Lipid Expert: High LDL Cholesterol Is a POOR PREDICTOR of Clogged Arteries | Nick Norwitz

Towards the end of college, I started developing GI upset with basically anything I ate. So I ended up becoming quite desperate, and after trying a bunch of medications that didn't end up really working to keep me in remission or help my symptoms, tried a bunch of different diets because I was desperate. Eventually I tried a ketogenic diet, and that's when my life really did change. My inflammatory markers dropped, I felt a lot better, and on my next colonoscopy there was no sign of disease. I was in biopsy-proven remission. It was my first lipid panel. My LDL cholesterol, my cholesterol total as well, along with my HDL, they all skyrocketed. So I did a trial where I experimented on myself using 12 Oreo cookies per day for about 2 weeks, and then I did a washout period and compared it to high-dose statin therapy, 20mg of rosuvastatin, for 6 weeks. The Oreo cookies were twice as potent at lowering my cholesterol, lowering my LDL, as high-intensity statin therapy. So that was me being intentionally provocative to get more discussion around the physiology of cholesterol changes in carbohydrate-restricted diets. The reason being is changes in cholesterol still remain like the boogeyman of low-carb diets, and I think they have so much clinical utility. We need to address this boogeyman and understand what's going on so that we can properly and broadly implement low-carbohydrate and ketogenic diets for people where they could be useful.

Nick Norwitz, given all the differences between people, our metabolic health, our gender, ethnicity, metabolic status, we could go on and on. How do we begin to uncover and figure out the best diet for us as an individual within this racket of different diet paradigms and so many conflicting ideas in the health and wellness space?

That's an excellent question. And I mean, I— the obvious thing, I'll start with the obvious. It starts with the realization that there is no one size fits all, that you have to start by considering who you are as a person, including your metabolic baseline. Are you metabolically healthy or unhealthy? And then what your goals are, what you're optimizing for, because any diet, you know, has an effect based on the consumer. And then, you know, you kind of have to aim your diet, your lifestyle in a particular direction, at least as far as optimization goes. And then from there, I think a lot of achieving metabolic health has to do with being observant and iterating towards your predetermined goal, which means seeing, you know, how does this intervention affect me, and then tweaking and tweaking and tweaking to get ever closer to what you want to be. And the kind of cool thing about it is you can always take it in a new direction depending on what you're trying to optimize for at any one point in time. And The thing I love about metabolic health in general is that, and the reason I don't like to say I'm a nutrition scientist or into nutrition science, is it's diet tribe agnostic. Like, it's about the outcomes. The proof's in the pudding. The proof's in the markers, your performance, how you feel. There's many different ways to skin a cat, and it's one of those things where it's like nobody can tell you otherwise if it's working for you. So that's my high-level vision. And in terms of like how to help people achieve that, or how people can achieve it for themselves, really. I think it's about finding that power in realizing that you really have more power than I think you give yourself credit for. I said this in a short the other day, and I was not being hyperbolic at all. Like, I've done a lot of formal education. Undergrad, I did cell bio and, um, biochemistry. Then I went to grad school for metabolism to do my PhD in that. Now I'm finishing up my fourth year at Harvard Medical School. It's over a decade paid a formal education and has not taught me even a tenth of what I've learned by just trying things on myself and experimenting. And that is something that's accessible to everybody. And we're living in an information age now where like people have access to platforms like this where they can learn about metabolic health and kind of get the crystallized knowledge background and to order, you know, kind of to frame their individual metabolic health journeys. That's my long-winded answer.

Well, we're in the situation in the modern world, at least in the West, where a lot of people are metabolically sick and they're somewhere on that continuum from insulin resistance all the way to type 2 diabetic. Let's talk to insulin resistance to start because this is gonna be a big catch-all category for a lot of people. Let's talk about what that is and then we can get into specifics of how to back out of that.

I mean, insulin resistance, as the name implies, is your body is— resistant or isn't good at listening to signals that come from the hormone insulin. So, you know, you release a basal amount of insulin. I just want to kind of say that because people are like, oh, you go low carb, your insulin goes away. No, you're always releasing some insulin unless you have type 1 diabetes. But generally, your insulin, you know, um, releases increase in response to food, in particular carbohydrates. And that's really important for kind of you know, orchestrating the hormonal milieu that should follow a particular environmental exposure, in this case carbohydrates, also protein, et cetera, et cetera, but primarily carbohydrates. And if you become insulin resistant, what ends up happening is your body tries to shout louder and louder and louder with the hormone insulin. So your pancreas, which produces insulin from its beta cells, will release more and more insulin to try to compensate for the fact that a lot of tissues aren't getting the signal. And so in pathological insulin resistance, what you have is increasing levels of insulin to try to offset the insulin resistance. Now, as you develop type 2 diabetes, your pancreas starts kind of getting fatigued. You can think about it like that. And so then the insulin release can't, um, compensate for the resistance. But there's an interesting element here, which is why there's such broad metabolic dysfunction and insulin resistance, is your body is not a homogeneous blob, um, specifically with respect to insulin resistance. So different tissues will become differentially sensitive to insulin. Some actually won't become that resistant, whereas others will become profoundly resistant. And the reason this is so problematic and causes the metabolic dysfunction is you're going to have some tissues that are getting overstimulated by insulin because your pancreas is trying to compensate. There's a lot more insulin around. And they're getting too much signal. So for example, your liver, the pathway that controls de novo lipogenesis, which is the generation of new fat, insulin can stimulate that and that pathway becomes— it doesn't become insulin resistance as much. So as your body's trying to compensate, it's signaling to your liver to make more fat, then you're getting fat produced and spilled out into the bloodstream and then you get hypertriglyceridemia. At the same time, another pathway in the liver that controls gluconeogenesis, which is the generation of sugar, which is supposed to be shut off by insulin, it becomes more resistant. So you're not able to put the brakes on that either. So you have too much gluconeogenesis and you're spilling out excess sugar into the bloodstream. So you can see how complicated this gets. That's even in one tissue where because of the heterogeneity of insulin resistance across the body, you get this broad metabolic dysfunction which can really screw people over.

That's an important layer to this. A lot of people aren't talking about the differentiation within cells becoming insulin resistant at different times and different pathways within cells.

Yeah.

Anything practical we can take from that piece, or is it just an interesting piece that we can be mindful of as we're navigating this?

Well, I think in general, maybe I'm an outlier in the way I see things with respect to my health, but, um, A lot of education for me is about giving people the tools and hopefully inciting curiosity to just be more invested in their health journey. When you understand what's going on inside of you, it makes it easier not only to adopt behavior change, but stick with those changes as you start to get this picture about what's going on in your body metabolically. So, when you have an appreciation for that complexity, I just think for some people it really helps inspire behavior change. That said, I mean, you can— we can talk about practicals with respect to insulin resistance. So for example, let's talk about actions at adipocytes, fat cells. If you're hyperinsulinemic, you have high insulin that's sending a signal to the fat cells to store a lot of fat. And so people who are insulin resistant and are hyperinsulinemic, they're going to be the ones that respond more poorly to dietary carbohydrates with fluctuations in glucose and also fluctuations in insulin where by, you know, when you eat, you eating, you know, there's energy in food and that energy needs to be partitioned somewhere. And actually a large part of obesity, at least one school of thought is that obesity is driven by maladaptive fuel partitioning, at least over the long term where like, look, I take in some energy, let's say I overfeed, And say I have my maintenance calories, right? And then I just eat an extra 1,000 calories. We know there's— excuse me. We know there's a lot of heterogeneity in how people respond. Some people will gain next to no weight and some people will just pack on the pounds. We know people in our lives that are in both camps. Well, what differentiates them? One way to think about it is fuel partitioning, which can be driven in part by insulin resistance. And if you're someone who takes that excess energy and partitions it into fat, what ends up happening is your fat cells expand, and then downstream of that, you get hungrier to make up for that, quote, "energy deficit," and you have decreased energy expenditure. So, the calorie balance kind of follows maladaptive fuel partitioning that occurs with insulin resistance. And you can see how that sets up a terrible vicious cycle, because let's say that happens. Let's say you eat, you eat a little bit extra, and those extra calories go into fat because you're insulin resistant and it's fuel partitioning into fat cells. Then you get hungrier and more tired, so you're spending less energy. So you're hungrier and you're gonna have a snack. What do you end up snacking on? Probably not hard-boiled eggs or sardines. You're probably gonna go for the cake or the potato chips or something else that's gonna spike your insulin, and your insulin-resistant state is also gonna further promote packing that excess energy back into fat cells. So you get this vicious cycle whereby the fattening, the adipocytes growing, drives binging, and then you binge on things that cause adipocyte growth, and round and round it goes. Versus, you know, the, the converse of that is if you're insulin sensitive, then, you know, you overeat, fuel gets partitioned into excess energy expenditure, and the whole cycle never really gets started in the first place. And you then maybe have an ability to make better food choices if you're not being driven by this hormonal hunger the whole time. So I think, you know, understanding that helps people maybe begin to break the cycle by making informed choices with respect to what they eat, rather focusing on what's going to promote better fuel partitioning, healthy metabolism in the long term, which is going to set you up for long-term success versus where a lot of people's minds are focused, which is trying to like, you know, restrict energy in the short term, which ultimately leads to, you know, metabolic and behavioral failure. And then you end up in a learned helplessness place where you're upset that you can't lose weight and you think your metabolism is broken when it's not. It's just that proper education has been provided, and where people are putting their efforts might not yield the biggest bang for their buck. It might even be hurting them.

Well, let's get really nuanced into the practical steps out of insulin resistance when it comes to diet. You talked about how likely somebody in that position, when they get hungry, is going to opt for chips or something that's going to re-spike insulin and glucose. Yeah. If somebody is overweight, insulin resistant right now, and, and they're eating a standard type diet What are the first steps dietary-wise you'd recommend to somebody to work back out of that?

I mean, I think it depends on you to meet someone where they are. So I do think that there is a particular metabolic advantage to carbohydrate restriction. I'm not gonna say it's the only diet to improve insulin resistance and, and promote weight loss, but you know, um, in terms of efficacy, even controlled for calories, low carbohydrate diets do appear to have a metabolic advantage. This has been shown in randomized controlled trials in metabolic syndrome, again, even matched for calories. So there's an advantage there and it makes sense, right? Based on basic physiology. You know, if you're eating fewer carbohydrates, then you are going to tend to have more stable blood sugar, more stable insulin, and you're gonna get less of the signal to that fat cell to store the fat. Okay? Which makes sense. And again, it is consistent with human literature where people who trade carb calories for fat calories, their energy expenditure tends to go up even when calories are matched. Metabolic syndrome appears to be reversed. And in reanalysis of popular other, you know, large randomized controlled trials like the DiETFITS analysis, when you look back at that, what you find is that the people who benefited the most from carbohydrate restriction were indeed those people who were more insulin resistant at baseline. That doesn't mean there might be a metabolic advantage in other people as well. So I'm pretty insulin sensitive. Might I have a little advantage? Perhaps. But if I were insulin resistant, the delta would be a lot bigger. So I think if you're someone who has insulin resistance, metabolic syndrome, obesity, you're going to be the person who benefits the most from some degree of— let's not even call it carbohydrate restriction, let's call it glycemic load restriction, because that's really what you're targeting. You're trying to keep your blood sugar more stable. So one could argue, you know, incorporation of fiber is gonna help with that as well. And technically fiber is a, you know, carbohydrate. And I'm not gonna say fearmonger about certain things like say some wild blueberries or some cauliflower. I don't think that's by any means, any way, shape, or form bad for you. But staying away from the pastas, the cereals, the grains and stuff like that will probably yield some positive results. So I'd say start there. But in starting there, I think in order to optimize for success, there's some things you have to get in place first, which is a supportive community, resources you're going to turn to, and thinking about how you're going to construct your environment to enable success. Because if you're living in a household or a living situation where you're inundated with candies and sugars and cereals in your kind of Achilles heel food, and also around people and in a social group who are going to be pushing these on you, I will tell you it's going to be very, very difficult to succeed. Because the hardest part I think for carb— about carbohydrate restriction for most people is peer pressure. Especially once you've adapted to these diets, they're really pleasant. Look, I don't miss bread or any carbs whatsoever, but I will still say even now after being keto for 5 years, there are those awkward social moments where people are gonna be pushing carbohydrates on you or pushing, you know, let's be more concrete and specific with like the unhealthy carbs, candy, sugar, sweets. And I think just priming yourself that those are gonna be real legitimate hard situations and you're gonna have to decide in this moment, am I prioritizing my health or not? And I'm like, I can't tell you what to do. I just like priming yourself for that. Will enable you to be more successful with the actual dietary intervention. So that's my spiel about starting carbohydrate restriction. In addition to that, other ways to lower your insulin and help treat insulin resistance, um, will be things like intermittent fasting could be helpful. And obviously the bread and butter, um, pun intended, things like getting proper sleep and getting exercise, uh, and stress reduction are always important. Although I realize, especially as a medical student, stress reduction always isn't like isn't always possible. So I feel a little bit hypocritical saying those things because you can't always hit everything perfectly, but those are the high-level things I think about.

If you're enjoying this episode, take a second and let me know by clicking like and subscribe below. Thank you so much. And now back to the show. I wanna come back to the piece of finding that community and creating that environment at home where you're not gonna be tempted by sugar and snacks. If you're doing this from a place of being metabolically unhealthy and maybe you're part of a family of 4 or 5 and everybody else is still living and eating that way you were before, what you're saying makes good sense, but in a practical sense, how have you seen that work for people where the family isn't necessarily on board yet with changing the food environment and even understanding where you're coming out with this change to support you psychologically as you evolve?

I mean, I think outwardly, in, in terms of words spoken, typically families tend to be pretty supportive if you just give a rationale. No matter who you are in the family, it's like, it's your family. Your family and your closest friends should love and support you. Um, however, there's always going to be kind of the subliminal messaging just because food is, for a lot of communities and families, love. So it's gonna be like continuously on offer and you just kind of prime yourself, brace yourself for moments of awkwardness, moments of even guilt to an extent. Like if I go, let's say my mom didn't, you know, wasn't aware I was keto and I was just starting off on the journey and I go home for a weekend and she makes my, you know, historic favorite dessert or like a pecan pie, or let's say you go to your grandma's house and your grandma makes you a pecan pie and she knows you love it. To like refuse that from a family member, it seems like you're rejecting their love. So figuring out based on how you know the people around you, what wording is going to be the best to be, you know, project a polite refusal or, you know, engaging in some degree of prophylaxis and priming people. It's like, look, give me some grace for the next X amount of time. I'm trying this thing. Here's why I'm trying it. I'd really appreciate your support in the form of not only verbal support, but just being mindful of the environment you create around me and the pressures you put on me, because I really want to succeed. I know you want me to succeed for my health. Um, and so I'm just asking you to like think about that and help me along this journey. Now, beyond that, I think The practicalities fall upon where you are in that family and friend dynamic. So for example, if you're the person who cooks all the meals, it's a little bit easier because you're cooking the meals, right? You can kind of control what other people are eating and/or make something for yourself in the meantime, or make something that like could have a side that is, you know, for the group. So let's say I was making like a Thanksgiving-style dinner I cook for my family. And let's say the rest of my family wasn't low carb, they are, but I could do, you know, like turkey and mashed cauliflower and candied yams. And then I could have the turkey and the mashed cauliflower, which is low carb, and just not serve myself the candied yams. But everybody else that could have that could have that. So, if you cook, it's a little bit easier. If you're not the cook, it becomes a little bit more complicated because then you basically have to become the cook or find a way to prepare it for yourself, unless you're going to put it on someone else to prepare food for you. Again, that's just navigating the practicalities. It could be that you have meals prepped and you just eat something different than everybody else at meal times. And that's fine if you're fine with that. But I think, you know, I can't tell you the solution in your group. What I would say is having a plan is important. Communicating that plan to people who you want to be your support network is also important. And if you don't have anybody you know, in your social network that's doing this with you, finding online communities, there are tons now on your preferred social media platform to encourage you and be your kind of accountability buddies, I think can be very, very helpful. I've been really taken by the extent to which like somebody on, you know, Twitter will just be posting about their journey. They'll be like, you know, this is the workout I just did, or here's a picture of what I just ate. And the community will tend to come around them and say, good for you, like you're doing awesome, or You know, if they slip a moment and are transparent about that, generally people will be like, "Look, it's all right. Like, you're doing so great. Like, get back on the horse," et cetera, et cetera. Those messages I think can be really powerful for people. So figure out who your accountability team is gonna be, make a plan, all of that. And I think that optimizes one's chances for success.

When somebody is new to this and they're beginning the dietary switch, and they're not metabolically flexible at that point, how do you recommend they get from A to B? Would you recommend more of a lower the carbs a certain percentage on a weekly basis to gain that metabolic flexibility, or how do you feel about somebody going cold turkey if they're on a standard type diet and just really cutting the carbs down right away?

I think it depends on who you are. I, I've seen it work both ways. Um, actually, when I started a ketogenic diet, it was funny. I tried going low carb first for a couple days. I'm like, "I'm gonna get my carbs below 100." I tried it for 3 days and I could not do it. And then I decided, "You know what? I'm gonna go below 10." And it was so much easier. For me, it was so much easier because I'm an all or nothing kind of person. You know what I mean? Some people are like that. Other people kind of need to titrate in. So it really is just how you work. There could be something to easing into it for obvious reasons. There could be something to going cold turkey because then you kind of, you know, we talked about that cycle earlier. You might remove the stimulus for that cycle so you don't kind of, you know, throw the match at the kindling, so to speak, with respect to your sugar appetite. Are you someone, if they have a little bit of sweet, if you're saying, "I'm gonna like titrate down," but they know if they have that Pringle or they, I guess that's not sweet, but if they have like, You're not gonna just eat the one Oreo cookie. So are you a person that can actually eat one Oreo cookie, or is it gonna be easier for you to say, "I'm committing to cutting out this group entirely," acknowledging that there might be an adaptation period that's not comfortable, but the grass could be greener on the other side? So again, bracing for that, being like, "Look, if I'm gonna try this, I'm gonna give it a full 6-week trial. I realize it might be a little bit uncomfortable during adaptation." but I'm going to kind of, quote, trust the process and hope it gets better. Actually, there's really interesting mouse data on fasting and amygdala activity. The amygdala is the fight or flight region of the brain, and they've done these experiments in mice where they measure amygdala activity. Specifically, I'm saying mice because while you can do some degree of measurements via like fMRI, they're actually looking for early gene expression, which requires decapitation and brain staining. So you're not going to do that in humans. That aside, When they introduce, say, food restriction to mice for 24 hours, there's this massive jump in amygdala activity, like a threefold jump. But if they then habituate them to fasting and then expose them to the same food restriction, so no food, say, for 24 hours, that which was a threefold jump in amygdala activity drops to zero. The reason I bring this up is because your brain will rewire and adapt, and your metabolism will rewire and adapt not to have that unplugged unpleasant stress response. And you can shift from being someone who's like, "I can't imagine fasting. That sounds so terrible. I can't imagine going 18 hours without food or 20 hours or, God forbid, 24 hours without food," to being someone who actually enjoys it. I definitely used to be someone like, "I'm going to eat 6, 7 times a day." And now if you told me like, "Nick, you had to eat 3 meals a day every day," I'd be like, "Ugh, that sounds so unpleasant." There's something very liberating once you can listen to your body's actual nutritional hunger. Then you just eat when you're hungry, you don't eat when you're not hungry. It becomes very liberating because then you're not tied down to eating all the time. And when you do eat, you can basically indulge and trust that your body is gonna handle things. That's kind of more advanced. I'd say that's when you can really trust your body to, quote, eat intuitively, which is kind of a funny term because we hear it all the time. And I think it's abused because it's like, eat intuitively. For most people who are metabolically unhealthy, their, quote, intuition is gonna tell them to eat junk. You can only truly eat intuitively when you're metabolically healthy and your true hunger for nutrition, like nutrition for your body, isn't being obscured by a hormonal rollercoaster driving pseudo-hunger. So I am for intuitive eating, but real intuitive eating, not virtue signaling YOLO intuitive eating.

Another layer on all this as you talk about that is the fact that we've been told to eat 6 times a day and that's actually good for our metabolism. So people that are actually trying to work with their metabolism and make conscious choices can go astray following conventional advice.

It's unbelievable to me— well, actually, it's believable, but unbelievable in the vernacular— the degree to which these myths get perpetuated and the degree to which authorities or self-proclaimed authorities speak about them with confidence without ever digging in to the basis for what are effectively myths. And I'm thinking about like one recent episode in particular where I was sitting in, let's say, um, a graduate level course on nutrition. Was not my favorite course. You probably can tell my eyes rolling, but where an instructor literally said that breakfast is the match that starts your metabolism and you're going to have metabolic damage, metabolic slowing if you don't eat breakfast. And, you know, in the room, I was probably one of the more informed students in that role on metabolism. But even those who had no background in metabolism kind of looked around and rolled their eyes a little bit. And nevertheless, And instructor was comfortable saying that as if it were metabolic fact when it's nonsense. It's made up. What do you mean breakfast is the match that starts your metabolism? So if I don't eat breakfast, I don't eat for 24 hours or whatever, my mitochondria are just going to go, "I give up. I give up. No more energy." Like, it's ridiculous, but it enters the common knowledge base and then just gets perpetuated as its own meme. Without any interrogation of the underlying data. So we have a lot of these myths that they do just like have their own life and it is, it is the definition of a meme. So anyway, I guess I don't like the term do your own research because I feel like it gives license for actually disregarding real data. But in this respect, at least question when you hear a bit of common knowledge What's the evidence base for this? Is it something that is legit or are people just blowing smoke because this has now entered into the zeitgeist?

Well, the 6 meals a day is one extreme.

Yeah.

But for somebody that is cutting back to say 1 meal a day or they're having multiple meals a day, say even 2 or 3 meals, but they're really bringing calories down, is there any merit to that quote-unquote breaking of the metabolism if we're really bringing calories down or we get hardcore into fasting and go to one meal a day or beyond?

I think with caloric restriction, yes. Not with fasting that isn't, you know, forcibly calorically restricted. With the whole one meal a day thing or longer fast, I'd say that's very individual. One, do you enjoy it? I don't think that there are big benefits to being a one meal a day person, say, versus being someone who eats in like an 8-hour window. With 2 meals a day or even 3. So, if it's pleasant for you and you can tolerate it, fine. But I don't think you're going to get this huge metabolic advantage from being a one meal a day person. Also, at least for me and just speaking from my own experience, one meal a day is really hard because it just causes stomachaches. The amount you have to eat if you're eating one meal a day and the fact that if you fast, right, your body gets— it's good for your GI tract to have a little bit of time when the highway of the GI tract isn't being, you know, Let's say there's not a lot of traffic on it. It gives time for repair. You can think about it like that. But systems in the gut do get downregulated and they take a little bit of time to get back online. So, if you're only eating once every 24 hours and you're throwing a huge bolus onto a GI system that isn't ready, it's a formula for GI upset. So, I find one meal a day quite unpleasant. Some people really love it. If you do, then great. If you tolerate it, then great. I just put out there, there is an art to breaking a fast. This isn't necessarily the thing we're going to dig into today, but just be mindful of that, that it might end up being really unpleasant if you're just like eating one huge meal. Also, if you're someone who would tend to like then make poor dietary choices during that one meal, I see that happen as well. So, I don't practice it. I think it's fine if people do. I don't think it's necessarily going to cause metabolic damage. Forced caloric restriction can cause metabolic damage, um, particularly yo-yo dieting for several reasons. Um, one thing it can do is, um, place an obesogenic fingerprint on your microbiome. So if you restrict energy, um, there can be changes in a lot of things in your body, but including in your microbiome and your microbiome kind of learns to become more frugal with the energy it's provided. And better at extracting energy. And the thing is, once you refeed, this obesogenic fingerprint— now I'm drawing mostly from preclinical trials at this point in time, but it does definitely line up with the human data. I think about the Biggest Loser trials— the obesogenic fingerprint remains. And so you kind of get like this staircase function, right? It's one way to think about it. Maybe it's the fearmongering way to think about it, but nevertheless, where you restrict, your body then has a change to be better at extracting calories. From your microbiome. You probably have more fuel partitioning in fat rather than lean tissue. And then you eventually break, you refeed, and even though you've gained the weight back, it doesn't reverse the obesogenic fingerprint. And now you're set up for, you know, being a little bit more behind the eight ball going forward. I will say I don't think it's just a, you know, upward stepwise function. Like if you've yo-yo dieted in the past, it doesn't mean you're doomed. These things are dynamic enough that they can readjust. And I've seen people's basal metabolic rates, or let's say, daily energy expenditure skyrocket with refeeding. There's mixed data on, you know, the size of the effect, but, you know, some RCTs like the Framingham Feeding Trial, I think it was somewhere on the order of 200+ calories with a carbohydrate-restricted diet at 20% kcal from carbs versus 60% kcal from carbs. I'm pretty sure that was it. Um, and in RCT, that was kind of like weight loss. So they were looking at energy expenditure, um, by virtue of like what you need to maintain a certain weight, swapping out calories anyway. So there was an advantage, but what I'll say is that has a lot of heterogeneity. So I've seen some people's metabolic rates, if they've been calorically restricted, upon refeeding, jump tremendously such that you get these paradoxical results where Someone might be restricting to 1,200 calories and have still a little bit of a muffin top, and they feed up to 2,000, 2,200 calories, even with an immediate change without titration, and they end up losing weight over 3 weeks and losing body fat. That does happen. And as much as you might think, oh, the person must be lying, you know, calories in, calories out is, you know, the law of all diets, it's the be-all end-all. Pause and think that that, you know, calorie balance is more a consequence than a cause of obesity. So it's more about your body— went over this earlier— telling the energy where to go through the hormonal system. Are you storing it in fat? Are you expending it? Are you putting it into lean tissue? And so if you have a change that also favorably changes fuel partitioning, you could have massive increases in things like energy expenditure, and you could be partitioning less energy into fat tissue. So it's perfectly feasible that somebody could go from a 1,200-calorie diet to a 2,000-calorie diet, and, you know, over a short time frame from that change, actually end up losing weight, and over the long time frame as well. Um, so long answer short, you can induce metabolic damage with caloric restriction, it can be recovered. Although the cycle of yo-yo dieting where you just focus on restricting calories and you break and you go back to restricting calories generally will put you behind the 8-ball and make it harder and harder to lose weight until you get that metabolic reset.

As you were talking about calories there, brought up for me an experiment you did where you had 4.5 pounds of butter in a week.

Yeah.

And actually lost weight.

Yeah.

So I think talking about this is a good way to illustrate the calorie piece and how it's just a portion of that story when it comes to weight loss, weight gain.

Yeah, I mean, I'm in here— it was, it was interesting. It was actually part of a cholesterol demonstration experiment that kind of flopped because I went to get the final labs and the lab just didn't draw the right labs, so I didn't have any final data. But the intent was actually to gain weight, but specifically gain weight on a ketogenic diet by overfeeding saturated fat rich source, butter. So I ended up eating well over 4,000 calories per day, which is higher than my normal intake, primarily by just slamming lots of butter. I ate over 4.5 pounds of butter in that week. And I ended up losing weight, which I think demonstrates a few things. One, people have different responses to overfeeding. I am not generalizing that as a response. I do not think the average person would lose weight by just adding butter to their diet. But the data show there's huge heterogeneity in terms of how people respond to overfeeding. A large part of it might be that fuel partitioning directs more energy in some people to non-exercise activity thermogenesis. This was even shown, variations in fat gain with non-exercise activity thermogenesis, I think in 1999 in Phillips et al. You can look that up. But basically, you know, if I overfeed, What happens? My body temperature goes up, I get really jittery, I bounce around, and I just expend that energy for the most part. Maybe I even overcompensate, which is why maybe my weight dropped. Let's call it— it was a small drop, so let's even call it no weight gain. But still, there's variations, and I'm at one extreme. Not everybody is at that extreme. But stop and think about that. Think about, like, if we can say that the calories in, calories out model is so profoundly inaccurate, say using like a Harris-Benedict calculator to get your basal metabolic rate, add on an activity factor, that some people could overfeed and not really gain any weight and other people could overfeed and gain much more weight than predicted, then what is the utility of that tool? The only reason calories, well, not the only reason, but let's say, post-hoc rationalization that exists that maintains calories in the psyche of people is you can always after the fact say something like, oh well, it's still calories in, calories out, because, oh, your body compensated and you burned more energy, or, oh, you didn't absorb it. Sure, but then you're putting, you know, that downstream. It's not a cause, it's a consequence. So just saying calories doesn't Calories don't cause obesity, which I maintain calories do not cause obesity, is not saying thermodynamics doesn't apply. It's just placing energy balance downstream of fuel partitioning and, you know, how your body's hormones direct the energy you take in, which is why I overfed Butter and didn't gain weight. So that was one takeaway from that. There are others as well, like the fact that acute interventions don't necessarily translate to chronic interventions. But yeah, no, I did do that. I ended up replicating it with an even higher feeding paradigm at 6,300-ish calories per day. And my estimated weight gain should have been 7 pounds over the period I was feeding. I did gain weight, but I only gained 0.7 pounds. So again, prediction of the calories in, calories out model wasn't that great. Post hoc, you could say, yeah, Nick, you just burn more energy. And I'm like, all right, fine. Give me something useful. And why? Ask why. Like, why is my body burning more energy? And how can we leverage understanding of that physiology in order to actually help people?

All right, I want to come back high level on all this and, and come back to our thesis here of that metabolically unhealthy person. Putting some of these pieces together that we've discussed here so far, it sounds like we want to lower the carbs Calories aren't so much something we need to factor in. Intermittent fasting could be a good tool to implement as well.

Yeah.

When it comes to carbs, for you, you're ketogenic and you're a proponent of the ketogenic diet, but how low-carb does somebody need to go? And if it is all the way to ketogenic, is there specific parts of being in ketosis and producing ketones that are adding benefit to regaining metabolic health?

I would say first, again, it depends on your use case. Ketogenic diets can be very helpful for particular disorders. So maybe ketones can be beneficial in— for me, I think it's inflammatory bowel disease that ketones actually do provide some degree of benefit in addition with an elimination factor. If you have a mental health disorder or, um, you know, an inflammatory autoimmune disorder or epilepsy Yeah, you might want to go full ketogenic diet, which might mean below 25, 20 grams of carbs per day. But if your goal is to reduce, you know, your insulin area under the curve and you're using this for weight loss and say metabolic syndrome, there's no particular threshold, you know what I mean? I can come up with different amounts. I can say 20% of your, you know, caloric intake. I could say less than 10% or less than, you know, 130, you know, you know, grams of carbs per day. It's all arbitrary. We like, as people, as humans who are trying to organize the world, to create categories in everything, especially in medicine and diet, where we say like, here are the criteria for this disease. Here's the threshold for diabetes, an HbA1c of 6.5%. The fact of the matter is your physiology does not care about the cut points we create. So I could tell you 50 grams of carbs. Does that mean you lose if you eat 51? No. It's just an arbitrary threshold. So, it really depends on a lot of factors like your activity level, your muscle mass, the more muscle you have, the more carbs you're going to sink, your, you know, total energy needs, stuff like that. That all aside, if you want a threshold for I think somewhere to start, low carb is typically considered less than 120-ish grams per day or less than 20% of your energy needs. And keto is more like less than 5% or less than 10% of your energy needs or less than 25 or 50 grams per day depending on different sources you read. So, those are some numbers you can think about.

I agree with you on the arbitrary nature of this. I just think it's important given the complexity within the nutrition world these days, even for somebody who is going in and doing the research and trying to learn for them and their family where there's so much conflicting information. And if somebody is metabolically unhealthy, they're gonna be tired, they're likely busy and maybe have all kinds of different obligations. We're all busy in the modern world. I wanna try and guide and handhold people best I can to starting to at least regain some metabolic health, regain some energy, start feeling better, looking better, and then they can come in, and experiment more over time and look at this more as a long-term individual experiment. But I just feel for people with the amount of information and the amount of conflicting information and, and again, coming to our conventional information of having multiple snacks a day and breakfast being the most important. And there's just so much out there. We need to really give people that guidance to get the ball rolling.

I agree. And this is somewhere where I do struggle because, you know, you ask a question, you've asked lots of good questions, and I know I have a tendency to not give a very direct answer. I could have just said 50 grams of carbs, and a lot of people will. And I think a lot of people are looking for those simple answers. My issue is I think a lot of the polarization and confusion and, um, you know, negative discourse on social media derives from people being a little bit, or influencers being very absolute, in part because it sells, because people will like to be told at some level what to do. I don't know how well that served us. So I'm more interested in telling people or teaching people how to think. So when you ask those questions and I'm like, look, here are some variables that you should consider in your own life context to understand what your needs might be. That's just the way I go about operating. It's the way I've kind of defaulted to. It probably has stunted my growth as a public voice. However, I think it's something that is missing a little bit too much, um, that, that nuanced element. And I realize different people are looking for different things. So if I'm not the kind of communicator you like, that's fine. But I do try to resist as best I can giving a threshold or an explicit direction without first explaining the rationale and caveats. And then after all that, if you want me to say a good place to start is X, 50 grams of carbs, then we can try that. But I want you to understand, listener, that I'm doing that rather arbitrarily, as is everybody else in the diet nutrition space. They just might not have the preamble to that point where they give you the relatively arbitrary recommendation.

That all makes sense. And as we go through this, as I think about what I'm trying to construct with you and create for people, it's It's to go into the weeds and the science and try and push people a bit to learn something new, and then to try and myself, or have you summarize it in a way that people can understand better and be practical with, and then to give people that starting point in the practical realm so they can have takeaways at the end of this to apply and build that momentum in their life.

I mean, a lot of it is just, yeah, somebody starts their journey and they're going to go to a bunch of different resources and listen to things. And they're only going to be a subset of things that stick in their brain that like when they're then later like driving or laying in bed at night, they're just thinking about this thing. So it's worth getting on and communicating things in many different ways because you never know what's going to stick for an individual. Um, so I kind of have fun with it and it's cool. Social media and getting on podcasts, it's good. Landing ground to test what resonates with people. I'm actually stealing that from Neil deGrasse Tyson. He was once interviewed and asked, you know, why he goes on Twitter. He's somebody who's pretty nuanced, pretty, you know, articulate. Why would he put out like one or two sentence tweets? And he's like, because as a communicator, it actually gives me a lot of data to say, like, figure out what words are going to hit. What words are going to resonate with people like on an emotional level and then get them to think intellectually? So I think that's an interesting way to frame what we try to do on different communication platforms, which can sometimes mean being provocative. Like I can give you a 5-hour lecture or 5-hour podcast, actually just dropped a 5-hour podcast with Simon Hill on lipids. I can also drop 6 seconds of being snarky about a Joe Rogan clip where he says calories aren't the problem, brother. It's sugar and bullshit, which I did. And yes, it gets 400-ish thousand views on Instagram. It's pretty easy to figure out what will resonate with people, but juxtaposing those things and figuring out how you can leverage the one, the short provocative things to, you know, suck people into the more nuanced content that's actually going to help them if they're willing to take the time and listen to it is kind of what the art of being a communicator is, I guess, in this space. So it's something I'm having fun figuring out.

I want to talk about carbs in the realm of sugar versus starches. We've been talking about carbs, you know, as a whole and bringing them down. We could put sugar in its own category, processed sugar, and, you know, being a human, all of us are going to have interactions with that at times, whether we partake or not, that's a different answer. But when it comes to, say, like white rice versus fruits and these different molecules under that heading of carbohydrates, let's talk about how you differentiate those, if at all, when we're looking at carbohydrates and bringing those down.

Right. The first thing I'll say is you definitely can reduce it into various categories and molecules that have different effects. So I can tell you about the metabolic effects or the glycemic index of something like sucrose, which is a disaccharide made of glucose and fructose. And we can talk about glucose and how it hits the bloodstream really quickly and will spike your blood sugar, about fructose. And fructose has some really interesting unique metabolic properties promoting de novo lipogenesis, the generation of new fat, despite the fact that it has a lower glycemic index, yada yada yada. I'm throwing out a lot of jargon there intentionally to point out We can dissect, and I'm very happy to, the metabolic impacts of different forms of carbohydrates. However, when we do that, I think sometimes we risk taking them out of the context of the foods that they're consumed as a part of, and that context really matters. So if I tell you something about fructose, and I do this routinely, talk about that, you know, as an abstraction, I want people to understand it's not necessarily saying something bad about blueberries, which have some fructose, not actually that much, but also many other compounds that will impact their overall impact on metabolic health. But with that said, high level, I would say you have your starches, which are things like potatoes, pastas, cereals, grains, rice. Which are kind of chains of glucose. Starch is the storage form of glucose in plants, just like glycogen is in humans. And so that gets broken down into simpler sugars. Um, it can get broken down pretty fast in some cases. So just because it's more complex doesn't mean it's not going to be broken down fast into simple sugars. And then you have the simpler sugars, things like, you know, lactose and sucrose are disaccharides, you have monosaccharides, which means single sugar like glucose and fructose and galactose. And very basically, things that are sweeter have simpler sugars provided you don't have non-nutritive sweeteners. So, you know, we can think in a category as well. What's sweeter, a ripe banana or a not ripe banana? A ripe banana sweeter. Why? Because actually it has more sugar. Um, or let's say take papaya and mango and contrast that to blueberries. Blueberries are not nearly as sweet. Why? They have less simple sugar. They have less sweet sugar. So as a general rule of thumb, things that are sweeter are gonna have more simple sugar. And again, as a general rule of thumb, these things are gonna hit the bloodstream faster. And all things being equal, which they aren't necessarily, they're gonna have a harder impact on your metabolic health. I'll pause there.

No, I mean, that's— this is what I'm looking at, just getting into some of the nuance here and how people— again, I'm gonna pull you back to the practical. Given that, is there anything on a practical level we need to consider when taking in these different foods, when we're extrapolating to our carbohydrates as a whole throughout a day or a week?

I think rule number one is generally eat real food, real whole food. The processing of carbs in particular generally will impact their glycemic index, how fast they hit the bloodstream. In fact, it's interesting, people talk about like, oh, ultra-processed foods are bad, yada yada yada, which I think As a heuristic, they are. When we investigate, well, what does that actually mean and why are they bad metabolically? Processing of fats and proteins doesn't necessarily cause adverse metabolic effects per se. I mean, olive oil is a processed fat, for example. Processing of carbohydrates tends to make them hit the blood sugar a little bit harder. So I think eating carbohydrates that are from whole foods is step number one. Then I think focusing more on like low-carb vegetables that are higher in fiber, all things being equal, even if the fiber is a proxy for a lower glycemic index, is useful. These things tend to be lower in overall carbs too. So if you think about like a side dish, I mentioned that mashed cauliflower earlier, like a big head of cauliflower or broccoli, there are some carbs there, but the carbohydrate load and the glycemic load are very low.. So I would definitely choose, say, having a head of roasted cauliflower. Maybe you can partially boil it, then you roast it, put on some like, you know, curry seasonings can be really nice as compared to something like candied yams. So focusing on low-carb vegetables, I think in the category of fruits, if you're gonna have fruits, the lowest glycemic load, the ones that hit your blood sugar the slowest and the least tend to be berries. Strawberries, raspberries, blueberries, especially wild blueberries, blackberries, whatever. Berries are typically pretty good as compared to tropical fruits. Bananas, papaya, um, watermelon, they tend to have very high glycemic indices, hit the blood sugar a lot harder. Doesn't mean you can't ever have them. It just means, you know, that mango and that blueberry are not equivalent metabolically speaking. The mango's gonna probably hit you harder if you have insulin resistance and metabolic dysfunction. So, you know, it's making those informed trades. If you're gonna have fruit, what fruit it's gonna be. And I would say generally blueberries will be a good option and citrus fruits as well, or berries in general and citrus fruits. In the category of more starchy-like foods, you can get some that are higher, if you're gonna consume these, higher in protein and fiber, things like quinoa, if you can make quinoa actually taste good, I'm not a particular fan. Or like things like lentil and legume-based carbohydrate substitutes like, like a lentil pasta or red lentil pasta you could do. There are also substitutes that are very low carb like shirataki noodles, which are made from like glucomannan fiber. Warning, they cause constipation in people predisposed to constipation. So if I ate them, I'd be clogged up for a while. But that's in part because they basically just soluble fiber. So they're gonna sop up water, they're gonna slow your digestive tract, which is gonna probably keep you fuller for longer. So if you're not worried about constipation, you wanna eat something that is carb-like, look up shirataki noodle keto stir-fry, and you'll learn how to make a great stir-fry with shirataki noodles, maybe various vegetables, chicken, that could be absolutely delicious and be a practical swap for you on a carbohydrate-restricted diet journey. There are lots of tips and tricks and things you can discover in this space once you go digging, including just changing the way you cook a particular food. So you can cook sweet potatoes in a way that optimizes, say, the resistant starch, which lowers the glycemic load, or even just focusing on, let's say, I'm going to, you know, boil this or steam it versus bake it. So like a baked sweet potato has a much higher glycemic load than a boiled sweet potato. You can actually kind of tell. Imagine baking a sweet potato. I don't know if you ever have it. You know how like it caramelizes and the juices come out and it has a really sweet flavor if you put it in the oven in tin foil? If you boil it, it doesn't have that. Those are metabolically distinct. Even though it's the same potato, you might have cooked it for the same time, they're going to have different impacts on your metabolism. So there's lots of levels here. And the reason I want to highlight all the levels, maybe there's some practicals that have been sprinkled in here, but there's always things to be curious about and tweak and learn. So you might be someone like me who likes to be all or nothing and wants to just go like, say, even full carnivore diet and just eat meat and eggs for a while. But if you're not that person, or even if you were that person and now you're trying to reintroduce carbohydrates, the fact that there are an infinite number of things to tweak and see if they work for you I think is pretty exciting and provides the basis for infinite hope and self-exploration, which if you can find the fun in that, like that is the key to success.

Let's take some time and go deeper into the carnivore piece. Let's talk about how— because this fits nicely into everything we've talked about so far and you've gotten into fiber a little bit and obviously low-carb's been a general theme of the conversation. Why not go all the way to no carb, only meat, only animal products? And I want to talk about that in a short-term sense and then longer term.

Again, I think the first question you have to ask yourself is, what am I optimizing for? I think if you're someone— actually, I'll just first say, I think carnivore diets are understudied and have therapeutic applications or probably have therapeutic applications in particular disease states. I know of lots of like clinical cases of people with severe treatment-resistant autoimmune and inflammatory disorders, including inflammatory bowel disease. We actually have one retrospective case series with some pretty impressive cases, um, in, in, uh, review right now, but where a complete elimination carnivore diet probably is tremendously therapeutic. Maybe where nothing else is, in part because of the ketosis induced, in part because of the elimination of things that could be irritants. And so if you're someone with Crohn's disease or ulcerative colitis or various autoimmune disorders, psoriasis even, um, this could be beneficial for treatment, therapeutic treatment of that disorder. Now I wanna be very clear, I wouldn't extrapolate from this This is the best diet, you know, this is the optimal primal human diet. I don't think that's the case. I think we evolved as omnivores. And my issue with discussion around the carnivore diet is that one of the things that keeps it fringe and hinders research on it is that people tend to get very evangelical about it and make claims like it is the optimal human diet. Uh, that claim is not supported by the literature, nor are claims like it'll improve longevity. That's not one you really hear a lot about, but like, I think people try to jump from like, somebody's recommending this diet for X, say I use it for inflammatory bowel disease, then they intuit for some reason that I believe it's a great diet for longevity. And it's like, well, how could you possibly argue that this promotes longevity? I'm like, I never said that. I'm not talking about that as the use case. So again, this works best when we caveat and target and are precise with our language, I would say carnivore diet potentially therapeutic for particular use cases acutely, probably will help a lot of people lose weight, probably will help with particular disease conditions. Long term, I will be skeptical or concerned about potential impacts on the microbiome, and I would not argue it's optimal for longevity. Um, speaking about the microbiome in particular, microbiome science is really messy. I don't think a lot of it's very solid. Speaking at a high level though, we are metaorganisms. What I mean by that is you have your human cells, you have many more microbe cells in you, and the composite there is the human microbiome metaorganism. And your microbiome massively influences your health.. And in general, more diverse ecosystems tend to be more resilient. I'm not just talking about the human body. Think about a rainforest or think about, you know, a coral reef. The more diversity there, the more resilient it is to environmental insults. And what is, you know, metabolic flexibility but resilience to metabolic insults? So from that perspective, I would say Over the long course of time, if possible, eating a whole foods varied diet has logical basis for being good. But it's also true that we really don't know what a healthy microbiome looks like other than the microbiome of a healthy person. And because of the world we live in now, some people might just not have microbiomes that can handle it. I'm one of those people. You know, if I could, I would love to eat like, especially Brussels sprouts with walnuts is the example that I always bring up because they would just wreck my stomach. But like, I love them, the taste, and I think they're healthy food stuff, but my microbiome can't handle it. And people can say, oh, you just do a protocol, titrate it in. Like, yeah, easier said than done. Changing your microbiome and protocols for that are really difficult. And just because a lot of us have grown up eating standard American diets or might have other insults. So for me, I had a fever when I was a, a tiny baby, a neonate, and I got, um, intravenous antibiotics. And we know that can screw up your microbiome potentially for life. Um, I think IV antibiotics as a neonate increase your risk of ulcerative colitis, which I developed by 500% later in life. I developed that in my early 20s. So I might just have a screwed up microbiome and need a more therapeutic diet that's lower in fiber. I do tend to eat lower fiber diets. And that's me. But I can separate what I think is best for me therapeutically from what kind of might make the most sense at a population level. But I don't know what boat you're in. So that's kind of my high-level take on carnivore. I think it's fascinating. I think it deserves further study. I think it can truly help people. I don't think it's the best diet for all human beings. And that's, of course, setting aside ethical and environmental issues, which are a whole different kettle of fish. That then get wrapped into this discussion about human nutrition because people just get emotional over this topic.

So I'd like to take some time and go a bit deeper into the fiber piece as a whole in a general sense, very high level, because it seems like low-carb, carnivore, keto world, there is a group of people that say fiber is bullshit, fiber is— they would say it's detrimental to your health and we don't need it. I'm obviously paraphrasing and bringing a lot in there. But then there's the people that are, they tend to be more in the plant-based world that talk about eating diversity and coming back to what you just said, building that diverse microbiome and getting as much different types of fiber from plant material as we can to facilitate that microbiome. So again, comes back to that confusion piece where you have people saying two opposite things, where fiber is either useless or detrimental, and then other people are saying it's the greatest thing and we need to focus on that. And it sounds like you're somewhere in the middle, but just talk a little more about how you feel about that, that realm.

I'm gonna tell you how I'm gonna communicate this, and it's gonna involve a flex for a purpose. Because I want to show that I actually do think about this deeply. So for those listening, I'll give a high-level answer so everybody can follow along, and then I'll dig deep enough that I almost guarantee even your most expert PhD plant nutritionist will not have known this. Okay. High level. Some people respond to fiber well. Some people respond to fiber poorly. This has been shown. There was a trial out of, I think it was out of Stanford, including Sonnengart, I think was the, the senior author. I forget which journal it was in, a Cell or Nature Press journal. I think it was Cell Metabolism or Cell Host and Microbe. I can send you the link. It was in 2021. But basically they showed that some people, I think it was about two-thirds of people, have fiber and they have an anti-inflammatory response, but one-third of people have fiber, they have a pro-inflammatory response. So high level, people respond differently. Okay, so it might be good for some, might not be good for others. Let's keep it simple there. Now, digging in a little bit deeper, one level— I'll go even level deeper— what predicts if somebody will have a bad response to fiber? It probably is their baseline microbiome composition. So in the study I mentioned, they did also find that people that had the bad response to fiber, where they had more inflammation, also had less microbiome diversity. So that raises the question, well, is the fiber bad or do you just not have the, um, machinery in the form of microbiome to handle it? So like, is exercise bad? No, exercise is not bad. But if you've never lifted before and you go try to deadlift 400 pounds and like pull a muscle, exercise isn't bad. You just weren't ready to handle that load. So, one could argue that you need protocols to improve your microbiome health. Again, these are difficult things. But, you know, I think one could argue for making the body more resilient to fiber, even just being a litmus test for overall health if it's possible. For some people, it might not be. For me, it might not be. Now, I'll give you a specific example about how fiber could be helpful. This podcast, I guess we're not live or anything, so this will probably drop after the video is released because it's a video I have in production. On a, uh, microbe called, uh, Dysulfovibrio. But, um, I was reading a lot of the literature recently about, um, GLP-1 and GLP-1, glucagon-like peptide 1. It's the hormone that drugs like Ozempic try to mimic. Massive weight loss benefits, at least when provided exogenously at supraphysiologic doses. But what we also know is that people with insulin resistance disorders PCOS, metabolic syndrome, obesity tend to have less GLP-1. So why is that? That's an interesting question. It's not really been known, but one thing that was just discovered, um, in this paper that I'll be covering is that there is a gut bacteria called Desulfovibrio, which, um, higher levels are associated with lower levels of GLP-1, um, in mice and in humans. And they were able to show a causal pathway. Again, you need mice models to show this causality, But basically whereby Dysulfovibrio produces a lot of hydrogen sulfide as part of its metabolism, overwhelms detox systems in the gut, damages mitochondria in L-cells that make GLP-1, leading to a GLP-1 deficit. Now there are various interventions that can, that can deplete Dysulfovibrio levels by competition, in part particular fibers. So there was a randomized controlled trial in 2015 showing that inulin fiber at just 5 grams per day for 21 days could deplete desulfovibrio levels by, I think it was 42%. And so what you can see here is a picture whereby you could have this biological cascade where having fibers, the right type of fibers, and someone with metabolic syndrome who has low GLP-1 could shift the microbiome in a way to deplete levels of a microbe that are basically poisoning the cells that make GLP-1 and thereby be therapeutic. And it's been shown that higher fiber, you know, in some trials improves, you know, signs of metabolic syndrome and insulin resistance. And it hasn't been known why. I'm not saying that this is the core mechanism. I just want to highlight that the metabolic and physiologic complexity here is intense and very cool. And highly specific. But unless you're someone who actually knew what I just spewed at you, I would suggest being humble in your claims about fiber because it's a very complex and interesting field. It's one of these Dunning-Kruger things where it's like the more I learn about it, the less I feel I know. And then there are people on the internet who are like, I know the answer. And I'm like, can you spell disulfide vibrio or tell me about hydrogen sulfide metabolism and how they affect, you know, L-cells in the GI system. And it's like, we need a little bit more humility in this space, I think, especially around carnivory.

How do you feel about trying to prop that up, the gut microbiome, using probiotics, different strains, different— there's so many different types of probiotics out there now.

I would say if you have the means, it's fine to try. There are some that are more reputable. I think Seed probiotic is probably the best one I know, just because the lab it comes out of and the studies that have been done on it. But in general, the data on probiotics is not that good. So if you're going to spend money on a supplement, I would not make it a probiotic if you have a budget. If you're a multimillionaire and you want to, you know, try around with different probiotics and see if it affects you, then great. But I have not found the data on probiotics to be that compelling. I think If you want to do the best thing for your microbiome without spending a ton of money, starting with fermented foods, kimchi, natto, properly fermented pickles. If they're actually fermented, they're going to be in the refrigerator aisle, just by the way. You're not going to go get like some, you know, pickles just at the, you know, jarred pickles that aren't refrigerated. But yeah, kimchi, natto, sauerkraut, titrating those in a little bit. The data show that that can help with microbiome diversity. So you can start there. If you want to add a probiotic, I don't think most are going to hurt you, but I have not been compelled by the literature yet.

And given what you said there about fermented foods, is that something you specifically take in your diet to get the different benefits from them, or is this something you can take or leave?

Take for what?

Take or leave. Is it something that you're specific about, like, oh, I'm gonna get sauerkraut, kimchi every other day, I'm gonna incorporate some within my keto diet just so I'm getting different benefits? Or is it just more when it, when it happens, that's cool?

Different strokes for different folks. I would say you— I, I could, I could put it in the category of if you're tolerant of it, then maybe it is something you can target to optimize. I would put it in that category. I don't think there's any singular food that people need, you know, but I think there are some that are just like good. Like, I always target fatty fish in my diet. Do people need to eat fatty fish to survive? No. I think they should eat them. Fermented foods is in that same category, whereas like if you already kind of like it and you would enjoy it, like you'd enjoy some like good sauerkraut, um, on like, you know, your burger, get it. You know, I, I do think it's far more likely to have benefit than harm, but if you don't like it, then don't eat it. Don't like force sauerkraut down your throat. Um, so, and then things like kefir, I really like making blends with, what is it, Red Mill Farms goat milk kefir. I prefer A2 Dairy. They don't sponsor me. Like I haven't mentioned any like sponsors or anything in this. It's just like the brands I would use. And so I might have some of that kefir with my breakfast. Maybe I'm having like smoked salmon and eggs and I'll just have a glass of kefir.

Trying to get at though, are you having that for specific benefits or you just like the kefir?

I would say I would have it for specific benefits. I think it's worth going out of one's way to consume fermented foods if you like them, all things being equal. If you don't, you don't need them, but I would say that they're probably worth targeting in a diet.

Got it. That's what I was getting at. And now that we're getting a bit of a tastier diet, no pun intended, with the fatty fish, the dairy, we know you're not such a big fan of the probiotics.

Yeah.

Let's talk about your diet as a whole over a day, over a week. And obviously this is going to change, but just as a general sense. And then I want to move into supplements and talk about what you think somebody, if they want to prioritize their money, would want to— what you value there.

My diet is, um, I'll emphasize my protein and fat sources because that's basically most of my diet. Protein, I eat, um, a lot of fish, a lot of sardines, a lot of salmon, um, and, uh, mackerel. So fatty fish. Um, every now and then I'll have leaner fish, um, or shellfish. I really like scallops when bought economically, shrimp, things like that. Um, for fat sources, I love extra virgin olive oil, I have a ton of it. Macadamia nuts. Now, I am sponsored by House of Macadamia, that is a partner. But they're a sponsor because I've been a macadamia nut monster ever since I went keto. They have some really interesting metabolic properties. They're a very rich source of omega-7. I won't dig into that, but I love the taste of macadamia nuts and I eat them every which way. As well as some other nuts as well. Peacans, pistachios. I do like tahini, which is pretty good. There's a lot of things you can do with tahini too in terms of dressing, like a little like garlic tahini dressing. When I do have vegetables, like over a little bit of eggplant or zucchini, I don't eat a ton of vegetables. Again, I'm not anti-vegetable, it's just I come from a place of having a very, very sensitive and vulnerable gut. So I operate best in my fiber intake is on the lower end just symptomatically. I don't know if it's good for my overall health, but right now I'm in a very like active and busy portion of my life and I'd prefer to spend as little time as possible in the bathroom, quite frankly. So that's my rationale for that. Not making any claims about longevity, just saying this is what I do and why. Oh, I missed eggs. I eat a lot of eggs. Greek yogurt, Faye, 5%. I'll often add extra fat to that in the form of olive oil, macadamia nut oil, or crushed macadamia nuts, maybe with a dash of vanilla. And, um, for fermented foods on occasion, sauerkraut, um, kefir. Um, and then beyond that, dark chocolate. I really like dark chocolate. My go-to brand is Tezo Wicked Dark. I tend to prefer 95%, but I go for Tezo. Um, sorry, I tend to prefer 100%, but they only go up to 95%. The reason I like them though is because, um, they've been tested and are low in heavy metals. And I know people have concerns about heavy metals in chocolate, about that cons— after that Consumer Reports. So they're low in cadmium and, um, lead. So because I really like chocolate, that's my go-to. Um, the ginger flavor is my favorite. Also, stone ground chocolate's crazy high in fiber for those wanting it. Like a little single bar that I'll have will have 16 grams of fiber, mostly insoluble, so it's a little bit less likely to cause bloating. So that would be a dessert for me. I very rarely eat fruit. If I do eat fruit, it would be something like a few wild blueberries, or I have a thing for cherries. You know, you get like the frozen red cherries that have been pitted. And if I ever feel— I don't usually feel like something sweet, but if I have them in the freezer, those red pitted frozen cherries, just like 3 of those maybe with some cacao nibs really sometimes hit the spot. Or if I have something sweet including cherries, blueberries, or even a little bit of honeycomb, I'll sometimes do it after a workout when my muscles are just like little sponges for sugar. If you're someone who's very active, you can do targeted carbs that way. Sometimes I find I recover better and have a better workout the subsequent day if I have, say, 30 grams, 50 grams of carbs after a hard workout. So yeah, I play with targeted carbs. And other than that, trying to think, ooh, cheese. I love cheese. Oh my God, do I love cheese. My serving size for cheese is whatever the block is. My number one cheese is Roquefort. You give me even like a kilogram of Roquefort, I probably could eat it in a sitting. Mm, manchego cheese is delicious. Goat cheese. Um, Cypress Grove Midnight Moon is one very good cheese that if you haven't tried it, you should go find. Uh, feta cheese, halloumi, fried halloumi, buffalo mozzarella. I do love cheese. I never used to like cheese, then I moved to England, and then I became a cheese snob after living there for a few years, uh, in the UK. So That are the high-level dietary intakes. I do eat chicken, I do eat red meat, I do eat pork. I just probably eat a lot more fish just because I like it. I've always liked seafood more.

So what about avocados?

Because of the high fiber load and the type of fiber, they tend to cause a little GI upset in me. So I will eat them. I think they're a great food. I wish I could eat more of them. Um, I just they cause a little bit of GI upset for me at this point in time. That's not a common thing. I don't think avocados are like typically a GI irritating food and I will eat them. I'll just eat them at a point in time when I, you know, don't mind being a little bit farty for the next 12 hours. So, if there's gonna be like romantic endeavors that evening, there will not be avocado at dinner. If I'm alone that evening, there might be avocado at dinner. I'll leave it at that.

All right, let's move into supplements.

Yeah. I, you know, I think everybody at least in the Northern Hemisphere probably should be taking vitamin D supplement, D3. Dose varies. I take 2,000 IU, maybe in the winter 4,000 international units. I think a quality omega-3 supplement probably could benefit most people targeting a total EPA and DHA dose of about 2 grams or more, I use Nordic Naturals. There might be benefits to certain things like krill oil because of the specific form of omega-3. You can delve into that if you want. I also just dropped a video on fish intake and it goes beyond with respect to fish, just omega-3s. There's some really interesting things with probably different forms of selenium there. So you can check out my channel for more on fish intake and the data on that with respect to all-cause mortality and cognition. But prioritizing getting enough vitamin D, getting enough omega-3. And then beyond that, the only supplements I'd recommend are those that are kind of tailored to you specifically. So like what your objectives and needs are. Some people on low-carb diets have trouble getting enough magnesium. So like a magnesium glycinate might help or magnesium threonate, especially if you're having trouble sleeping. Some people swear by that. You know, for gut health, there are some butyrate supplements that people have used that I've heard are helpful. You know, making sure you're getting enough calcium. So if you don't eat dairy, along with vitamin D, probably taking a calcium supplement. Again, you can see, and probably a vitamin K2, MK-7. A lot of these are just based on what your individual use case is. Is. But other than that, I don't recommend a lot of supplements. I recommend trying to get things mostly from Whole Foods. Um, not the grocer, just whole food ingredients. Grocer is kind of expensive. But, um, yeah, I'd start there. If you want to take a multivitamin, take a multivitamin if it's going to cover your bases.

Well, let's come back to the food piece. You mentioned the fact that you're a big fan of olive oil and you mentioned macadamia nut oil. Which for me brings up seed oils, which is a very controversial topic in the health and wellness space. How do you feel about those? Are you using any of those in your cooking? I'll have you expand on that. Yeah, sure.

So first thing I'd say is like, we need to— every time we say seed oils, I think we need to be very specific as to what we're talking about and what we're extrapolating to. Are we talking about the fryer oil at McDonald's? Or like processed corn oil and soybean oil. Soybean oil isn't even— and corn isn't even seed oil. You know, these aren't seeds per se. Generally, I see it bleed into things that are high omega-6, which is considered a fragile fat. Specifically linoleic acid is the omega-6 people talk about a lot. So you hear seed oil, you're going to hear other terms like omega-6 or PUFA, which is polyunsaturated fat, including omega-6 and omega-3. Or linoleic acid. I'm going to speak broadly to that category of fat type because I think we can agree, even if we don't agree on the reason, like highly oxidized fryer or fryer oil at McDonald's or like, you know, corn oil or soybean oil and like a clear plastic container at the grocery store probably isn't the healthiest choice with negative metabolic impacts even going beyond the calories. That might be a little controversial in some circles, but I think I could stand by that statement. What I would say and where I'd like to put the emphasis is with respect to omega-6 and linoleic acid, because I think there's a lot of fear around then having anything that's high in these fats, the omega-6 fats. I would say I do not think the data support that eating whole foods, whole natural foods rich in omega-6s necessarily damaging. There are data that omega-6 to 3 imbalance, say in the serum, can be damaging, but it doesn't necessarily translate to, oh, you need to optimize your omega-6 to 3 dietary intake to a 1 to 1, because these polyunsaturated fats get processed in quite complex manners. So I think there are a lot of healthy foods high in the, quote, seed oil omega-6 linoleic acid. Those that I consume include walnuts, pecans, sesame seeds, and sesame seed butter, tahini, that I mentioned. And I think these are perfectly fine to have as part of your normal diet. If you want the proof in the pudding, I eat, say, tahini liberally, and macadamia oil too, but it's actually not high in omega-6. It's the one nut that's very low in omega-6, or one of the nuts. But I've gotten my omega-6:3 ratio tested in my blood, and it's a perfect 1:1. With an EPA/DHA index of 17.2%. So like, I challenge you to find someone with a ratio as optimized as mine and then ask them what they eat and if they're avoiding, quote, seed oil or omega-6 rich foods. So basically, like, you can still eat tahini and walnuts and have a great omega-6 to 3 ratio. So I would not avoid those foods for that reason. French fries at McDonald's, I'd avoid them. So, you know, kind of a boring moderate stance there. I will say I find the idea of the impact of omega-6s broadly on metabolism interesting in an area ripe for exploration, but I'm not convinced by the data existing now that they are uniquely harmful. And I would say if you want to have, if you like those foods and want to crumble a little walnuts on your salad, of a tahini dressing on your eggplant or your chicken, then totally go for it. I don't think it's gonna hurt you.

You quickly touched on omega-7s and the fact that they're in macadamias. Talk about other foods where we can find those and what their special benefits are.

Omega-7s— so you've probably heard a lot of omegas. Omega-6s are the linoleic acid. Most people are scared of that one. Omega-3s are like in fatty fish and people like that one. Omega-7 is one that you don't hear about a lot. It's called palmitoleic acid. It's actually a monounsaturated fat. It can be found in like buckthorn oil, which is kind of esoteric. Other than that, macadamia nuts are the primary source. Um, macadamia nuts, uh, I think they're 20% total fat is palmitoleic acid. And the interesting thing about palmitoleic acid is, um, it's actually the founding member of a group of dietary hormones. Called lipokines. Lipo meaning fat, kine is kind of the suffix for hormone in a lot of settings. So hepatokine is hormone from the liver, osteokine is hormone from the bone, myokine hormone from the muscle. Lipokine in this case means from dietary fat. Adipokine is from your body fat. Um, terminology aside, I think it was Cao et al., C-A-O, 2008. I think it was Cell, maybe Cell Metabolism. That first coined the category lipokine based on palmitoleic acid and its broad metabolic effects, um, which appear to be overall beneficial in things like improving insulin sensitivity, which we mentioned earlier. Um, you can watch my omega-7 video on the details for that. I don't want to dig too into the weeds now because it is such a messy topic. And it's also one of those examples where doing the science on it actually becomes very complicated because it's not just a matter of, oh, eat omega-7 from macadamia nuts and then measure it in the blood and then measure outcomes because there are also endogenous pathways which are influenced by carbohydrates. So actually eating macadamia nuts and eating a bagel can cause the same spike in palmitoleic acid, but from different sources with different impacts. There can be conversion from other fats, including fats that are primarily found in animal products and like ruminant meat. So it ends up being a very complicated area to study, which I find very cool. But it's a— on balance, the data suggests that dietary palmitoleic acid, especially from macadamia nuts, or including from macadamia nuts since it's the main whole food dietary source, has metabolic benefits that will improve insulin sensitivity among other things. And that's consistent with the literature on macadamia nut supplementation, which I only know of one study looking at weight outcomes with macadamia nut supplementation. I think it was at something like, I think it was like 15 to 30 nuts per day, like 1 to 2 ounces of nuts per day. And people were like, oh, they're high in calorie, they're gonna cause weight gain. This is only a 4-week trial. And even after 4 weeks, this, it wasn't powered for weight loss, but there was a statistically significant drop in BMI, which kind of grates against the whole calories out, calories out, calories in, calories out concept. Like eating the super high fat food and then people from this intervention are actually having weight loss. Why? Well, fuel partitioning. And we're back to that topic we spoke about earlier. So I do not think they should be feared for calories. I think that they have cool metabolic benefits potentially and You can link more resources for that if you want. But, um, yeah, big fan, big fan. There's a lot of fun things you can do with them too. Versatile food.

You mentioned the fact that part of your health journey was ulcerative colitis. Let's take things right from the top and talk about when your health started to degrade, and we'll go through the process of different things you tried and what led you to where you are today.

My gut issues started acting up at the end of college around age 21. Up until that point, I really had no food aversions at all except for maybe Marmite. If anybody's had Marmite, it sucks. It's terrible. It's awful. But other than that, I had no food aversions. But towards the end of college, I started developing GI upset with basically anything I ate and then started having pretty profuse bloody diarrhea, which you have in ulcerative colitis. Got really bad to the point that it really just undermined my academic career and my social life. And I ended up in and out of intensive care, palliative care while I was starting my PhD at Oxford. So I ended up becoming quite desperate. And after trying a bunch of medications that didn't end up really working to keep me in remission, I— or help my symptoms, tried a bunch of different diets because I was desperate. I tried the standard diets that people will tell you might help for IBDs and IBSs, which are low FODMAP and specific carbohydrate. Didn't really affect me. I tried then pescatarian, Whole30, Mediterranean, vegan, vegetarian, basically any diet that you can imagine that's a common diet. I tried it. Eventually I tried a ketogenic diet and That's when my life really did change. My inflammatory markers dropped, I felt a lot better, and on my next colonoscopy, there was no sign of disease. I was in biopsy-proven remission, which is how I got interested in the whole metabolic health space to start, because it was just so curious. There are no human randomized controlled trial data on ketogenic diets for inflammatory bowel disease, and yet it worked profoundly well, which led me to the conclusion that, you know, this could be a potent metabolic health intervention and metabolic health interventions have a lot of potency, probably for a lot of diseases, but they're not gonna be recommended as standard of care until we do the trials to quote, prove it. And the research infrastructure right now is not set up to incentivize trials in metabolic health because the business model isn't clear. So that's sort of my journey into the space. And that's the short story of how I found a ketogenic diet for ulcerative colitis.

Talk about the part of your journey where you noticed your LDL going up, and then we'll talk about the experiment you did and the controversy. And there's a lot we can get into within that, but talk about how far into ketogenic was it before you noticed, "Oh, my LDL has really got an upward trend." I don't—

it was my first lipid panel. I don't remember how long after starting keto that was. It was on the order of, weeks or months. 'Cause I got pretty normal testing. I would be surprised if it was more than 3 months after, although I don't remember the exact date. But yeah, my LDL cholesterol, my cholesterol total as well, along with my HDL, they all skyrocketed. My baseline on a mixed standard American diet-ish was 95 milligrams per deciliter. And in my first test, I think it jumped up to like 320 or 350, I forget which. And then it started to continue to climb. Up to well over 500 at some points, which is jaw-droppingly high. Um, I'll, I'll zip through a lot of the backstory, but basically me and colleagues including Dave Feldman, who was the first person to observe that lean insulin-sensitive people who go low carb tend to have massive increases in LDL cholesterol as part of this triad of high LDL, high HDL, and low triglycerides, the lean mass hyper-responder phenotype. What we're finding is that indeed there's an inverse association between body mass index and probably body fat as well, and LDL rise, whereby the leaner you are and also the more insulin sensitive as measured by triglyceride to HDL ratio, um, the higher LDL tends to go. This has now been shown in a meta-analysis of 41 randomized controlled trials. Uh, first author Soto Mota et al. in the American Journal of Clinical Nutrition.. But yeah, leaner people, larger jumps in LDL. That's curious. And what we're discovering, or at least the model we have that makes a lot of accurate predictions, is that this phenomenon results from a change in fuel trafficking, what we call the lipid energy model, whereby if you're lean and insulin sensitive, when you shift, shift from carb burning to fat burning, and lean insulin sensitive people are better at doing this, then The free fatty acids released from your fat cells end up getting taken up by the liver and then shuttled back out of the liver in a storage form, triglycerides that are on these very low-density lipoprotein, VLDL particles. And then at muscle and fat tissue, these particles get turned over. And basically the turnover process results in this very high LDL, the very high HDL, and the very low triglycerides, this triad. And, um, So our understanding of this physiology allows us to make predictions that we can then test. One of the predictions is that you should be able to reverse the phenotype, lower the LDL by adding back carbohydrates. And we'd shown this in an interventional trial and case series before, but I didn't think there was enough discussion around it. So I chose to prove that it worked in style. Which to me meant lowering my LDL cholesterol with Oreo cookies. So I did a trial where I experimented on myself using 12 Oreo cookies per day for about 2 weeks. And then I did a washout period and compared it to statin therapy, high-dose statin therapy, 20 milligrams of Crestor, which is rosuvastatin, for 6 weeks. And long story short, or the punchline was The Oreo cookies were twice as potent at lowering my cholesterol, lowering my LDL, as high-intensity statin therapy, which is a shocking finding even in n 1, especially if you could predict it. And it's totally consistent with our data, um, our model and prior data. So that was me being intentionally provocative to get more discussion around the physiology of cholesterol changes in carbohydrate-restricted diets. The reason being is changes in cholesterol still remain like the boogeyman of low-carb diets. And I think they have so much— low-carb diets have so much clinical utility. We need to address this boogeyman and understand what's going on, including understanding the mechanisms behind the physiology and also understanding risk profiles so that we can properly and broadly implement low-carbohydrate and ketogenic diets for people where they could be useful.

Alright, a lot of follow-up questions to this. Starting with, you mentioned it was pretty early on that you noticed your LDL and different blood markers changing on a ketogenic diet. You're finally getting symptom relief from your ulcerative colitis, but your LDL is skyrocketing. What do you do at that time? Are you— because obviously it's this paradox where you're getting symptom relief, but you're watching your LDL go up. The way I understand, and you can get into this too, you were very conventionally minded at that time, so you're probably—

and you—

and this is new to you, so you're probably really concerned about the LDL going up. So take me back to that time where it's going up but you're, you're feeling better in your gut and what you do.

Yeah, I think it was disconcerting to start. I will say at the point in time I was in the headspace. I mean, put yourself in my mind. I've now spent like a good long while being mentally depleted, physically emaciated, and I'm finally feeling great for the first time in a long time. And I have the promise of a future back. My cholesterol goes up. Yeah, kind of scary. But quite honestly, I was more in the mindset of, thank God I have some life back. Um, and now we have this cholesterol problem. 'Presumed cholesterol problem, let's figure that out.' And honestly, my curiosity overwhelmed my concern because it was such a weird finding. Like, why the heck? I was eating like salmon, avocado, Brussels sprouts, eating basically no red meat or dairy. Why would my LDL over triple? What's going on here? And it was just so perturbing. That was my main emotion, trying to figure it out. So I don't know. I mean, I guess there was an element of fear. I've mentioned that before. So it would be dishonest to say there wasn't any, but my predominant emotion was curiosity and why this was occurring. Because I also know at the same time, like, I'm not going to have a heart attack overnight. So there's something quirky going on here metabolically. So I didn't jump towards saying I need medication for this. It's like, I want to understand what's going on here, and then I'll consider my options. And I've been considering my options for the last 5 years.

And you mentioned earlier the fact that this lean mass hyper-responder phenomenon happens when somebody is insulin sensitive, they're on a ketogenic diet, and then there's the 3 parameters where LDL goes up, HDL goes up, triglycerides come down. How common is that? Do you see people that are young, healthy like you, metabolically healthy, insulin sensitive that don't have this happen, or is it pretty much a given for somebody that's in your boat?

We don't know the answer to the exact penetrance. I would say the majority of people who are lean and insulin sensitive and active who go very low-carb ketogenic will see some sort of signal, um, going towards the lean mass hyper-responder phenotype. I think it's a pretty near universal metabolic response. I can't promise it's gonna be in 100% of cases. I don't know what percent exactly, but it's to the point where I feel I could go to your average gym, pick someone who had never done low-carb before, look at them and be like, I could turn you into a LeMess hyper-responder and be pretty confident about that. So we still need to do the study. Actually, we're designing that study right now. To figure out what exactly predicts conversion because there's gonna be other things that modify the phenotype as well. But I think it's very common among lean insulin-sensitive people who go low carb. It just so happens that most people aren't low carb and/or if they're low carb, aren't lean and insulin sensitive, which means at a population level, you know, it's not that common because how many people do you know who have six packs who are keto? Small pool of people. So yeah, I would say it's probably pretty common among that population.

All right, so we know it's common in this population, common in people who are metabolically unhealthy to have a high LDL as well, not to this extent, but it's, it's common knowledge that that is a risk in the conventional world for cardiovascular disease. Which there's a lot of different nuance to pick at here and there's probably still a lot of unanswered questions, but in both of those camps, given your focus in this area, somebody who is in your camp, metabolically healthy, high LDL, any concern there? And then what can we take from that and bring into the metabolically unhealthy person LDL rising, have we missed the mark there as well?

Yeah, I would say, um, one thing to highlight is like the levels we're seeing in lean mass hyperresponders, comparing it to like the average quote high LDL is like saying that, you know, a gorilla, like a silverback gorilla and a spider monkey are both primates. Like they are two hugely different classes of just order of magnitude changes in LDL. But also LDL is a very crude parameter. It's just a cholesterol fraction in your LDL particles. So, you know, you get more information by looking at the LDL in the context of other markers like the HDL and the triglycerides, which tells you a little bit more about like what's going on in terms of the underlying physiology. And also it's worth mentioning that Generally in health and medicine, the etiology, the cause is relevant with respect to the outcome. There's data in JAMA Cardiology from 2020 showing that different drivers of high LDL, be it no known genetic cause versus monozygotic or, sorry, monogenic or monozygotic, we're not having twins, monogenic or polygenic familial hypercholesterolemia, they do tend to have different outcomes even for the same LDL levels. So, high-level cause matters. Um, now what we have here is a completely new metabolic phenotype and a completely new driving cause of high LDL, presumably in lean mass hyperresponders with a lot more particle flux. And all you get is this, you know, when you get a snapshot is like, you know, what are the levels in the blood? It doesn't actually tell you how much flux there is through the system. So it's not telling you, for example, is there decreased clearance of particles or, you know, actually increased absolute clearance, but you just have so much more production and turnover of these VLDLs. And that's going to be very different than someone with a broken LDL receptor or metabolic dysfunction. So with respect to lean mass hyperresponders, we don't know the risk profile and we have every reason to believe it would not be the same absolute risk profile as a metabolically unhealthy person. Now, with respect to your other question, what can we learn from lean mass hyperresponders to apply to the general population? I would say if we are right and this is a metabolic phenotype that is very common along among lean insulin-sensitive people, what that means is there is something here to learn about basic healthy human physiology, or let's say basic adaptive human physiology. Adapt is probably a better word. And that could unlock knowledge that could lead to innovations for the entire human race. I think we often like to try to figure out what the actionable takeaways are in this moment. For, you know, the person listening, I'd encourage people To also accept the fact that sometimes, actually a lot of time, just pursuing a curiosity, especially a metabolic one, can pay dividends even if you don't know what that's gonna be. Prime example that's probably on everybody's minds right now is the invention of these new weight loss drugs. Whether you like 'em or you don't like them, you're pro or you're against, it's clear they're changing the obesity medicine landscape. Ozempic, Wegovy, Tirzepatide, Mounjaro. Um, where do they come from? They initially come from in the '90s studying Gila monster venom, which is a lizard that makes venom that has a compound that acts like a GLP-1 receptor agonist. And so there were some curious scientists who studied that. How they would never have known that almost 30 years later this would change obesity medicine. They were studying a lizard's venom and why it screwed up things metabolically. In that case, like, why does it have this phenomenon? I would say it's the same with lean mass hyperresponders, or maybe a better analogy is the same with Brown and Goldstein, who studied homozygous familial hypercholesterolemia, which is a super rare genetic condition. They got the Nobel Prize and changed the lipidology landscape. So just because at a population level lean mass hyperresponders are not common because most people aren't lean and low carb doesn't mean studying their physiology as an extreme example of what might be underlying human physiology, couldn't unlock truly revolutionary insights into how our bodies work.

Coming back to the Oreos, they brought your LDL down 71%. Could you have gotten the same result with sweet potatoes?

Yeah, we've done this in other patients with various carbs, starches, and fruits especially. But the fact is nobody was talking about those studies. So I just chose the most provocative thing I could possibly imagine. Based on our models, you know, the source of carbohydrate with respect to LDL lowering specifically doesn't matter. That doesn't mean that it doesn't matter for your overall health. I think it'll be healthier having more sweet potatoes, fewer Oreo cookies, but with respect to the singular biomarker, If you're a lean mass hyper-responder, it's more about having carbohydrates in your diet and putting more glycogen in your liver, more carbs in your liver to kind of turn off the flywheel of lipid energy model, so to speak, that reduces the LDL. So sweet potatoes would work. Choose your favorite carby dish, pizza, french fries, gnocchi, pretzels, doesn't matter. Oreos, Nutter Butters.

Part of where this becomes really critical is for people like yourself who are dealing with a health challenge, your ulcerative colitis, where you're using the diet therapeutically to keep that at bay. And we could probably give a number of different examples, people with mental health challenges that are on a ketogenic diet. What I believe you did, and I want you to talk more about this, is even though you're introducing the Oreos, which was giving you around 100 grams a day of carbs, you were taking in exogenous ketones to maintain a therapeutic benefit. Can you talk about that inclusion?

So there were two reasons I included exogenous ketones. One was because typically when I have introduced carbohydrates without, um, maintaining ketosis through exogenous supplementation, I would tend to drift into flares. I can tell because there is blood in my stool. I've done this before where I have at least for a short period of time some exogenous ketones at high doses and it appears to maintain IBD, inflammatory bowel disease remission. My IBS, which is separate, does get irritated, like my stomach was not happy. But for me, ketosis at least over short periods of time appears to provide some, let's say, buffer room. That was one reason. The other reason I actually did it, this was two birds with one stone, is it was methodologically cleaner. Although it sounds like I'm doing two interventions, and technically I am adding the Oreos with the ketones, it controlled for the state of ketosis. So when I was on the statin and when I was on the carbs, the Oreos, In both cases, I was in ketosis. So there isn't the argument to be made that, oh, it's because you went out of ketosis that your LDL went down. And that was something I was trying to defend against. Transparently, I was doing it specifically because of commentary that had been raised that was not substantiated by prominent lipidologists, specifically Thomas Dayspring, who had tweeted several times that ketosis Lowers LDL receptor expression. And that had stirred a lot of controversy. People were taking it as truth, even though there's no data to support that. I've asked them for citations. I provided my own, including a human RCT with the ketogenic diet and a rodent model with exogenous ketosis where LDL receptor expression of the liver actually went down. There aren't data that appear that ketosis reduces LDL receptor expression. However, methodologically, in my experiment, it was cleanest to control for ketosis in order to defend against this accusation that, oh, it's because you're out of ketosis. So, you know, this was in large part a publicity stunt to get attention on our research. So I was very aware of what criticisms might be levied and therefore thought it was clever to include exogenous ketones to control for that variable. Along with other clever Easter eggs and defenses, if I may say so, that were sprinkled into that paper. But you can look for those yourself.

So experiment aside, you have this phenotype where when you're in ketosis, your LDL is skyrocketing again with the change in triglycerides and HDL. What are you doing as a metabolically healthy person day in, day out, or are you doing anything to help keep that LDL down? Are you having periodic sweet potatoes, any carbohydrates in any kind of protocol fashion to manage LDL?

The answer, the short answer is I'm not. Um, the add-on to that is I would not recommend the same necessarily for other people. My approach has been I need this diet therapeutically. So carbohydrate reintroduction long-term really isn't on the table. Even, you know, first of all, exogenous ketones aren't necessarily pleasant to take at high doses, plus they're expensive. And the long-term effects of mixing carbs and exogenous ketones is unclear. So I'm not doing continued Oreo protocol or carb cycling. I've tried a couple medications, was intolerant to both of them. And I've gotten a coronary CT angiography after having these levels for quite a few years, and I have clean arteries. So presuming that there's no jack-in-the-box phenomenon where I suddenly develop a heart attack from no measurable plaque on a coronary CT angiography, angiography, which measures both calcified and non-calcified plaque, then my perspective is I have buffer room for this research area to develop, to to see what my risk profile is. And all things being equal in an area of lots of unknowns, my decision has been not to sign up for pharmacotherapy for life. I could change my decision based on outcoming data, and I would not necessarily recommend the same for other people. If you're, you know, Medicaid, given your family, consider your family history, consider your personal history, consider what competing comorbidities you have and what you know, why you're on a ketogenic diet. I think it's very reasonable for the average lean, healthy person who doesn't have metabolic complications to just have a freaking sweet potato. That's what I would do if I didn't have a history of colitis. If I had a history, personal family history of cardiovascular disease attributed to high cholesterol, or if I had plaque on my CT angiogram, then I would probably be aggressive with some form of therapy. The fact of the matter is I have no measurable plaque despite high levels. I need this diet therapeutically, and the medications I've tried have had negative side effects for me. So I'm watching, I'm waiting, I'm measuring, and I'm reevaluating along the way.

LDL aside, any other reason you've considered having periodic insulin spikes? I know you did a video on mitophagy. And the impact of insulin on that, obviously there's still insulin being secreted with fat and protein, so it's not like you're not secreting any. But do you think there would be, or have you considered any other benefits you could be getting from having periodic bigger spikes in insulin?

Yeah, I mean, I think in general biology operates well in cycles. Insulin is an anabolic hormone with positive impacts with respect to, you know, growth, including in the brain, sufficient insulin signaling. I would say I'm probably getting enough of an insulin spike via just my normal diet. Like I do eat a lot of protein. That's gonna gimme insulin spikes. It's also gonna gimme some, you know, a degree of glucagon response. I'm probably getting sufficient just through the feeding and fasting cycles that I have. Probably get every bang for my buck that I'd want. There's also individual contributions of, you know, my own genetic background with respect to my APOE status, whole different kettle of fish, whereby carbohydrate restriction might be more beneficial for me as compared to your average person with respect to my brain health. I mean, you definitely don't need carbohydrates for your brain health. All things being equal, feeding and fasting cycles, maybe with a little bit of carbohydrate, one could try to extrapolate based on some data that's been done. If you wanna look up the work of Mark Mattson, he has some nice papers on glucose ketone switching in the brain, but I'm not super convinced that one would yield measurable metabolic benefits from insulin spikes, from reintroducing carbohydrates beyond what we've just discussed with respect to potential improvements in lipid parameters. If you consider those changes improvements, and then things that happen with just anabolic growth signal. If you're trying to put on mass, if you're trying to bulk, carbs are probably your friends, all being equal. So, you know, if you're, if you're a world strongman and you're trying to deadlift 1,000 pounds, please don't go keto. It will not work for you. At least I have no reason to think it would.

So, but other than that, no, I wouldn't go chasing insulin spikes throughout our conversation. Non-nutritive sweeteners came up, and separately, the GLP-1 agonists, including Ozempic. Last question for you as we wrap up here. Let's bring those together and talk about allulose and how somebody might want to use that therapeutically as a sweetener to help increase GLP-1.

I would just talk about some of this with someone recently because I think it's very easy to fall into a logical trap, which is like, interestingly enough, allulose does promote GLP-1 production and there are now data showing that it probably has anti-obesogenic effects, at least in preclinical models where you say feed mice a Western diet and give them stevia versus allulose. This is out of the Bikman lab, allulose appears to protect against obesity in these mice, which is very interesting. So one could jump to the conclusion of, oh, we know GLP-1 causes weight loss. We know allulose promotes GLP-1 production. We know allulose can have an anti-obesogenic effect, at least in mice. So therefore allulose increases GLP-1 to promote weight loss. But That logic is flawed on a few fronts. High level, this could be something that is true, true, and unrelated, where there are possible metabolic benefits, but they're not mediated via GLP-1 because actually the GLP-1 levels induced by allulose probably at least again, in, in mouse models, a fourfold increase in portal vein levels, which is nothing to shrug at, still isn't like Ozempic, which is supra physiologic levels, right? So, and that stick around for a long time. So I'm not convinced the metabolic benefits of allulose are per se due to GLP-1, although there does appear to be a pretty interesting signal in the literature. And it has a lot of other effects as well, inhibiting enzymes that break down sugars, like break down sucrose. Activating hormone-sensitive lipase at fat cells, which interestingly enough is one of the mechanisms of action of Mounjaro, which is tirzepatide, which is more powerful than Ozempic. So there might be like mechanistic overlap there. With respect to allulose, I think the reason I find it interesting is in the universe of non-nutritive sweeteners, including rare sugars and natural sweeteners like stevia and Artificial sweeteners. I used to be of just a general negative opinion, and by and large it's not something I think people need by any extent. And I think that there are certainly some that are harmful, like sucralose and aspartame, but there's such a heterogeneous and interesting group of compounds. And the practical me realizes that we're not getting sweet out of the diet anytime soon. So then the question arises, well, what is the best possible option for people? And the literature keeps on pointing back and back to allulose. I think stevia and monk fruit are benign. Erythritol, there's some questions about. I'm not that concerned about it. I would stay away from sucralose, saccharin, and aspartame. And then allulose is the one that might even be beyond benign but actually beneficial. The literature on that is, expanding, and I'm just very interested to follow it and contribute to it. Um, because, you know, I would love to see it displace regular sugar and fructose in the food supply. And I think it would be a pretty awesome natural experiment and a tool for people to use who are struggling with metabolic syndrome, um, insulin resistance, to potentially optimize their lifestyle within the confines of being someone who's always gonna want sweet in their their life. And there are those people. So it doesn't spike insulin, it doesn't spike glucose. In fact, it attenuates, lowers glucose and insulin rises when sugar is also consumed. It does produce or stimulate the body to produce GLP-1 very interestingly, and has a lot of other metabolic impacts beyond just displacing fructose that I find fascinating. So yeah, the company that produces it that I'm affiliated with, I'm on their scientific advisory board, is RX Sugar. Um, so you can check them out. I do have a discount code, um, that the CEO Steve would be upset if I didn't share, which is NICK20. I don't get any profits from sales. I'll be very transparent. I don't use a lot of allulose myself. I'm on the scientific advisory board because I find the compound interesting and I realize it can be a tool for some people. So check it out if you want. I have a whole breakdown video on it. It's one of my more popular ones called The World's Healthiest Sugar, and I'm looking at this crazy brownie on it. But, um, I do think it's an interesting— I think it's a very interesting molecule.

And you do have another video titled something like Nature's Ozempic. Is that still— it sounds like your thoughts have changed since then a little bit.

I regret that title, to be perfectly honest. I might delete that video. It's one of my most popular older videos. The reason I don't— the reason— okay, the reason I think I'm fine with the title in general, and I'll use the term is because what does Ozempic do? It mimics GLP-1. So GLP-1 is effectively, quote, nature's Ozempic. That's a fair analogy to draw. And there's also GLP-1, quote, nature's Ozempic deficits in obesity, metabolic syndrome, PCOS. So I think framing it like that, just because it's a word that's in the zeitgeist, Ozempic, basically using nature's Ozempic as a surrogate for GLP-1, is fair. Where it can be misleading is the suggestion, which I did in the one video, which I— it's not something I'm proud of. Again, I might just take that video down. It hasn't caused issues and it's an older video when I— before I was thinking about this, but I don't want people to be misled to believe that having something that is a foodstuff that promotes GLP-1 production by the body is going to have the effect of Ozempic. Where you like, you know, automatically lose 16% of your body weight, you know what I mean? Because Ozempic is a whole different class of medications.

So yeah, I can always change the title to and put a little disclaimer at the top.

I could. I mean, I'm not above just deleting videos. Apparently the algorithm, I heard from somebody, really hates when you delete videos.

I've heard that too. I don't know how true it is.

I've been— have you heard that? I have.

Again, it's just something I've heard. I don't know how true it is.

Yeah. Well, anyway, it wouldn't prevent me from deleting the video. Generally, I monitor YouTube comments pretty closely. I think I've clarified this in future, so I don't think I'm misleading anyone. If for whatever reason it becomes a problem where I just feel that it was being misrepresented, I've deleted videos before. I'm pretty hardcore about precision and accuracy. So when I have something I don't like, I delete it. Like I had this one video on fructose. Metabolic syndrome, making down a cell metabolism paper. And there was a Cre-Lox system, you know anything about like, you know, expression models and Cre-Lox. And I like listed some like string of letters with reference to the intestine versus the liver and mix them up in the Cre-Lox models. And like it went over, I think 99.99% of heads. It bothered me so much that I messed that up. I deleted the video just entirely. So maybe I'll delete this other one, but for now it stands. Um, just because quite honestly, practically, it's in the background growing my channel. I recorded on my iPhone, has over 100,000 views. People seem to like it. I think my messaging is pretty clear. I go down and break out, you know, I'm not just like on a soapbox, like, here's a Nature's Communication paper, here are the data, let's talk about them. So, you know, I'm just showing the data. Um, but with all these things, I think it's worth auditing your messaging, thinking about, you know, what you might have screwed up and just being honest with yourself and non-defensive. I'm at the very beginning of this journey as a content creator, really, I only became serious or more serious about it, like now in 2024. So I'm like, very ready to evolve and grow and have people say, yeah, you did a bad job here. And so right now, like every video, or every month or so I can go back and be like, oh, I could have done that better. But that's kind of part of the growing process, right?

And to be fair, there'll be things from this conversation I'm sure both of us will disagree with 10 years down the line, and we're creating it with good intent and sharing how we feel at this moment with science and experience. And, and yeah, it's, it's definitely gray. And I think that part of being a good scientist is being willing to change your, you your hypothesis and the way you look at things. So you're just continuing to evolve and learn just like we all are.

Yeah. I love the growth mindset.

All right, Nick, really enjoyed this conversation. We're gonna link up your YouTube channel, your social media, everything in the show notes. Thank you. I hope we can do this again someday.

This was awesome. Thanks so much for having me.

Now that you're done, you're gonna wanna stick around here and catch this other incredible episode. You don't wanna miss it. I'll see you over there.

Getting fat is a normal process for many animals, and they do it to protect themselves during times when food is not around.

So what's really interesting is officially, people who are overweight are high energy.