Omega-3 Fish Oils: The Greatest Nutritional Health Discovery Since Vitamins:

An Interview with Professor Jørn Dyerberg, M.D. By Richard A. Passwater, Ph.D.

http://www.drpasswater.com/nutrition_library/dyerberg.html
© 2010 Whole Foods Magazine and Richard A. Passwater, Ph.D.

Part One; The Discovery

Reduce your chance of dying a sudden death by 45% (1, 2)! Reduce your risk of dying from sudden cardiac death by 90% (3). Reduce your chance of developing Alzheimer’s disease by 45–50% (4). Stay younger longer (5, 6)! Reduce the inflammation and pain of rheumatoid arthritis and the pain of osteoarthritis arthritis and other inflammatory diseases (7, 8). The litany of health benefits from omega-3’s goes on, but hopefully, these are enough to get your attention so that you will read on about this miraculous dietary supplement. We will discuss the details of these studies in a later installment of this series.

Recently, a low level of long-chain omega-3 fatty acids had been purposed as a risk factor for heart disease. The new risk factor is based on measuring the fatty acids in red blood cells, and is expressed as a percentage of EPA + DHA of total fatty acids. An omega-3 index of >8% is associated with 90% less risk for sudden cardiac death, as compared to an omega-3 index of <4%.

Admittedly, to some, omega-3s are starting to sound a bit old. What could be new about them? Plenty! And, of course, since everyone knows about them now, it’s hard to envision that it took a small handful of brilliant and dedicated scientists to discover their importance to human health.

Modern mankind is deficient in the omega-3 fatty acid nutrients. In recent years, the biologically functional omega-3 fatty acids in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid ( DHA), have been the second-most important dietary supplement, ranking just behind general purpose multis (multivitamins and minerals). Now, it seems that in a couple of market segments, fish oil supplements have become the leading supplement.

The Nielsen Company, a market research firm, reports that sales of omega-3 products showed a 42% growth in 2009 (9). ConsumerLab.com reported in February that fish oil/omega-3 supplements were used by 74% of respondents of their survey (up from 71.6% in 2008), followed in popularity by multivitamins, which were used by 72% (down from 73.8% in the prior year) (10).

The popularity of fish oils is largely due to their health benefits and convenience of supplemental form. Fish are important in the diet, but difficult to include often enough for maximum benefit. Also, the purity of refined fish oils allows more of the important omega-3s to be consumed without the burden of the impurities of whole fish, which include mercury and PCBs.

Nearly everyone in the civilized world knows of at least some of the health benefits of these marine lipids. EPA and DHA are primarily found in cold-water fish, but it seems that few people, aside from scientists, know of the primary discoverer of these health benefits, Jørn Dyerberg, M.D. The story has been more than 40 years in the making and he had to go to nearly the end of the earth to uncover it. His complete research is well-deserving of a Nobel Prize.

Several billions of people live and have lived on this planet and yet relatively few have ventured deep into the Arctic Circle. Nor have they made a major health study that betters the health of millions of people. Dr. Dyerberg has done both.

Dr. Dyerberg, professor and Dr. Med.Sc., has made several discoveries that elucidate many of the health benefits of omega-3 fish oils. Dr. Dyerberg made five scientific expeditions to Northwest Greenland examining the association between fish oil intake and coronary heart diseases in Eskimos. Dr. Dyerberg, who is Danish, hypothesized that the rarity of coronary heart disease among the Inuit population could be due to the omega-3 fatty acids in their diet consisting largely of seal and cold-water oily fish. Together with his fellow researchers, he went on to elucidate the unique physiological effects of these fatty acids. His research opened new fields leading to thousands of health studies by many. His own research encompasses more than 350 scientific publications primarily concerning blood lipids, atherosclerosis, the blood coagulation system, omega-3 polyunsaturated fatty acids, trans-fatty acids and pro­staglandins.

In 2007, Dr. Dyerberg was honored by the American Heart Association in “Recognition of Outstanding Scientific Contribution for the Advancement of Heart Health Worldwide.” In 2008, he received the American Dietetic Association Foundation’s Edna and Robert Langholtz International Nutrition Award. Hopefully, the Nobel Prize committees are studying his research.

Dr. Dyerberg has served as chief physician and head at the Aalborg hospital. He has been a professor in Copenhagen since 2001 and is currently a medical and scientific advisor to Napro-Pharma Ltd. (Norway) and Unilabs Ltd. (Denmark).

Passwater: Dr. Dyerberg, I first learned of your research in 1981 thanks to a visit to my laboratory by Dr. Tom Sanders of Queen Elizabeth College in London. He was aware of my writings questioning the prevalent thinking that heart disease was simply a matter of eating too much cholesterol and he thought that I would be interested in your seminal findings. He told me about your forays to Greenland and showed me your 1971 to 1981 publications. This meeting led to my writing of the first book on fish oils in 1982, called EPA—Marine Lipids (11).

 The first thought that went through my mind was, “What in the world were you doing in the cold, cold Arctic when you could be working in a nice warm clinic or laboratory.” I could envision you and your colleagues riding dog sleds and trying to convince the Inuits to give you blood samples.

So, let’s start at the beginning. Dr. Dyerberg, why did you want to become a physician in the first place?

Dyerberg: I have never had any other idea for my professional life than to be a doctor. During my studies and the first two to three years after, I aimed at becoming a specialist in medicine (internist). In the course of that, I was appointed to Dr. H.O. Bang’s laboratory in Aalborg Denmark, where I was fascinated by the research possibilities that position offered. After a period at the pediatric and neurological departments, I returned to the clinical-chemical specialty with Dr. Bang, a decision I have never regretted, and I have spent the whole of my professional career in that specialty.

Passwater: Okay, then why did you travel to the end of the earth to study the health of the Greenland Inuits?

Dyerberg: It started in 1968 when an editorial appeared in the Danish Medical Society’s weekly journal, pointing at the unusual pattern of diseases among our Danish co-citizens in Greenland, the Eskimos or Inuits as they are called today. The anonymous author stated that it was an obligation for Danish researchers to study this issue “before it was too late,” meaning before westernization of the Inuit society took over.

Passwater: Even though Greenland is some distance from Denmark—actually being in North America while Denmark is in Europe—Greenland had been an “autonomous country” within the Kingdom of Denmark and thus many Danes had settled there.

Dyerberg: Yes. Among the many differences between the Greenland Eskimos’ disease pattern and the Danes’ disease pattern (including Eskimos who moved to Denmark) were that the Greenland Eskimos had a surprisingly low death rate from heart diseases, in spite of the fact that their traditional diet was based on seal and fish and consequently rather high in animal fat. Animal fat is considered by many to be a risk factor for coronary heart disease due to the increase in blood cholesterol. The Eskimo findings appeared to be paradoxical.

Passwater: You say surprisingly low. Wasn’t it only about a tenth—just 10%—of the U.S. rate of heart disease?

Dyerberg: Yes, we computed the death rates from coronary heart disease and found that the age standardized death rate for males aged 45–65 years in Greenland at that time was 5.3% compared to 40.4% in the United States. At that time, I was a resident physician in Dr. Bang’s laboratory. Dr. Bang had visited Greenland in the 1950s during a measles epidemic, and suggested that we should go to Greenland to examine the Eskimo’s blood lipids using an analytical method I had developed for my Ph.D. thesis for measuring lipoproteins in blood, a method that could be performed under field conditions (12). We managed to collect a modest sum of money to finance the trip, and together with a laboratory technician, we made our first Greenland expedition in 1970.

Passwater: A strong analytical background is important to scientific discovery. I have had the opportunity as a director of an analytical research laboratory to help many scientists, even Nobel Prize winners, use advanced analytical tools to help elucidate their discoveries.

You used the word, “expedition.” I doubt that in 1970 you could just go out with a load of scientific equipment and catch a plane to a remote Eskimo village. In 1981, when I first read your research papers, I envisioned you traveling by dogsled. Am I right?

Dyerberg: Yes, as you can see by these photos from our later expedition in 1976. The first (see Figure 1) shows a view from the sled as we were sledding 100 miles on the sea ice to Igdlorssuit. The name of the village translates to “The Big Houses.” Perhaps you recognize the word “igloo” in it. Igdlorssuit was a settlement with 100 inhabitants and approximately 800 dogs.

Passwater: It seems that everyone needs eight huskies to power their sled. The photo makes me feel cold just looking at it. It also reminds me of the old motivational expression that “the view changes only for the lead dog.”

I would guess that the only “experience” most of our North American readers have with dog sledding is from seeing TV news reports of the Great Iditarod Sled Race. We may have some readers in the northern states and Canada who have actually taken joyrides on dogsleds for short distances for recreation near where they live. However, very few of our readers have taken a real dogsled expedition across the frozen tundra and frozen sea. What most of our readers they normally see on the news is a bunch of excited dogs barking happily at the start of the race.

Dyerberg: The experience of dog sledding all depends on the weather! We were happy to do the two long tours on sea ice from the main city Uummannaq to the settlement Igdlorssuit (now called Illorsuit) about 100 kilometers to the north. Uummannaq is a town of 1,500 people today and is the northernmost ferry point. Igdlorssuit is directly north over the sea ice of the Uummannaq Fjord. We had blue skies during the days of the midnight sun during our travel. The temperature ranged from about –10 to –20 degrees Celsius (minus four to plus 14 degrees Fahrenheit) and low wind. That makes such the experience perfect. In harsh weather, it can be quite the opposite. At that time, dog sledding was the only transportation available in winter time. Now, I believe they have snow scooters.

Passwater: Wise planning! The only time I was above the Arctic Circle was in North Finland in October 1993 and I was not so fortunate. I was there during the period when it was mostly dark and very much colder than I like. My hosts from the University of Jyvaeskylae took us north on a side-trip and we had a long and happy celebration to help us deal with the darkness and weather.

How about the dogs?

Dyerberg: When you start out the dogs are eager and barking, but they quiet down as they have to do hard work for a long time—the tour took 10–12 hours, with two to three stops for making tea and feeding the dogs. The behavior of the dogs depends solely on the driver. We had experienced Eskimos as drivers, but of course we also tried to run the pack, but in vain. You have to know the commands and to use the whip to direct the dogs, and both are plain impossible. It is rather slow driving, the dogs cannot run fast with a heavy sled (we brought a lot of gear) and you are asked to run along with the sled now and then to ease the dogs’ burden. This is not easy as we were in a dress that does not invite running, as you can see from my photos. You do not stop for fishing; the sea ice was 1.5 meters when we sledded the approximately 100 km each way on it. There are some unpleasant issues as well, but there was no other way of getting the research done.

One of the dogs in each pack is the boss, which he rather often has to state, so both while sledding and resting there are often fights, which often leaves the lines entangled and “soiled.” It can be quite a job for the driver to disentangle them with his bare hands and often with the help of his teeth!

We were hungry when we reached our destination and glad to enjoy some Eskimo food.

Passwater: Well, maybe it wasn’t as “glamorous” as I envisioned. This second photo (Figure 2) shows that at least you could stop to rest occasionally. That must be you on the right.

Figure 2: Melting snow to make tea while the dogs rest. Dr. Jørn Dyerberg is on the right. Reprinted with the permission of copyright owner, Dr. Jørn Dyerberg.

Dyerberg: Yes, here we are taking a rest for both the dogs and the people. Yes, I am on the right on the sled having a cup of warm tea sitting next to our technician. That is a primus stove at our feet for melting snow and boiling water for our tea.

Passwater: I guess it is either water or tea made from melting the snow. Any other drinks would be too heavy and bulky to carry by dogsled.

Dyerberg: Right. In this April 1976 expedition, we were collecting food items in winter time from the Eskimos. There were eight of us on eight dogsleds. There were Dr. Bang, myself, two technicians for preparing the samples, a practical guy, a dietician for doing food interviews, Dr. Hugh Sinclair from England and an expedition leader Ivars Silis—a later well-known arctic photographer—and 88 huskies.

We stayed and worked at Igdlorssuit for about four weeks and returned to Uummannaq the same way. From there, we took a boat down to Srd. Stromfiord and flew back to Denmark.

Passwater: At the time, did you sense you were on an adventure or just working?

Dyerberg: We knew that we had data that had never been collected before, but we had at that time no idea of the magnitude of our findings. The omega-3 concept was still some years ahead of us.

Passwater: Studying a people’s diet is one thing, but you started with blood samples. What were you looking for?

Dyerberg: We collected blood from 130 Eskimos in a fasting state, returned to Denmark, analyzed their blood lipids and lipoproteins and published the results in The Lancet in April 1971 (13).

Passwater: Even though the word “omega-3” was not mentioned in that seminal paper, it was the birth of the omega-3 story, and the study has since been classified as a “Nutrition Classic.”

Dyerberg: We found, in spite of their high-fat diet, that the Eskimos had favorable blood lipid levels. Yes, their cholesterol levels were lower than what we found in Danes, however their blood cholesterol levels were not low enough to explain the marked difference in heart attacks compared with Danes and Americans, thus we had to look for further explanations.

Since we realized that it was unlikely anyone would ever be able to reach these people again before their diet and lifestyle were altered due to the changes being brought about by modern travel and accessibility improvements, we felt it was our duty to analyzes and publish as much as we could before it was too late. We used everything at our disposal including an old gas chromatograph in our lab. At least in the future, others would be able to know as much about 1970-era Eskimo blood lipid profiles as we could determine with our 130 blood samples.

Passwater: If it was already an old chromatograph in the early 1970s, it must have been a single-column instrument without temperature programming and without capillary columns. That would have really been a difficult analysis. So, you expanded beyond gel electrophoresis and your procedure for lipoproteins. In the 1970s, gas chromatographs and other analytical instruments were not as sophisticated or as fast as they are today. What could you hope to find other than the most basic blood evaluations?

Dyerberg: We were just testing for everything we knew about, but we did notice a couple of extra peaks in the fatty acid analysis of the blood samples—peaks that we had never seen before.

Passwater: Aha! Mystery compounds X and Y. Very interesting. If you didn’t happen to have the proper separation column and instrument settings, you may never have detected those extra peaks.

For our readers not familiar with gas chromatography, the different peaks represent the presence of different compounds as they elute from the separation column over time. So, here you were finding an indication of compounds never seen in human blood samples before. They were in the blood of Eskimos currently living in Greenland, but not in Eskimos who had moved to Denmark.

Dyerberg: Yes, we didn’t know what compounds they indicated, but it was reasonable to believe that they were fatty acids.

Passwater: But, you had to know just what these mystery compounds were for sure. Where did they come from? Could they be related to heart disease? If so, how?

Let’s take a pause and resume our chat next month. Stay tuned, readers, to learn how Dr. Dyerberg solved these riddles. WF

References

1. Dietary Supplementation With N-3 Polyunsaturated Fatty Acids And Vitamin E After Myocardial Infarction: Results Of The GISSI-Prevenzione Trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico.
2. C.M.Albert,et al., “Blood Levels of Long-Chain N-3 Fatty Acids and the Risk of Sudden Death,” N. Engl. J. Med. 346 (15), 1113–1118 (2002).
3. H.Leon,et al., “Effect of Fish Oil on Arrhythmias and Mortality: Systematic Review,” BMJ 337, a2931 (2008).
4. E.J.Schaefer,et al., “Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease: The Framingham Heart Study,” Arch. Neurol. 63 (11), 1545-1550 (2006).
5. R. Farzaneh-Far,et al., “Association of Marine Omega-3 Fatty Acid Levels with Telomeric Aging in Patients with Coronary Heart Disease,” JAMA 303 (3), 250–257.
6. R. Farzaneh-Far,et al.,“Telomere Length Trajectory and its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study,” PLoS One 5 (1), e8612.
7. B.Galarraga, et al., “Cod Liver Oil (N-3 Fatty Acids) as a Non-Steroidal Anti-Inflammatory Drug Sparing Agent in Rheumatoid Arthritis,” Rheumatol (Oxford) 47, 665–669 (2008).
8. D.Fritsch, et al., “A Multicenter Study of the Effect of Dietary Supplementation with Fish Oil Omega-3 Fatty Acids on Carprofen Dosage in Dogs with Osteoarthritis,”J. Amer. Veterinary Medical Assoc. 236 (5), 535–539 (2010).
9. S. Starling, “Nielsen: Omega-3 Sales Grow 42 Percent,”www.nutraingredients-usa.com/content/view/print/275814,accessed Feb. 1, 2010.
10. ConsumerLab.com Newsletter Feb. 1, 2010,http://view.email.consumerlab.com/?j=fe54177877610d757611&m=fef61d78716705&ls=fde910737d6103747010717d&l=fe651670746d067f7613&s=fe2e107576600d7f711670&jb=ffcf14&ju=fe2c1670766601787c1d70&r=0
11. R.A.Passwater, EPA—Marine Lipids (New Canaan, CT, Keats Publishing, 1982).
12. J.Dyerberg and N. Hjorne, “Quantitation of the Lipoprotein Complex by Agarose Gel Electrophoresis,”Clin Chim Acta 33 (2), 458–461 (1971).
13. H.O.Bang,et al., “Plasma Lipid and Lipoprotein Pattern in Greenlandic West-Coast Eskimos,” Lancet 1 (7710), 1143–1145 (1971).

Part Two: Solving the Riddle

Last month, we chatted with Dr. Jørn Dyerberg about his major health discovery of omega-3 fatty acids in human health. While that part of the interview with Dr. Dyerberg was in press, another major confirming study was published that should be noted. In a large multi-year study, Dutch researchers reported a 62% lower risk of fatal heart attack in people consuming a modest amount of EPA and DHA (approximately 230 mg/day) from fish as compared with those consuming small amounts (approximately 40 mg/day of EPA and DHA) (1).

Getting back to our main story, last month Dr. Dyerberg recounted his expedition into Greenland to discover why these remote-living Eskimos had about only one-tenth the heart disease incidence of many western countries including the United States and Denmark. The sojourns were hard physical work, and now comes the difficult detective work of solving this scientific riddle.

Jørn Dyerberg, M.D., professor and Dr. Med. Sc., has made several discoveries that elucidate many of the health benefits of omega-3 fish oils. He made five scientific expeditions to northwest Greenland examining the association between fish oil intake and coronary heart diseases in Eskimos. Dr. Dyerberg, who is Danish, hypothesized that the rarity of coronary heart disease among the Inuit could be due to the omega-3 fatty acids in their diet consisting largely of seal and cold-water oily fish.

Together with his fellow researchers, he went on to elucidate the unique physiological effects of these fatty acids. His research opened new fields leading to thousands of health studies by many. His own research encompasses more than 350 scientific publications primarily concerning blood lipids, atherosclerosis, the blood coagulation system, omega-3 polyunsaturated fatty acids, trans-fatty acids and prostaglandins.

In 2007, Dr. Dyerberg was honored by American Heart Association in “Recognition of Outstanding Scientific Contribution for the Advancement of Heart Health Worldwide.” In 2008, he received the American Dietetic Association Foundation’s Edna and Robert Langholtz International Nutrition Award.

Passwater: Dr. Dyerberg, when we left off, you were telling us about how you had discovered two before-unknown peaks in your gas chromatographic analysis of the blood samples from the Greenland Eskimos. You had reason to believe that these peaks were due to unknown fatty acid compounds in the blood.

Dyerberg: Yes, and if they were fatty acids, I would have to learn more about determining which ones they might be. So, I sought help in the interpretation of our results from Dr. Ralph Holman at the Hormel Institute at the University of Minnesota, who was the leading fatty acid analyst of the time.

Judging by the position of the peaks, Dr. Holman postulated that we had found omega-3 fatty acids in blood, quite possibly EPA and DHA.

Figure 1: Chromatogram shows two previously unexplained peaks. A chromatogram produced by a gas chromatograph plots the concentration of the components in a sample against time. Larger compounds in terms of molecular weight take longer to elute from the separation column. Dr. Jørn Dyerberg’s analysis of blood lipids from the Eskimos showed two later eluding peaks than observed before. Since the two peaks eluted later, this indicated that they were larger molecular weight compounds than the fatty acids normally observed previously.

Passwater: As I see the omega-3 story, you are the defining scientist, and your detection of these two unknown compounds in the blood of the Eskimos was the defining event that has led to an advance in nutrition that can favorably impact everyone’s health. These early chromatograms should be in a scientific museum such as the Smithsonian.

EPA and DHA hitherto were neither recognized as essential nutrients nor reported as constituents of human blood or tissue, and their function was completely unknown. Well, trying to find the answer to your question of why the Inuits had dramatically less heart disease has taken you to the end of the earth and now back to the United States where you had studied earlier.

Now that we are speaking about identifying the presence of omega-3 fatty acids, let’s just take a moment and review some basic biochemistry terminology for our readers. The omega-3 family of fatty acids is defined as fatty acids that have their first “unsaturated” carbon as the third carbon from the “omega” end of the molecule. Fatty acids are components of fats similar to how amino acids are building blocks of proteins. A fatty acid has several carbon atoms strung together like a chain with an “acid” functional group [COOH] at its beginning carbon atom. The “acid” group is easily identified because it is the only group in fatty acids that contains oxygen atoms. Not surprisingly, this first carbon atom in the fatty acid “backbone” or “chain” is designated as the “alpha” carbon.

The end of the fatty acid farthest from the acid group is called the “omega” end, which is sometimes called the “methyl end.” This carbon atom is said to contain the terminal methyl group (CH₃) (see Figure 2). If a carbon atom is not fully saturated with hydrogen, it is said to be “unsaturated” and is linked to a neighboring carbon atom, which is also unsaturated by a double bond. The location of the first double bond counted from the omega end denotes whether a fatty acid belongs to the omega-6, omega-3 or other omega family. Humans cannot interconvert omega-3 and omega-6 fatty acids to each other, nor can they make either of these fatty acids from scratch. Additionally, as we will discuss in the next installment, all omega-3s do not function in the same way, and importantly, not all omega-3 fatty acids are biologically equal. Humans cannot readily convert significant amounts of shorter omega-3 members to EPA and DHA.

Dr. Dyerberg, in your analysis, you found compounds that were very long-chain fatty acids (based on the time it took for them to elute from the separation column of the gas chromatograph) and omega-3 or whatever, this was new information.

Figure 2: The two ends of a fatty acid are usually designated “alpha” and “omega.” Here, this “stick and ball” Kekulé system molecular model is of butyric acid. The “balls” represent atoms and the “sticks” linking the atoms represent the “bonds” which are a sharing of electron paths that act as a force to hold the atoms together. Butyric acid—a simple saturated (only single bonds) fatty acid having a chain length of four carbon atoms (carbon atoms shown in red, hydrogen atoms are shown in grey)—is shown. The alpha end is the end having the acid group, which has two oxygen atoms (shown in blue). The omega end contains the terminal methyl group (CH3) and also is called the “methyl end.”

Dyerberg: Yes, I even had to learn the names of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Dr. Holman knew them from basic fatty acid chemistry outside of the body, but as far as I know, no one had studied them in human blood before or knew that they existed in the body.

Nothing at all was known about the effects of EPA and DHA in human biology at that time! It was known that a deficiency in the omega-3 fatty acid alpha-linolenic acid (ALA), with 18 carbon atoms and three double bonds, caused skin problems in rats, but nothing on the effect of the long-chained omega-3 fatty acids. At that time, polyunsaturated fatty acids meant omega-6 fatty acids from vegetable oils.

Figure 3 shows the chemical structures of these three omega-3 fatty acids.

Figure 3: Here, we switch from the “stick and ball” model of molecular structures to the “shorthand” molecular system to better focus on the differences between the chemical structures of three important omega-3 fatty acids, ALA, EPA and DHA. In these models, the atoms are not represented as balls. Carbon atoms are not labeled and are merely shown as bends in the structure. Hydrogen atoms are not labeled unless they are part of a radical group. Oxygen atoms are labels as “O.”

Passwater: As I mentioned, we will discuss the biochemistry of various omega-3 family members in the next installment of this series. This is important to understand why the biological functions of EPA and DHA are different from ALA and why humans can transform only a very small amount of ALA into EPA and DHA. Therefore, all omega-3s are not of equal importance to our health.

How did you confirm that they were indeed EPA and DHA?

Dyerberg: Dr. Holman gave me some pure EPA and DHA samples. I returned to Denmark and used these pure compounds as standards in the analysis. The chromatographic peaks that we observed were confirmed to be EPA and DHA. The Eskimos indeed had appreciable amounts of EPA and DHA in their blood.

Passwater: Could you tell if the EPA and DHA were present in their blood as free fatty acids or were they present primarily as components of triglycerides? As information for our non-chemist readers, fatty acids normally occur in nature as components of a larger unit commonly called a triglyceride, which is composed of three fatty acids on a glycerol backbone. Biochemists prefer to call triglycerides by the more descriptive name, triacylglycerols (TGA).

Were the fatty acid peaks due their being liberated from triglycerides during the sample preparation for fatty acid analysis by gas chromatography?

Dyerberg: We found EPA and DHA in all plasma lipid classes, free fatty acids, triglycerides, cholesterol esters and phospholipids. In looking for them, we also found them in plasma from Danes, but to a much lesser extent (2).

Passwater: Did you have any idea at this time how EPA and/or DHA could be relevant to heart disease?

Dyerberg: No, but we also noticed that the Eskimos’ blood samples were lower in another fatty acid, called arachidonic acid (AA). At that time, there were new scientific discoveries coming out of Sweden and England showing that blood clotting, among many other things, was regulated by components called prostaglandins.

Passwater: Prostaglandins are now recognized as members of a larger family of oxygenated fatty acids called eicosanoids. In the 1930s, a compound that originated in the prostate that caused a reaction in the uterus was discovered. But, it wasn’t until about 1973 that Hamberg and Samuelson discovered that compounds with similar structures affected platelet aggregation and, in turn, platelet stickiness and blood clotting.

Dyerberg: Yes, prostaglandins were synthesized in the body from AA. AA is an omega-6 polyunsaturated fatty acid found in meat. It has a chain length of 20 carbon atoms, the same number as EPA; but AA has only four double bonds, while EPA has five. The important difference, though, is that EPA has its first double bond in the omega-3 position and AA has its first double bond in the omega-6 position (see Figure 4).

Figure 4: A comparison of the chemical structure of the omega-6 fatty acid, ALA, to that of the omega-3 fatty acid, EPA. The double lines represent double bonds between carbon atoms. Counting from the omega end, the first double bond in arachidonic acid is at the sixth carbon, thus, it is called an omega-6 fatty acid. Omega-6 is sometimes written as Ω-6, n-6 or w-6.

We then hypothesized that the shift in Eskimo blood from AA to EPA and/or its 22 carbon omega-3 cousin, DHA could “tune” their blood clotting into a less active state by changing the prostaglandin formation to components generated from EPA and/or DHA, thereby diminishing the risk for clots in their arteries and consequently their risk of heart attacks.

Passwater: This is where I found your research to be extremely exciting. Up until this point, I found your research very enlightening, but with this information, I found it to be compelling. So, I set about writing the first book on omega-3s nearly 30 years ago in 1981 based on your research. The book became one of the first of the Good Health series by Keats Publishing (3). The role of platelet aggregation and blood viscosity in heart disease made a lot of sense to me. You just don’t have a myocardial infarction unless and until you have a blood clot. Keeping the blood slippery and free from clotting will reduce the probability of having the common heart attack called an acute myocardial infarction (AMI or MI). We can discuss that later in Part 3, but for now, let’s continue with the detective story.

Your search for the answers took you from Denmark to Greenland to the United States. What did you do next?

Dyerberg: In Dr. Hans Olaf Bang’s lab, we investigated whether EPA could give rise to the formation of prostaglandins with an effect on blood clotting. This we found, and it fitted with our hypothesis of an “anti-clotting” effect of EPA.  Then, we went back to Greenland to study the Eskimos’ blood and diets again.

Passwater: The journeys—scientific and physical—add up in years and distance. Physically, you have gone from Denmark to Greenland to Denmark to United States to Denmark and now back to Greenland.

What additional factors did you study on this trip?

Dyerberg: We then confirmed that EPA and DHA affected the clotting time of the Eskimos’ blood. This could be studied by measuring the Eskimos’ bleeding tendency. We examined this during new expeditions to northern Greenland, finding that the Eskimos actually had a longer cutaneous bleeding time. In 1979, again in The Lancet, we reported our results in a paper entitled “Haemostatic Function and Platelet Polyunsaturated Fatty Acids in Eskimos” (4). This paper also became a “nutritional classic.”

Passwater: Your findings at this point certainly were fascinating. Humans certainly don’t produce many long-chain omega-3s in their bodies, so then you had to answer where did the EPA and DHA come from. Polyunsaturated fatty acids are associated with plant foods, not animals. The snow- and ice-covered Arctic with their long periods of darkness is not conducive to growing plants, so isolated villages depended mostly on fishing and whatever else they could find hunting for food. The classical “Food Pyramid” for United States citizens has fats, oils and sweets in the smallest section with the recommendation to use them sparingly. I used to make jokes about the Eskimo food pyramid being composed of their main food groups of raw blubber, boiled blubber, fried blubber, baked blubber and roasted blubber. It was only a joke, but it made a point.

How did you connect Omega-3 fatty acids in the blood to Omega-3 fatty acids in the diet?

Dyerberg: As you know, not much was known at that time about EPA and DHA. What we found was that although fish and seals don’t make EPA and DHA themselves, they consume and concentrate these omega-3 fatty acids from the foods they eat. EPA and DHA are synthesized in the biosphere in the sea by algae. They then pass up the food chain via bigger and bigger organisms and finally via fish or, as for the Eskimos, seals that live on fish, into humans.

When we returned to Greenland, we collected food from the Eskimos using the cumbersome double portion technique, homogenized the food and froze it for transportation to analysis in Denmark. We found that the Eskimos ate approximately 14 grams of EPA and DHA per day! (5)

Passwater: Wow! Fourteen grams of EPA and DHA a day! And, most recommendations today are for at least one gram of EPA and DHA a day.

Getting back to your detective story, the next question then became whether the positive effects on the heart of omega-3 fatty acids from fish and fish oils that you found in the Eskimos could be transferred to our society by supplementing our diet with omega-3 fatty acids from fish oils?

Dyerberg: That’s a question that today, after nearly 40 years of research and after the undertaking numerous studies in volunteers and in patients with heart diseases, can be answered with an unambiguous “yes.” A 2009 survey of the preventable causes of deaths in the United States concludes that 84,000 deaths per year are attributable to low dietary omega-3 fatty acid intake (6)!

Furthermore, we have today obtained in-depth insight into how this beneficial effect is brought about. The studies have found that omega-3 fatty acids from fish oils have several positive effects; these effects work in combination, thereby lowering the risk of heart attacks. The same is true for patients already suffering from heart disease.

Passwater: How exciting. Let’s take another pause and pick up again here next month to discuss some of these effects of omega-3s and the clinical results that have been found. It is staggering to realize how much benefit has come from your pioneering discoveries. WF

References

1. J. de Goede and J.M. Geleijnse,et al.,“Marine (n-3) Fatty Acids, Fish Consumption, and the 10-Year Risk of Fatal and Nonfatal Coronary Heart Disease in a Large Population of Dutch Adults with Low Fish Intake,” J. Nutr. 140 (5), 1023–1028 (2010).
2. J. Dyerberg,et al.,“Fatty Acid Composition of the Plasma Lipids in Greenland Eskimos,” Am. J. Clin. Nutr. 28 (9), 958–966 (1975).
3. R.A. Passwater,EPA—Marine Lipids(New Canaan, CT, Keats Publishing, 1982).
4. J. Dyerberg and H. O. Bang, “Haemostatic Function and Platelet Polyunsaturated Fatty Acids in Eskimos,”Lancet2 (8140), 433–435 (1979).
5. H.O. Bang,et al.,“The Composition of the Eskimo Food in Northwestern Greenland,” Am. J. Clin. Nutr. 33 (12), 2657–2661 (1980).
6. G.M. Danaei,et al.,“The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors,” PLoS Med. 6 (4), e1000058 (2009).

Part Three – The Basics of How EPA and DHA Bring Health Benefits

Do all omega-3 fatty acids provide heart benefits? Does the ratio of EPA to DHA matter? Is EPA good for the heart while DHA is good for the brain? Does it matter if EPA and DHA are present as free fatty acids, triglycerides or ethyl esters? Several misconceptions have arisen over the years and some readers may be surprised at the answers to these questions.

We have been chatting with Dr. Jørn Dyerberg regarding his major discovery of omega-3 fatty acids in human health. In the June 2010 issue, Dr. Dyerberg recounted his expedition into Greenland to discover why these remote-living Eskimos had about only one-tenth the heart disease incidence of many Western Countries including the USA and Denmark. Last month, we discussed the detective work required to solve the scientific riddle. In this session, we will discuss how EPA and DHA function and clarify several issues concerning omega-3 fatty acids in general.

 Jørn Dyerberg, M.D., professor and Dr. Med. Sc., has made several discoveries that elucidate many of the health benefits of omega-3 fish oils. Dr. Dyerberg made five scientific expeditions to Northwest Greenland in the 1970s examining the association between fish oil intake and coronary heart diseases in Eskimos. Dr. Dyerberg, who is Danish, hypothesized that the rarity of coronary heart disease among the Inuit could be due to the omega-3 fatty acids in their diet consisting largely of seal and cold-water oily fish. Together with his fellow researchers, he went on to elucidate the unique physiological effects of these fatty acids. His research opened new fields leading to thousands of health studies by many. His own research encompasses more than 350 scientific publications primarily concerning blood ­lipids, atherosclerosis, the blood coagulation system, omega-3 polyunsaturated fatty acids, trans-fatty acids, and pro­staglandins.

 In 2007, Dr. Dyerberg was honored by the American Heart Association in “Recognition of Outstanding Scientific Contribution for the Advancement of Heart Health Worldwide.” In 2008, he received the American Dietetic Association Foundation’s Edna and Robert Langholtz International Nutrition Award.

Passwater: Usually in science, when one question is answered, other questions are raised. You sought to uncover why Eskimos had only a fraction of the heart disease normally observed in Western Nations. You found a difference in EPA and DHA content between the blood of Eskimos and that of Danes and North Americans. This raised the question: From where did these fats come? You were able to trace their origin to diet. This raised the question: What biochemical effects did they have? You verified that EPA and DHA had effects on cardiovascular health in terms of improved (longer) blood clotting times, improved blood lipid (triglycerides, cholesterol, etc.) levels and a better balance of prostaglandin (PG ) formation. This raised several other questions. Is either EPA or DHA more important? Can other omega-3 fatty acids have similar biochemical effects? Can other fatty acids be converted into EPA and DHA in the body or are EPA and DHA themselves essential fatty acids?

Let’s start with the very basics of the concept that some types of fats are essential to life. At one time, fats were considered merely unessential sources of calories. Now, we understand that fats are important components of every cell and the many compounds made from fats are involved in controlling thousands of functions. We now recognize that a balance of omega-3 and omega-6 fats that is close to the balance of fats of the Paleolithic diets to which man has been exposed for many thousands of years is a better fit for our genetic makeup than the more recent agricultural diets and the modern fast-food diets.

The concepts of “vitamin F” and “essential fatty acids” were developed decades ago, but no one knew much else about the biochemistry of fatty acids. Drs. H.M. Evans (the discoverer of vitamin E in 1925) and George O. Burr demonstrated that fat-free diets impaired the growth and reproduction of laboratory animals in 1927 (1). They viewed this as a vital factor in fats along the lines of a vitamin and called this factor “vitamin F” at first. Drs. George O. Burr and Mildred M. Burr introduced the concept of essential fatty acids (EFAs) during the next two years (2). Specifically, linoleic acid (LA)—a C18: 2 omega-6 fatty acid that cannot be made in the body—was involved. The deficiency symptoms noted were basically scaly skin and an increased consumption of water. These symptoms were eliminated when LA was added to the fat-free diet. It wasn’t until about 1970 that it was realized that EFA were critical to the retina. Now, EFA are recognized as being essential to normal growth reproduction and good health.

Dr. Dyerberg, wasn’t that basically all that was known about essential fats when you found appreciable amounts of EPA and DHA in the blood of the Greenland Eskimos?

Dyerberg: Yes, at the time we made our original observations in Inuits, the essentiality of (omega-6) fatty acids was related only to these basic issues, and the focus was on linoleic acid. The omega-3 series was not considered and the discovery of derived products (as the prostaglandins) was in its initial state, and the relation of EPA and DHA deficiencies to increased Ischemic Heart Disease (IHD) was unknown. IHD is the medical term for reduced blood flow to the heart. Over the years, interest in the health benefits of consuming omega-3 fatty acids EPA and DHA has also been aimed at the intake of the EFA alpha-linolenic acid (ALA, 18: 3 n-3), which in other mammals can be converted into EPA and DHA. In man, however, it can only be converted to a small extent.

The focus of interest has in that respect been twofold: whether ALA has health benefits of its own and whether the conversion of ALA to longer chained omega-3 fatty acids in humans is sufficient to produce desirable tissue levels of EPA and DHA.

The concept of “essential” polyunsaturated fatty acids (PUFAs) is a bit odd in a way, in that very few essential functions are known of the prime essential PUFAs linoleic acid (18: 2 n-6) and linolenic acid (18: 3n-3). Linoleic acid has a function in the water barrier of the skin, but no essential functions are known related to linolenic acid. Their longer-chained derivatives, arachidonic acid (AA) (20: 4 n-6), EPA (20: 5 n-3) and DHA (22: 6 n-3), are truly the “essential” fatty acids when it comes to their function and effects in the body.

Passwater: The Institute of Medicine states, “ALA is not known to have any specific functions other than to serve as a precursor for synthesis of EPA and DHA” (3). Heart health involves more than the old concept of EFAs. What is important to heart health goes beyond growth and maintenance and the classical symptoms of EFA deficiency of scaly skin and thirst. Cardiovascular optimization involves the two long-chain omega-3 fatty acids EPA and DHA, and their intermediary docosapentaenoic acid (DPA) (22: 5n-3). The only fatty acids for cardiovascular optimization are EPA and DHA. Let’s look at the basics of EPA and DHA.

We have mentioned earlier that the body is very inefficient in producing either EPA or DHA from the more common plant-based omega-3s such as ALA from flaxseed oils and a similar C18 omega-3 fatty acid from other plant oils and certain fish, stearidonic acid (SDA).

Animals do have enzymes that can add double bonds and lengthen the fatty acid (desaturation and elongation) in polyunsaturated fatty acids, but not after the omega-9 position in the fatty acid. (Plants can introduce new double bonds between an existing double bond and the terminal methyl group.) Animals can increase unsaturation to a very limited extent, but can’t change an omega 6 into an omega-3, nor can they make omega 6 or omega 3 fatty acids.

Dr. Dyerberg. Please elaborate on the ability for humans to make EPA and DHA and how does this relate to heart health?

Dyerberg: The body can form a small amount of EPA and DHA from ALA. However, this is inadequate for best cardiovascular health.

Omega-3 prostaglandins (PGs) and other essential metabolites such as protectins (complementary regulatory proteins that protect cell membranes; also called CD59 or MIRL) can be made only from EPA and DHA. A small amount of omega-3 PGs can result from ALA after the body converts it to EPA or DHA. ALA contributes only a little to the heart health benefits attributed to EPA and DHA since only about 1–5 % of ingested ALA becomes EPA and next to nothing DHA.

Passwater:   Billy Shakespeare pointed out that a rose by any other name is still a rose and the famous quote; “a rose is a rose is a rose” was soon born. Dr. Dyerberg, is an omega-3 an omega-3 an omega-3 (suggesting that all omega-3s are equal) or are there major health differences between the omega-3 fatty acids?

Dyerberg: Consumers should be aware that just having “omega-3” on a product label doesn’t mean that it is necessarily heart healthy. The consumer should be interested in how much EPA and DHA are present. If the omega-3 is from ALA, then little of it will be converted into the form of omega-3 that produces heart benefits which is EPA and DHA.

It can be concluded that to obtain desirable levels of plasma and tissue long- chained omega-3 fatty acids by supplementation, far lower and dietary acceptable doses are effective when supplementing with the preformed fatty acids such as fish oil-based supplements, than by giving the precursor ALA. To obtain desirable heart health benefits with ALA intake, this cannot be achieved by supplementation, but necessitates substantial dietary alterations.

The effect of ALA intake on cardiovascular risk markers is comparable to that of linoleic and oleic acid, and dietary changes reducing the intake of saturated fat and increasing the ALA intake are consequently advisable.

With regard to supplementation, ALA (often derived from flaxseed oil) has only minor effects on cardiovascular risk, probably due to the low conversion rate to long-chained omega-3 fatty acids.

Passwater: Is this conversion dependent on the rest of the diet?

Dyerberg: Yes, as an example, excessive omega-6 fatty acids such as the amount present in typical western diets can reduce the already meager amount of conversion of ALA to EPA.

Passwater: Please allow me add some background information here. The conversion of ALA to long-chain EPA is influenced by diet as well as genetics. The high levels of linoleic acid (LA) in western diets inhibit the low rate of ALA conversion further. If one consumes very high amounts of ALA and very little LA, the conversion of ALA to EPA can be enhanced, but it still falls short of what is required for optimization of heart health. This is why the diet of the Eskimos was protective against heart disease and the diets in western nations were not. This is the “why Eskimos don’t get heart attacks” story of Dr. Dyerberg’s research in Greenland is what we are discussing.

If one wishes to focus on preventing IHD, then one should focus on EPA and DHA. Our focus is on optimization and not merely deficiency. The state of knowledge and consensus of experts in the field is that ALA conversion to EPA is too inefficient to rely on for optimum heart health. Most scientists in the field agree and note the most recent studies confirm the lower range of conversion (more towards 1% than 5%) among those consuming standard western diets (4). A 2001 study using radioisotopes to follow the conversion found that “Only about 0.2% of the plasma ALA was destined for synthesis of EPA.” (5)

Even if the conversion is many times higher in some, whatever the figure is, it isn’t enough to produce the heart benefits produced by EPA and DHA. One percent or ten % is not 100%. If ALA did produce sufficient conversion to EPA and DHA, there would have been no need for Dr. Dyerberg to go to Greenland and find EPA in the blood of the Eskimos. There would have been ample EPA in most peoples’ blood from ALA present in these diets and people would have only ten percent of the IHD…

This is not to say that ALA is of little value or that it produces no benefit. It is an essential fatty acid and has multiple health benefits including benefits to overall cardiovascular health, as well as many benefits that we have yet to elucidate. Whole flaxseed also has merit because it supplies fiber and ALA. ALA is good and should be in everyone’s diet, but, ALA does not significantly contribute to the strong heart benefits of EPA and DHA which are due to the eicosanoids (derivatives of C20 fatty acids) that have been the focus of this discussion.

This point was the focus of a 2006 systematic review entitled “Omega-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies” was published in the American Journal of Clinical Nutrition. (6)

Earlier that year in the same journal, Dr. L. Arterburn and colleagues concluded, “A large proportion of dietary alpha-linolenic acid (ALA) is oxidized, and because of limited interconversion of n-3 fatty acids in humans, ALA supplementation does not result in appreciable accumulation of long-chain n-3 fatty acids in plasma.” (7)

Not only do we do highly inefficiently convert ALA to EPA, but adult humans do not make DHA from ALA. Adults cannot meet the needs of DHA for the developing fetus for neuro and brain development without dietary DHA. In infants, very high amountsof ALA did result in some increase in blood DHA in two studies. (8.9)

The International Society for the Study of Fatty Acids and Lipids (ISSFAL) published their official statement on ALA supplementation and conversion to long-chain polyunsaturated fatty acids in humans in 2009 in the peer-reviewed journal for experts in this field, Prostaglandins, Leukotrienes and Essential Fatty Acids. (10) The ISSFAL is a body of over 500 lipid scientists.The meta analysis and review was conducted by Dr. J. Thomas Brenna of Cornell University, Dr. Norman Salem, Jr. of Martek Biosciences, Dr. Andrew J. Sinclair of Deukin University (Australia) and Dr. Stephen C. Cunnane of the University of Sherbrooke (Canada). The ISSFAL statement concludes, “With no other changes in diet, improvement of blood DHA status can be achieved with dietary supplements of preformed DHA, but not with supplementation of ALA, EPA, or other precursors.” The statements of the ISSFAL can be also viewed at www.issfal.org.uk/lipid-matters/issfal-policy-statements/ official-policy-statement-number-5.html.

ALA supplementation can increase EPA slightly, but not optimally. However, the evidence clearly shows that precursor supplementation does not increase blood levels of DHA whether the supplement is ALA, EPA or stearidonic acid. The only known means to increase blood DHA by supplementation in adults is through the consumption of preformed DHA. Dietary DHA and blood/breast milk DHA has a remarkably tight dose-response relationship. (11)

A point of confusion in studies regarding fatty acids is whether the study involves supplementation or replacement. As Dr. Brenna points out, “In considering dietary interventions, seemingly conflicting results can be reconciled by attention to two concepts: supplementation versus replacement. Supplementation is the addition of a dietary nutrient with no other change in the diet. Replacement is the substitution of one food for another. In the case of ALA, supplementation is achieved by the addition of an oil rich in ALA, such as flax or perilla oil, to an otherwise unchanged diet. The major change in the diet is an increase in ALA, with insignificant changes in other fatty acids. Replacement would be achieved by substituting an ALA-rich cooking oil such as canola for ALA-poor oils such as corn, safflower, sunflower and peanut. Importantly, replacement also significantly alters the dietary proportion of the omega-6 PUFA, linoleic acid, a factor that is often overlooked in the interpretation of such studies. Linoleic acid competes with ALA for conversion to long-chain PUFAs and influences the answer. (12)

Two studies out of the 21 studies reviewed by the ISSFAL showed that conversion of ALA can be improved, but not to optimal EPA or DHA levels) In one study, DHA increased by an impressive 21%, when high-ALA perilla oil was used as cooking oil in place of moderate-ALA soy oil over 10 months. Perilla oil has about 15% linoleic acid, compared to more than 50% linoleic acid in soy oil, and thus linoleic acid was reduced to less than a third of pre-intervention levels. (13) In the second study, the researcher instructed the participants to avoid foods high in linoleic acid, in addition to the supplementation with ALA. (14) Good luck with that.

The Food and Drug Administration (FDA) has examined this question and  announced on September 8, 2004 the availability of a qualified health claim for reduced risk of coronary heart disease (CHD) on conventional foods that contain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acids. (15) The qualified health claim does not apply to ALA.

Passwater: Now, let’s resume our chat with Dr. Dyerberg. Dr. Dyerberg, are vegetarians usually sub-optimally nourished in terms of EPA and DHA even if they eat ample ALA say from flaxseed sources? Are vegetarian diets overly rich in omega-6 fats as well?

Dyerberg: My answer is yes. It should, however, be stressed as I mentioned before, that if the diet is altered substantially, as the vegetarians’ and even more so the vegans’ are, the conversion of the 18 carbon PUFAs to their longer derivatives is enhanced. As the vegetarian diet generally is very rich in omega-6 fatty acids, I would recommend a supplementation with EPA and DHA.

Passwater: Would vegetarians be better off taking DHA derived from microorganisms or ALA?

Dyerberg: As mentioned, I would recommend that vegetarians—and especially vegans—do add an EPA/DHA supplement to their diet. Whether this supplementation is based on fish oil or on algae is, in my opinion, of no importance. It is the fatty acids that work and your body does not differ between their origins.

Passwater: As our long-term readers realize, I often ask the same question in a couple of different ways as a means of emphasis and clarity just to be sure that everyone understands the issue. Let me repeat. So, in order to get the heart benefits, now so widely attributed to omega-3s, we need specific omega-3s—the long-chain EPA and DHA. Are EPA and DHA of equal value to the body? Can the body interconvert EPA and DHA?

Dyerberg: Both EPA and DHA have essential functions in the body. We do not know in detail all these metabolic processes. EPA and DHA can be inter-converted in the body to a certain extent, but especially the conversion of EPA to DHA is modest. Both fatty acids are present in marine food, and I see no reason to spend a lot of money in producing and supplementing with “stand alone) substances such as EPA (alone) and DHA (alone). The human biology has developed with foods containing EPA and DHA (and AA!), and it is for me not a meaningful nutritional issue to search for the pure substances.

Passwater: At first, your research centered on PG formation from EPA and DHA. You linked the presence of EPA and DHA in the diet of Eskimos to a better balance of PG. Specifically, you found that EPA and DHA balanced the production of the PGs responsible for increased clotting time, blood platelet protection and vascular function to reduce blood platelet aggregation.

Now, research has moved to include membrane function and phospholipids. Your research has expanded into the role of EPA and DHA in forming better membrane phospholipids, which result in more fluid and thereby healthier membranes. The result is better health throughout the body in all systems. Thus, we can understand the better health that EPA and DHA produce beyond heart benefits. They affect every cell in the body via their important role in every cell membrane.

Evidence has emerged describing the biological essentiality of DHA for vision and the brain, its function and behavior. Most of the dry weight of the brain is lipid (fat) because brain activity depends greatly upon the functions provided by lipid membranes. The brain is 60% fat, and DHA is the most abundant fatty acid in the brain, comprising 25–35%. DHA is found in even greater concentrations—50–60%—in the retina.

Drs. Michael Crawford and Andrew Sinclair have shown that the brain needs DHA for its structure, growth and function. Drs. Gene Anderson and Nicholas Bazan have shown that vision requires docosahexaenoic acid (DHA). Dr. Claudio Galli has shown that DHA is important in learning.

We have discussed EPA and DHA in regards to eicosanoid balance. Is the association of DHA with brain health due to its relationship with membrane fluidity and neurotransmitters? Is this an oversimplification or is there scientific basis for such an association? Is EPA needed just as much as DHA for brain function?

Dyerberg: DHA has both structural and functional effects in the brain, and so have its derivatives, the protectins. But, EPA also seems to have essential roles related to brain function. A recent metaanalysis of randomized, controlled trials actually finds that EPA, but not DHA, appears to be responsible for the efficacy of omega-3 long-chain PUFA supplementation in depressed individuals (16).

Passwater: On May 26, you were a featured speaker at the opening session of “A Celebration of DHA: Discovery, Achievement and Challenges for Global Health 40 Years On” at the Royal Academy of Medicine in London. A goal of the conference was to call for a new focus to be placed on brain disorders and ill mental health; they will be the top two burdens of ill health worldwide by 2020 and are the greatest threat to humankind today.

Do you see an important role for fish oils in reversing this trend?

Dyerberg: One of the most interesting nutritional findings in recent decades has been the effect of dietary factors on modifying age-related cognitive decline (dementia).

Several studies have found a negative association between intake of long-chained omega-3 fatty acids and the risk of dementia. In the Framingham Heart Study, the top quartile of plasma DHA levels was associated with a significant 47% reduction in the risk of developing dementia (17). I find these positive results in dementia, especially Alzheimer’s one of the most promising fields of research in the huge area of omega-3 science.

Passwater: With attention being given to DHA for brain function, when did we realize that mothers’ milk contained DHA?

Dyerberg: In recent decades it has been realized that mothers’ milk contains both EPA and DHA, however in varied amounts dependent on the omega-3 intake of the mothers (18). The DHA/EPA ratio is generally from 2: 1 to 1: 1, but in Italy, mother’s milk contained more EPA than DHA (0.17 and 0.12 wt% respectively) (19). Consequently, DHA and EPA as well as AA are essential for newborns as the content of mothers’ milk is considered the “gold standard” for the composition of food to the newborn.

Passwater: Forgive the redundant question, but I want to make this point clear. Does it matter what is the ratio of EPA to DHA in the diet? Does a higher ratio of DHA mean more goes to the brain? Are supplements having more DHA than EPA more suited for brain health and are supplements with more EPA than DHA better for heart health?

Dyerberg: Again, to me it is a nutritional issue. Marine food sources contain EPA as well as DHA in various amounts and in various relative amounts. As long as you get enough of both, either from food or from supplements, it is fine. This means 200–300 milligrams of each of these fatty acids per day.

Passwater: EPA and DHA are best known for their heart and brain benefits. However, a dazzling amount of research involving EPA and DHA is increasingly being associated with reduced inflammation, which has an impact on many conditions from arthritis to athletic recovery to heart health to cancer. Does this property of fish oil involve the PG-3 family of prostaglandins?

Dyerberg: A steady and increasing number of scientific publications have appeared, now reaching tens of thousands, broadening into areas we were not aware of when the omega-3 arena was opened by us. This includes: anti-inflammatory effects in rheumatic disorders, possible effects in mood and psychiatric ailments, and positive influence on the development of the brain and nervous system in newborns.  All the above results relate to the long-chained omega-3 fatty acids EPA and DHA.

Several studies have demonstrated that omega-3 fatty acid supplementation attenuates the inflammatory process in chronic inflammatory disorders (e.g., rheumatoid arthritis) (20). This effect has been used in the treatment of various autoimmune disorders and lends support to the notion of an anti-inflammatory effect of omega-3 fatty acids in IHD prevention. It also supports the explanation for the benefit of low doses of omega-3 fatty acids in coronary heart disease.

The anti-inflammatory effect of long-chained omega-3 fatty acids was first noticed when examining the chemo-tactic potency of leukotrienes generated from EPA compared to the leukotrienes formed from AA. Leukotrienes are proinflammatory agents synthesized in the white blood cells (leukocytes). Leukotrienes derived from AA exhibit 10- to 30-fold greater potency than the EPA-derived leukotrienes.

New families of locally acting anti-inflammatory substances generated from omega-3 fatty acids, termed resolvins, protectins and isoprostanes have recently been identified. These components control the duration and magnitude of inflammation. Given the potent actions of leukotrienes, lipoxins, adhesion molecules, resolvins and protectins in human disease, the intake of EPA and DHA may attenuate the development of atherosclerotic diseases.

Passwater: EPA and DHA affect the risk of heart disease in many ways ranging from the anti-clotting effect that you elucidated in the 1970s to rhythm-normalization of the heart beat to triglyceride level affects, and as we are now finding, also to anti-inflammation affects.

I like to look at the anti-inflammatory effect as just as important as any other risk factor in heart disease. Omega-6s produce the chemical messengers of inflammation. Chronically, this leads to silent inflammation and the smoldering fires in the arteries and heart that lead to many diseases. Omega-3s lead to the chemical messengers that produce the opposite effect. A balance of both is needed.

In addition to the omega-3 and omega-6 fatty acids we have been discussing, there are also omega-7 and omega-9 fatty acids. Omega-9 fatty acids are generally the monounsaturated fatty acids such as oleic acid common in the Mediterranean diet.

Omega-7 fatty acids generally seem to behave worse than saturated fatty acids. Omega-7 fats behave like saturated fats, not the monounsaturated fats that they are. Omega-7 fats raise LDL and lower HDL. There is no known role in the body for omega-7 fatty acids.

Are omega-9 fatty acids of value, and if so, what role do they play in the body?

Dyerberg: Omega-9 fatty acids such as oleic acid have good organoleptic qualities as a constituent of olive oil. The omega-9 monounsaturated fatty acids do not share the cholesterol-increasing properties as saturated fats, and are therefore recommended to constitute 10% of our daily energy intake.

Passwater: Why COLD water fatty fish? Would fatty fish from the tropics also have EPA and DHA? Why are cold water fish usually cited for their EPA and DHA content? Is it because they need more body fat to survive the cold and thus have more stored EPA and DHA? Or is their diet different?

Dyerberg: The content of EPA and DHA is higher in cold water than in tropical marine fish. The reason may be that EPA and DHA have low melting points, thereby keeping the cells in the body of cold water fish in a flexible state in spite of the low sea temperature.

Passwater: Most fats in foods are in the form of triglycerides. Triglycerides are the most compact and calorie-dense compounds that can be converted into energy in the body.

During digestion, the fatty acids are stripped off of the glycerol backbone of the triglycerides? They are reassembled later in the lymph and via the veins that reach the liver. They can then be burned for energy, used to make phospholipids and eicosanoids or converted back into TG for storage in fat cells.

Today, fish oil supplements are available in various forms. Regarding supplements, does it make much practical difference which form the fish oil is in (triglyceride, phospholipids, ethyl ester, free fatty acid or whatever)?

My preference is the basic triglyceride form that is produced merely by rendering. However, there are products that have been concentrated after further distillation and even available as highly purified ethyl esters. The latest research that I have seen suggests that all are about equally absorbed. The triglyceride forms enter the lymph and bloodstream earlier than the ethyl esters, but in the long-term, all are about equally absorbed, though at different rates at different periods of time. Again, I prefer the more natural distribution of EPA and DHA on the middle carbon of the glycerol backbone of the triglyceride, rather than the more randomize distribution of EPA and DHA on all three carbons that occurs during heavy distillation and the reformation during condensation of the distillate in the second position.

Is there any meaningful difference?

Dyerberg: Generally, the various fatty acid formulations (triglycerides, ethyl esters, free fatty acids, phospholipids) are well absorbed, especially when taken along with a meal. We have earlier found that triglycerides compared to ethyl esters, are somewhat better absorbed. At the recent International Society for the Study of Fatty Acids and Lipids meeting in Maastricht, a study was presented finding exactly the same results.

Regarding the stereochemistry of the fatty acid position in the triglyceride molecule, several studies have documented that this has no effect on the bioavailability of the fatty acids.

Passwater: How much EPA/DHA do you recommend daily?

Dyerberg: The average intake of marine omega-3 fatty acids in Americans is low (approximately 200 mg/day), and for many it is zero! It is far below what today is considered for a target intake in the United States, namely, 400–500 mg/d of EPA + DHA. For pregnant females, we recommend a daily intake of DHA on 200–300 mg, due to the special need of DHA for the fetus’ brain development.

Passwater: Thank you, Dr. Dyerberg. Let’s pause once again and resume our chat with a look at some of the research with fish oil that documents the health benefits with which we began this conversation. WF

References

1. H.M. Evans and G.O. Burr, “Increased Efficacy of Subcutaneous when Compared with Intraperitoneal Administration of the Ovarian Hormone,”Am. J. Physiol.77 (3), 518–210 (1926); H.M. Evans and G.O. Burr, “A New Dietary Deficiency with Highly Purified Diets,” Proc. Soc. Exp. Biol. Med., 24, 740–740 (1927).
2. G.O. Burr and M.M. Burr, “A New Deficiency Disease Produced by the Rigid Exclusion of Fat from the Diet,”J. Biol. Chem.82 (2), 345–367 (1929).
3. Food and Nutrition Board, Institute of Medicine of the National Academies, Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (The National Academies Press, Washington, D.C., 2002).
4. Fats of Life Newsletter, ”Fat Basics” www.fatsoflife.com/fat-basics.php, accessed June 24, 2010.
5. Pawlosky RJ, Hibbeln JR, Novotny JA, et al. Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans.J Lipid Res.2001; 42: 1257–1265.
6. Wang, C., W. S. Harris, et al. (2006). “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 Nutr84(1): 5-17.
7. Arterburn, L. M., E. B. Hall, et al. (2006). “Distribution, interconversion, and dose response of n-3 fatty acids in humans.”Am J Clin Nutr83(6 Suppl): 1467S-1476S.
8. Clark KJ, Makrides M, Neumann MA, et al.J Pediatr1992;120(4 Pt 2):S151-S158.
9. Jensen CL, Chen H, Fraley JK, et al.Lipids1996;31:107-113.
10. Brenna, J. T., N. Salem, Jr., et al. (2009). “alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans.”Prostaglandins Leukot Essent Fatty Acids80(2-3): 85-91.
11. Gibson RA, Neumann MA, Makrides M.Eur J Clin Nutr1997;51:578-584
12. http://www.fatsoflife.com/article.php?nid=1&edition=arch&id=1670&issueid=72

13. Ezaki O, Takahashi M, Shigematsue T, et al.J Nutr Sci Vitaminol (Tokyo) 1999;45:759-772.
14. Mantzioris E, James MJ, Gibson RA, et al.Am J Clin Nutr1995;61:320-324.
15. http://www.fda.gov/SiteIndex/ucm108351.htm
16. J.G.Martins, “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 (5), 525–542 (2009).
17. E.J.Schaefer,et al., “Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease: The Framingham Heart Study,” Arch. Neurol. 63 (11), 1545–1550 (2006).
18. P.Guesnet,et al., “Blood Lipid Concentrations of Docosahexaenoic and Arachidonic Acids at Birth Determine their Relative Postnatal Changes in Term Infants Fed Breast milk or Formula,” Am. J. Clin. Nutr. 70 (2): 292–298 (1999).
19. G.Serra,et al., “Fatty Acid Composition of Human Milk in Italy,” Biol. Neonate 72 (1), 1–8 (1997).
20. R.J.Goldberg and J. Katz, “A Meta-Analysis of the Analgesic Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation for Inflammatory Joint Pain,”Pain 129 (1-2), 210–223.

Part 4: The Major Studies

In the introduction to our chat with Jørn Dyerberg, M.D., I briefly mentioned a few of the reasons why readers should be interested in learning more about fish oil. Dr. Dyerberg’s discoveries led to our understanding of why the long-chain omega-3 fatty acids, EPA and DHA, are so important to our health.

In Part One, I called your attention to the following: “Reduce your chance of dying a sudden death by 45% (1, 2)! Reduce your risk of dying from sudden cardiac death by 90% (3). Reduce your chance of developing Alzheimer’s disease by 45–50% (4). Stay younger longer (5, 6)! Reduce the inflammation and pain of rheumatoid arthritis and the pain of osteoarthritis arthritis and other inflammatory diseases (7, 8). The litany of health benefits from omega-3s goes on, but hopefully, these are enough to get your attention so that you will read on about this miraculous dietary supplement. We will discuss the details of these studies in a later installment of this series.

“Recently, a low level of long-chain omega-3 fatty acids had been purposed as a risk factor for heart disease. The new risk factor is based on measuring the fatty acids in red blood cells, and is expressed as a percentage of EPA + DHA of total fatty acids. An omega-3 index of >8% is associated with 90% less risk for sudden cardiac death, as compared to an omega-3 index of <4% (9).”

In Part 2, I noted another important large multi-year study in which Dutch researchers reported a 62% lower risk of fatal heart attack in people consuming a modest amount of EPA and DHA (approximately 230 mg/day) from fish as compared with those consuming small amounts (approximately 40 mg/day of EPA and DHA) (10).

This month we will chat with Dr. Dyerberg about the details and meaning of these studies.

Jørn Dyerberg, M.D., professor and Dr. Med. Sc., has made several discoveries that elucidate many of the health benefits of omega-3 fish oils. Dr. Dyerberg made five scientific expeditions to Northwest Greenland in the 1970s examining the association between fish oil intake and coronary heart diseases in Eskimos. Dr. Dyerberg, who is Danish, hypothesized that the rarity of coronary heart disease among the Inuit could be due to the omega-3 fatty acids in their diet consisting largely of seal and cold-water oily fish. Together with his fellow researchers, he went on to elucidate the unique physiological effects of these fatty acids. His research opened new fields leading to thousands of health studies by many. His own research encompasses more than 350 scientific publications primarily concerning blood lipids, atherosclerosis, the blood coagulation system, omega-3 polyunsaturated fatty acids, trans-fatty acids and prostaglandins.

 In 2007, Dr. Dyerberg was honored by the American Heart Association in “Recognition of Outstanding Scientific Contribution for the Advancement of Heart Health Worldwide.” In 2008, he received the American Dietetic Association Foundation’s Edna and Robert Langholtz International Nutrition Award.

Passwater: Dr. Dyerberg, there are so many important studies that show the health benefits of fish oil. It’s hard to pick just a few to chat about, but let’s start with one of my favorites: The 1999 GISSI Study (1). This study caught the attention of many clinical researchers and influenced the thinking of “official” organizations that make dietary recommendations. The GISSI study used supplements of 850 mg/day of total EPA and DHA.

Dr. Dyerberg, what is important about the GISSI Study? What is the take home message for us?

Dyerberg: The GISSI study was the second large clinical trial examining the effect of an increased intake of EPA and DHA on coronary heart disease. The first was the Diet and Reinfarction Trial (DART) (11). The DART study (published in 1989) involved 2,033 men recovering from myocardial infarction. They were randomly allocated to receive advice or to receive no advice on each of three dietary factors: an increase in fatty fish intake, a reduction in intake of certain fats (saturated fat) with an increase in others (polyunsaturated fatty acids, PUFAs) or an increased intake of cereal fiber. The men advised to eat more fatty fish had 29% lower two-year all-cause mortality; the other forms of advice did not have any significant effects (12).

The Italian GISSI-Prevenzione trial (published in 1999) was even bigger, involving 11,300 persons! The trial showed that three-year treatment with low-dose omega-3 PUFAs (850 mg/day) was associated with a significant total mortality reduction of 21% in patients who survived a recent myocardial infarction or heart attack (starting treatment within three months from symptom onset). An analysis of the causes of death showed that among all cardiac causes, sudden cardiac death was the most affected by n-3 PUFA, which was reduced by 45%!

Passwater: I like to use slides based on three studies in my lectures. The most important message that I see in these studies is that those persons in the highest quartile of EPA and DHA combined intake have only about 10% of the cardiac risks of persons in the lowest quartile of EPA and DHA intake. The data from Dr. D.S. Siscovick and colleagues looked at a patient cohort nested within the famous Physicians Health Study and found that those persons in the highest quartile of EPA and DHA intake had only 10% of the risk of sudden cardiac death of normal people (90% reduction in risk of sudden cardiac death) (14). We haven’t even discussed the importance of EPA and DHA in normalizing heart rhythm and preventing abnormal heart rhythms that can lead to sudden heart death (3).

Figures 1–3 are based on these three studies and I think they present compelling graphics that should get everyone’s attention.

Dr. Dyerberg, these three studies add considerably to the body of science that shows that EPA and DHA reduce the risk of death from cardiovascular disease. We owe you a lot for your pioneering research and further elucidation of the science that has led to these studies. What should people conclude from these and similar studies?

Figure 1: The odds ratio (relative risk) of having an acute coronary syndrome is inversely associated with the combined EPA and DHA content of the blood. Acute coronary syndrome is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischemia. Acute myocardial ischemia is chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease (also called coronary heart disease). This content can be conveniently expressed as the percentage of EPA and DHA in the total blood cell membrane fatty acids. This percentage is referred to by Dr. W.S. Harris et al. as the “Omega-3 Index.” Figure 1 charts the EPA and DHA intake as three groupings: low (<4%), intermediate (4–8%) and high (>8%). The odds ratios were calculated to include possible confounding factors including age, race, sex, diabetes, hypertension, family history and various serum lipids. Data are from R.C. Block et al. (13).

Figure 2: Relationship between total EPA and DHA content (expressed as the Omega-3 Index) and the risk for primary cardiac death. Primary cardiac death is the sudden cessation of heartbeat and cardiac function, resulting in the loss of effective circulation. It is also called primary cardiac arrest or sudden cardiac death. Data are from Dr. D.S. Siscovick and colleagues (14).

Figure 3: Relationship between the total EPA and DHA (expressed as the Omega-3 Index) and sudden cardiac death. Data are from Dr. C.M. Albert and colleagues (2).

Dyerberg: There are several conclusions, but to me the most obvious is that we are in a nutritional deficiency of long- chained omega-3 fatty acids. In the United States, the average daily intake of EPA plus DHA is 100–200 mg. In 20% of U.S. citizens, the intake is close to zero! The recommended intake is 400–600 mg/day, and in pregnancy and lactation, women should consume 300 mg of DHA/day.

Passwater: Wow! The intake of EPA and DHA is close to zero in 20% of U.S. citizens! Holy smoke! And, the U. S. Daily average is about 100–200 mg, instead of the recommended 400–600 mg! On average, U.S. citizens are getting only a third to a sixth of the recommended amounts, and I feel that the 600 mg recommendation should be higher. We seek optimal health, not average health. I personally lean more toward the 1,000-mg level for healthy persons and more for those with health problems. This is still far short of the 14,000 mg you found in the Eskimo diet (15).

Let’s turn to another critical health problem. Dementia and Alzheimer’s disease may become the most important health problem as the population ages. There have been studies showing that EPA and DHA may become more important to counter these problems. I mentioned the study by Dr. E.J. Schaefer and colleagues in the introduction (4).

Dr. Dyerberg, what does this study suggest to you?

Dyerberg: That the field of long-chained omega-3 fatty acids in human nutrition is broadening rapidly. The necessity of a sufficient daily intake of EPA plus DHA is maybe even more convincing when considering brain health, that with respect to heart health! Several studies have reported that the risk of developing dementia—as Alzheimer’s disease—is inversely related to the intake of long-chain omega-3 fatty acids. This is maybe most convincingly shown in the Framingham study finding that a mean DHA intake of 180 mg/d was associated with a significant 47% reduction in the risk of developing all-cause dementia (4). Studies from the Netherlands, France and Italy find the same relations.

In one study, researchers examined omega-3 fatty acid erythrocyte membrane content and cognitive variation in late adulthood (16). Dr. L.J. Whalley and colleagues found that total omega-3 PUFA and DHA concentrations in erythrocytes were associated with benefits for cognition in persons aged 64 to 68 years.

There are 5.2 million people in the United States living with Alzheimer’s. Alzheimer’s is the seventh-leading cause of death. The direct and indirect costs of Alzheimer’s and other dementias amount to more than $148 billion each year.

Passwater: Our goal is to help people not just live longer, but to live better longer. I mentioned two studies that may impact on just this very idea—living better longer. In the studies that I mentioned in the introduction to this series, it was found that fish oils protected telomeres from shortening. A telomere is a region of repetitive DNA at the end of a chromosome that protects the chromosome from deterioration. Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality.

Dr. Dyerberg, do you see fish oil as improving our general health beyond reducing the risk of overt diseases, but also in helping us live better longer?

Dyerberg: Results from New Zealand illustrates that an increased intake of long-chained omega-3 fatty acids may help us not just to live longer, but to live better longer. In the New Zealand Adolescents and Adults study of 2,416 persons above 15 years of age, researchers found that there was a significant positive trend in mental well-being across the quintiles of the ratio of EPA to AA in serum phospholipids (17). The longevity issue is convincingly illustrated by the findings that those in the highest quartile of omega-3 fatty acid blood levels experienced the slowest rate of telomere shortening. But, other studies have also found similar relations.

In a Norwegian randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk, they observed a tendency toward reduction in all-cause mortality in the n-3 PUFA groups that, despite a low number of participants, reached borderline statistical significance (18).

In The Heart and Soul Study, blood n-3 FA levels were inversely associated with total mortality independent of standard and emerging risk factors, suggesting that reduced tissue n-3 FA levels may adversely impact metabolism (19).

Passwater: Research soon took us from primarily cardiovascular studies to protection against the inflammatory diseases. I mentioned two studies related to arthritis in the introduction (7, 8).

Dr. Dyerberg, how do you see the role of EPA and DHA in reducing inflammation?

Dyerberg: The omega-3 polyunsaturated fatty acids possess potent anti-inflammatory activities. Some of the effects of omega-3 PUFAs are brought about by a modulation in the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases.

Passwater: Well, your pioneering research certainly has extended into many areas of health for all people. It seems as if there are new studies about the benefits of EPA and DHA being published nearly every week. They extend the role of these long-chain omega-3 fatty acids from artery health (20) to cancer prevention (21–26). Dr. Emily White and her colleagues at the Fred Hutchinson Cancer Research Center studies 35,016 postmenopausal women who did not have a history of breast cancer for six years and found those who regularly used fish oil supplements had a 32% reduced risk of ductal breast cancer. They concluded, “Fish oil may be inversely associated with breast cancer risk.”(26)

There are so many thousands of research articles published now that I bet it is difficult for even you to keep track of all of the published articles.

Dyerberg:  The number of scientific publications on the health effects of EPA and DHA has increased enormously since our original publications in the 1970s, and the number of human studies is now above 9,000! This is of course nearly impossible to keep check on—my own database has now reached number 2,846 and is still growing. I consider myself privileged to have been a co-initiator of such an important science.

Passwater: On behalf of myself and our thousands of readers, I thank you for your time and patience in chatting with us over these past four months. It’s been a remarkable and truly enjoyable experience. Your explanations as well as your research will help countless millions of people. WF

References

1. Dietary Supplementation With N-3 Polyunsaturated Fatty Acids And Vitamin E After Myocardial Infarction: Results Of The GISSI-Prevenzione Trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (1999).
2. C.M.Albert,et al., “Blood Levels of Long-Chain N-3 Fatty Acids and the Risk of Sudden Death,” N. Engl. J. Med. 346 (15), 1113–1118 (2002).
3. H.Leon,et al., “Effect of Fish Oil on Arrhythmias and Mortality: Systematic Review,” BMJ 337, a2931 (2008).
4. E.J.Schaefer,et al., “Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease: The Framingham Heart Study,” Arch. Neurol. 63 (11), 1545-1550 (2006).
5. R. Farzaneh-Far,et al., “Association of Marine Omega-3 Fatty Acid Levels with Telomeric Aging in Patients with Coronary Heart Disease,” JAMA 303 (3), 250–257.
6. R. Farzaneh-Far,et al.,“Telomere Length Trajectory and its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study,” PLoS One 5 (1), e8612.
7. B.Galarraga, et al., “Cod Liver Oil (N-3 Fatty Acids) as a Non-Steroidal Anti-Inflammatory Drug Sparing Agent in Rheumatoid Arthritis,” Rheumatol (Oxford) 47, 665–669 (2008).
8. D.Fritsch,et al., “A Multicenter Study of the Effect of Dietary Supplementation with Fish Oil Omega-3 Fatty Acids on Carprofen Dosage in Dogs with Osteoarthritis,” J. Amer. Veterinary Medical Assoc. 236 (5), 535–539 (2010).
9. W.S.Harris, “The Omega-3 Index as a Risk Factor for Coronary Heart Disease,”Am. J. Clin. Nutr. 87 (6), 1997S–2002S (2008).
10. J. de Goede and J.M. Geleijnse,et al.,“Marine (n-3) Fatty Acids, Fish Consumption, and the 10-Year Risk of Fatal and Nonfatal Coronary Heart Disease in a Large Population of Dutch Adults with Low Fish Intake,” J. Nutr. 140 (5), 1023–1028 (2010).
11. M.L. Burr,et al., “Diet and Reinfarction Trial (DART): Design, Recruitment, and Compliance,”Eur. Heart J. 10 (6), 558–567 (1989).
12. M.L. Burr,et al.,“Effects of Changes in Fat, Fish, and Fibre Intakes on Death and Myocardial Reinfarction: Diet and Reinfarction Trial (DART),” The Lancet, 2 (8666), 757–761 (1989).
13. R.C. Block,et al., “EPA and DHA in Blood Cell Membranes from Acute Coronary Syndrome Patients and controls,”Atherosclerosis 197 (2), 821–828 (2008).
14. D.S.Siscovick,et al., ”Dietary Intake and Cell Membrane Levels of Long-Chain n-3 Polyunsaturated Fatty Acids and the Risk of Primary Cardiac Arrest,” JAMA 274 (17), 1363-1367 (1995).
15. L.K.Whalley,et al., “n-3 Fatty Acid Erythrocyte Membrane Content, APOE Varepsilon4, and Cognitive Variation: An Observational Follow-Up Study in Late Adulthood,” Am. J. Clin. Nutr. 87 (2), 449–454 2008).
16. F.L. Crowe,et al., “Serum Phospholipid n 3 Long-Chain Polyunsaturated Fatty Acids and Physical and Mental Health in a Population-Based Survey of New Zealand Adolescents and Adults,” Am. J. Clin. Nutr. 86 (5), 1278–1285 (2007).
17. G. Einvik,et al.,  “A Randomized Clinical Trial on n-3 Polyunsaturated Fatty Acids Supplementation and All-Cause Mortality in Elderly Men at High Cardiovascular Risk,” Eur. J. Cardiovasc. Prev. Rehabil. 2010 Apr 10. [Epub ahead of print].
18. J.V. Pottala,et al.,“Blood Eicosapentaenoic and Docosahexaenoic Acids Predict All-Cause Mortality in Patients With Stable Coronary Heart Disease: The Heart and Soul Study,” Circ. Cardiovasc. Qual. Outcomes 2010 Jun 15. [Epub ahead of print].
19. C.A. Fahs,et al.,“The Effect of Acute Fish Oil Supplementation on Endothelial Function and Arterial Stiffness Following a High-Fat Meal,” Appl. Physiol. Nutr. Metab. 35(3), 294–302 (2010).
20. M. Ligo, T. Nakagawa and Y. Iwahori, “Inhibitory Effects of Docosahexaenoic Acid on Colon Carcinoma Metastasis to the Lung,”Br. J. Cancer75 (5), 650–655 (1997).
21. J. Kim,et al.,“Fatty Fish and Fish Omega-3 Fatty Acid Intakes Decrease the Breast Cancer Risk: A Case-Control Study,” BMC Cancer 9, 216 (2009).
22. E.J. Ramos,et al.,“Effects of Omega-3 Fatty Acid Supplementation on Tumor-Bearing Rats,” J. Am. Coll. Surg. 199 (5), 716–723 (2004).
23. H. Toriyama-Baba,et al.,“Organotropic Chemoprevention Effects of n-3 Unsaturated Fatty Acids in a Rat Multi-Organ Carcinogenesis Model,” Jpn. J. Cancer Res. 92 (11), 1175–1183 (2001).
24. A. Wolk,et al.,“Long-Term Fatty Fish Consumption and Renal Cell Carcinoma Incidence in Women,” JAMA 296 (11) 1371–1376 (2006).
25. Brasky, T. M., Lampe, J. W., Potter, J. D., et al. Specialty Supplements and Breast Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev 19(7); 1696-1708 (2010).

© 2010 Whole Foods Magazine and Richard A. Passwater, Ph.D.