Keto Saved My Life — The Future of Metabolic Medicine | Nick Norwitz PhD MD

I often say the most remarkable thing about my story is it's not at all unique. People suffering with chronic diseases to become desperate to try something that's out of the mainstream and then it works. And then you're left bothered about why nobody told you about this before.

Welcome back to the Health Longevity Secrets Show, where we push the limits of human potential and unlock the secrets to our health and longevity with your host, Dr. Robert Lufkin. In this episode, Dr. Nick Norwitz, a PhD in human metabolism and a freshly minted Harvard MD, shares how disease nearly ended his career before a specific diet put him in complete remission. We dive into why evidence-based doesn't always mean best care, how wearables and CGMs are rewriting the rules of diagnosis, and while— why tools like keto fiber, fermented foods, and even GLP-1 medications can radically change the future of metabolic and brain health. Stick around for some great tips. And now, please enjoy this week's episode. Hey, Nick, welcome to the program.

Thanks for having me, Rob. Nice to be here.

It's, it's so good. As I was saying offline, it's so great. I've, you know, followed you for a long time. It's, it's always It's always great seeing someone that you respect and follow and learn from to finally meet, if only it's from Zoom from California to Boston. But still, that works. And you're one of the— you know, you're truly a leader in the metabolic space, as your degrees show and everything. And before we jump in, though, you have an interesting story that that our listeners may not have heard yet. Maybe you could start off with that and just kind of tell us how you came to be interested in this area and become so passionate about it.

Thanks. Thanks for the generous intro. It feels weird being referred to as like a leader in the space. I feel like I'm just getting my lift off, but I guess that'll come, come in my story. So for those who, you know, don't know me, don't know my name, my name is Nick. I'm a 29-year-old living in Boston, Massachusetts. I just finished up my time at Harvard Medical School. And have somehow found myself in this metabolic health space. So how did I get there? Well, I grew up in a medical and scientific household. Both my parents are actually academic physicians, both MD-PhDs. And I always loved science. I always held the highest respect for medicine. So it was just kind of the default that I would practice my exploration of science through the practice of medicine. So I always envisioned becoming a physician and becoming an academician, a scientist. So, you know, MD for sure, maybe a PhD. And so as I was going into finish up college, I went to college at Dartmouth in Hanover, New Hampshire, and then going on to grad school, I went to Oxford for my PhD in human metabolism, in particular brain metabolism, before going to medical school at Harvard. At the end of college and at the beginning of graduate school, I was really struggling with inflammatory bowel disease. So specifically ulcerative colitis. For those who don't know, apologies for being graphic, but people get IBS, like tummy troubles, constipation, diarrhea, and inflammatory bowel disease a little confused. To be clear about what I was experiencing in my everyday life: bloody diarrhea a dozen-plus times per day. I was deteriorating physically, and because of the uncontrollable nature of the disease, um, the pain and ultimately the malnourishment that resulted from just not being able to eat well, I started to really deteriorate. So I went from being a pretty competitive athlete, even at age 17 I was a sub-3 marathoner, I was setting like push-up records in high school and was very academically inclined, to being pretty not only frail physically but withdrawn socially and not struggling academically in the I'm having trouble choosing the right answer on an exam kind of struggling, but Academics become really hard when you can't like sit for an exam because you're worried about having to run to the bathroom streaking red, or, um, you know, just being able to spend enough time in lab because you're having medical emergencies. So when I was in grad school, I was in the hospital a lot, at least at the beginning. So I was really losing a lot of myself. Um, and while all my opportunities were nice on paper, I was just like deteriorating as a person. Um, that brought me to a place of desperation. I think a lot of people have been there. I don't need to talk about what it was like, but anybody who's been there has a loved one who's been in that kind of space, headspace, knows that you're willing to try anything. So I got to this point where I diverted from the mainstream and what is quote-unquote evidence-based. We can get into, you know, why I put quotes around evidence-based later if we have time. But I started trying different things, not out of expectation but of desperation, and eventually I found a ketogenic diet was tremendously impactful for my inflammatory bowel disease and overall quality of life. So I went into remission clinically based on biomarkers, based on biopsies on my colonoscopy, and complete remission, like my disease was gone. That allowed me to finish up my PhD and go to medical school and complete medical school. So sorry, I'm being long-winded, but the point is that personal experience really framed how I went through my graduate-level studies and how I went through medical school. And what I started to notice was that my story arc was patterned. I often say the most remarkable thing about my story is it's not at all unique. People suffering with chronic diseases to become desperate to try something that's out of the mainstream, and then it works. And then you're left bothered about why nobody told you about this before. So I'm going to kind of leave it there as to how I got interested in this space. I'm not leaving with a chip on my shoulder or salty. I have a little bit of a different perspective, but that is what originally drew me into metabolic health, ketogenic diet, healthspan, longevity, and looking at the science through a very different lens than I ever could have imagined.

And, and your, your journey is, is really unique. You know, you, you said you, your PhD at Oxford in, in essentially metabolism-related things, and then and then to one of, you know, top medical school, finishing a medical education at Harvard Medical School. And so I guess the question is, what, how were those different in changing your views of metabolic health as you went through those? And, you know, I've got a 16-year-old daughter who's asking me, hey, Daddy's a doctor, should I go to medical school? Should I go to science to study this or that? Well, how is that, how is that experience informed your, your view through the process? And if you had to do it again, what would that look like?

Yeah, that's a very good question, an important question to ask and a difficult question to answer. Um, you know, for me, I think the thing that, that caught my attention most about medical school is observing what was not taught. And what was not cared for. And the kind of things that, you know, I got up and read about in the pages of Nature, Cell, Cell Metabolism, Science is omitted from medical school. And it's not omitted because, you know, the instructors don't think it's important. It's omitted because of, I think, the larger incentive structures that determine what is modern conventional medicine. Let me unpack that a little bit more. I am not the kind of person that will promote conspiracy theories around Big Pharma wanting to make us sick. I don't think there's malintent in the medical system, the pharmaceutical industry, etc. I think the problem is a little bit more complex in that we have a particular business model in medicine that is predicated on this idea of pills and procedures are reimbursable and make money. So there's an industry to develop these, and some of these can be life-saving. It's really amazing what we can do in certain circumstances, particularly acute care circumstances. But that does leave a large deficit around the metabolic health diseases that are plaguing society. And so I think the reason the metabolic health interventions that might be so efficacious for metabolic health autoimmune inflammatory diseases don't get a lot of play is because the most powerful interventions are not necessarily the most lucrative ones. And so one thing I want to point out and unpack is that quote unquote evidence-based care is not actually optimal care. And what I mean by that is, let's take my experience as an example. A ketogenic diet saved my life. I can't point you to any randomized controlled trial saying, hey, a ketogenic diet is good for inflammatory bowel disease, because they've never been conducted. So it's not that it's not efficacious, it's that the study's never been done to check the box to make it standard of care. Why has the study never been done? Because to do it well is a $10 million study. It's very difficult to conduct, and nobody wants to fund it because nobody's going to make money. It's not because they're evil, it's just because the spotlight of biomedical sciences and what eventually becomes medical standard of care is directed by incentive structures in a business model. And so I had a very different perspective on what evidence-based care is going through medical school, given my experience, than what I imagined it to be before. Because I imagined it to be like, you know, what it sounds like, this great virtue signal, the best care.. And I realized it wasn't that. And I think I, I became really bothered by that fact, not angry at anybody, just sad because that circumstance sets us up for what we have, which is a metabolically sick population that's not getting healthier because we're not looking for the solutions in the right place. And we're not looking for the solutions in the right place because the current business model doesn't incentivize that. So I do think there's a solution, and this is where I'm very optimistic. Which is exactly what we're doing here. With the rise of public access to information and social media, which has its pros and cons, you don't have to wait for something to become conventional standard of care to gain access to tools that can literally save lives. So that really changed my passion, redirected me towards, you know, getting the research done and communicating about it. Now, I guess my answer to the question, how do I see medicine? I see medicine as an evolving team sport. And my position on that team, I feel, is more situated towards exploring and developing the research and communicating that research more so than necessarily sitting one-on-one with a patient in a clinic, which is what I imagined when I was 15. Um, so yeah, that's my answer.

Yeah, I mean, I, I think you and I are on the same page on that. I've, I've heard people say, and I've, I've experienced this with my, my colleagues practicing medicine, is that, that doctors are— doctors really don't make us healthy. They just make us less sick, you know? And, uh, doctors are very busy managing disease. And these chronic diseases that you mentioned begin so many years beforehand that that opportunity for prevention really isn't taken advantage of by doctors just cuz they don't have the time and the business structure's not set up for it. There's no reimbursement. So I'm with you. This is such an exciting time, this whole new field where people at home draw their own blood, you know, and they send it off, they follow markers, and they get healthy even though they're not— maybe they haven't crossed the border for being sick yet, but they're, you know, they're making themselves healthier and healthier and healthier. This wellness movement is so exciting. You How do you— are you on the— what's your take on that?

I think it's incredibly cool how people are being empowered with their own data. You mentioned like, you know, testing your own data at home, biomonitoring. I think that biofeedback, having your data in your own hands and combining that with education is incredibly powerful. I really have seen it transform lives, and I think as the wearable biohacking, whatever term you want to use, space is evolving. We're just going to have more and more tools for people. I was just talking with, I don't know if you know Michael Snyder at Stanford. He's— sure, yeah, of course. Yeah, yeah, leader, leader in, um, in advanced multi-omic testing. But some of the work they're doing, just to kind of give an example of how this is evolving, they were looking at different causes of diabetes Now, people might not be aware, um, there are kind of 4 primary causes of, uh, even type 2 diabetes: muscle insulin resistance, liver dysfunction, beta cell dysfunction, and incretin dysfunction, so GLP-1. Now, the reason I'm bringing this up is because in each individual who has like prediabetes or diabetes, there's usually a dominant underlying pathology. And based on which of those 4 is dominant in that individual, the effective treatment structures are potentially going to be different. Um, so if you have muscle insulin resistance, you know, building up muscle mass might be not as powerful, and different drugs might work as opposed to, say, somebody with, uh, beta cell dysfunction. And you also might be responsive to different foods. We can go another rabbit hole on that. But the reason I bring it up is because if you think about how rudimentary our testing is for, like, diabetes— like, what's your average blood sugar? All right, diagnosis. Or oral glucose tolerance test, you just take You know, a time point, a single time point. But what they did in their research, and there are many more like this, is they did like state-of-the-art testing to figure out, okay, in one cohort what the underlying pathologies were. Then they used machine learning and big data sets, uh, attached continuous glucose monitors to people, which now is, you know, over-the-counter available. And through the machine learning algorithm, The AI basically could decode a pattern from the shape of the glucose curve, not the point at 2 hours, but like exactly how it rose and fell and dipped at different points and see within that the underlying pathology with pretty good sensitivity and specificity. So the reason I bring this up is because this kind of technology in the coming years is going to be built into like phone apps. So you can have a Dexcom on your arm, eat some grapes, and not only will it say, hey, your blood sugar went up, but it's going to say, hey, your blood sugar went up and the exact shape of this curve tells me that your type of diabetes is primarily caused by beta cell dysfunction, not muscle insulin resistance, and that means you should do XYZ with precision. Like, that is where we're going, and that's cool.

That—

yeah, that is so, so exciting. Yeah, yeah, shout out to Mike Schneider, his company. He's done some— some of his companies, the one with, uh, the multiple blood tests, uh, 500 metabolomic markers, is exciting. Anyway, he's going to be on the podcast coming up, so we'll get to hear from him. But that is That is so exciting. Back to your, back to your thing with the inflammatory bowel disease. I mean, the, um, uh, you, you basically, um, you, you published a case series on ketogenic diet/carnivore, and I assume it's the ketogenic part, not necessarily the carnivore part, but about anyway, about for IBD, um, which— what did you learn from that?

Yeah, again, this is occupying the space of there isn't good RCT-level evidence. So we do the best we can with the resources we have. Resources I have are pretty minimal, but what I can do is say, hey, are there other people like me? What are their stories? And also, does this make sense physiologically? So effectively what we did is we collected patient cases from 10 patients who had originally attested to having put their disease into remission with a carnivore or ketogenic diet. I'll get into why carnivores skew in a moment. And then we didn't just take their word for it, but we went and we made sure they had a clinical diagnosis of inflammatory bowel disease confirmed on colonoscopy, so Crohn's or colitis. And then we did, you know, a formal medical case history, did dietary records including prospective dietary records. So, you know, we tried to do this all by the book and get as much detail as possible. And basically we were able to document that in these self-selected cases, they were pretty incredible stories like mine of reversal, or at least complete remission of inflammatory bowel disease. People that have been on many harsh medications, some people that have had, you know, parts or even their entire colon removed, and even that wasn't efficacious. And then they changed their diet and they went into remission. And, you know, we shared some quotes in the case series about patients talking about their own experience, but people talking like, I'm literally a different human being now. Like, I suffered with this disease for so many years, and then I changed my diet and I become a new person. I have like a new light in life. And we were focusing on that case series on inflammatory bowel disease, but it's a pattern we see recapitulated again and again and again in the literature. A big trial just came out of Ohio State for ketogenic diets for depression in college students. Again, the same pattern. Um, just to briefly speak about the mechanisms. So, you know, we have clinical narratives saying this potentially can work. It makes sense physiologically too on many levels. So first of all, there's the elimination aspect. There's probably a component of like you just eliminate certain things from your diet and that might be therapeutic. Fiber actually might be one of them. We'll talk about that in a minute. But also ketones are very healing. They're anti-inflammatory. Including in the gut, and they help with stem cell renewal in the gut. So you're reducing inflammation in inflammatory bowel disease, changing macrophage polarity, helping with, you know, the intestinal stem cell niche, stem cell renewal. All this is in literature. And then there may be an additional benefit therapeutically of fiber elimination in ulcerative colitis and Crohn's disease. It's actually known It's not talked about, but it's pretty well known that fiber elimination is therapeutic in treatment-resistant cases of Crohn's disease, particularly pediatric. So if kids aren't resistant, they'll put them on these fiber-free liquid diets. In about 60 to 85% of cases, the kids go into remission. And the reason it's not talked about more is because it's assumed to be quote-unquote unpalatable and unpleasant. But it's funny because this is actually like conventional care medicine, eliminating fiber, not in the ketogenic sense in that particular case, but putting two and two together, you take fiber elimination and keto, you could have a high-fat carnivore diet. And setting aside the stigma that comes with that quote-unquote extreme diet, there's just a lot of biological rationale for thinking, hey, this could be very powerful in inflammatory bowel disease. And I just want to head off the criticisms on that, which is at no point did I say, hey, that means carnivore is best for all humans, or hey, carnivore is like the best for longevity. I didn't say that. But when you're talking about particular disease conditions and treatments, you need to like specifically talk to that disease state. So my interest in writing that case series was to kind of raise the questions, could ketogenic and carnivore diets really be life-saving in inflammatory bowel disease in particular, which is pretty debilitating condition, I can tell you from experience.

Yeah. The, the, the whole idea of ketogenic diets or being in ketosis, it's, it's fascinating how, you know, like you say, inflammatory bowel disease, well, depression, Alzheimer's disease, cancer, diabetes, heart disease, you know, there, there's evidence almost, almost any of the chronic diseases, there's an advantage to being in ketosis as a basic, basic metabolic mechanism. Before we talk about that, let's just define— if somebody wants to be in, in a healthy diet, what does a ketogenic diet mean for you? Or what is— how do they know? I mean, urine ketones are not that reliable after— so what, what if I want to be in a healthy ketogenic diet, what should I do?

So, the first thing I like to say is ketogenic diet or the ketogenic diet, it's a pet peeve of mine, is a misnomer. There is no the ketogenic diet, right? Because unlike other diets that are defined by, you know, the source of the food, like, you know, plant-based from plants, animal-based from animals, Mediterranean, presumably from the Mediterranean region, a ketogenic diet is just defined by the metabolic state of ketosis. So it's perpendicular to other diets because it's defined by a metabolic state. So practically speaking, it does mean you need to keep your carbohydrates low. There are different thresholds, it's going to depend on your age, body size, activity level, but I would say below 25 grams of net carbs is probably a ketogenic range. You can measure that with a finger stick. They do have breath meters and urine sticks, they're not as good. And the urine sticks, to your point, will only last and/or work for the first, you know, several weeks to months. But I would say a finger stick, it's not very painful. In fact, as a little fun tip, don't go in like the middle of your finger. If you go to like the side of your thumb, it's usually less painful. There's less sensors there, so you barely feel it. I have no affiliation, but I use Keto Mojo, and you just kind of want to test the same time every morning, maybe an hour after waking, before eating, and see where your ketone levels are at, targeting a level above 0.5 millimole is generally the threshold for what's called nutritional ketosis. So if you're achieving that, which you can do by eating below 25 grams of carbs per day for most people, then you are, you know, ketogenic. You're on a ketogenic diet. That can mean very different things for different people. Can be carnivore, can be vegan, can be anything in between. So my job here is not to be prescriptive on like what that looks like for any individual.. But that's a ketogenic diet.

And for people who don't have access to Keto Mojo or other specific ketone monitors, let's say I'm wearing a CGM, if I keep my glucose really flat with no spikes at, at all, is that an indicator that I'm, I'm very few carbs, right?

Yeah.

I would say I'll probably intuit it more off the carb count. I'm saying if you're below 25 grams, you're probably going into ketosis. A glucose level doesn't necessarily indicate ketosis. Um, I wouldn't also like— things can spike glucose that can actually promote ketogenesis in the longer term. So say you do like a hard workout, your glucose is going to spike. Or you're going to sauna, your glucose is going to spike. Um, but that won't necessarily hinder your ketogenesis over the long term. Now, if you're doing HIIT exercise, the ketones will go down for a moment. But I wouldn't suggest trying to figure out if you're in ketosis off of a CGM.

So, so ideally we want to be in this healthy metabolic state. We want low carbs, we want to be in ketosis. Um, uh, seed oils, yes or no? Or do you want to weigh in on it?

Oh, that's— we need like 6 hours to talk about that. I think actually about, uh, no, I want to, I want to delve into it a little bit at a high level because I think it's a very misunderstood area. Actually, I just got out of a 3.5-hour debate with Paul Saladino on Danny Jones around it. So people listen to that. But yeah, at a high level, I think the first question we need to ask about, I mean, somebody says seed oils is what are we actually talking about? If we're talking about highly processed industrialized oils that have been heated, refined, have chemical additives to them and have been put into like a, you know, clear plastic bottle on the shelf, Basic logic precautionary principle would say you probably can do better. And I'll say what'll happen is the fats can get damaged. Um, you know, there can be chemicals that have been added to these oils that can actually damage your body. But the reason I want to caution against the whole seed oil fearmongering broadly is because what I see in social media is this inappropriate logic domino chain where a lot of the focus is placed on omega-6 fats. So sometimes seed oils and omega-6 are talked about interchangeably. So polyunsaturated fats include omega-3 and omega-6. People have heard maybe omega-6 linoleic acids talk about as quote unquote inflammatory. If you look at the literature, it's not that clear cut. I mean, higher levels of omega-6, including higher tissue levels, actually associate with better outcomes and lower levels of inflammation. I'm not saying you should go eat 10 handfuls of walnuts, but I just want to raise the idea that it really depends what you do with these omega-6 and linoleic acid, both outside the body and inside the body. Have they been heated and refined? If you're eating them What is your metabolic state? So for example, if you have obesity, your fat cells make certain enzymes, ones called myeloperoxidase, that can oxidize fats and polyunsaturated fats as compared to somebody who's leaner. So say obesity might be a more omega-6 susceptible state, as can aging. And then there are, you know, lifestyle interventions that can change the fate of omega-6 when you eat them. So for example, If you expose yourself to cold, your brown and beige fat turns omega-6, particularly linoleic acid, into a compound called 12,13-DiHOME, which actually has anti-aging properties on the heart. It fights against perivascular fibrosis. This is in, in human trials. They've shown that you can increase levels of this cold exposure and that they decline with age. We don't need to go into the molecular details about all the different fates of omega-6. The high-level point is omega-6, not bad per se. Theoretically, could you overdose it? Maybe. But don't fear walnuts, tahini, whole natural foods. Highly processed industrialized oils, you can probably do better. I like cooking with ghee and avocado oil and then dressing with olive oil or maybe some sesame oil.

But yeah.

So before we leave ketosis in general, the diagnosis, so I'm I'm having a key, uh, metabolically healthy diet. I'm in ketosis. I'm low carb, seed oils, maybe, maybe not. We'll see. Well, avoid the highly industrialized ones. Yeah.

Highly.

I would avoid those ones and fried foods, certainly the high temperature things and all that. So we'll leave that. What about adding on, um, intermittent fasting or extended intermittent fasting? I'm already in ketosis. What is there any added value to that? Metabolically.

I think they go hand in hand. So intermittent fasting or time-restricted feeding can naturally enhance ketosis. Um, also if you're already low-carb keto, then you're very good at burning body fat. So it should be a lot easier to time-restrict feeding. So for example, I do, you know, either an 18:6 or a 16:8, which means basically my feeding window is 6 or 8 hours on average per day. I like that more 'cause I don't really feel like eating in the morning. I wanna be light when I have my workout and I, it's just easier and nicer to have two large meals rather than like this snacking and grazing bit. So I actually think they pair together very nicely. And there is very little disadvantage except maybe for those people who really struggle to get in enough protein, but that's pretty rare. Maybe for like older women who for some reason can only tolerate like 20, 24 grams of protein per meal. But for the most part, 2 meals a day, 8-hour feeding window, it's pretty doable. Longer-term fasts can just get you into deeper ketosis. There probably are some additional, uh, ketone-independent benefits. So biomolecules that go up when you just restrict overall food intake, you know, it's, it's a cost-benefit analysis. If you fast for 7 days, you're gonna lose some lean mass. So if you're like a very lean person already with not a lot of fat or muscle to lose, I'd probably say it wouldn't be my preference to do a whole week-long fast, but they can be done safely. And so prolonged fasts for like, you know, a day or two, if you enjoy them, probably do have some additional benefits, but they're not a must if you don't enjoy them. That's what I'd say. They're like lifestyle flexibility and nice little metabolic challenges.

Yeah. Yeah. In the, in the break, we were talking about your interest in neurodegenerative diseases. I mean, the ketogenic diet helps the whole spectrum of metabolic disease, which for many cases, neurodegenerative disease has a strong metabolic component, we're finding out. So tell, talk about your interest in that and what you're doing there.

Yeah, no, my PhD was actually on the particular topic of ketones in neurodegenerative diseases, so I'm somewhat well read on them. Maybe my brain's not working now. There's so much we could talk about.

I mean, here, here's one, one question while you're thinking. People always ask about exogenous ketones and certainly for Alzheimer's disease, famously with Mary Kelly and others who've written anecdotally about, you know, Mary Newport. Newport. Yeah, sorry, not Mary Kelly. Yeah, Newport. Yes. My Alzheimer's is kicking in. But how, how exogenous ketones work. Seem to work for some patients, not all patients, but some patients with Alzheimer's disease, just like ketogenic diets do. Whereas going a little bit different but similar, mental health, talking to Chris Palmer and, and others in that space, I specifically ask them about, about exogenous ketones and they go, no, doesn't work. You have to do it from a diet. It was interesting that, that I wonder why that is.

I think, okay, so the diet has— a ketogenic diet has particular benefits over exogenous ketones. One benefit will be higher overall levels of ketones in terms of steady state, because when you take an exogenous ketone, for the most part, it spikes it and then it drops back down. So say, for example, when you're sleeping, levels are going to be low if you're on a mixed diet having exogenous ketones. Um, in addition, there's other components of the diet that just might be beneficial in addition to just the ketones themselves, you're shifting your entire metabolic state towards more of a fat-based metabolism rather than just adding on a biomolecule. And that said, I do think that there are benefits that can be exerted from exogenous ketones alone. I think in terms of correcting or supplementing for metabolic deficit in glucose metabolism, there can be benefit. So in manifest Alzheimer's disease, generally glucose metabolism is very impaired. So giving an exogenous ketone source or something like coconut oil or MCTs that help make more ketones that are very ketogenic, it can improve symptoms in cognition, at least acutely. To what extent it's protective, it's not exactly clear. And the same could be true in things like depression. I mean, ketones are anti-inflammatory, reduce neuroinflammation, that can have direct effects on cognitive health. In fact, certain cytokines, inflammatory molecules in the brain, themselves operate as neurotransmitters and can change mental state. So one's called, for example, IL-17. Itself acts in, in the brain. It's an inflammatory molecule as a neurotransmitter that turns up anxiety. But yeah, I do think more broadly the ketogenic diet would have benefits. So I'll, I'll give you an example in mental health. A new paper just came out in, I think it was Nature, about autophagy and depression. One of the really interesting things they found was there's a, a brain region called the lateral habenula, and it's kind of the depression center for the brain. And what happens is, in depression, the cellular recycling process of autophagy gets turned down in this brain region, and that leads to a buildup of particular receptors. The receptors in question that build up are called glutamate receptors. Glutamate is the excitatory neurotransmitter in the brain. It's like the gas pedal. So effectively, what happens is you're putting the gas pedal down on the depression center of the brain, and feelings of despair just turned up. Interestingly, um, a lot of different medications in humans that we know help treat depression— so ketamine, selective serotonin reuptake inhibitors, SSRIs— um, they actually converge on this pathway even though they act through distinct mechanisms. They do converge on this pathway, which is interesting for many reasons. But point being, I think there's probably human relevance. The reason I bring all this up is because Fasting or ketogenic diet, things that lower your insulin level, tend to modulate and increase autophagy. So, it could be a way of stabilizing basic processes like that in the brain to help treat mental health disorders, neurological disorders. I think the best use case for ketones will be as topping off on top of a ketogenic or low-carb diet. So, if you want really high ketones, you can't just restrict carbs. You probably need to restrict protein and go on very high fat diet. And that can be pretty hard, like a 3:1 or a 4:1 ketogenic diet. So 3 grams of fat for every 1 gram of protein, protein plus carb, or 4:1. It's very difficult to do. So imagine instead of doing that, doing a 1.5 or a 2:1 and then adding on exogenous ketones as kind of a booster. I think it's probably the best case for them.

Oh, that's good. Yeah. Interesting. Yeah, that's a great strategy for that. Jumping, jumping back, quick follow-up question to fiber before we leave that. Um, obvious, obvious benefits, inflammatory bowel disease. It makes sense, you know, uh, fiber elimination. Yeah, getting rid of fiber for those patients. What's your, what's your position on fiber and gut health for everybody else as far as metabolic disease?

I think if you're going to go with the most people most of the time approach, Fiber from whole foods, most people most of the time, I think is gonna have a net benefit. I am not anti-fiber by any measure despite me not eating a lot of fiber. My issue comes in with the blanket and umbrella statements of it's, you know, everybody needs it and more is better. I'm not for those platitudes. I think rather than focusing on like net fiber amount, I would say for most people, most of the time, having a diversity of fiber sources, because fiber is a tremendously diverse set of biomolecules, is probably where you're gonna reap the most reward. And also adjust to tolerance. So, you know, if eating a lot of fiber is causing you GI upset, maybe back off and consider, you know, what dose is appropriate for you and what other interventions might be helping you achieve the outcome that you're interested in. So for example, if you're interested in microbiome diversity and anti-inflammatory effects of plant-based foods in particular, you're better off focusing on fermented foods and fiber. So a study came out of this, I think it was Sonnengart, uh, 2021, I believe, out of Stanford, um, looking at fermented foods versus, um, or fiber in, uh, people. And what they found was fiber was anti-inflammatory in most people, not a huge effect on microbiome diversity, but it was pro-inflammatory in a subset. So there are pro-inflammatory responders to fiber. Now, to add a level of nuance, these people were the people that at baseline had lower microbiome diversity, so it's possible you could train up your microbiome. A little bit more complicated than that. But, um, they found fermented foods basically had a universally anti-inflammatory effect. So, you know, if you're thinking about foods for gut health, I would say start off with low-sugar fermented foods. Kimchi, kefir, natto, things like that, fermented pickles are gonna be the biggest bang for your buck before you just go like smash a head of broccoli. Makes sense.

Yeah.

That, that sounds great advice. The switching around a little bit out here, we're in California and JAMA just came out a few months ago, I guess, with an article there. They mentioned that at least one study numbers showed that the number of obese and overweight people, which is most people, most adults in America, were actually decreasing slightly. First time in 40, you know, 40 years. It might be an artifact. It may be, you know, sample size, all sorts of things. But they attributed it possibly to GLP-1 agonists. You know, we're out in Ozempic country. What's your take on this really controversial topic? Obviously, they're proven, you know, they're— they've shown effectiveness for obesity and, and type 2 diabetes, and there's a growing list of other indications that are seemingly unrelated, right? You know, fatty liver disease and, and, you know, sleep apnea and all. How does it all fit into metabolic health? Where do you stand on that?

So GLP-1s are interesting. The first thing I'll say is the data are compelling, not just for obesity but for other, uh, health conditions. Um, and there probably is a lot of promise for microdosing, uh, and pathways that we don't fully understand. So for example, we now know, at least in animal models, GLP-1s inhibit an enzyme that generates the amyloid oligomers that are toxic in Alzheimer's disease— not the plaques, but the actual toxic oligomers. Different point. Point I'm making is, are these cool drugs and a pretty impressive medical innovation that I think are a good tool that should be deployed? Yes. My caveat to that is we can't lose sight of the forest for a tree. So I think where the metabolic health, low-carb wellness community, whatever you want to call it, gets irritated is when they feel that society's saying, hey, this is a silver bullet. Nutrition and diet is too complicated, too hard, don't worry about it. And I want to just point out these things aren't mutually exclusive. So my opinion is the best possible use case for GLP-1s is as a catalyst for lifestyle change. I'll give you an example. We now better understand this phenomenon of food noise. Some people might have experienced it, some people, you know, might not have intensely, but this like food chatter in your brain when you try to restrict and avoid and make healthier food choices, those foods that are your compulsion. And we know that different people have different, you know, food noise volumes. And if your food noise volume is turned up too high in the modern food environment, it can be very, very difficult to stick to a healthy, you know, lifestyle plan. Now imagine if I could turn down the food noise knob in your brain so you could just make a smarter choice, so that when you're at the office and somebody brings in donuts, you can't do much about it. You have that moment of lesser food noise to say, hey, hey, I'm not going to have that donut. I actually prepared by bringing some hard-boiled eggs and avocado. I'm going to eat that instead. So one thing GLP-1s do is they turn down the food noise. We actually know how this happens in the brain. There was a paper in Science on this particular topic. I can send it to you if you want. But the idea that it decreases pre— increases pre-ingestion satiety, fancy term for turns down food noise. So think about that for a minute. You're giving somebody a tool that then enables them to make a smarter, healthier lifestyle choice. So I think that needs to be more the conversation around GLP-1s. Are they incredible metabolic tools? Yes. Are they being deployed at a population level for their optimal use case to be a catalyst for lifestyle change? No. I was gonna say I don't think so, but I've sat in enough weight loss clinics to know that I think the deployment could be better. So that's my answer. Good tool, could be used more responsibly.

Yeah. Fascinating. And so, so much we have to learn about, about all these metabolic pathways. Well, like GLP-1, the idea that they, through dopamine pathways in the brain, not only turn down food noise, but also, you know, half the people lower their alcohol use, you know. Yeah., you know, all the addictions— shopping, porn, gambling— people start to go down. And junk food too, and other things. But it's, it's fascinating. They're, you know, at some level they're, they're changing the motivation. And, and this is Tiede Center in a broad sense, like you say, they're a tool like any other.

And I think one thing that the metabolic health space needs to get on board with, and I think a lot of people already are, although the most extreme voices usually get the loudest mics, We celebrate people getting healthier. If you use GLP-1s as a tool, that's not cheating. That is, you have used a tool at your disposal. Use a ketogenic diet, use a plant-based diet, I don't care. If you get healthier, if you take control of your life through whatever tools you have at your disposal in an ecosystem that is built to put obstacles in front of you, that's awesome. So I don't want people to feel discouraged about exploring it as an option. I don't think it's required, I don't think it's a sign-on-for-life kind of thing if you don't want it to be, but it's a tool that people should not be ashamed to use.

Yeah, yeah. And like you say, the sort of metabolic health space, a lot of the people in it are in the lifestyle space, which I certainly support and I'm a big fan of. But the fascinating thing about GLP-1s, if you don't change your lifestyle and you take GLP-1s, you will get sicker. You know, if you don't lift weights and you don't, you know, add protein, you will, you will develop weight loss and sarcopenia rather than just a healthy weight loss, you know.

Yeah, they're powerful medications with side effects. And I think any discussion of, you know, pharmacotherapy deserves acknowledgment of the risks and benefits. And depending on what space you're in, I think it's overinflated with discussions about risks or benefits of GLP-1s. Again, depending on what space. There are other areas where I think we do need to be more responsible by talking about the risks. But that's another kettle of fish. Actually, no, I will, I will open this Pandora's box even though I don't have a lot of time for it because we were speaking about GLP-1s. There was a trial out. I don't know if you heard me talking about it on statins and GLP-1s. And this is one of those things that just shocked me, not because of the metabolic effect. It actually is quite intuitive. Basically, there was a human controlled trial that found statins slash GLP-1 levels. Again, talking about GLP-1 receptor agonists, the fact that the most profitable drug class in history, not GLP-1 receptor agonists, statins, slash GLP-1 levels like in half in humans, and it doesn't get talked about, is shocking for obvious reasons. People listening can put two and two together if they're a human adult with a few brain cells. And that is not to say you need a GLP-1 if you're on a statin, and it's not to say statins are even bad. It's just to say, hey, These drugs have effects that are potent biologically, and we should have a full conversation about what these are so that people can make informed decisions and so that they have the opportunity to offset them if they can. So in this particular trial, they actually had a solution for offsetting the GLP-1 smashing effects of statins. It has to do with bile acid supplementation. Different topic, but point being There's a lot of very siloed conversations and imbalanced conversations. If you're taking a medication, it's a very high chance it's going to have both benefits and risks. And it's up to you to figure out how that risk-benefit analysis falls for you. To the pro, to the con. Usually it's clear, not always.

Great message. And the whole idea of personalization of all these things like type 2 diabetes, 4 different types, like, you know, that's important. And we're not doing that now nearly enough. We, we should. And hopefully more and more in the future we're going to see that. We're almost out of time. Maybe we'll maybe just end with like, what are you most excited to, to publish or build next? Or is there anything we didn't talk about that you want to hit in the last couple of minutes?

Oh yeah, no, uh, a million and one things. As I mentioned, I like— I'm a few months out from medical school and it's been an absolute whirlwind. Involved in a couple companies, building up my social media base. Right now I'm having the most fun on Substack. So if people want to check me out on one place, they can find me Nick Norwitz on any social, last name N-O-R-W-I-T-Z. My Substack, you can find it at staycuriousmetabolism.com, is where I hit the most data as it comes out. So generally up very early in the morning reading Cell Science, Nature, and then trying to communicate in fun ways. So, you know, there's some new papers on very odd amino acids that can fight age-related muscle loss. There was this new study that blew my mind out of Nature on how stress makes glucose in the body. So literally a direct hot wire from the brain to the liver when there's stress saying, hey liver, turn up glucose generating enzymes. It's actually kind of crazy. The methodology they use is beautiful, like injecting viruses into animals that can travel up neurons and they glow. It's like inject it into the liver and if it is connected directly to the brain, you will see a glowing green signal in the brain and they show that. So It's the kind of science I review at least 3 times per week. I'll have a deep dive on some new science. So staycuriousmetabolism.com. I love engaging with people, but you can find them pretty much anywhere.

I'm trying to spread it. It's great. Let me sneak one last question. It is out of the box, out of the blue. How are you most excited? Well, how do you, how do you use generative AI, large language models, agents most in your work? Or what do you see the, the, what are you most excited about that for?

That's it. Yeah, for me it's very helpful for ideation. So I'm not that great with AI, but I'll use ChatGPT to like, you know, expedite my process. So what I'll do is like, I'll read a paper and I'll like auto-dictate a script. And then I'll just put it into ChatGPT. I won't ask it to write it for me, but I'll ask for feedback and ideations like, hey, is there a better hook here that can like resonate with a layperson or an analogy or like a fun title? And so I help, it helps me with my ideation. Um, all the legwork and the reading and then like the original drafting is me, but just in like cleaning it up, I think it's very good for a feedback buddy. At this point in time. I don't think it's like, I wouldn't use it to like write original stuff. I think one of the issues is pretty bad about like scientific citation. But yeah, we'll see. Also, as I build up my team, I mean, one thing to know in medicine and science is like, it's a team sport. You know what you're good at, you know what you're not good at. Tech is not necessarily my thing. So my goal is to build a team of people who can say, hey, now there's this new AI tool., you know, let's play with that. So sometimes it's fun. Like I have a voice clone that'll read my newsletters. If you go there, you can click and there's like AI Nick. He's 11Labs for that, I think. No affiliation, but, uh, yeah, it's pretty cool. And I think you need to become savvy with it. I'm not super savvy with it, but I like to explore.

Be careful. Don't let it take over and start doing all your stuff. I know. AI Nick.

People can usually capture that. There's some big influencers. I won't name names, but somebody pointed out, they put up like a, an image and they're like, this reference is wrong. And it was a PubMed idea, like that was just not a paper. Uh, and it's because like they clearly used AI and it hallucinated. I know of this individual and this seems very par for them, but something like that can end up creating a big embarrassment. And there's very little recovery once it's clear you're using AI to generate your science because it does hallucinate science. So I'll be cautious about that. No worries.

This has been wonderful, Nick, getting to know you a little bit better. And thank you for spending time with us. And I'm looking forward to great things with you and connecting again in the future.

Thank you so much. Appreciate you having me.

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