Your Doctor Is Watching the Wrong Number. LDL, ApoB & Heart Risk Explained. - Dr. Kevin Maki

24:35Dr. Gabrielle Lyon:Or we create these guidelines. These guidelines then inform schools, military, again, nursing homes, anyone that receives federal funding. And that's why these are created. There's a range for everything. The challenge becomes if we over, and as I'm saying this, I still think protein is finally having its moment. It's really important for aging, for sarcopenia. And then on the same hand, I think that the 10 % saturated fat, which why are we, again, you're probably so sick of hearing about this, but becomes a challenge because if we look at how we are framing the conversation, 10 % saturated fat, the reason typically people are saying to reduce that is because of its impact on cholesterol, LDL cholesterol.

25:28Dr. Gabrielle Lyon:And if 50 % of the population has an LDL cholesterol and are low risk of 100 milligrams per deciliter, and 25 % of the population has higher LDL cholesterol above 130, then as we restrict saturated fat, we're no longer talking about dietary recommendations. If we are doing it to target that LDL of 130, just go with me here, we are now talking about medical intervention. And so when we say we should reduce to 10 % saturated fat and we have healthy foods like an egg that might have higher, you know, even though it has a total of, what, one gram, six grams of fat and a portion of that is saturated fat, then by definition that egg is not going to be considered healthy.

26:20Yeah. I think, you know, eggs actually aren't super high in saturated fat. I would also say that red meat, in terms of LDL cholesterol, it's not really the fat in red meat that is raising LDL cholesterol. It's the cholesterol content. So in a study we did just recently, we had people eat two servings a day of red meat.

26:46Dr. Gabrielle Lyon:Which study was this? Was this the effects of diets containing beef compared with? Beef compared with chicken. Yeah, this is a great study. We'll link it. Yeah, so we had people consume two servings a day, which is more than is recommended, but the objective of this study was to look at cardiometabolic risk factors, especially those for diabetes. And so we took people with pre-diabetes for a month. We gave them two servings a day of beef, and it wasn't especially low-fat beef, and we gave them two servings a day of chicken. Now, chicken has less saturated fat than beef, But if you look at the fatty acid profile of beef, roughly half is saturated and half is unsaturated.

27:29And of the saturated fat, half of that is stearic acid, and stearic acid is fairly neutral with regard to effects on LDL cholesterol. So at the end of four weeks on the chicken diet, the LDL cholesterol concentration in our sample was 112 milligrams per deciliter. At the end of the four weeks with the beef diet, the LDL cholesterol level was 112 milligrams per decil. It was exactly the same.

27:58Dr. Gabrielle Lyon:Couldn't plan that, could you? And we couldn't plan it. In fact, I double and triple checked the numbers because I thought, this can't be true. This is a typo. But we showed the same thing in a study we published in 1999 when we compared beef and chicken. So again, the question becomes, is it the total amount of saturated fat in the diet, or is it the balance of saturated and unsaturated fats in the diet that is most important for LDL cholesterol? And the answer, I think pretty conclusively, is it's the balance, and not just of saturated and unsaturated fats, but other factors that raise or lower LDL cholesterol.

28:39Could you rank the importance of the balance?

28:45Dr. Gabrielle Lyon:So the balance between, so now you're not talking about omega-3 and omega-6 because there's a ratio there that we have spoken about that is probably very important. Yes. You are now talking about the actual food matrix composition of the fat within the food. The kind of, is it the kind of fats or the kind of saturated fat and the kind of monounsaturated? Yeah. So saturated fats, we talk about saturated fat, but it's actually a number of different types of fatty acids. Do you know Tom Brenna? I do, yes. He came on the show. He was hilarious. And his episode comes out on Tuesday. Oh, looking forward to that.

29:27So, you know, we've got some saturated fatty acids, 12 to 16 carbon saturated fatty acids, neuristic, lauric, and palmitic acid that raise LDL cholesterol. And then we've got stearic acid that is pretty neutral. And then we've got monounsaturated fatty acids, like you find in avocado oil and olive oil and peanut oil, and those lower LDL cholesterol. And then we've got polyunsaturated fatty acids, and they lower LDL cholesterol mostly. But you've got two varieties of those. You've got omega-3s and omega-6s. So the main omega-6 polyunsaturated fatty acid is linoleic acid, and that lowers LDL cholesterol.

30:23Dr. Gabrielle Lyon:Notably, if someone has LDL cholesterol above 130, we have to make the decision, is it genetic? Is it diet? We decide that we are going to really double down on this balance of fatty acid profiles. how do we, and we say it's going to lower it, is it going to lower it in a clinically significant way? I'll let you answer that. I think the answer is yes, it can. And so we did a study where we gave people all of the food they consumed. And we gave them 54 grams a day of either extra virgin olive oil or corn oil. 54 grams, meaning we're talking tablespoons? Or tablespoons a day. Now, they didn't go down.

31:09They mixed it into things. And both of them lowered LDL cholesterol. So with the corn oil, it was about 11%. And with the olive oil, it was about 3.5%. But the olive oil had some additional beneficial effects. It lowered heart rate and it lowered blood pressure. And we think that's because of the polyphenols that are in the olive oil. And so I think there's good news for seed oils. And we can talk more about seed oils.

31:42Dr. Gabrielle Lyon:Seed oil inflammation, start the press, yes. There's good news for seed oils, and there's good news for olive oil and avocado oil and so forth. I think they have generally beneficial effects on risk factors for cardiometabolic disease. And there's a lot of controversy, and we can get into controversy about seed oils. Yes. I mean, I don't really, but okay. But we just finished a study. It's published currently online. It hasn't appeared in the journal yet, where we looked at linoleic acid in relationship to biomarkers of inflammation. So hold on to that thought. If somebody starts with an LDL cholesterol level of 130 milligrams per deciliter, and you lower that by 10 percent.

32:34Well, you know, over a long period of time, that can be important. So in general, if you lower LDL cholesterol by one millimole per liter, and one millimole per liter is about 39 milligrams per deciliter, you're going to reduce risk over five years by 20 to 30 percent. And it depends on the characteristics of the person, but over five years by 20 to 30 percent. But if you lower it and keep it down by one millimole per liter for 40 years, you lower risk by over 50 percent, about 54 percent.

33:18Dr. Gabrielle Lyon:Meaning there's a 55 percent less likelihood of, is it a major cardiac event? Major adverse cardiovascular event, which is basically heart attack, stroke, or revascularization procedure. Okay. And so that's why we say lower for longer is better. And so genetic variants that lower LDL cholesterol by just a small amount, but are maintained throughout a person's life, they really do lower risk much more than you would expect based on results from clinical trials that are only five years or so in length. And that's in someone who has a higher risk profile? Yeah, is that? That's, in these studies, these are called Mendelian randomization studies.

34:08They're just looking at people who inherit, you know, either a genetic disposition toward higher or lower levels of LDL cholesterol.

34:20Dr. Gabrielle Lyon:My follow-up question to that would be, if someone has or their level is at 100 and we lower it to 70, do we then impact risk? The answer is yes. And almost certainly we do. Across the risk spectrum, lower always seems to be better. There doesn't seem to be any threshold below which, you know, you don't see additional benefit. But, of course, if you're talking about drug therapies, there's risk involved in drug therapies. There's costs involved in drug therapies. Some people have side effects. And so because of that, you have this situation where you don't want to put everybody on cholesterol-lowering medication.

35:02But people who have a high enough risk, it is demonstrated in lots of randomized controlled trials now that if you lower LDL cholesterol, you lower risk. It happens across the risk spectrum. But, of course, the greatest absolute benefit is going to be in people who are at the highest risk. That's the highest risk.

35:24Dr. Gabrielle Lyon:Yeah. And that's typically less lifestyle. That's more, I mean, it's obviously a combination. But it's always a combination. But you would say that there is this genetic risk that seems to kind of trump everything potentially? So at one end of the spectrum, you have people who have familial hypercholesterolemia and they have high levels of LDL cholesterol throughout their lives and they have very high risk. And then at the other end of the spectrum, you have things like A-beta-lupoproteinemia, where you have very, very, you know, almost no ApoB in circulation, and they have very low risk. And then you've got all sorts of genetic variants that put people in different places on the spectrum.

36:10And what we see very consistently is the higher the level of LDL cholesterol, the greater the risk. And we see in clinical trials, if you lower the level of LDL cholesterol with all kinds of interventions, we have many drug therapies. We even have something called, you know, that was done with ileal bypass surgery to lower LDL cholesterol. I know that seems kind of crazy now, but that lowered risk. And so we have all kinds of interventions that have been shown to lower risk. You lower the LDL cholesterol, you lower the risk.

36:41Dr. Gabrielle Lyon:LDL cholesterol is that clinical biomarker. If you lower, do we know the effect of, so if you lower ApoB, do we know at what, because ApoB contributes to obviously cardiovascular disease, when you lower LDL cholesterol, what is the relationship between that and lowering ApoB? Or is it multifactorial? Yeah, it's pretty closely related. So when you lower LDL cholesterol, you almost always lower ApoB. ApoB doesn't go down quite as much. So if you lower LDL cholesterol by 30%, you may lower ApoB by 20%. And so we use LDL cholesterol as the clinical marker. But what we're really doing is lowering ApoB.

37:28I think it all relates to the number of atherogenic particles that you have, even though there may be a little bit of gradient across different types of particles and how bad they are. I think that we shouldn't worry about that little gradient. We should just worry about keeping the number as low as possible.

37:45Dr. Gabrielle Lyon:Do you think they'll ever switch over? I mean, because you're kind of in the know that they'll switch over from thinking about LDL cholesterol to ApoB? I'd love to see that. A new guideline came out. They acknowledged ApoB. They acknowledged that ApoB is a better predictor. But they did not give a strong recommendation to measure ApoB in everyone. They basically said people with elevated triglycerides, you should measure ApoB. Which is so weird because elevated triglycerides, that's a carbohydrate problem. It is a carbohydrate problem. So saturated fat raises LDL cholesterol, but carbohydrates raise triglycerides.

38:26And so, you know, when we talk about what people eat too much of, about 50 % of the calories in the average American diet come from carbohydrates. And largely, those are refined starches and added sugars. And that's a place where I think we would do very well to substitute some of the calories from added sugars and refined starches with calories from things like protein and unsaturated fatty acids.

38:56Dr. Gabrielle Lyon:If you could have reworked the guidelines in the way that perhaps is taught to clinicians and consumed, no pun intended, by the public, would you say that it makes more sense to say, okay, if you have elevated triglycerides, you are the person that we're going to focus on perhaps lowering your carbohydrate ingestion by below 130? Let's just say, so if the RDA, Recurrent Dietary Allowance, is 130, and chances are they're getting double that, right? And that you are someone, based on your blood levels, should reduce your carbohydrate intake versus if you are someone who has LDL cholesterol that's above 130, perhaps you are someone that should focus on your saturated fat.

39:39And I would say that we have to separate the American Heart Association scientific statement, which is a basic statement for the public on maintaining optimal cardiovascular health. And then I would point to a different statement that I was involved in generating, and that's the NIAID, Nutrition Interventions for Adults with Dyslipidemia. And in the NIAID document, we do exactly that. We say, well, if you have elevated triglycerides, here is where the focus should be. If you have elevated LDL cholesterol, here is where the focus should be. If you have both, then you need to think about both of those sets of recommendations.

40:21And so I think our recommendations are more specific to people with lipid issues that you're trying to address with diet.

40:30Dr. Gabrielle Lyon:That is helpful because ideally then that's much more specific and meaningful for the person versus, okay, just reduce your saturated fat or, you know, eat this number of carbohydrates. If, you know, the idea that we shift from macronutrients to the profile of fatty acids, which is really not something that is discussed often, how far along are we? For example, if I, you know, I still see patients, our medical process is called Strong Medical. I mean, it's kind of a good name. Nope. rather than, you know, weak and decrepit medical, but strong medical, very, you know, we believe in building stronger humans.

41:16Dr. Gabrielle Lyon:Early on in my career, we would do fatty acid profiles. And again, I started my career many years ago. We didn't necessarily know what to do with it. How are we looking? And also because nutrition, the flux is so fast. How can we, you know, as you're talking about these profiles and these matrix and these ratios? One thing you hear a lot about is the omega-6 to omega-3 ratio in the diet, but then also in the blood or in red blood cells, as an example. And people say, well, a high ratio of omega-6 to omega-3 is associated with adverse outcomes. Well, that's kind of true, but it's more nuanced than that.

42:05Higher omega-6 in the blood is associated with better outcomes. Higher omega-3 in the blood is also associated with better outcomes. So when they say a higher ratio is problematic, what's really problematic in my view and my interpretation of the available evidence is that most people are not getting enough omega-3 fatty acids. And so I like the omega-3 index, and the omega-3 index is a way to assess, are you getting enough omega-3 fatty acids? I think that a level between 8 and 11 percent, and what do I mean by percent? That's red blood cell membranes have fatty acids, and if 8 to 11 percent of the fatty acids in red blood cell membranes are EPA plus DHA, eicosapentaenoic acid, docosahexaenoic acid.

43:02I know you practice that. I've been immersed in fish oil for many years.

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43:58Dr. Gabrielle Lyon:Whether you're navigating a plant-based diet or a lower protein diet or you're simply on the go, Perfect Amino offers a sophisticated, low-calorie way to ensure your tissues have the raw materials required for maintenance and recovery. I personally never travel without the Perfect Amino tablets. It makes hitting those daily targets seamless, especially on the road. If you're interested in trying Perfect Amino, go to bodyhealth.com and use the code LION20, L-Y-O-N 20, to get 20 % off your first order. When you have 8 % to 11%, that's associated in observational studies with the best outcomes. Now, I have to acknowledge the evidence that we have is mostly from observational studies.

44:48We have some randomized controlled trials. The results have been kind of mixed, and I have some ideas about why that might be. But basically, what I try to do myself is I try and maintain my omega-3 index between 8 and 11 percent. The average in the U.S. right now, we just looked at a sample of a little over 2 ,000 people, and it was almost identical to the average in the U.S., around 4.6 percent. I would have guessed that. And so how much EPA plus DHA do you need to get up to 8 if you're at 4.6? And the answer is about a gram and a half to do two grams a day. So most people are not going to eat enough fish to get to that level.

45:33Dr. Gabrielle Lyon:How much more damaged fish would you have to eat? I think that it would require about, if I'm doing the math in my head, which is a dangerous thing, I think it would require about four servings of fatty fish a week. And very few people are consuming that level. And so I take an omega-3 fatty acid supplement to maintain that. And here's the interesting thing. I was taking a supplement, and then I was at a meeting with Bill Harris, and Bill Harris founded a laboratory called OmegaQuant, and they measure this omega-3 index. And so I was at a meeting, and he said, hey, you want to give me your finger?

46:15I'll stick it and I'll put the blood on a piece of paper and I'll measure your omega-3 index. And I was very confident that because I took a supplement every day that I'd have a level that was, you know, eight or very close to it. No, 4.7. And so I said, wow, I would not have expected that. And it turns out there's a lot of variability. So two people can eat the same amount of omega-3 fatty acids but have very different omega-3 index values. So I personally, and this is not any organization recommending this, this is just my own opinion, I think that maintaining an omega-3 index in that range is very helpful from a health perspective.

47:03I think omega-3s are very much involved in the balance of inflammation and resolution. So you have inflammation that's an active process, and you have resolution that's an active process that shuts down the inflammation. And a lot of the benefits, I think, of omega-3 fatty acids come from influencing resolution and maintaining a proper balance between those two things. And then also they have effects on platelet activation, which I think is important because when a person has a heart attack or a stroke, what's typically happening is they have a place where they've either had a fissure or erosion in a plaque.

47:44And then a clot, a thrombus, forms at that location and then stops off the blood flow. And so if you are tending to over-clot, it's going to make you more likely to have an event. So two people at the same level of atherosclerosis, the same level of plaques, one may be at higher risk of an event because of being more apt to form a big clot. And the other person who's less apt to form a big clot may never have an event, even though there's a lot of atherosclerosis.

48:17Dr. Gabrielle Lyon:The amount, and you're saying this omega-3 index amount in the blood, should be from your perspective and from the literature between 8 and 11. I agree. We shoot for around 10 for our patients. As you're talking, I'm thinking there's some in red blood cells and then there's some in the tissue. Obviously, we're not doing tissue biopsies. do some people have higher, is there a genetic variation where some people have higher tissue saturation than others potentially? Yeah, we have kind of limited evidence, but the evidence we have, when you look at different tissues, the level in buccal cells from the cheek, the level in heart tissue in heart transplant patients and some other tissues, the red blood cell membrane level correlates very strongly with the level in other tissues.

49:16And so I think it's the level in the tissues that's most important for maintaining membrane fluidity and also for having these effects as they relate to inflammation and resolution.

49:31Dr. Gabrielle Lyon:Is there any utility in measuring things like steric acid, some of the other fatty acids that you had mentioned profile-wise? I think clinically right now, probably not. But in terms of what they can tell us, the different fatty acids have different relationships to diet. So when it comes to linoleic acid, which is the main fatty acid in seed oils, linoleic acid is an essential fatty acid. So body doesn't make it. So if it's in your bloodstream, it came from your diet. And so linoleic acid correlates very strongly with dietary linoleic acid. So linoleic acid in the blood, very good marker for dietary linoleic acid.

50:15Same thing in red blood cells. So red blood cells reflect the diet you've eaten over, you know, several weeks, whereas in the blood, it really reflects mainly the diet that you've eaten in the last few days. Now, when it comes to other things, saturated fatty acids, well, then it gets a little more complicated because some comes from the diet and some comes from conversion of carbohydrate into mainly palmitic acid, which is a saturated fatty acid. So that's more complicated. And then with the monounsaturated fatty acids, that doesn't seem to correlate very well with how much you have in the diet.

50:53So with a major... Where does it come from? Is it just within the tissue? Yeah. So you get interconversion of fatty acids. So as an example, stearic acid, which is a saturated fatty acid, gets converted to oleic acid. And so that's one of the reasons that it doesn't raise cholesterol, because most of it is converted to oleic acid. So it's a little bit complicated. But the two kinds of fatty acids where what is in the blood gives you a good indication of what is in the diet are the polyunsaturated omega-6s and omega-3s. And so, you know, it's not a perfect correlation, but it's a good biomarker for what people are eating.

51:37And I talked about inflammation and seed oil.

51:40Dr. Gabrielle Lyon:Yeah, I'm looking here. You know, you can't go anywhere without hearing that seed oils are driving inflammation and chronic disease. Right. And RFK Jr., our HHS secretary, has promoted this idea that seed oils produce inflammation, mitochondrial dysfunction, and are basically problematic from a health perspective. And the first thing I have to say is we have a very limited database from randomized control trials where we look at outcomes like heart attacks and strokes and incident diabetes and so forth. So got to acknowledge that uncertainty. But having said that, the data we have would fairly strongly, in my opinion, support the idea that linoleic acid from seed oils is associated with health benefits.

52:31So I mentioned the study we did that showed linoleic acid lowered LDL cholesterol. Okay. then a lot of the narrative is that linoleic acid can get oxidized and then that can trigger inflammation. And so if that was clinically important, what you would expect to see is the higher the linoleic acid level in the blood, the higher the level of inflammation.

53:00Dr. Gabrielle Lyon:But when we say inflammation, you're saying oxidized LDL particles? How are we... We have biomarkers of inflammation. The most commonly used one is C-reactive protein. And so if a higher linoleic acid intake in the diet was driving inflammation, you know, the linoleic acid was getting oxidized and then that was causing an inflammatory response, you'd expect higher linoleic acid in the blood would be associated with higher levels of C-reactive protein. So I mentioned this study. We had a little over 2 ,000 people. It was the AGIS study. Now, one of your recent guests, David Allison, he and I were co-principal investigators for the AGIS study.

53:52And it was a COVID-related study. It had nothing to do with diet. But we were interested in whether COVID infection would change the cardiometabolic risk factor profile. So we measured a lot of things at baseline and then during follow-up as well. But we used the baseline data, a little over 2 ,000 people, and we looked at the fatty acids in blood. And the higher the linoleic acid level in the blood, the lower was the C-reactive protein. level. We also looked at four other biomarkers of inflammation. So three of the five that we looked at showed this relationship, higher linoleic acid, the lower the level of the biomarker of inflammation.

54:42And we created a composite of all five, and it was like a stair step, higher linoleic acid, lower biomarkers of inflammation. And when we look at the limited data set we have from clinical trials that are intervention studies. This was observational, but it does not, our results do not support the narrative that linoleic acid is pro-inflammatory. When we look at randomized clinical trials, we either see a neutral effect or we see a slightly favorable, by favorable I mean lower inflammation, when more linoleic acid from seed oils is consumed.

55:24Dr. Gabrielle Lyon:Do you think the confusion perhaps is maybe seed oils are used as a term, a proxy for processed, the fat in processed foods, or is it hydrogenated? Because there's probably a ton of different seeds. Yeah. So when you look at things that are high in fat, so olives and avocados, for instance, how do you get the oil out? You really just squeeze them and the oil comes out because they have enough fat in them that you can do that. So it's called cold pressed. I wonder if I should try that with my avocados. Yeah. So anyway, I've never tried it. So I don't know what that's there. Something's good for the kids to do.

56:03I've actually done studies with avocados. And so, you know, avocados are great and they're high in monounsaturated fatty acids. But avocados, olives, you just squeeze them, get the oil out. It's cold pressed. to get the oil out of something like a soybean or corn or canola seeds, also known as rape seeds.

56:27Dr. Gabrielle Lyon:Where does this idea that seed oils are driving, I mean, it exploded? Honestly, there are a few vocal influencers online who have promoted this idea. They must have brought it somewhere. There must have been some misinterpretation of perhaps foundationist science. Well, I think that it's based on biochemical pathways. So there are two biochemical pathways that I think are the culprits here. And I'll also say that there are some animal studies that suggest that these might be important, but they don't seem to be important in humans. So the first one is that linoleic acid can be converted to arachidonic acid.

57:11Now, arachidonic acid competes with omega-3 fatty acids for enzymes that create things called leukotrienes and prostaglandins. Well, the arachidonic acid, when it's a precursor, it generates versions of these things that are more inflammatory and have more of an effect to promote blood clotting than the ones generated by omega-3 fatty acids.

57:42Dr. Gabrielle Lyon:Are you saying this is mechanistic or in clinical outcomes? This is mechanistic. So that is true. But here's the rub. The rub is linoleic acid can be converted to arachidonic acid, but that saturates at a very low intake. So in an average American diet, you're way above that saturation level. So the higher the linoleic acid intake, you don't see any increase in arachidonic acid. But here's how you lower your arachidonic acid level by taking enough EPA and DHA omega-3s. When you do that, you see the arachidonic acid level in the blood dropping. So I think part of the benefit of EPA and DHA, which I recognize is mostly from observational studies, so we've got to be a little careful in over-interpreting those.

58:35But I think some of the benefit, which I think is probably there, relates to higher omega-3 index being associated with lower circulating levels of arachidonic acid. So that's one. The other is this oxidation question, and I just think the evidence we have does not support an important role for oxidized omega-6 fatty acids in human health, at least for the things that we have looked at. I can't say that I've studied everything, but for the things that we've looked at, there's no evidence of an adverse effect.

59:13Dr. Gabrielle Lyon:The other thing that comes to mind is this idea that there are polyphenols and there are these other components that we get from olive oil, probably avocado, which may have an inflammation-lowering effect. Potentially, it seems as if. And I wonder, and this is just speculation on my part, is if seed oils are or these oils are kind of devoid of, it's kind of like the equivalent of eating boiled chicken. You know, maybe we are not exposing our body to the natural food matrix compounds that would come with these types of oils. Yeah. And I think there, this is one of the reasons that I talk about a diet that is rich in whole grains, fruits and vegetables, nuts, seeds, legumes, non-tromptuble oils.

1:00:06I'm trying to eat all of that. And seafood. So I say, well, you know, let's have a variety of things. And do I think you should be, you know, having tablespoons of corn oil, for example? No, I think having enough omega-3s is important. And I think that the higher the omega-6, there's probably some ceiling on that. But from the observational evidence, the higher the omega-6, the better things look and the better the outcomes have been in observational studies.

1:00:42Dr. Gabrielle Lyon:So we don't need to be afraid of seed oils. So I don't think we need to be afraid of seed oils. But what I would say is, well, don't eat exclusively seed oils. Eat some seed oils, you know, canola oil, corn oil, but include some olive oil. And if you want to have some avocado oil, that's fine. Mix it up and also eat these plant sources where you're going to be getting the compounds that are coming along with those. We don't necessarily understand all of them. There are thousands of them. So if you eat, you know, a balanced diet that has lots of sources of fatty acids, focusing, you know, on the unsaturated fatty acids and getting enough of those, I think that you're likely to have a better profile than somebody who focuses on just seed oils or, you know, is on, say, a carnivore diet where there is almost none of those.

1:01:41Now, for certain individuals, you know, they may respond well to a carnivore diet. There are lots of anecdotal reports of people with autoimmune conditions responding to that. So I'm not saying that absolutely there's never a case where that might not be worth a try. But I think for most people, a balanced diet is what you're looking for.

1:02:04Dr. Gabrielle Lyon:Is there a moment in time where we will get to, I really find it fascinating, this idea of we're talking about monounsaturated, we're talking about saturated, but, and also Tom Brenna was mentioning this, that there's, you know, so many different fatty acids that I just can't help but think about this idea of personalized nutrition, that a fatty acid might be relevant for me, say, at a higher level than might be for you. And if we're ever going to get there to that, because right now we get the big markers that we're looking at. We're looking at LDL cholesterol, We're looking at ApoB. But when we think about really doubling down on that food matrix and subsequently the metabolomics of it.

1:02:50I think we have a lot to learn. And I'll say two things. One is we're not doing a great job of just controlling the big risk factors for cardiometabolic diseases. You know, my flash glick.

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1:03:45Dr. Gabrielle Lyon:AMP AI uses your resistance to adjust sets and reps in real time so you are always training at the level that your body needs. No second guessing, no wasted time, and by the way, it has everything that you need. Your body responds to progressive stimulus. and you need to do that correctly. You don't want just random workouts that you find out online or you find online. It mounts to your wall, takes up almost no space and gives me access to hundreds of movements from strength training to high intensity work. I am telling you, I love this technology. It is beautiful, it is on my wall and it is a system that meets me where I'm at regardless of the day.

1:04:32Dr. Gabrielle Lyon:If I need some recovery, it's there. If your goal is to build muscle, get stronger, no more guesswork, and be consistent, go to AMP.ai. Check it out. That's AMP.ai. Training should be effective, and it doesn't have to be complicated. So there's a lot of work to do in just dealing with those risk factors, managing blood pressure, managing lipids, managing carbohydrate metabolism to minimize the risk of developing diabetes for people with prediabetes. Okay, so there's a lot of work to be done there. Then scientifically, I think that there's a lot of potential for identifying subgroups of people who are going to respond differently.

1:05:14I'll give you one example. There are these fatty acid desaturase enzymes, and there are different subsets. So you can have sort of subset A or subset B, so they're genetically perfectly determined. And it does seem that there is a different inflammatory response, depending on the type of FADS enzyme type that you have. And so we have a lot to learn about these things. So I think for the most part, we can study large groups of people and say, this is what happens on average. But that doesn't mean it's always going to be what happens in an individual case, because both the phenotype and the genotype, phenotype being those characteristics that you can observe and genotype being the genes that the person brings to the party, can influence response to dietary and drug interventions.

1:06:10Dr. Gabrielle Lyon:I hear you say that, but I also have to just highlight you've done a really good job. You guys can Google, you can check out Dr. Kevin Mackey's Google Scholar page, but you You have been able to answer certain questions that I think people have been asking for a long time, like red meat versus chicken. What is the effect, all things being equal, on lipid profiles? It's the same. And I'll also say that we looked at lots of other things. We looked at C-reactive protein as a biomarker of inflammation. We looked at responses for the hormones that control glucose metabolism. Absolutely no difference.

1:06:49And it's a short study. We have to acknowledge the limitations, but the problem that I see with a lot of the observational evidence is that you have all sorts of correlations. So as an example, higher red meat consumption is associated with higher risk of developing diabetes, but— What's the mechanism of action now? How is that working is my question. There are some plausible mechanisms that could explain it. But you might expect that if you do feeding studies, then you would see differences. We haven't seen that. We need longer studies and so forth. But one of the problems is that higher red meat consumption, as an example, is associated with higher risk of dying in an auto accident.

1:07:39Dr. Gabrielle Lyon:Or eating margarine and maim. I think that you have a lot of difficulty because you can't statistically unravel all of these things. So higher red meat intake is associated with adverse lifestyle habits. And so that's an issue. And I'll just give one quick example. And I don't want to get into the, you know, COVID vaccination controversies, but I'll say that there was a huge study in France where they looked at the French population. And the study was in almost 30 million people. and about 22 million people had been vaccinated and about 6 million people had not been vaccinated against COVID. The people who were vaccinated had 25 % lower total mortality.

1:08:34And you say, wow, COVID vaccines saving lives left and right. But they also had 25 % lower mortality from auto accidents. Do we think that COVID vaccination is making people a better driver? Well, the answer is no, it's probably not. It's probably a healthy user bias. People who got vaccinated on average were healthier than people who didn't. The COVID vaccination was associated with 80 % lower death from COVID. And I would suggest that that was probably a combination of healthy user effect plus an actual benefit of the vaccine. And so, you know, that's an example of how you can have something, an association that is present but is not causal.

1:09:25And it's really hard to untangle that.

1:09:29Dr. Gabrielle Lyon:And then on top of that, we have to recognize that we have inherited scientific beliefs. We do. As much as we would hate to admit, I'll just give you a few of my favorites. The idea, and you're going to laugh at me because you are a legitimate scientist. So I'm going to start with this simple one. You should wait an hour after you eat to then go swimming. Right. You know that there's absolutely no scientific data. For example, no scientific data. Even potentially the 10 ,000 steps came from a study in Japan from a pedometer. company. Yes. And interestingly, subsequently, lots of studies have been done and they do actually tend to show that you get benefits at less than 10 ,000 steps, but it really starts to plateau beyond 10 ,000 steps.

1:10:23So it seems like they got it about right in terms of where you're going to get most of the benefit, but who knows where they came up with that.

1:10:31Dr. Gabrielle Lyon:What about the drink a glass of water. Drinking a glass of water, absolutely no scientific support for that. And then I'm going to make a big jump. You're not going to like this jump. Okay, I'm ready. But when we think about the idea of a healthy diet, well, people say, well, that's obvious. Fruits and vegetables and grains and proteins. And in my mind, I'm thinking, yeah, but is it? Is this, you know, because breakfast was a construct. construct, the idea that we'll have cereal, you know, all of these things, I mean, I think left to someone's own devices or just allowing a human in the wild, which we don't have, I think, okay, well, maybe there's a relationship with the protein leverage hypothesis, but we, I just have to check myself, you know.

1:11:21The trouble is we have all of these things that we may believe or we may have been taught. And I've been around long enough and doing this long enough that some of the things that I was taught in my training turned out to be not only not true, but the opposite turned out to be true.

1:11:37Dr. Gabrielle Lyon:You had mentioned butter and saturated fat. Was that the story? There was one thing that we talked about, I think, maybe last year, a year and a half ago. Well, butter is interesting because, you know, dairy fat is high in saturated fats. And butter will raise LDL cholesterol. By how much? Well, the answer depends on how much you eat and, you know, your responsiveness and so forth. But butter will raise LDL cholesterol. But the same amount of saturated fat in cheese has a pretty neutral effect or a very modest effect. So it turns out it's more than just the saturated fat. And then to add further to it, dairy fats have some specific fatty acids that you don't find elsewhere in the diet for the most part.

1:12:25That are protective? That may be protective. So in observational studies, these particular fatty acids, so they're odd carbon, 15-0, 17-0 saturated fatty acids.

1:12:36Dr. Gabrielle Lyon:I was going to ask you about it, but I didn't know if I wanted to bring it up. You know, in observational studies, again, we have to be careful because we don't have randomized control trials. But in observational studies, higher levels of those are associated with more favorable cardiovascular and metabolic outcomes. So I was going to ask you about that. For example, does that mean that we should supplement with carbon-15 or something like that? So, I mean, there's a product, Fatty 15. It's getting a lot of attention, a lot of people promoting it. And what I would say is I'm waiting for the clinical trials in humans to show me a benefit.

1:13:16Now, is it conceivable there might be a benefit? Absolutely.

1:13:19Dr. Gabrielle Lyon:And I've thought a lot about this just because that's what I do. And, you know, I'm a very fun Friday night type of gal. Let's talk about fatty acids. Let's talk about fatty acids, yeah. But for those that are not eating high-fat dairy, then essentially their diet would be devoid of that. Right. And in my mind, what are the things that we're missing? Potentially fatty 15. And there is data for, you know, animal models. And then in humans, I, you know, I've tried it. I think the original data came from a veterinarian who was studying dolphins. That's right. And so, you know, having said that, what I'd like to see is clinical trials in humans that show me that when you take this, it moves a needle.

1:14:01Now, what we found in a study we did comparing full fat to low fat fermented dairy products, we looked at the red blood cell fatty acid profile and we saw no change. Over 12 weeks, we saw no difference at all. That's surprising. And I was surprised. And in conversations with some folks who have data that are not published, I can't talk about the details, but they've said the same thing. We couldn't find any change in, say, red blood cell membrane levels of fatty acids. Now, that doesn't mean there isn't a potential benefit. I just think we need to do the studies to find out.

1:14:43Dr. Gabrielle Lyon:I don't know how we got lost on that tangent, but I think it was the things that you were surprised by, and it was the high-fat dairy potentially. Yeah, high-fat dairy did surprise me a few years ago. So we've done a more recent study, but a few years ago we did a study and we compared dairy foods to foods that are higher in carbohydrate. And the dairy foods had more saturated fat, and they did not raise LDL cholesterol. And I was surprised by that at the time. It was not what I was expecting. And we were focusing in that study on blood pressure. And dairy intake has been associated with lowering of blood pressure.

1:15:22So we saw no effect on LDL cholesterol, which I expected to find. And then we saw no effect on blood pressure either. But we did see in a subset that had endothelial dysfunction that their endothelial function was improved when they were consuming the dairy. So as often is the case, you do a study, you have certain expectations. Sometimes it turns out the way you expect, sometimes it doesn't. And often you end up with more questions than before you started.

1:15:54Dr. Gabrielle Lyon:You've been a career scientist for how long now? 35-ish years. Have you found your ability to tolerate not getting the answer that you want has improved over time? You know, honestly, from early in my career, I just wanted to know the answer to the question. And I would go in with expectations. And what I've found is my predictions are about like predicting the sex of a baby. I'm right, about half the time. and certain things have been very consistent. We see it over and over again and other things have surprised me. And there's a great expression, which is the greatest scientific discoveries are rarely heralded with a cry of Eureka.

1:16:37More often, it's more like, huh, that's funny because it gives you, you know, you expect one thing, that's not what happens. And then you have more questions and you can design more studies to address those questions because lots of things, as I said, that I was taught turned out to be not only untrue, but the opposite turned out to be true. And this has left me realizing that, you know, it's great to think you know something, but really check the evidence. And then often we have to acknowledge our uncertainty and we have to do the studies to really understand what's going on.

1:17:16Dr. Gabrielle Lyon:You've been working on, I mean, And you've been very busy, so I think I have one, two, three, four, five, I don't know, 10 new papers from 25 to 2026. Quite a few new papers that are coming out. We've been busy. Do we know the effect, both short-term and long-term, on meaningful biomarkers like HDL? I think I told you Faden Magos. Do you know him? He's on with Atherton. I know of him. I don't really know him. He's a very dear friend. He's hilarious. He lives in Greece. He can come visit anytime. And he's really big into exercise. And one of the questions I have is that as we start to recognize muscle as this organ of longevity, is truly an endocrine organ just as important as the heart, what are the changes by utilizing muscle?

1:18:16Dr. Gabrielle Lyon:What are the overall changes that we would see with both short-term and long-term with HDL and LDL? So exercise has lots of benefits. And so it favorably affects lots of risk markers for cardiometabolic disease. And sometimes it's underestimated because it has a little bit of an effect here and a little bit of an effect here and a little bit of an effect over here. Yeah. Also, what I tell people, insulin sensitivity, I think, is a really important factor in both cardiovascular disease and diabetes risk. Well, when you exercise for about 48 hours after you exercise, you have improved insulin sensitivity.

1:18:57And so what I tell people is it's like a pill that you take. It just takes you 30 minutes to swallow it. And if you stop taking your blood pressure drug, your blood pressure will go up. Well, if you stop exercising, your insulin sensitivity will get worse. And so I think exercise has lots of benefits. Now, as far as HDL cholesterol, one of the main things exercise does is it increases the clearance of triglycerides. You know, whenever you lower triglycerides, you tend to raise HDL cholesterol. So I think the most consistent effects of exercise, as far as lipids go, is to lower triglycerides, raise HDL cholesterol.

1:19:39And then, you know, there are both shorter-term immediate effects and then longer-term effects. And so exercise is one of those things where the observational evidence, I think, pointed us in exactly the right direction that higher exercise is associated with more favorable outcomes for all kinds of things.

1:20:02Dr. Gabrielle Lyon:And again, whether it's resistance training or cardiovascular activity, I think that we've just... Both are really important. And I think resistance training has been the somewhat ignored stepchild in the exercise arena, but that's changing now. That is changing. And, you know, as I was thinking about today's episode, we have pre-diabetes markers. We have ways in which we can risk stratify MACE or cardiovascular disease. And I was thinking, we don't really have great preclinical sarcopenia measures. Or, you know, all of a sudden, someone becomes sarcopenia. Well, we know that that didn't happen.

1:20:48Well, here's the thing. We talked when we were, before we were recording, we talked a bit about AI. There's something called Jevons Paradox. And Jevons Paradox says when you make something cheaper, you will increase the demand for it. And so everyone's worried that all of these jobs are going to be eliminated by AI. And that's true. There will be some jobs eliminated by AI. But using imaging, medical imaging, as an example. Well, what we're going to have is a situation where you need one-fifth or so of the number of radiologists to read the images that are created. So you can read just as many images and you need one radiologist instead of five to review the images.

1:21:39But that's going to bring down the cost of doing the imaging. And so you're going to have a lot more imaging being done. So eventually you'll probably need more radiologists. If you're doing 10 times as many scans and you need one-fifth as many, you know, for a given number of scans, but you're doing 10 times as many. You need more radiologists, not fewer. Well, I think that imaging is going to really benefit from AI. And I think that we're going to be able to use imaging much more effectively and precisely to measure things like sarcopenia and to measure things like progression of atherosclerotic disease so that we can test interventions and we can also stratify risk much better than we can today.

1:22:30So very excited about the potential for imaging to really revolutionize preventive medicine. And what is that called?

1:22:41Dr. Gabrielle Lyon:What was the? Jevons paradox. Jevons. I've never heard that. Yeah. So Jevons was an economist and realized that, you know, every technological revolution, people are afraid that jobs are going to be eliminated. And, you know, when Henry Ford created the assembly line to create cars, it did eliminate all the buggy whip manufacturers, but it created other jobs. And so I think that the concern about AI eliminating too many jobs, it's going to displace people, but I think ultimately it will result in more jobs, not less. Oh, I'm always interested in your perspective because you have been, I don't know if the right word is decades ahead, but you've been thinking about things.

1:23:33Dr. Gabrielle Lyon:And I think good scientists are thinking about things before they're happening because they have questions. Yeah. And one thing I've learned is, you know, science in large part is about understanding how things work so that you can make predictions. But I think we also need to be humble about what we know and what we don't know. And so we also have to understand that a lot of predictions don't come to pass. Especially the weather. I have a closing question for you. If someone wants to reduce their long-term cardiovascular risk and live a healthy life from an evidence-based perspective, what are the few things that they should be doing?

1:24:14Well, the first thing is know your risk factors. The big numbers are the ABCs. So A1C, which relates to glucose control, B is your blood pressure, and C is your cholesterol level, so LDL cholesterol. So know your ABCs. And then have a healthy lifestyle. So that is a healthy diet, physical activity, including getting your steps in, resistance training, stress management, and adequate sleep. I was hoping you were leaving that out. And avoiding tobacco. echo. So, you know, if you do those things, you're ahead of a large percentage of the population. And I think we've got good evidence, some things stronger than others, but I think we've got good evidence that if you do those things, you're going to really improve your chances.

1:25:02Dr.

1:25:02Dr. Gabrielle Lyon:Kevin Mackey, it is always such a pleasure to have you on. Thank you so much for your time. Thank you for the invitation. It's really been fun.

1:25:15Thank you.