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.


  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


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.


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.


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

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.


  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)

The Real Facts about Metabolically Healthy Obesity

One of great paradoxes of our obesity epidemic is that many obese individuals appear to be quite healthy. This makes the true believers in the Holy Grail of BMI as the standard for good health quite livid. They know in their hearts that obesity is a mortal sin. Early this year the Centers for Disease Control (CDC) published another in a long series of articles demonstrating that being overweight significantly decreases your likelihood of dying compared to being “normal weight” (1). Immediately Harvard Medical School went on a rampage crying foul. So you can imagine the delight of the weight-loss experts when a new meta-analysis demonstrated that “there is no healthy pattern of increased weight” (2). Take that, you silly scientists at the CDC. Unfortunately, this article represents another case of a meta-analysis creating meta-confusion.

When you state that someone is metabolically healthy obese, it means just that—they are healthy. So how can you look at someone and say they are healthy? You have to look for accepted signs of health, not whether or not they fit into designer clothing. Fortunately, there is a health ranking of obese individuals that is not based on their actual weight. It is called the Edmonton Obesity Staging System (EOSS). Obviously to be included in this ranking system, an individual has to be obese (BMI > 30). But now they are ranked in terms of health as shown below:

Stage 0: Normal blood pressure, blood glucose, and blood lipid levels and no physical or psychological impairment to being obese.

Stage 1: Existence of subclinical risk, such as borderline hypertension, impaired fasting glucose, elevated liver enzymes, mild physical symptoms, and mild impairment of well-being.

Stage 2: Established chronic disease (hypertension, type 2 diabetes, sleep apnea, osteoarthritis, etc.) and moderate limitations in physical and psychological well-being.

Stage 3: Established end-organ damage (heart attack, stroke, heart failure, etc.) and significant physical and psychological impairment.

Stage 4: Essentially the walking dead.

My definition of a healthy obese individual is someone who has an EOSS Stage 0 ranking.

So using these EOSS definitions and the NHANES III data from 1988-1994, how many people with excess weight are actually healthy using the standard definitions of excess weight: Overweight being a BMI of 25-30, Grade 1 Obesity having a BMI between 30-35, Grade 2 Obesity having a BMI between 35-40, and Grade 3 Obesity having a BMI > 40?

Overweight Obese 1 Obese 2 Obese 3
U.S. Population 50M 23M 10M 6M
Stage 0 15% 8% 5% 5%
Stage 1 28% 19% 17% 10%
Stage 2 47% 59% 64% 67%
Stage 3 10% 14% 14% 14%

The total number of overweight and obese Americans falling within the four rankings of EOSS accounted for nearly 90 million Americans. You can also see that there is great heterogeneity within each category of excess weight, but between 5 to 8% of obese patients are quite healthy regardless of their weight.

If you have an EOSS Stage 0 ranking regardless of your weight, you are healthy. Obviously, the more things wrong with you health-wise regardless of your weight, the more likely you are to going to have even more health problems in the future.

And here is the problem with the article that generated so much glee at Harvard Medical School—the researchers didn’t distinguish between truly healthy obese (EOSS Stage 0) and not-so-healthy obese (EOSS Stage 1). In fact, 9 of the 12 studies they included for their meta-analysis defined being “healthy” as not having metabolic syndrome (2). To have metabolic syndrome requires having three very different unhealthy factors. The other 3 studies included defined “healthy” as having two or less risk factors for metabolic syndrome. This means someone with hypertension, elevated blood glucose, or elevated triglycerides would be considered “healthy” in this meta-analysis (2). I guess I come from the old school, in that I wouldn’t consider such people healthy.

Now if you go back to the earlier study published by the CDC, these researchers used a very simple clinical end point that can’t be fudged (1). This end point is called death. Their data clearly points out that overweight people had a significantly a lower death rate than normal-weight people. That’s a hard fact. And the Grade 1 Obese individuals have about the same death rate as normal-weight individuals. If the CDC had used the EOSS system instead of relying on BMI, then it is likely that every grade of obese person with an EOSS Stage 0 would be living longer than normal-weight individuals.

Another recent study has indicated that metabolically healthy obesity (again using mixed patient populations) may be a transitory stage (4). However that study also used a combination of EOSS Stage 0 and Stage 1 patients within their definition of “metabolically healthy obese”. When you separate the truly healthy obese (EOSS Stage 0) from the not-so-healthy (EOSS Stage 1), you find that EOSS Stage 0 patients (regardless of their levels of obesity) maintain their health over a long time period (more than 16 years) as shown below (3).


The EOSS Stage 1 individuals in all weight classes become progressively less healthy with time. So if you combine the truly healthy obese (EOSS Stage 0) with not so healthy obese (EOSS Stage 1), then you might come to the wrong conclusion that the concept of metabolically healthy obesity doesn’t exist (2,4).

So what’s the real linkage between weight and mortality? It depends on your levels of cellular inflammation as I explained in my book Toxic Fat, published in 2008. And the less cellular inflammation you have at any weight, the healthier you are. The best measure of your levels of cellular inflammation is the AA/EPA ratio. It should be between 1.5 and 3. The average AA/EPA ratio for Americans is about 19 (5). As you reduce cellular inflammation, the severities of all forms of chronic disease are reduced regardless of your weight.


  1. Flegal KM, Kit BK, Orpana H, and Graubard BI. “Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.” JAMA 309:71-82 (2013)
  2. Kramer CK, Zinman B, and Renakeran R. “Are metabolically healthy overweight and obesity benign conditions?” Annals of Internal Medicine 159: 758-769 (2013)
  3. Padwal RS, Pajewshi NM, Allison DB, and Sarma AM. “Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity.” Can Med Assoc Journal 183:E1059-E1065 (2011)
  4. Appleton SL, Seaborn CJ, Visvanathan R, Hill CL, Gill TK, Taylor AW, and Adams RJ. “Diabetes and cardiovascular disease outcome in the metabolically healthy obese phenotype.” Diabetes Care 36:2388-294 (2013)
  5. 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)

More Cholesterol Madness

This week the American Heart Association announced a doubling down on its bet on cholesterol and heart disease.  It certainly wasn’t because there was a sudden epidemic of heart disease, because death rates have been falling since 1970 (20 years before statins were introduced).  Nor has there been any new clinical data showing the benefits of lowering cholesterol levels. Although for the last 20 years the use of statins has been said to be the end of the scourge of heart disease, it still remains the number-one killer of Americans.

Furthermore, these newest guidelines essentially recommend that not only should more Americans be put on statins, but they should also start at the highest dose possible.  In actuality, this “dose” is where the toxic effects begin to appear.  What are the toxic effects?  They include muscle weakness, reduction in cardiovascular fitness, increased diabetes, and memory loss.  Whatever happened to the Hippocratic oath of doing the patient no harm?

    All of this might be justified if there were any indication that cholesterol is the driving force behind heart disease.  Unfortunately, the facts simply don’t support the hype.  Remember, before statins arrived in 1994, saturated fat was the villain in heart disease, not cholesterol (1).  Yet in 2010, Harvard Medical School published epidemiological studies that made the connection between saturated fat and heart disease very tenuous at best (2).

So what if cholesterol is not the cause of heart disease?

Actually, there is another drug that also reduces mortality from heart disease, yet doesn’t lower cholesterol.  It’s called an aspirin.  What aspirin does do is to reduce inflammation.

The inflammation versus cholesterol battle for what causes heart disease has been raging for decades.  What gave the cholesterol boys the upper hand was it is easy to measure blood cholesterol.  With the advent of statins, it was simple for doctors to repeat the drug company mantra to their patients, “If your cholesterol levels are high, you are going to die”.  Great marketing, but poor science.

Just to illustrate the importance of reducing inflammation versus LDL cholesterol on mortality from heart disease, we can look at the heart disease mortality rates in 2004 both Japan and the United States (3).  The Japanese had a death rate from heart disease that was 71% lower than Americans, although their LDL cholesterol levels were virtually the same.  What was different between the two populations were their levels of inflammation as measured by the AA/EPA ratio.  The Japanese levels of inflammation were 76% lower than Americans.  These changes are shown in the following figure.

Figure 1.  Per Cent Differences Between Japanese and Americans


Even without advanced statistics, I think you can see there is a much better correlation between the reduction of the AA/EPA ratio between the Japanese and Americans relative to the reduction in mortality from heart disease than there is between differences in LDL cholesterol levels in Japanese and Americans relative to mortality from heart disease.

    The only way to explain this new madness for lowering cholesterol is it is a last-gasp effort of the cardiologists, who have spent their entire careers on the cholesterol bandwagon and will defend their faith to the death.  Unfortunately, it may be their patients who will have to pay the ultimate price for not being told the real enemy is inflammation.



1.  American Heart Association.  “Dietary guidelines for healthy American adults.  A statement for physicians and health professionals by the Nutrition Committee, American Heart Association.”  Circulation 77: 721-724A (1988)

2.  Siri-Tarino PW, Sun Q, Hu FB, and Krauss RM.  “Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease.”  Am J Clin Nutr 91:535-546 (2010)

3.  Sekikawa A, Steingrimosdotir L, Ueshima H, Shin C, Curb JD, Evans RW, Hauksottir AM, Kadota A, Choo J, Masaki K, Thorsson B, Launer LJ, Farcia ME, Maegawa H, Willco BJ, Eirksdottir G, Fujyoshi A, Miura K, Harris TB, Kuller LH, and Gudnason V.  “Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanes, Korean, and Americans.”  Prostaglandins Leukotrienes and Essential Fatty Acid 87:11-16 (2007)

YWikipedia: Y (named wye plural wyes) is the twenty-fifth letter in the ISO basic Latin alphabet (next to last letter) and represents either a vowel or a consonant in English.

Anti-aging made easy

Anti-aging diets have been around since the 15th century, starting with the books written by Luigi Cornaro. Although I addressed the history of Luigi in my book The Anti-Aging Zone written more than a decade ago, it bears repeating. Finding himself near death at age 35, Luigi Cornaro went on a strict calorie-restricted diet consisting primarily of an egg yolk, some vegetable soup, small amounts of locally grown fruits and vegetables, a very small amount of coarse, unrefined bread and about three glasses of red wine per day. He wrote his first anti-aging book (The Sure and Certain Method of Attaining a Long and Healthful Life) at age 83 and his third book at age 95. He finally died at age 99. At the end of his life he was still mentally sharp and physically active.

Isn’t that what anti-aging is supposed to be? Living a long and full life. But do you have to embark on such a restrictive diet? Can’t you just take a pill or alter a gene? In the Aug. 29th issue of Cell Reports, there is an article that suggests it might be possible to alter such a gene (1). The gene in question mTOR expresses two proteins mTORC1 and mTORC2. mTOR is shorthand for “mammalian target of rapamycin”. Rapamycin is an antibiotic isolated from the soil of Easter Island and is also a powerful immune suppressor. It has been demonstrated that the earlier you give rapamycin to mice, the more you slow their aging process (2,3). In this study researchers genetically reduced the activity of mTOR gene by 75% so it was like giving rapamycin at birth. As might be expected, there was an even greater increase in overall lifespan of the mice corresponding to adding another 16 years of life to humans. These genetically altered mice also appeared to maintain their cognitive skills to a greater extent than the controls, but on the down side they also had less muscle mass and bone density. More ominously, the genetically altered mice also appeared to be more susceptible to infections in old age, suggesting that their immune systems were compromised.

OK so you get some tradeoffs by inhibiting mTOR gene expression: A longer life with greater frailty and decreased immune function as you age. Obviously, you don’t want anyone tinkering with your genes because no one knows the outcome. However, you can tweak gene expression using diet.

One way to reduce mTOR activity is to simply reduce the levels of the amino acid leucine in your diet. This is because leucine stimulates mTOR. If you stimulate mTOR, then you build bigger and stronger muscles. That’s why body builders use a lot isolated dairy protein powders that are rich in leucine as well as eat a lot of egg whites (an even richer source of leucine). On the other hand, vegans don’t eat dairy or eggs and therefore get very little dietary leucine, and their lack of muscles show it. Unfortunately, one of the biggest problems with aging is lack of muscle mass and a less than optimal immune system. So just turning down mTOR activity is probably not sufficient for healthy aging. On the other hand, calorie restriction (like that of Luigi Cornaro) stimulates another gene known as SIRT1 that causes the increased expression of the “enzyme of life” (AMP kinase) that controls metabolism and slows the aging process. You can also stimulate SIRT1 by consuming lots of polyphenols. Can’t you just fine-tune both mTOR and AMP kinase and maximize your quality of life as you age?

Of course you can by having a dietary program consisting of consuming small (but not excessive) amounts of leucine in the blood throughout the day. You can do this by eating no more high-quality protein than you can fit on the palm of your hand. This is about 3 ounces for women and 4 ounces for men. This will activate the mTOR that is necessary to build and maintain muscle and bone. By consuming large amounts of non-starchy vegetables, you are consuming polyphenols that stimulate AMP kinase. By doing both, you are constantly balancing mTOR and AMP kinase but without the rigid calorie restriction undertaken by Luigi Cornaro nearly 500 years ago. You are still restricting calories, but now in the range of 1,200 to 1,500 calories per day compared to the estimated 600 calories per day that Luigi was consuming.

Just to cover your bets since you would be consuming more leucine than Luigi did, you need to counter balance that with more polyphenols most likely by supplementation. Consuming one to two glasses of red wine per day is one way to get extra polyphenols. A better way is to use purified extracts rich in polyphenols, but without the alcohol. Finally for good measure, you want to take at least 2.5 grams of EPA and DHA as that level has been shown to increase the levels of telomeres that further decrease the rate of aging (4).

But isn’t that the Zone Diet? Of course it is, and that’s why I wrote The Anti-Aging Zone more than a decade ago. It was true then, and it is still true today.


  1. Wu JJ, Chen EB, Wang JJ, Cao L, Narayan N, Fergusson MM, Rovira II, Allen M, Springer DA, Lago CU, Zhang S, DuBois W, Ward T, deCabo R, Garilova O, Mock B, and Finkel T. “Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression.” Cell Reports 4:1-8 (2013)
  2. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA,Fernandez E, and Miller RA. “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.” Nature 460: 395-395 (2009)
  3. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R; Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, and Strong R. “Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice.” J Gerontol A Biol Sci Med Sci 66:191-201 (2011)
  4. Kiecolt-Glaser JK. Epel ES. Belury MA. Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, and Blackburn E. “Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial.” Brain Behav Immun 28:16-24 (2013)

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.


  • 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)

“Biggest Loser” or best Zoner?

A few weeks ago I spoke at the American Society of Bariatric Physicians. Later in the day I heard an interesting lecture from the lead dietician for the TV series “The Biggest Loser”. In this lecture, she disclosed all the keys for successful weight loss in the individuals on the show.

The first was incredibly careful screening just like you would do for a clinical trial. This is to make sure you have incredibly motivated people, who aren’t depressed or have other existing medical conditions, such as heart disease. In other words, you stack the deck. Considering that after the first pilot show in 2004, there were 225,000 applications for the 2005 series, there is no problem in recruiting motivated people. Just to make sure the motivation is maintained, the contestants get paid while they are on the show in addition to the big payoff for the winner at the end of the series.

Next contestants are isolated in a “camp”. Consider this to be like a metabolic ward where they only have access to good food for the next 10 to 16 weeks. This means no white carbohydrates and no artificial sweeteners other than stevia and all the meals made for them.

According to the speaker, the real secret is that they are fed a Zonelike Diet with 45 percent of the calories coming carbohydrates (primarily non-starchy vegetables and fruits) with a very limited amount of whole grains, 30 percent of the calories from low-fat protein, and 25 percent from good fats, such as olive oil or nuts. The typical calorie intake for the females is 1,200 to 1,600 and for the males about 1,800-2,400. The typical 300-pound contestant will consume about 1,750 calories per day. Finally, you spread the balanced calories over three meals and two snacks during the day.

Of course, you never see the contestants eating their Zone meals and snacks or the dietician discussing nutrition with them because that makes for boring TV. So most of the time you see them being yelled at by their trainers. That makes for exciting TV. In fact. the more tears they shed by being intimidated, the better the ratings.

So what happens to them after they leave the show, no longer get paid, and are surrounded by their favorite foods? About 50 percent regain the lost weight. But the other 50 percent have found out that the Zone Diet isn’t that hard, and now they have a clear dietary plan for a lifetime without being yelled at by drill sergeant-like trainers.