing this new sausage publication (1).

That notwithstanding, the problem with these types of published studies is that they miss the point of what causes heart disease in the first place. It is not fatty acids or cholesterol, but inflammation. The best way to measure inflammation is the ratio of AA to EPA in the blood. This was first reported in the New England Journal of Medicine some 25 years ago (3). High-dose fish oil in healthy volunteers (5 grams of EPA and DHA per day) reduced the AA/EPA ratio from 21 to 2.5 within six weeks. During that time many of the additional markers of cellular inflammation also dropped. When they stopped the omega-3 fatty acid supplementation, the AA/EPA ratio gradually returned to its initial high level with a corresponding increase in the depressed inflammatory proteins to their initial levels. A very nice intervention study.

Then there is the disturbing fact that Japanese males have essentially the same LDL cholesterol levels as Americans, but Americans have 3.5 times the age-adjusted death rate. In fact, the LDL cholesterol levels of the Japanese having been rising since 1980, whereas American’s LDL cholesterol levels have been dropping. In addition, Japanese males in the study were about 7 times more likely to smoke than Americans. Let’s see, rising LDL cholesterol levels coupled with more smoking, but they have 72% fewer deaths from heart disease (4). Maybe the AA/EPA ratio as a marker of inflammation might be a key? The AA/EPA ratio of the Japanese in that study was 2.6, whereas the Americans were 11.1. Actually the Americans in this study were less inflamed than the general American population that has an AA/EPA ratio of 20 (5). But even in the above study, the Japanese AA/EPA ratio was 76% lower than the Americans (4). Let’s see, the Japanese had 76% lower inflammation and 72% lower mortality from heart disease compared to the Americans even through their LDL cholesterol levels were the same and they smoked like chimneys. If I was a betting man, I would put my money on doing an intervention study to see what the effect on heart disease would be if I lowered the AA/EPA ratio. That’s exactly what the Japanese did with the JELIS trial that was one of the largest cardiovascular trials ever undertaken with some 18,000 subjects (6). All of them had high cholesterol, so all of them were put on statins. The average AA/EPA ratio of these subjects was 1.6 compared to the 20 in Americans (5,6). Half the subjects were then given more omega-3 fatty acids. If the meta-analysis study recently published was valid (1), then these extra omega-3 fatty acids would have no benefit especially since everyone was getting a statin. Actually, just the reverse occurred after 3 ½ years. Those who lowered their AA/EPA ratio had 20% fewer cardiovascular events compared to those that didn’t see a change in the placebo group. Further sub-group analysis indicated that the change in the AA/EPA ratio was the overriding factor (7) behind these cardiovascular benefits. This is a complicated way of saying that if you lower inflammation, you lower cardiovascular risk.

So the next time you read about a meta-analysis study on the lack of effect of fatty acids on heart disease, ask to see a real intervention trial that lowers the levels of inflammation. When you do, then you see a very different picture of the role of fatty acids in heart disease than you do by reading more sausage studies (1,8). And if you do an intervention trial with omega-3 fatty acids, make sure that you lower the AA/EPA ratio to the level found in the Japanese. Based on published dose-response studies, this will take a minimum of 5 grams of EPA and DHA per day (9). Up to this point in time, no such cardiovascular studies have been conducted with that level of omega-3 fatty acids. If you are not using at least that level of omega-3 fatty acids to study cardiovascular disease, then you are probably using a placebo dose and should expect placebo results.

References

  1. Chowdhury R et al. “Association of dietary, circulating, and supplement fatty acids coronary risk.” Ann Intern Med 160:396-406 (2014)
  2. Mozaffarian D et al. “Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults.” Ann Intern Med 158:515-525 (2013)
  3. Enders S et al. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” New Engl J Med 320:265-271 (1989)
  4. Sekikawa A et al. “Serum levels of marine-derive n-3 fatty acids in Icelanders, Japanese, Koreans and Americans.” Prostglandins Leukot Essent Fatty Acids 87:11-16 (2012)
  5. Harris WS et al. “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)
  6. Yokoyama M et al. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.” Lancet 369:1090-1098 (2007)
  7. Matsuzaki M et al. “Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease.” Circ J 73:1283-1290 (2009)
  8. Rizos EC et al. “Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.” JAMA 308:1024-1033 (2012)
  9. 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.” Am J Clin Nutr 91:1184-1194 (2010)

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)

What’s in it for us?

In this day and age when we hear about selfish genes and winner-takes-all outcomes in evolution, it is refreshing to come across a scientific paper that redeems your faith in doing the right thing. In this case, there is strong support that being a giving person may let you potentially have a longer lifespan (1).

This research focused on hedonic behavior. There are two forms of hedonism. One is the classical desire for pleasures that are simply self-gratification. The other is called eudaimonic hedonism that comes from striving toward meaning and a noble purpose in life. Classical hedonism is deeply embedded in our genes. That’s why we eat to stay alive and have sex to propagate the species. That’s also why it is also highly related to fame and wealth so that you can get more food and sex. On the other hand, eudaimonic hedonism appears to motivate us toward more complex social and cultural activities that go beyond our individual lifespans.

One of the reasons why stress reduction is so important in living a good life is that there are a number of genes that seem to be up regulated in response to extended periods of stress and uncertainties. In particular, these are pro-inflammatory genes. This is known as the conserved transcriptional response to adversity or CTRA.

What this study did was to take healthy people and through a series of questions determine the balance of the two types of hedonism. Not surprisingly, nearly 80% of the subjects had higher levels of self-gratification (what’s in it for me) compared to those who had higher levels of eudaimonic hedonism (what’s in it for us). Then the researchers looked at the levels of activity of the genes that comprise the CRTA cluster of genes. Those who fell in the self-gratification group had higher levels of pro-inflammatory gene expression (as well as decreased expression of the genes required for immunity) compared to the subjects who were in the group that had a higher level of eudaimonic hedonism. These changes in gene expression should translate into a longer and healthier life. There is some indication that this may be true (2,3).

Conversely, it is known that increased inflammation reduces hedonic well being (4,5). This would explain why high-dose omega-3 fatty acids rich in eicosapentaenoic acid (EPA) seem to have such clinical benefits in treating depression (6-8).

So if you want to live a longer (and probably better) life, then try to start thinking of others beside yourself. If that is too hard, then consider taking high-dose fish oil rich in EPA. You will be happier, probably have a longer and healthier life, and may even become nicer to your fellow man.

References

  • 1. Fredrickson BL, Grewen KM, Coffey KA, Algoe SB, Firestine AM, Arevalo JMG, Ma J, and Cole SW. “A functional genomic perspective on human well-being.” Proc Nat Acad Sci USA 110: 13684-13689 (2013)
  • 2. Hummer RA, Rogers RG, Nam CB, and Ellison CG. “Religious involvement and U.S. adult mortality.” Demography 36:273-285 (1999)
  • 3. Helm HM, Hays JC, Flint EP, Koenig HG, and Blazer DG. “Does private religious activity prolong survival? A six-year follow-up study of 3,851 older adults. J Gerontol A Biol Sci Med Sci 55: M400-405 (2000)
  • 4. Dantzer R, O’Connor JC, Freund GG, Johnson RW, and Kelley KW. “From inflammation to sickness and depression: when the immune system subjugates the brain.” Nat Rev Neurosci 9:46-49 (2008)
  • 5. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, and Irwin MR. “Inflammation-induced ahedonia.” Bio Psychiatry 68:748-754 (2010)
  • 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. Nemets H, Nemets B, Apter A, Bracha Z and Belmaker RH. “Omega-3 treatment of childhood depression: a controlled, double-blind pilot study.” Am J Psychiatry 2006 163:1098-1100 (2006)
  • 8. 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)

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)

Meta-analysis study on fish oil effectiveness is fatally flawed

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.

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)

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)

Meditation: Push-ups for the brain?

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)
  4. Luders E, Clark K, Narr KL, Toga AW. “Enhanced brain connectivity in long-term meditation practitioners [In Process Citation] Neuroimage 57: 1308-1316 (2011)
  5. Grant JA, Courtemanche J, Duerden EG, Duncan GH, and Rainville P. “Cortical thickness and pain sensitivity in zen meditators.” Emotion 10: 43-53 (2010)
  6. 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)
  7. 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)
  8. 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)
  9. 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)
  10. 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-
  11. 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.

How to eliminate 50 percent of all coronary events

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.