Dietary Fat, Cholesterol, Cardiovascular Health & Disease, Carbohydrates, Dietary Guidelines, Food Industry & Diet Research | Ronald Krauss | #131

Nick talks to Dr. Ronald Krauss, a physician and researcher at UCSF who studies the relationship between diet & cardiometabolic health. They discuss: saturated vs. unsaturated fats; carbohydrates & fat synthesis; "good" vs. "bad" cholesterol; official US dietary guidelines and how they're established; funding of research by the food industry; and more.

More content on the science of diet & metabolic health: https://substack.com/search/diet%20metabolism?focusedPublicationId=513528&searching=focused_posts

Transcript

Full episode transcripts & show notes at Nick's website: https://www.nickjikomes.com/show-notes

Nick Jikomes
To start off with and get us talking about some of this stuff is what did you have for breakfast this morning?

Ronald Krauss  4:24  
Well, I do have half maybe an ounce or less of orange juice to get started then I have cereal, which is a called Fiber One it's pure fiber with no sugar. And I put food on it. And some nuts. A mix of fruits, BlackBerry, blueberry, strawberry and raspberry so it's a colorful mix of foods. sprinkle some cinnamon on it. Have some milk, which is by the way Do not fat milk and coffee and half a bagel? With a bit of butter?

Nick Jikomes  5:10  
And is that? Is that something you've always eaten? Or is that is that how intentional is that breakfast given who you are and what you study,

Ronald Krauss  5:17  
it's totally intentional. And I do this breakfast, three times, usually three times a week alternating with breakfast where I have a single egg with, with big oil, so we have melon as part of my food. So no, I do the cereal and the foods intentionally Oh, in banana, I forgot about the banana. So it's really a mix of everything. I know how to use my Epsom nutritional health benefits. And that's how I drive my breakfast.

Nick Jikomes  5:49  
And so why is that your breakfast? What are some of the key? What's sort of the macronutrient profile there that you're aiming for? Well,

Ronald Krauss  5:57  
I don't Well, let me just say the outset I don't, I don't really try to hit a specific set of numbers I'm I'm although I'm number oriented and very data centric and my research, I don't feel that using percent distribution of calories for the macronutrients is all that helpful. I just think it's, we should be thinking about food composition over overall dietary patterns. And what what has been shown is that once you've picked the right foods and the right dietary patterns, that routine distribution takes care of itself. You don't start there, you can end there if you want. But where I start is in your question with the with the fiber cereal, because I think we in general don't get enough to fiber. And there's a real issue, which we may talk about, perhaps today regarding types of carbohydrate, and whether carbohydrate is good, bad or indifferent. And that depends a lot on the way that carbohydrates are prepared. So I choose the cereal. And I'm not, I don't have a disclosure here, I just found that this, this particular banned Fiber One has a very high quota of true fiber, unprocessed carbohydrate, and no sugar. So that forms the core. And on that, just as I was saying, I just take all the plant based nutrients that I can acquire the phytochemicals that we get from these variety of fruits. And include that just as a basic component of a, of a healthful diet, which, again, don't, most people don't get enough fruits and vegetables. So I really focus very heavily on those aspects and extends into dinner as well, where I usually have several different vegetables at once and, and occasionally some fruits. So so that's really the driving force is both choosing carbs, because I do like carbohydrate, but I want to be careful in the hypercar privacy. So I've been very much involved with reducing carbs in the overall diet as a means of improving metabolic health, particularly for individuals who may be at risk for heart disease and diabetes. But carbohydrates from the right sources contain nutrients as well as fiber. And so that's something I'm very focused on as much as anything else. And

Nick Jikomes  8:29  
when we think about carbohydrates, you know, one thing people talk about is just overall amount of carbohydrates someone consumes, but there's different types of carbohydrates. What are some of the major different types of carbohydrates that are

Ronald Krauss  8:43  
out there? Well, carbohydrate, as with many of our other nutrients, can be extremely complex chemically, with many, many different forms that arise from different sources. But the major categories that I think about to try to sort of simplify that start unprocessed carbohydrates at the top of the list of priorities, where there has been no grinding up of the external capsule, and usually dark rather than light. And that source of fiber has been shown to have health benefits both in the GI tract and perhaps in metabolic conditions as well. And a lot of that is called also called insoluble fiber. Because there's a second category of carbohydrate foods with fiber that is soluble, soluble carbohydrate is a second category so type of fiber is the second category and that comes from foods such as oatmeal, which i By the way, he periodically substituting it for the favorite cereal and it can be taken even as supplements, I use them for some patients who have cholesterol problems, cyber fiber has been shown to reduce cholesterol. So that's it. And that's found, as I mentioned in oatmeal, but there's there's other sources as well, it's commercially available in a form called psyllium. Then moves from those two categories of healthy carbohydrates to ones that get progressively more problematic and potentially problematic as the carbohydrates get processed. To remove the, the outer shell, capsule were a lot of the fibers contained. And you're going to get white white starches. White rice, pastas, potatoes, again, the ones that are white, have been more processed. And they tend to have effects that can aggravate metabolic traits that we're concerned about. They're not unhealthy, but they just don't have the best properties to them. And then my moves to an app, try to simplify this as much as possible. Sort of the bottom of the list are carbohydrates that are simple sugars, which are completely different category but are considered as part of carbohydrate intake, because they're contained both within foods that we select, even from some of the healthy foods, but also have, oh, actually, I should have mentioned how to eat low fat yogurt, I forgot to mention that that's part of my breakfast as well, which has 80 calories per serving, and some fruit, but very little sugar, because a lot of the yogurts, for example, do have added sugar and this many foods that are out there, both packaged and unpackaged that contain sugar and mounts that can be quite detrimental to metabolic health. So added sugar is definitely at the bottom of the list. And there's all kinds of complexity in between. But those are kind of the spectrum of carbohydrates. generally think about

Nick Jikomes  12:07  
what about so there's a lot obviously there's a lot of sugar out there in our food environment. But what about like natural so when we think about fruit, for example, fruit often has a lot of sugar naturally, are some fruits higher in sugar How's how's that sugar that sucrose different other forms?

Ronald Krauss  12:25  
Well, the answer is yes, their fruits differ in their sugar content. I'm not a food scientist. So I don't have those numbers, I think my tongue but it's very easy to assess that just by the taste. the sweeter the fruit, the more the sugar. That's that's comes from fructose. glucose, which is another simple carbohydrate does not have the sweet taste that fructose has. So we're dealing with fructose, which is a special form of simple sugar that is found on both the truth is found in in foods that have added sugars because it's part of sucrose, which is the thing we usually use to sweeten things. It's a molecule that has both glucose and fructose. And it's the fructose that has the metabolic metabolic effects, at least in the things that are most closely connected with. It excess adiposity metabolic conditions that can increase heart disease risk can be aggravated by by fructose. So within food however, not only is there variation in the fructose content, but unprocessed fruit, that is when you have rounded up and made juice out of it will contain that that fructose and the sugar is in a form that's attached to usually forms of fiber. So it's the context in which the fructose is consumed. That can attenuate the metabolic impact of the sugar by slowing down its absorption, maybe even reducing its absorption to some extent. Because when when takes a slug of pure sugar, and it's in its isolated form, or an added sugars, such as sodas you can get a really big spike in glucose which stresses the insulin machinery and can ultimately promote changes in the ability to handle that sugar as the insulin capacity begins to be stretched too far. So within fruit one, as I mentioned, does not get that that slug usually if you're not if you're not using a process we could be using. So I mean the guy just take this on the basis of tastes and oranges which I which is my one concession to sugar is a little bit of juice does have sugar and that something doesn't want to overdo but within its natural form within the orange self that Not only is there less sugar, because we put generally does not eat as much sugar coming from the National fruit as one does from the juice. So it's a, it's a better way to consume fruit. And then when it goes down the list is fruits get less sweet. It's because they have less sugar. And within even a category, I mean, again, this is just a personal experience, you can buy different forms of apples, and there's a huge heterogeneity in the food supply, you can get some apples that are sweeter than others. And it's very hard to get this information from any kind of inventory, the USDA keeps a list of composition of foods, which one can get lost in huge database. But even with that information, you don't know for sure when you're buying your fruit, which I do myself, I go shopping for my own food. And I can only tell you know, in the case of sugar, for example, what is sweeter than others and they send even a range of different apples. And over time even they can vary. So it's a it's an efficient, it's a very difficult thing to actually get into that level of quantitative data. Because so much depends on where the where the food is coming from how it's processed, even the time of year. So it's it's it's one of the reasons that nutrition science is so challenging. Yeah,

Nick Jikomes  16:24  
obviously, I mean, this is an inherently complicated subject, because there's just so many facts known and unknown out there that have to do with nutrition and how our bodies respond to it. One of the things I want to do in this discussion is give people a sense for how ideas and guidelines get set and how they evolved over time. And I thought we could start with going back to the mid 1900s. And there was this thing called the Diet Heart hypothesis that was formulated and became highly influential. Can you just briefly summarize what that was and sort of how it came about for people?

Ronald Krauss  17:03  
Okay, well, that's something I've been deeply involved with both personally. And historically, although I didn't get involved in the fields until a couple of decades later. I inherited a lot of that early information about my own work from it, as well as my recommendations that I've promoted for dietary guidelines. But it starts really, even earlier than 1950s, when it was shown in the early 1900s, that a cholesterol can form plaques in the arteries and lead to heart disease. And so so so blood cholesterol was recognized as a risk factor for heart disease early on. But what happened in the, in the 40s, and 50s. I think the died heart hypothesis to referring to relates to the work of people like Ancel Keys, who did studies showing quite properly, actually, that high intake of saturated fats in the diet increases blood cholesterol levels, and particularly the low density lipoprotein or LDL, bad cholesterol, and connected the dots both in terms of the relationship of dietary saturated fat intake to cholesterol levels. And also, ultimately, the heart disease risk that was not just his work. In fact, it was, over time, a series of observations that made those made those connections which haven't challenged and flooding work that I've done as being perhaps misleading in terms of the causal relationship of saturated fat to heart disease, but that was really the basis for the designation of the Diet Heart hypothesis really focused on saturated fat. But a bit early on, there was even when in retrospect was a real error in considering total fat as the equivalent of saturated fat so that the guidelines early on were focused on limiting total fat intake with the secondary, objective, hidden objective in a way of of limiting saturated fat and lowering cholesterol, but it was in the context of overall low fat diets, which also then carried with it a shift from fat content, this gets into the macronutrient composition. If you're dropping one thing, you're going to increase something else unless you're reducing total calories. And the increase was in carbohydrates, which was really the wrong direction to go. But to your question, that relationship between saturated fat cholesterol and heart disease has formed the basis for dietary guidelines over the years McGovern, Commission, which started off the whole USDA HHS dietary guidelines process, which happens every five years, originated with the McGovern report that I highlighted the importance of saturated fat in heart disease risk as a major feature of that. And again, it was in the context of limiting total fat, not limited carbohydrate. And that really has sort of stayed with the guidelines in one form or another. I'll just mention historically, that I sort of came into the picture much later, editing those guidelines. And both in my own research, which we can talk about, as well as work of many others, came to realize that there were some real holes in that that mechanism have led to a misunderstanding of how to manipulate the case of heart disease risk, at least in the context of the population, which was progressing from early days, even before the 50s when the people tended to be more active, and were perhaps more sensitive to dietary cholesterol and saturated fat. But over the years, and we can talk about this as well be sort of converted to a society where the majority of individuals are overweight, and have metabolic issues connected adiposity. And guidelines that were focused on just lowering cholesterol by reducing saturated fat no longer covered the metabolic problems that individuals face when they go up this so called metabolic syndrome. So the population has changed. But the guidelines have been really slow, to evolve to really meet the differing metabolic responses of individuals in the current population, and they continue to emphasize.

Nick Jikomes  22:08  
So. So if I'm hearing you correctly, it sounds like you know, roughly in the mid 1900s, if we go back a few decades, the thinking was, well, saturated fat appears to raise blood cholesterol levels, blood cholesterol is correlated with bad cardiovascular outcomes. And from that, the conclusion was basically drawn in terms of how the guidelines were set, that one should minimize not just saturated fat, but total fat, and replace that with carbohydrates. And so at the time, sort of when that was the thinking, and that became influential, what was actually like the strength of the evidence, were these coming from randomized controlled trials, were these mostly just correlational observations that were made? How good was the evidence at the time for this idea?

Ronald Krauss  22:59  
Right. So that's, that's a, that's a good question. And I'll try to keep the answer simple. But there's some aspects of this that really require some detailed explanation. As you mentioned, there's really two sources of data that can be used to try to establish causality. When is randomized controlled trials, where when takes a population and assigns them to one or another diet and looks to see what the consequences are in terms of health outcomes. The second is observational data, taking usually recorded data, historical data, self reported data, and dietary intake and connecting that with various other measurements. But ultimately with with outcomes. Both of those approaches, and particularly the observational data can be can be flawed, in terms of how one interprets causality. Because it's not as simple as either a genetic test where you know, you've got one gene doing one thing, and that causes a certain outcome. That's, that's as close as we get to causality, I think it'd be search matures. In terms of treatments. Again, it's easier to establish causality if one uses a single molecule drug, such as a statin drug, which lowers cholesterol, we know the cause of that cholesterol lowering statins. When it comes to diet, we have all these variables, which we just talked about, plus the fact that when you're changing a macronutrient, such as route against carbohydrate, if you're changing that distribution, you can't really be sure what the, if any outcome related heart disease is due to that change per se, because there's too many other variables that are changing. You can't control all of it. And observational data are even more deeply flawed because when it's dealing have historical records or patients or their recordings or intakes, and they're being analyzed. But as much as one can do to try to validate that type of questionnaire approach in particular, it still has some serious questions as to whether this is really a valid measure, particularly diet over time. Whooping Harvard School of Public Health has done the best job, or one of the better jobs around in terms of trying to standardize that approach, but it still is inherently flawed. And it's really dependent on statistical considerations that also carry some downside in terms of how would you interpret the causality. So it is difficult to establish in both of those systems, but if you want me to go back to your question, the randomised trials were carried out in this, I think in the 60s. I can't remember the exact dates now. But there, there were several large randomized controlled trials, in which the goal was to examine the role of dietary fat and heart disease risk. And we summarized summarize that those trials in various ways, did show that diets that were limited in saturated fat, and were higher in another form of fat, unsaturated fat, particularly polyunsaturated fat, which is the the chemical sense quite different from saturated fat. Those diets where saturated fat was reduced, and polyunsaturated fat was increased, did lower heart disease risk, there have been criticisms of each of those studies that I won't go into in terms of various features that kind of dampen the conviction of causality. But the main issue that I've pointed out, which has been overlooked in general, is that those diets were very high in polyunsaturated fat, which is the kind of fat that comes from seeds and nuts, for example, and sell oils. There's a whole contingent of people that feel that saturated fat can induce other adverse effects. But in these studies, the intake was very high. And we can't be sure whether it's the reduction in saturated fat or the increase in polyunsaturated fat that was responsible for the benefit. And that has evolved in the observational studies to considering the ratio of saturated fats and polyunsaturated fat in the diet as an index of metabolic impact or disease risk. But when doesn't know really, whether it's the numerator, or the denominator is the polyunsaturated fat, good guy and saturated fat neutral, fat bad? Essentially good. You can't you can't. I

Nick Jikomes  28:12  
see. So they did studies where they looked at saturated and polyunsaturated fat intake, saturated fat, saturated fat went down and polyunsaturated went up, they saw some benefits in terms of health outcomes, but they can't be sure if it's one or both of those is it the saturated fat going down or the poly going up?

Ronald Krauss  28:29  
It was interpreted as this actually affect me that I mean, all the guidelines since then, it's definitive, so called, reports from American Heart Association, that justify current guidelines, for example, point to those randomised trials as a key element in making the connection between saturated fat and high risk, but but really did not consider the fact in my view, that there could be benefits through very high intakes of polyunsaturated fat that were responsible for the benefit. And saturated fat was really just a sort of a neutral background component. That would be the extreme other interpretation of those studies, which has not been generally talked about. Yeah, and

Nick Jikomes  29:07  
one other thing that strikes me as being potentially relevant to especially when we look back at studies that were done years and years ago, and try and interpret them interpret them, for people today is let's just say okay, you look at those studies, and then someone decides, I want to say increase my polyunsaturated fat intake or decrease my saturated fat intake. You know, at the time the studies were done, when someone eats polyunsaturated fats, or the food or the foods that we're giving them those fats different back then than they would be today. Right. And so I want to talk more about how these dietary guidelines are actually established. So like, literally, how does this process work? How do they determine which studies to consider when they set like you when they set the USDA dietary guidelines, how do they evaluate the studies? And and what does that look like?

Ronald Krauss  30:09  
Well, that's that's a question that has a lot of issues that have been raised recently in particular about the process. A room originally, as I mentioned, they evolved from the McGovern report and related data from individuals who were selected based on their expertise in this area, to come up with formulas for dietary guidelines that were as much as possible at that time, based on ways of estimating the distribution with the optimal distribution of various fats and carbohydrate carbohydrate intake, for example, should be advised the general population. So that was based on a committee process that evolved subsequently, to and I don't remember exactly the time course of when the transition occurred. But over the subsequent years, at some point, this was formalized into a five year cycle of dietary guidelines that were generated and aren't being generated by committees. At least, there's recommendations for these guidelines that are established by committees selected for their expertise in various aspects of nutrition and health. And they meet every five years, and prepare reports, those reports are have been based on what was thought to be the available evidence to support the recommendations that that committee came up with. And that process has undergone some serious evaluation and criticism based on the way that the evidence is presented to the committee and the kind of evidence that's available to present to the committee. So, again, I'm lecturing, I can't give you the exact timeline. But I think maybe, probably about 10 years ago, I was part of a committee that was appointed by the National Academy of Sciences, the Food and Nutrition board, in the Institute of Medicine, to provide the evidence at that time to support or at least to allow veteran guidelines processes to to evaluate the effects of various macronutrients. And that was really the first time there was ever a targeted effort to an unbiased, global way as much as possible, assemble data. So we met for quite a long time, it was quite a intensive effort, because we had to cover fats and the different kinds of fats, carbohydrates, protein, cholesterol. And it was a very extensive process. And that presented data which eventually led to some it moves the needle a little bit on the dietary recommended intake, some fat and carbohydrate, which we can talk about, perhaps, if you'd like but the that has only been done once that was a one time effort. And since then, the guidelines them even more than 10 years ago, at least the last several, five year cycles. Well, they've certainly alluded to that inventory that we assembled, have tried to update as much as possible, as much as they thought possible. The evidence base, making their recommendations that's been criticized because it hasn't always been up to date in the release cycle. I've been part of a group that have published critiques of that process. And as a result of those critiques. There was a there was a another panel convened by the National Academy, which I couldn't serve on, because I was conflicted in terms of some of my other research. But I was an advisor to that process, which was aimed not at the guidelines of themselves, but at the process by which the guidelines are developed and a series of recommendations were made, including the way the evidence is developed and keeping it up to date, making it transparent, dealing with conflicts of interests that may be represented by the members of the committee that should be considered in the end as part of the assessment of their product. So this and we just published a paper recently, I think it's been published I can't remember. I think it's been published where Where we pointed out that those guidelines have really not been fully adhered to, in the last cycle. So we have a current cycle, the student in 2025, I don't know where that stands, I certainly have not been in touch or involved with that current cycle. But the at least there has been recognition that through this report and through other critiques, that the evidence base has to be strengthened beyond what's currently used. The other important aspect of the dietary guidelines process is that everything I've just talked about relates to the work of a committee, a committee of scientists, health, health scientists, and people that have expertise in various aspects of Nutrition has also been concerned about the effect on the environment, which was a little bit beyond the health effects of the foods themselves. So it's a mixed set of disciplines that form this committee. But their report is not, does not represent the guidelines themselves. That report is provided to the US Department of Agriculture, Health and Human services departments, which jointly oversee the production of the dietary guidelines that are actually implemented, for policy purposes and for public education. And they don't always accept the specific recommendations of the Science Committee, and there has been concern about that, because of what I think could be obvious concerns that the USDA in particular, has a mission not only related to food and, and the health of population, but also the agriculture industry itself. That can, despite efforts to avoid those conflicts, nevertheless, there's a concern that some of the ways that the scientific report has been implemented at that level, have been influenced by considerations that go beyond the science. I

Nick Jikomes  37:08  
see. So these committees of scientific experts, that's that's simply one input that goes in to how the USDA and these organizations set these guidelines, there are other inputs coming in from other places. I don't know if it makes sense to talk about what some of those other inputs are, even within the scientific committee, you mentioned, you know, the possibility for conflicts of interest, what are some of those conflicts in that that you've seen over the years?

Ronald Krauss  37:32  
Well, I don't want to point to point fingers, in part because I've, I've had my own conflicts in terms of where research support comes from, which has led me to be involved in some activities without others, where those conflicts could come into play. And the reason for this is one that I'm very sympathetic to, which I think can be strongly justified. And that is, nutrition research, particularly regarding effects on chronic disease, long term health outcomes of dietary changes, is extremely difficult to do. It's, it requires teams of investigators, proper study should have many participants, there should be long term, and we start getting into providing ideally providing the foods themselves as a way of assessing their, their the impact of the diet and health outcomes. All of that is an extremely challenging set of issues that make these projects quite expensive and difficult to support. We have government support coming from the National Institutes of Health, primarily some from the USDA, that have supported research and supported some of my own research. And there certainly is interested within those agencies for providing strong science. But the scale of research and the costs of research and the number of issues that have to be dealt with, really exceed the capacity of those Institute's to support. So we so we as a group, and although I'm sort of moved away from this in my own research, but over over the years, I was part of this group that was really relied very heavily on support from industry, to have the funds and the resources to be able to do studies on that scale. And the key is, as much as possible to separate the work of the project from the interests of the sponsors, and in those cases, and that can be difficult and sometimes almost impossible to prove to a critical public saying well, are these results really true results? Or have they somehow been influenced by the sponsor? So the problem is that many of these experts on the committee getting to your question, have done research, which is perfectly good research published in high impact, which you which would not necessarily be questioned. But in those cases, there was a significant support coming from food industry sources that could be the basis for challenging.

Nick Jikomes  40:17  
So it sounds like just like the nature of this research is that the study is to be done properly at a large enough scale with a high enough sample size and to be done well, there's so much that goes into it, it's so resource intensive, that it's it's so expensive, that there's not enough funding coming from places like the NIH, etc. And so a lot of it then is, is also receiving funding from industry. And because something gets funded from industry, that doesn't necessarily automatically mean it's, it's contaminated in any way. But there's always that concern.

Ronald Krauss  40:51  
Right? But the best. That's, that's exactly right. That's he just described what I was really getting at that, that that is a fact of life in nutrition research, at least as it relates to long term health consequences of the major macronutrients. We really require, in most cases, some ancillary support. And that, and that can come from industry and the way that that's dealt with or should be dealt with, is when publications appear, there really should be a statement saying that these results are not influenced in any way by the sponsor. And that can be true. For example, let me give you my case, as an example. When I started off looking at dietary effects and heart disease risks and lipids in particular, I was facing some of the same issues you discussed, I didn't get a grant from NIH at the time, it was a very small grant, I think we studied like six people it was it was intensive study, this tiny group of individuals, and I realized at that time, that wasn't going to cut it. So I took advantage of an opportunity offered by the National Dairy Council to fund a large program, which was initially a million dollars a year for five years of being Senator which I was really excited about the opportunity that presented for doing things at a scale, we talked about and doing mechanistic studies, as well as human intervention trials. It was highly competitive. They awarded one grant and it was our so we actually got that Senator funded through this amazing resource. And it raised all the issues we just talked about, how are we going to conduct the science in a way that was not connected to the sponsorship, and we and so that's, that's the sort of thing that we dealt with and should be dealt with. Establish at the outset. If you're taking research funding from groups, such as National Dairy Council, you want to be sure that what you're coming up with at the end is not somehow incorrectly assigned benefit to things that should not be

Nick Jikomes  43:02  
when when a group like that sets up? You know, when they decide to fund research like that? How exactly do they advertise it? Are they just saying we want to give someone money to do research in general and dairy? Are they how specific are they getting in terms of what the funds should be used for?

Ronald Krauss  43:18  
That's an interesting question. It takes me back. I mean, this this grant, in fact, this goes back to believe it or not 1989, which is when this program, Mr. Webb got started. And it was, it was advertised to people in nutrition research in person nutrition at university was, so the announcement was widely distributed. So there were quite a few applicants for this from from across multiple institutions. And so that process, I think, was fairly undirected, there wasn't an effort to fund specific people, I can tell you, I didn't expect to be funded. I was thrilled when it turned out we were funded. But there was nothing in advance that would steer that way or any other way. On that side of things. Then it underwent. And so and this was the brainchild of the scientific leadership at the National Dairy Council, which does have a science arm. It still does. And and what they asked for was important findings related to diet and health. And we're obviously very interested in the role of dairy in that regard. That's was certainly one of the driving forces to establish the science that would I think their view, strengthen the case for some features of diet and health that could be favorably affected by dairy so that clearly would be in the background. For the day formulation of this program. But when it was actually delivered as a, as a request called the Request for Applications RFA, it was it was sent out as a, as an RFA with a broad categories of work that would be funded genetic work through working clinical trials. So and this is the way NIH functions as well, it was very much based on an NIH, the Federal model, where the various components of the program would were suggested in the announcement. And then we were asked to respond to those components in ways that would be considered appropriate for the grant program that underwent pretty rigorous peer review. Which is, of course, also should be part of any process for research, whether it's industry sponsored or not, but because of the scale of the funding, in particular, and the unique nature of this program at the time. Of course, I don't know who I don't remember who the reviewers are, but they were. Our proposal which was sent in in response to this RFA was reviewed at the two levels both by external scientific reviewers and also within the National Dairy Council and also the USDA, which oversees Dairy Council. I should mention that the funding that was used to support this program comes from something called the Checkoff Program, which provides a certain amount of money that comes in I forget what the exact rate is, it's a, you know, a few cents, or whatever per dollar of dairy products that are sold, or allocated, have been allocated to marketing of dairy. But that category was divided into research as well. So there's both research and marketing and and that amount of money was available through this Checkoff Program for the research side. And the research was separated from market, we weren't marketing, we were involved in the research side. And as I said, that was rigorously reviewed. And we subsequently in our papers since then, because I, we were able to renew this program for a couple of decades actually stayed with this support, which continued to generate observations that were both publishable, relevant to human health, but also of interest to the sponsors. And those are all reviewed and published in peer reviewed journals. And I think many back can't remember exactly how we handled this initially. But the important thing is that we were in our contract with the sponsors, ensured that we could write whatever we needed to write based on our science without any input from the sponsors at all. They were given the opportunity to look at the papers before they were published, particularly if there were any intellectual property or patent issues involved, which there haven't been my case. But that was strictly for review. And they could comment, but they had no ability to in any way impact what we actually were saying. And, and that is the important safeguard that one really has to enforce. And I think that kind of people that we are consistent, that had been considered and had been involved with the dietary guidelines process, I'm sure are all understand that and practice that approach. But it nevertheless unpaper leaves this connection, which is which you can't erase that that connection, just as it is something that can always be used to challenge results. So

Nick Jikomes  48:53  
when we think about what the USDA dietary guidelines say today, with respect to dietary saturated fat, dietary cholesterol, and cardiovascular disease, what are the guidelines say to that today? And what is your view on how well those guidelines reflect the totality of the relevant literature here?

Ronald Krauss  49:12  
Okay. So this is another big question. And you'll pardon me if I have to spend a bit of time giving you all the reasons that I can bring to bear and answering all the issues that I've been involved with myself, as well as those we've heard from working brothers in the field. So the guidelines relatively early on, considered the need to limit saturated fat as a key element, particularly, specifically for our disease prevention by lowering blood cholesterol. That's the that's the argument that has stood the test of time in terms of how the guidelines are currently developed and implemented. It could point of 10% of calories of saturated fat was established early on. That is the guidelines. Did it continue to recommend that individuals limit their intake of saturated fat to less than 10% to reduce the risk of heart disease that was embedded in the guideline for total fat, which was the federal guidelines set around 30%. That's been some liberalize recently, I should mention that there was a there were guidelines. I could have mentioned this earlier, that were also developed for heart disease health by the American Heart Association. And just as a brief aside, I became chairman of the American Heart Association nutrition committee a couple of decades ago, and inherited these prior guidelines for totally saturated fat as well as other elements of the diet for heart disease health. And I wrote a chair to the committee that wrote a set of guidelines in I think, 1996, ultimately, that really extended the previous approaches, adopted both by the government in their in their guidelines, as well as American Heart for a total and saturated fat. But at that time, I was doing work on my own, which we can talk about, perhaps, as part of this discussion a little bit later, that convinced me that that cut point was really not based on anything specific to that 10% figure. And that was really also consistent with what we found in the report that I had mentioned earlier, convened by the food nutrition board. And we recognize that that 10% figure was really a way of just hitting a level, that would reduce the average intake of saturated fat and the population at least in those years. And thereby lower blood cholesterol levels and heart disease risk. So it was set as a target, not because of 10%, or some magic number, but because that seemed to be a feasible goal that could be achieved in the population as a way of pushing the risk of the population down for heart disease. So that has stood up. So the question is, Is that appropriate at all. And I can give you a whole set of concerns that we've raised and published that, that, in my view, at least, challenge, the idea of having a specific cut point like that at all. And it starts with the fact that saturated fat is really a way of describing a particular class of fat fatty acids, which constitute fat there's a fat molecule has three fatty acids attached to it, a glycerol backbone that forms of triglyceride can also be phospholipids, and other fats, but the term saturated is applied when the bulk of those fatty acids have all of their bonds, saturated with hydrogen can discuss the chemistry if anybody's interested. But that's that's where the word saturated comes from, is that these are a particular form of fat that have this property, as opposed to fats that had the same number of fatty acids, but that don't have as much of the saturated fat component have more fatty acids that in which the hydrogen is not saturating those bonds. So there's, they become unsaturated, either myelin saturated when there's one, one bond that is, loses the hydrogen, or polyunsaturated where there are several and there's different classes, both mono unsaturated, and polyunsaturated. And there are different classes of saturated fat. So we have a across the board, a huge heterogeneity in the chemical nature of both the fats themselves saturated, unsaturated polyunsaturated, but within each of those categories, such heterogeneity, and that certainly applies for saturated fat. Yes, it's in particular. So having said that, one can ask, Well, why have a saturated fat cut point? Why not talk about specific fatty acids? Well, that gets really complicated because we don't get the data in make sure you don't have the outcome data that gets back to the point where we're not going to do a study where we change one specific fatty acids usually, and follow somebody for 30 years. Make sure they're following the diet and see what happens. It just, you just can't do that. It's not feasible. Yeah. So that that that's that's the reason for the lumping. So the lumping is based on this evidence, which is uncontroversial. That if when substitutes saturated fat for either unsaturated fat carbohydrate, one does raise the LDL cholesterol. That's, in most cases, not everybody. There's variation in that response, for example, people that are obese and we published a paper and others have shown, if you're overweight, kind of paradoxically, you don't get that effect at all.

Nick Jikomes  55:17  
But But in general, if you increase saturated fat intake, you increase LDL cholesterol

Ronald Krauss  55:21  
for the population in general, as I say, there's variation in that and doesn't apply to everyone. But yes, and we and others have shown that repeatedly. So there's, across the population, that relationship is well established. Similarly, there is evidence which supports this guideline, that raising LDL. And also the other direction, lowering LDL affects the risk of heart disease. unfavorably favorably. If you lower LDL, you see a proportional reduction in risk. But that may depend on the way the diet is changed. Whatever the way the saturated fat, or the when I'm sorry, it may depend on the way the cholesterol is lowered, and saturated fat and have some effects that differ from other mechanisms for lowering cholesterol, limiting saturated fats, such as statin drugs. So you can't necessarily extrapolate from the data in which lowering LDL has been connected with heart disease, to make the connection with saturated fat. And again, there's multiple reasons for that, one of which is the heterogeneity of the saturated fat. The other is the foods that the saturated fat is contained in. So using so so one of the enduring underlying aspects of our criticism of this guideline is a focus on saturated fat as a class, as opposed to specific foods containing low saturated fats which differ in the potential for different saturated fats, they have different effects, substitution of other nutrients, how that reduction is achieved. So about custom Patty 13 years ago, now, we decided to do a review, and ultimately performed what's called a meta analysis, which is a formal statistical analysis of studies that have been thought to support the relationship of saturated fat to heart disease risk through this cholesterol mechanism. And as we talked about, a few minutes ago, that included the randomized clinical trial data, and even a few trials since the early ones, but more much more data coming from the observational epidemiological data where she has large populations and tries to connect the dots in terms of her disease. And what we found is that literature at that time failed to show a significant relationship between saturated fat intake itself per se. and heart disease risk if you try to just as much as possible from typically epidemiological studies, is to just narrow in and saturated fat intake, as a as a component of diet as assessed by these imperfect tools. If you use that data, one could really not show significant relationships or disease risk, and that created a fewer at the time it was I was sort of somewhat prepared for it, but not the intensity of pushback, because here we were taking down one of the principles of the three C's risk reduction. And in my case, since much of my research is focused on LDL, that was a little bit ironic, because I certainly never backed away from the importance of healthy on heart disease risk. But we could not we could not connect those dots. And there may be many reasons for that, starting with the foods themselves. And what were the things we talked about in terms of the context in which the saturated fats consumed. But here's where I'm going to take a little tour through an aspect of this that relates to the LDL side of things. When I began my, my own research on lipoproteins, or at least one I could continue to do work that I started when I was actually in medical school, but went on to study lipoproteins in a lab at the University of California Berkeley, which was really the lab where lipid protein science was first started really in a way that allowed the study of different kinds of lipid proteins that could be isolated, prepared and analyzed in depth. My research really focused on LDL and the fact that LDL is not just cholesterol And it's cholesterol is component of what we call an LDL particle. And the particle is a spherical molecule that is circulating in the blood that transports cholesterol. So when you measure LDL cholesterol, you're measuring the cholesterol in that particle. But there's many other features of that particle have come into play when it comes to the biological effects of the particles. And just kind of over the years, there's been progressive acceptance, I think widespread acceptance of the fact that it's the LDL particle that we should be considering as the vehicle that brings cholesterol into the arteries for plaque formation, not just the cholesterol content of the particle, but the article itself. And getting back to my early work in the lab, using the tools that were available in that really superb, the research environment with a lot of expertise in separating lipoproteins. We discovered, since we discovered that LDL was not a single class of particles, that there will be particles represent a spectrum of particles that can be differentiated based on their size, particles can be smaller or larger. And as they get larger, the more lipids including more cholesterol, so it has a spectrum of particles, ranging from larger cholesterol which LDL to smaller cholesterol depleted particles. And what we discovered and it which has subsequently been confirmed repeatedly, is that counter intuitively, somewhat paradoxically, the strongest relationship of LDL particle starts disease risk was not with those particles that contain more cholesterol, but in the smaller particles called small dents that are a distinct class of particles, which have been shown to have properties beyond their cholesterol content, which can form the basis for a more toxic effect.

Nick Jikomes  1:02:14  
Ronald, I'm hearing some tapping in the background.

Ronald Krauss  1:02:16  
Oh, that may be me. Yeah. Okay,

Nick Jikomes  1:02:19  
so so it's not purely the cholesterol per se here has something to do with the particle size,

Ronald Krauss  1:02:25  
with it yet with it with the type of particle itself. And the particle size is a way of identifying these particular particles, the smaller ones that have these more damaging effects on the artery, including, for example, the fact that they are more likely to stay in the bloodstream and larger particles because they are taken up less effectively by the liver. So in order to get cholesterol out of the body, and this is the basis for all of our efforts to lower blood cholesterol. Most of us are focused on promoting means of increasing LDL removal from the blood. That's the way statins work, for example, by interacting with receptors at the cell surface in the liver, those smaller particles are have less ability to bind those receptors. And it's been shown that as a result, they circulate in the blood longer. And as a result of that there's greater exposure to tissues, particularly the artery itself where the blood is circulating, that can trap these particles. So this prolonged residence time is a big issue that may point the finger and the mechanism, at least part of the mechanism for the relationship of these particles to heart disease risk. But it's also been shown that they can enter the artery relatively easily, partly based on their smaller size. And they also have physical properties that cause them to bind more tightly to the artery. Sometimes, we think of just things going into the arteries, that's the only direction but we know that things go can go in and out of arteries that these particles can go in and that much more trouble getting out so they get trapped. And once they're trapped, it's been shown we showed and others have shown that they are more readily oxidized, they undergo oxidative properties once they are taken out of the plasma. We don't have an antioxidant environment to protect them from oxidation. That oxidation promotes a number of changes which lead to inflammation and the buildup of plaque by mechanisms that extended the damage due to the cholesterol itself so that inflammation becomes a big part of the evolution of a plaque from a more benign to a more malignant form that can cause heart attack and stroke and when it's in the brain, that inflammatory aspect initiate it back vaccination as another feature of the small LDL that to which the risk has been attributed and all of that is in relation to a larger project. Those which can have these effects, but to a much different degree. So that taking going back to the question of diet and LDL, led me to include in my proposal for this program that I described earlier that we initiated a number of years ago, one of the major projects was to test the current idea at the time, that a low fat diet would be beneficial for heart disease risk, and we hypothesize that that would benefit those small LDL particles, because that's what we thought would be a mechanism for the benefit of reduced dietary fat. But what we found is what changed the direction of my own research and led to some other impacts on the field is that following that traditional diet, low in fat, and high in carbohydrate, actually had a rather small benefit. And the people with heart disease risk who had more than small LDL, we, we classified them as what we call pattern B, small LDL versus pattern A, which is largely ovo, these are two distinct subgroups of the population, the pattern being individuals, that was at higher risk. So it's some benefit, but at the same time 25% or so, of those who had a normal lipid profile, which we call a pattern A actually converted to pattern B, sub low fat, high carbohydrate appeared to worsen the risk in a subset of individuals who converted to this higher risk pattern. As a result of this diet. Can we subsequently showed that this is not related to the fat content changing? It's related to the carbohydrate content change?

Nick Jikomes  1:06:48  
So for about one in four people, increasing your carbohydrate consumption has this effect

Ronald Krauss  1:06:53  
in that particular population? Yes, it Yes. And we also, I just want to say that this was a healthy non obese population. we and others have shown subsequently, that if when it's overweight, or obese, that there's a much higher prevalence, so this high risk trait and and we now know that body weight, particularly, or we call this out of paucity fat in the belly, or fat in the liver, for that matter, in excess can drive this straight as well. And so so in the end, it's two separate mechanisms, one involving carbohydrate, the other bulking body fat, that can contribute to the formation of this small LDL profile.

Nick Jikomes  1:07:45  
So how, how good what exactly are drugs like statins doing? And how effective are they doing? What did they change in terms of blood markers? And how good are they at in terms of cardiovascular disease risk?

Ronald Krauss  1:07:59  
Okay, so statins were just a huge breakthrough in the field as a means of lowering heart disease risk, and their efficacy has been shown repeatedly in terms of heart disease risk reduction, what are they doing these to risk reduction? That's the question. So it starts with cholesterol statins, specifically block the activity of an enzyme called HMG, co reductase, a very specific inhibition of that enzyme, which is a crucial enzyme for cholesterol synthesis by the liver. As a result of that effect. The liver goes through a series of responses that result in increased levels of these LDL receptors that suck more LDL out of the blood, bring it to the liver. So the net result of this mechanism is a lowering of LDL, mainly through production through an increase in clearance from the blood into some extent pipe, reducing the synthesis of these elect proteins as well. So the LDL lowering effects are well established. What we've shown, and others have shown is that this effect is more pronounced for the larger LDL particles, and that this molecule could very small LDL and more resistant and that's because of the feature I mentioned earlier, that the particles have a lower affinity for the LDL receptor. And so there's just so much to say there's a net reduction in everything else. So there's, so there's up to a 50% reduction, but the more potent statins, the higher doses 50% or more reduction in LDL particles, which includes most of the small LDL, but not all of them. That's a benefit. And the second mechanism, which is also I think, very important, goes beyond cholesterol lowering, because by inhibiting this enzyme we can also reduce products that are inflammatory inflammatory, and as I mentioned, inflammation is a key element of plaque development and conversion to them. or dangerous form that can cause heart attacks and stroke. And Statins have an anti inflammatory effect. And a marker for that is called C reactive protein or CRP, which a friend and colleague of mine, Paul Becker, has been instrumental in establishing as both a marker and potential target perceptions because statins lower CRP as an index of their anti inflammatory effect. And the combination of those two mechanisms, I think, are really important for the ultimate benefits of Statins have been shown to have what's

Nick Jikomes  1:10:33  
the relationship between dietary cholesterol intake and blood cholesterol levels?

Ronald Krauss  1:10:38  
Okay, so that's another question. This one, I'll try to just zone in the fact that when I was assigned to this committee that I mentioned, for the food nutrition board, National Academy of Sciences, I was given the task of writing the chapter of this volume on dietary cholesterol. That was my, my topic. And I knew something about it. And as I said, I was at that time involved with the American Heart nutrition committee. And we were continuing to advocate at that time, a generally accepted historical recommendation for limiting cholesterol intake to 300 milligrams a day, which is equivalent of about 111, half egg yolks per day, something in that category. That, of course, comes from other sources as well. And fats contain cholesterol. So all of that was a guideline that was out there. And I was charged with as part of this process, assembling the evidence to support that guideline. And what we came up with was that there is an effect of dietary cholesterol, but cholesterol levels and his LDL cholesterol in particular. But the magnitude of that effect, was really pretty tiny. Certainly compared with, for example, the saturated fat effect we just talked about, dietary cholesterol has a small effect, which if when extrapolates that to its predicted effect in heart disease risk, it would take a population of the world with a huge population to prove that that was a deleterious effect. It was it was so small, and certainly did not support a particular number. Because there was a continuous relationship. Of course, risk and the cholesterol levels both down its cholesterol intake went down. But the net change in those measures in those outcomes was was really not enough. In our in my view, try to get this in the report to justify that guideline, which could be used as a benchmark, but not based on specific science. So speed forward for, I don't know, another 1015 years. And the US Dietary Guidelines, as well as the American Heart Association finally recognized that this was not something that they should really be pushing based on the science. And so that cholesterol guideline has been taken out of the guidelines, which finally, I think represents the right moves scientifically, I should mention that most of the cholesterol that enters our system is actually produced by the body, the amount we consume, if it's two to 300 milligrams a day, for example, within that guideline, should be compared with this seven or eight or 900 milligrams per day coming from a synthesis of cholesterol by the body by the liver, and other tissues. And so when Laura's dietary cholesterol, when is not taking out a major source of cholesterol entering the system, plus which there's a lot of variation in how cholesterol is absorbed, there's receptors involved that can cause a relatively big response to Daedric and others that small response. So we have the mechanism, we have a huge variation in the sensitivity of any given individual to dietary cholesterol. And it's very difficult to set a number that it would apply to. So

Nick Jikomes  1:13:58  
if a lot of the cholesterol is produced internally, why does one have high cholesterol? What are the causes of someone getting very high cholesterol levels?

Ronald Krauss  1:14:07  
Okay, so let's start with the very high cholesterol levels because that's the easiest to talk about. Some of the groundbreaking work that ultimately led to a Nobel Prize, a doctor school, Senator Brown, we're studying this was based on individuals who have what's called familial hypercholesterolemia. They have a genetic form of elevation of LDL, is characterized by a number of features, including importantly, affected family members, parents who carry one or more parents who carry this diagnosis. And it was well established through many studies, that if one has a more severe form of this condition, which we call FH from anemia, when it's at high risk of heart disease, and when has the most extreme form when one inherits the gene from both parents LDL cholesterol levels can go through the roof that can be four or five or six times normal. And younger individuals, even children who have this condition can have severe coronary plaque development and heart disease. And what have one copy of the gene which is present in about one to 200, or 250, individual population not rare, it's not super common. But it's certainly not rare when it's susceptible to the same trait, and we're going to have LDL levels that are high. And the basis for that is mutations and the gene for the LDL receptor that prevent uptake by the liver of LDL particles prevents the LDL from binding. And so that cause is absolutely well established. And that everybody with this genetic trait will get a heart attack, there's variation, and other factors that might affect risk. But in general, there's a very strong connection between the presence of this gene and its consequences on LDL, and the risk for heart disease. So it starts there with these very high levels. To give you an idea of the numbers, we generally consider LDL cholesterol levels of less than 100, to be in a healthy range for most people, but we're for those at higher risk. People that have the severe form factor clustering, I just mentioned, the debt levels of five or 600, people that have the intermediate form with this one dose of the gene, and have levels of a 300 to two to 300. And so we've established the level of 190 as a cut point, again, somewhat arbitrary, but it's the point at which if you have levels above that you're very, very likely to have inherited, you know, that gene or or other similar genes that block the removal of LDL from the blood. So that mechanism is well established. Beyond that. Genetics has given us a lot of data about other genes, as well, that gene as well as others have been studied extensively in relationship both LDL levels and heart disease risk. And so we have ways of collecting genetic information that can allow us to get a risk score that is how many traits are one carrying, and this is across the whole genome across all genes. You can you can scan for genes that have individually less extreme effects and LDL but collectively can have a significant effect, higher score higher risk. That risk score has been related to heart disease risk as well. So there's genetic evidence both with the extremely high level but also with the more conventional LDL levels below 190. That genetic factor is, for the most part, affecting the ability to clear LDL out of the blood can show causality of LDL and heart disease, right, so, so genetics is a big part of the diet plays on top of that. So in terms of the spectrum of things that can affect LDL, genetics is kind of the backbone framework, which we all inherit either tendency to high LDL or not, depending on what our parents have given us genetically. On top of that, we have diet, we just talked about the effects of dietary saturated fat and cholesterol. I mentioned that the dietary cholesterol effect is for most people pretty small, looking behind some high responders, saturated fat. Depending on how one produces the diet can be reduced beyond what people conventionally eat, which is in the range of maybe 12% of calories, if you go down to six or 7% of calories, you can induce LDL. But for most people, it's less than 10% reduction. It's not a big reduction. I can't give you the exact numbers from different studies. But it's a it's a relatively small effect that can be amplified. By including some of the fibers we talked about soluble fibers in particular in this diet. And that's been developed that can reduce LDL by as much as 20%. Using those principles, which begins to be at the rate that we can achieve status, as I mentioned, the more potent status can reduce LDL even further.

Nick Jikomes  1:19:22  
So in in general diet has quite a modest effect on on cholesterol levels. But one way you can lower the goal is to reduce saturated fat intake, in addition to getting soluble fiber. Yes,

Ronald Krauss  1:19:36  
those are two dietary approaches that can lower LDL and certainly for people that have LDL levels that may be due to underlying genetic predisposition. They nevertheless may be responsive to these dietary changes. In fact, they often are, and we can sometimes bring the levels down. Having said that, I'll say one more thing about the diet and that is related to the dietary guidelines. The issue we discussed earlier, saturated fat has most of its effect on large LDL particles. It has, for most people a very small effect, and the little guys, and the smallest LDL. So when when, conversely, lowers LDL by saturated fat reduction, we published this a couple of years ago, as well as previously, when lowers the large LDL but has relatively minimal effects in the small LDL. So that gets back to one of the reasons to support what we talked about earlier, trying to connect saturated fat to heart disease risk by simply looking at LDL, the overestimate the benefit, because the major effect is on the particles that have a smaller effect than risk. And if we're not affecting the particles that are so prevalent in the population now that have a greater effect, these these very small guys are really very minimally responsive to saturated fats. So the dietary effect varies across the spectrum of LDL, it also varies across individuals, in part to their genetic nature. So it's another complicated question I mentioned earlier, a moment ago, the people that are obese, interestingly, don't respond to saturated fat, they make enough of their own saturated fat dietary effect, that's relatively minimal. Consequences. So So that's so so that's it diet and genetics. And then adiposity, as I mentioned, can raise LDL, but it raises the small LDL, so lowering body weight is effective and lowering small LDL particles can also affect the larger ones, but less less prominently than these other components I mentioned, that had been saturated fat and cholesterol. People always ask me, Can stress be a factor? The answer is yes. But it's very hard to quantitate. And it's, it's usually, if there is an effect, it's not enough to really enter into a formula to predict cardiovascular. That's about that's about it for the causes of cost. elevations, the population. When

Nick Jikomes  1:22:13  
we talk about HDL cholesterol versus LDL cholesterol, these are commonly referred to respectively as good and bad cholesterol. Is that a useful shorthand to to refer to these? Do you think we should be using those terms? Is it really as simple as one's good and what's bad? So you should want higher levels, one lower levels and the other one? How much more nuanced is actually there? When we talk about good and bad cholesterol?

Ronald Krauss  1:22:40  
I'd say every question you've asked so far, is, is a question that has a very extensive set of answers not trying to be careful about not making it too to limit too difficult to follow. In terms of the LDL and bad cholesterol we just reviewed, actually, one of the concerns I have is talking about LDL cholesterol, the cholesterol kind of LDL does not give an indication of the small LDL particles for example, it's it's it's weakly correlated with with the particle distribution. And, and therefore, it's, it's somewhat flawed. It also includes another category of lipoproteins that we didn't mention for the fishy hanos. who may be listening to this. I just mentioned there's a category called remnant lipoprotein cholesterol. So we have LDL, which is the low density lipoproteins that we have these random particles which are actually even larger, they're actually larger than the large LDL, but they are derived from breakdown of other particles caused called VLDL. Very low density lipoproteins that start off in the liver containing triglyceride, as well as cholesterol and as they're metabolized. It's it's like this right gets lost they produce these remnants. These remnants are how the atherogenic. So we have the LDL spectrum differences across large versus small LDL, but LDL cholesterol. Also, the standard clinical measurement also includes remnant cholesterol. So one of the reasons and I think one of the major reasons that LDL cholesterol has been pinpointed as bad cholesterol is because it includes these other components. It's not some simple single entity. Calling it good cholesterol, I'm sorry, calling it bad cholesterol this term is really for that reason oversimplification but it's at least in the right direction. I mean, this is a this is higher risk when it comes to HDL. HDL also contains cholesterol. It's a smaller particle has less cholesterol and LDL, in most individuals at least. And its levels have been very strongly related inversely to heart disease risk such that people that are walking around with higher HDL levels tend to have lower heart disease risk than individuals who have lower levels of HDL and those cut points were below which HDL reduction appears to be quite harmful for many people. There's genetic reasons for that. It can also be lowered if you're overweight and certain, again, to varying degrees across the population, but obesity contributes to low HDL. And that is correlated with higher heart disease risk. However, there have been two categories of research that have challenged the assumption that changing HDL either in either direction would affect heart disease risk, one is genetic, and that is that as opposed to genes that affect that will be held that we talked about a few minutes ago. The genes that specifically affect HDL, the collection of genetic effects in HDL, have not been shown to be correlated with heart disease risk. So people carrying genetic traits that, for example, raise HDL do not appear to be at lower heart disease risk as a result of those genes. So that's one line of evidence which is been used to challenge the assumption that if you have low HDL raising HDL would be beneficial. And there's an another category of, of data that supports that conclusion. And this is based on trials, particularly involving vitamin called niacin. nicotinic acid, has been known for decades to lower cholesterol but also increases HDL levels can increase HDL levels quite substantially. We can discuss these trials in more detail. But the bottom line is that the effect on HDL of those trials involving niacin could not be connected to the heart disease risk, as well. So that has sort of challenged the assumption that simply having a correlation of HDL with heart disease risk, which does exist, doesn't really guarantee that something that changes, HDL is going to have the predicted effect. That argument by the way also applies to LDL. It's another one of the arguments I've used to challenge the assumption that what we know about LDL is related to heart disease risk. We know statins can reduce LDL and reduce heart disease risk. But do we know that the dietary effect on LDL is beneficial. There have not been studies that have really focused on as I discussed earlier, there was a large trial, I'm going to go back now to my other line of evidence on the audio side, where a large population of women groups called Women's Health Initiative were treated or advised to follow that there was lower in saturated total fat, higher carb. And at the end, there was really no significant impact in heart disease risk of that diet. So so one can infer from the relationships that we know for LDL HDL is being called good and bad, that changing them in any particular way is going to be beneficial. And that also depends on other effects of the diet goes back to the argument I was making earlier, the challenge saturated fat guideline. It really need to consider other effects of foods beyond cholesterol lowering to all saturated fats have that effect. And if you give me a minute to sort of sidetrack back to that topic. What I mentioned is that there is data to support that certain types of saturated fat, particularly those found in dairy foods. This is not, this is not my research. So I'm not conflicted as saying this type of thing. are associated with improved cardio metabolic health features that could predispose example to diabetes and metabolic risk of heart disease that are benefited by the fatty acids or get rid or associated, as I say, with benefits of these fatty acids. And so there is some evidence, which is the subject of some controversy and continual reevaluation, that the same amount of saturated fat the total amount of saturated fat derived from dairy in particular, and other sources of saturated fat, non dairy meat, truck oils, have different effects in heart disease risk. The dairy context has other effects that will be on cholesterol that can impact heart disease risk. So reducing dairy fat intake, carries potentially the downside of pulling away those those fats that may have beneficial effects. This is particularly related particularly connected with another way that dairy products are consumed, and that is to ferment from intense fermented products, such as yogurts, and cheeses, and, and those fermented products that could be for the yogurts have also been associated with cardio metabolic benefits. Again, these are cross sectional, some interventional studies. And so again, it points to the fact that simply labeling a product as simply harmful effects dude To help you're raising components, such as saturated fat have, do not necessarily relate to heart disease risk. And then finally getting back to that same arena of way. I've been concerned about continuing to focus on saturated fat as the criterion for advising. ways of reducing heart disease risk. The dietary guidelines is that mentioned, for example, that most of the cholesterol synthesis that we find that the body is produced by synthesis from tissues, including liver, the same is true for saturated fatty acids. Most of the saturated fatty acids that circulate in our body are synthesized by the liver process called the normal epigenesis. And so at dietary saturated fatty acids can contribute to the body's pool of saturated fatty acids. For most individuals, and particularly those individuals who have these metabolic disturbances that are derived from excess adiposity, for example, we call it metabolic syndrome who have insulin resistance and predisposed to diabetes, those very prevalent individuals that a large segment of the population is actually producing a whole lot of saturated fatty acids, from carbohydrates as their carbohydrates drive this de novo lipogenesis process. And that just points the finger exactly at the opposite direction from reducing fat and points to direct fingers. Again, it's supporting the argument for reducing de novo epigenesis and fructose, which he talked about even earlier, as a specific sugar that drives some metabolic problems that lead to heart disease and diabetes. Fructose drives de novo lipogenesis, that's higher levels of fructose produce more the saturated fatty acids. And And here's where, like with cholesterol, what's circulating in the blood is not the same thing as what we consume. What we see in the blood is endogenous saturated fatty acids. And once they're in the blood, they can be harmful. Saturated fat, fatty acids do have harmful effects. But it's the circulating saturated fatty acids impacted more by most people by carbohydrates and fat, that drive this. And those effects can include both lipid synthesis, lipid metabolism as well as inflammatory processes that can contribute to heart disease risk. I

Nick Jikomes  1:32:30  
see. So those when we go back and think about those original guidelines that sort of made the inference from the data, which wasn't proven that if you decrease saturated fat and replace that with carbohydrates, not only was the saturated fat decrease, probably not having at least as big an effect as they hoped. But actually, replacing those with carbohydrates was promoting lipogenesis and actually increasing circulating saturated fatty acids, right,

Ronald Krauss  1:32:56  
and they're not affected. Again, if you have a diet that's extreme, which is low in saturated fat, high saturated polyunsaturated fats, and the carbohydrates are coming from healthy sources, plant based whole grain etc, that effect would be minimized. But in practice, the way the guidelines have impacted the population and the food industry, which really made the best effort to comply with those earlier guidelines that promoted carbohydrate at the expense of fat, included foods that really were driving endogenous, saturated fat production could have adverse effects, and other other mechanisms as well.

Nick Jikomes  1:33:35  
When we think about the different classes of fatty acids, so saturated monounsaturated polyunsaturated, there is heterogeneity even within those categories, but if we think about them at that level, the degree of saturation is related to how easily they can become oxidized. Is that true?

Ronald Krauss  1:33:58  
Yes, that may not be always the important mechanism that affects the biological effects. However, the differences in the structure relate to metabolic control through enzymes that pull away hydrogen atoms. Progressively, bands change from saturated unsaturated when there's multiple unsaturated bonds within the chemical structure of a fatty acid, it does become more readily oxidized. That may have mixed effects, it may not necessarily that form of oxidation, that's not clear, is recent. Some people feel that there's an adverse effect, but it's not clear to me that that's significant enough to warrant concern. Again, this kind of stuff because so complicated, I don't want to make it overly complicated. But within polyunsaturated fatty acids, there are two general categories which we didn't discuss. M one is where there's a specific unsaturated bond. And what's called the n minus three position, those are called omega three fatty acids. And another whether the first button is in the sixth position, those are called omega six fatty acids. They're derived from different sources, omega three fatty acids can be derived the diet from flaxseed. But the form of mega three fatty acids that appears to have some metabolic benefits is mostly found in fatty fish who develop high levels of these omega three fatty acids. And that's been the study the source of many studies trying to relate those fatty acids to benefits including heart disease risk reduction, those are complicated by the fact that some studies have shown benefit, but more recent studies have not. So it's still an area of some controversy. That's as opposed to the Omega six fatty acids, which are the find the major source of polyunsaturated fat in the diet coming from seeds and nuts and various oils that have these effects, including associations with lower heart disease risk, as well as lowering cholesterol levels. So that's just another element of heterogeneity that segregates these two forms, etc, fatty acids,

Nick Jikomes  1:36:19  
when you get omega sixes, from whole foods, like nuts, and things like this, that are unprocessed and have have the fatty acids intact, do those Omega sixes have a different effect? compared to if you cook them with them at high temperatures in the form of say, a vegetable oil?

Ronald Krauss  1:36:38  
Yeah, well, this is, this is a topic that I have been exposed to, by interacting and even publishing with colleagues who have made the point that that type of processing can have adverse effects on the structure of these that could be detrimental. I personally, you know, accept accept the, the arguments. To some extent, I just don't know personally whether I feel that this is another factor that should cause people to avoid, perhaps taking after high temperatures. But this is not my area of expertise. And I've tried to avoid making any conclusions based on what I see is a very complex literature and a lot of controversy in this field. It occurs to me there is yet one other consideration regarding fatty acid heterogeneity, and that is what's called trans fatty acids. And fatty acids are distinguished from what are called sis fatty acids, by having hydrogen atoms and both the top and the bottom of the structure going in opposite directions from the main structure, whereas assists unsaturated fatty acids have those unsaturated hydrogen LM sitting in the same direction. So what we see in practice is what we've what has been shown in various studies, both interventional and observational, is a strong association of trans fatty acids. With with heart disease risk, and those are often found in highly processed fast pipettes that undergo high temperatures, as you said, can generate these trans fatty acids from the way the oils are processed. And that is, I think, generally be the band isn't adverse effect, which has led to changes in the food industry in the restaurant industry, that have greatly limited the amount of saturated fat, the gram saturated fat that we're exposed to transparent saturated fat that we're exposed to, even to the point of putting this on the food label, and making conclusions based on whether they meet a certain criterion for having unmeasurable amounts of transfer. That's an important another important type of average needy of fatty acids, that could be considered in heart disease risk assessment. Having said that, it was even heterogeneity among the trans fatty acids, there's different forms of trans fatty acids, and not all of them necessarily have the same effect. So it really gets complicated. But again, in terms of trying to simplify the categorization, we have, you know, the sort of broad category of saturated fat, we have the broad category of mono and saturated fat, which is, for example, eliquid. We didn't talk about that. Canola oil is another one that has one of these double bands. In the structure that we have polyunsaturated fat, we will make it six Omega three, then we have trans fat versus, versus the normal cysts form. And we have heterogeneity within each of those categories. So yeah, we've got a full plate below. have characters in this game?

Nick Jikomes  1:40:04  
In general, just directionally speaking in general for the United States? How have how have dietary fat patterns of intake changed over time? Are we getting more polyunsaturated today than we used to? Are we getting less saturated fat, what have been some of the major patterns there, say over the last 100 years? Well,

Ronald Krauss  1:40:24  
I don't have enough of a handle on that time span, to give you exact numbers, but I can tell you that one of the consequences, and we think it's due to the guideline process, over the last several decades, has been a reduction in the average consumption of saturated fat and throw some numbers, which I'm not going to stand behind and have them in front of me. Nor do I have the exact figures, but something in the range of 14 50% of calories and saturated fat was not uncommon in the old days and even higher. And in many cases, the average consumption has now been reduced to something between 11 and 12%. Saturated fat intake has come down. And some people think that that's a beneficial consequence of the guidelines. And I can't argue against that. And I think that may be part of the reason why cholesterol levels the population are dropping somewhat because of that, but it's but we expect it to be relatively small effect, but it's in the right direction. At the same time, we've had this corollary of reducing total fat and increasing carbohydrate at the expense of fat. And that that has changed, I can't give the exact numbers there. But for example, just throwing some numbers out, which I can't be exactly sure, you know, something like half of total calories, 50% or so, or more rare coming from carbohydrates. or less, I should say it started off in the old days. And I don't know if it's 100 years, or 80 years or whatever, but carbohydrate intake was maybe 45 to 50%. In general, the guidelines push that up to 50 plus percent. So the guidelines push the carbohydrates in the other direction. Where we are now I don't have the exact numbers, but we're not at the 45% level. And, and for example, from a metabolic standpoint, my own studies, and those of others have suggested that we probably should go back to 45 or less as a target to try to reduce some of the metabolic adverse effects of carbohydrates overall use natural sugars. It's it's all of these process sectors and carbohydrates in particular, that contribute to that 50 plus percent. So, so I'm happy to answer your question in detail. But it's this this general trend that we think has resulted, in part, at least from the dietary guidelines that have been promoted and the food industry's efforts to meet those guidelines.

Nick Jikomes  1:42:59  
In one of the papers of yours that I looked at, and you kind of you mentioned something earlier, I asked you about the macronutrient macronutrient composition of your breakfast, I think, and you said you don't think about things in terms of, you know, hitting specific numbers for yourself. And I know that you've written about something called the food and diet matrix. So what is this?

Ronald Krauss  1:43:20  
So that's considering the effect of the foods as we actually eat them, which contain these chemicals. They contain the fatty acids, they contain the sugars, and starches. But they are contained within what we call a food matrix. And I touched on one example of that in the case of fruits, where we see that the sugars in particular can be embedded in a food that has a lot of fiber that embraces the sugar and affects its metabolism. So that food context of a whole fruit versus a processed juice, for example, is maybe an extreme example of the food matrix affecting its metabolic effects. In the case of fats, there's studies which also points in the matrix as being important. I mentioned the fermentation process, for example, which appears to generate beneficial changes in in carbohydrate quality that had been associated with cardiometabolic risk benefit. But in the case of cheese, it's been shown and this varies across different cheeses, of course, but in general, the same amount of saturated fat and cheese has a much smaller effect on LDL cholesterol than that affecting the effect of st minus saturated fat and butter. So there's a few studies showing that saturated fat saturated fat may be equivalent across those two forms of dairy the contract which the saturated fat is consumed within cheese due to something about the matrix appears to change its its its metabolic impact, and probably its effect on heart disease risk. So, so that that's the food matrix angle, which has really not been well enough studies, or maybe it's certainly not enough to be able to point to ways of assessing that analytically that could be translated to dietary guidelines.

Nick Jikomes  1:45:28  
Yeah. So I would imagine in general here, just to help people think about it, right, if if scientists study the effect of like an isolated macronutrients, the body, it may or may not have the same effect in the context of Whole Foods a versus Whole Food be because there's just so many interacting pieces here that affect how each of each of the components is absorbed and used by the body is that basically it?

Ronald Krauss  1:45:53  
Well, that's a big part of it. But that that there's two other things to consider. One is the effect of other components in that same food, that could be influencing the effects that have nothing to do with either the matrix or the nutrient of interest that just sort of coming along for the ride. And particularly for plants, for example, there's just, I don't know, dozens or hundreds of what are called phytochemicals that are contained within fruits and vegetables that we don't we measure some we can measure some of them. But we don't have specific evidence that one or another of those nutrients has an effect. So that's kind of a second axis by which the food context could have a unexpected effect, either good or bad, that would not be predicted from a particular component of the food. And then the third thing, and the final thing that supports a concern about a food context is not just the foods, but the overall dietary pattern. Because we can study individual foods, perhaps. But what we really consume is, is dietary patterns, we consume foods with other foods, we consume classes of foods together, in some cases, and and others. And so there's the context, not just to the food matrix, but the overall dietary pattern. So I'm glad to say that the Guidelines Advisory Group at least, and I think the guidelines themselves have been good have been certainly in the last edition. And hopefully in the future additions, will emphasize the role of dietary patterns overall, being that exceed the information that we can get from trying to put numbers around the individual components and their percent of the diet, the overall dietary pattern should be considered as a major goal. And there have been studies, for example, involving what's called the Mediterranean dietary pattern, which itself has different versions, depending on where you are in Mediterranean world. But in that program, which is, again, a number of different dietary effects that go well beyond effects and cholesterol has been associated with improved heart disease risk, as well as other metabolic benefits. And that's been promoted as one of the ways of achieving a healthier dietary pattern. But again, we really would, would benefit from having much more data to support this, and tell people exactly how they should be implementing these diets, because they don't always go to the literature and see what what other studies read what the studies were using. They need to get guidance that's much more specific, and we don't have enough data yet in that direction to really document benefits.

Nick Jikomes  1:48:40  
Well, Dr. Krause, we've covered quite a bit so far. We've only got a few minutes left, are there any final thoughts you want to leave people with about anything that we've talked about the general subject of diet and metabolic and cardiovascular health?

Ronald Krauss  1:48:56  
Okay, so one can step back, maybe at the 20,000 foot level, not the 30,000 foot level, and say that there are certain aspects of diet and cardiovascular health in particular, that I think we can stand behind. based on evidence that I mentioned, that is not always perfect, not always sufficient to assure causality, but which is sufficiently compelling to generate some healthful, overall dietary patterns. And I mentioned the Mediterranean diet, but within that diet, I think there's evidence to support overall benefits. Can again through mechanisms that we fully understand of a variety of vegetables and fruits of plant based foods and healthy carbohydrate foods that are not processed carbohydrates that those plant derived foods should be in a variety of them should be consumed? I think goes no cholesterol issue of course me being able to point to a specific component yet and say that's what you should be doing, it's really related to the overall dietary pattern. And that I think should be considered as a, as a goal in one form or another, to try to achieve. And I mentioned that one of our one of our own studies where we looked at the effects of dietary protein, we didn't talk about dietary protein, I'll just throw that in. Okay, since we didn't discuss that. There has been issues regarding is red meat worse than white meat. And how did that compare with non meat sources, we actually did a study where we looked at not heart disease, it was not that kind of a study, but we looked at the LDL and other lipid levels. And we found that if we consumed a non meat protein as a major source of protein, that there was a global level of LDL than with either that meet high meat or the the high white meat or the high red meat diet, I mean, from either mostly from file versus beef, and other sources, their LDL levels were similar and higher than the plant based diet. So that gives us one other axis to think about, and that is a source of protein. And along those lines, I should probably also come back to one other issue we talked about, and that is the omega three fatty acids, which as I mentioned, are enriched in fatty fish such as salmon, certain certain tunas, sardines, herring, are all rich in these quantities launching mega three fatty acids. There's some evidence and again, it's observational evidence for the most part, that has LinkedIn high intake of those sources of Omega three, with improved cardio metabolic overall heart health, that have not been necessarily be produced by the officials themselves, not necessarily by the Omega three component. But this gets back and part of the food context issue we just discussed. So I'm I'm in favor, in addition to having this overall, balanced diet with plenty of plant based protein sources include at least one or two portions of fish a week, to provide whatever benefit that might provide, and then choosing carbohydrates that are unprocessed. And I tell my patients that I could consult me, again, I talked about my cereal, my fiber cereal, which is has a very high fiber content, when should look at the label of foods and look at the fiber content, look at the sugar content, and limit the sugar and try to make the case of these carbohydrates maximize the fiber intake. So So those categories I think are major kind of bottom line dietary recommendations, which are more global, more general. And what's been shown is if one follows dietary patterns like that, including even the Mediterranean diet, one can back generate a percent distribution of calories. So you can learn one of those diets giving us if he was interested. And it turns out, they're pretty much conformed to what we try to recommend this not having too much carbohydrate, not having too much saturated fat from for many people. All of that sort of comes out in the end. But it's not necessarily a crutch. I don't think it should be the criterion, nor should it be considered the mechanism for benefit of those diets. It's really a marker of intake. But the real, the real effect of these diets is coming from the foods and the dietary patterns in which they're consumed.

Nick Jikomes  1:53:38  
All right, Dr. Ronald Krause, thank you for your time.