← The Neuro Experience
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- [00:00]
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What do we care about now? Why are we even having these conversations? And the common knowledge is that once you lose weight, you gain it back quickly. We've probably all heard that, but one has to ask the question.
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Nick Norwitz, Ph.D. and Harvard Medical student, a rising star in the world of metabolic health.
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My life's mission to make metabolic health mainstream.
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We explore the complex interplay between metabolic health and chronic disease, focusing on the misunderstood relationship between lipids, cholesterol and risk factors for conditions like cardiovascular disease and Alzheimer's disease.
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These are all metabolic diseases that manifest when the body's metabolism, how we use energy, including mitochondrial function, gets out of whack. We need to have a discussion.
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Right now, the average human is at the mercy of social media. You can have someone who is highly specialized, but then you've also got somebody, you maybe read an article and the one who looks better more often will win. We're going wrong there.
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I know people want the simple answer. Like some influencers say, lower is better. The truth of the matter is, if you want that, I am not your guy.
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B
For the average listener, could you just break that down to me?
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A
Number one rule.
- [01:18]
B
Nick, I think you've been famous for doing N of 1 experiments which I want to know more about what inspired you to do that. But before we do, you speak a lot about metabolic health. We hear about it a lot. I've interviewed many people on the podcast regarding it, but I think we still need to align ourselves with a definition that we all understand. So let's open up by first understanding what is metabolic health?
- [01:45]
A
That's a great question. Coming up with the definition of metabolic health is really hard. It's kind of like porn. You know it when you see it, but it's hard to pin down. And you can look at a bunch of different markers of metabolic health and kind of get, you know, an assessment. Things like triglyceride to HDL ratio, ratio insulin levels. I still don't have a fantastic definition for it. The last time I was put on the spot and asked in like Instagram Live, what is your five word definition for metabolic health? I said your best life insurance policy or something like that. So I think it's a fair question and I also think it's fair to claim that it is vague. But the way I like to think about it is metabolic health describes when the processes that govern your body's hormones and energy usage are aligned in a manner as to minimize chronic disease and optimize performance, mental health, physical health and performance. So I think, you know it is a big umbrella term, but it's something that resonates with a lot of people now. But it just refers to so much that it's hard to pin down. I guess what we call in science, like an oper, operationalization of the definition, like what are the key variables? There isn't a strict definition of metabolic health, but it's something that we do kind of discuss in the abstract, which is annoying.
- [03:10]
B
Yeah, I actually noticed that you didn't say the word mitochondria in your definition.
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A
I didn't per se. I mean, that's one of the players therein. But that's kind of like. I mean, defining metabolic health with healthy mitochondria kind of seems like a turtles all the way down kind of thing, where it's like it doesn't actually answer the question. So functionally speaking, when I think about metabolic health, I guess another way to think about it is what do we care about now? Why are we even having these conversations? It's because there's an epidemic of metabolic diseases, chronic diseases that have to do with dysfunctions in how the body's metabolism, how we use energy works. This includes obesity, diabetes, any endocrine disorder, and even some extents, cardiovascular disease and cancer. These are all metabolic diseases. And dementia. These are all metabolic diseases that manifest when the body's metabolism, how we use energy, including mitochondrial function, gets out of whack. And what we really need at a high level is not pills and procedures for metabolic disease, but metabolic therapy for metabolic disease. Doesn't that kind of make sense? And so another way to define metabolic health or metabolic medicine, if you want to use a different term, is more like that. That approaches and protocols that help optimize the way your body runs in order to reduce the risk of these chronic metabolic diseases that society is plagued with. Dementia, obesity, diabetes, cardiovascular disease, etc.
- [04:43]
B
I. It's funny when you put it like that, metabolic medicine, I actually haven't you. I haven't heard of that term yet.
- [04:49]
A
Yeah, I mean, there aren't like, the semantics in this space are constantly evolving, I think, because sometimes, you know, a term will come out and then it will have some sort of taint over time and then you have to like redefine it. Like, functional medicine is developed to taint even nutrition. Science to some extent has developed a table, like my parents describe what I'm doing to sometimes, like family members or friends, like, Nick's into nutrition. And I cringe a little bit because I know the association that people have with nutrition science. Like, all right, my Plate like balanced eating. It's kind of a fluffy science. And I get that because I was there where I had this really simplistic heuristic. I'm like, oh, we know what healthy diet is, we know what nutrition is. And that's because the research space has become polluted with platitudes and bad research. But when you really dig into it, it's the hardest science there is. If you're looking in the right places, you know the new literature on how our bodies work, our metabolic health, we can talk through studies that have even come out in the last week or so about new metabolites that have been discovered that act in the brain to suppress appetite. Or long term studies looking at like, you know, sugar rationing and the development of children over time, the development of chronic diseases. Like there is so much gold here, but it's kind of hidden in a pile of, I think I can say shit on podcast. Sorry for profanity here or there, but yeah, but yeah, it's, it's, it's something, it's a space that I think is in wanting of some new terminology. So things like metabolic medicine, I'm just throwing out there, see if they resonate.
- [06:20]
B
Look where right now I think the average human is at the mercy of social media, which is literally leveled the, the, the playing field. It's like you can have someone who is highly trained, highly specialized, extremely well read, have probably conducted their own rcts on Instagram, this platform that delivers education to the world. But then you've also got somebody who's never read a book, never been to university, maybe read an article on Peter AA's website, probably not, but maybe they've read an article in Cosmopolitan magazine, they've gotten a snippet of it, they're putting that on Instagram. So you then you've got these two people in the same room on the same platform delivering education, and the one who looks better more often will win. And so that's where I think we're going wrong there. Do you agree with that?
- [07:13]
A
Well, wrong or right, it's a really interesting thing to bring up because there is such a list of pros and cons. And I think it's important to start with what the reality is today. And the reality is today we are living in the information age, when people just do have access to information. And there's an incursion between academics, academia, J Tower academia and social media, where people are exposed to new information and honestly the academic world is forced to interact with, with the media world, which really changes the game because there's a subset of academics who are like, they just want to sit in their J Towers, do their work. And I was that for 10 years. But then you. And you kind of think of yourself as like, oh, like, this is beneath me. Getting and doing Instagram reels or like, YouTube videos has been easy. So I'm not even going to compete in that area because I know what real science is. The rigor and going through the methodologies and, you know, sitting in the conferences using our jargon. It's a club that it's very easy to get your ego wrapped up into because you just spend so much year, so many years, so much time, so much training to be part of this club. It almost seems to step down to then engage with the broader public on these topics. And it's incredibly frustrating, I can tell you, because you described this juxtaposition, right, of the Instagram influencer who can kind of spew nonsense and just get, you know, for clicks, because that's the currency of the realm. And then the academic was actually trying to, to communicate nuanced science. But at the same time, you still have to compete in the area of engagement, and that's not a fair battle. Right, but, but I will say there is a democratization of science or a potential to democratize science with this approach, because you do have to tear down the walls. There is a force interaction, and it creates a serious challenge for people like me, academics who are like, look, I spent the last 11 years doing undergrad and MD, PhD. I know what it's like to do science. I know how to do wet lab research, run clinical trials, all of that. But at the end of the day, I want to empower people with knowledge. And if I'm going to do that with maximum efficacy, I need to get in these spaces and talk directly to people as a communicator and find creative ways to compete in this engagement ecosystem to draw people in and have them listen to the nuanced science. Even if it's an unfair playing field where I'm competing with people who can just go for the gross clicks based on shallow clickbait, which I will differentiate. And we'll talk about this with respect to my n equals 1 from legitbait, where you put things in a very provocative package. But it's like a Russian nesting doll approach where I'm like, here's the thumbnail. Now let me tell you a story and video. Oh, by the way, here are like 10 papers you can read that I've written on this if you want to go to PubMed. So there's different ways you can approach it. What I like to think of is like, look, we're living in the information age. People have access to information. Let's get out there and have cool conversations. And the challenge is on me and other academics and people who want to be nuanced in the space to just find a way to communicate in an enticing and engaging way and still get the nuance across. And it's a challenge that I'm not perfect at, but I'm kind of enjoying that learning process.
- [10:34]
B
Yeah, it's something that I'm not perfect at either. I. What I get challenged with is seeing multiple people on Instagram, this space, talking about the brain. So you've got these neuroscientists, right, who wonderful. You know, they're able to communicate science in an effective way. But when you, and you're, you know, you're in your last year of your md, so you've evidently now seen patients, you've, you've done some rotations and you can probably admit that reading science but also dealing with a patient are two different things, right? You can get all the science in the world. However, when you, when you talk about this, n of 1, you've got a patient right in front of you. That is the real deal. This is something that a lot of people are not privileged to when they are, you know, producing content on Instagram. I'm an intraoperative neurophysiologist. So on any given day, I am actually in an operating theater with neurosurgeons communicating with them, dealing with a neuro oncological case. You know, just recently there was a young girl who had a spinal tumor, which we won't get into. And that's like a real case. You're seeing the spine open, you're seeing the brain. You're seeing how a neurosurgeon communicates and how he navigates throughout that surgery, which could go anywhere from 5 hours to 24 hours. You just don't know. And you're privileged to that information and you can see that. And then to go and just see someone on Instagram, just paste something like, did you know that lion's mane is good for your brain? I think to myself, wow, you know, I'm in the, the. I'm right now I'm seeing a neurosurgeon who has studied 20, 30 years to be here to study the brain. From the intricate blood vessels that supply the brain with its energy source. To a young person 25 years old, which is they're reading something that they got off the media somewhere and they're just putting that out there into the world. That's where I have a problem with, with, with the social media information age.
- [12:30]
A
Yeah, I mean it's not a perfect system. That said, I, I, I, I do love the enthusiasm coming from different channels and platforms and outlets and the fact.
- [12:42]
B
That these, not everyone's bad, not everyone's out there trying to do bad things.
- [12:45]
A
Yeah, well that's, that's almost the problem is like where you have people with, with good intent who are getting things. Well, I guess, you know, it's, it's all opinion but like quote wrong and, and misleading in that extent. But through like how do we cultivate in social media a short form social media in particular, not like long form podcasts, a culture of nuance because the extreme stances are what get engagement. There's a clear incentive structure there to become ever more polarized and kind of attack the other. So I think, you know, it does set up a problematic incentive structure on social media. But you can still like again it's about doing the best that you can in the space that you have and then ideally using it to pull people in to more, you know, long form nuanced content. That's the ideal kind of hook them in and bring them down the rabbit hole with you.
- [13:45]
B
Well, I think this podcast is going to be very educational for many reasons. We're going to be talking about various topics that you're interested in. You've got a wildly successful YouTube channel which we're going to get into. But before we do, I think we're also going to be discussing some nuances in health, especially some myths or common misconceptions. And we can first start with metabolic health. And I want to know what do you think the most misunderstood aspect of metabolic health is, especially in relation to lipids and cholesterol?
- [14:22]
A
Yeah, there are a lot of strong stances on lipids and cholesterol, in particular ldl. Some people refer to it as the bad cholesterol. And I think the number one thing to keep in mind is that none of these individual markers, let's say ldl, can be taken out of context. They are context dependent. There are different ways to look at it. But like I think simply stated, if you just have this number in myopically focus on it in isolation, then you might come to a conclusion as based on the algorithm, I think we should intervene on this or not. But that misses the Big picture, what is the metabolic health context that is wrapped around this individual biomarker, which one informs how harmful that might be itself as a causal agent. But also, and this might even be more important by understanding the metabolic context, which, by which I mean like, you know, medical history, but also like personal dietary context and other markers, it does inform the why behind why a particular marker might be high or low. So let's take LDL cholesterol for example. And I was just saying that there are different reasons that say LDL cholesterol can increase. And understanding the physiology behind the why is really important. Now, before I get into it, I just want to use an analogy, very simple one, maybe overly simplistic, but because we're speaking about the central nervous system and CNS tumors, like imagine, you know, somebody is 7ft tall. They could be 7ft tall because they just have really, really tall parents, or they could be 7ft tall because they have a pituitary tumor secreting growth hormone. If all you looked at was that single outcome metric height, you'd miss the bigger picture. And the underlying physiology is going to inform the outcome. Just being tall because you have tall parents and having a brain tumor are two very different states. It's actually similar when it comes to lipid levels. You could have high LDL because you have a dysfunction in the gene that picks up the LDL particles. You could be very sensitive to saturated fat. You could have metabolic dysfunction, metabolic syndrome and obesity, or in a particular niche case, although this is the niche case, I have expertise in the so called lean mass hyper responders. You could have high LDL because your body is responding to your dietary context, in this case carbohydrate restriction in order to get fuel to the rest of your body. And the high LDL is the result of an epiphenomenon, kind of like a result of your body's metabolic response. And all of these probably will have different consequences with respect to how much plaque you build up or don't build up in your arteries, and therefore whether or not it's reasonable to intervene, what your actual risk is and importantly, what interventions will have, what effects. And I've demonstrated this, we've demonstrated this in various studies, including interventional studies. And my n equals 1 where if you understand the physiology, you can end up generating results that you can predict a priori, but that seem paradoxical, almost like they're a joke. And that's the idea behind some of the experiments we do. So one I published on earlier this year was the Oreo vs. Statin study.
- [17:47]
B
That'S your most famous. I looked at it, I think that's got the most amount of views.
- [17:51]
A
Yeah, yeah. Well not only the most amount of views, but when we publish the paper there's ways you can track the attention metrics on a paper. And this Oreo versus statin paper which is on Pubmed, you can look it up, has something like 20 times the metrics of your average nature paper and 15 times the metrics of your average New England journal, which are like top medical journals in the world. I think any JM is the top medical journal. So it got around. We'll get into the why behind that. But the experiment that I did there was actually compared in myself supplementation with Oreo cookies. So a whole sleeve per day I just added onto my diet. I didn't even swap out fat, I just added it on. I did that for 16 days. Then I had a three month washout period and I compared it to high intensity statin therapy, 20 migs Crestor, in this case for six weeks. Now just taking a step back, like, you know, statins are a multi billion if not trillion dollar industry. They're the standard of care for lowering LDL cholesterol and reducing cardiovascular disease risk by affecting this particular variable in conventional medicine. So how could cookies possibly outperform this trillion dollar drug or class of drugs on the metric which it's designed to lower? And the results of the study were the Oreo cookies were twice as powerful in one third the timeframe@ lowering LDL. And it's not a joke, it's an outlier response, but it's predictable and based on the understanding of the physiology. Now I did that experiment for a couple of reasons. One was to draw attention to our larger body of work and we can talk about the reaction to that, but you know, another was to try to provoke discussions that I thought needed to happen because it's no secret that, that there are a lot of platitudes and let's just say problematic quote, common knowledge topics in the health space. And if you try to push against convention, you can sometimes be met with derision or people will just ignore you. And there's different ways to circumvent that. And one way is to be provocative and make hard observations, ask hard questions and force conversations that need to happen by leveraging grassroots interest. And this is one of the really powerful things that we can get into. I try to be transparent about my motivations, but with respect to how I as a researcher can not only use social media as A communicate communication platform to teach people. But how I can then leverage the enthusiasm for interesting, provocative new ideas back against academia in order to force conversations that need to happen and, and fund research that I think needs to happen because there are some multimillion dollar trials I want to do. Guess what? The NIH isn't giving a 29 year old with a YouTube channel multimillion dollars, but philanthropists will and help me fund my research in collaboration with colleagues that I know, you know, at Stanford, Harvard and elsewhere. H indexes of 200. Like, it's really interesting how you can actually leverage social media in order to do research in controversial areas where the conventional paths would not invest. So this is actually a way to analyze proper research, quote, proper research into big ideas through enthusiasm that you can provoke through a freaking YouTube channel or Instagram. It's actually pretty cool.
- [21:32]
B
Yeah, no, I love that. I'm trying to, you know, you were just giving me like so many thoughts right then because I'm trying to really fund research in women for Alzheimer's disease. So that, that spans so many different areas. But I think that we're understudied, which I don't know if you have the same opinion being an academic, but I feel like there's so many different areas that we can tap into when it comes to research on females. My area is Alzheimer's disease, so I'm going to try and do the same thing, but I don't want to miss this. I. I know that you said this is opening the gates. This experiment, the ORO experiment is opening the gates for broader conversations for the average listener who doesn't have the same, I guess, academic level as you. Could you just break that down to me and give me two possible conversations that you would like to see happening in this space as it relates to LDL lipids and your N of 1 experiment.
- [22:25]
A
Sure. So to provide a little bit of context for the why behind our research, Ketogenic diets are rising in popularity and they're rising in popularity for a reason. They were first designed in the 1920s for pediatric epilepsy and they became more popular for like diabetes, obesity. But now we're finding they have clinical use for a broad range of conditions, even in randomized controlled trials. You mentioned Alzheimer's. Look up Philips et al and pubmed. They did an RCT with Alzheimer's disease and ketogenic diets and it performed well. Parkinson's disease, multiple sclerosis. A paper just came out. Mental health conditions, autoimmune conditions, like the span of potential Applications for ketogenic diets is broad. However, there's a big clinical obstacle to the implementation of ketogenic diets, which is this cholesterol question. Because for whatever reason, some people who go on low carb diets, especially ketogenic diets, see a rise in their cholesterol, in particular LDL cholesterol and associated marker apob, if people are interested in apobiology, and this is thought to constitute an increase in cardiovascular risk based on, as academics would say, the preponderance of evidence. But here's the thing. Most people actually don't see increases in LDL and overall see improvements in cardiovascular risk on ketogenic diets even when saturated fat is increased. But a minority see these astronomical increases in LDL levels so high that if you tell your standard clinician, they will think you're making it up or you're mistaken. Even if you're a Harvard medical student with a PhD, they're like, you must have misread this. This is impossible. This is equivalent to a 1 in 1 million genetic condition. It's that astronomically high. And nevertheless, we're seeing this and we're seeing more modest increases, and that scares people. So it scares people off from using ketogenic diets. But the hard question we have to ask is why? Why are some people seeing increases in LDL cholesterol? And you know, if you're a superficial thinker, you can go to the hand wavy answers. Oh, some quirk of genetics. Oh, it's a saturated fat. Because saturated fat's easy to blame for everything, right? But it doesn't square with.
- [24:37]
B
It's more nuanced than that.
- [24:38]
A
So here's an observation, actually one that we published on in a meta analysis of the human randomized control trials and low carbohydrate diets. And I'm not forgetting your question about the two conversations I want to have, but this is actually important framing. One thing we found now in multiple papers, including our meta analysis of randomized control trials, is that there is an inverse association between body mass index and LDL change on low carb diets. So the leaner you are, the higher your LDL goes. Generally, the leaner and quote, more metabolic health, more metabolically healthy. You are. So lower triglycerides, higher hdl. It's the people who are metabolically healthy and lean who see increases in ldl, which is weird. In fact, if you break people up or you break the studies up according to the WHO's BMI classes. So like healthy weight, you know, 18.5 to 25 kilograms per meter square BMI. Overweight, class one, class two obesity. The only group of studies where LDL increases on low carb diets as a population is the lean people, not in the populations with overweight or obesity. In fact, if you go to Class 2 and above, LDL actually goes down. If you go on the individual participant level, there's an inverse association too, really, the leaner you are, the higher your LDL goes up. This actually translates to individuals too, whereby we see cases where an individual, I know this one where an individual started with a BMI of 43.2. I think it was so, you know, well into the class 2, 3 obesity range. And their LDL was congenitally, by virtue of what their genes were low. So Even at that BMI, their LDL was in the 80s, which is considered good by conventional standards. They went on a ketogenic diet, they started to lose weight, they lost more weight and more weight and more weight, and their weight continued to drop. Their LDL stayed pretty low until they got close to that lean, healthy range. And right around BMI of 25, even though physiology doesn't know about who cutoffs their LDL skyrocketed to the 200s, which is crazy. That's, that's a two, that's 150% increase. And they didn't change their diet massively. They were still eating the diet that was causing them to lose weight. But something happened when they got lean where their LDL was up. So one needs to ask the question. This seems paradoxical. Why is it the lean healthy people, which are a minority, who are seeing the increases in ldl? And understanding that physiology will help us understand why LDL goes up and potentially what the consequences are too. Our explanation at a very, very high level. It's called the lipid energy model, and basically it says when you're lean and metabolically healthy, when you go on a low carb diet, your body, when your liver sugar scores drop, shifts really hard into fat burning mode. In fact, if you're lean and metabolically healthy, this happens a lot more than if you have obesity. You burn fat locally. So your fat tissue is going to give off little free fatty acids. Your muscle is going to burn them locally, but you need to traffic that fat throughout the body. The fatty acids are circulating in your bloodstream. They end up getting taken back up by the liver and then shipped back out in a storage form aboard VLDL particles, which are the precursor to these LDLs that everybody's scared of. And so Basically what's happening is you're having more circulation of fat through the system. And this predicts an increase in LDL actually, along with increases in HDL to very high levels, the HDL cholesterol particles and decreases in triglycerides. So you end up with this pattern of super, super high ldl, super high HDL and low triglycerides, particularly in lean people. And because of the physiological driver that I just explained, there are certain predictions that boggle the mind. Like according to this model, if you add back carbs of any sorts, LDL should go down. It does. That's why Oreos will lower my LDL better than statins. Or because this is an energy related phenomenon. Right. If you need to traffic more energy, then the model predicts your LDL should go up. I've done that experiment too, where I just increase my daily step count by 10,000 steps per day. My LDL jumped by 50 milligrams per deciliter. There are lots of predictions and they all tend to bear out to the extent. And we can talk about another N equals one experiment I just did where I can use a vegan ketogenic diet to increase my cholesterol as compared to more carnivorous diet based on my understanding of the physiology. So we can get into the weeds and the mechanisms of each N equals one experiment. But the big picture point, the big picture point here is understanding the physiology. The individual's physiology allows you to predict very weird outcomes and then intervene in creative ways to have a potent metabolic effect. And I would generalize this well beyond the cholesterol discussion to say each of us is a unique metabolic organism, and the way we approach medicine right now is through kind of a one size fits all approach. And so even if a majority of people are going to be helped by drug X that has been shown in randomized controlled trial Y to help the majority, a large proportion actually probably won't benefit. And to some extent, all of us are going to fall into that category one way or another. So to truly address metabolic disease, we need to understand the physiology and then target the root physiological dysfunctions or idiosyncrasies in order to have that effect. And when you understand the physiology, you can raise your cholesterol with a vegan diet, you can lower your cholesterol with Oreo cookies. And this isn't a joke. I can put like clickbait packaging around it to get people, you know, enticed. But like we're publishing papers on this, it's backed by complementary data in Randomized control trials, human.
- [30:33]
B
Like how does this help the, the, the average person who looks at their LDL and they have no idea. And this is the thing, right? You can get your drug, you can get your blood drawn by anybody, right? It's a phlebotomist, really. It's a two day course, but it's who is analyzing the blood work. That's what I always say first and foremost. But let's just say the average person gets their LDL and they're in that high range. It says red. You know, The LDL is 1, 150, right. Regardless of HDL, because we know that ratios exist as well. So let's just say they get that. What are they trying, what are you, what are they trying to glean from this information now?
- [31:11]
A
Right, so I'm not here and you're not here. I know to be prescriptive about individuals, medical cases via social media. Number one rule, don't get your health, you know, prescriptions from social media. But what I want people to be able to do is think deeply, ask the right questions and then assess when other people are thinking deeply as well. So the high level here is you see this number, then the next thing you think is what is the context wrapped around this number? Do I have a family history of cardiovascular disease? Have I gotten functional testing like a CAC score or a ccta and is there plaque in my arteries? Am I metabolically healthy or metabolically unhealthy? Could I be a lean mass hyper responder? In which case maybe sweet potatoes would lower my LDL much better than a statin. So it's starting to just ask the questions about, okay, what is the context wrapped around this and what questions do I have to ask either myself or in collaboration with my healthcare practitioner to get to a place where I'm comfortable with, you know, um, I would say if people want the action item with respect to, you know, if they find their LDL is high. The literature is pointing more and more towards the power of functional testing. So when I, what I mean by that is scans, like a CAC scan or a ccta, which looks not just at calcified plaque but at soft plaque. And from that you can get a lot of information because it's like if you have lots of plaque, you probably should be conservative and lower every risk factor you can correct. Alternatively, if you've had a high cholesterol for a long time and you're metabolically healthy and you get a scan and there's no plaque, well, it suggests that Even after the long period of exposure, you haven't had accumulation. So your risk profile is then different. And then you have a different, you know, calculus to your decision. And that doesn't mean taking a statin or dietary change is wrong, but it does mean you're just like weighing different variables. And so I know people want the simple answer. Like some influencers say lower is better. The truth of the matter is, if you want that, I am not your guy, because I hate that. And the reason I hate that is because it's so devoid of context than to be basically useless. And I understand why people use that kind of term like lower is better. What they're really saying is APOB and ldl, they're independent risk factors. So if you lower them, all things being equal, your risk will go down of specifically cardiovascular disease. But what's left out of this is one, it doesn't say how much your risk is going to go down. Could go down by a lot. It could go down by an infinitesimally small amount. It also doesn't say what the costs of the intervention are, because every intervention, drug or lifestyle change will have other effects that vary by individual and whatever the intervention is. So it's not as. And also, you're only lowering your risk, presumably of one disease state where there are other disease states which might have an increased risk with the intervention, either that we know about based on existing literature or that we don't know about, because certain drugs haven't been tested over the long term. And we can dig into all of that. But again, the point here is when it comes to the individual case, and this is the art of medicine, it's never as simple as, here's a number on a lab sheet that's in the red, which is where the lab sheet marks it, red, because it's out of range. We need to lower that with this drug. You can't just take that little keyhole vision and decide. And if you do, I think it's the detriment of the individual or potentially to the detriment of individual.
- [35:06]
B
This is where the vegans fight with the carnivores who fight with the nutritionists who fight with the X, Y, Z. Everybody's got a different viewpoint. You can talk to a neurologist who is a vegan, but then you can talk to a neurologist who is a. A carnivore. And it's like the general public is confused.
- [35:30]
A
Yeah. And they to some extent. Well, you could say confusion is like, you know, the first step towards you know, comprehending a greater nuance. I think one of the issues with these diet tribe debates and people can look for this is the topics tend to really bleed into each other. So I'll give you an example. I just did a, a paper on plant protein sources for longevity because people say plant protein sources, you know, are better for longevity than animal protein sources. And I deconstructed. I think it's really weak argument based.
- [36:07]
B
I was going to say, based on what Sirtuin activity.
- [36:10]
A
You really have to dig into the, the like, you know, supplements of supplements and go back to question years from the 1980s to understand like, why this is so screwed up. Because it could be like, first as an example, like there was this, you know, paper published. It was a big paper and they had all these analysis, which I think were really problematic. But at the end they're trying to put together some plausible reason how this could be in effect. And it's super hand wavy. And one thing they actually point to is like, oh, different IGF levels. But then you have to go to the supplement of one of their references to find out that, oh, in the study they're referring to, they're not actually referring to just animal protein. They lumped soy protein in with animal protein because it better told the narrative. So they're actually referring to the tofu just as much as they're referring to the steak. The average person isn't going to pick that up. You can watch the video if you want, but the point of me bringing it up was in the video, I never make the counterclaim. I never say a carnivore diet is good for longevity or touch on other topics that are related to these different dietary choices. So things with respect to, you know, animal conservation or environmental concerns, because these are all important but separate topics, but in social media they tend to bleed into each other and people become biased. And you can have this Mont and Bailey thing where you start talking about one thing like, okay, there's a claim about plant protein being good for longevity. Let's unpack that. And then you can see in the comments or the responses, people go on tangents about like, oh, well, this, that and the other about longevity and conservation and welfare and carnivore diets are bad for X, Y and Z. I'm like, we are talking about that. Let's remain focused on the question at hand. That becomes really difficult. And so what I'm saying is the tribalism makes it difficult to have nuanced discussions on particular topics. And if, if I were to generalize further with respect to the cholesterol topic, because this is something I come into a lot. It's like I have a re, like precision. Verbal precision is so freaking important here. Because at no point have I said LDL doesn't matter, or even LDL and Applebee aren't quote with respect to cardiovascular disease, but saying yes, I admit based on the data at hand, this is part of the causal pathway of cardiovascular disease. Yes, it's necessary in the development of atherosclerosis, but it doesn't then follow this is the most important risk marker or that you have to lower it in all cases when it's high. Those are distinct things that we can hold at the same time. And I think people hear a buzzword like LDL is causal and then they just like react like either they're in the yes or the no camp and you can be in the yeah, it's causal. But also at the same time, if it's high, it doesn't mean you have to lower it. And we still need to ask questions about why is it high and what is the risk in this context. So to finally circle back to the question you asked about, if I could have two conversations, important conversations about this lipid topic, I think I'd have two conversations, one with respect to mechanism. So I would want to have a conversation of why does LDL go up and why does the reason matter? Where we could actually pick apart differences like what is familial hypercholesterolemia, what is a lean mass hyper responder and why are they so different and what can we learn from those differences? And then the other question I'd have, so you have the mechanism discussion, then you have the risk discussion. The risk discussion starts in the premise that this is a risk factor. However, just because something is a risk does not tell you the degree of the risk or what you need to do about it. Because there are risks imposed by interventions, be those pills or lifestyle changes. And so that discussion that you asked about was like, what does the individual do? Let's go through different patient cases.
- [40:22]
B
Yeah.
- [40:22]
A
With high LDL and say how could risk differences here based on non apple b, non LDL factors influence people's decision making and how do we go about actually making conservative, responsible choices, which in some cases might be statin therapy and in some cases it might not be. And just to have an open minded discussion about that, because the etiology, the physiological cause does matter with respect to risk. And really importantly, we need to have a discussion with respect to risk and mechanism. Of, like, what are the boundaries of what we know and what we don't? Because, like, with respect to lean mass hyper responders, people just say like they are. They stand on a pedestal to say, like, this is or isn't a high risk profile. And like, we don't know. We have one study, one preliminary study on it. We're asking the question, what is the risk profile? This is a totally legitimate scientific question. Don't put words in my mouth that I said it's low risk. I'm saying this is unique. We've never had a population like this before. We have so much to learn from them. And doesn't this patient population deserve to be studied to understand what's going on in their own body, mechanistically, and also what the risk profile is? Because nobody who's not lying through their teeth can tell you they know the risk profile.
- [41:42]
B
But I think this is also, I think it's prominent in actual patient care. And it brings up public health policy right now, because who is spending, what physician is spending more than 15 minutes in the public setting? Unless you're, you know, if you're going to a private, you know, doctor and you're paying a lot of money, how long are they spending with the patient to get to the bottom of this? Not that long.
- [42:06]
A
That's true. And that brings up another. There was like a short back and forth I had on Twitter the other day where somebody told me, in their opinion, the best thing somebody can do with a large platform is give broad pieces of advice that would work for most people most of the time. And I push back on that. And the reason I push back on that is because if we take a step back for a moment and look at how people are feeling about health advice given by either the government or by conventional medicine, it's not controversial. Just takes two eyes and a couple ears to notice. People are pissed off. There is a gap of trust. People are frustrated. And I think one of the major points of frustration is even if you don't know the nuances of the science, you can tell when you're being condescended to, and it feels really shitty. And I think people pick up on that, on the condescension where they're like, all right, you're not smart enough to understand the nuances here. I don't have the time to explain them to you or even try to explain them to you. So here's the thing that should work for most people. Eat more fiber, eat less saturated fat, yada, yada, yada. You Know the platitudes, eat a balanced diet, whatever that means, and it pisses people off because it's hollow, it's empty, it lacks nuance. And so I appreciate, and I fully acknowledge that sometimes getting into the weeds, the verbal precision, the nuance can confuse people. I am not denying that I have confused people. I'm not saying I won't confuse people again. In fact, I kind of like when people get confused, provided they can follow up on that curiosity. But my challenge to the audience, not just mine, is to chase that confusion and be like, is there someone here, someone here who's actually trying to help me learn and think properly and understand the nuance? You might not get it immediately, but I think it's more dangerous to shill out platitudes than it is to potentially confuse people by trying to communicate nuance, even if it's difficult and even if it's going to generate confusion sometimes.
- [44:16]
B
Yeah. What I love most about what you do is you fight back at very popular people about your differing opinions. I've seen you, I. I don't know if you would call it a fight back, but I've seen you discuss the multiple claims that is made by Lane Norton, which you've been really, really vocal about.
- [44:36]
A
Yeah, I mean, I. Here's the thing, I. I fancy myself a strategic person and I can hold my punches when it's strategic. But at those times when bridge building efforts do fail, and I've tried to build quite a few bridges with Lane, I don't have trouble standing up to bullies in that particular case to provide a little bit of context, because you brought it up. It's like I had reached out to offer him actually collaboration on. I said I'd let him look at the Oreo versus that before it was published and then give him, you know, credit for giving input because I was just trying to, like, you know, throw out an olive branch for something that I knew, jump on. But then what happened was Lane engaged us in a group chat. Me, my friend Dave Feldman and Professor Adrian Sotomota, our colleague on the meta analysis of randomized control trials that we were talking about. And now if anybody knows Lane, what does he love to talk about? The randomized control trials. So we're in a DM stream, spending our time corresponding over the human randomized control trials, our research on human randomized control trials. And we, you know, are answering all his questions, including about the physiology, some of the oddities, say, in the Oreo versus statin paper or what he found to be oddities. And kind of just taking him at. At good faith like that. He was actually interested and curious and wanted to platform nuance. We also offered to have a discussion with him or if for whatever reason we weren't palatable guests. Our colleagues like Professor William Cromwell, who actually trained Thomas Dasepring, who trained Peter Attia in lipids. He's been doing lipidology for over 30 years. William Cromwell will come discuss this with you on your channel. What Lane ended up doing is solo coverage of the Oreo vs. Statin study where he completely ignored the meta of RCTs, which is kind of hypocritical. Then also misrepresented the physiology. He screwed up on the physiology, even though I had explained it to him multiple times and had screenshots of those explanations and several other things that I thought were just not representing our literature. Now it is the literature we've been publishing on. So if you're going to go and misrepresent it, I'm going to correct you. And the thing that really pushed me over the edge there, you know how Lane is with respect to his, let's just say he has a aggressive personality. So when people were asking him genuine questions, he was getting rude, saying, I'm a F word PhD. You're just a F word eye doctor. Sit down. And I'm like, look, dude, the thing here, you can see it in the video coverage. I just took my phone out and did a response video. I took screenshots from his responses is like, I don't care if we are on different sides of the quote diet tribes or at least optically there. I see a lot of opportunity to have a nuanced discussion in platform nuance. But if you're going to hypocritically ignore the meta of RCTs, screw up on the physiology of our literature, even though I explained it to you, and then bully people asking legitimate questions, yeah, I'm going to stand up to you and I don't care what our relative follower counts are.
- [47:36]
B
What was his claims? What was. Where was the miscommunication?
- [47:40]
A
Well, one, he was, you know, ignoring the broader literature around this and singling out the Oreo vs. Statin study as an n equals 1, which totally is. I'm not pretending like, let's be clear, I'm not trying to change guidelines of the Frickin Oreo vs. Statin study. It was intended to be engagement bait to have people then look at the broader literature that we want people to discuss. Like the meta of RCTs which is where Lane could have played such a valuable role. As somebody who says he values these things, he ignores that. He ignores our positions with respect to risk, and instead of chooses to cherry pick out, like, extremist followers and highlight theirs so that it can kick keto in the butt. And then he just screwed up on some of the physiology. Like, with respect to. There was a triglyceride phenomenon where my triglycerides actually went down. He said that contradicted our model. It actually is entirely consistent and was predicted by our model, which was in the paper. And I explained it to him multiple times. So we just screwed up. And then he was just bullying people. So it's like, you know, I. I felt at liberty to correct him, especially because he was wearing a T shirt that said data over feelings, and then bullying people with these extreme emotions. And I'm like, do you not see the irony here? Like this? This. You're not being data driven. You're trying to pander to your base by, you know, keto bashing, which is a great sport. I get works. And the thing with Lane, and by the way, I'm saying all this because, like, I have tried extensively to talk with him. I am willing to bury the hatchet. I'm not a guy that. That holds a grudge. But because it keeps coming up, like you brought it up, I will correct the record on these things because I actually think it's an interesting case study in, you know, how these quote, wars arise and how different people respond, and you can kind of just take it on the chin and roll forward. That's not how I do it. I thought it deserves some correction. And, you know, after the correction, he did not respond well. He got really upset that I had the audacity to correct him. And, you know, all that said, if he wants to say, look, I was going through a hard time in life, I didn't do the best coverage. Let's forget about Nick. Let's have a conversation. Platform nuance. That'd be great. Like, I don't need to do victory laps or anything. Like, I was correcting the record on our literature. If you actually want a platform nuance, then fantastic. Like, I have no desire to have a feud with anybody, but if somebody is resistant to having the nuanced conversation and they make an error, I'll correct them. I don't care who they are.
- [50:22]
B
So, no, no, I. Look, that's the beauty of it, right? It's a. It's a platform that gives everybody a free pass to say whatever they Want, which is very true with the current administration that's happening here in the United States on the 20th of November. Yeah, so, but I do want to discuss because I know that, you know, we've been going for 50 minutes now and one thing that I got really excited to discuss with you is the phenomenon of the ketogenic diet. We mentioned it briefly but I just want to go into more so mechanism of action of phb because I think it's really interesting, uh, some of the. So I'm currently writing a systematic review which is, which, you know, what is like, it's a, it's killing me right now. Uh, I think I'm going blind. But so many studies are coming up on the effectiveness of ketones for Alzheimer's disease patients, but also those who we call in the pre dementia state, cognitive decline state just to help with better energetics in the brain. But I, it's hard for me to, I'm nowhere near in the nutrition space. So why don't we break it apart by understanding how the ketogenic impacts, the ketogenic diet impacts metabolic health, cognitive function, etc.
- [51:39]
A
Fantastic. So the way I want to break this down is I want to describe like the two natures of ketone bodies as I see them from a high level and so how it might work broadly for these different neurological diseases. And then I want to go into, let's go into two specific. There were two big papers that came out in the last week. One about a new secondary metabolite of ketones and then one about the microbiome. And so we can give some specifics but at a high level. Ketone bodies have two natures. The one nature as an alternative fuel substrate. So if your mitochondria, your cells aren't very good at using sugar, glucose, which is characteristic of Alzheimer's disease, there's decreased glucose uptake and glucose burning in the brain, then you can provide this alternative fuel and this can provide an energetic rescue of sorts. Right. If your engine is not good at using this one fuel and you provide another fuel, you might get some energetic rescue, which is fantastic. So that's the one nature. The other nature, which is, I think the more important but underappreciated one, is that ketone bodies are potent hormones. They circulate in the blood, they bind to receptors on cells, including G protein coupled receptors in cells. They can modify the activity of proteins that change gene expression, the histone deacetylases bhb. The ketone is also itself what's called a post translational modification Which I know you know, but basically where it can bind to different proteins and change their function, it actually attaches physically to over 1400 different proteins and changes the function of each of those proteins toggles them to be more or less active. And so really, in addition to being a fuel, it can overhaul the metabolism and gene expression of cells throughout the body. And through these dual natures it does things like reduce inflammation, it decreases oxidative stress. And that phenomenology, broadly speaking one would think can affect a broad range of conditions, especially in the central nervous system. So there's promise in Parkinson's disease and there's promise in Alzheimer's disease, other diseases like multiple sclerosis. So those are kind of the two broad actions. What I'd also point out is that there are actions that are maybe indirect, like through changes in the microbiome. This was recently shown in a study on multiple sclerosis. Let me see.
- [54:13]
B
Yeah, I brought that up. Also I'm trying to bring a diet dependent host metabolite shapes the gut microbiota to protect from autoimmunity.
- [54:24]
A
Yes, I'm trying. Oh, that was the indole lactate one, right? Yes, yeah. So this was one where basically they showed that, that ketogenic diets could shift the microbiome in a manner that changed. That generated another metabolite, one called indolactate from bacteria in the gut. And that shut down inflammatory cells. Shut down inflammatory cells actually throughout the body. So there were decreases inflammatory cells in the brain. So there are these dual natures. Plus it can act through, you know, things like the microbiome. And there it might act through being turned into. This is very new secondary metabolites whereby. And this, you know, this was for appetite suppression. But a study just came out in cell eight days ago where they find that there's this enzyme that combines the ketone body beta hydroxybutyrate with amino acids. The most common is phenylalanine, but various hydrophobic amino acids and that this acts on the brain to reduce appetite. So there are many, many ways through changes in gene expression, through becoming secondary metabolites, through modifying the microbiome from. For acting as an alternative fuel substrate through which ketogenic diets can affect neurological and autoimmune conditions and mental health conditions, changing things like you know, gaba, glutamate balance excitatory and inhibitory neurotransmitter balance, change serotonin and dopamine levels. I'm kind of doing this shotgun description because the way to think about this from A clinician or clinical. And then like scientific point of view is metabolism is such a complex and messy web that you can do the clinical trials and you can say, does this have an effect? Then you can do the mechanistic studies in mice where you knock out specific genes and you dissect pathways. Those are really complementary. On the one hand, we are now describing all these different ways. We have lists of dozens of. By which ketogenic diets could plausibly impact these conditions. And on the other hand, now we're doing clinical trials that show they do work. To what degree different pathways are more, you know, carrying more of the weight of the therapeutic effect in different individuals in different disease cases, we don't really know. But I would say there is tremendous, there is tremendous progress being made in this sphere and more and more progress will be made if we invest in this research. The difficulty is, with respect to the clinical trials, it's pretty freaking hard to get funding, especially via standard channels. So that creates one other obstacle.
- [57:07]
B
I know, and it's also the whole thing. You've got the old nuanced discussion of people really not understanding if they're in a ketogenic state, but they're taking these exogenous ketones, which are now just marketed and sold absolutely everywhere. And I think people are just not understanding how to take them, why to take them. I do see a lot of people taking these ketone shots, a liquid form. But then there's also. It's just, it, it's, it's a, it's a, it's an area that is exciting to me, but is also nuanced as well.
- [57:35]
A
I agree. I would say high level with respect to exogenous ketones. I, I'm not a. Bear in mind. I, I did my PhD using exogenous ketones. So if I have any reason to be biased, it's biased for them. But my general opinion is they're not that useful for most people most of the time. Yeah, they can be useful in specific athletic circumstances, in conditions where you need therapeutically high levels, which could be very difficult to achieve via standard diet. So, you know, if you go on a standard ketogenic diet, your ketones might be between 1 and 2 millimole. For certain conditions, it might be helpful to have it like at like 4 or 5 millimole. And to get that, you can either go on a very, very restrictive hard ketogenic diet where you really limit not only carbs, but like you're limiting protein. So 87 or 90%, 3 to 1 or 4 to 1 ketogenic diet. Calorie percent of calories are coming from fat. And like a 90 fat diet, that's hard to do. So if you can use exogenous ketones instead and eat a little bit more protein liberally, then like I see that as a use case or for people who are just kind of getting into it and they need a bridge. So like if you find that ketones really give you energy and suppress your appetite, which they do for some people, it might actually have to do with this new paper that just came out and variations in this gene that binds amino acids to ketones. It's a whole nother discussion. But if you empirically find in your N equals one life, that you try this and it makes you feel great, then I think as a bridge it's fine. So it's fine to toy with. But I don't think you're going to get the bang of a ketogenic diet from a ketone supplement. And if you do use it, the salts and the 1, 3 butan dial that ketone IQ makes, they're not very potent. So you can measure the levels in your blood or mcts. Your levels aren't going to go up much. You really need a ketone ester or a free BHB to get them to go high, which are a lot more expensive. When we were doing my PhD, a shot or a whole day's dose of ketone ester cost over a hundred dollars.
- [59:38]
B
Oh, wow.
- [59:38]
A
And, and, and it tastes terrible. Like.
- [59:44]
B
Yes.
- [59:44]
A
Gasoline and nail polish.
- [59:46]
B
Yes.
- [59:47]
A
To the point that like when I would give it to clinical trial participants, I, I'd be like, I brace them. I'd be like, look, I know you're committed to this. I know we have a good rapport going. You like me. I like you. I will warn you, you're gonna hate me after this.
- [60:03]
B
Oh yeah.
- [60:04]
A
It can't be that bad. And they drink it and they're just like, they just turn like, I hate you. I can't believe you're making me do this. It tastes terrible.
- [60:10]
B
It tastes terrible. That was my biggest issue with it.
- [60:13]
A
It's pretty freaking bad.
- [60:16]
B
We're definitely gonna have to do a part two. I just want to end because we, we've got to really dig into your n of 1. But I think we're gonna have to do an entire episode on that. I do want to end with a wonderful paper that you've sent me that I've, I've been trying to break it apart apart ever since you sent it to me, which is epigenetic memory of obesity.
- [60:34]
A
Yes. So let's talk about it. Yeah. So this just came out. Let me get the date on that. Is it like three days ago? Yeah, I think so.
- [60:44]
B
On the 18th of November.
- [60:45]
A
Yes. So in Nature, Nature is a pretty highly regarded journal. It was entitled Adipose Tissue retains Epigenetic Memory of Obesity after weight Loss.
- [60:54]
B
Interesting.
- [60:55]
A
This was pretty fascinating. So we all know the phenomenon of like a yo yo diet where people, like, lose weight and they gain weight back. And the common knowledge is that once you lose weight, you gain it back more quickly. We've probably all heard that. But one has to ask the question, is that just a behavioral phenomenon or is there something metabolic going on? And there were hints in literature previously that there probably is something metabolic going on. And a pretty classic example is studies of biggest loser participants who lose the weight, but then they gain it back. But even once they gain it back, their basal metabolic rate is slowed below baseline, which is interesting. So it's like, is there some sort of scar that's left on the body imprinted somewhere in our metabolism of a prior obese state? So if you lose weight and become lean, are you the same as a person who's always been leaning. And this paper came out, which was really fascinating, which basically says that fat cells retain memory of having once been the fat cells of people with obesity. So what they did in this study is they looked at fat cell samples and other tissue as well from humans who had had obesity. I think the BMI cutoff was 38 and above, but who had underwent bariatric surgery. One of a couple different types of bariatric surgery. I think it was roux en Y and sleeve gastrectomy. And then they had lost weight, at least a quarter of their body mass, I believe. And then they looked at their tissues again and compared them to people who were lean, like, had always been lean. To see, you know, is lean lean, or is there some sort of fingerprint that is left in the fat cell? And what they found is that the fat cell actually had a memory coded into the epigenome. How the genes are tagged and expressed. The way I kind of described it in my Twitter thread is like, all the cells in your body have your entire genetic code. What makes a skin cell a skin cell, an eye cell, an eye cell, and a bone cell a bone cell, the different genes they express. And your genetic code is kind of like a book in different cells. Open the book to different pages and read those pages, and you can also bookmark in dog ear, different pages. You can kind of think of that as like epigenetics. Like you can add a bookmark here, you can add a dog ear here, so it's easier to get to the pages. And what they found is that fat cells of people who had been obese, even if they didn't any longer have obesity, had an epigenetic memory such that they tended to be more pro inflammatory, produced inflammatory cytokines, which is not good, and had down regulated metabolic pathways like fatty acid oxidation and fat burning. Now, I will say there are some more questions raised and limitations to this paper. So the one thing was they were looking at patients with bariatric surgery, not with diet induced weight loss. Now, they used a mouse model of diet induced weight loss and had similar results. So I do think these would probably generalize, but one, we don't know. You know, losing weight, say on a ketogenic diet or other, you know, healthy lifestyle pattern would have the same effect. Also, we don't know if the scar fades. So they looked at people two years after bariatric surgery. Now, two years is not a short time period, but obesity develops over years to decades. You don't just wake up one day with a BMI over 38. The timeframe over which these individuals had been leaner, bearing in mind they didn't immediately get bariatric surgery and drop from a BMI of 38 to a BMI of 25. It took time, is actually pretty small. I wonder if it was 10 years down the line, would that epigenetic memory still be there or would it fade over time? Which is actually a very hopeful message, I think. And I think it's a highly probable event because what it says is, or this is one way to interpret it from like a silver linings perspective, is yeah, if you've had obesity and you're, you've just lost weight, you might be a little bit behind the eight ball, metabolically speaking, as compared to someone who had always been lean.
- [64:51]
B
But.
- [64:52]
A
But maybe if you stick with it long enough, it gets easier because this epigenetic memory may be phased. That's speculation, but I think it's a, a highly probable event. And then another question that arises is there was actually epigenetic memory in other tissues, like the endothelial cells that line blood vessels. So this could have impacts on cardiovascular risk. But what about like neurons and brain cells? Where else do the metabolic insults that we've been exposed to either through prior obesity, environmental, you know, pollutants, prior, just extreme stress, maybe from like MD PhDs training. Where are those epigenetic memories harbored and what effects are they having on us today? And then maybe what we can intervene to do to change them. So it's a really cool paper. I have a video on it in production that obviously I'll drop on my YouTube channel and I have threads and newsletters on it already. But what I would say, just as like, if you found that complex and interesting, that is what I think about when I think about nutrition science and metabolic science. I know it's confusing and frustrating and you're going to use platitudes left and right, but that kind of cool science is what I love. It's what I love to communicate because I feel like by understanding that we gain so much power in order to like leverage and optimize our lives. And I see this in people, in patients, how they really can like transform their existence just by getting metabolically curious and hearing things like the things I just said and not, you know, glossing over them and thinking, cool, I want to learn more. And once you kind of unlock that metabolic curiosity, I mean, like, I think it's the number one tool in people's arsenal to becoming metabolically optimized and healthy.
- [66:34]
B
Oh, look, it affects every area of life. I have a friend who, I tell you, one of my very closest friends, over a two year period, she was trying to fall pregnant. She was doing everything and once she got more metabolically fit, she ended up, she ended up falling pregnant naturally. But what happened was she went and did the whole IVF process, which is, you know, egg freezing and then, and then mixing the egg and sperm, et cetera. But she, her fertility doctor said you'll get more of a better response, I. E. Whether it's through natural conception or whether we're going to draw out more eggs if you become leaner. And so she went down this path of metabolic health and fitness and, etc, and it yield much better results. So it doesn't just affect how you feel, maybe your, your lipid profile, but also it can affect fertility as well.
- [67:28]
A
It affects everything. Do you know Dave Dana? So should I? You should. You should look him up. He's not a scientist, he's not a researcher. I highlight him in a paper or an op ed, not a paper I published on paving the path for N equals one science. Because my whole shtick is like, everybody can be an N equals one scientist. You don't need medical or scientific training. It's just about identifying in your life what outcome matters to you. Hypothesizing about what will improve that outcome, then testing it and then assessing the results with curiosity, not self criticism and then just iterating. And he basically, you know, this was a guy that I met when he, I met him, he was over £400, suffered from depression, financial strain. But he's one of these people who was just like, I'm motivated to get healthy and I am going to engage in the n equals 1 science process, ask questions about my health, try to implement things, assess things as I can and iterate with curiosity, not judgment. What happened was not only did he end up losing more weight than I weigh and looks fantastic, he ended up, you know, his financial affairs got in order, his mental health's incredible, he got married, he finished an MBA and I got fired as his quote, effective coach. If you look him up, he's now standing in Venice beach, muscle beach with Arnold Schwarzenegger training and going to Arnold's house. I am not kidding you whatsoever. So this was someone who was like, he, he now posts videos from back when he was over 400 pounds, depressed, eating pizza in bed in his boxers to hanging out with Arnold Schwarzenegger, being married with an MDA mba, buying his house and fixing it up with his girlfriend and their new cat Peaches. Like think about how that life transformed.
- [69:18]
B
Oh yeah.
- [69:19]
A
One metabolic health approach. And he didn't have a medical or scientific background. He just was like, you know, I'm curious about my metabolic health and I'm going to create a support system around me and just engage in this process of being like, you know, I'm interested. Will this help me? Will this not help me? Did it help me? Did it not help me? Why not? Let's try this other thing and just iterating and iterating and iterating and you end up in a place that you could never have imagined. And I really believe everybody can achieve that. I truly do.
- [69:47]
B
My last question just before we wrap up is what are your thoughts on Tirzepatide?
- [69:53]
A
Tirzepatide. So I mean the GLP1 agonist class of medications generally, or Tirzepatide specifically?
- [70:00]
B
Tirzepatide specifically, because I know it crosses over to both GLP1 and GIP. GIP, yes.
- [70:07]
A
So I have not done a deep clinical dive. My understanding is in addition to the GLP1 effects, tirzepatide has effects on the GIP axis, which is another incretin hormone and tends to have a little bit stronger weight loss effects than the standard GLP1s. I, you know, I'M interested in that secondary GIP effect because of the mechanism of action. So specifically as I understand it, I forget what journal this was published in. I think was Nature Metabolism. But there are GIP but not really GLP1 receptors on fat cells. And one of the things that Tirzepati does through its chronic agonist effect on adipocytes fat cells is effectively make the fat cells more flexible, more metabolically flexible. It combined there and in the fasted state enhances lipolysis and in the postprandial after feeding state increases glucose uptake to help stabilize blood sugar levels. So simplified. I think one of the things it does beyond GLP1s is actually enhance metabolic flexibility. So from a first principles perspective at the fat cell, I think it's a pretty cool mechanism that I would be quote fond of. I'll send you the paper on that if you want in a video I, I, I did on it. But I think you know, with these, this generation of weight loss medications I have mixed feelings. My, my, my, my high level feeling about the obesity medicine ecosystem in general is it's a really dangerous game to presume we're going to pharma our way out of this and just you know, lose sight of the bigger picture which is metabolic health and lifestyle. Like this is if this becomes an arm war between pharma and Big Food, Big Food is going to win and pharma to some extent in that they're making money, the individual is not going to win. So we shouldn't get complacent with respect to our food environment and lifestyle interventions. But in the best circumstances I do think that these medications on an individual level can act as catalysts for lifestyle change. But we now know how GLP1s work to some extent in the brain and the dorsal medial hypothalamus to reduce food noise and you know that, that, like that, that chatter around food and the need to you know, grab a piece of food if it's out in front of you, you know, what is your Achilles heel? Food. And if you can then give somebody something that gives them the moment in their mind and the pre ingestion satiety to see the food out in front of them be like, you know, I really don't think the cupcake is good for me. I'm actually going to like, you know, make a healthier food choice. I do think that these medications can help some people as catalyst to lifestyle change in a difficult food environment that they wouldn't be able to achieve otherwise. So I, I think they have their place. I just think on a population level, it's a dangerous game to be playing to be like, this is the solution, let's throw them out like candy. Which I know is, is a hyperbolic expression of what's really going on, but not that hyperbolic. You look at our food environment and you look how people talk about this. It's like we really do need to address the root cause. So I think tirzepatite is interesting for the reasons I just explained mechanistically. I'm not going to preach to any individual about whether they should or should not take it. I would just say big picture. We should not lose sight of the big picture, which involves the food ecosystem and making the right health choices. And if this can be part of the solution, a catalyst and fantastic.
- [73:34]
B
Well, Nick, I am so happy that we're, we're now friends and I, I love the conversations we're having. I love what you're doing with everybody with your degrees, actually. I love how you're putting it out there into the world and explaining it the way that you do. It's very different from the way that everybody else is. I definitely think we need to do a part two, most likely a part three because we, we sent a structure to each other and I think we got through like a third of it. So I'm excited for that. We're going to put everything on, but most you, most of the time you're hanging out on YouTube, correct?
- [74:05]
A
Yeah, I'm on Twitter, I'm on YouTube. I'm trying to become more active on Instagram. Those are my big three. I have a newsletter website I'm trying to get everywhere because I'm told that's what you should do.
- [74:16]
B
So yeah, I love that.
- [74:18]
A
Like I'm like 6ish months in of being serious. But the YouTube is the funnest because you actually get the bandwidth. Like I'm going to break down through the lens of Harry Potter of like, you can get creative fun with the thumbnails. Like, I do enjoy the YouTube the most.
- [74:31]
B
I love that. I'll link everything below. Thanks, Nick.
- [74:34]
A
Thank you so much.