Jay Feldman 0:05
Your Omega three supplements may be causing more harm than good. And we'll be explaining why today in Episode 106 of the energy balance podcast, a Podcast where we explore health and nutrition from the bioenergetic view, and teach you how to maximize your cellular energy to maximize your health. Today's episode is part two of a three part series, exploring the relationship between omega threes mortality and lifespan. And in today's episode, we'll be going over the studies showing that fish oil and cultivar oil supplementation increase oxidative damage in humans, even in the triglyceride form, alongside antioxidants. We'll also be going over why omega threes are harmful in both healthy and unhealthy humans, the harmful metabolic and hormetic effects of omega threes and why omega threes are not beneficial due to or misses. And we'll also be going over the research showing that omega threes do not improve chronic health conditions or mortality in humans. To check out the studies and articles and anything else that we reference. Throughout today's episode, head over to Jay Feldman wellness.com/podcast where you can find the show notes for today's episode. And with that, let's get started.

Anyway, that brings us now to the studies looking at the actual consumption of omega threes in humans and the direct effects of that. And so we'll be looking specifically at how just like we saw in that rat study, increasing the consumption of omega threes in humans, both from fish oil and from EPA DHA individually increases lipid oxidation, which of course is associated with decreased lifespan increased aging, and is generally something we would argue as a reason not to consume these things. And large amounts are not to go out for a way to consume it. Again, despite the association studies. And I do want to make a point here I believe it was when I was talking with Dom. If not, it might have been somebody else. But I think it was with him. He mentioned that he thinks there could be a difference between consuming EPA and DHA individually and the ethyl ester form versus consuming fish oil in the triglyceride form. Maybe it was Thomas de Lauer, I don't remember who mentioned that. But that doesn't seem to be borne out in the research. And I and I made a point here to include studies looking at both fish oil, which would be in the triglyceride form, and EPA and DHA individually, and it doesn't really suggest that fish oils any better. So just wanted to mention that real quick as we get into these studies. Yeah, yeah, I don't have too much to add there. So in this first study, it's titled mitochondria Omega three and the route of mitochondrial reactive oxygen species. And this is just a kind of overview paper where they discuss this as a whole, it's not digging into. It's not like a specific individual study, which we'll be getting into after, but it's kind of a good summarizer and so they state dietary intake of Omega three polyunsaturated fatty acids, and consequently the increase in Omega three content of membrane lipids may be dis advantageous to health because reactive oxygen species induced oxidative oxidation of omega threes within membrane fossil lipids can lead to the formation of toxic products. Susceptibility to peroxidation of PUFA is by ROS raises the question of the adverse effects of Omega three dietary supplementation in this case, specifically on embryonic development, and prenatal developmental outcomes. So of course, omega threes are suggested for those in that population, women who are pregnant, and this is questioning whether it's a good idea, and they then go on to state that dietary supplementation of Omega three PUFAs is known to reduce lipid peroxidation. In organ and tissues of women and animal models. The consequence of PUFA supplementation is toxicity related to the end product of lipid peroxidation. dietary intake of Omega three PUFAs may therefore be detrimental to cellular function, as the oxidation of these fatty acids by ROS can induce the formation of toxic products, which is potentially mutagenic and atherogenic. The disturbance of the cellular redox balance and associated damage to membrane integrity and mitochondrial function has been identified as causal factors of chronic inflammation, atherosclerosis, and neurodegenerative diseases. We'll be digging into specific studies looking at what happens when you give this group fish oil and what was the result. But this is just kind of a an overview, looking at a handful of different studies and just sharing some general ideas as far as why we might want to be concerned about things. Just yeah, the reason I included this is because I think it's important to have that direct corroboration at the research. Yeah,

Mike 4:48
I know there's gonna be some people in the audience are gonna be like, well, there's this study that says that fish oil does this or does that or it has, it's actually an antioxidant and In some studies, it does show this antioxidant function. But it's not because it's not being paroxetine, what winds up being happening, what winds up happening is the fish oil or the omega three fatty acids are so libeled approximation that they do indeed, per oxidize both spontaneously, and from enzymatic processes. And then the mediators that they produce actually signal cell defense responses to minimize oxidative stress, like they're some of the most potent signalers. They they interact with the same gene elements that respond to things like cigarette smoke and diesel exhaust and things along those pathways. Be just in terms of like, their, their signals have a degree of toxicity, the lipid peroxide signal all these different pathways. Now, there are some mediators that have this and that effect, specifically. But in general, there's a general upregulation of a lot of the lipid peroxidation products, both from omega threes. And from omega sixes, in interacting with this, the specific pathway is called the Nrf2 pathway. We're not going to get into that inside this specific podcast, but it's a defense pathway. So it's, again, it's a hormetic response, but it's functioning through lipid peroxidation, which is just not ideal overall.

Jay Feldman 6:22
Yeah, and one of the studies that we will go through here talks about the activation of PPARs, and other increases in beta oxidation enzyme activity. Yep. In the same vein of this hormetic response, which we'll discuss, it's a great point. And I would recommend that anybody who is not familiar with our view, for me says goes and checks out that series that we did, and a couple articles I wrote on it as well. Because yeah, a lot of the things that we're told are beneficial happen to work very similarly to things like cigarette smoke, and chemotherapeutic agents and industrial pollutants. And I think that, as a baseline should be something that leads us to question and concern regarding using something like this as a supplement. And it's a great point, Mike, something we talked about also in that fatty liver series, which I'll refer back to as well, where the Omega threes have the supposed benefit for lipids by you know, lowering LDL, but they do so by causing oxidative stress in the liver, which actually prevents the export of fatty acids from the liver, which, again, looks good on paper when your doctor looks at your labs, but doesn't actually mean that it's something that's beneficial. On the whole. So very important context.

Mike 7:30
Thank you for sharing. Yeah, just important, though, how this thing is working? And is it working through a mechanism that you want to optimize? Or is it same type of deal with? It's the same type of idea with statins? Right? Are we going to lower cholesterol? Because we just to lower it? Or are we going to address the underlying reasoning of why it's why it's raised in the first place, and fish oil is like congruent in that in that same vein, or that same, like, way of thinking about the problem?

Jay Feldman 8:00
Yeah, yeah, totally, totally. Alright, so I'm gonna go through a few of these other studies looking at lipid peroxidation as an effect of consuming increased amounts of omega threes. And this title or this paper is titled responsive urinary malondialdehyde to factors that stimulate lipid peroxidation in vivo, and states that the composition of dietary fatty acids had a major influence on MDA malondialdehyde excretion in fed animals being the highest for animals fed omega three fatty acids from cod liver oil, intermediate for those fed Omega six fatty acids from corn oil, and lowest for those fats, saturated fatty acids from hydrogenated coconut oil. So just pause there MDA, or malondialdehyde is a lipid peroxide product. So this is what happens when those lipids get damaged. And we're seeing increased levels of these things being excreted. So increased levels of them happening indigenously, from the animals that consume higher levels of Omega three is specifically from cod liver oil, which again, it's very important to consider here, we're not talking about isolated fatty acids, and whatever it is, we're talking about the supplements that many people are taking, and them increasing lipid peroxide products. We also I think, referenced this study in that episode, where we talk more about how the for oil. Now the next thing that was mentioned here, I think is also very telling. So it says fasting produced a market increase in urinary MDA, which tended to be higher in rats previously fed cod liver oil. Adrenocorticotrophic hormone ACTH. And epinephrine administration also increased urinary MDA further indicating that lipolysis either releases fatty acid peroxides from the tissues, or increases the susceptibility of mobilized fatty acids to oxidation. The reason why I want to include this just kind of like the formulas tangent, I mean, we've talked considerably about the problems with fasting. And I can link back to those points and an article I've written as well. But something that Dom had brought up was, well maybe it's okay for a healthy person to have enough omega threes because they're going to be in a low oxidative stress environment. But if or an unhealthy person, maybe they need to be more concerned. Now this is despite the fact that normally these are recommended for non healthy people to become healthier. So if that's the case, if someone's already healthy, what's the point in some ways, and also, it's still huge, because then you're still saying, Okay, if anybody has any health issue, anything from hypertension to cancer, don't consume omega threes, that is very different from the general narrative of consuming omega threes that helps with everything. And all cause mortality and all of that. But the other thing here is fasting, increased MDA, and it did so more so so increased lipid peroxide peroxides forever for all groups, but it did so the most in the group fed cod liver oil. So this is not a matter where of over healthy, you're fine. If you're healthy. You experience oxidative stress all the time, when you do your fast when you exercise, when you do cold thermogenesis, whatever it is. Now we've talked extensively about those things. Again, I'll reference to her Mesa series and things like that. And this is part of the reason why we don't recommend intentionally reducing stress for the benefit of stress itself, instead doing it for specific effects in context that makes sense, like proper amounts of exercise and things like that. But even in a healthy individual. And watch, he talked about this as well, and athletes in a moment, in one of these other studies, even an unhealthy individual, you're leaving yourself more susceptible to greater amounts of oxides of oxidative stress. Anytime you're introducing yourself to oxidative stress, which is nearly always there's your that stress is unavoidable. We've talked about this too, in the hormesis series. And so I think, I think it's a pretty weak argument to say, Well, if you're healthy and not experiencing oxidative stress, you're right, when just a fast or a bout of exercise or anything else will do so.

Mike 11:42
Yeah. The other thing I want to mention here, specifically with both with all these things, so what they're talking about here, specifically, they say with adrenal cortical tropic hormone, EPA and epinephrine administration increased urinary MDA, further indicating that light pollicis either releases fatty acid peroxides from the tissues, or increases the susceptibility of mobilized fatty acids to poor oxidation, I think, when you think there's a couple of things going on there. So first, the rats that are fed the cod liver oil have now stored these fatty acids inside their fat tissues. And so one of the functions one of these, these hormetic pathways that are induced by the polyunsaturated fats that we mentioned was pee pars. And so again, we're gonna get into this and probably an entire another episode, but PPAR gamma signaling, which is up regulated by fish oil and the lipid peroxides by fish oil, induce the storage of these fatty acids inside the adipose tissue. So it's kind of like a protective mechanisms as well what were all these lipid peroxides coming from, okay, shove them in the fat tissue. And so now what winds up happening and this goes to your point j is that when you're put under any circumstance of stress, so if you're fasting or as an example here, you have a release of epinephrine which you can have an exercise which you can have and during exam stress which you can have if you're startled, which you can have under numerous circumstances, and it also releases adrenocorticotropic hormone, which is the pre the signaling molecule before you get to cortisol, when you release these hormones, and then these hormones mobilize fat stores, so they basically say, hey, we need more substrate, alright, fat, pump out the fatty acids and you start pumping out the fatty acids. If you've loaded your fat stores up with fish oil, corn oil, so omega threes and Omega six is when they start to get liberated. Now you have an increased oxidative stress, because you are liberating a bunch of unsaturated fatty acids. And they're saying that they increase the their that the hormones and cells are increasing the likelihood of these fatty acids being pro per oxidize. I think just liberating the fatty acids into circulation will allow them to become proxies because they are proxy dies under many circumstances relatively easily. But then the other thing to keep in mind is that these hormones, and we've talked about this in other episodes, Dr. fatty acid oxidation and fatty acid oxidation in and of itself, drives an increase ROS in the mitochondria. So you have a dual fold effect if your tissues are loaded with polyunsaturated fatty acids, your fat tissues, and whenever you're put under any type of stress, you're going to liberate these fatty acids those fatty acids are going to if they're high in a in an unsaturated fats will probably put oxidize just in liberation process and circulation. And then there are also these hormones are driving fatty acid oxidation, which will increase ROS as well. And and now you have an increased ROS in the mitochondria and then you have an increased lipid peroxides and then fats that are likely to become lipid peroxide. So it's like a it's a recipe for disaster overall loading your tissues up on these fats. And again, the polyunsaturated fatty acids are kind of like dynamite that just hanging around and in any type of stress I suppose situation is going to be that spark that's going to light the fuse. So it's, it doesn't make any sense. As you're saying to use these to help to for healthy people to stay healthy. If they're starting to load their tissues up of these fats, you start putting them under distress and now you're gonna, their bodies are going to collapse under the under the the lipid peroxides that are being developed from from these different circumstances. So yeah, it's it's, it's not a good idea. And this, this stress, and this goes with kind of like the against the hermetic ideas is like, fasting overnight induces a release of stress hormones, have being startled, getting emotionally upset, having a workout going for a brisk walk, can upregulate some of these hormones, it's not that you don't ever want to upregulate these, but to try to like, constantly push for these different hormones and then load your tissues up on saturated fatty acids. It's just a terrible combination, a long run, it's how you would I, at least from my perspective, take a healthy person and then make them unhealthy. is like one of the best ways to do it.

Jay Feldman 16:09
Yeah, yeah, absolutely. I think that's a great way to put it. Yeah. Now that you're likely questioning your Omega three supplementation, you'll likely want to know what you should do instead. So if you're dealing with symptoms like chronic cravings and hunger, low energy or fatigue, joint pain, weight gain digestive symptoms, like bloating, or slow motility, if you're dealing with brain fog, or poor sleep, or hormonal imbalances, or any other low energy symptoms, or chronic health conditions or issues, then head over to Jay Feldman wellness.com/energy where you can sign up for a free energy balanced mini course, where I'll walk you through the main things that you can do from a diet and lifestyle perspective, to maximize your cellular energy and resolve the symptoms and conditions. So to sign up for that free energy balanced mini course, head over to Jay Feldman wellness.com/energy. And these next studies will corroborate that as well and they are looking at healthy humans, this one in particular was looking at healthy humans and they excluded any signs of you know, someone being unhealthy consuming a lot of alcohol, smoking, medical conditions, which includes anything as small as hypertension, you know, high blood pressure hyperlipidemia. So if you have high cholesterol, you were excluded. So this is just healthy humans. And the title of this paper is lipid oxidation during omega three fatty acid and, and vitamin E supplementation in humans. And they state that it was supplemented with omega three fatty acids, EPA and DHA increased in plasma phospholipids and plasma MDA and lipid peroxides. Increased breath l came out output did not change significantly and vitamin E intake did not prevent the increase in lipid peroxidation during Manhattan oil supplementation. So this is a fish oil. So they used fish oil had increased EPA and DHA and the phospholipids. And vitamin E did not prevent the increase in lipid oxidation. The results demonstrate the results demonstrate that supplementing the diet with omega three fatty acids resulted in an increase in lipid peroxidation as measured by plasma and D release and lipid peroxide products, which was not suppressed by Vitamin E supplementation. So if you're very healthy, not a single, you know, issue as far as hyperlipidemia, hypertension, obesity, smoking anything else, and you're consuming antioxidant, quote unquote, like vitamin E, and you're consuming fish oil, you're going to have increased lipid peroxidation due to the fish oil. So just exactly what we were just discussing what you were discussing, as far as this being a bad idea for healthy and unhealthy humans, based on these results. Yeah,

Mike 18:40
and this is something you can see this in cell culture studies as well. They'll expose the cells to increased amounts of arachidonic acid and DHA, and then they'll expose them to something like hydrogen peroxide or whatnot. And then we'll also expose them to vitamin E simultaneously. And the vitamin E protects some but not entirely from the lipid peroxides that are formed. And this is also something I don't like uses as evidence. But Dr. Peat had mentioned previously that vitamin D doesn't fully protect against what goes on with the with the polyunsaturated fatty acids. And that's also not to mention that the vitamin E may not is won't be able to fully protect against the metabolites either. So you have not only the lipid peroxides. But then you also have the metabolites coming from the polyunsaturated fatty acid sources as well.

Jay Feldman 19:28
Yeah, yeah, it's great, you know, great points. And yes, like, introducing some vitamin E, especially in like directly to a cell can certainly help but in general, the consumption is not going to be enough to outweigh this. And so when we were in that are referencing back to that fatty liver series, using vitamin E or chelating iron helps to prevent some of the peroxidation and the effects of polyunsaturated fats in the liver. But again, pretty sure that was an in vitro situation, so it's only going to help so much and still certainly doesn't make vitamin E supplemented. Good idea. But as we continue on looking at omega three is in healthier people. This is a study looking at six weeks of of omega six, excuse me six weeks of omega three fatty acid supplementation in Judo athletes. The title is effect of six weeks of omega three fatty acid supplementation on oxidative stress in Judo athletes. And the quote states The aim of this investigation was to assess the effects of six weeks of EPA and DHA supplementation on rusting and exercise induced lipid oxidation and antioxidant status in judo lists. significant interaction effects were between supplementation and time on resting MDA concentrations, and our max were found with elevated values in the Omega three long chain PUFA group after supplementation and no change in the placebo groups levels. The authors observed a significantly greater nitric oxide and oxidative stress increase with exercise in the Omega three long chain PUFA group than with placebo. These results indicate that supplementation with Omega three long chain PUFAs significantly increased oxidative stress at rest and after a judo training session. So, in these healthy people, even at rest, we're seeing increased lipid oxidation just like these previous studies. And if you add some source of increased oxidative stress, even a quote healthy one through exercise, you see even greater increases in oxidative stress, kind of like what we talked about in the past with low carb, where at baseline you have all sorts of worse outcomes with our citizen stress hormones and everything. But you're also increased in terms of your susceptibility to stress hormones and their downstream effects anytime you introduce a stressor on the system, and so we see the same thing here with the Omega threes. Yeah, yeah, I

Mike 21:43
don't have too much to add to the judo one specifically, I think I think we are. I think we're getting the point across as far as oh, what I do want to add specifically. So two things before, I think you mentioned that vitamin D supplementation may not be a good idea, may not be a good idea. But I think he meant to say Vitamin E supplementation is still a good idea. It just doesn't fully solve the problem of lipid oxidation.

Jay Feldman 22:10
And then the I must have misspoke, because I do think vitamin E supplementation is a good idea. It just is unable to fully account for the consumption of these things. So I think what I was trying to say was that just because you're consuming omega or sorry, just because you're consuming vitamin E doesn't mean that it's then okay to consume or a good idea to consume omega threes.

Mike 22:27
Yeah, exactly. I didn't think you meant to that way. I think it was just the phrasing. Um, then the second piece I want to mention is I can same thing I can hear somebody saying, Well, my omega threes are this special form, and they have, you know, like, what's it some type of antioxidant like all these antioxidants present, and it's an amber bottle, and I've refrigerated it. And it's never been, it's never been above X temperature. But we have discussed previously, that number one, you're going to be introducing these fats now at 98.6 degrees, which is body temperature. And then the other thing is just going through the digestive process itself is likely to oxidize the Omega three, especially if you have any type of iron inside that meal. So just other things to keep in mind that because I can already see that for I will my my omega three supplementation won't do that. It's like, most likely it will.

Jay Feldman 23:27
Yeah, yeah. And there are a couple studies that we'll be going through. And we went through it in that other episode, looking at you know, called of oil and fish oil and how it will still oxidizing the intestines and internally, there's also some papers here looking at fish oil with antioxidants, and also pharmaceutical grade fish oil as well in different contexts. So they do really control for that. So yeah, that's a great point to mention, though. And this next study the the reason I'm want to bring it up is because it also is one that notes on the loss of omega three fatty acids as a result of lipid oxidation. And so the title of this paper is enhanced level of omega three fatty acid and membrane phospholipids induces lipid peroxidation and rats DHA. And so I believe this is the same one that we had referenced earlier, but just mention it again here. I'm just going to read the bolded points, which states that DHA oil intake negatively influenced lipid oxidation and both plasma and liver bussel lipid peroxidation. And plasma and liver was significantly higher than control. And they did look at a few different types of DHA. It was DHA in triglyceride form, and ethyl Ester form and in phospholipid form and the phospholipid form lead to the least amount of fossil lipid peroxidation. But it did in terms of the plasma and liver but it did still have an effect. But the only thing that they mentioned is as a result of the lipid peroxidation. So they stayed farther down during microsolv lipid oxidation there was a greater loss of omega three fatty acids mainly DHA than of the Omega six fatty acids including arachidonic acid. And they also just to say this next to the or these next couple of sentences are just kind of nice to wrap it up the state these results indicate that polyunsaturated of omega three fatty acids is the most important target for lipid oxidation. This suggests that the ingestion of large amounts of DHA oil enhances lipid peroxidation. In the target membranes, where greater amounts of omega three fatty acids are incorporated, thereby increasing the production visibility and possibly accelerating the atherosclerotic process. Yep. Yep, I think the message is getting very clear. Jaysh. Crystal, yeah, that's good crystal. That's good. This one I wanted to include because of what you mentioned earlier, which was the presence of added antioxidants. And so the title of this paper is lipid oxidation products are elevated in fish oil diets, even in the presence of added antioxidants. They state that purified corn and fish oil diets, with different types of concentrations of antioxidants were evaluated for oxidation products, the AI and recommended level of antioxidant addition, and even the addition of 100 times this level, although decreasing the level of oxidation products failed to totally prevent oxidative deterioration and diets high in fish oil. Furthermore, other antioxidants added an excess to the fish oil diets also failed to completely suppress oxidative deterioration of the diet. And in addition, one fed daily to mice for a period of four weeks, cause an accumulation of lipid peroxidation products in certain organs, including the heart, skeletal muscle, and mammary glands. And in the carcass, these results provide evidence that in the preparation, official diets, the addition of antioxidants at the end recommended level or even level substantially higher, 100 times higher, does not completely suppress oxidative deterioration of experimental diets. Yep. I think it's I know, it's self explanatory, but it's, you know, just going through these it's like, it's, it's helpful to just see the results of these studies.

Mike 27:02
No, of course, I agree. I just, it's, as we go through it, we're just gonna see every time we had fish oil, or large amounts of of DHA, you're seeing increased amounts of lipid peroxidation products. And vitamin E is not protecting it specific. Other antioxidants are protecting against it. And it's even happening in Healthy People. And it's happening in response to it's even worse when you get fish oil, and then you have stressful situations. So there's just like, we're still waiting for this context, where it's going to be good to drastically increase this limit proximation through fish oil.

Jay Feldman 27:40
Yeah, well, as you mentioned earlier, hormesis has to be the only explanation. And that's why there's this is the last study I want to mention here talking about direct metabolic effects of Omega three consumption. And the effects on the pro oxidation. And this one is talking specifically about the fat oxidation side of things, among other things, but very parallel with what you were talking about earlier with the hormetic mechanisms as a result of harmful effects of the fish oil. And just for reference, for anyone who hasn't seen that series. The idea behind hormesis is that you're causing some damage, you're causing some stress, you're causing an issue. And then the body reacts to that with an upregulation or reverse trying to reverse the process. And some people view this most people viewed this as a positive thing. But we've actually pointed out that the evidence doesn't corroborate that. And instead, this is a pretty bad way to try to lead to improved health. And so this study is looking at this in the context of omega threes, and there's quite a few others as well, maybe I know, you alluded to a couple, but, so we can reference those in the notes. But in this one, the title is dietary Omega three highly unsaturated fatty acids affect mitochondrial fatty acid beta oxidation, capacity and susceptibility to oxidative stress. In Atlantic salmon. It's also interesting that they're doing this in a animal that is normally going to have very, very high levels of omega threes, and it still cause these sorts of issues. So Atlantic salmon were fed four different diets for 21 weeks delivered levels of Omega three highly unsaturated fatty acids ranged from 11% of the total fatty acids in the low Omega three diet to 21% of the intermediate diet, and 55 to 55 and 58%. In the high omega three diets. Increasing dietary levels of omega threes led to increase in percentages of these fatty acids in liver lipids. The group fed the highest level of DHA had higher expressions of peroxisome proliferator activated receptor, this is P par beta and the fatty acid beta oxidation genes Acyl-CoA oxidase and carnitine palmitoyltransferase to compared to the low Omega three groups, the high omega three groups had reduced activity of mitochondrial cytochrome c oxidase and beta oxidation capacity together with increased activities of superoxide dismutase and caspase three activities. The percentage of mitochondrial cardio Lipin was three point One in the highest Omega three group compared to 6.6. In the intermediate group, these data clearly show an increased incidence of oxidative oxidative stress in the liver of fish fed the high omega three diets. So I know there was a lot there. But I think really important things to explain. So one that we've mentioned, I believe, in the past talking about Omega three and Omega six is, is that one of the one we're producing energy, we talked about the issues with the phospholipid membranes being unsaturated, one of the main complexes complex four of the electron transport chain, I said was cytochrome c oxidase, and it has lipid components. And when those are replaced when they're more when they're less pro oxidizable, when their mono are saturated fats, well, those are replaced with more unsaturated fats like omega threes, it leads to major issues that leads to increased oxidation and decreases the function there. And when you have poor oxidation there, it actually will remove those omega or those complexes from the electron transport chain, which is how they saw here that there is less than half of the cardio Lipin in the highest Omega three group versus the intermediate group, and Accardi. Lipton being involved in cytochrome c oxidase there. So that's, that's one thing that I wanted to mention. Another thing, if you actually looked through the study, they showed that there was a dramatic like, basically zero beta oxidation in the highest Omega three groups. In other words, their ability to produce energy was incredibly suppressed by these high levels of omega threes. And so as a result, you saw an increase in upregulation of the genes for fatty acid oxidation, and those enzymes, as well as the poor beta activation and expression. And from the hormetic standpoint, normally, they would point to a study like this and say, Look, omega threes are good, yes, they decrease beta oxidation. But look, they increased all these things that helped to increase it. So this is actually good for you. But when you look at the study, despite the increase in expression of all these things, their capacity for fat oxidation was nearly zero, it was it was incredibly low. Despite all these hormetic reactive adaptation effects, which is the same thing you see in diabetes and other chronic health conditions, you see up regulations of things like autophagy, and uncoupling and response to hormesis. And then you see worse outcomes, it doesn't actually improve the outcome, it doesn't actually give you the the effect that it's supposed to that's purported to. So you see that here, in addition to seeing, of course, the increased oxidative stress and things like that from the high omega three times, I think the

Mike 32:36
most interesting piece of this, for me is the effects are surprising, especially considering what you see in all the mice, the rat and mouse studies is that this is actually in salmon. So salmon are organisms that generally have higher amounts of omega threes in their tissues, specifically to deal with living in a very cold environment. And they're, they're responding negatively to really high intakes of omega threes and high end and incorporation of high amounts of omega threes into their tissues. And the effects are again it. The other thing I find really interesting here is that the the cells are up regulating these, these adaptive responses, these, these stress responses, the PPAR beta, and then the the PPAR beta helps up regulate fatty acid oxidation and whatnot, in response to the inability to actually oxidize fats appropriately because of the damage to the the mitochondrial function from the high amounts of omega threes. So it's, it's yeah, the the time course, I think is really important when you're trying to understand these mechanisms, its lipid peroxidation, damages mitochondrial function, and also triggers or signals, hey, we have these damaging products present, let's upregulate all these pathways to deal with them. And so even when you look in some of the other cellular studies or some of the rat studies and you look at it, the provision of DHA and nine omega threes and fish oil and things like that, you see oh glutathione s transferase is higher o glutathione. Levels reduced glutathione levels are higher. Oh superoxide dismutase levels are higher. Oh, what all these different antioxidant enzymes are higher heme oxygenase expression is higher, right. And it's like, that is not a good thing. Especially because you'll look at like the control groups, and the control groups will actually have less of those antioxidant enzymes, and less of the signaling. It's like, Oh, see, look, this is the benefit of upregulated all these things, and it's like it up regulated these things because it was causing problems. And so then the cell had to respond and protect itself from the lipid peroxides from the damages energy production systems and start to detoxify the lipid peroxides and the lipid mediators that are produced from these types of fatty acids. So that's that's a really important piece is damage or or danger signaling and then the upregulation? Versus like, is the cell having a better antioxidant capacity because you have less reactive oxygen species and less lipid peroxide. So you just have more antioxidants substrate, vitamin C, vitamin E, glutathione, whatever the reason is, because you're not having all of the oxidative stress versus inducing oxidative stress, and then having the response. And or the other thing here is are you having improved? Are you having increased energy metabolism or upregulation of some of these different things, because the cell is like responding to having a high ATP state and increasing mitochondrial production and energy flux or is it energy is so damaged, that you need to upregulate defensive pathways to try to get things going, again, to try to move things along. And so the context is super important. I think this is a great example this. And again, this is in salmon. So like, salmon are technically supposed to have a decent amount of omega threes in their tissues, you would think that they had some type of evolutionary mechanisms to be able to handle omega threes. And so the fact that you're seeing this trend is just, it's kind of interesting overall.

Jay Feldman 36:16
Yeah, absolutely. And it was a very, very high omega three diet, but still just interesting to point out and do it, again, the larger notion within hormesis, that if you're having issues with damage not being cleaned up, right, don't have enough autophagy. Or if you're having issues with mitochondrial respiration, where you're not producing energy, well, what you need to do is you need to create more damage. That's how you get it cleaned up. You need to impair mitochondrial respiration to activate backup systems to force mitochondrial respiration. That is the perspective as opposed to let's actually fix mitochondrial respiration of why you're not producing energy. Let's actually increase the capacity for cleanup so to speak, or let's reduce the amount of damage being produced through other means that aren't actually creating more damage. Like even just on the face of it when you actually get underneath the flashiness of hormesis. And, you know, buying fancy saunas and, and cold baths and doing, you know, fasting and ketogenic diets, all these things that are unique and different, and on the forefront, so to speak right now, or consuming fish oil falls in that same category. Again, if you want to dig beneath that and get below the flashiness, and actually read, see what see what it is, like, see it for what it is, and also see that it's the same perspective, the same argument that the industrial chemical companies are making for polluting the environment and say, you know, it's the same argument that the doctors are making for why cigarette smoke is good for you and things like that. I mean, then you really start to like, it really starts to fall apart without even getting to the research, which then I think is even further. So. Yeah, it's nice to see omega threes fall into that same category. And I don't have anything else to add here as far as showing them increasing lipid peroxidation. Other than I would just add also, that not not not only is this just a problem on its own, but we also very clearly see associations, as you were alluding to between increased oxidative stress increased lipid peroxidation. And every chronic health issue aging, you see this in human to cheat and other species. I mean, this is very clearly not a good thing. So yeah, I think it's, it's really important evidence to consider. Alright, so the next handful of studies that we'll be going through are going to be showing that the increased consumption of omega threes through supplements doesn't actually improve chronic health conditions or mortality in humans. And of course, this is despite increasing the Omega three content of the phospholipids, which we know to happen when we use Omega three supplements. So this is seeing inaction. You know, this is actually looking at the randomized control trials where omega threes are given and seeing if there's actually an improvement in outcome. And I will say there is conflicting research here, some studies support it, some meta analyses support it and say that there is some benefit, and some do not. We're just going to be highlighting the ones that are, you know, made major meta analyses, recent ones looking at this, and showing that there's really not much of an effect. And again, you can you can find conflicting data here. But that alone is enough to say that, or at least to not be able to say convincingly, that there is a benefit to Omega three consumption. So that's really the main point we want to drive home here is, is that there, you know, there, there's quite a bit of evidence that this is not actually any beneficial, or necessarily harmful either. In these contexts. The other thing too, is that with these meta analyses, they're all going to vary based on the details based on which trials, they include which ones they don't, what they consider to be high quality evidence, how they weighed the different trials. And so that's why you're going to get conflicting data. And it's all a lot of it is interpretation. It's based on author's interpretation, and then the person who's reading it their interpretation, so it's Just like anything in, quote, science, there, it's not black and white. But anyway, we're going to be highlighting a lot of these papers that do suggest that there's no benefit to Omega three supplementation and humans for chronic health conditions or for mentality.

Mike 40:15
Yeah, I think the overall point here is, is that it's not necessarily a settled situation on the on omega threes specifically, because you, you have some evidence where there seems to be some benefits, at least indirectly. So it doesn't necessarily mean that the Omega three supplements are beneficial and of themselves. For example, the studies that we covered discussing the the associations between the red blood cell and total red blood cell phospholipid, concentration, omega threes, and then total mortality. So you know, there's that piece of evidence, which is largely indirect. And then you have a mixed bag of evidence over here on this side with Omega three supplementation use in humans, and then the subsequent outcomes from there. And you also have a degree of mixed bag of evidence in fish consumption. And like fatty fish consumption versus lean fish consumption, in terms of the benefit, and we'll get into that in terms of the benefits of those and different types of outcomes. And then you also have some mechanistic underpinnings where omega threes could actually be highly problematic. And then there also his research, they're showing that these omega threes or sources of Omega threes, can be highly problematic through multiple mechanisms to lipid peroxidation incorporation into the membrane change in mitochondrial mitochondrial energy dynamics, or energy production and things along those lines. So it's when you're like weighing all of these pieces together. It's like, all these things for me, give me pause before I say, Okay, well, this section of data or this set of information, saying, Oh, this is a good thing to do. And then when you start and so like, when you bring this next context, in, that we're going to jump into when we start to see, it's kind of a mixed bag, then it's also it means for me that okay, I need to do a bit more digging, to figure out why, where this where the discrepancy is, and what is it exactly going on, because there's that there has to be a reason, or some some explanation for why in one circumstance, you're having all these problems. And in these other circumstances, perhaps with some of the indirect measures, you're starting to see some of the different benefits. So I think this is important to see for the whole, that there's like multiple contexts and a larger picture to look at here. And then the discrepancies in these different areas make things very important to be to give pause before you know, you start slamming cans of mackerel and things like that.

Jay Feldman 42:53
Yeah, or even worse, you know, Omega three supplements. Yeah, and, you know, we've gone through the pretty clear mechanistic data, you know, data, both in humans and animals showing a lot of mechanistic problems with lipid peroxidation, when it comes to increasing the consumption of omega threes, and then there will be will, you know, we've gone through some pretty clear data and animals as well. And we'll come back to, or go back through some more data in animals showing that showing the effect on lifespan and mortality, and those, the value in doing that. And of course, not everything between a rat and a human is the same, although a lot of the physiology is very, very similar. But part of the problem with looking at a human trial of a couple of years out of an eight year lifespan, is there's a lot of other variables going on. It's way harder to control, other variables, other aspects of diet and whatnot. And also, you're just looking at a very small snapshot in the lifespan, whereas you can take a mice or a rat and give them more omega threes for their whole lifespan, and see what happens. You know, throughout that time, it's it, there's a lot more that can be controlled, and it's over a much longer span. So anyway, well, we'll dig into this research here showing that in humans at the, at most, it's really, there's not any sort of conclusive evidence suggesting that supplementing with omega threes is beneficial for these for these chronic health conditions, which are often the things that they're suggested for heart disease, depression, and not from there. So to begin, there's a study, a meta analysis titled association between omega three fatty acid supplementation, and risk of major cardiovascular disease events, a systematic review and meta analysis. This is from 2012. Just share a couple of quotes, states: of the 3635 citations Retrieved 20 Studies have 60,000 plus, patients were included reporting 7000 Plus deaths, almost 4000 cardiac deaths, over 11 are over 1100 sudden deaths and 1800 37 myocardial infarction is at 14 190 stroke. Overall Omega three PUFA supplementation was not associated with a lower risk of all cause mortality, cardiac death, sudden death, myocardial infarction or stroke based on relative and absolute measures of association. So pretty good sample size here, pretty large meta analysis looking at quite a few studies, and they're pretty clear conclusions of no benefit to the Omega three supplementation. You have anything else to add, before we go on to the next couple? Like?

Mike 45:29
Nope, I think that one is, I mean, overall, pretty clear? Well, I think this one would probably be more helpful, then the RBC phospholipid piece of information to determine whether you should actually take omega threes. Again, it because in the previous in the previous set of arguments that we brought about with this is that multiple things can adjust red blood cell phospholipid Omega three content. And so you're does supplementation, yes, that is one of the factors that can change the RBC phospholipid Omega three content. But here you're actually seeing what is the associated the outcome is there's like, is it going to lower mortality or affect cardiovascular outcomes or anything like that, if you're going to take fish oil, because that's ultimately the implementation that you're getting to? So here, it's basically you're seeing the implementation of, okay, we're going to take fish oil, and then we're going to and then there's multiple studies here, and then we're going to analyze and see, okay, does it actually make a difference from all these studies? And at least according to this meta analysis, there's not a not a mass or significant difference, both in relative and absolute terms. So this is actually for the implementation perspective of taking fish oil. This is, I think, a better piece of information than relying on the RBC phospholipid data.

Jay Feldman 46:44
Right? Yeah, these are these are meta analyses of interventional trials. Not not looking at associations in epidemiology. Yeah, like the red blood cell lines. So these next few papers are going to share some quotes from our all Cochrane Reviews, there's one from 22,004, and one from 2018, and then one from 2020, where they're doing further meta analyses, looking at omega three fatty acid supplementation for cardiovascular disease. And, you know, you can see that they've been looking at this for nearly 20 years, you know, doing these major meta analyses, and nothing's really changing there. There's one very small kind of minor change. But the most part the evidence isn't really changing based on these reviews. Search one, they stayed omega three fatty acids for the title is omega three fatty acids for prevention and treatment of cardiovascular disease. This is from 2004. And so in this paper, they were looking at 48 randomized controlled trials and 41 cohort analyses. The pooled trial results did not show a reduction in the risk of total mortality or combined cardiovascular events. And those taking additional omega three fats with significant statistical had heterogeneity, sensitivity analysis, retaining only studies at low risk of bias, reduced heterogeneity, and against adjusted no significant effect of omega three fats. So just to explain that a little bit further, they were looking at a ton of different control trials. And overall, there was no reduction in the risk of total mortality, or combined cardiovascular events in those taking omega three supplements. Although they said there's heterogeneity. So what that means is that some studies showed benefit, some studies maybe showed negative effects, but overall, there was still no benefit, but it was just very mixed the results were but then when they only looked at the studies at low risk of bias, that reduced the heterogeneity. So the studies with low risk of bias were much more conclusive. And, and there was much less discrepancy, and they largely showed that they showed no significant effect of omega three fats. To go on with the next part of the quote, here, they state restricting analysis to trials, increasing fish based omega three fats, or those increasing short chain Omega threes did not suggest significant benefits on mortality or cardiovascular events in either group. So group analysis by dietary advice, or supplementation, based on risk of cardiovascular disease, or omega three dose suggested no clear effects of these factors on primary outcomes. So in this part of the meta analysis, they looked at just consuming extra fish, just consuming short chain omega three fats, just looking at dietary advice versus supplementation, looking at different doses, all of it suggested no clear benefits in terms of omega three fat supplementation. So, again, this was 2004. But I'll share some quotes from the more updated versions, largely suggesting the exact same thing. So in their next analysis, and again, I do think it's worth going through these papers a little bit or at least just including these quotes because they get very clear on what they're looking at the Yeah, it'll just help to add context, but

Mike 49:55
and the Cochrane the Cochrane Reviews are kind of the gold star 100 of these different reviews like a lot of people in at least within research holds Cochrane to a very high esteem. So if when they put out analysis or using these topics, these are usually some of the best reviews available.

Jay Feldman 50:15
Yeah, yeah, it's a great one. Thanks for mentioning that. So this next one omega three fatty acids for the primary and secondary prevention of cardiovascular disease, it's from 2018, also Cochrane. The state there we included 79 randomized controlled trials in this review update, and found that 25 Were at low summary risk of bias trails were of 12 to 72 months duration and included adults at varying degrees are at varying cardiovascular risk, mainly in high income countries. Most studies assessed long chain Omega three supplementation with capsules, but some used long chain Omega three or ala rich or enriched foods or dietary advice compared to placebo or usual diet. They go on to say meta analyses and sensitivity analyses suggested little or no effect of increasing long chain Omega threes on all cause mortality, cardiovascular mortality, cardiovascular events, coronary heart disease, mortality, stroke, or arrhythmia. This is the most extensive systematic assessment of the effects of omega three fats on cardiovascular health to date, moderate and high quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health. This is evidence mainly from supplement trials. Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias that go on to say that there is evidence that taking omega three capsules does not reduce heart disease, stroke or death. There's little evidence of effects of eating fish. So this was a much more recent review, stating very clearly, all the same things. No little or no effect on mortality, cardiovascular health, whether we're looking at supplements, whether we're looking at eating fish, whether we're looking specifically at EPA, DHA, no benefit to cardiovascular events, stroke arrhythmia, not from there.

Mike 52:02
Yeah, and I again, I think this puts into perspective of, is there something else going on with the RBC phospholipid omega threes, more so than just taking fish oil supplements or eating large volumes of fish now, or large volumes of fatty fish? This is not to say that there's not a benefit to eating seafood and fish, it just may be that the benefit is not directly related to omega threes. Although here, you know, they're the there's little they're saying there's little evidence effects of eating fish specifically. So perhaps those benefits of eating fish are not playing out in the randomized control trials here in the analysis. But overall, again, that's not to say not to eat fish.

Jay Feldman 52:42
Right? Yeah. And we would generally recommend low fat fish, low Omega three fish, and right again, it's important. Yeah, yeah, and seafood and things like that. But, again, it's important important, important to point out here that when they separate the trials based on moderate and high quality evidence versus trials with higher risk of bias, there is a clear difference in what they're seeing. And that's part of what's so difficult about looking at research is those possible biases, who is funding the research all those things, where their perspectives are coming from and how they're analyzing things. And when those things are looked at, by presumably objective third party source, do you see a clear difference, and we talked about this with the status in the past as well, where, you know, as soon as they introduce stricter rules, in terms of how the research could be carried out, then all of a sudden, you start to see different results and, you know, on from there, so, anyway, moving on to the more recent of the Cochrane Reviews, short quote here, just basically showing largely the same. This one is from 2020. It's titled omega three fatty acids for the primary and secondary prevention of cardiovascular disease, same title, just the updated version. And this one, they included 86 randomized controlled trials and found that 28 Were at low summary risk of bias, meta analysis and sensitivity analyses suggested little or no effect of increasing omega threes long chain Omega threes on all cause mortality, cardiovascular mortality, cardiovascular events, stroke, or arrhythmia, they did find that increasing long chain Omega threes may slightly reduce coronary heart disease mortality, although this was low certainty evidence and coronary heart disease events, again, low certainty evidence, overall effects did not differ by trial duration, or long chain Omega three dose in pre planned subgrouping or meta regression. There's little evidence of effects of eating fish. So again, here when it comes to the most important things like all cause mortality, cardiovascular mortality, and all of that there's still little or no effect of the long chain Omega threes, but they did find with some of the more recent papers based on low certainty evidence that there might be a slight reduction in coronary heart disease events and mortality. So you know, I would say that I'm not sure how valuable that is, if it's not also coming along with benefits all cause mortality. And again, there's low certainty evidence obviously there's a lot more to be done here as far as research goes, but it is worth mentioning that there might be something there, at least based on on this analysis, but I'll leave it at that. Yeah,

Mike 55:11
I think there's too many other points here too, that are that bringing into question specifically, where you're seeing some benefits with coronary heart disease mortality, but not other areas of cardiovascular function. And you're also seeing perhaps the benefit with the supplementation, but then not the fish, which the question would be if the fishes also containing omega threes, why is there not a benefit? Is it because there's other components that would be negative, but that's kind of questionable considering that fish generally is assumed to have mostly beneficial components, maybe trimethylamine oxide or TMA was like the one thing that people would like argue against fish for to some extent. But yeah, overall, it's kind of it seems conflicting, because it there's not a congruence you with the other pieces in conjunction with this low certainty evidence for the cardio the coronary heart disease events.

Jay Feldman 56:06
Yeah, yeah, yeah, definitely. I don't have anything else to add there. But you want to go ahead and share the next one, make?

Mike 56:13
Sure so the next one that we're looking at here is titled associations of omega three fatty acid supplements used with cardiovascular disease risks. This is a meta analysis of 10 trials involving 77,917 individuals, and it's from 2018. So they start here and they say, previous meta analysis, or meta analyses of omega three fatty acid trials, which are limited by being incomplete, including trials of dietary advice to increase fish consumption, or failure to distinguish the effects and a wide range of subtypes of cardiovascular disease. And contrast, the present meta analysis demonstrated that omega three fatty acid supplementation had no significant effect on fatal coronary coronary heart disease or any other cardiovascular disease subtypes. So basically, what they're saying here initially, is that previous meta analysis had some issues in terms of what they the trials that they were analyzing, so basically, some of them were looking at just in increasing fish consumption, or, or they weren't distinguishing the different types of cardiovascular disease. So in this one, they specifically corrected that. And they demonstrated that they've specifically looked at omega three fatty acids, supplementation, and they found that it didn't have any significant effect on coronary heart disease, or any other cardiovascular disease subtypes. So instead of looking at trials that were saying, Oh, we're gonna have fish, or we're going to have advice to increase fish, or a domain or three supplementation, they narrowed in on omega three supplementation, and then instead of just kind of like looking at heart disease in general, they went in and looked at coronary heart disease and other subtypes of cardiovascular disease. And they basically found that there wasn't any benefit when they got very specific about the types of questions they were asking about the research. This. The next quote here is they say this meta analysis of 10 randomized controlled trials involving 77,917 participants demonstrated that randomization to trial arms with omega three fatty acid supplementation for a mean of 4.4 years had no significant effect on either of fatal coronary heart disease, non fatal myocardial infarction, which is a heart attack, stroke, revascularisation events. So that's kind of you're going in and you have a blockage in the heart, they can put a stent things along those lines are any major vascular events. Importantly, this meta analysis also demonstrated no significant effect on major vascular events in any particular subgroups, including prior vascular disease, diabetes, lipid levels, or statin use. Likewise, the present president meta analysis showed no significant association of omega three fatty acid supplementation with all cause mortality or cancer. And basically, they're saying the data wasn't shown for this, but they didn't find a significant association there. So essentially, the what they're looking at here is 10 randomized trials with a huge population 77,000. They looked at the mega three use for foreign it almost four and a half years. And basically, they didn't find the benefit in multiple different subgroups of cardiovascular disease. So that strokes, that's heart attacks, that's having to go in and have revascularisation. So getting stents put in or having the balloon angiography, the balloon angioplasty to open up the veins or cabbage or anything along those lines. And then essentially, they also didn't see a benefit with all cause mortality or cancer. And this is I think, this study is very important and very specific or this this meta analysis is very important, very specific, because it got very precise about the types of questions it was asking and it was specifically what is the effect of Omega three supplementation on these these different outcomes. So these different subgroups of cardiovascular disease, and then all cause mortality and cancer, and that narrowing these things down is, I think, quite important overall to the picture because the ultimate goal is to parse out, where's the benefit actually coming from with fish consumption? Or Omega three consumption? Or is there benefit between the two? Because if omega threes are not the actual beneficial component of fish, then taking the supplement to have omega threes who achieve these benefits, because there's some indirect associated values, but you're not actually seeing the benefits when you use the supplements, it makes the supplements largely moot, it makes it probably, and then the question and the other piece, I think, to add to this is, if you have no negative effects of omega threes, then not only would it be like no or mood is there actually a negative effect that could occur from taking the Omega threes long term, and that's what you want to parse out. And again, it's like, if you had a substance that was showing a benefit, and it didn't have these, this other side of it, where oh, there's perhaps some negative components, then at the minimum, it doesn't have a negative effect, or it doesn't have any effect. And then at the maximum perhaps, is actually beneficial. And for certain, you know, you can think of something like this, where you're taking like certain B vitamins that are water soluble, and as long as you don't overdose them. For most people, they may actually have a beneficial effect. And the downside is relatively minimal. But the problem with omega threes is that there may actually be pretty significant downside, and the mechanisms for this are already laid out, which is where, which is why we're doing this entire podcast, essentially, is to put all these in context. And so basically, you're seeing with these different trials, the supplementation is not actually having a benefit. And as you start to get more specific on the research that you include in your analysis, and you start to get more specific on the types of questions you're asking about the research, you start to see that the benefits are not actually playing out, the way that we see. And this is becomes especially important again, because there's multiple logical steps that you have to go through here. If, if my omega three content in my red blood cells decrease decreases my risk of mortality. And I know that omega three supplementation will increase my omega three content, my red blood cells, then you're assuming that taking omega threes will decrease your mortality. But we're seeing here is that taking omega threes is not doing that. So there must be some other modifying factor in the middle as far as omega three content in the red blood cells. And this is an even worse is that the omegas? Taking the Omega threes may actually be worse, because we have these known negative mechanisms. And so it's important to have that entire context. Before you make, or at least for me, before I make decisions about taking omega three specifically, I want to fully understand, do they have does the mechanism makes sense? Is there associations there? And And are we also seeing benefits when these things are given in real life?

Jay Feldman 1:02:56
If they have absolutely. I don't have anything to add. But there are just a couple more meta analyses to to, to mention here that are important. So this is this one is from 2020. It's the strength trial. So it's titled The effect of high dose omega three fatty acids versus corn oil on major adverse cardiovascular events in patients at high cardiovascular risk, the strength of randomized clinical trial. And this is particularly important because this is in patients at high cardiovascular risk. These are largely patients who are on statins as well. And so these are the patients who should be helped the most presumably, if omega three fatty acid supplementation is helping for cardiovascular disease risk. And so if there was ever a population to see any benefit, it would be the most at risk population. And what they found there's two quotes here. The first states that when 1384 patients had experienced a primary endpoint event of a planned 1600 events, the trial was prematurely halted based on an interim analysis, they indicated a low probability of clinical benefit of Omega three ca versus the corn oil comparator, and the Omega three CA This is a formulation it's a carboxylic acid formulation of EPA and DHA of long chain Omega threes. They're comparing that to corn oil. So again, they stopped this trial early because it was indicating a very low probability of any clinical benefit. The next quote They state among statin treated patients at high cardiovascular risk, the addition of Omega three ca compared with corn oil to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support the use of this omega three fatty acid formulation to reduce major adverse cardiovascular events in high risk patients. So of course, this is the patients that are supposed to be helped the most with omega threes. And they were finding here that that was not the case. I

Mike 1:04:43
think but even even worse, that they didn't find the benefit in the in the like groups that should see the most benefit is that they didn't find benefit compared to corn oil, which is like it's you know, it's not it's not like there's like a Oh, they didn't find benefit compared to olive oil, which there's other benefits or nothing. Yeah, it's like those corn oil, which should have arguably made everything worse. Because it also is proxy sizable. It's also a precursor to inflammatory mediators. And it's usually not like a high quality oil that you want to consume on a regular basis. Right.

Jay Feldman 1:05:22
So even if there was a benefit, you could have chalked it all up to a negative effect of the corn oil. But there wasn't even a benefit. It's like, we talked about this with the weight loss research on ad libitum. Feeding or sorry, the calorie restriction and lifestyle research on ad libitum feeding and everything in in rats were all you know, they have these rats who are calorie restricted, and these rats who eat at the bottom, and the ones who are calorie restricted happen to live longer. And then you've come to find out that it's actually just because the ones that are fed up libido are extremely unhealthy and have a shorter lifespan than normal. And it's not actually because there's any benefit of calorie restriction. But you're not even seeing that here. You're not even seeing that there's a benefit relative to corn oil, which would presumably be worse. So you could even argue that if we know corn oil to be worse than and fish oils are equal to that, then that's a pretty bad outcome. That's That's pretty. Not very good support for fish oil supplementation. So

Mike 1:06:13
yeah, so you have the high risk group, and then they also got corn oil, and there still wasn't a benefit to the they actually had this they actually stopped the trial, which right stopped it early. Like, yeah, which is really not good overall. Yeah, yeah. Yeah. Okay, so the next one here is titled Omega three polyunsaturated fatty acid supplementation in the prevention of cardiovascular disease, and this is a 2016 paper. The first quote here, they start out, they say eight randomized control trials and two meta analysis were included. In patients with pre existing cardiovascular disease, only one of five included randomized control trials demonstrated a reduction in cardiovascular cardiovascular events with Omega three polyunsaturated fatty acids. However, the effect size was minimal, and the study was limited by an open label design and a lack of placebo control. We'll get into that in just a sec. To meta analysis concluded a mega three PUFA is do not reduce cardiovascular events in addition to standard evidence based therapy and patients after myocardial infarction of so myocardial infarction for anyone who doesn't know is a heart attack. Of the three predominantly primary prevention randomized controlled trials, only one demonstrated a minor reduction in major current coronary events, however, was also an open label study. Furthermore, the safety of Omega three PUFA should be considered while data from randomized controlled trials have not demonstrated serious safety concerns. Omega three plus can increase the risk of bleeding and may interact with other medications that affect hemostasis, such as anti platelet agents and warfarin. last quote here, they say there's currently a lack of evidence to support the routine use of Omega three poopers and the primary and secondary prevention of cardiovascular disease. Pharmacists are ideally situated to engage in patients in the discussions of the lack of benefit and possible risk of Omega three polyunsaturated fatty acids supplements. I think the first thing to point out here is they do mention that there's risk and it's the bleeding and interaction with other drugs, but it's also the lipid peroxide, lipid oxidation. And then the incorporation into two mitochondrial membranes, which, which we've kind of discussed ad nauseam at this point. So those are other things that I would add to that. And then it's also kind of what you're getting at before j, where you see studies that had a high risk of bias, but then when they eliminated them from the Cochrane analysis, they weren't really finding a lot of benefit. And basically, this quote, this quotes here are indicating like what these biases could include, or what could show like, maybe not as high quality data as some of the other trials. And you see this here with open label designs with lack of placebos showing the benefit with with omega threes are the open label studies overall showing the benefits so it's, yeah, basically, when you start to get like much more, stringently controlled studies, or stringently constructed studies with the Omega threes, you're really not seeing the benefits overall. Then this is specific to cardiovascular disease.

Jay Feldman 1:09:18
Yeah, yeah. And it's one thing if those less rigorous studies that are open labeled no placebo, higher risk of bias are showing the same thing as everything else. And you can say, Okay, well, yeah, they're all leaning in the same direction of benefit, but they're not those are the outliers that are suggesting benefit and the ones that are more rigorous are not they're not suggesting any any benefits so yeah, I think that it's these these analyses really go pretty far to demonstrate that and yeah, I don't have too much to add Of course, it's it's nice to see some warnings here about about possible dangers, even if they are really not even touching anywhere near the what we would argue are the real dangers of it. of the Omega threes. But

Mike 1:10:02
yeah, the other thing I want to I do want to add here is when they are showing benefits, the benefits are largely via the are largely shown in conjunction with low effect or small effect

Jay Feldman 1:10:15
sizes. Right, right, right. Yeah, the effect size was minimal. It said, yeah,

Mike 1:10:19
exactly. So effect size for anybody's unaware of showing the, like, the amount of significance is saying this is this is a high probability that this happens. And an effect size tells us like how large the effect actually is. And so if you have a smaller effect size, you're really not seeing much of a benefit, you're seeing a very marginal benefit, even if it is significant, meaning it's unlikely to be a function of chance. So yeah, it's, that's not a good, this isn't really like a good argument. At least these aren't showing for supplementing Omega three specifically. Because even if you were even if say the benefit was even there, if it's very marginal, then and there are other risks for it, then the question now again, becomes risk versus reward. And, again, they're starting to discuss some of the risks of this. But there's also others that are not really discussed overall. And again, like, as you already mentioned, before j this is also a timeframe. What's the risk of using these things across the lifespan of rat studies, it's easier to see and sell studies, rat studies, worm studies, yeast studies, easier to see these things because they have such a short lifespan, whereas with humans is like, good luck trying to figure out the effect of omega threes over the course of a human's lifespan. And, you know, like, when, when we're all when our children grow up, then they will have the knowledge. So it's like, yeah,

Jay Feldman 1:11:42
yeah, yeah. And I'm excited to get into to that research. Also looking at what happens in offspring with Omega three supplementation in some of these animals. So very relevant speaking of, of what will happen to the, to the children evolve the Omega three mega medicated parents. Anyway, I that's as far as the actual studies I wanted to share here. You know, I don't want to go into any others, I just wanted to look at the major ones looking at mortality and cardiovascular disease. But as far as the trials looking at, and meta analyses, looking at everything, from depression, to anxiety, to macular degeneration, ADHD, anxiety, IBD, dementia, Alzheimer's, schizophrenia, pregnancy outcomes, infant outcomes, these are all things that people will point to a study here or there that it says suggest some benefit, and people will talk about using omega threes for these purposes all the time as being beneficial. But just like these studies that we shared, the evidence is not conclusive. For those things, either. A lot of the papers, a lot of the meta analyses are showing, at most a very small effect size, and the vast majority of time, no benefit or no, or sometimes even a negative effect. So I would just keep that in mind when it comes to any of these other disease processes as well. But you know, it's it would take too much time to dig through the research and share some of the quotes everything from each one, I think the point kind of got across.

Mike 1:13:12
Yeah, I do want to add something here specifically is that, for example, when they're when they're talking about that the Omega threes may interact with other anti platelet medications or blood thinners like warfarin. Some of the benefits that are described to omega threes, as far as creating pro resolving mediators and inhibiting access platelet aggregation and things along those lines, like those specific mechanisms are of benefit. But the thing is, is you can get those benefits without having to rely on something like omega threes that come with other problematic factors that we've kind of mentioned ad nauseam here, so and minimizing inflammation or inhibiting the Cox enzyme, or creating specific mediators, for example, aspirin can create similar mediators that help to minimize an inflammatory response. Like that's helpful. A blood thinning response inside cardiovascular disease is also helpful for many reasons. And then in hitting things like neuro inflammation or whatnot in these in these different states, or adjusting inflammation in the digestive tract, etc, etc, etc, or balancing out perhaps an extremely pro inflammatory profile that's very high in Omega six and increasing Omega three intake and adjusting the high cost annoyed mediators that are produced are probably like, to a degree beneficial, but again, on the spectrum of benefit, ideally, you wouldn't have a high amounts of either of these highly profitable fats, and overall, you would keep your eye cost annoyed inflammatory mediators low so it's like, perhaps there is some benefit from the Omega threes and these particles for these specific mechanisms. But there's also problems with the Omega threes and these mechanisms can and be hit through many other substances and options. And then the other thing is like having them in and of themselves on the problem like as far as spectrum of optimization, they're not on the on the far side towards more optimal, even if they have some of these specific benefits in these very specific contexts. It without taking consideration the other side effects them, like sure, you could make an argument for it. But I think it's important to always have those other pieces in context.

Jay Feldman 1:15:29
Yeah, and even with those other mechanisms, you know, like the anti inflammatory effect, being something that actually works through immunosuppression. I mean, there's, I think I would even be careful to hold on benefits, I would say that they are certain effects, but just like, the suppose that effects here, the larger context says at all and is, is incredibly important, as opposed to just saying, hey, look, it has this effects. Let's take the Omega threes. So yeah, I'll certainly be linking back to previous episodes where we've brought about some of that context. I did want to just mention one other area here looking at Fish Oil supplementation and insulin sensitivity and diabetes, being something that I'll cite some research looking at that and actually showing some negative effects in terms of official supplementation on insulin sensitivity, or array, we're going to end that episode there and pick back up in part three, where we'll be going over the studies showing that omega three consumption decreases lifespan and increases disease processes. We'll also be going over the potentially harmful effects of Omega three usage during pregnancy on offspring. We'll be going over the data and native culture showing that omega three intake does not improve cardiovascular disease or mortality. And we'll also be discussing the extremely healthy populations that consume high carb and high saturated fat diets with almost no omega threes. If you did enjoy today's episode, please leave a like or comment if you're watching on YouTube. And if you're listening elsewhere, please leave a review or five star rating. All of those things really do a lot to help support the podcast and are very much appreciated. To check out the show notes for today's episode, where we'll link to the studies and articles and anything else that we referenced, you can head over to Jay Feldman wellness.com/podcast. And if you're looking to optimally support your metabolism, and lose weight and improve your digestion, get amazing sleep, rebalance your hormones, boost your energy, and so much more with clear action steps and strategies along with personalized guidance from me, then head over to Jay Feldman wellness.com/solution where you can find all of the information for the energy balanced solution program. This program includes customized health coaching, a video library which includes videos on restoring gut health, losing weight without destroying your metabolism, boosting your metabolism, getting amazing sleep, how to rebalance your hormones and tons more. It also includes resources like a sample meal plan and supplement guide, as well as a private community. So head over to Jay Feldman wellness.com/solution to check out all the details. And with that, I'll see you in the next episode.