Is omega-3 beneficial because it resolves inflammation?
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In the 1980s, Dr. Harris and his colleagues discovered that omega-3 had the surprisingly profound ability to reduce triglycerides. To this day, prescription forms of omega-3 are explicitly indicated to reduce high circulating triglycerides. Yet, despite this indication and the evidence that omega-3 is broadly and potentially powerfully cardioprotective, Dr. Bill Harris no longer believes triglyceride reduction is central to the benefits of high omega-3 intake. Instead, he explains how omega-3 as a resolver of inflammation has begun to take center stage both as a player in cardioprotection and in a multitude of other promising dimensions of benefits to human health.
Dr. Patrick: Have you looked at the correlation of the omega-3 index with inflammatory biomarkers?
Dr. Harris: Yeah. And as you expect, we, again, we did this in Framingham. We looked at 10 very different inflammatory biomarkers in the plasma in patients in Framingham and correlated it with the omega-3 index and all 10 of them, the higher the omega-3, the lower the marker. So it's across the board. It isn't just, you know, CRP. There's also some phospholipase A2...PPLA-2, you know, LpPLA-2 to this one which is a kind of inflammatory markers. Well, very different. It's not very different chemical than CRP. Some bone-related inflammatory markers were reduced in association with omega-3. So it's there. And giving omega-3 does lower inflammatory levels.
Dr. Patrick: Right. So I was going to say like for people like there's the mechanism by which these inflammatory markers lower...I'm sorry, which omega-3s lower the inflammatory markers and there's a wide variety of them. So you have, you know, for a long time, I always thought of EPA being the, you know, anti-inflammatory, omega-3, which isn't entirely accurate because all these metabolites of DHA and EPA are...
Dr. Harris: Are anti-inflammatory. Well, not just anti-inflammatory, they're pro-resolving of inflammation, which is the flip side of, you know, you can either prevent an inflammation from starting, which may not be good because inflammation at one level is important. But if you don't have the omega-3s onboard, the active process of shutting down the inflammation once it starts, that shutdown is inhibited. So the inflammation stays longer. So Charles Serhan is the guy who's discovered all of these, what he calls some specialized pro-resolving mediators, which with all due respect to Charlie, I think it's a silly name. I mean, there's no molecule in the body that doesn't specialize. Come on. Water's specialized. I mean, so if they're pro-resolving mediators, they're molecules made from EPA and DHA, that... And some that are made from arachidonic that are also suppressive. Lipoxin A which is the one from arachidonic. So that whole field of...it isn't just that they're anti-inflammatory, they're pro-suppression, pro-suppressing of inflammation, which is the important piece.
Dr. Patrick: Right. Because as you mentioned, you're talking about, you want to be able to activate your immune system when there's a pathogen, you know, that's there, but you don't want it to remain active and spiral out of control. But in the context of just, let's say not a pathogen, let's talk about this low level of just chronic, you know, immune activation in this chronic, you know, inflammation that can be caused from a variety of lifestyle factors.
Dr. Harris: Sure. Just obesity.
Dr. Patrick: Exactly. Obesity. What role do these specialized pro-resolving mediators, the SPMs as they're called and resolvins, and protectins and...
Dr. Harris: Protectins and maresins, and poxytrokins and poxytrins and...there's a bunch of them now. It's actually a bewildering array of molecules that have been discovered made from EPA and DHA that operate on different cell types and different receptors through different mechanisms but at the end of the day, they suppress an inflammatory response and keep it from getting out of control. So I don't really know the answer, how the presence of those resolving mediators plays into the chronic inflammation of someone who's just got a lot of adipose tissue. I assume it will just keep a damper on it, keep it down. And what we saw in Framingham was all these mediators are inversely related to the omega-3 level. And these people aren't chronically inflamed. Oh, well, I mean, they're Framingham people in their '60s, so maybe they are like typical Americans. So there's a ton of research to be done. And then, of course, drug companies are very interested in taking some of these molecules that are made from omega-3 and making them drugs that can be used. Okay, fine. Good.
Dr. Patrick: One of the reasons I'm asking is because, you know, this chronic inflammation is at the root of, you know, many different diseases, cardiovascular disease, you know, dementia, cancer, a lot of the diseases that you were mentioning in the Framingham study and also in your large, you know, 17 study cohort. And so, you know, the question is, is that, so let's talk about in the context of cardiovascular health, for example, you know, you mentioned the REDUCE-IT trial with the high EPA, there was a dramatic lowering of triglycerides.
Dr. Harris: No.
Dr. Patrick: No. That wasn't the REDUCE-IT trial?
Dr. Harris: It didn't lower triglycerides very much. I mean, it was 15%.
Dr. Patrick: Fifteen percent. Okay. So I guess that's not dramatic, but that's what a lot of people talk about when they think about cardiovascular and omega-3 and...
Dr. Harris: Think about triglyceride lowering.
Dr. Patrick: They think about triglyceride lowering.
Dr. Harris: That's the indication that the FDA gave these drugs because the only way to get these nutrients turned into drugs and approved by the FDA as a drug is it's got to affect some risk factor that the FDA believes in. And when it all began with Lovaza, they said, you lower "Oh, look, we can lower triglycerides by 20%." And that was enough to get them an indication for people with triglycerides over 500. That's the limitation. Only Vascepa is indicated for reducing risks for cardiovascular events because it's the only one that's been shown to do that. Lovaza has never been tested for lowering cardiovascular events. It's the EPA plus DHA product, but it's approved for triglyceride lowering because, I mean, that's what we saw back 40 years ago, is it does that, but I don't think that's the mechanism by which omega-3s are cardioprotective.
Dr. Patrick: What do you think the mechanism is?
Dr. Harris: I think it's much more likely to be an anti-inflammatory mechanism and anti-platelet.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
An omega-3 fatty acid found in the human brain and the meat of fatty fish. DHA plays a key role in the development of eye and nerve tissues, and is essential for normal brain function in humans. DHA may also reduce the risk of Alzheimer’s disease1 and cardiovascular disease, and may be useful in treating certain inflammatory conditions, such as rheumatoid arthritis. Dietary sources of DHA include krill oil and the meat and roe of salmon, flying fish, and pollock. [1] Patrick, Rhonda P. "Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease." The FASEB Journal (2018): fj-201801412R.
An omega-3 fatty acid found in the meat of fatty fish. EPA reduces inflammation in the body and helps counter oxidative stress in cells. It is crucial for modulating behavior and mood and has demonstrated beneficial effects in managing anxiety and depression. EPA may reduce risk of developing certain chronic diseases such as cancer or cardiovascular disease. Dietary sources of EPA include herring, salmon, eel, shrimp and sturgeon.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A member of the specialized pro-resolving mediator family of polyunsaturated fatty acid metabolites. Lipoxin A is produced during the metabolism of arachidonic acid. It exerts anti-inflammatory effects.
A prescription-only dietary supplement used to manage high triglycerides. Lovaza contains the ethyl ester form of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). It is typically used in combination with exercise and diet.
A member of the specialized pro-resolving mediator family of polyunsaturated fatty acid metabolites. Maresin is produced in macrophages during the metabolism of docosahexaenoic acid (DHA). It exerts anti-inflammatory properties.
A group of metabolites produced from the oxidation of polyunsaturated fatty acids. Poxytrins participate in blood clotting and exert anti-inflammatory and antiviral properties.
A member of the specialized pro-resolving mediator family of polyunsaturated fatty acid metabolites. Protectin is produced during the metabolism of the omega-3 polyunsaturated fatty acids docosahexaenoic acid and n–3 docosapentaenoic acid. It exerts anti-inflammatory and neuroprotective properties.
A member of the specialized pro-resolving mediator family of polyunsaturated fatty acid metabolites. Resolvin is produced during the metabolism of omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. It exerts anti-inflammatory effects.
A molecule composed of a glycerol molecule bound to three fatty acids. Triglycerides are the primary component of very-low-density lipoproteins (VLDL). They serve as a source of energy. Triglycerides are metabolized in the intestine, absorbed by intestinal cells, and combined with cholesterol and proteins to form chylomicrons, which are transported in lymph to the bloodstream.
A prescription medication used to reduce the risk of heart attacks. Vascepa contains the ethyl ester form of eicosapentaenoic acid (EPA), a type of omega-3 fatty acid. It works in the liver and bloodstream to reduce triglycerides. In contrast to Lovaza, which includes DHA, Vascepa is EPA-only and often given as an adjunct to cholesterol-reducing drugs called statins.
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