The Peter Attia Drive - #380 ‒ The seed oil debate: are they uniquely harmful relative to other dietary fats? | Layne Norton, Ph.D.

Episode Date: January 19, 2026

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Layne Norton is a nutrition scientist and accomplished power athlete,who returns to The Drive for a conversation that departs from the show's usual format. In this episode, Layne presents the evidence-based case that seed oils are not uniquely harmful under isocaloric conditions, while Peter steelmans the strongest versions of the opposing argument that seed oils are inherently harmful. They examine how scientific bias and evidence are evaluated, revisit the historical randomized controlled trials that shaped the seed oil controversy, and explore the mechanistic biology underlying LDL oxidation and atherosclerosis. Along the way, Layne unpacks the chemistry and processing of modern seed oils, assesses evolutionary and ancestral nutrition arguments, clarifies the relationship between seed oils, ultra-processed foods, and contemporary dietary patterns, and situates these questions within the larger context of lifestyle factors that drive cardiometabolic health. Layne concludes by offering practical considerations around dietary fats, cooking oils, and real-world food choices. We discuss: The idea behind this episode, biases, and evidence-based thinking [5:15]; The four core arguments behind claims that seed oils are harmful [12:30]; The Minnesota Coronary Experiment (MCE) [14:30]; The differences among saturated, monounsaturated, polyunsaturated, and trans fats, and why those differences matter for cardiovascular disease [18:30]; Missing trans fat data as a confounder in the Minnesota Coronary Experiment, other limitations of that study, and the challenge detecting meaningful differences in hard outcomes through nutrition research [24:00]; The Sydney Diet Heart Study (SDHS): an attempt to address the "duration problem" by enrolling a much higher-risk population [28:30]; Debating whether evidence from randomized trials supports the idea that seed oils are uniquely harmful once major confounders are removed [34:00]; The Rose Corn Oil trial: an often-cited study used to argue against polyunsaturated fats [36:30]; Three studies where replacing saturated fat with polyunsaturated fat produced different results than earlier trials [41:30]; Layne's explanation for why the evidence is pointing towards cardiovascular risk reduction when substituting polyunsaturated fat for saturated fat [47:30]; What Mendelian randomization says about the causal role of LDL cholesterol in ASCVD [56:45]; The compounding effects of life-long exposure to high LDL cholesterol [1:06:45]; Does the linoleic acid (omega-6) content of seed oils cause inflammation? [1:13:45]; Does the linoleic acid (omega-6) content of seed oils increase oxidized LDL? [1:19:30]; Layne's analogy to explain why lower LDL particle number outweighs higher per-particle oxidation risk when comparing polyunsaturated fats to saturated fats [1:26:15]; The role of oxidized LDL in CVD: exploring differences in a diet high in polyunsaturated fat (seed oils) versus high in saturated fat [1:28:00]; Examining whether industrial processing and solvent extraction of seed oils—especially residual hexane—could plausibly cause long-term harm [1:34:00]; The evolutionary and "ancestral diet" argument against seed oils [1:40:45]; Weighing concerns about industrial processing of seed oils against the totality of metabolic and cardiovascular evidence [1:47:30]; Practical considerations around dietary fats, cooking oils, and real-world food choices [1:50:00]; Comparing the health impact of seed oils with that of caloric intake and activity levels, and how to prioritize interventions [2:00:15]; More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure

members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.com forward slash subscribe. My guest this week is Lane Norton. Lane is a nutrition scientist and accomplished power athlete and a very evidence-based thinker in the space of diet and metabolic health. And while Lane's been on the podcast many times, today's episode is a little bit different from sort of the usual podcast dynamic.

Now, originally, this was supposed to be our first in a series that we've been toying with, which is kind of a debate episode. I've talked about these a little bit on other podcasts, but the long and short of it is I wanted to do a debate that was going to be incredibly rigorous. In fairness, I've never really seen a podcast debate that was anything other than nonsense if I'm being blunt. And the reason is the format is basically impossible because people can make up anything they want, they can cite anything they want out of context, and no human has the capacity to know the entire body of literature up front. And therefore, it's very difficult to counter claims.

Regardless of whatever the topic of discussion is, I've just never found this appealing. And so over the past year, we've been sort of noodling this idea of, well, what if we ran a debate like a court case? And of course, in a court case, everybody has to sort of present their evidence up front during a process called discovery. And that allows both sides to view the evidence of the opposing arguments along with their own arguments in equal time. That way, there's no ambiguity about what's being presented. We came up with an idea, which was we were going to start with this first topic, which is to be the seed oil debate, which I'll clarify a little bit more in a moment. And the idea was we'll take two very thoughtful individuals who have opposing views, and we did just that. So Lane was on the side of the argument, which was that seed oils are not harmful. We had an individual who took the opposite point of view on that. The idea was that Lane and this other individual would share all of the information that they planned to present with our team and with each other, and that I would serve really here as a moderator of this discussion, and my research team would serve as the fact checkers, and that you as the public would basically

serve as the jury to my judge. However, the individual on the other side of this argument, for reasons that I'm not entirely clear, decided that they just didn't want to do this, and we felt that it was still a worthwhile topic to explore, and while the format of today's podcast is, in my view, not as potentially interesting as it would have been had we done the original debate. We still think that it brought a lot of value. So what I did was I kind of attempted to steal man the argument against seed oils and therefore allow Lane to represent the pro-seed oil position for why seed oils may or may not be harmful when consumed in isochloric quantities relative to other fatty acids. That really is kind of the jugular question here, which is, I don't

think anybody would dispute that consuming excess anything is harmful. So consuming excess calories in the form of seed oils versus mono-unsaturated fats versus polyunsaturated fats versus carbohydrates. Probably not many people are going to debate the downside of that. But what we were really trying to understand is, is there something that under even isocoloric conditions would make seed oils particularly metabolically harmful? So in this episode, we're going to discuss the role of bias, evidence evaluation, and scientific interpretation as a lead-in to this. The historical randomized control trials that shape the seed oil conversation, the mechanistic biology of LDL oxidation and atherosclerosis, which is central to this argument, or at least one of the arguments,

the methods of oil processing and the chemistry behind modern seed oils, how evolutionary and ancestral arguments fit into these nutritional debates, the relationship between seed oils, ultra-processed foods, and modern dietary patterns, the broader lifestyle factors that influence cardiometabolic health, and then ultimately practical considerations around dietary fats, cooking oils, and real-world food choices. So in the end, I think we salvaged a lot of hard work that had gone into the preparation for the debate over the course of a year. And ultimately, I think you're going to find a lot of value in this. So without further delay, please enjoy my conversation with Lane. Lane, thank you for making another trip out to Austin.

Always. Pleasure to be here. Okay, this is going to be kind of a different episode. So I'm going to set this up and we're going to give it a shot. So originally, we were planning to do this as our inaugural debate series. People have heard me talk a little bit about how I desired to do a debate series, which was to have two people on who had opposing views on a topic. But I've been very vocal of my criticism of debates on podcasts in that I think I could charitably call them useless, which is to say anybody can sort of say anything. And in real time, it's almost impossible to verify

what people are saying. And it's not to say that people are necessarily lying. I think it's that people are maybe taking liberal interpretations or not interpreting things the same way. And it would be much more valuable if everybody could be looking at the same thing. So anyway, we had this whole idea where we were going to have two people that were going to pre-submit all of their evidence to me and my analysts, so the entire research team, and everybody was going to agree up front what the papers were, what the questions were that we were asking, what the data were. And during the process of the debate, people could only reference things that were pre-submitted. In other words, we were going to make it feel a lot like a courtroom. And I say that through the lens of we have a

process in court where you have discovery and the opposing lawyers have to submit everything. So So this idea made a ton of sense. My role was really to play judge, not jury, the public, the people listening to this would be the jury. They would ultimately be the ones that would decide. And the first topic we're going to focus on was the one we're going to talk about today, which is seed oils. How long did we spend on this? About nine months a year, maybe? Oh, I think it was over a year when we started talking about. So we identified you as the person who would speak to the argument that seed oils are not uniquely harmful. We identified another individual who seemed incredibly qualified to speak to the other

side of this debate, which is to say that seed oils do pose a unique nutritional risk. And for reasons, I honestly don't even remember that individual at some point just decided they didn't want to do it. I think there was some concern that my personal view leaned more towards the side that seed oils are probably not that harmful. I always am pretty vocal about my biases and I was very vocal about stating, I don't really see something here, guys. But I was also clear to point out that I'm simply the judge and not the jury and ultimately the jury decides and they're going to also decide if I can be a fair judge. Nevertheless, the person decided not to do this and that left us asking the question, well, it is still a topic that people care about and therefore

we view ourselves on this podcast as kind of the authority about going really deep on topics that matter. So we thought we would do it anyway. However, we are going to do this a little different than a normal podcast. Instead of just a regular interview, I am actually going to make my best attempt to steal man the case for the other guest who is not here. Because again, in the process of whatever we spent a year together, I did come to better understand the arguments for why a person would think seed oils are uniquely harmful as a class of fatty acids. So with all of that said, would you like to add anything before we jump into this? I think that when speaking to bias, I think it's important to point out that everyone has bias.

Everyone has personal beliefs they developed, and that is just a human characteristic. There's no way to get rid of that. I have my own personal beliefs. But what I will say is, I'm very upfront about my biases. If we're on a topic where I have a different opinion than perhaps the consensus of the literature or some other experts who I do consider to be good evidence-based experts, and I have a different opinion, I will say, hey, look, this could be my bias showing here, or I have a bias towards this. I understand what this literature says. Here's why I think that maybe it doesn't capture it all right now,

and I think that that's about as best as you can do. And one of the things I told a friend the other day was people think that funding or money is by far the biggest driver of people essentially not sticking with the evidence. And I would say that in some cases that's true, but I think that personal beliefs are actually just as powerful, if not more powerful. I mean, look at how many people spend hours online arguing over politics that get zero money from arguing about politics. I just think that the current day and age with social media, with clickbait, that things are very information siloed and there can be a lot of talking past each other. And I hope today what we can do is present this evidence and I will acknowledge where I think that

there is something really there. And then I will also explain why I think overall my view is accurate and in line with the best data available. And just to be clear up front, if anybody has a bias against seed oils, it probably should be me. I came from a lab that was very much in line with the lower carb way of thinking of maybe saturated fat isn't as bad as we thought, maybe LDL doesn't matter. And I got into graduate school in 2004, when that was a pretty popular idea that, okay, well, maybe it's not just saturated fat, LDL, maybe it's the particle size, the oxidation status, LDL to HDL ratio.

And what I'll tell you is I said those things for a long time and eventually changed my mind with the evidence. And just to point out one more thing, my research was funded. I got money from the National Dairy Council, the National Cattlemen's Beef Association, and the eggboard. I'm painting with a broad brush, but I would say most of the very, very rigorous anti-seed oil people tend to err on the side of either low-carb, animal based, or carnivore. And if anybody has a bias towards high-quality animal protein, it's me. So I just want to start there and say that I think a lot of people when the research conflicts with whatever their viewpoint is, they immediately jump to funding source or think that there's something nefarious going on. And what I will say

is the scientific method is perfect. It is a perfect method, but it is done by people who are not. And that is why it is so important to look at the overall consensus of the evidence and looking at the different converging lines of evidence, which is something you'll probably hear me talk about a lot today because I do think there's a lot of converging lines of evidence here. And that can give us a relatively strong or weak amount of confidence in how accurate something is or a statement is. And so I just want to put all that out there because when you're looking through scientific research or you're scrolling social media, if you have a bias towards something, you can always find a study or phrase something in a way that supports whatever you wish to be true.

And so that is why it's important. I think people like what you and I do, which is trying to cut through that noise that other people who aren't equipped to read research simply can't do. I'm going to tell you what I've heard as the four main arguments for why seed oils should be viewed as potentially harmful. And we're going to kind of talk through these, not necessarily in this order, but I'm going to kind of go through these. One comes down to the mortality literature on some of the large RCTs. We're going to talk about two in particular. In other words, when we go back and look at the literature, particularly in the era when people began to appreciate that saturated fat raised at the time it was total cholesterol.

Eventually, when it got fractionated, it became another subset of that called LDL cholesterol. We saw the association between LDL cholesterol and ASCBD. The question became, hey, can we substitute something else for saturated fat, think margarine versus butter, to lower cholesterol? So a couple of these studies were done, and these studies, while lowering cholesterol, did not lower mortality. We're going to talk about that. We're then going to get into some really mechanistic stuff and talk about LDL through the lens of oxidation. You alluded to this a little bit with your change in thinking around LDL particle size, but this goes kind of a step further than just particle size. And we get into the really granular biochemistry of what is happening

to an LDL particle that renders it pathologic versus maybe not so much. We're then going to talk a little bit about not just the seed oil per se, but the industrialization of how a seed oil is refined. And in other words, is there something about the process of making a seed oil commercially that introduces something that's harmful as a byproduct? And then finally, we're going to talk about this from maybe an evolutionary or first principles perspective, which is, look, if we were having this discussion a hundred years ago, there were no seed oils and people were a lot healthier. So maybe the introduction of seed oils should be viewed as potentially problematic. So let's kind of start with the Minnesota Heart Study.

So I've talked about the Minnesota Heart Study before. This is a study that took place in the 1960s. I believe it ran seven years-ish. It's notable because it was carried out in an environment that would be very difficult to do today. It's very difficult to do long-term nutritional studies with complete control over what your subjects eat. And yet that is essentially what this study was able to do because it was carried out in institutionalized patients. So these were mentally institutionalized patients. They were in patients in a hospital.

And the experimental design was quite elegant, which is the subjects were divided. into two groups. One group was given a diet that was higher and saturated fat. The other group was given a diet that was lower in saturated fat, but had an isocholoric substitution of polyunsaturated fat. I believe it was mostly linoleic acid that made the substitution. So in other words, you can think of this as substituting saturated fat like butter, lard, meat for other sources, but the oils would of course then be the canolas, the safflower, as sunflower, sunflower, hours, things like that. Yeah, I think in MCE it was mostly corn oil and then margarine. Yep. Now, here's what was really interesting, Lane. This study completed in, I believe,

1973. So I think it ran from 66 to 73. I think that was the seven years of the study. And the study found that indeed, the total cholesterol of the patients on the higher polyunsaturated fat diet, again, this was isochloric. It wasn't like we were playing tricks with calories no, no, no, this was, they were getting the same amounts of calories from the macros even. It was just, we were substituting saturated fat for plant saturated fat. The patients on the low saturated fat diet had a significant reduction in total cholesterol. At the time, that was the only tool you had at their disposal. You didn't even have LDL cholesterol, let alone APOB or particle size or any of that stuff,

but you saw that total cholesterol went down. Interestingly, and much to the surprise of the investigators, mortality did not. This was such a surprise to the experimenters that they, chose not to publish the results of this study for another, I believe, 13 years. So the Minnesota Hart experiment or the coronary Minnesota, I forget, there were several different names for it, but this study was not published until the 80s. But as someone trying to make the case that there's got to be something wrong with polyunsaturated fats, how could we otherwise explain that there was no improvement in mortality despite the fact that total cholesterol went down? And total cholesterol went down

quite a bit. We don't have the data to say if it was astrogenic particles that went down, but given the magnitude by which it went down, you have to assume at least the fraction of LDL cholesterol went down with it, even if HDL cholesterol went down with it as well. So let's maybe start with that study and say, doesn't that at least suggest that there could be something nefarious about the substitution of lard to those polyunsaturated fats? Yeah, and this is probably the single most popular study that gets cited by people who are making the case that polyunsaturated fats are actually bad for you compared to saturated fat. I want to be really clear. When I make any criticisms of this study, I think it was a very well-designed

study for the tools they had at the time and what they knew at the time. And so it's always easy to Monday morning quarterback these things. But I think it was a very well-designed study. The big takeaway was for every, I can't remember exactly the number, I think it was a 30 milligram per decilator decrease in cholesterol, total cholesterol, that there was like around a 20% increase in mortality. 22%. Yeah. So the biggest thing that I'm going to say right off the bat that really confounds all these outcomes

is the inclusion of trans fats. So the polyunsaturated fat group, they were getting quite a bit of their polyunsaturated fats from margarine. Margarine at the time was around 25 to 40% trans fats. And we know that trans fats are absolutely atherogenic. Can we pause for a minute? I maybe should have done this earlier. We should probably tell people the difference between a saturated fat, a mono-unsaturated

fat, a polyunsaturated fat, and a trans fat as a subset of polyunsaturated fats. Let's go one in one just to speed this up. A saturated fat is a hydrocarbon where every bond is saturated. That means there are no double bonds. So every carbon is attached to another carbon, but it has two hydrogens on it. They can swiggle around, and that gives it unique properties. So one of the properties of a saturated fat is it is more likely to be solid at room temperature. There are a whole bunch of reasons that are going to come up later when we talk about why

saturated fat plays a role in cardiovascular disease through its impact on LDL receptors and cholesterol synthesis. But that's what a saturated fat is. So then tell us what a monounsaturated fat is. So a monoensaturated fat means there is one double bond in the fatty acid chain. Important to point out when it comes to these double bonds and why this probably makes a difference is it changes the fluidity of these membranes because fatty acids and lipoproteins, in particular, particular, they're not just like individual fats. They're arranged into what are called my cells, which basically the polar head of the fatty acid is on the outside, and in the inside you have all the fatty acid tails. And the reason for that, of course, is that if it wasn't that

way, they could never travel around our body, because to travel through the medium of our blood, you have to be able to be repelling water on the inside, hydrophobic, while being attracted to water, hydrophilic on the outside. Correct. So you have all these tails kind of pointing towards the center. And then if you think about even on cells, the phospholipid bilayer, the tails are pointing towards each other. And for natural unsaturated fats, like mono-unsaturated fats or polyunsaturated fats, most of those double bonds are what are called cis double bonds. And I don't want to get too far into the biochemistry of it, but essentially, if you have a cis double bond, it puts a kink in the fatty acid tail. If you have a trans double bond, it doesn't change it. It still essentially, essentially, looks like a saturated fat in terms of structure besides the double bond. And it's actually easy to picture that. I almost wish I brought a chalkboard to draw on. But anybody who's taking a biochemistry class will remember this.

But a cis double bond forces the two carbons up or down. But they are on the same side of the double bond. So that's the real kink. Whereas a trans double bond, you have a carbon here, a double bond, and then the other carbon is here, that stays much straighter than if you force the kink up or down. And as we're going to talk about later when it comes to like LDL aggregation and whatnot, the actual membrane fluidity is actually very important when it comes to the progression of cardiovascular disease. So the membranes and the fatty acid composition of these lipoproteins

actually becomes very important. And it's very important to keep that in mind. But when we're talking about unsaturated fat, it's important to point out that trans fats are very unique in terms of of the research literature very clearly showing an atherogenic effect. Yeah, and the atherogenic effect of trans fats was so significant that they have effectively been banned by the FDA. It's also important to understand how they came about. When the belief and realization around saturated fats, which have been, I think probably over demonized historically, when that took place, food makers looked for a substitute.

And you brought up an interesting point a moment ago, which is if you have a trans fat, you can have something that is not saturated, but behaves as saturated. So if you think of one of our favorite saturated products, it's butter. Of course, as maybe we will talk about later, there's no food that is purely one thing. So it's not like butter is just saturated fat. In fact, it's probably made up of mono and polyunsaturated fats if my memory serves correctly, as is even the fattiest rib eye. And actually has some natural trans fats in it as well. Low, low amounts. But what makes butter appealing is that it is solid at room temperature. So in an effort to create something that looked, felt, tasted, and behaved like butter, and we were going to deprive you of saturated

fat, we had to put in something that at least behaved like saturated fat. So when that margarine that was made up of high amounts, 25% is really high, 25% of that is trans fats, initially, thought that was a win because you got the benefit of solid at room temperature. It was only after a few years we realized, actually, this was creating far more heart disease than we were seeing even with saturated fat. And part of that is likely because, and again, as we'll talk about in a little bit, it makes the membrane very rigid because those fatty acid tails can get packed in tighter with saturated fat and trans fat, whereas when you have those kinks with mono and polyunsaturated fats, it essentially creates space in the membrane. And that is actually very critical in terms of

particle recognition by the LDL receptor and also aggregation. But we'll get into that a little bit later. So not only do you have trans fats being able to be packed into lipoproteins in a similar way as saturated fat, but now they have a double bond that can be oxidized as well. So you're getting kind of the worst of both worlds with trans fats. So do we know how much trans fats was consumed by the low saturated fat group in the Minnesota Cornary Experiment? So as far as I understand, we don't have the specific numbers. We just know that it was likely a significant portion of the polyunsaturated fat based on they essentially got a lot of their polyunsaturated fats from either corn oil or margarine. Now, as far as I know, we don't know the exact composition of each.

Was Chris Ramston at the NIH, who I believe did a reevaluation of this? Was he able ever to identify the raw data on that? I'm not sure to be quite honest with you. I didn't see it anywhere. Maybe if people smarter than me are watching or familiar with it, I would love to know if they did. I do know there's some other studies where they kind of looked at dietary adherence by looking at LDL in the blood or looking at like

linoleic acid incorporation into lipoproteins. But as far as this specific study, I don't think they did. We have to remember, as you said, this study started in 1966. So this was very shortly after it was identified and accepted that saturated fat

raised cholesterol and that that seemed to have a pretty strong association with heart disease. So when it came to doing this study, they had no reason to suspect that these trans fats were going to be uniquely deleterious. And the other thing that's, I think, important to point out, two things are important to point out with the MCE. The second is that during the time that this study was going on, I think laws changed, where people who were in psychiatric wards could just check themselves out.

And so many of the people in this study were not continuous. In fact, it kind of threw a wrench in the researchers' protocol, because I think they had originally planned that these people were going to be continuously, housed in these psychiatric wards for the duration of the study. So now you've got another confounder where, okay, they're going in for a period of time, and now they're coming out, and we don't know what they're consuming while they're out. Now, what I would say if I was going to make a counter-argument to that is, well, this is why randomization is important because the likelihood is, okay, if they're changing what they're eating while they're out, it should affect both groups. Yeah, it's probably equally distributed. So I think that's a far less significant criticism.

compared to the inclusion of trans fats. And then I think the other thing that's important to point out is it's really hard to do very long RCTs in humans. And this is something uniquely difficult when you're trying to do cardiovascular disease research with hard endpoints. Because cardiovascular disease is not something that develops in a couple of years. It develops over the course of decades. And so, Peter, for example, what I like to compare it to is investing.

if you and I start investing, same time, and I get into a mutual fund that on average, over the course of, let's say, 40 years, gets me a 9% return. And you invest in something that gets 8.5%. If we look a couple years out, there's really not going to be that much difference. I mean, statistically, in terms of significance, probably won't be a significant difference. But if we look 40 years out, there's going to be a major difference. it's important to understand and we get into the mechanisms of LDL cholesterol. This is a total lifetime exposure risk. And so when you have people coming in who we don't know what their baseline LDL was, because now if we were doing this experiment, what would probably happen is you would randomize the groups based on their baseline LDL or based on some other marker,

maybe calcium score, whatever it is, so that you can have some degree of confidence that you don't have differences at baseline. But they didn't know any of this stuff back then. They didn't have those tools available to them. And so I think it's also important to point out when you're looking at these studies where I think the average follow-up time in this study was about one to two years, that's a pretty short period of time to actually see any real differences in progression of cardiovascular disease and to try and actually find hard endpoints. And as we'll talk about here with some of these other studies, the overall number of deaths are very, very low. Even to the point in one trial, the corn oil trial. Let's talk about that trial, because I was going to

say, to get around your point about duration, the Sydney heart study, which is the one you're referring to attempts to solve this. So it was a much smaller study than the Minnesota coronary experiment, which had nearly 9,000 subjects. This one had a little under 500 subjects, but they were selected to be very high risk. So each of these men had just suffered an MI. So you took a group of men who had just suffered an MI, but they were in the fortunate group at the time who didn't die. And remember, back at the time of the Sydney Heart Study, you were most likely to die from a heart attack. So you're already pre-selected to be pretty lucky. You haven't died, but your risk is now very, very high. The baseline characteristics of this group were as follows. Their baseline saturated

fat intake was 16% of total calories. Their PUFA intake, that's polyunsaturated fat, intake 6%. So the instruction set for the intervention group, they were randomized, the low saturated fat group was instructed to increase PUFA to 15% and reduce saturated fat to 10%. Now that's not draconian, but of course these people, they were not housed. The manner in which they were doing this was basically through safflower oil and safflower margarine. And let's talk about what happened. So in this, In this study, there was a higher mortality in the control group, meaning the group that stayed on the saturated fat, and it was 32% versus 20% at three years, which again, it's good in a bad way. It's good that you can see a high mortality in three years because you've started with such

a sick group. So, again, this would at least suggest that that group that lowered saturated fat, raised polyunsaturated fat, they had a higher mortality risk in a short period of time. it could suggest that there's something wrong with the safflower oil. Yeah. And important to point out, a lot of anticidal people will specifically talk about linoleic acid, and safflower oil is very high in linoleic acid. So the strengths of this study, it was longer, like you talked about, and these were people

who already had cardiovascular disease. So the likelihood that you could see more hard endpoints during the duration of the study was higher. Now, that also comes with the opposite side of the coin, which is they already had a cardiovascular disease event. They've already had a lifetime of accumulation of plaque. So how much difference can you really make on this truck that's already rolling down the hill? Again, the main criticism of this study, which I think is, quite frankly, the biggest confounder

with these trials is the inclusion of trans fats. A large portion of what they consumed was sapphire base. margarine, which at the time, again, was 25 to 40% trans fats. It's really difficult to pick out. Is this a polyunsaturated fat problem, or is this specifically a trans fat problem? And I would say, and I will argue, that the human randomized control trials that were not confounded by trans fats were actually probably better design studies and better powered. But I acknowledge that, okay, we're seeing some of these trials where higher cholesterol in the blood is actually associated with lower mortality. One other thing it's important to point out is really sick people.

Sometimes you can have what's called reverse causality, especially with cholesterol. And let me explain. Once you get to a certain age, wasting diseases become a problem. High cholesterol or low cholesterol, more specifically, low cholesterol can actually be an indicator of kind of just over. overall poor health, that people with really low levels of cholesterol, they're more prone to wasting. It may be more of a downstream effect than it is an upstream effect. And so this is where it's really hard to pick out these sorts of things because it does get confounded by the reverse causality, especially in people who are really sick.

But even though the Sydney heart health study was, as you said, a longer study, it was lower number of people. and even though they'd had a cardiovascular event, the overall number of deaths was still pretty low, I believe. I think it was somewhere around, I think it was under 100. Yeah, total deaths were pretty low, 37 in the treatment group, 28 in the control. Right. And that's a situation where when you're comparing 28 versus 37,

just a few deaths, this is where you can have a sampling error, just a few deaths would have swung the significance. And if you look at the confidence interval, the confidence interval nearly crossed the one. And when a confidence interval crosses the one... Now, was that in the original analysis? I know in the Ramsden reanalysis, it was 1.03 to 2.8.

Was that what was originally published? I actually don't recall if that was what was originally published. Or maybe that was the original one. No, I'm sorry, that was the original published, I believe. Yeah. That confidence interval is relatively wide, considering the risk it's showing. And so because, of course, the studies that support my contention, there's limitations on those as well. But I think the most powerful thing if I was going to pick it out,

it's really the inclusion of the trans fats, which is through no fault of the researchers of their own, because when these studies were done, they just didn't know that trans fats had that effect. Okay. So again, I'm playing the role of, I believe seed oils are bad. So the biggest contention we would have if we go through the RCTs is because these RCTs were done at a time when trans fats were the substitution fat du jour. I don't know how we're going to reconcile that. Basically, it comes down to do I believe that trans fats are less problematic than you believe? Because if I believe that trans fats are actually not harmful, then that would take away your argument. You wouldn't have an argument. Is there any other argument you've got besides trans fats?

on this? I think the relatively short duration is another thing because if we talk about some of the other studies where it wasn't confounded by trans fats, some of those were longer, let me put a different way. Let's just say we take the trans fats out of it. Let's do that. And this was in the Ramsden reanalysis as well. If we include all the human randomized control trials looking at substituting polyunsaturated

fats for saturated fat, the overall effect is null. There was no effect one way or the other. When you say that, you're referring to the largest Cochrane analyses? There are two, correct? Yeah. Ramsden also did an analysis, I believe, where some of the trials that showed a benefit to Pufo were confounded by the fact that there was omega-3s included in them. Now, I would argue that if you look at the literature on omega-3s, it's actually not super

strong that they decrease hard cardiovascular disease endpoints, but nevertheless, it's a confounding variable. So he took those out and then showed, okay, when we take out omega-3s, we see an increase risk. But of course, that still includes the trans fats confounders. So if we just include both and lump them all in together, the net overall effect is that one way or another, reducing saturated fat, raising PUFA, it was equal risk. And so what I would say, if the statement is seed oils are uniquely deleterious to human health, even if we take the trans fats out of it, and if you're going to allow those to be included, you have to have, I call it logical symmetry, which is if I'm

going to allow this confounding variable to support my point, I also have to allow your confounding variables to support your point. Otherwise, we just got to find the ones that take both of them out. And so in that case, the net effect is still no harm. What's the other confounding variable, the EPA and DHA? Correct. If you want to start talking about some of these other studies, I will touch on the one other study they cite is the Rose Corn Oil trial, which I, quite frankly, I don't know what to make of it because it was only like 70 people in the entire thing. Yeah, it was 26 people in a control group, 26 people on an olive oil group, and 28 people in a corn oil group. So again, this is a two-year study. This was in people with significant cardiovascular disease.

So the people in the control group, business as usual, three of those people died. five people died in the olive oil group, but eight people died in the corn oil group. Sorry, that was total deaths for what it's worth. Cardiac deaths, one in the control group, three in the olive oil group, six in the corn oil group. Now, again, the confidence intervals on this were very large because the sample size was very small. This one is a bit challenging because the participants were given their oils. You could think of this as kind of the early version of the Predomed study where it was a free living study, but the participants were given olive oil when they were in the olive oil group.

There were three groups. There was low fat, and then there was high mufa, high mono-unsaturated fat through olive oil, and you were given a bottle of olive oil every week or through nuts, and you were given the nuts every week. So here it was a free living study, but you were given your corn oil or you were given your olive oil. other than that, we don't have dietary recall. Now, the benefit, not confounded by trans fats. There was no confounding with trans fats here. So that would be a positive.

But I think the first thing I would say is, I think you said this, the cardiovascular disease deaths were one, three, and six. Yes. I don't know what to make of that. Those are such small numbers that you're so prone to sampling errors where if you'd had 10,000 participants, that's very likely going to get lost in the wash. and let's just take the olive oil group.

Even people who are anti-seed oil typically acknowledge that olive oil is heart healthy. Well, you had three times the deaths from cardiovascular disease in the olive oil group compared to the control group. And so it doesn't fit with the evidence we have and it's so small.

And like you said, the confidence intervals, I mean, if we want to talk about a confidence interval being wide of 1.03 to 2.8 as being wide, the confidence interval in this, I believe, was like, 0.6 to 37. So not statistically significant either. No, no.

It was absolutely massive. And here's where my PhD advisor used to say, if you tortured the data enough, it will confess what you wanted to show. And so if you just say, well, there was six times the number of deaths in the polyunsaturated group, you're technically correct, but you're leaving on a really big portion of the data. And again, when we plop all these studies into the meta-analysis, don't take out any confounding variables, what do we see? We see a null effect. Now, if we take out the trans fats, there was a meta-analysis, I think, in 2017 where they put together all the trials,

there were human randomized control trials looking at substitution of polyunsaturated fats for saturated fats, not confounded by trans fat. This was a very clear benefit to substitution. I think it was around 20% reduced mortality risk. No, it was even more. I mean, I had, have the luxury of cheating because I'm looking at the actual figure. So the Rose Corn Oil trial has the largest hazard ratio of any trial ever done of this. I don't know, of any trial, of these trials. It was 4.64. What that means is there was a 364% increase in risk if you took corn oil. But it did not reach anywhere near statistical significance to your point because the hazard ratio confidence interval, the 95% confidence interval, was 0.58 to 37.15.

So if we limit ourselves to this body of literature and the 1, 2, 3, 4, 5 studies, we do not achieve statistical significance, though we do have a trend towards risk. That trend is 1.13, meaning a 13% relative risk increase. If we include the trans fat. Yes. So this is a bit of a messy analysis to your point because we're including the MCE, we're including Sydney, but we're also including rose corn oil. We're just trying to get as many bodies as possible through the engine of the meta-analysis,

and we don't reach significance. In fact, the only study that reaches statistical significance is the Sydney Heart Study. That had a 74% increase with a confidence interval of 1.04. to 2.91. So it got there, but I guess your argument is going to be yes, but they were at 25 to 50% trans fats. So there's a tough one to score, Lane, because on the one hand, it looks pretty bad for polyunsaturated fats here. Every time you eat them, it just seems to move you in the wrong direction, except for the Linolaic VA study. Well, there's a few different human randomized control trials. So the VA study, so there's several strengths to this study. Tell us what the

study was about. So it was in veterans homes. The food intake was controlled. They provided it to the participants. And it was, I think, around 850 participants. And the average follow-up, I believe, was just under nine years. So that's actually a pretty long study for this, not confounded by trans fats. And they did show, again, I don't have the raw numbers in front of me, but I think it was around a 20 or 30 percent reduction in risk. It was, though it did not reach statistical significance. It didn't have a wide confidence interval. It was actually quite narrow, but it crossed unity. So it had a 18% reduction in overall risk, but it was 0.56 to 1.21 was your confidence intervals. But this is one that's on the other side of what you said a moment ago. They included omega-3s, if we believe that. So the question is, did the omega-3s help or was the study underpowered? Is that why it didn't reach statistical significance? Or does it just not matter? I mean, this is why we do meta-analyses, because when it comes to single studies, sometimes, especially when things are messy like this with hard endpoints, even if 800 people sounds like a lot,

when you're trying to get hard endpoints like mortality and cardiovascular disease events, it's pretty small. It's pretty small. There are some other trials out there. The Oslo Heart Health study, that was only 400 people, but that showed, I think, like a 47% risk reduction. again, confounded by omega-3s. Then there was probably one of the strongest studies, I think, is the Finnish hospital study. And the reason is not confounded by trans fats, not confounded by omega-3s, people did each diet for six years, so it was a crossover design. So I guess it's important for me to cover what a crossover design is briefly. So a crossover design is when you take people and you have them do both treatments.

Now, there are downsides. The downside is, okay, what about a crossover effect where, okay, maybe you have, let's say, a cardiovascular event on one of the diets, but you did the other diet before that. So is it from the diet you're on now or is it from the previous diet? The way researchers attempt to get around that is by essentially making the order in which they do both diets split so that there's 50% of people did one diet. first and then the next diet and then they reverse it. Usually you do that by randomizing each individual person. Now here's the weakness of the study. They didn't randomize individually. They had two hospitals. One hospital started with one diet, one hospital did the other diet, and then they switched them after six years.

Completely makes sense. Understandable. Logistically, it makes sense. Yeah. Otherwise you're trying to like figure out if Bob in bed A is on this diet versus Sally in bed B. Exactly. I understand. why they did it for sure. I guess if you were going to try and make the argument that this introduced a lot of bias, the argument you would make is that perhaps there was inherent characteristics about one hospital versus the other that were more prone to people getting cardiovascular disease. I would say that risk is probably pretty low, but it's an argument that can be made. The benefits of this is it was 1,200 people, but since they crossed them over, effectively it was like 2,400 people.

One of the benefits to a crossover experiment is you can up your power. I hope somebody listening is sharper than I am in my statistics because it's been so long, and I used to know the answer to this. I think it's actually even more impressive than 1,200 to 2,400. I think it's even more, not to overuse the word power, but it's even more powerful statistically when you do a crossover because every person gets to be their own control. Exactly. And that is probably the largest benefit.

which is, as you said, it's the way you do the T-tests and the statistical comparisons. Each person is their own control. Because when you're doing a parallel group design, which is where you just have one group on one diet, one group on the other diet, you are assuming that the randomization process randomly distributes the baseline characteristics that may be different between groups to where they're equally distributed amongst the groups. But you don't know that for sure. But when you cross over, now you're guaranteed.

I don't want to say guaranteed, but you are very confident that inherent baseline characteristics are now no longer a confounding variable. And it's likely that the people's overall lifestyles are going to be similar throughout the course of the experiment. There's less risk of bias from inherent lifestyle differences as well. Somebody having more stress versus less stress, those sorts of things. And in this study, again, not confounded by trans fats, not confounded by omega-3s and pretty well-powered for a long duration, six years on each diet, 12 years overall, and they saw a pretty significant reduction in the risk of cardiovascular disease, events, and mortality.

Yeah, 41% reduction in the treatment group that was, and just to give folks what the actual intervention was. So the high saturated fat or control arm was 18% saturated fat, 4% polyunsaturated fat, 3 to 4. They gave some wiggle room. The treatment group was 14%. So they increased to 14% polyunsaturated and cut saturated fat in half to 9%. These were kind of similar targets to the MCE study. I want to say they measured linoleic acid and tissue too.

I believe they did that. I don't know. If I'm wrong, I'll eat crow. but I think that they actually looked at like tissue and blood biomarkers of linoleic acid and showed an increase in linoleic acid content to verify the dietary treatment worked. What would be your best explanation for this? Because again, the finished study, I mean 41% relative risk reduction in cardiovascular disease with that low saturated fat, high polyunsaturated fat, and the confidence intervals are really tight.

I think, again, this is why this is a situation where, okay, I'm acknowledging. acknowledging what seems to be a negative effect of polyunsaturated fats in some of these studies. But I'm explaining why I think that the studies that show a reduction in risk are on balance better. Again, not making a criticism of the researchers because, as we talked about, I think they did the best they could at the time with the information they had. So this isn't an indictment on the researchers whatsoever. But when you look at these studies that showed a reduction in risk, they're longer, they're typically better controlled, and they don't have the inclusion of trans fats. I think those things are the most powerful movers.

So we think that that is the best explanation for why the Finnish heart study came up with a different answer. Yes. There was a meta-analysis in 2017, and I can't remember the name of the lead author, but they basically did a meta-analysis of the studies not confounded by trans-transfurt. fats. Now, they included some of the ones that had fish oil in them, or omega-3s, rather, but they showed overall, again, I want to say it was around a 21, it was 29% reduction in risk. So again, if you look at the Ramsden analysis, in their best case for polyunsaturated fats

being bad, it's a smaller increase in risk, and the confidence intervals are very wide. So let me play devil's advocate for a moment. And again, this is sort of a, maybe a silly argument. But what if this says more about saturated fats harm than polyunsaturated fats benefit? Well, and this is a situation where when you're doing nutritional studies... You have to substitute something. Right, right, because... If it's going to stay isochloric. One of the things, when we were talking about doing this debate with the other individual,

I was very clear in saying, I'm not saying that there's no deleterious effect to seed oils whatsoever, because added oils in the diet are a major source of calories. And excess calories are not innocuous. So we have to compare apples to apples, which is when you are substituting in a one-to-one ratio, what is more beneficial? The reality is, I think you could take any food or any nutrient, and you can find both positive and negative pathways that it activates. The question is not whether or not a nutrient or a particular food activates positive

or negative pathways. and I say that very broadly, because as you and I both know, there's not really such a thing as a positive or negative pathway. But just in general, there could be positive and negative outcomes. What matters is, on balance, what is the net effect? And I explain this, I'll use another financial example. So we're talking about these pathways. We're talking about mechanisms, which are important. If an outcome exists, there's a mechanism or mechanisms to explain it.

But those are like single stocks. an outcome, like a cardiovascular disease event, that is like a mutual fund. And so what I mean by that is I could take a mutual fund that's doing really well, say up 20% year over year, but I could find a few stocks in it. I'm like, oh, you don't want to invest in this. Look at these, they're down like 50%. But what matters more with those individual stocks that are down or the overall mutual fund is killing it? You care about what the overall mutual fund is doing. And just an example of this, smoking decreases the risk of Parkinson's disease. This is a very consistent effect in the research literature. But on balance, I don't think anybody's going to say smoking is good for you.

We should just point out to listeners. It appears to be the nicotine that is causing that benefit. I don't want anybody with Parkinson's disease or at risk for Parkinson's picking up cigarettes. If you're going to do anything, just choose some nicotine. Choose non-tobacco nicotine, please. But perhaps a better comparison would be, we know, I believe aspirin is an anticoagulant overall. But it also activates some pro-coagulant pathways. But the overall effect is anticoagulation. So if I just wanted to pick out and say, well, look, it activates these pathways, not that it doesn't matter, but on balance, on balance, it is a net positive for anticoagulation. And so when it comes to looking at polyunsaturated fats versus saturated fats, and we will get into the mechanisms of these,

yes, there are mechanisms that exist that would suggest that polyunsaturated fats can have a negative effect. But on balance, there are more mechanisms that exist that show saturated fat to be a negative. To circle back to your original question, is this a effect of polyunsaturated fats being beneficial or saturated fats being a negative? I think it's almost impossible to disconnect those two questions because when it comes to nutrition research to do it accurately, you're looking at substitutions. So if you're going to take saturated fat out, you've got to put something in. And so if we at studies where you substitute carbohydrate for saturated fat, not really much change. I would say that probably depends on the type of carbohydrate very much. If you were doing like fiberd-insources

of carbohydrate, I'm pretty sure you'd see a reduction in risk. Mono-unsaturated fats, there appears to be a reduction in risk of cardiovascular disease. It appears to be not quite as powerful, at least in the cohort studies, as polyunsaturated fats. But again, since we have to substitute something, let's make it very basic. if there was no net, if polyunsaturated fats didn't do anything cardioprotective, it's still cardioprotective in that when you put them in in place of saturated fat, you have improvements and outcomes. I would argue that there are mechanisms in place that explain why polyunsaturated fats are cardioprotective. My point I'm making is I think it's difficult to disconnect those two

questions. Do we know if the Cochran analyses on this question have blended and included the studies across those that contain trans fats and those that don't? The one from 2017? Yeah, when they look at all the Pufa versus SFA studies. No, so they specifically excluded ones that were confounded by trans fats. Ramsden had one where it included basically all of them, net effect being null, nothing. And when he pulled out the ones that were confounded by omega-3s, they showed a negative effect of polyunsaturated fats.

With trans fats still in? But with trans fats still in. Okay. And Cochran had no trans fats, but did have omega-3s. But did have omega-3s. But did have omega-3s. And had a slight benefit to Pufa. Yeah, well, pretty decent. I think what did you say it was? It was 23%, or no, 31%. Oh, no, 31%. Yeah, 29 or 31%. Yeah. Yeah, somewhere around there. I I apologize for not remembering the raw numbers. There's a lot floating around in there. Has anybody done the analysis of excluding omega-3, excluding trans fats? Well, I mean, you're basically down to. You're down to very few studies.

I think you're down to like two studies. I just want to ask you a question. I apologize to interrupt. That's good. When you say omega-3s, are you talking linoleic acid or are you talking e-P-A-D-H-A. I believe they're specifically talking about the EPA-D-HA. But I know like alpha-linoleic acid. Yeah, alpha-linoleic acid is omega-3 as well.

Alpha-Linaleic acid. Although, no, that was part of it. That was part of it as well. Because it doesn't convert very. efficiently to EPA and DHA. So does that mean that these studies that contain omega-3s are going out of their way to supplement with EPA and DHA, which of course you can really only get in high quantities from marine sources? It wasn't clear in the research literature I read. It was just basically like, yeah, there was some omega-3s in the diet. There's basically, I think, two studies that were

not confounded by trans fats, not confounded by omega-3s. And that was the finished study that we talked about, and then stars, which stars was not looking at hard cardiovascular disease endpoints. This was looking at plaque progression. So I believe this was a one-year study, and they looked at either people doing low-saturated fat, higher-unsaturated fat, versus higher-saturated fat, lower-polyonsaturated fat. And they looked at the progression of plaque. So not hard outcome, but I would say that the strength of this is, since you are looking at the progression of what we know causes these myocardial events, even if you don't have a myocardial event, you can get a really good idea of what's going on. And so, for example, and I'm just going to make a hypothetical here, you could

have somebody in one of these other studies where they got right up to the point where they got like a 99% blockage, but no myocardial event in the time where they were measuring it, and they just came up as that's a risk reduction. But in reality, they had disease progression. Right. So the benefit of this is you still get a harder endpoint than just biomarkers, but you can get a little bit more granular than just looking at, I guess, the way to describe mortality and cardiovascular disease events is big blunt instruments. So let's talk a little bit more about these mechanistic things now, because again, most of these trials were done with a brute force tool of, like, the hardest outcome is all-cause mortality. But again, that's a high bar. When you do clinical trials, you trade off

between outcome and barrier to outcome, for lack of a better term, right? So if you want to use all-cause mortality, that is the ultimate measuring stick, but it's a high bar to clear. And then you can go disease-specific mortality. Okay, we're now going to look at coronary death. Then you can go one step lower, and an example would be Mace, major adverse cardiac event, where we're going to use heart attack and stroke and cardiac death. And then you can go one step below that, and say, well, we're just going to look at a change in cholesterol, or we're going to look at a change in LDL cholesterol. And you get more and more insight into disease process,

or I guess below Mace, you would go disease progression. Right. It would be your next thing. Yeah, yeah. Let's go from the macro to the micro. Before we do that, you may disagree. But I think now it would be a good time to talk about the Mendelian randomization studies, unless you want to do progression first,

or unless you want to do the mechanism first. Okay. Do you want to talk about Mendelian randomization through the lens of LDL? Yes. Okay, so first off, I think it's important to point out why I'm bringing this up now. Because when it comes to these studies, I think that these are the most powerful. Because as you mentioned, mortality is a difficult outcome to get. It's a high bar to clear. The benefit to Mendelian randomization is that essentially you have a lifelong randomized control trial.

Now, Mendelian randomization takes advantage of the fact that at birth, genetic variants are randomly assigned. So in a research study, if you and I are in a research study, Peter, the research is just going to, through whatever randomization process they have, okay, Peter, you're doing this, Lane, you're doing this. Completely random. Mother Nature actually does that by design, which we now know identified, I think around a dozen variants that will essentially change your LDL cholesterol levels. They're variants that deal with LDL clearance, LDL production, how much cholesterol you absorb. There's all different kinds of Now, the benefit to this is you can look at someone's lifelong LDL cholesterol exposure and attempt to see what is the risk of mortality and cardiovascular disease. That is very powerful. And these are studies where some of these have hundreds of thousands of people in them. And again, the randomization of this process by nature is so important because now we can, if we see differences between groups, we can assume it's due to that assignment of that genetic

variant versus some kind of confounding variable. Now, there's a caveat here, which is, for a Mendelian randomization to be useful, a couple things have to be true. What you said has to be true. There has to be genetic assignment to the variable of interest. That's true for many things. It's true for height. It's true for body composition.

It's true for many psychiatric disorders. I mean, there's lots of things for which genetics play a significant role. And LDL, cholesterol, turns out to be one of them. But this is the other important thing that people often forget when talking about MR, which is that those same genes cannot have a direct impact on another variable that affects the outcome of interest. Because if they do, your randomization just got wonky. For sure, and that's why they do tests for pleiotropy, which we talk about. And when I talk about the results, I'm going to explain why it's very unlikely that these differences were due to pleiotropy.

But it does require us to make one assumption. And this may seem tic-tackey, but I'm trying to be logically consistent here, which is, this is not a lifelong test of saturated fat versus polyunsaturated fat. This is a lifelong test of what we expect to happen to LDL cholesterol by substituting polyunsaturated fats for saturated fats. Stated another way, this is a test of LDL causality. Correct. It's a leap to then make the statement about what does nutrition do to this. I'm going to give you another example of this that is off the beaten path,

but related to LDL, but unrelated to our topic. And I believe I included this in my book, although it may have got left on the editing floor. I know I wrote about it. I can't remember if it made the final cut. And it came down to the question of, so this is, me taking off my debate had and just doing an aside on MR because it's interesting. A handful of studies showed that people with lower cholesterol were more prone to cancer.

And so the concern became, well, gosh, we shouldn't be lowering people's cholesterol in an effort to prevent heart disease if it increases the risk of cancer. And of course, on average, that didn't seem to be the case. But there was always one study that might have suggested that. And you never knew if there was a confounder because cancer. You weren't randomizing to find that. So this is where MR became potentially valuable, provided you believe that the genes that regulate cholesterol, synthesis, absorption, and LDL receptor expression don't also regulate a cancer

process. And if you believe that, then the Mendelian randomization was quite clear that there was no relationship, neither good nor bad, between LDL, cholesterol, and cancer. So that meant that LDL had no causal role one way or the other on cancer, whereas, as you'll probably talk about it, has a relationship towards ASCBD. So that's a great explanation. And I think it took me a while to wrap my head around Mendelian randomization when I first started reading about it. But these really were the studies that made me change my mind on LDL. I want to point out the strengths to this, lifelong exposure, which, based on the lipid hypothesis, we would expect to see a linear effect of lifelong

exposure to LDL on the risk of cardiovascular disease and mortality. And you can get a large number of subjects for their lifetime. And it's randomized. So it's not a cohort study. Those are the benefits. The one downside is, again, we're having to make a leap of, okay, we're not directly measuring people eating saturated fat versus polyunsaturated fat. But I would say that this leap is pretty small because it is very well established that increasing saturated fat intake increases LDL cholesterol, and increasing PUFAs decrease LDL cholesterol, and raising PUFAs and lowering saturated fat significantly decreased LDL cholesterol. I think in most studies you get around a 15% change in LDL cholesterol

from substituting in polyunsaturated fats for saturated fat. Now, I will tell you, there's a paper from, I think it's Forens in 2012. It was the first big MR study with cholesterol. And if you look at the figure where they take all the genetic variants and you look at how the line goes almost straight through it. I mean, we're talking about an R of probably above 0.9, which in studies like this, that is an incredible association. For every one-millimeter reduction in LDL, which is about 37 milligrams per decilator. I think it's 39.4 milligrams per decilator, yeah. there was a 50 to 55% risk reduction in cardiovascular disease. Again, the pleiotropia argument is pretty

much null and void because it didn't matter what kind of variant it was. If it increased LDL clearance, if it decreased production, no matter how it affected the metabolism of LDL cholesterol, it had the same dose effect. The only exception to that was some of the CETP variants, which when it came to drug trials as well, CETP variants, basically I believe they raise HDL and they lower LDL. But, and here's the big point, the lowering of LDL with those variants and those drugs, it lowers the cholesterol mass, but there's a discordant lowering of APOB or LDL particle number. So every single LDL particle has an APOB protein on it. And when we get into the mechanisms, this is going to be very central to the lipid hypothesis.

If you lower cholesterol mass, but your APOB doesn't drop that much, you basically have just made each particle smaller. And what we see is in that particular subset of variance, there is a small risk reduction, but it's basically explained by the small decrease in APOB. You don't get the predicted risk reduction that you would get with reducing LDL cholesterol. But amongst the variants that decrease LDL and correspondingly decrease APOB, it is a very, very very consistent effect. Again, regardless of the genetic variant, it has the same risk reduction. And then we look at the statin trials, regardless of the way that LDL cholesterol gets lowered, and there's different statins that work different ways, it is the same dose response, which is about 22%. Yeah. So I was going to ask you, why do you think that when we look at the totality of the Mendelian

randomization? And Tom Dayspring has a figure that lays every single MR study, every single RCT study, and every single observational epidemiology study on the same graph with three lines, basically the linear regression through each. And what do you think is the best explanation for the following observation, which is when you do all of the MR studies, and just, again, so people, especially because most people are listening to us, not watching us, so I don't want to use my hands too much. But on the X axis, you have LDL concentration. And on the Y axis, you have mortality or cardiovascular mortality. And as you pointed out, these lines are just going straight down, meaning as LDL cholesterol is going down, either genetically or through drugs,

cardiovascular mortality is going down. But why is it that in the MR study, which in theory would be the most pure study, every millimole or every roughly 40 milligrams per deciliter reduction in LDL cholesterol is giving you 50 to 55 percent reduction. but when you do the same thing with a statin, you still get a benefit, and that benefit appears non-ending, but it's only 22%. Doesn't that tell us that statins are bad? Well, again, as you mentioned, there's still a risk reduction. Yeah, let me state it in another way. Does that suggest that while statins are net positive, they're doing something bad?

So this is because think about when people are getting on statins. So I say this as somebody, my bias should be that I hope that LDL cholesterol is not bad because my whole mother's side of the family runs high LDL. Even with low saturated fat diet, even with high dietary fiber intake, I run about 150. I started taking a statin when I was 40 years old. But my endothelium, my blood vessels, have already had 40 years of LDL exposure at that level. And so even if I get on a statin at age 40, every single day to the day I die, there is still some LDL cholesterol that has penetrated that endothelium and has contributed to some degree of atherosclerosis. I mean, I had a coronary calcium score done and it was pretty low.

Overall, my net risk was very low for my age because I have good insulin sensitivity, all those sorts of things. Important to point out as well, when we're talking about LDL, we're not saying everything else doesn't matter. This is an independent risk factor is what I'm saying. Insulin sensitivity, metabolic health, all those things still matter. These are not mutually exclusive. but when you have a genetic variant that lowers LDL from the day you are born, your entire circulatory system is exposed to less LDL cholesterol. And when it comes to how much gets into the intima, it is concentration dependent. And it's basically dependent on the number of particles in your bloodstream with APOB that are under 70 nanometers.

because any lipoprotein under 70 nanometers in diameter with an APOB can penetrate the endothelium and get retained there. So when it comes to these Mendelian studies, the reason you see such a powerful effect is just a time effect. Because most people, when are they going to, I don't know with the average age that somebody's prescribed to statin, but I'm imagining it's probably around my age. Yeah. So you're really just looking at the difference in like that investment analogy we used earlier, 40 years, you'll see a big difference. but if you start investing from the day you were born, in 70 years, you're going to see a massive difference due to compounding interest. And while it may be kind of a rudimentary comparison, these problems compound over time. And so what you're doing with somebody who has high LDL,

put them on a statin, you're obviously like pumping the brakes, but that truck still started rolling down the hill. Whereas with people who have lifelong low LDL, it never really got started. Yeah. I want to point out one more thing. Important to point out, there was a regression. They looked at each, you know, one-millimeter-mole reduction. So regardless of the variant, same reduction. And in the drug trials, the statin trials, regardless of how the statins worked, also with surgeries, like I think it was a little bypass or things that reduce LDL through absorption. No, I think different drugs that are independent of the mechanism by which LDL is lowered. Yeah. You'll see the same benefit. And then also with diet.

reduction of it in terms of the risk when they look at some of these cohort studies. If you want to argue it's pleotropy or you want to argue it's possibly something else, it's a really hard argument to make when it is a very consistent effect and the dose is also very consistent. When we talk about converging lines of evidence, there's an argument to be made, which is not necessarily the argument we're having today. I won't even attempt to steal man it. I'll just state it. The argument is that if you look at all the literature of statins and you see reduction in mortality, that doesn't mean that it's because it's lowering LDL. It could be because it's doing something else. It's lowering inflammation or it's doing something else. And you're arguing that that's a tough

argument to make in light of all of the MR coupled with all the clinical trial data. If that was the case, you would see a difference in the dose response. You would see inconsistencies in the trials with similar designs. I'll give a comparison that's kind of out of left field, but maybe it'll make the point. And that is, for example, I don't believe that unprocessed red meat specifically is inherently carcinogenic.

And the reason is, even though you see it come up as carcinogenic in some of these cohort studies, the effect isn't always consistent. And when they control for overall diet quality, where people are eating enough fruits and vegetables, because again, people eat more of one thing, thing, they tend to eat less of another. When you control for some of the overall diet quality variables, you don't really see a consistent associated with red meat with cancer. Now, I could be

wrong, but I'm just not convinced by it. But when it comes to dietary fibers effect on cardiovascular disease and cancer, there's a dose response, and it is very consistent in the research literature. In fact, I'm not really aware of hardly any study looking at dietary fiber and reducing the risk of cardiovascular disease, cancer, and mortality, that doesn't show a benefit. I mean, if there's a forest plot of all the studies out there, everything is going to be the protection side. When you have that consistency, even though you could argue, well, it could be other things, it could be other things. I guess if you want to make the what aboutism argument, it's hard for us to ever like actually say something causes something else. I mean, maybe it's not the smoking that causes lung cancer

because we can't really do randomize control trials on smoking because it wouldn't be ethical, but we feel very strongly because of the dose effect and because of the consistency of the results. So I get that argument that can be made, but I guess I would say, well, then what do you think it's doing? What would explain this very consistent effect? It typically just ends up being an argument of, well, you don't know for sure. And it reminds me of, in graduate school, I was giving a talk on leucine content of dietary protein sources, and we did a dose response experiment with different dietary protein sources that varied in the leucine content. And pretty much showed almost a perfect association between

the amount of leucine in those protein sources, the ability of those protein sources to increase plasma leucine and the effect on protein synthesis. And I had people that were other scientists in the audience say, well, but you can't say that. These other protein sources, they have different other amino acids in them. It's not just lucene. There's other things that are changing. And I said, okay, do you have anything else that would explain this? It was kind of like they didn't really have much to say. And so, yes, I grant that it's possible. It's just highly improbable based on the data. Okay. So what about the idea, though, that if you're eating a diet that's high in polyunsaturated fats or seed oils, to be specific, we acknowledge now you're getting a lot of linoleic acid. Well,

you now have LDL particles. Maybe you have not only fewer of them, but they have more linoleic acid in them. And linoleic acid can easily be converted to arachidonic acid, which is inflammatory. And we know that the single most important part of atherosclerosis is indeed the oxidative inflammatory process. In fact, people don't die because their coronary arteries just slowly get occluded. They die because the body in an effort to repair and respond to the oxidative damage in the artery walls creates an immune response. So inflammation here is the game. So are you not concerned with the fact that a diet that is high in linoleic acid, which is the precursor to arachidonic acid, is going to lead to more inflammation, more oxidative,

LDL and therefore ultimately more atherosclerosis, even if you see lower LDL cholesterol. So this is going to be the really fun part of this talk because I learned so much about this through researching this stuff. Let's just take the broad 10,000 foot view first, and then we'll zoom in on the mechanisms and talk about the lipid hypothesis, because it's important to understand what it is and how this disease progresses so that then we can unpack it. all these side quests. And I'll take what you said a step further. Precursor to aeracadonic acid, which is a precursor to prostate glandin production, which are inflammatory. Also, and you did briefly mention this, polyunsaturated fats, much more prone to oxidation than saturated fat. And we do

know oxidized LDL is more atherogenic on a per particle basis, and people who have MIs, people who have cardiovascular disease, they have higher levels of oxidative LDL. So really, when we nail it down, I believe that's one of their big core arguments, is when you substitute polyunsaturated fats for saturated fats, you are creating an unstable lipoprotein, more prone to oxidation, and that is what is going to cause this disease to really progress. Let's unpack this a little bit. From a 10,000-foot view, if that were true, what we would expect to see is people who eat more linoleic acid have higher rates of heart disease. And what we see is, what we see is that. the opposite. I think there was a study that came out a cohort study looking at, like, I think it was

over a million people from various different countries showing that people who had higher levels of linoleic acid intake had lower levels of cardiovascular disease. What was that a substitute for? This was a free-living study, right? This is cohort. So they're just looking at how much do linoleic acid do people eat. And what was the primary source of linoleic acid? I'm not sure. I think they just looked an overall dietary linoleic acid. If I really dug back into the paper, they might list some of the primary sources. But of course, these people are probably substituting linoleic acid because they're healthier people to begin with. Healthy user bias. What I would say when it comes to healthy user bias, what you typically see is like no effect of something that should be bad or it'll be inconsistent

in the research literature. But it's hard to argue converging lines of evidence. If you're position is that seed oils are uniquely dialyce. It's hard to argue converging lines of evidence when one of the major things you really should see is if people eat more than all the aleic acid, the effect should be so powerful. If they're the primary driver of cardiovascular disease, which is what some of these people claim, that effect should be powerful enough that even if they were doing other healthy behaviors, that you should still see something, and certainly not a protective effect. To take it one step further, because dietary recall studies are problematic, anybody who's ever done some of these knows. I mean, I don't even remember what I ate yesterday.

But one of the great things about the fatty acids you eat, the essential fatty acids you eat, is if you eat more of them, it shows in your tissues. If you take an adipose tissue sample, if you take a blood sample, you will see more of that essential fatty acid incorporated into your lipid, your phospholipid bilayer of your cells. And indeed, in studies where they look at tissue amounts of linoleic acid, they see the same thing, a reduction in risk of cardiovascular disease. So this is from a 10,000 foot view, to me, that's a pretty damning thing right off the bat. And what I would say is, if you're going to argue that polyunsaturated fats are bad for you, we've got to argue that saturated fat is really bad for you.

Because if, again, I think this were a logical consistency is important. If the data existed showing people who ate more saturated fat had lower rates of cardiovascular disease, if you even thought about talking about saturated fat being bad, the people in the anticidal camp or carnivore camp would lose their minds. And so it's kind of like this picking and choosing of what data I want to talk about that fits. So we don't see that. We also don't see that when people eat more linoleic acid, they don't produce more economic acid.

That conversion apparently is already kind of at saturation. Just eating more linoleic acid doesn't have a feed-forward effect. you're not actually getting more arachidonic acid production. So I think the prostate glandin pathway is not something we really need to be too concerned with, because again, we'd expect to see increasing amounts of arachidonic acid. Now, this is where I think the oxidized LDL is the argument that I struggled with the most before I really dug into this. So I'm going to talk about the lipid hypothesis, and then I'm also talk about why it's so

important to understand where LDL gets oxidized. So the Libid Hypothesis basically states that really any non-HDL cholesterol that is under 70 nanometers in diameter, which VLDLs can fall into that, LDL obviously falls into that, IDLs can fall into that, depending on the IDL, but basically any lipoprotein that contains an APOB molecule, or an APOB protein, that the lipoprotein is under 70 nanometers in diameter can penetrate the endothelium. Now, just penetrating the endothelium and getting into the intima, and this is concentration dependent, and this has been very well established in the mechanistic literature. But just penetrating the endothelium is not enough to cause progression of cardiovascular disease because those

molecules can come back out into the bloodstream. What can happen is that APOB molecule or that APOB protein can be enzymatically modified into a proteoglycan. Basically, enzymes, inside the intima can act on that APOB. That enzymatic modification causes that LDL or VLDL or whatever particle it is to be retained inside the intima. Once retained, that causes an oxidation. Oxidation, oxidation can increase on those lipoproteins. That can attract macrophages. As you pointed out, the immune response. Those macrophages begin to engulf some of these, these. These These LDL particles can start to clump together, or VLDL particles or whatever particle, they start to clump together in a process called aggregation.

Macrophages infiltrate, inflammation, trying to, again, repair this, but those macrophages then engulfing them, this produces foam cells. And over time, you also get more, I think the smooth muscle starts to thicken as well. And this is eventually what's leading to kind of this closing of the blood vessel. Now, oxidation is part of this process. One of the core components that you mentioned of this anticed oil hypothesis is that, okay, if you have lipoproteins that have more polyunsaturated fats, they are more prone to oxidation. That is true.

But we need to understand where oxidation is occurring. I think anticid oil people would have you believe that the oxidation occurs in the plasma and that those oxidized LDLs in the plasma, those person are. penetrate the endothelium, and that causes the progression of cardiovascular disease. Less than 1% of LDL is oxidized in the plasma, because LDL is mostly cleared pretty quickly from the plasma. It's like an hour or two. It's on the time course of hours. Once APOB is enzymatically modified, that LDL can be retained for weeks. And in your plasma, you have antioxidants, vitamin E, vitamin C, beta carotene, those stabilize those polyunsaturated fats, and you don't

really have that much oxidation occurring in the plasma. But in the microenvironment of once it penetrates the endothelium gets inside the intima, in that microenvironment, it's thought that those antioxidants are not as available. And so the oxidation can begin to occur there. So what's the proof? So you're saying that because, Because plasma ox ldl concentration is such a small fraction of total LDL concentration, say 1%, that means that we're not getting a lot. But it could be a lot if that 1% disproportionately aggregates inside the subendothelial space. I mean, you don't need a lot of LDL particles to cross the endothelial barrier, right?

I'm glad you brought up aggregation because that's important here. So remember when I said there can be positive and negative aspects that you activate for any nutrient you're talking about. So aggregation, once you have LDL inside the intima, and you have this oxidation occurring, you have these things occurring, aggregation is how these cells clumped together. Lipoproteins that are enriched with polyunsaturated fats, per particle, they are more prone to oxidation. Yes, inside the intima. But keep in mind, what gets into the intima is concentration dependent. Polyunsaturated fats overall lower the amount of LDL getting into the intima. So you have less getting in, less being accessible for oxidation,

since it occurs there, mostly, not the plasma. But a bigger point is, there's other aspects of these lipoproteins that make aggregation happen. So when we talked about polyunsaturated fats increase membrane fluidity, one that actually helps with LDL receptor recognition. It helps LDL get cleared, so you have less than the bloodstream. But two, the APOB molecule itself is less prone to enzymatic modification on LDLs that are enriched with polyunsaturated fats compared to saturated fat. Further, LDL molecules are enriched with saturated fat. Their membranes are stiffer and more rigid because of the packing that we talked about, whereas those enriched with polyunsaturated fats are less rigid. They're more fluid.

and that has a big impact on aggregation. There's an enzyme called sphingomyel myelanase, which when it acts on a saturated fat-enriched LDL molecule inside the intima, it rapidly produces seramides, and those seramides actually, for a lack of a better term, can collapse these particles and cause them to clump together much more readily. So all that to say, oxidation is part of the process of aggregation,

but how much those aggregate is a more important factor than oxidation of PUFAs, because the oxidation is bad because it increases the aggregation of these molecules. So the overall effect is, okay, polyunsaturated fats decrease the number of particles that are getting into the intima. They also overall decrease them being retained there. The APOB is less prone to modification, and they are less prone to aggregation if they are retained there, compared to lipoproteins that are enriched with saturated fat. So think of it this way. I really spend a lot of time trying to come up with an analogy for this, because I realize a lot of

people who are listening to this, their heads are probably spinning, because mine was spinning when I was reading about this at first. Think about the LDL cholesterol in your bloodstream, or let's just say apobie containing particles in your bloodstream, being a bonfire. And there's a whole forest around it. Now, the forest around it is your blood vessels. And if you start a forest fire, that's cardiovascular disease. Now, bonfires, they give off sparks. Let's say each spark is an LDL particle. You don't want the force to catch on fire. If you have polyunsaturated fat enriched fatty acids, maybe each individual particle is a little bit more flammable, right, or a little bit more prone to oxidation. But when you eat high polyunsaturated fats versus saturated fat, your bonfire shrinks

quite a bit. The amount of LDL in your bloodstream, strings cut a bit. You give off way less sparks. Way less sparks hit the forest. And oh, by the way, if I was being actually accurate, some of those sparks are much more likely to bounce back into the fire compared to staying in the forest where they can start a fire.

Also, these particles tend to, even if they get into the forest, these sparks, they tend to not clump up and be prone to causing a forest fire. They tend to scatter. That's polyunsaturated fat in red. lipoproteins. So even though on an individual level, the sparks may be a little bit more flammable, the bonfire for saturated fat is way bigger. It casts off way more sparks, and those sparks are

more likely to clump together and start a fire compared to the fire from polyunsaturated fats. That's about as good of the analogy as I could come up with. And you're rejecting my idea that even though only a small fraction of LDLs are being oxidized in the periphery, that those ones don't disproportionately concentrate in their ability to either make their way into the endothelial or sub-entithelial space and get retained, I feel like we're potentially overlooking that as a potential driver, right? Because LDLs can traffic in and out of the sub-endothelial space. So the question then becomes, what are the factors that would increase retention, adhesion, oxidation, and then the cascading effects. And do we not believe that an oxidized

LDL versus a non-oxidized LDL would be more atherogenic? On a per particle basis, yes, an oxidized LDL is more atherogenic. In the periphery. So you're saying like in the bloodstream. Yes. I know it is inside, but I want to make sure we would agree that potentially it would also be more atherogenic outside because it has a greater probability of becoming retained and remaining oxidized and inciting the inflammatory response. It's just such a small amount that gets oxidized. Has anyone looked at a study where, you know, ask the question if you are on a high polyunsaturated or seed oil diet versus a high saturated fat diet and you normalize for total LDL, which obviously will be quite different,

do you have an equal percentage of oxidized LDL in the periphery? Say it again one more time. Let's just assume you put somebody on a high saturated fat diet, somebody on a high seed oil diet, and let's assume that the Pufa person, the seed oil person's got an LDL cholesterol of 100 milligrams per deciliter. Okay. And the high saturated fat diet person is going to be at 200 milligrams per deciliter. Okay. And let's just assume that that's concordined with APOB.

So same number of particles. Two X the particles, two X the concentration, I mean. Right. Do we expect there to be the same ratio or delta or fraction that's oxidized? or do we think that the person on the high seed oil is going to have disproportionately more ox ldl in the periphery where you can measure it? And therefore is likely, even though their gradient is less favorable, they might get more particles in there. There was one randomized control trial. I think they fed soybean oil and saw oxidize LDL and the periphery go up.

But again, you're talking about like increasing from like, let's say, and I'm making a numbers up. but it's on the order of, okay, normally maybe 0.5% is oxidized, and now it's 0.7.8. That is such a small number compared to once a particle gets inside the intima, the rate of oxidation can, I think the estimates I saw were anywhere from 30 to 80% of those particles. And in fact, I actually had a long conversation with Tom Dayspring about this, trying to understand it, because if oxidized LDL in the periphery was really driving cardiovascular disease, why have the studies where they give a bunch of antioxidants not decreased cardiovascular disease? Because when we do that in animals, so they've actually done these studies, I think it's in rabbits,

where they'll put oxidized LDL into their bloodstream, and they will see atherogenesis progress. But when they do it with antioxidants, that doesn't happen. And that is because where most of that oxidation is occurring is inside the intima. So your biggest lever to actually reduce your over amount of oxidized LDL is just to prevent as much getting into the intima and retained as possible. And then when we look at people who have higher levels of oxidized LDL, it's typically a downstream effect of how much LDL got into their intima in the first place. Because even after it gets into the intima, retained for a while, oxidized, some of those oxidized molecules can still come back out into the bloodstream. And so, yes, we do see people with greater amounts of cardiovascular disease,

Do we know if the oxidized LDL that we measure in the periphery was oxidized in the periphery, or is escaped LDL that was oxidized in the endothelial space? I don't know the exact answer to that question because that would be difficult. You'd have to do some sort of metabolic tracer study. You'd have to track it for a really long time, at least weeks to months, to see if that happens. I don't know for sure. I will attempt to answer the question as best I can. in people who undergo myocardio infarctions, so where you have this kind of rupturing,

they do see short-term oxidized LDL go way up coming out of the, presumably that's because it's coming out of the intima since there's that rupture. But have they ever done a study to like kind of link it together with like a stable isotope? I'm not sure about that. But again, I think the important point is that the less APOB that gets retained inside the intima, the less chance there is for overall oxidation to occur. And really, aggregation is the end point that's much more important. Oxidation is only bad, quote unquote, because it's more prone to aggregate. But we know on balance that saturated fat enriched particles are more likely to aggregate

than polyunsaturated enriched particles due to the differences in membrane fluidity, as well as the ability for APOB to be modified, and because of the spingo myelin content and seramide content of the saturated fat-enrich molecules. So again, I would say, let's say I grant that those polyunsaturated fats per particle, more prone to oxidation. You're still having to weigh it against the other things that progress cardiovascular disease, and on balance, you're still better off with the polyunsaturated fats because they do lower the amount that gets into the intima. they lower the amount that gets retained because it's less likely that APOB will get enzymatically modified. And then those saturated and rich particles, because they're rigid, because they produce

ceramics, they're more likely to clump together and cause that fatty streak and that lesion. Okay. So let's consider something else, though, which is for me to get a bottle of corn oil or any of the other seed oils on your table, I have to do a lot of industrial processing. I have to heat these things up, I have to refine these oils, I have to use industrial-grade solvents to extract them. It seems very likely that both of those processes can contribute to the negative impact of them, independent of what we might see if we were talking about something pure. In other words, everything we've talked about so far is assuming a pure form of linoleic acid. But what if I'm now saying, yeah, but I'm going to heat, reheat, cool, bastardize this molecule,

and oh, by the way, I'm not going to be able to get all the hexane off this molecule. And I needed to use hexane to extract it. We don't like to talk about it, but food processing is big industrial chemistry. And what I would say is the actual processing of the seed oils removes oxidants and removes some impurities that are maybe negative. there are some things that do increase. We'll talk about that. But let's start with the hexane itself. So to get the oils out of these seeds, you need to either do mechanical or chemical extraction. Now, I think most people would say, well, I'd rather have the mechanical extraction, right, because

less chemicals. But it is much more costly. The yield is lower, and economics is a thing. Is that an opportunity? Can you go into a grocery store and choose to have safflower oil that was mechanically extracted versus chemically extracted? I actually have no clue, but I would imagine there are probably places that do sell it. Pay more for it. For sure, for sure. So let's talk about why hexane is used. So they take these seeds, they wash them with hexane.

Why hexane? Well, hexane is a non-polar solvent. And when you're dealing with oil, polar solvents are much more popular because most things or most things that we try to get are polar. Most things like to interact with water. It makes sense based on our biology and our biochemistry. Oils are different. oils you have to do very unique things to.

Hexane is a non-polar solvent, so it will mix with these oils, and it has a relatively low boiling point so you can evaporate it off. These seeds get washed with this hexane, it extracts the crude oil. So now you've got the oil mixed with hexane. Well, now they bubble steam vapor through the oil, and that evaporates off the hexane. Now, I will tell you that the steam and the temperature is pretty low. in order to really start getting oxidation of seed oils, it depends on the oil specifically,

but most of them, you've got to be well over 200 degrees Celsius and you've got to do it for hours. If we're talking about in like a large fat, I think I read like soybean oil, if you heated at like 240 degrees Celsius for like three hours, you will start to get a percent of the oil being oxidized. But even after like five hours, it's still pretty small percentage points of oil.

oxidation. And this process of removing the hexane is on the order of minutes or an hour or 90 minutes. Like, it's a pretty short period of time. And hexane's boiling point is, I believe it's 69 degrees Celsius. So you only got to heat it up to a point a little bit above that to start getting it off. Now, okay, can you get all of it off? Well, as anybody who's had basic chemistry, you know that no compound you synthesize is 100% pure. I mean, you can get 99.99% but you always have residual atoms in You always have residual molecules in there. So the question becomes, all right, how much hexane is in the end product and how much is required to cause harm? The hexane in the end product, most of them are well under one part per million.

In fact, a lot of them have non-detectable levels of hexane, which means there's probably some in there, but the instruments we have to measure it simply aren't sensitive enough to pick that out. So the amount of hexane in these oils, I believe the research paper I read, was anywhere from 0.05 to 0.5 parts per million for most of these oils. Hexane specifically, the danger with hexane is not from ingestion. It's actually from inhalation. So people who have had toxicity from hexane is from inhaling it. When you actually look at how much hexane you'd have to get, I try to look up hexane poisoning cases where somebody died. It doesn't exist. There's a case where a guy drank, like literally drank straight hexane and basically,

got a tummy ache. They've done rodent studies where they were able to get toxicity and death, but basically, just to get mild liver and neurotoxicity, it was 5,000 milligrams per kilogram of body weight. Now, when we do human equivalent dosage, that dosage becomes smaller. But let me just put it in perspective as a bottom line. I did the calculation on this. What you would need to consume from hexane to even have mild side effects, what you would need to consume is 11,340 kilograms of oil at one time. Okay, but that's to die. No, that was for mild side effects.

Okay, but how do we know that accumulation of hexane or some other industrial solvent couldn't be leading to a chronic process? We've just talked about how all the diseases we care about, whether it be neurodegenerative diseases, you know, or cancer or cardiovascular disease, these things don't happen overnight. They don't happen in weeks, months, even years, many times they happen in decades. And so if we're talking about a lifetime exposure to these things, how do we know that that's not increasing our risk? When we talk about lifetime exposure from something like LDL, that's a relatively high concentration in our bloodstream, and it's always present. You always have a baseline level of LDL. You don't

really have baseline levels of hexane in your bloodstream, I don't think, at least not to any appreciable level. And there is a process through your body where your body converts this to something innocuous and gets rid of it. So really, when it comes to things that don't, what we call bioaccumulate, the question is, if we have some of this, is it an amount that can be cleared quickly enough to where there's not negative outcomes? And what I would say is, okay, the example I gave was the amount of oil you need to consume to possibly get mild side effects. If anybody wants to, okay, say, let's just say your body couldn't process this out. Who's drinking 11,000 kilograms of oil in their lifetime? I think probably almost no one. So I just don't see the possibility for hexane having a negative outcome

for people, especially when you consider that it's very, very low concentration, it doesn't bioaccumulate, and your body has a way to process it out, and the amounts that you get are incredibly small from these seed oils. Okay. Now, let's consider the fact that about 100,000, years ago, less than 3% of total food availability was made up of linoleic acid. Today, that number is, I mean, it's probably closer to 10%. What I read, because I actually read a book that was anticetyl, because I was trying to understand the arguments. The figure they quoted was a 75x increase in linoleic acid over the last like 150 years or so. Okay, that's even more than what I've got. So that's an enormous increase. Huge. To make it.

get even more stark, this means that we did not evolve in an environment where people were consuming seed oils in much quantity at all. And yet today, people are probably getting 10 to 15% of their total calories from these things, right? Some people do, yeah, for sure. And tissue levels are up more than 100%. Yeah. Isn't there just sort of a first principles argument to be made here that says, how would that be a good thing? How would that be anything but negative? Yeah, and this kind of gets back to the, we're starting to tie into the naturalistic argument. So what I will say is, again, you have to be logically symmetrical with how you approach these things. And even people who think they eat natural these days, the human diet now is not in any way, shape, or form what it used to be.

So people will point out, well, look at how these vegetables and fruits and plants have been modified. Yeah, but we've done the exact same thing to our animals. if you think having a fatty rib eye is a ancestral diet. It's not. Those cows are much different than they used to be, and it's not wild game.

These are very different things. Take that out of it for a moment, though. Try to really zoom out and think about what is the purpose of biology? The purpose of biology is to pass on your genetic material. So when it comes to survival and longevity, and I'm sure you're very well familiar with this,

there's a reason things start to kind of go downhill after like age 40 or whatever. It's because you're past breeding age. Evolution's done with you. You've done what you can do. You've passed on your genetic material. Hopefully you can stay around a little bit longer to raise the next generation, but you've done your job. The idea of longevity living a very long life,

that's not really something that's essential to a species surviving or even thriving. Some of the most prevalent species on the planet don't live very long. What matters is that they get to pass on their genetic material, that the favorable traits are passed on in the genetic material. When it comes to cardiovascular disease, yes, rates of cardiovascular disease have gone up because you actually have the chance to get cardiovascular disease now, because you're not killed by a virus, or you're not killed by a warring tribe, or you're not killed by bacteria. Even if we go back into the 1860s, this book I read, one of the things that said was

cardiovascular disease is a 20th century disease. didn't exist before that. No, it existed. People just fell over dead and nobody knew why. And for the most part, people didn't have much chance to get cardiovascular disease. I think you, forgive me if I'm wrong, but you stated basically, if you live long enough, everyone at some point will get some form of cardiovascular disease. It's just a time and exposure issue, as we talked about. This massive increase in cardiovascular disease, which, oh, by the way, I point out that everyone lives longer now. I don't know if it dipped recently, but I think we're still right around like the longest age lived on average. The point being, even in the 1860s, if you live past age 10, I think your average life expectancy

was still something like 55 to 60 years old. So most people didn't have the chance to get cardiovascular disease or they died from something else. And again, I mean, this is back when we used to bleed people to try and treat them, get rid of the toxic blood. We didn't have the tools to understand what we were looking at. This is one of those arguments that people, when they say, well, everybody's sicker now, we're more unhealthy now. That's true. That is true. But part of that is we just have had the chance to get unhealthy. And evolutionarily, I will also say, we're taking one step out like we do with the MR studies. But LDL cholesterol, high LDL cholesterol is not ancestral. If we look at the best estimate we have of what our

ancestors did, which is the Hadza, which are basically a tribe that are essentially untouched by humanity. We have studied them quite a bit because this is our best guess as to what ancestral was. The foods they eat, it's about as untouched as you can get. If you look at the LDL of the hodzah, who have very low rates of cardiovascular disease,

almost non-existent rates of cardiovascular disease, they're 50 to 70 on average. I think they even had one hodzah who was like under 30. I think they only found one hodzah individual who is over 100 LDL, I would argue, again, we're not talking about linoleic acid, obviously, but we do know that linoleic acid lowers LDL. I would argue that what the anti-seed oil people would suggest should be an ancestral diet is not supported by the evidence

either. And so, regardless, there's a reason naturalism has its own fallacy associated with it, because you can find a lot of things in nature that are horrific toxins. You can find a lot of synthetic things that are quite good for you. And so I think we tend to romanticize the past on every single level, right? Like we romanticize past relationships. We romanticize like 50 years ago things were so much better. There was less crime. And then when you actually go pull up the FBI statistics, it's not even close. Crime is way lower now. But we romanticize the past and we romanticize how things used to be. And what I would say is that I don't think what we think might be natural is necessarily a good barometer

for what is conducive to living the longest, healthiest life. I think you're kind of getting the order reversed. Mankind evolved in this environment where I think one of the reasons we were able to thrive is we were some of the most adaptable creatures out there, obviously smarter as well,

but being so adaptable to our environment helped us greatly. Because we used to think, well, the strongest survive. And really, we know it's actually the animals that are most adaptive. survive. So when we look at all the data together, the question really shouldn't be, did we evolve eating seed oils or did we evolve eating this? The question should be, based on the best evidence we

have, what is the overall net effect of these things? And I mean, again, like we were talking about the processing earlier, I'll just run through a few more things. They say, you know, sodium hydroxide gets used. There's very little of that in the end product. Activated clay gets used. Basically, if we look at these things, the amounts that you would need to consume of this oil, and these are all theoretical negative effects, assuming that, for example, pure sodium hydroxide stays in the incompat, which we know, it basically turns into soap and water when you have a chemical reaction. But even if the amount you put in stayed in there until the end, you still need to eat two to 700 kilograms at one time of the oil. When we look at the end product of the oil

manufacturing process. It actually decreases the amount of oxidated, so there's a measure that can use like a peroxide status to look at how much is in there. It goes down by a factor of about five to tenfold. And then another measurement of like the aldehyde amount in the crude oil versus the actual refined oil is much lower. Now you do have, I think, polymerized trisoglycerides increase a little bit. You do have some trans fats formation during this process. It's about 0.5% of the oil. But they're all so low, then it's very far below the threshold of what would cause negative effects. Now, there's no safe amounts of trans fats, but again, we're taking this on balance. If we have this refined oil with a very small amount of trans fat, but we know it lowers LDL so much, and then we

have all the other mechanistic data, what we call the converging lines of evidence, the mechanism is clearly elucidated. The cohort trials agree with it. And then the studies that are not confounded by massive amounts of trans fats, agree. The Mendelian randomization trials, agree. I guess the one other point I would make is linoleic acid and polyunsaturated fats. When we trade them out in a one-to-one ratio for saturated fat,

they either have neutral or positive effects on inflammation, liver fat, insulin sensitivity, and overall metabolic health. And that's been very clearly shown in numerous studies. So again, if we boil down to it, regardless of what we think was an ancestral diet, which we don't even know if that's necessarily the healthiest diet. On balance, if you're going to make the argument that polyunsaturated fats are bad, you have to be okay with the argument that saturated fat is really, really bad.

Okay. So how do we land this plane for folks? If you're out there and you're trying to make sense of social media, you know, it's sort of funny. I was out at a restaurant recently, and the menu made a point to say there were no seed oils used in the preparation of the food. So this is clearly a part of the popular zeitgeist. I'm pretty sure that the chef at that restaurant isn't familiar with a single argument that has been made here today. So we're talking about an argument that has sort of transcended a scientific discussion. So seed oils are culturally persona non grata. The question is, is that warranted?

you have, I think, fairly convincingly argued, no. So for the individual listening to us, is there a precautionary principle? If someone says, you know what, Lane, I've heard everything you've said, I can't poke holes in it, but why should I go out and eat seed oils? What would you say to that person? I would say, okay, if you don't want to consume seed oils, fine, but find something to displace the saturated fat in your diet with. So leaner cuts of proteins of meats of meats lower saturated fat sources of protein. And I guess while mono-unsaturated fats don't seem to have the same effect

on LDL cholesterol as polyunsaturated fats, they do lower it when exchange for saturated fats. They do appear to be cardioprotective to a certain extent, doesn't appear to be as cardio-protective as polyunsaturated fats. But if you are concerned and you're not going to listen to logic that we've laid out here for three hours, okay, try and find some mono-unsaturated fats.

So like olive oil, avocado oil. There's other sources of oils that you could use that are still relatively cardioprotective or beneficial. And I didn't point this out when talked about the processing. It should be pointed out that this is unique and that when these oils are in a large volume, the rate of oxidation is low, even with heating. By the way, all the heating in the processing of these oils is done under a vacuum, which means there's no oxygen, which means virtually no chance for oxygen. even when heated. In restaurants, however, when you are frying something, especially if you are

frying in a thin layer of oil, the research shows going from like a, I want to say it's like a one centimeter to like five centimeters of oil, huge difference in how quickly oxidized and negative products will start to form. And if you are having oil that you are frying, refrying in over and over and over, yes, certainly with a thin layer. within 20, 30 minutes, you can start to have significant amounts of these negative products accumulating. And then if you have it in a vat and it's being heated all day, yeah, you're probably going to have a significant amount of oxidized, trans fats. So would we be better off when it comes to heating oil using lard?

In other words, if I'm going to have French fries, should I at least have my French fries made in lard as opposed to polyunsaturated fat and seed oil? So here's what I'd say. Both are bad. Let's just say, I understand that French fries are hypercaloric, and let's just put that aside. I'm going to have French fries sometimes. So when I do, do I want McDonald's going back to Lard or do I want them sticking with whatever seed oil they're using? That's kind of a hard question to answer, right? Because you have competing mechanisms at play here. And if we don't have a human RCT looking at frying with one way versus frying with another way, and I'm not aware of any, but maybe there will be some. Maybe a young potential scientist listening to this would want to do this, but looking at, okay, what happens with LDL and then the components of LDL? But you're answering this purely through an LDL lens.

Right, right, right. Yeah. Is there any other reason to care? It just feels to me intuitively that at least when you heat up the saturated fat, you're less likely to introduce more Ross and other things. And by the way, if I can control my LDL through other means pharmacologically, do I really care about my saturated fat consumption? We'll touch on that here at a second. So, yeah, the saturated fat is less prone to oxidation. Again, when we're looking at balance, what's going to negatively affect cardiovascular disease the most, I don't know. What I would say is, if you're going to have French fries, just have the French fries. If you want to have it fried in lard, okay, fine, whatever. You can decide what you want to do. You're basically saying, don't treat my fries in lard as health food. No, that's actually a really important point you bring up. You have to understand. People think food companies care about which foods you buy. They just want you to buy. They just want you to buy. buy. And so the pivot to, oh, we're going to have tallow or lard or whatever, food companies

don't care. It's okay, well, we'll just make those then. That's fine. Oh, you don't like Red Die 40? Yeah, we'll take that out. And then we'll market about how healthy our cereal is now. We're marketing how healthy our french fries are. The danger becomes, this really only becomes a problem if you're consuming French fries pretty regularly. And then we have to ask the question, all right, which is worse out of these two really bad options? But when you're, marketing as some kind of victory that, okay, we're using beef towel or using lard or whatever it is as opposed to seed oils, if you're not having this sort of communication, people, what they're going to interpret that as is, oh, these are actually healthier now. I can eat more of them.

I think that's one thing I've realized as being so in tune with the public and reading comments on social media over years and years and years, I realize how if I'm not extremely careful with how I word things, how misinterpreted it can get. I think as communicators, like in a format like this, this is great. And when you say, like, how do people navigate on social media? That's where it's really tough, because it's not this, right? It's 30 seconds. How can I hook somebody in? Five reasons why seed oils are toxic. That's going to get a lot of attention. And they're going to list things that there is an element of truth to every single thing that they say. But they are leaving out all of the context that we just put multiple hours into covering. I mean, I hope this podcast gets

listened to by, you know, hundreds of millions of people, but the likelihood is pretty unlikely. What's more likely is somebody puts up a TikTok and it goes viral and 10 million people see it. I think it's very difficult to communicate this stuff with the public. To them, there are so many mixed messages. Peter, I hear this all the time where people say, you know, I don't trust scientific research because one study says this and one study says that, and they all contradict each other. And what I say to people is I say, did you actually read the study? Or are you just looking at the social media hot takes? Because my guess is you're probably looking at the hot takes. Because what we just did going into those studies, when they seemingly have a weird outcome,

I can tell you almost any time, 99% of the time, when I've seen a headline or a social media hot take on a study, that I go, that doesn't make sense. And then I go and read the actual study. 99 times out of 100, I walk out going, oh, okay. I see what? why they found what they found. Either the way the control group was designed or the difference in levels between groups or whatever. My PhD advisor used to say, if I wanted to design a study to show no effect, or the study to show an effect, easiest thing in the world. And so again, this is why we look at converging lines of evidence. We look at what does all the evidence state. And what do the most high quality, most rigorously controlled studies find? Yes, there are elements of truth to the

criticisms of seed oils. But on balance, when we look at these hard outcomes, when we look at what we are very sure we know to be true, I think one of the things to point out in science, you can never prove anything, right? We can only disprove things. But we can have relative degrees of confidence in various data. I would say, I have a relatively high degree of confidence that APOB containing lipoproteins are atherogenic, based on everything I've read, the converging lines of data, especially the Mendelian randomization studies, especially the statin trials. I feel relatively confident about it. Could I change my mind? Sure, but it would take a lot of data over a long period of time. Now, you ask one question that I want to circle back to. Why care

about nutrition if you can just control this with statins? No, that was in the context, I think, of why care about the effect on LDL if you can pharmacologically regulate that anyway, and therefore should we be focused on other negative health benefits in the case of the fry? That was really my question. Oh, I see what you're saying. So let's take care of the LDL piece and then now oxidation or aldehydes or whatnot become more important. I was asking that specifically in the context of the frying oils. That makes sense. Yeah. And cooking. Yeah, I don't have a great answer for that because I think one of the other frustrations with the general public is when we point out limitations of studies, you and I know, we're not necessarily saying, hey, these researchers are idiots. They did it wrong. They should have done it this way. Every study has limitations. Every single study that's ever been. done in the history of mankind. There is no unifying study that explains the entire universe. So pointing out limitations is not necessarily saying that a study is bad. It's just pointing out, okay, we've got to be careful how much interpretation we give to this, how broadly we interpret it. And yes, there are studies that are more well designed, well conducted, that have more statistical

power, that have better measurements. And scientists try to account for that when they look at, okay, how much weight am I going to give to something? But again, at the end of the day, if I have to give a recommendation for people on this stuff, I would say, when it comes to seed oils, if you don't want to consume them, okay. I would just say, try to limit your saturated fat, eat enough fiber, but outside of that, there's so many bigger levers that you can pull for your health than just worrying about seed oils. Put up a thing a while back, I said, the average calorie consumption in the United States is 3,500 calories per day. And the average physical activity is less than 20 minutes per day. You're spending all this time worrying about what your fries get fried in. Not you specifically,

but just people in general. We're stepping over $100 bills picking up pennies. Again, I'm not saying don't worry about the little stuff, but you've got to keep it in context of what really is driving so much disease in the developed countries. A lot of it really is an energy toxicity issue. Just to put a final bow on this, if you're looking at the macro trend of declining health in the last 50 years, you're going to argue that caloric imbalance and activity levels are contributing how much more than increasing seed oils? A little bit more, a lot more, medium more. I would say a lot more. Here's why I come to that.

So there's no direct comparisons. I'm going to say it right now. I'm going on a limb. these are tenuous assertions by me, my opinion. You look at the hazard ratios for mortality, talking about obesity. You're not talking about, we're talking about like class three, class four obesity, even with healthy blood markers, healthy obesity. You're not talking about 20, 30 percent.

You're talking about 80 to 200 percent. You're talking about massive increases in the risk of mortality. When you're talking about things like exercise, I mean, you talk about this all the time, your strength, your lean mass, your activity levels, enormous predictors of how long you will live to the order of hundreds of percentage points of magnitude when it comes to VO2 Max, grip strength, overall strength. I don't think there's anything unique about grip strength. It's just a proxy for overall strength.

And so, again, that's not to say, hey, if you can make adjustments that make a benefit overall, I don't want to be a what-aboutism person either. but just make sure that your time effort is being spent in your mind space. I got that from you. I liked what you said about that. Your mind space is being spent on the things that will move the lever the biggest. And okay, so you're controlling your caloric intake, you're exercising regularly. You don't want to eat seed oils?

Cool. Don't eat them. But I would also say, try to limit your saturated fat as well. And try to make sure your LDL is under control, get your APOB measured. I mean, these are things that are modifiable. So if you can modify them, why not? And the last thing I will say, because people do this too. I am not saying, and I don't think that you would say that APOB and LDL are the only things

that drive cardiovascular disease. Blood pressure, cardiovascular fitness, insulin sensitivity, inflammation. These things all matter. They all matter. We are just saying, and I'll give an example, you can have high LDL, but every other factor is low and your overall risk for cardiovascular disease might be low. You can have high LDL and you might live to 90, 100 years old. That can happen. But there's also people who smoke for long periods of time and live to be old. That doesn't mean that you should smoke or that it's not negative

because statistics are just probabilities. These are just probabilities. These are not hard. This is definitely going to happen. So of course, you can always find an individual to show a difference. But All we are saying, or all I am saying, is that everything else being equal, having your LDL lower, is better all things being equal to having it higher. All right. Well, Lane, I think that kind of brings this discussion to an end. I don't think this was necessarily as interesting as it would have been in its original format, where we could have done it as a genuine two-person point of view. I tend to agree with the point of view you've put forth. My own nomenclature on this is that we're majoring the minor and minoring in the major. I just don't think this matters all that much, frankly. And my lack of enthusiasm around this topic is probably palpable. I also think I'd make one final point to what you said, which is there is another confounder with seed oils, which is that they tend to show up in low quality foods. And therefore, if you make the decision to restrict your

seed oils, you are probably doing a net benefit to yourself because you are simply going to eat less Oreos, less potato chips, less junky salad dressings, and crappy sauces and things like that. So the substitution effect will probably work in your favor, but you don't have to be maniacal. If, for example, when you're making a salad, you prefer the taste of safflower oil or canola oil over olive oil doesn't seem like you're killing yourself by doing it based on the data. and you probably don't need to go to restaurants that are adamant that they exclude seed oils. Because if it's a good restaurant, whether it uses seed oils or not, it's probably using good ingredients otherwise,

and you're probably going to be just fine. Yeah, I mean, you make a great point about, it's probably more about what comes along for the ride. Another comparator real quick, like sugar intake. People cut out sugar and they say, well, it felt better. You cut out a bunch of junk food. But then you have people who get maniacal with it and start cutting out fruit. because fruit has sugar. Biochemically, it's basically the same thing once it gets in your body.

Now there's a bridge too far. And I would argue the same thing that I think most people who are experiencing negative effects from seed oils just have an overall probably low quality diet. This isn't a problem for people who are going, you know, I think I'm going to cook with some canola oil today and maybe use a seed oil-based solid dressing here and there. I think that that's probably not what's happening and what is happening is people are eating a lot of potato chips, French fries, whatnot. And then the kind of anti-establishment people come out and they say, look at how much our seed oil intake is increased. And we did what the government told us to. Yeah. So my only wish that come from this podcast in addition to public education is if you are a restaurateur and you're listening to this, please take the no seed oils used off your menu.

It insults me and it insults anybody who's been patient enough to listen to this episode. So with that, thank you. Thanks for having me. This was fun and a really cool educational experience. I loved it. So thank you for having me and let me wrap about this stuff for a couple hours. Thank you for listening to this week's episode of The Drive. Head over to peteratia-md.com forward slash show notes if you want to dig deeper into this episode.

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