Best Tools for Gut Health & Weight Loss | Dr. Chris Thompson

Dr. Chris Thompson, MD, Professor of Medicine at Harvard Medical School, Chief of Interventional Gastroenterology at Mass General Brigham in Boston, and Co-Director of the Center for Weight Management and Wellness, is a world-renowned expert on gastroenterology, metabolism, nutrition, and obesity medicine. He explains how your GI tract regulates hunger, fullness, and blood sugar, as well as the gut microbiome, metabolic health, and weight loss. We also discuss common GI tract issues and which particular tests or interventions are actually useful. We discuss both GLP-1 medications and non-GLP-1 approaches to weight loss. Given that gut health is vital to all the organs of the body, overall health, and longevity, our discussion ought to be of interest and practical value to everyone, including, of course, those struggling with gut health or weight loss challenges. Thank you to our sponsors AG1: https://drinkag1.com/huberman Function: https://functionhealth.com/huberman Lingo: https://hellolingo.com/huberman LMNT: https://drinklmnt.com/huberman Our Place: https://fromourplace.com/huberman Timestamps (00:00:00) Dr. Chris Thompson (00:02:16) Digestive Tract, Gut Hormones & Nutrient Absorption (00:08:06) Colon Microbiome & Colon Cancer Screening (00:11:13) Sponsors: LMNT & Lingo (00:13:40) Swallowing Problems & Zenker's Diverticula (00:16:08) Bowel Movements & Constipation (00:18:28) Fiber, Resistant Starch & the Gut Barrier (00:21:50) Intermittent Fasting & the Gut Microbiome (00:23:38) Fermented Foods, Microbial Diversity & Butyrate (00:27:12) H. pylori, Stress & Stomach Ulcers (00:30:20) GLP-1 Medications: Benefits & Limitations (00:33:42) Lower GLP-1 Doses, Weight Regain & Muscle Loss (00:37:35) GLP-1 Side Effects, Food Noise & Apathy (00:39:49) Bariatric Surgery & Medical Innovation (00:46:07) Sponsor: AG1 (00:47:44) Hunger & Satiety: Ghrelin, CCK, GIP & GLP-1 (00:50:01) Retatrutide & Combining Hormonal Targets (00:52:55) Ultra-Processed Foods, Overeating & Leptin (00:55:32) Incretin Discovery, Exendin-4 & the Gila Monster (00:59:35) Endoscopic Ultrasound & Pancreatic Biopsy (01:07:40) Early Metabolic Markers, CGMs & Fasting Insulin (01:13:06) Insulin Resistance & Metabolic Flexibility (01:15:53) Sponsor: Function (01:17:35) Patient Data, Screening & Treatment Adoption (01:26:31) AI, Robotics & Improving Procedures (01:29:27) Choosing a Surgeon & Measuring Procedure Quality (01:35:29) Image Guidance & Hyperspectral Imaging (01:37:19) Sponsor: Our Place (01:38:56) Diagnostics & Targeted Metabolic Treatments (01:42:45) Gastric Bypass, Foregut Exclusion & Diabetes (01:47:59) Duodenal Liners & Mucosal Resurfacing Research (01:52:58) Gut Permeability, Inflammation & Fatty Liver (01:59:39) Artificial Sweeteners, Fructose, Fats & Omega-3s (02:05:00) Resistance Training, Zone 2 Cardio & Intervals (02:06:31) Weight Set Point & Metabolic Adaptation (02:08:13) Endoscopic Sleeve Gastroplasty & Fundus Ablation (02:10:30) Magnetic Intestinal Connections & Combined Treatments (02:16:52) GLP-1 Gene Therapy Research (02:22:13) Innovation, Problem Solving & Teamwork (02:25:58) Zero-Cost Support, Sponsors & Neural Network Newsletter Disclaimer & Disclosures Learn more about your ad choices. Visit megaphone.fm/adchoices

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

  There's all sorts of evidence that if you don't have a lot of fiber, your microbiome's not healthy. Feed your microbes, you know, they need to be fed. And what they eat is fiber. Okay, that's what you want them eating. You want them eating fiber. And if you're not feeding them fiber, they'll eat your mucus layer. Okay, and we already talked about how thin that barrier is. And all of a sudden, they start eating your mucus layer. They're not producing the butyrate you need. And the butyrate's needed to maintain the tight junctions. Right? So there's layers to this. It's like a snowball effect that if you're not feeding those microbes, the microbiome and keeping it healthy, you're going to run into all sorts of, all sorts of trouble.

• 0:35Andrew D. Huberman?

  Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life.

• 0:44Andrew D. Huberman?

  I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Chris Thompson. Dr. Chris Thompson is a professor of medicine at Harvard Medical School. He is also the chief of interventional gastroenterology at Mass. General Brigham in Boston. He is a renowned expert on the intersection of gastroenterology, metabolism, nutrition, and obesity medicine. And in today's episode, Dr. Thompson explains how to improve your gut health, including the roles of your diet, gut microbiome, and gastrointestinal motility, as well as how your gut communicates with the rest of your body, which of course includes the gut microbiome, but as you'll learn today, much more. Dr. Chris Thompson is a guest on this podcast

• 1:27Andrew D. Huberman?

  because he's not just a GI tract and obesity medicine expert, he's also credited with having created an entire new field of treatments and perspectives on GI and metabolic health. So the knowledge he shares today is truly at the cutting edge and applicable, which is why by the end of today's episode, you will have a clear understanding of how your gastrointestinal system works, and you will have a set of new, modern, evidence-based tools for improving and maintaining your gut health. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Chris Thompson.

• 2:12Andrew D. Huberman?

  Dr. Chris Thompson, welcome.

• 2:14Speaker 00

  Thanks so much. Good to be here.

• 2:16Andrew D. Huberman?

  A lot of us hear these days about the gut microbiome, the gut-brain axis. We hear about GLP drugs that help people lose immense amounts of weight and stop feeling this food noise thing, and on and on. But can we start by just having a conversation about this tube that is the digestive tract? And get real basic? And just educate people a bit on what happens that stimulates them to want to eat? Why perhaps for certain periods of day or night, they don't want to eat? And then what the passage of food through us looks like it is a series of steps? This is such a critical part of our biology and our lives.

• 2:56Speaker 00

  It's becoming more and more complex all the time, right? The gut, and it does a lot of things. So it's obviously involved in digestion, but it's also an endocrine organ. You can hear it called the second brain, right? So there's a lot of different ways we think about, about the gut. And it is compartmentalized, and each, each area has a different job. So first you have, you know, the esophagus. And its job is to just kind of move the food into the stomach safely. And it's thick, right? It has different lining, so it can handle things that might be a little rougher. And it pushes sequentially, you know, down to the stomach. So it's taking that food bolus and driving it into the stomach. And you can have all sorts of problems in your esophagus, right? So each one of these organs has, you know, things it's supposed to do and then things it doesn't do well. Sometimes people don't swallow well. It gets too tight at the bottom.

• 3:41Speaker 00

  There's a condition called achalasia, where it's just the bottom of the esophagus doesn't relax, right? And so we have procedures we can do in my line of work, where you can tunnel down in between the layers of that esophagus. It's very thin, you know, a few millimeters. You can tunnel down into there and cut that muscle to relieve the obstruction. So.

• 3:57Andrew D. Huberman?

  What are the symptoms of that?

• 3:58Speaker 00

  So inability to swallow.

• 4:00Andrew D. Huberman?

  So what do they do? They choke?

• 4:01Speaker 00

  Yeah, they feel like they're choking. So they'll, they'll swallow food. It'll get down and stop. And then they'll feel pressure. They'll feel really uncomfortable. If they drank some fluid with it, it might start coming back up. It'll just stay there. And then sometimes they'll have to, you know, induce vomiting to remove it. It's very uncomfortable for them. And it's not a terribly common condition, but it's becoming more and more frequent. I see it every week. So that inability to swallow. And you can get that inability to swallow for other reasons. Actually, they're far more common. Chronic heartburn. If someone has reflux, you know, that burning sensation, that can damage the lining of the esophagus, and it can lead to precancerous conditions called Barrett's esophagus, which is something that, you know, needs to be treated, looked at, and kind of followed. But with time, it can actually cause scarring. So you get a stricture.

• 4:46Speaker 00

  So it's kind of very fibrotic tissue there. That's another reason why people might have difficulty swallowing. There's other reasons as well that are more obscure. But, so that's the job of that esophagus, just to move the food down safely. And a lot of times, it doesn't work. Then you have the stomach next, right? First, what the stomach does is it stretches to accommodate and accept a meal. Right, so it stretches. Normally, it's like a tube in your, you know, in your abdomen. But then when you start to smell food, it starts stretching and becoming more like a bag.

• 5:13Andrew D. Huberman?

  Really, just the odor of food?

• 5:15Speaker 00

  Yeah, it can, it can stretch, relax, to accept that meal. And if it doesn't do that properly, it's, it causes symptoms like nausea. Right, so. So then it accepts the meal, and it has to do its job, which is to break it down and pass it on. So that the stomach now isn't just transporting, it's breaking it down. And it does that mechanically. So in the fundus, the top of the stomach, is holding that meal. That's what kind of stretched up to hold it. And then the rest of the stomach's working on it. So the body of the stomach, next segment, is breaking it down, is grinding the food into smaller bits. Acid is part of this as well. The stomach secretes acid. And then the bottom of the stomach, called the antrum, will push the food out slowly into the duodenum. Right, that's the first part of the small bowel. Satiety, satiation, all becomes part of this

• 5:59Speaker 00

  because the stomach's what secretes ghrelin. And we'll talk about that probably more later. But the stomach secretes ghrelin. And so this is part of your satiety signaling. All sorts of problems with the stomach, right? So similar to the esophagus, food might not leave, you know, as it should in the right, in the right timing. So it can happen due to ulceration in the stomach, scarring, or something called gastroparesis, where for a variety of reasons, it might be post-viral. It might be due to diabetes, neural hormonal kind of origins of this. The stomach just doesn't empty as it should. People have nausea and vomiting with that and other problems, so. Then you get into the small bowel. And the small bowel's job now, typically, you do a little digestion so early on because you have pancreatic and biliary secretions going in there.

• 6:44Speaker 00

  But its main job is going to be to absorb calories. Right, so that's absorbing calories and moving it down. It's very thin, it's one-cell thick. Has about the surface area of like a pickleball court.

• 6:54Andrew D. Huberman?

  One-cell thick?

• 6:55Speaker 00

  Yeah, so one-cell thick. The lining is one-cell thick. That's the barrier.

• 6:58Andrew D. Huberman?

  What's the cell type, just to?

• 6:59Speaker 00

  Antero, enterocytes, yeah.

• 7:01Andrew D. Huberman?

  Those must be some really sturdy cells.

• 7:03Speaker 00

  Columnar epithelium, yeah. So, well, they're pretty sturdy. They, they rely more than just the cell itself to, to, to maintain that barrier. There's certain cells called goblet cells that produce mucin, and that creates a nice, thick layer there that help as, as another part of the barrier. They have something called tight junctions, right? Between the cells, which are complex little structures that are part of that barrier as well. And there's immune cells in there. There's other elements to that barrier, but it is one-cell-thick. So that's why the stomach, you know, the esophagus and stomach have got a good job of processing that, processing that food so that it's, it's safe to go down through the small bowel and be absorbed. All sorts of issues with the small bowel. Similarly, you can have different diseases that affect that,

• 7:46Speaker 00

  you know, select disease, Crohn's disease, et cetera, different inflammatory conditions. And what we're learning now, and we'll hopefully get, get into, is it plays a central role, we think, in metabolic disease. And that's kind of what's very exciting, is its role in obesity, diabetes, and other similar conditions. And then eventually you have the colon. And that's where your microbiome is the star, right? The colon. Its job is to usually just absorb water. Most of the nutrients are gone by then. But it does play an important role as well. And it is working hand in hand with your microbiome to, you know, to, to make sure that you are producing. It really is, it's mostly butyrate, I think, that's mostly involved there,

• 8:29Speaker 00

  where the microbiome is producing short-chain fatty acids. And one of them, the most important probably, is butyrate that has a lot to say about your metabolism as well. That's involved in the satiety signaling. And you have a lot of GLP-1 produced from the colon, again. So you're, you're getting these kind of endocrine function of your colon that's very involved, and then it passes. So, and again, diseases in the colon, colon cancer is a big one, right? So colon cancer screening is important. People, typically now, I think they move the age back to 45. Everyone should start getting screened and make sure, you know, they don't have cancer. You can do it different ways. There are genetic tests you can do like Cologuard. And if you do that, you have to do it every, every few years, but you can do that. You can do screening colonoscopy every 10 years if it's normal. And there's other things you can do as well.

• 9:14Speaker 00

  CT colonography is not as common and other tests, but those are the two most common. It's important, important to do that.

• 9:19Andrew D. Huberman?

  How common is colon cancer?

• 9:21Speaker 00

  In our line of work, it's the, it's the most frequent cause of, of cancer, unfortunately.

• 9:25Andrew D. Huberman?

  Are more people being diagnosed because of more diagnostic procedures? And are more people surviving colon cancer?

• 9:33Speaker 00

  The survival rates are definitely improving due to screening programs, right? So that's, that's important. So it is definitely important to get screened. Also, screening earlier helps. So for instance, starting at 45 is better than many people who started at 50, and they wouldn't get until 55 or 60, right? But also, if you have a family member that has had cancer, you want to start at 40. Or if they were younger, you want to start 10 years younger than when they were diagnosed, right? So you want to start that screening process. Really, it's very effective, you know, and it's important, important to do it. And I think that things like Cologuard and other genetic tests are going to keep getting better and help because you don't have to have that kind of very uncomfortable screening procedure. Colonoscopy is not, it's not a great way to do screening, right? You shouldn't have to have a relatively invasive procedure to be screened for something. You know, it should be something you just do a blood test or a stool study or something like that.

• 10:18Speaker 00

  And I think we're getting there with technology, and that will definitely show dividends. Because you can have the colonoscopy to remove the lesion, which is something that we can do. It's, it's a newer technique where we can actually go in and remove these very early cancers endoscopically. So we call it organ-sparing surgery. So you don't have to actually remove a piece of the colon anymore. You can just kind of, you know, take, take the lining where that precancer is residing. It's a complicated procedure, but it's easy for the patient. You know, they keep their colon, they go home the same day. And these tests, you know, are, are easy ways to diagnose those patients and get them in for proper care. So very important. So that's pretty much the quick overview of the gut. And it plays, one thing we haven't touched on too much yet is its role in, in really, you know, satiety

• 11:03Speaker 00

  and, and kind of how it's involved in processing of food in detail and the kind of endo, endocrine system that's involved.

• 11:13Andrew D. Huberman?

  I'd like to take a quick break and acknowledge one of our sponsors, Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium, all in the correct ratios, but no sugar. Proper hydration is critical for brain and body function. Even a slight degree of dehydration can diminish your cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium are vital for the functioning of all cells in your body, especially your neurons or your nerve cells. Drinking Element makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. My days tend to start really fast, meaning I have to jump right into work or right into exercise.

• 11:56Andrew D. Huberman?

  So to make sure that I'm hydrated and I have sufficient electrolytes, when I first wake up in the morning, I drink 16 to 32 ounces of water with an Element packet dissolved in it. I also drink Element dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I'm sweating a lot and losing water and electrolytes. Element has a bunch of great tasting flavors. In fact, I love them all. I love the watermelon, the raspberry, the citrus, and I really love the lemonade flavor. So if you'd like to try Element, you can go to drinkelement.com/huberman to claim a free Element sample pack with any purchase. Again, that's drinkelement.com/huberman to claim a free sample pack. Today's episode is also brought to us by Lingo. Lingo is an everyday wearable that tracks your glucose 24/7.

• 12:40Andrew D. Huberman?

  Glucose drives a lot of key processes that support energy, body composition, and long-term health. When glucose is constantly spiking and crashing, that's where we can start to see metabolic dysfunction. And over time, that can even progress to prediabetes. Right now, about 115 million adults in the US have prediabetes. Most don't know it, and a higher percentage of men have it than women do. Often, there aren't clear symptoms of prediabetes early on, so people don't tend to look into it. But the fact is that metabolic health is shaping how your body functions every day, whether you feel it or not. Tracking your glucose with Lingo can help you see how food, activity, and stress impact your glucose throughout the day. I personally have used Lingo, and it's been an invaluable tool for improving my metabolic health.

• 13:24Andrew D. Huberman?

  If you would like to try Lingo, Huberman Lab listeners in the US and UK can save 10% on a four-week plan. Just visit hellolingo.com/huberman for more information. Terms and conditions apply. Again, that's hellolingo.com/huberman. Couple of questions that no doubt will resonate with people because they're fairly common, and you'll tell me if they're of concern or not, depending on the frequency. We'll start at the top of the GI tract. People will say sometimes that they eat, and some of the food seems to go up their nose. They know this because if they blow their nose, they might get some food particulate. It sounds like something that's not entirely uncommon based on the number of questions I get about it. What's going on there? Why would...

• 14:07Andrew D. Huberman?

  I get asked a lot of questions, some of them truly weird and rare, and some of them weird and less rare, and I'll put it in the second category.

• 14:14Speaker 00

  That could be a variety of different things, and this is the area that I do work in, right? So it can be an oral-forensic transfer problem where the hypopharynx is transferring food into the esophagus. That can be ENT thing. It can actually be functional medicine as well, where you can work with a speech pathologist that teaches people how to swallow better. They might have to change the quality of the food they're eating, the thicker food. They might have to turn a certain way to swallow, and there's ways they can actually train people with kind of biofeedback to learn how to swallow better because that part's still under your control a little bit.

• 14:45Andrew D. Huberman?

  They're not swallowing well.

• 14:46Speaker 00

  Yeah, and with age, that can happen, right? With age, that can happen. Now, the next thing that can contribute to that is if they have high tension in the first sphincter up above, which is the upper esophageal sphincter. That's the sphincter that separates the top of your esophagus from your mouth, basically. And that can be have high tension. And what I see a lot is something called Zenker's diverticula, which we haven't talked much about. There's a few different little pockets that can form high up in your esophagus, near that sphincter. There's different names for how they, you know, kind of where they exactly occur. And with time and with age, this is like a herniation of mucosa through the muscle, and it creates a pocket, and that can actually trap food. So when people are eating, the food goes into the pocket and then comes back up and can go out their nose or sit in there, which is very uncomfortable for them, right?

• 15:30Speaker 00

  That's another way you can have problems swallowing. And that can be fixed very easily. We go in through the mouth, actually make a tiny incision, and just kind of take down the septum that's part of that pocket, opening up the pocket so that the food can leave. So it's important to do it early, too, because people can actually, this, it looks like an inconvenience initially, right? It's, you know, you're not swallowing well, food is, you know, is not where it's supposed to be necessarily. The problem is when people then aspirate, and that food goes in the lung, and then it can lead to scarring in the lungs, and eventually it can really cause problems. So it is something that should probably be taken seriously and looked at, even though it sounds funny, you know? It is something that can be a real problem.

• 16:08Andrew D. Huberman?

  There's a weird thing about GI tract and bowel movements in particular, which is the following. With babies, with puppies, and to some extent with ourselves, but especially with babies and with puppies, we sort of, because they can't speak, we have a couple of like key readouts that we intuitively understand reflect their health. One is the color of their skin, the eyes, like if eyes are looking glassy or tired, you know? And the quality or lack thereof of their bowel movements, quality, frequency, et cetera. But then something happens where speech comes online, and we get, you know, toilet trained,

• 16:50Andrew D. Huberman?

  and then everyone's responsible for like understanding like their own bowel movements, right? And then we're never really told like what's healthy bowel movements, but we all kind of know what's normal for us or not normal. I'd be lying if I didn't say like, these are important metrics of health.

• 17:04Speaker 00

  Yeah, well, there's so much you can tell from bowel movements, okay? So the rule of thumb is, you know, you don't want to have more than three a day, and you don't want to go longer than three days without having a bowel movement. So that's kind of the general rule. And you want it to be one formed bowel movement, you know, or a couple. You don't want little tiny pebbles. That's called scibula stool, and that's a sign something's going on. But there's a lot you can tell. How much are they taking enough fiber, right? The World Health Organization published something in The Lancet years ago on fiber, fiber synthesis, I think they called it. And they found that, you know, the vast majority of population really doesn't, especially Western countries, just are not getting enough fiber, which is obviously concerning because that causes a lot of issues long-term, right? Which we'll get into.

• 17:48Speaker 00

  But if you're having these scibula stools, if you're, if you are constipated, meaning you're having a bowel movement more than once every three days, and they're hard stools, that's a sign you're not getting enough fiber. So that's one thing you really have to think about, right? Additionally, there's other things you can tell after procedures, you know? If a procedure, if a bowel movement's very dark, tarry and shiny, that's a sign you have blood in your GI tract, right? So there's different things you can tell from the stool that are important to keep an eye on, but in general, that's kind of the rule of thumb, you know, with bowel movements. Having more than three a day is probably leaning towards being too loose, right? And if you're not having one every three days, you're probably bound up, and then you really have to think about fiber.

• 18:28Andrew D. Huberman?

  As I recall, the recommendations were for adult men, 35 grams of fiber per day, and for women, 25. And obviously, that's not accounting for variations in body weight and height and all the rest, so does that sound about right?

• 18:42Speaker 00

  Yeah, that's about right, and it kind of depends on the quality, too. There's a couple of others really interesting studies that came out recently, just within the last few years, looking at the importance of fiber related to certain conditions. Like one was fatty liver, right? And fatty liver was an interesting, interesting study. They were using resistant starch, like level two, so basically raw powdered potatoes, something like that, right? And they were supplementing, I think it was at 40 grams, and they found that when they did that, they actually saw a significant improvement in fatty liver, which is phenomenal, right? And it was, you know, relatively weight stable. So it has important treatment effects. Another group actually studied it and looked at insulin sensitivity.

• 19:26Speaker 00

  So they did clamp studies, you know, where they would kind of really be able to detect insulin resistance and kind of try to look at kind of glucose utilization and clearance. And they found that with this RS2 type, you know, resistant starch, too, they were able to improve insulin resistance and insulin sensitivity as well. So fiber is very important. It's not just about the bowel movements, right? It's also about, you know, really just having, you know, health. It probably helps the microbiome. There's all sorts of evidence that if you don't have a lot of fiber, your microbiome's not healthy, right? You get less diversity in your microbiome. There's different studies that have looked at that. It is important to have that fiber, and that constipation is an early window into it, right?

• 20:09Speaker 00

  It's an early sign, maybe you're not getting enough fiber.

• 20:13Andrew D. Huberman?

  Yeah, I make it a point to eat fruits and vegetables because I like them, but recently I started supplementing with a powdered psyllium husk, and some of them actually taste pretty good. And my expectation is I was going to feel really bloated. It's quite the opposite. Not that I had gut issues before. If it was normal, it had like hyper-normalized, things actually made post-meal, subjectively, the sensation just like feel good, feel great. And I didn't expect that. I thought, okay, more fiber. I think a perception people have is like more fiber, more regularity, and more bloat. And I think that's a, that might be true for some people, but it certainly wasn't my experience. And I think that if, I feel like the messaging on fiber to the general public is pretty lousy, meaning people are told to take it.

• 20:58Andrew D. Huberman?

  That's great. They're told all the time, but I think people think, oh, if I have a lot of fiber, I'm going to be really gassy, I'm going to be really bloated. But as you pointed out, it's not just about regularity and speed of digestion. It's about creating a healthy milieu for the gut. I think if more people knew that, they'd probably make a move to consume more fiber.

• 21:15Speaker 00

  Totally. It's like feed your microbes, you know, or they can eat you, right? And it's kind of true, right? Because they need, they need to be fed, and what they eat is fiber. Okay, that's what you want them eating. You want them eating fiber. And if you're not feeding them fiber, they'll eat your mucus layer, okay? And we already talked about how thin that barrier is, and all of a sudden, they start eating your mucus layer. They're not producing the butyrate you need, and the butyrate's needed to maintain the tight junctions, right? So there's layers to this. It's like a snowball effect that if you're not feeding those microbiome and keeping it healthy, you're going to run into all sorts of, all sorts of trouble.

• 21:50Andrew D. Huberman?

  Raises some interesting questions about intermittent fasting. I think very few people are doing long-term fasts of more than a day or so. I mean, it does happen, but most people, a lot of people do sort of time-restricted feeding, or they'll skip breakfast. You know, I'm one of those people, most days just by default. I had a colleague, friend at Yale who studied microbiome, and I said, oh, so does fasting improve the gut microbiome? And he said, no, actually, during the fasting period, your microbiome starts eating up your digestive tract, which is what you're saying. But then he said, but then the rebound often is, puts you at a slightly better place afterward. So it's tricky. Should people avoid intermittent fasting if they're having gut issues? I know we don't want to make any broad recommendations.

• 22:32Andrew D. Huberman?

  It's highly contextual, but based on what you said, it seems that it stands to reason that you might want to avoid having your stomach empty for... Very long periods of time outside of sleep.

• 22:43Speaker 00

  I don't see it as being a major issue. I think there are benefits of intermittent or time restricted eating intermittent fasting probably would outweigh that risk. You know, you need to give your pancreas time to relax, you know, you need to have insulin come down. If you're eating frequently, your insulin levels are already up, always up, and that that causes problems. So I do think the benefit of the time restricted eating definitely outweighs that that potential risk.

• 23:09Andrew D. Huberman?

  No, great to hear, especially as somebody who just by default doesn't eat breakfast or and just don't get hungry till 11.

• 23:15Speaker 00

  I skip breakfast as well, but there's studies because initially they actually used to say, well, you have a cortisol spike in the morning and, you know, you're more likely to store the food you take in if you eat in the morning. Turns out, maybe that's not so true. It might be better to actually have, you know, eat earlier and then have your fasting windows start in the afternoon, right? I think doing is better than not doing it. I still I still skip the breakfast.

• 23:38Andrew D. Huberman?

  The topic of fermented foods, low sugar fermented foods as a possible benefit for gut health has come up since Justin Sonnenberg and colleagues have published that the study. It there's a small number of people in that study, admittedly, but that taking in some low sugar fermented foods really helped lower the inflammatome. They didn't look specifically at, as I recall, symptoms of gut irritation or things of that sort. But what are your thoughts on low sugar fermented foods? So we're not talking beer. We're talking kimchi, sauerkraut, brine.

• 24:10Speaker 00

  I think they're important and they're missing in the Western diet, which is an issue. And I think there's the study you referred to, actually, I think they compared it to to fiber, right? It was it was fermented foods to fiber. And with the fermented foods, you had reclaimed some diversity in the microbiome, which was great, as well as the reduced inflammatory markers where the fiber didn't seem to do that. And you saw all these benefits in these other fiber trials that we're talking about with the resistant starches, right? So it stands to reason that we'd probably see that as well as we do more research in the fermented foods. They're beneficial for a variety of reasons, you know, one, they're prebiotic, right? So you're feeding your microbiome things they want, which is phenomenal. And it's already kind of started, it's a little partially digested, which is really helpful.

• 24:55Speaker 00

  And and they're also a little bit of a probiotic as well, because you do have some, you know, some live cultures in there, right? And you usually have Bifidobacterias, Lactobacillus, or something like that in them and a variety of other things as well. So it gets the ball rolling, right? So it's sort of like when you're trying to grow something, you want to plant the seeds, but also have the fertilizer and whatnot. And this, this is what fermented foods do for you. So I think, you know, that that's, that's very helpful. And it's all about maintaining this, this kind of healthy microbiome that can produce things like butyrate, which have a lot of, a lot of benefits we can talk about. You can't just take butyrate and then it's not going to make it to the colon, right? It needs to be in the colon

• 25:37Speaker 00

  to have its to have to have its effect. And so what these bacteria do is they kind of, they, they will kind of cross feed in a sense, right? So you have those first layer of bacteria that will take the fiber and break it down, and they create acetate and lactate and whatnot. And then that can then be used by other bacteria. So you're feeding the other, the other bacteria that can then turn that into butyrate, you know, and things like that. And the butyrate is magical, right? So that will feed your colon cells, your colon cells live on that. But butyrate is needed for those tight junctions. Butyrate, you know, does all sorts of things via GLP-1 pathways and satiety pathways. So it has a lot of different, a lot of different roles that it's playing. Additionally, it keeps your bowel acidic, right? So like these

• 26:22Speaker 00

  short chain fatty acids and, you know, acetate and whatnot. And that's great to make sure you are protected from certain pathologic organisms that might want to take, take root, right? So the aerobic organisms and the other organisms that you don't want, don't survive as well in an acidic environment. So really important to, to, to take these fermented foods in addition to fiber.

• 26:46Andrew D. Huberman?

  Do you make it a point to consume them?

• 26:48Speaker 00

  I do, yeah. I, I like kefir or kefir and everyone has to say that, right? I like, I like that. I think it's phenomenal. Yeah, it's good. Kimchi is good, you know, sauerkraut. There's all different types, yogurt, you know, there's there are different types, I think, that everyone should be able to find. It's kombucha, you know, and it's certainly missing in our diets. So I think it's, it's important to, to, to recommend it to folks, do.

• 27:12Andrew D. Huberman?

  Canker sores and ulcers. My understanding for a long time is they were caused by stress or wounds to the mouth. And then, you know, a couple of folks won a Nobel Prize for identifying a soil based bacterium that causes ulcers. And I loved that Nobel Prize year, you know, as a scientist, like some people watch the Super Bowl, like, you know, like who, you know, who won the Nobel Prize? And it's never surprising who wins. It's at least for the sciences, right? It's often surprising who doesn't, but let's leave aside that, that component. But that was a very surprising set of findings, right? Like a gut bacterium is causing ulcers. And I love the findings, but at the same time, I think many, many millions of people, hundreds of millions, billions across history would say, stress

• 27:56Andrew D. Huberman?

  gives people ulcers. So there's something going on there that's more than soil based bacterium, right?

• 28:02Speaker 00

  Yeah, definitely.

• 28:03Andrew D. Huberman?

  And that's the problem with these, you know, the way the media covers these findings, like, it's not all that you ingested the wrong soil. Stress can give you ulcers, right? Or am I missing something?

• 28:13Speaker 00

  Stress can play a role, you know, it is, it is certainly complicated. So Barry Marshall was phenomenal in Australia, and he found H. pylori could cause gastric ulcers, right? And he had to consume, no one believed him, he had to consume him himself, consume it, and then he had gastric ulcers.

• 28:28Andrew D. Huberman?

  I love it when scientists do self experimentation.

• 28:30Speaker 00

  That's crazy, right? But that was phenomenal, right? And he proved H. pylori, and we need to treat that, right? And that actually, H. pylori was actually found even in Nazi, the Iceman, if you remember, Nazi, the Iceman, he was this, like, 5,000 year old, you know, Homo sapien in the, in the Italian Alps, he was found frozen, right? So you could actually get into his stomach and see what was in there.

• 28:51Andrew D. Huberman?

  He dies stressed.

• 28:52Speaker 00

  He dies stressed. He had H. pylori in his stomach. I think he's been around a long time. It's kind of interesting. There's other lessons there, like, like a loss of diversity of the microbiome, right? With industrialization, we have far fewer species and less genetic diversity in our microbiome. But regarding ulcers, so I actually did study this in gastric bypass patients a good bit, right? And it was not a bacterium that was causing it, right? Sometimes it was a relative ischemia. Type 2 diabetes causes kind of microvascular ischemia. Smoking can cause microvascular ischemia. In gastric bypass patients, the small bowel doesn't, it's a distal part of the small bowel from lower down that's connected to the stomach, and it doesn't have bicarbonate that's being

• 29:37Speaker 00

  secreted from pancreas in the area. So there's no way of neutralizing acid. So if the pouch, which, you know, we can get into the anatomy here, but if the pouch of the gastric bypass is too large and makes acid, the duodenum now has no, or the jejunum actually has no natural defense against that. So acid clearly plays a role. And if you're stressed, it can produce more acid, right? So generally, there's probably multiple hits. We don't fully understand things, but clearly, it's not just an infectious organism. And it kind of depends on individual circumstances and susceptibilities, but ulcers are certainly something that can occur short of a bacteria.

• 30:12Andrew D. Huberman?

  So important for people to hear that, you know, because one thing can cause something, it doesn't mean it's the always the case that.

• 30:19Speaker 00

  Yeah.

• 30:20Andrew D. Huberman?

  So let's talk about metabolic health, hunger, obesity, weight loss. These are areas that, you know, square in your wheelhouse. Can't have this conversation without talking about the GLPs. Most everyone has heard of these things nowadays. Millions and millions of people, I've heard, I don't know if this is true, as many as 20% of people 18 and older have taken or are currently taking a GLP, or either, you know, Zempic, Monjaro, soon Redetrootide will be out to market. What's your thought on these compounds? Are they the perfect solution to weight loss?

• 30:52Speaker 00

  Well, I'm grateful we have them, right? Obesity is, is a serious problem. And all the, all the metabolic issues that are kind of there with obesity need to be addressed. And we weren't doing much with it, unfortunately, until the GLP-1s came around. So GLP-1s are fantastic from that standpoint. They're not perfect, you know, there's limitations, but they're, it's much better to have them than not have GLP-1s for sure. There's issues with, with certainly adherence, unfortunately, right? So there's, there's a number, over a million people a month are coming off GLP-1s, right? And that's for a variety of reasons. About 30% come off GLP-1s in the first month, and then 50% or so by, by the end of the

• 31:35Speaker 00

  year, right? So, and it's not specific to GLP-1s, you see that with any medicine. You see that with, with blood pressure medicines, you see that with cholesterol medicines.

• 31:44Andrew D. Huberman?

  What's the, can we say what the primary driving force is in the case of GLP-1s? Is it the side effects? Is it they don't like having to pin themselves?

• 31:52Speaker 00

  I think because the number is so curiously similar to all the other medicines, maybe there's some underlying thing where people just don't like taking medicines frequently.

• 31:59Andrew D. Huberman?

  That tracks.

• 31:59Speaker 00

  That might be part of it. I think that, you know, sticking yourself is, is probably for some people, they don't want to jab themselves once a week. That might be something, they get needle fatigue. That's probably there. I think when you take a medicine orally every day, it gets hard to remember to take it. And then I think there are issues with, with how you ramp them up to the effective dose and side effects. I think there's ways you can do that, you know, safely going step by step. But nausea is an issue with some of these, you know, muscle loss is an issue. There's different features there. And then additionally, you know, long term, this, this is, you know, you're taking a super physiologic dose of something, and we don't know what the long term ramifications could be. So even though I believe the benefits outweigh the costs, right? You're treating obesity.

• 32:43Speaker 00

  We know obesity is a problem. We don't know, you know, GLP-1s would be a problem long term. That does weigh heavy on some people's minds, and that might be why they stop as well. So in my practice, where we do endoscopic therapies, over 85% of people have already been on a GLP-1, and either they're struggling on it, or they've come off.

• 33:00Andrew D. Huberman?

  80?

• 33:00Speaker 00

  85%.

• 33:02Andrew D. Huberman?

  Wow.

• 33:04Andrew D. Huberman?

  Yeah, again, we don't want to get too far into the sociology and psychology of medication adherence, but it is interesting that so many people come off meds. But then there are meds like SSRIs and things like that, which I think can benefit certain people, like people with like full-blown clinical OCD, they've been extreme, they've saved lives, right? But then they're over-prescribed. I feel like, especially in the United States, people like their prescription drugs. So if they're stopping, I feel like there's got to be a reason. I mean, aren't we the biggest consumer of prescription drugs in the whole world? Like, people love their drugs. Like, you know, I've heard about the nausea. I don't, there are a number of people now who are quote-unquote "microdosing" the GLPs

• 33:46Andrew D. Huberman?

  and finding that they're getting some benefits without taking the prescribed amount. I'm not recommending people do that, you know? I guess talk to or don't talk to your doctor, they probably won't approve. But I know when people are doing that, I think initially it was because of cost and actually pen sharing, but also people feeling like, oh, I get the same effect. So is your sense that when, because of the way clinical trials are done, there aren't, often there aren't like really nice dose responses, that you're just kind of comparing, they're so expensive to do these trials that they're going, you know, two doses, you know, moderate, high versus placebo? And then that's what the doctors have to work from? Do you have any knowledge of whether or not the lower dosing brings, takes people away from side effects and then you're seeing fewer of them?

• 34:30Speaker 00

  I think it's actually very useful. So that's, you know, the approved dosages are kind of just an effect of our regulatory system, as you've alluded to, right? And it's too expensive to do different doses. Plus, it takes away personalization. You know, we're all trying to get to precision medicine and personalized medicine, and that's what microdosing allows you to do. And the first time I heard about microdosing was one of my patients, and he was a physician, and he came in and he said, you know, A, it's too expensive, you know, B, I don't feel great on it, and C, I'm doing this thing, or I take the pen and I inject it into a sterile vial, and I use an insulin syringe, and I'll take a small amount out and I'll give it to myself. And he said, I'm doing great, you know?

• 35:13Speaker 00

  I don't feel nauseous, my weight is staying off. And, you know, he was a physician, so he was familiar with, you know, the equipment, if you will. And that was the first time I came across it, and I was like, wow, that's actually, that's a great idea. So a lot of my patients actually do microdose these things. And, you know, generally, you get up to the point where you want to lose weight, you get to that dose, you're losing weight, you're losing weight. And then for maintenance, rather than just stopping it, because if you stop the GLP-1s, there's problems, right? This is not meant to be stopped, these are kind of lifelong medicines. Instead of stopping it, just go to microdosing, and you'll find a spot, hopefully, you know? Not everyone does, but you'll find a spot where you keep the weight off, you feel good, and you're not, you're not taking as much of the med.

• 35:54Speaker 00

  Now, the problem with coming off of them is, especially with the original drugs, you know, like semaglutide is an example, right? Where when you lose weight, about a third of the weight you lose would be lean mass, right? So most muscle, right? Maybe some bone, et cetera. And the problem is when you cycle on and off, right? So say you come off of it and you put your weight back on, you're not putting the lean mass back on, okay? You're putting the fat back on. So now, you've shifted your body composition to be less favorable than before you were on the GLP-1. And then you go on it again, and you lose weight again, and you lose a little more muscle. And then you go off, and you put more fat on, not more muscle. So now, basically, you're taking your body composition and shifting it, you know, worse every cycle. So there has to be a game plan.

• 36:37Speaker 00

  If you're coming off the GLP-1, you need either to microdose it or have a bridging plan to a procedure or something else, which, you know, will keep the weight off for you.

• 36:46Andrew D. Huberman?

  Are there any good studies showing that resistance training can offset the muscle loss from a standard or microdose of one of these GLP drugs?

• 36:56Speaker 00

  Yeah, resistance training, definitely. I'm not familiar with one that was the primary outcome of the focus, right? But you can actually see that that does play a major role in maintaining muscle. And that's with anything, it's not just GLP-1 medications. It's with the first-generation medications, it's with any surgical procedure or endoscopic weight-loss procedure. You know, if you're doing resistance training, you tend to maintain your muscle, because the body realizes, hey, I need this muscle, I'm not gonna, I'm not gonna get rid of it as the person's losing weight, right? So when there's a caloric deficit, the body's looking for what it can do to, you know, to maintain, you know, energy levels, if you will, and you don't want it chewing up the muscle to do that.

• 37:35Andrew D. Huberman?

  The side effects that I see getting the most coverage are increased feelings of apathy, general, you know, food noise is down, alcohol appetite is down, appetite for life is down. You hear this, but I don't know that, how accurate that is, right? Social media is a weird place, because certain things get amplified out of proportion to the real data, often. The other one is that GLPs can cause blindness, these GLP drugs. But it turns out that's in a very, very rare set of individuals that have this optic nerve head kind of ischemic opportunity. So like, so yes, the GLPs can make certain people blind, but yes, also, it's a very

• 38:19Andrew D. Huberman?

  small number of people, so you want to get screened for this structural thing in the eye. But it's not true that, like, GLPs are making people go blind all over the place. So what I'd like to ask is, when patients come to you and they say, like, I didn't like the GLP, or it wasn't working for me, are they telling you why? Are they saying, look, it made me feel nauseous? Certainly, you know, if they lost their vision because of it, but is there some resounding themes there?

• 38:41Speaker 00

  There are. I think that muscle loss, honestly, is one of the bigger ones, right? And it might just be subtle, like ozempic face, ozempic butt, right? You're losing some muscle in places where it's noticeable. Other people actually truly develop sarcopenia, I think, right? Where you have significant loss of muscle. It's rare, but those are people that they're not really exercising a whole lot when they take it, and they might have had a predisposition to it in the beginning, right? Just to start with. So in people that I'm concerned about that, it's good to get a DEXA scan beforehand, right? Make sure you have adequate muscle mass, and if you don't, you really have to think twice about if you want to do the GLP-1, right? Or if you want another avenue to try to lose the weight. And you definitely have to start hitting the gym.

• 39:22Speaker 00

  I think that's the most common thing, is muscle loss in obvious places or sarcopenia developing. The other one's nausea. A lot of folks do get nausea on the higher doses, and they will not lose weight in the low dose, right? And if they go on the high dose, they feel nauseous. So that's another issue. Some people say it stops working. I mean, that might be because, you know, of that, of that similar issue, they don't tolerate the higher doses. Those are the primary reasons that I hear.

• 39:49Andrew D. Huberman?

  Maybe we can move a bit towards some of the surgical procedures, and I always like to remind people, there's basically two ways you can affect your brain and body. You've got chemical methods and mechanical methods, so, you know? And when I think of quote-unquote "stomach stapling," I think of that purely as a mechanical thing. You're making the stomach smaller, make people feel full earlier in the meal, is my naive view of this, right? But of course, it stands to reason that you're also removing tissue, and so you're going to change the chemical milieu of the environment. I'm sure that you'll tell us that, you know, both things are involved and what. We had this thing called stomach stapling for a long time. Why did we need the GLPs? Now, some people say, well, that's a surgery, but I think in today's conversation, hopefully

• 40:31Andrew D. Huberman?

  we'll convince people that surgeries can be done less and less invasively now, and can be done with tools that make it seem a lot more like a dental cleaning, maybe a bit more, than the idea that, you know, you're cutting open the body and taking things out, laying them out on a table, putting them back in, this kind of thing. Because people's minds go all sorts of crazy places, trust me, including mine, when we hear surgery. Why did we ever need the GLPs? We had stomach stapling.

• 40:57Speaker 00

  So surgery, it really started back in the 50s. University of Minnesota, I think, was the first place they did it. And the first procedures were focusing on malabsorption, right? So the idea was, they're going to bypass a portion of the small bowel so that you don't absorb your calories, okay? And it was called a jejuno-iliobypass. But this procedure was awful, right? So the people did lose weight, but the problem was they created a long, blind limb. So there was, there was no actual food going through the limb, okay? So you connected the jejuno, which is the kind of early small bowel, to the very bottom small bowel. And the rest of the small bowel was still in there, but it wasn't, no food was going into it. So you had bacterial overgrowth in there. You had all sorts of problems.

• 41:40Speaker 00

  You had, the fat that was being malabsorbed was binding calcium. And so calcium, you didn't have calcium in the bowel, so what happens is the oxalate, which normally binds calcium, gets absorbed, and then it binds calcium in the body and the kidneys. So you're having all sorts of renal failure issues, and it was a disaster. It went on for years, right? Because, you know, people were desperate, but it was a very bad procedure. And it was replaced by something called gastric bypass, and I think that came about probably in the mid-60s. Mason, I think, was the surgeon that came up with this. So his goal was to avoid the problems with the GI bypass and, you know, still get a treatment effect. And he did, right? So he thought of this as restriction. So when you eat stomach stapling, the stomach is smaller, so you have some element of restriction.

• 42:24Speaker 00

  And then also an element of bypass, where you're not absorbing all your calories. Turns out, that's not really how this thing works, really, but that's what he thought was going on. And then, from there, you keep moving forward, you have all these other procedures, lap bands, adjustable gastric bands, that was just purely restrictive. It worked. True stomach stapling, which was, I think, the VBG, and now the sleeve gastrectomy. So these are the real surgeries. And, you know, they were created at the time, just conceptually, thinking about either restriction or thinking about malabsorption, but they work entirely different than what they thought.

• 42:57Andrew D. Huberman?

  I have a question about your profession, generally. I'm guessing there are not large-scale clinical trials of each of these surgeries, like they're doing, you know?

• 43:06Andrew D. Huberman?

  5,000 of these surgeries comparing to the existing surgery. So how much license do physicians, do surgeons have? Say, you know what? I'm very familiar with this tissue. Maybe I just like graft these two, cut out the middle. That's the part that absorbs stuff. Oops, okay, actually big problems and modify. And then, cause I mean, there's, there are other things, but there are few things greater in terms of trophies for a physician, knowing some physicians. Aside from the great feelings they get from healing patients and saving lives. Let's, let's be fair, having a procedure named after you that saves lives. Like that seems to me like that's like the ultimate thing. So there's gotta be a huge incentive for physicians to do it on that basis, which might sound all like ego, but there's another facet to this, which is no, and we know this

• 43:51Andrew D. Huberman?

  from science too, like you can read about the brain, but if you get your hands on brains, record from them, slice them up, look at them under a microscope. You just like a familiarity with the tissue of interest, especially in the context of the whole person who's coming back and saying, I don't know. I'm still hungry, less hungry, but I got this pain on my left side. You know what that pain could be. Are there any procedures that you would love to be able to do? Cause you have the sense that it could really help people, but the red tape is just too thick that it doesn't even make sense to try and develop that procedure?

• 44:23Speaker 00

  I don't think so.

• 44:24Andrew D. Huberman?

  Okay, that's good.

• 44:24Speaker 00

  I think the proper channels are workable. I do think that there are compassionate use cases where you need to make exceptions. And then they have expedited protocols for that. I remember one time I had a person that was bleeding and it was bleeding that was chronically going on and couldn't be stopped. And we needed something that was not yet approved in the United States, it was approved in Canada. And the person, they had no other option, right? And so we were actually able to get within, you know, 12 hours approval to use it as compassionate use and it worked for the patient. So there's even pathways for that, right? So I think there's always, you know, there's always a way to use that. It slows it down. Yeah, you're excited to do something, right? And it does slow things down, but, but I think it's always workable.

• 45:06Speaker 00

  Now, there are other examples of where you have a device that's approved for one thing, that the company doesn't want to get it approved for everything, cause they have no money to do that. So you use it off label. That happens every day in every hospital.

• 45:19Andrew D. Huberman?

  Just like drugs are used off label.

• 45:20Speaker 00

  Yeah, right. Same thing, right? So, so like we use wires when we're, when we're accessing a bile duct to remove a stone, right? That wire has not been approved for that. It was approved for some vascular indication, right? And we've been using it that way forever because no company ever went through and did it. So the whole field's based on this, but it was never approved for that. So, so there are examples where you use your clinical knowledge and you use a device that's approved, it's approved, but just not approved for that indication necessarily. And so there's, there's that, and that does require medical judgment, it happens on a daily basis. But if you're developing something truly new, generally the proper channels are very workable. And actually, a lot of times they give you even better ideas, like, oh, why don't you think about checking these studies? Like if you're doing this, check this gut hormone, right?

• 46:01Speaker 00

  So they have, you know, a lot of times they, they give good feedback that helps the study, you know, improves the study.

• 46:07Andrew D. Huberman?

  I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 just launched their newest formulation called AG1 Pro. And right now you can get an extra 20% off your first subscription. AG1 takes the clinically backed AG1 formula, which is a blend of vitamins, minerals, probiotics, and adaptogens, and adds three important new ingredients, creatine monohydrate, calcium HMB, and zinc carnecine. It has five grams of creatine monohydrate to support muscle strength and performance, along with brain health. Calcium HMB to support muscle recovery and reduce muscle breakdown. And zinc carnecine to support and improve the lining of your gut. Some of these ingredients I personally was already taking, separate from the AG1 formula. So it's great to see all three of them now in the new AG1 Pro.

• 46:52Andrew D. Huberman?

  As you may know, I've been taking AG1 every single day for about 14 years now. That means I discovered it and started taking it daily long before I even knew what a podcast was. I continue to take it and back it here on the podcast because it is an excellent formula. And it's now even better with the AG1 Pro formula. For a limited time, you can get an extra 20% off your first subscription to AG1 Pro by going to drinkag1.com/huberman and using the code BACKTOROUTINE. So that's with a numeral two, back numeral two, routine. Just go to drinkag1.com/huberman. When it comes to the chemicals associated with hunger and satiety, maybe you just kinda like list out the, the big players. So we're talking about the GLPs, which obviously play a role in satiety and other things, hence

• 47:37Andrew D. Huberman?

  the side effects. So what are some of the big ones that we don't hear about so, so much anymore because of the GLPs?

• 47:44Speaker 00

  Yeah. Well, it starts with, ghrelin's a big one. That's the hunger hormone, right? So that goes up and it is produced in the fundus of your stomach. And when that-

• 47:52Andrew D. Huberman?

  The fundus is the-

• 47:53Speaker 00

  The very top of the stomach, the top thin part of the stomach, right? The kind of where the esophagus comes in. And a lot of the ghrelin's produced there. And when that's how you're feeling hungry.

• 48:04Andrew D. Huberman?

  So it leaves the gut, travels to the brain-

• 48:07Speaker 00

  Yeah.

• 48:07Andrew D. Huberman?

  And stimulates hunger.

• 48:08Speaker 00

  Yeah.

• 48:08Andrew D. Huberman?

  What a beautiful mechanism. You're the top of the gut, you're like, I haven't seen food in a while. I'm still, you know, I have to say, I'm perseverating in the background about this, this thing that the gut expands in anticipation of food and that that's odor based. So does that mean that the olfactory neurons are communicating with the gut directly? Or are they talking that insulin goes up and then the gut expands?

• 48:28Speaker 00

  Insulin actually does go up too. So insulin is before you eat, you'll have a little spike in insulin too, right? So I don't, I don't know if they ever figured out exactly that mechanism by which smell, you know, tasting food early on, triggers, seeing food potentially, right? Triggers this whole process to start. But before you swallow any food, right? You already have insulin coming up a little, your stomach's already starting to stretch to accommodate the meal. So maybe some of it's learned as well. I don't know, but I'm not sure of those mechanisms, but it's very interesting how it's a critical role, right? It certainly is involved.

• 49:03Andrew D. Huberman?

  When was ghrelin discovered? I should know this.

• 49:05Speaker 00

  Oh man.

• 49:06Andrew D. Huberman?

  This is like over 30 years ago?

• 49:07Speaker 00

  Yeah, it was, it was, it was a while ago.

• 49:09Andrew D. Huberman?

  Okay.

• 49:10Speaker 00

  So after ghrelin, that's your hunger hormone, right? When you eat, it drops and then, you know, it comes back again sometime after the meal. So ghrelin's one to watch, cause we actually, we actually use ghrelin, we work with ghrelin. It's one of the mechanisms we, we use to, to get our treatment effects with endoscopic procedures and with surgical procedures too. So that's ghrelin. So then after it kinda, the food leaves the stomach, right? Then you have your CCK, which goes up, right? Which CCK will cause the gallbladder to dump bile, but it actually also will be a satiety signal as well. And it, that, that's secreted from the first part of the duodenum there. And you also have peptide YY and GLP-1, of course, they're big ones. Before you get there, I guess GIP from the K cells approximately too. GIP's like GLP-1, it's kinda similar.

• 49:55Speaker 00

  It's not, it's not quite as potent. People think of it as Batman and Robin with GLP-1 and GIP, right?

• 50:01Andrew D. Huberman?

  People might be curious to know that this drug, Red A True Tide, that the more cavalier peptide curious folks are already getting off from compounding pharmacies and gray market, black market. Red A True Tide, as I understand, promotes GLP, GIP, and glucagon to, I think the clinical trial Lilly ran showed a 30% reduction in body weight, which is really striking. So it's kind of curious that this GIP never really took off as a drug, a druggable thing. But, you know, GLP seems to be like the heavy gun, but now by combining with other things, maybe you actually get some synergistic effects.

• 50:37Speaker 00

  It does help. I think it helps with nausea. So it allows you to have higher doses, potentially of GLP-1 with less nausea. So GIP, I think, plays that role. It has a role in insulin sensitivity as well. And it does some of the same stuff GLP-1 does, and it's synergistic, I think. But what's interesting about the glucagon is potential muscle sparing there, right? So glucagon, among other things, you know, glucagon is usually up when your insulin is down and vice versa, right? And its job is, is to say burn fat, right? That's its main job. It also causes you to dump your, your glycogen out of your liver a little bit, but the main job with glucagon being up is says burn fat, right? So it's kinda nice that they're adding that as a muscle preservation, as well as, as

• 51:21Speaker 00

  a way of helping to burn some of the fat potentially.

• 51:23Andrew D. Huberman?

  Yeah, these pharmaceutical companies, however, a bunch of people might hate quote unquote, big pharma. I mean, they're putting hundreds of millions of dollars into the, the research. Kind of an amazing case of like 20 years ago, there was nothing for, for druggable for obesity, as I understand. And what was there was mainly stimulant based, like the fenfluramine and like this kinda thing.

• 51:45Speaker 00

  Yeah, the valve issues, but you had, well, you had fentramine, right? Which was a sympathimimetic really. And-

• 51:52Andrew D. Huberman?

  Speed.

• 51:53Speaker 00

  Yeah, basically.

• 51:54Andrew D. Huberman?

  Mother's little helper type thing, right? Right? I mean, and nicotine, you know, there's a whole set of conversations there. Some people think that when we, you know, basically abolished smoking, people started eating more. And then America got fat and then snack foods and highly palatable. And there are a lot of things, right? Moving more, eating more, highly palatable foods and less fiber. But now nicotine's back in oral forms, is back big time, mostly with men, but also with women. And a lot of people like it because it's an appetite suppressant. I'm not a fan for a bunch of reasons. Raises blood pressure, highly addictive and so on. But it's interesting, right? Like people have struggled for, forever to like, how can I eat, enjoy food, but not eat too much?

• 52:38Andrew D. Huberman?

  Whether it's a compound that we know, you know, a drug that increases the compound we already make, like GIP, or we're taking something to make us move around more. And like you said, sympathimimetics, it's like stimulants. It's like a human obsession. Why can't we just eat enough and not too much?

• 52:55Speaker 00

  I think it's obviously metabolic dysregulation and there are layers of it. The processed foods, which you touched on, certainly is an element to it, right? There was a study done, I believe it was in Bethesda and an NH study, when they had like 20 subjects and they randomized and crossed it over. And they could either have whole foods or they could have processed foods. And the people that were eating the processed foods, they could eat at will, they were eating like 500 calories more a day. So it is something that you do in, in your normal environment. If you're eating stuff in a wrapper and you're eating it, you're inclined to eat more of it. And not only are you eating more of it, right? It's easier to digest, right? You're getting bigger glucose spikes and you have a lower thermogenic effect of food, right? So it really is, it's probably also not doing great for your microbiome, cause there's less fiber in it.

• 53:40Speaker 00

  And so that is playing a big role, starting the ball rolling for sure. And then there's different, there's different layers to it. Then you have your, your PYY and your GLP-1, which the GLP-1, um, you know, it's triggered by anything, but glucose tends to trigger more of it. And then the PYY, um, that's more, you know, your proteins and your fat. It does something similar. You stay full longer, I think, and with a, with a big, heavy fat and protein meal, probably because of the, the PYY. Um, uh, that's something that's been very hard to drug, right? They didn't have a healer monster to solve the problem that, uh, the GLP-1 did. But, uh, it's, it's also very potent and they both come from the L cells and the distal small bowel and the colon. And, uh, those are, those are kind of all the, the major players.

• 54:25Speaker 00

  You also have leptin in the background. Now that's more of a thermostat, if you will, that gets involved in a set point and things like that. And it's, that's secreted from your fat cells. And if, and it's almost proportionate to fat. So if it's high, you know, generally you're going to probably eat less. If it's low, you're going to eat more. But there's all sorts of problems with leptin resistance and other things like that too that complicate it.

• 54:45Andrew D. Huberman?

  I remember coming up through science, like leptin was all the rage. Um, it's discovery, it's cloning. And everyone thought, okay, their drugs gonna, are gonna come along to mimic or stimulate leptin and we're going to solve the obesity or overweight issue. But it didn't really pan out. Why was that?

• 55:05Speaker 00

  I think leptin never panned out in large part because of leptin resistance. Right? I think the hypothalamus and the, uh, the brain itself is, is just becoming resistant to it because it's so high in people with obesity for so long. Right?

• 55:19Andrew D. Huberman?

  So they're saturated. They've got a lot of fat, a lot of leptin, receptors are, are clogged.

• 55:23Speaker 00

  There's a little grade inflammation, we know, in, in, in those tissues and, and you eventually just, yep, you don't respond to it anymore. And so, so the, the drugs just didn't pan out. I think that, um, with, with the GLP-1s, it's another story. Right? I think, you know, incretins in, in general, we've talked about incretins. We've been talking about these, these hormones that are produced in the gut. They go into the blood and they do something. So the concept first came about in the 1930s and it was in, it was in London. And they basically were, um, grinding up animal duodenum. Okay. And they were emulsifying it and injecting it back into the animal in the vascular system.

• 56:01Andrew D. Huberman?

  Science in its not crudest form, but history, this is 1930s jokes. Science is not that old, you know, real science.

• 56:09Speaker 00

  Right? That's nitty gritty, right?

• 56:11Andrew D. Huberman?

  That's pretty crude.

• 56:12Speaker 00

  And the idea for that was secretin. So someone had found secretin, right? And that was, that's a hormone produced in the duodenum that goes to the pancreas and says, secrete fluids for digestion. So exocrine function of the pancreas. So this person thought, well, wow, if the duodenum secretes secretin, maybe it secretes something else. So they, they did this study and in the animal, the blood glucose fell. And like, holy cow, right? This, something in the duodenum is causing glucose to fall. Phenomenal. I'll call it incretin because you have secretin, I'll call it incretin. So that was, that was where it started, 1930s, right? And then there's another lab, Sheila Sherlock's lab in, in London. And she was famous for being one of the kind of, you know, founding physicians that, that started the field of hepatology.

• 56:56Speaker 00

  And she was trained in some medicine and some, some internal medicine, some surgery. And they had this concept, but what they had access to was this new tool, which is wherever you see innovation, right? They had access, access to this way of actually detecting and measuring insulin. And so they did a very interesting study where they gave subjects a set amount of glucose intravenously, and then they measured the amount of insulin that was produced. Then they gave them the exact same amount of glucose orally, and they found they produced much more insulin. All right? So this was something they, they, they coined the incretin effect.

• 57:29Andrew D. Huberman?

  But is that based on taste?

• 57:31Speaker 00

  So they had no idea, right? But they knew the insulin was going up and they thought it probably, because the only other research that was out there was from this, this old 1930s study where it was coming from the duodenum, it was probably due to that incretin. Then there's other studies, you know, that come after that, they, they get, get closer and closer to it. Right? So eventually what ends up happening is, uh, in, in the, um, Lilly Labs, I believe it was, there was a physician named Bell who actually, he, he, he had a pre-pro glucagon. He ends up, you know, cloning that. And then from that, you get GLP-1 and GLP, GLP-2, right? And so he now is, he now, we now have GLP-1, we've identified it.

• 58:12Speaker 00

  And then there was this physician, um, Blossom, I believe was the name, in, in London again. And this guy did some phenomenal work. So what he ended up doing is now we had GLP-1, so he could actually study it. He found GLP-1 was in the bowel where we thought it was. He also, um, found out that when you actually gave glucose, GLP-1 increased in the blood. And then he actually infused GLP-1 and found that when he infuses it, insulin goes up, glucose goes down. So now all of a sudden, we had a real sign that what, what this incretin was, and it was GLP-1. Very exciting work. The problem was you had to infuse it, right? For it to work, because it gets chewed up really quickly by, uh, dipeptidylpeptidase that chews it up.

• 58:53Speaker 00

  There's something on the end terminus of it that is susceptible to that. And, uh, that's the part that binds the receptor, so you can't really get rid of it. Uh, and then it was in the Bronx in the nineties when there's a Dr. Eng and he's studying healer monsters. And in the healer monster, he finds this thing in the healer monster's venom that looks very much like GLP-1. It has one, uh, substitution, like second, second, uh, yeah, amino acid in from the end side. Otherwise it looks just like it'll bind a receptor, the C's a little longer and different. But this is, um, you know, uh, extended for, uh, and basically this is the, the molecule he discovers and this is what ends up becoming all the GLP-1s.

• 59:34Andrew D. Huberman?

  Now, these healer monsters don't have to eat very often, so makes a good candidate to, to study. So you do surgeries of various kinds. The people are coming to you, they, have they all tried GLPs and they don't like them or they're not working for whatever reason? Or they'll microdose it, but it's not solving the problem? And, um, what sorts of surgeries were you trained to do? And then at what point did you become the doctor I referred to earlier, uh, who seeks out IRB approval to build something better? Like I'm a, I guess if there are multiple themes in today's discussion, but one of them is if the really great physicians look at a problem, they look at the tools they've got to solve that problem. And if they're not working for any number of patients, they build something better

• 1:00:18Andrew D. Huberman?

  or different, or they, they increase the array of, of tools. So tell us that story. How does, where, where did that start and where are we at, where are you at now with that?

• 1:00:29Speaker 00

  Really for me, it started in, in fellowship. So I'd moved to Boston to, to learn interventional gastroenterology. Right? So this is not, you know, colonoscopy and whatnot. It's, it's doing procedures, mostly focusing on pancreatic, biliary, so pancreas and biliary conditions. And the, the big problem at the time was really pancreatic cancer diagnosis. And so I was moving there to learn a new procedure, uh, that they called endoscopic ultrasound. So you'd be able to put a scope in the mouth, into the stomach and small bowel, and then use the ultrasound probe that's embedded in its tip to see the structures just outside the lumen and you could gain access to them. You could put a needle in them and that held a lot of promise. You could maybe ablate lesions with it.

• 1:01:10Andrew D. Huberman?

  So you're feeding a needle through a tube, you're watching it on a screen, right? So you're not, you're not using the, you're, you're not opening up the, the abdominal cavity.

• 1:01:19Speaker 00

  Yeah. So you can do it through this, through the mouth. So it's a natural orifice, you go in through the mouth rather than opening up, which for pancreatic cancer, a lot of times that's how they would do it. They would go to surgery, open the belly up and get the biopsy, right? To see what it was. Uh, because it was really hard to make the diagnosis. And so I wanted to learn this new technique where you just, the patient goes home the same day, they don't feel anything. Right? So I thought it was phenomenal. When I got there, I'd, I'd done a master's in health evaluation science at Penn State before, before going. And I thought that I would be doing epidemiologic research. And when I got there, the, my, my, my mentor, Bill Brugge at the time, was a pioneer in this ultrasound. And, um, he, he, he gave me a needle and said, hey, this thing doesn't work to make

• 1:02:04Speaker 00

  the diagnosis pancreatic cancer, I need you to try to fix this. Right? And he was right, the thing didn't work. Unfortunately, like we had about a 50/50 chance of getting a diagnosis with the needle. And it's because it was, it was designed like a hypodermic needle, like you get an IV placed, right? The IV is not taking chunks of tissue out of you. It was designed to atra medically split the tissue and that's the needles we were using.

• 1:02:25Andrew D. Huberman?

  Designed to deliver stuff, not take stuff.

• 1:02:27Speaker 00

  Yeah. So I kind of figured out what the problem was. I didn't know the solution, honestly, but I gave them my report and the company thought it'd be too expensive to fix and we didn't really do much with it. But it still went on. I was a couple of years in the practice on faculty there. And, you know, we still had the problem of, you know, you, you, you take these F and As, finding the last aspirations of it and you wouldn't have an answer. And you have people that wouldn't want to have a major surgery having their pancreas taken out without an answer. And then they'd have worsening cancer. And then by the time you'd be able to make the diagnosis, it'd be too late to treat them and help them. So that's where I started kind of entrepreneurial stuff, right?

• 1:03:06Speaker 00

  And so my first, my first company, I guess you'd say, was based on that. And I needed a team, you know? And one of the engineers had the brilliant idea of how to change that bevel design, up raising the money. I knew what the clinical problem was and that and whatnot, but you needed a team to fix it. So I hired engineers and we got together and we came up with a needle that could biopsy the pancreas without causing pancreatitis or any problems. And it has been wonderful because that really became very instrumental in helping a lot of people to get the diagnosis earlier. So we're saving lives with that. But now we look forward to the fact we have preserved cellular architecture. So you could do, you know, precision medicine. You can actually test different drugs on the tissue and see what it's going to respond to.

• 1:03:51Speaker 00

  You can do immunostaining and it's a lot better than just having a few shaved cells. So that was the first time I really got involved in trying to solve a problem, like you say. And that was before I started diving into metabolic disease where I've spent really a large part of my time, but that was what started it off.

• 1:04:06Andrew D. Huberman?

  So just like earlier, you know, saying the mechanical influences and chemical influences over our health and biology for what I call like reading from the body. Like people get a sleep score or your heart rate or blood pressure, that's reading. Obviously you're not writing to the body, but you have a structure and you have functional readout. So like if, you know, someone goes, I have a pain in my side and you go, okay, well, you, you give them an ultrasound, there's a massive thing there. Like you've got a structure that doesn't belong there, then you can decide to cut open, right? I hear biopsy, people hear biopsy, they go, boy, you're getting poked with a needle, this kind of thing. But I might shock a few people, but if you told me that I could come into the clinic

• 1:04:45Andrew D. Huberman?

  and spend one long day under anesthesia and get completely non-damaging biopsies of every single one of my major organs to grab a few cells here and there through the mouth or heck, even if they had to make a small incision one place and then zip me back up and send me home and I can just say, okay, like I'm, let's just look at all the cells. Let's see what's, you know, let's see if I have any issues. A lot of people will be like, why would you do that? Well, I'd rather do that than walk into the clinic at 72 and go, I've got this pain or I'm not sleeping well or I'm sweating or I have this bump here. I mean, in the end, we end up diagnosing ourselves. Well, we either drop dead, diagnose ourselves, or someone else diagnoses us, right?

• 1:05:24Andrew D. Huberman?

  And so with a procedure like yours, I'm kind of inclined to say like, would you just get it? You seem healthy. Have you done it to yourself? Can I come in and get it just for checking things out? We take blood tests now. People go, what's my testosterone, my estrogen, my luteinizing hormone, my lipids, my, you know, small, you know, LDL, APOB. 20 years ago, if you wanted to get a blood test, 15 years ago, and you didn't have a problem to motivate that, it was thousands and thousands of dollars at best. It was very hard to find people that give you these, now it's trivially inexpensive for most people. So I feel like we're kind of going that way with biopsy.

• 1:06:07Andrew D. Huberman?

  So how soon are we going to just be doing biopsies with non-damaging procedures?

• 1:06:12Speaker 00

  So I think a lot of times with biopsy, you have to be very targeted to get the tissue of interest, right? So even in the pancreas, like we said earlier, you know, you could be even in the area that looks like a lesion, like a tumor and not getting cancer cells out. So I think that you have to be very, very targeted, but then once you do get the tissue, you can do all these stains and you can really figure out what's going on. Is there genetic predisposition to it? Is there some way it'll respond to one drug over another? I think that's phenomenal, but I would like to see the diagnostic studies become less and less invasive so they can scale easily. So the one problem with procedure-based diagnosis, I like procedure-based treatment. I love it. It's better than surgery. You know, going through the mouth and rather than making an incision in the abdomen, I

• 1:06:57Speaker 00

  think has benefits for the most part. But when you get diagnostic studies, similar to colonoscopy, there's a scaling problem, right? So when a patient has to come in and spend an hour with a doctor or two hours, that doctor is taking care of one patient for two hours and he's outnumbered, right? Everyone needs screening and it becomes very complicated. So I would love to see innovation and technology go where we have minimally invasive ways of diagnosing things, whether it's via your smartphone and AI or it's via minimally invasive scans and blood tests are great because it's quick and easy to do. And we're not even doing, talk about metabolic health. You know, there's several things we could be doing non-invasively at home right now that we're not doing to catch it much earlier.

• 1:07:39Andrew D. Huberman?

  So jazz.

• 1:07:40Speaker 00

  Well, so an example is most of the time we're waiting for hemoglobin A1C, right? And that's the marker of diabetes and that's going to be the thing that, you know, once you have an A1C or a high APOB, which they're probably not checking, maybe, you know, an LDL C or something, right? Once those are high, we know there's a problem. However, there are signs much, much earlier than that. And so metabolic dysregulation follows a fairly predictable sequence, right? First, it's calorie excess, right? So it's in the Western diet, it's usually glucose, right? So you have too much glucose around you. You can have too much saturated fat too, but too much glucose. And then you have too much glucose, you could catch that by doing a CGM, right? So that's one way you could do it, a continuous glucose monitor.

• 1:08:24Speaker 00

  You could then see if you have particularly glucose spikes to certain foods. And if your glucose is shooting up to 200 with certain meals, you know you're sensitive to that and maybe you should change how you're eating it. Try to eat it after having something fatty, maybe avoid it, right? So because we know this is part of a sequence that's going to lead to problems. And this goes back to the Whitehall 2 study, which, to give relevance here, so the Whitehall 2 study was on British civil servants. It was a prospective kind of longitudinal thing. And they found that, they followed all sorts of metrics. One of them was insulin. Fasting insulin was one thing that they followed. They followed other things as well. And they saw that if someone had high fasting insulin, they're more likely to get diabetes long-term. So, and it was a long period of time. It was like a 10, 15-year time.

• 1:09:07Speaker 00

  They could detect this thing 15 years earlier, they could do something about it, right? But no one does because no one looks for fasting insulin. And the other thing that's very relevant here is there's another study, it was the UNC-NHAN study, okay? And that's another large database, it's more cross-sectionally looking at a point in time. And what they found was that less than a third of people that are lean are metabolically healthy. That's crazy. 12% of the whole population, less than a third of lean people are metabolically healthy based on their parameters. And their parameters looked at waist circumference and glucose and blood pressure and whatnot, right? So looking at metabolic signals. The word there is start looking early and don't look with the traditional things, okay? We have to look at other things, getting back to metabolic syndrome ideas. So first, you could check for glucose, so glucose spikes, a CGM can do that.

• 1:09:51Speaker 00

  I wouldn't say wear it all the time. Get one for a month or two, learn what spikes your glucose, see if something spikes your glucose and adjust it. Next, you have fasting insulin, okay? So the next thing that happens is first, in anybody, they have the insult of excess calories. The excess calories comes, that's what happens. Insulin's job is to take that sugar and push it into the cells because glucose is really bad for the body. We know this. If you look at end-stage diabetes where they can't control their glucose anymore, they go blind, you know, they have kidney failure, it's killing the vasculature. It's sticky. Glucose is sticky, it glycates things, it causes problems. So the insulin's got to get it out of the bloodstream. So next, in the sequence of metabolic dysregulation is high insulin levels, fasting insulin goes up. So you can get a fasting insulin level. That's the next thing you check, right?

• 1:10:36Speaker 00

  It's not a lot to ask for, it's an inexpensive test and you can see if you've evolved into that problem where now you have chronically high insulin levels. And part of that, honestly, is due to eating too frequently and could be eating, you know, certain things that are, you know, high fructose corn syrups or things that, that basically, you know, have a high glycemic index or load that's going to cause your sugar to spike. So, and the problem is if you're eating every few hours, insulin goes up and it spikes, it drives the glucose out of your blood, but then the insulin stays high, okay? It doesn't go right back down. It stays high for a few hours. So if you're eating every few hours, you always have this high insulin, that's going to lead to other problems. And the next thing that happens is ectopic fat, right? So your fat exists in different areas. You have subcutaneous fat, that's where it's supposed to be.

• 1:11:21Speaker 00

  That's your depot for energy and it's healthy there, has different ways of growing. Then you have visceral fat, which is really in your, your omentum, you know, it's a, it's in the abdomen and in your mesentery in the abdomen that's around the bowel, okay? So that's kind of your visceral fat. Then you have your organ-associated fat. You have some fat around the heart, you have some fat around the kidneys, et cetera. It's kind of supposed to be there. They're all adipocytes, they're all fat cells. Their job is to store fat and release it, right? That's what they do. Then the last bucket is ectopic fat. And ectopic fat is where you have fat in cells that it's not their job to store fat, right? Like liver cells or muscle cells or pancreas cells. And that becomes, that becomes a problem.

• 1:12:04Andrew D. Huberman?

  It's like Wagyu beef.

• 1:12:06Speaker 00

  Yeah, it's like Wagyu beef.

• 1:12:08Andrew D. Huberman?

  Yeah, those cows are, they're not, they don't move, they're overfed, it's, yeah.

• 1:12:13Speaker 00

  And, and that, that's, you know, that's another problem, right? So that's the next phase of metabolic dysregulation. And they've done all sorts of great studies that are showing exactly from each step, what happens and how you get there, right? And so that's when you get fat in your muscle and you get fat in your liver. And that's bad, fatty liver is very bad. And then that is what goes on to insulin resistance. Okay, so for the fat, how can you look for that? Well, you can do a waist circumference measurement, waist to height ratio. You can get a DEXA scan that'll tell you if you have visceral fat or, you know, if you have a lot of secretaneous fat, a CT scan, MRI, other things will do it too. Or an ALT, look at a liver test measurement, right? That's amino transfer rates in your liver.

• 1:12:53Speaker 00

  And usually, you know, that'll signify some inflammation. So, you know, that's the next level, right? And then you have insulin resistance, which that's a little harder to check. That's a combination of, there's a formula that you can do to look at that. It's a, it's a fasting blood glucose and a fasting insulin level. And you multiply those and divide it by a constant. And if it's greater than two, you have insulin resistance. So that's the next, next phase of it. And then finally, you have metabolic inflexibility. Your body is supposed to change between calories, right? What is burning? If your fasting is supposed to be burning fat and if your eating is supposed to be burning some element of carbs, depending on what you eat. But if you have carbs in it, it should be burning the carbs, right? And so you can develop metabolic inflexibility as the next phase of this, once you have insulin resistance, where when you're fasting,

• 1:13:38Speaker 00

  you're not really accessing your fat anymore. Your fat's still there. It's burning more of your glycogen stores and God forbid it's chewing up muscle, right? But it's, it is no longer accessing the, the fat stores it's supposed to be accessing. And then when you eat, it doesn't shift over to burn the carbs well either. Kind of just, it doesn't know what to do. So that's a loss of metabolic flexibility. And by then, you're getting near the time when all of a sudden something's going to happen. Cause once you have a loss of metabolic flexibility, they've shown in studies that you're more likely to gain weight and develop obesity. You're more likely to start losing beta cells. You start burning out your beta cells and they became apoptosis and you lose beta cell mass. And you start having all sorts of other problems. So this is a very kind of typical sequence that you see. It can happen in other ways, but that's a typical sequence that's backed by science and different clinical trials.

• 1:14:24Speaker 00

  And each, each step of that way, you have a study you could do to find out about it. The last one, the metabolic flexibility is a little harder because you have to do, kind of go on to do a breath study for that, where you're looking at gas exchange. And it's very accurate, actually, because we know that there's a respiratory exchange ratio. Athletes do this to optimize performance. You can do this where you get a DEXA scan a lot of places. They'll tell you how many calories you're burning or what you're burning. And basically, it's, you know, first law of thermodynamics and you're burning calories. But it's a ratio of a volume of carbon dioxide divided by a volume of oxygen. When you eat carbohydrates, carbohydrates have an equal number of carbon and oxygen. So it doesn't require much oxygen to, to burn the carbohydrates. But when you burn fat, it requires more oxygen.

• 1:15:08Speaker 00

  So if that ratio is like 0.7, so it's, it's volume of carbon dioxide or volume of oxygen, that means you're using more oxygen. That means you're burning fats, right? And if it's one, you're burning carbs and then there's an in-between. And so this is a great way to see if you're metabolically flexible. Eat fat, see what happens. Eat carbs, see what happens. Do it fast, see what happens, right? And you sit in a chair and you breathe for half an hour. There's companies that are actually developing at home methods doing this too. There's a few of them. And actually, one of them recently, I think, now has one that does both the oxygen and the carbon dioxide.

• 1:15:35Andrew D. Huberman?

  I think it's like a little box that you breathe into.

• 1:15:38Speaker 00

  So, I mean, you can do everything, right? So, and then, or you can just wait until you have diabetes and your A1C goes up. And so, yeah, there's a lot of things that we should be doing before we do the standard test of looking at your fasting glucose and looking at your hemoglobin A1C.

• 1:15:53Andrew D. Huberman?

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• 1:16:38Andrew D. Huberman?

  In a follow-up test, I could confirm that this strategy worked. My blood lipids are now back exactly where I want them. Comprehensive lab testing of the sort that Function offers is just so important for health. I mean, how else are you going to know what's going on under the hood? And while I've been doing blood work for years, it used to be time consuming, complicated and expensive. In fact, I used to spend thousands of dollars per year trying to get this kind of data. And the data, frankly, were not all that good. But now with Function, it's extremely easy and affordable. A Function membership is only a dollar a day, $365 a year. And if you think about the information it provides and the health challenges it helps you avoid and the proactive things that it can do for you to enhance your health, I truly look at it as a savings. To learn more, visit functionhealth.com/huberman

• 1:17:23Andrew D. Huberman?

  and use the code HUBERMAN for a $50 credit towards your membership. Again, that's functionhealth.com/huberman. It's gratifying to hear that you put the CGM pretty early on that list, very early, in fact. I mean, I, I don't, I want to be clear. I'm neither complaining about, nor am I trying to turn you against your colleagues. But I'm going to just be really blunt from, and these are my words and my words only. I want people to understand this, like, I mean, I've gone public many times saying, hey, like as the cost of blood testing comes down, this is awesome. You get a window into lipids, hormones, things that can be very informative, whether you have issues or not.

• 1:18:07Andrew D. Huberman?

  And the pushback on that from the medical community, not all, because I have friends in the medical community who will quietly say, yeah, I'll totally do that test. I take that test, you know? But many of them just say, oh, great. Now patients are going to be coming to me saying like, I need to, do I need to be worried about this? Do I need to be worried about this? I said, I actually put a post out recently that as the cost of a whole body MRI comes out, it's going to be interesting to see what happens. I have neurosurgeon friends who tell me about life-saving procedures they, they do all the time. The neurosurgery community was super angry, it generated some press. This week, actually, this is how the, the tables kind of turned. There's a celebrity, I forget their name, who took one of these types of scans from a company I have no affiliation with, by the way.

• 1:18:50Andrew D. Huberman?

  I took a PRANOVO scan and identified a malignant issue that could be cut out and very likely save their life or at least extended it. So I get it on the one hand, why a lot of physicians are worried about people walking around with a lot of data. I heard the same about CGMs. Okay, I'm going to try not to rant here. It was like, oh gosh, who needs to know that glucose goes up, glucose comes down? In the absence of diabetes or prediabetes, like you can have a glucose spike. We don't want people walking around neurotically worried about eating a grape, which I totally understand. Your body can manage these things. But now that CGMs have been out for a couple of years, I don't hear much pushback. Yeah, if somebody wants to use CGM for a couple of weeks and see how they reacted to different foods,

• 1:19:33Andrew D. Huberman?

  post-exercise, post-poor sleep, et cetera, cool. So it's kind of wild to me that physicians don't want patients to have data. But here, I'm hearing something very different. You're saying, yeah, I think people should pay attention to how they're regulating their blood glucose.

• 1:19:48Speaker 00

  The problem with medicine is it moves very slow, right? So a lot of people are going to want your randomized control trial, another randomized control trial, maybe a few more and then a meta-analysis.

• 1:19:58Andrew D. Huberman?

  Understandably.

• 1:19:59Speaker 00

  And then maybe a guideline.

• 1:19:59Andrew D. Huberman?

  Understandably, but from a patient perspective, people want data now. And if they can get it inexpensively, and by the way, these are, are they called elective or elected?

• 1:20:09Speaker 00

  Elective, yeah.

• 1:20:10Andrew D. Huberman?

  They're elective, if, they're elective procedures. So no one's saying you have to get this done.

• 1:20:14Speaker 00

  Yeah.

• 1:20:14Andrew D. Huberman?

  It's an option.

• 1:20:15Speaker 00

  Yeah.

• 1:20:16Andrew D. Huberman?

  I don't get it.

• 1:20:17Speaker 00

  Yeah.

• 1:20:17Andrew D. Huberman?

  Can't wrap my head around it, guys.

• 1:20:19Speaker 00

  It's unfortunate that there's, there's a reason for it, obviously do no harm, right? There's a reason for it, but by the same token, it does not necessarily do the patient any favors by waiting for something that's, that is logical and makes sense, right? And there's enough evidence for this sequence of events, if you will, for metabolic illness, all the way back to syndrome X in the eighties, right? We know there's this constellation of things. And we also know that if you don't act early, you're much less likely to have a good treatment effect. If you start treating someone once they have diabetes, it's much harder to get them back to healthy and normal. They've already lost beta cell mass.

• 1:20:56Andrew D. Huberman?

  Or peripheral, I mean, they could have loss of their fingertips and toes, or sensations, excuse me, their fingertips and toes.

• 1:21:01Speaker 00

  And now, before, I mean, we might not have had access to things. We had access to fasting insulin, right? But think about this, so say you don't get the CGM and you have fasting insulin, right? And the fasting insulin is normal. You don't know if step before that is a problem and they're going to have problems with fasting insulin. Or if it's abnormal, you need the CGM to learn how to eat, right? Because that fasting insulin's high for a reason. You're spiking your insulin, or you got to figure out why you're spiking it, right? So, so then you go back to the CGM and you learn, and I don't, I don't have any stock in a CGM company either. You got to learn how to eat to not spike your insulin in that case. Now, if you're taking a bunch of, you know, saturated fat, that's not great either. You can't be on super high saturated fat with an APOB through the roof. But, you know, either way, it's not good, right?

• 1:21:43Speaker 00

  So most of the time in western, western countries, it's, it's the glucose and insulin that are the problem. And that's the very beginning of it. So why not learn about yourself, take some responsibility, right? And learn and, and prevent these diseases from, from going on. And I do hope physicians are more open to kind of encourage this as well, where we start acting earlier. It's going to, it's going to be better for the, you know, for the population in general.

• 1:22:08Andrew D. Huberman?

  Because I could see why physicians would be very reluctant towards self-directed interventions. I get it. But here, we're just talking about getting data. And it's voluntary, the costs are coming down. And as you point out, having data early is better than having data late when it comes to physician-guided interventions.

• 1:22:27Speaker 00

  So what I've, what I've heard in this regard is, you know, I, within conversations is, well, the problem is a patient's going to then figure out they can eat junk food, like, like, like something that's really bad for them, you know? Some greasy fatty thing that's unhealthy for them, going to, you know, put their, you know, APOB through the roof. And they'll think it's okay because it's not showing up on their CGM. I think that's not giving the patients enough credit. Cause generally, if you're getting a CGM, you probably are, are trying to do the right thing. So I think it's, how will they use the information? Could they accidentally not be informed enough to, to use that information appropriately? And could they do the wrong thing? But again, I think more information is better, almost in all circumstances with diagnostic stuff.

• 1:23:09Speaker 00

  Now, I agree with this MRI thing being concerning because you might have a lot of little lumps and bumps there that now you're doing diagnostic studies for that could increase risk, right? So, because diagnostic studies could increase risk and also could be a burden on the healthcare system. But More from me, I still think more information is better. We just have to find better ways of doing the follow-up confirmatory diagnosis. There might be other ways we can do it, looking for metabolic activity of tissue like PET scans or whatever, doing other things rather than a biopsy and something that would increase risk.

• 1:23:39Andrew D. Huberman?

  Okay, well, thank you. I wasn't asking you to take my side in the argument, but since you threw out CGMs first, I just kind of took that as an opportunity. I think my, I won't name names, but let me put it this way. Whenever I get that sort of pushback, I'll go to people I know in the field and I'll say, I'm not looking for confirmation that I was right and they were wrong. So tell me what I'm hearing here. What's beneath, what's the layer beneath what I'm seeing? And almost inevitably, they say the same thing. Give it 20 months. This will be standard. And that happened with CGMs. No one balks at the idea of a CGM. Yeah, you want to put that thing on, you can afford, you want to get some data. Like most physicians I know now are comfy, but at the beginning, it was like all the pushback in the world. That's really wild how, so wait 20 months

• 1:24:22Andrew D. Huberman?

  and this will be a non-issue is what I keep hearing again and again.

• 1:24:26Speaker 00

  Well, even when you have procedures that have gone through rigorous evaluations and they have FDA approval and they're ready. You have so many people that are reluctant to send patients for them, right?

• 1:24:40Andrew D. Huberman?

  Why is that?

• 1:24:42Speaker 00

  I think it's in the culture.

• 1:24:43Andrew D. Huberman?

  Are they afraid they'll do it wrong? It's like a new skill to learn?

• 1:24:46Speaker 00

  That could be. So some of these procedures, you can't learn them in a weekend course. You know, you have to have a year or longer learning some of these things. And so for a physician who wants to add something to their practice, that's, they're not going to dedicate a year to it. They might do a weekend course and realize it's too hard and then they don't, they don't adopt it. The problem is the people that do adopt it and they're not ready. So then doctors referring go, huh, this procedure's been around for six months or a year. It really has great data in the clinical trials, but does the guy down the street know how to do this after doing a weekend course? And so they're reluctant maybe for that reason. So just give it time, wait until it's, maybe insurance is not covering it yet, right? Wait to see if the insurance companies think it's a good idea, then maybe we'll start sending patients. So it just, it moves slowly.

• 1:25:31Andrew D. Huberman?

  Yeah. Well, I don't want to hover on this too long, but I have a friend who's really into cars and he told me that in the mechanic and automobile community, a similar thing, like as things became more and more computerized, there was a lot of pushback because it makes it hard for auto shops to do their work. You know, it changes, the field changes and you need more tools. Sometimes those tools are expensive. You need training and people like to hold on to the way they were trained. This is absolutely true of most every field. Adapt or die, or your patients die there. That's why, you know, if you don't adapt, your patients will die. I have to imagine that there are good surgeons, there are

• 1:26:12Andrew D. Huberman?

  mediocre surgeons and there are exceptional surgeons. Are there places where you've brought in devices or machines that could offset the mediocre and lousy surgeons or surgeons by day, a little sleep deprivation? So I'm not just saying like bad surgeon, good surgeon, but there, so what has come into the field that's allowed you to do your work more effectively and others to do the work more effectively?

• 1:26:39Speaker 00

  Most devices we see are kind of incremental improvements, a little bit of better wire, you know, devices a little more ergonomic. But what I see kind of happening more recently is AI starting to have an impact where it can actually coach you through procedures.

• 1:26:54Andrew D. Huberman?

  How does that work? Do you have an earbud in or something?

• 1:26:56Speaker 00

  On the screen itself, it's like a heads-up display, right? And on that heads-up display, it will actually give you information. So you're not just seeing the images you're working on. It can actually highlight certain structures you want to work on. It can actually point to something where you want to put your stitch, right? And it can count the stitches as you're placing them and tell you if they're close enough together. It can change the shape of the stomach as you're working on the stomach to let you know if you're having a good treatment effect. This is something that we never could have done before.

• 1:27:20Andrew D. Huberman?

  This is in real time?

• 1:27:21Speaker 00

  Real time, yeah. Which is phenomenal, right? Now, it's not widely available. You got this in research centers, right? But you actually can see this happening in real time and it's phenomenal. So you see that in more and more, it's happening in different surgical procedures where AI is kind of real-time coaching you and in endoscopic procedures. Additionally, there's the hope for robotics to help as well. And we've done a lot of research in our lab on robotics and how it can take trainees that are learning a new, very complicated procedure and shorten their learning curve dramatically. And we'll randomize the trainees and have them do the traditional way. Like this is usually resecting a tumor from the colon, leaving the colon in place. That's a very complicated procedure and/or from somewhere else in the stomach or whatever. And the fellows will learn, they'll spend

• 1:28:06Speaker 00

  a couple of weeks training in both modalities and then they will struggle horribly with the original way. That's why it takes two or three years to learn how to do it. They'll sit down with a robot and be almost good as an expert. So robotics are very interesting. And now, in the future, we haven't done it yet, but when you start layering on AI and automation with the robots, now you may have a big win. And we've seen this before with different surgeries as well, with intuitive surgical robots when they first came out years ago. It democratized the field. It took mediocre surgeons and it made them excellent. And the excellent surgeons were still excellent, right? But it really helped the ones that were struggling.

• 1:28:41Andrew D. Huberman?

  How do the excellent surgeons feel about it in keeping with our previous discussion? Seriously, like, is it, is it, is part of, it's like, is it like athletics? Like people want to be, they want a hierarchy of performance for themselves. They don't want patients dying at the hands of poor surgeons. But I would think that if do no harm is really the true central core of medicine, then every person in a field would want more people being healed, independent of their own stature as a physician.

• 1:29:13Speaker 00

  Yeah. I think they're supportive of robots, but I think that a truly exceptional surgeon is probably just going to be better without the robot. And you know, the robot is just, it's going to, it's going to make you worse.

• 1:29:27Andrew D. Huberman?

  How do I know if I'm getting a truly exceptional surgeon?

• 1:29:30Speaker 00

  That's a good question.

• 1:29:31Andrew D. Huberman?

  Understanding, am I getting the best physician for this thing is really hard to determine.

• 1:29:37Speaker 00

  Yeah, that's common across all medicine, right? And even as I'm looking for a doctor for something, it's hard to find the right person. I'm in a massive medical center, you know, and have great connectivity, but knowing who truly is the best is complicated, right? So some things we rely on are volume, case volume and historic case volume. So how many procedures do they do? That's important. And probably even more important, how many have they done over the course of their career? So if you're having a procedure, you want to know volume because volume is important. It's not the whole story, but volume is important, right? And we need in medicine, honestly, to move more towards objective metrics. And this is one thing AI can do for us, right? I'm involved in a healthcare delivery platform.

• 1:30:17Speaker 00

  It's called Everself. And what it does basically is the doctors that are doing these procedures are held to a certain metric, right? So it starts with just collecting the data, you know, finding out what their weight loss outcomes are, finding out how many stitches they place per procedure, looking at their procedure time, looking at their complications. So you're grading all that. But the next layer is putting this AI on top of it where the AI not only can it coach you through the procedure, it can give you a grade at the end of the procedure. It can be very specific and it can tell you, you placed this many full thickness sutures versus this many. You want 100% of your stitches to be full thickness. Maybe the doctor's putting in 70 that are full thickness. That's not good. This number of sutures were close enough together, some were too far apart. It will give you a grade. This is the pattern you use. This is the volume of stomach you reduced

• 1:31:02Speaker 00

  to buy. It'll give you a grade at the end of that procedure. And that grade is incredibly important. And then the idea next would be is to share that data so people know kind of what grade you're getting. It'd be great to share that with governing bodies that do credentialing. So people that are truly underperforming, maybe they should get a refresher, right? It would be nice for patients to be able to select, you know, who they're going to go to based on objective metrics. And AI can do this probably across the board with other things as well. So that's part of it. We've seen this a little bit with ADR, adenoma detection rates in colonoscopy, where they used to publish that and they stopped doing it. So doctors were expected to have a certain number of polyps they'd see per colonoscopy and they'd report that. That was something, there was another way. But then the problem was all the patients wanted to go to one or two doctors that had high DRs and their

• 1:31:47Speaker 00

  wait times became enormous, right? And then patients couldn't get access to them. That's a problem as well, but there should be a reasonable cutoff where a certain level of expertise is required. And I think AI, you know, hopefully will help us get there.

• 1:32:03Andrew D. Huberman?

  I'm excited by what you told me about how AI can provide real-time data and prospective data about how the stomach will change shape with the opportunity to make the adjustments as you go, as opposed to having the patient heal up and have to come back in for another surgery. Years ago, I saw something amazing. A neuro-ophthalmologist friend allowed me to sit in on something. He said, you know, people forget that surgeons wear microscopes on their eyes, right? They wear these like optics that allow them to see things bigger, obviously. But then there are all these new tools that, you know, like a little drop of fluorescein, a little bit of like innocuous liquid that creates a contrast for the surgeon

• 1:32:48Andrew D. Huberman?

  or for the eye doctor to see what is what and not cut the wrong tissue. It seems like such an obvious thing, but I was told that for, you know, 100 years, the same procedure had been done without that. And so eye surgeons had to essentially guess based on their intuition, their training of what was tissue to preserve, what was healthy, what was unhealthy tissue. I mean, these, what seemed like kind of simple to us now technologies have improved the margins of safety, have improved the, you know, outcomes tremendously. And so the idea that you would have AI combined with really good microscopes, either worn on the eyes or you're looking down a microscope, better surgical tools. To me, it just seems obvious,

• 1:33:29Andrew D. Huberman?

  like yes, yes, and yes. But a lot of people hear AI, they hear robot and they hear surgery and they go, oh my goodness, like what if the, they go to the extreme. I think with AI, people think it can go rogue, has a mind of its own. So I don't want you to give false assurance that that's not going to happen, but when you sit down to do a procedure and you're getting information from AI, where does your trust come from? That it's giving you good information as opposed to faulty information?

• 1:33:55Speaker 00

  Yeah. So the AI is trained on thousands and thousands of procedures, right? So more than I've done, right? So, which is good. And so it recognizes patterns. So you have to use your clinical judgment and you're not doing, you're not using this AI kind of blindly. You're using your clinical judgment and you might ignore it sometimes. You don't have to follow it. Now, if it becomes the time where you're automating Operative robots using AI.

• 1:34:20Andrew D. Huberman?

  Like suture placement.

• 1:34:21Speaker 00

  Yeah, that'd be different if it's doing it itself. That's different. But for this, where it's just suggesting where you put a stitch, or showing you were a blood vesselist, I think it's a huge advantage. So we do these procedures that are very technical, where you tunnel, you know, you're creating a potential space in the esophagus. So back to that earlier person that couldn't swallow, right? They had trouble swallowing because they had achalasia. So the procedure, how we do that is we go in through the mouth. We inject a little fluid under the mucosal layer to lift it with a pocket of fluid. We make an incision in that and we take the endoscope and we slide under in between the mucosal layer and the muscle. We dig all the way down to the bottom of the esophagus and then we cut through the muscle. When you're doing it, there's vessels in there and they're hard to see. AI can actually see those vessels because it's got pattern recognition and color them for you

• 1:35:05Speaker 00

  so you don't hit the vessels as you go, reducing your chance of hitting a blood vessel.

• 1:35:09Andrew D. Huberman?

  Beautiful.

• 1:35:09Speaker 00

  So that's just one example. If something has a very complicated procedure and you're certain, you're making certain aspects of it a little easier.

• 1:35:16Andrew D. Huberman?

  We think that physicians are looking at the equivalent of a medical textbook with coloring, but it's not. It's black and white and gray and beige. And there are certain structures that look different that are contrasty and look different.

• 1:35:29Speaker 00

  So now with endoscopic ultrasound, it's not even color. It's all gray. So when we're doing endoscopic ultrasound, we talked about looking for a pancreas tumor. It's all gray. It's just different shades of gray. There's no coloring to it. Now you can, you can turn on a button to see if there's blood flow, right? But it's all gray. So years ago, in my lab, I was trying to use image registration so I could take a CT PET scan and I could link it to the angle of the probe and you could see a CT scan fluctuating in the probe of the ultrasound and lay the ultrasound over it. And then you get an idea of the tumor you're looking for, the lesion you want to biopsy or whatever. It was too hard to do. It would take three hours of preparation to be able to set that up. You could never scale that. Now with AI, other groups are doing similar work now and it's, it's almost automated.

• 1:36:14Speaker 00

  So I'm hoping that we'll see image registration with these very advanced imaging tools that are being used help us with diagnosis and hopefully even with therapy too. They're doing something now called hyperspectral imaging and they're doing it in surgery as well. There's several groups doing this. One group in London is doing phenomenal work. They're using all these narrow bands of wavelengths, just tons of wavelengths. And they're finding out that each tissue actually has a fingerprint. So you can actually use this, this hyperspectral imaging to fingerprint tissue and you can actually see margins of tumors with this. It's very interesting without giving a die anymore. So you still want to give it for lymph node testing or whatever. Sometimes they'll inject something into a tumor and then look to see if it gets into lymph nodes. That's different. But this is if you're actually looking for margins or for lesions.

• 1:36:58Speaker 00

  And it's just with light technology, it's amazing. So that's what LEDs are doing, right? In different kind of cameras, right? So instead of CCD chips, you have CMOS, right? And so with newer technology, even though it seems incremental, with LEDs being able to fluctuate the wavelengths of light and your chips being able to read it faster and better, we're able to make better diagnosis. I'd like to take a quick break to acknowledge our sponsor, Our Place. Our Place makes my favorite pots, pans and other cookware. Surprisingly, toxic compounds such as PFASs or forever chemicals are still found in 80% of nonstick pans as well as utensils, appliances and countless other kitchen products. As I've discussed before on this podcast, these PFASs or forever chemicals like Teflon

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• 1:38:52Andrew D. Huberman?

  I feel like one structure that we could, conceptual structure that we could put on things, I'm realizing today is medicine has a couple of different ways to determine what's going on, for better or worse. One is the stuff that comes out of the body. And we do this with babies, like, oh, their, their mucus looks really green. We do this, maybe I have a sinus infection. It comes out of the body or with bowel movements. Or we're not so good at gauging the color of blood, kind of things. Or then we have the surface of the body, pallor of skin, how the eyes look. Do we see, you know, stuff that we don't normally see? And then, you know, the age-old story where it was like phrenology, which was like, you know, complete bogus. But it was like, oh, can we, it figures things out from the way things are changing at the level of the,

• 1:39:36Andrew D. Huberman?

  the shape of the skull is complete nonsense, right? But as we go in, we're still trying to do this, right? X-rays let us see, you know, fractures and things. You know, you don't want too much X-ray radiation. But the goal has always been to get more information with, with less invasive procedures. And I feel like now we have blood tests so you can pull stuff out of the body. And it's kind of wild that in 2026, this is where we're at. I think it's super exciting, but you know, hasn't, I don't know, 50 years ago, the tools were really crude there. But I think they might still be kind of crude now compared to where they are in 10 years. Are you hopeful that in 10 years, you can go into a tube, 20 minutes later walk out

• 1:40:21Andrew D. Huberman?

  and we might be able to scan with good enough resolution? Do you have any tumors anywhere? Compare that to a blood test and you're good to go?

• 1:40:30Speaker 00

  I don't know if we'll get there. I'm hoping, right? Because we are seeing capsule technology improve. We're seeing imaging technology improve and blood tests improve. And there's all sorts of things you can do with, with kind of genotyping, things and whatnot. I think that's exciting. But where we are seeing improvements, I think, are in learning about physiology and how things work and then being able to do a targeted approach. So you're not just doing that with drugs where GLP-1 is. Actually, GLP-1 isn't really targeting a deficit necessarily. There's different ways you can treat things. You can either find a pathology and treat the pathology, right? Like cutting a tumor out is kind of like treating a pathology that's not supposed to be there. Or you can take normal physiology and augment it, right? And that's what they're doing with GLP-1. There's not like some horrible GLP-1 deficit that's totally clear.

• 1:41:12Andrew D. Huberman?

  They're ramping things up thousandfold over what they would be in even the healthiest person.

• 1:41:16Speaker 00

  Yeah.

• 1:41:16Andrew D. Huberman?

  Most people don't know that, by the way. They think that like the GLPs are bumping things up like two or fourfold. It's like, no, never before in human history, at least to my knowledge, have people walked around with this level of GLP-1 circulating in their blood.

• 1:41:29Speaker 00

  Yeah, you're supposed to have a little tiny amount that's produced in response to a meal, right? And then it goes away, you know? And it's kind of like, you know, relatively speaking, not, this is super physiologic doses. You're bathing the area prostrina in this chemical, right? And it's like, it's not functioning like in a physiologic way. Our GLP-1 is secreted, it's nutrient responsive. It's secreted from L cells, right? And then it does its job. It goes to the pancreas, says produce insulin. It goes to the stomach, it says slow emptying. It goes to the brain, it says you're full. It does things like that, right? And it does it in response to a meal and it's in much smaller doses, like you've said. So medicines have done this for a while where they kind of see something as a mechanism they can augment or they see a pathology they can treat. But that augmenting is very interesting.

• 1:42:13Speaker 00

  And surgery, for a long time, wasn't doing that. They were just thinking, oh, I'm going to make you malabsorb calories. I'm going to make this tight so you feel full quicker. But now that we're understanding mechanisms and there's some great research that's gone into this, we can actually develop targeted therapies. And I think that's what's very exciting. It's more so even than, than a new device. It's being able to do targeted therapies and get better outcomes with that. And where I started with this is in fellowship. So I saw, you know, I saw a patient with a gastric bypass. So they have a gastric bypass anatomy. They have a small gastric pouch, like I mentioned, and a bigger stomach. And a patient was sent to me that had bad reflux. They had weight gain after the gastric bypass

• 1:42:58Speaker 00

  and their diabetes came back. Their diabetes was gone, but now it'd come back. So the surgeon basically said, hey, take a look at this patient. See if they have an ulcer, what's going on? They're having all this pain and heartburn. Find out what's going on. So I went and looked and there's this little hole between the pouch, the new stomach and the old stomach. And I thought, well, maybe the acid's produced in the other side. Maybe the acid's coming up through that fistula. And we had a new device. It was a suturing device that you could actually put in through the mouth and put stitches in. I thought, maybe this suturing device, I could use it to close that hole, right? So I waited until I was on faculty a few months and I talked to the surgeon, he was supportive. So again, this is kind of that thing, are you inventing something? The procedure is FDA approved, the device is FDA approved. The procedure is not. No one's closed a fistula with this.

• 1:43:42Speaker 00

  But we talked to the patient, you know, we told them we weren't sure if it was going to help or not. We tried to do it, they were willing. And we did the procedure, closed the fistula. And so I was hoping the reflux would stop. The reflux stopped, but the person started losing weight and the diabetes went away almost immediately again. And that was for me, and this is 2003, 2004, 2003. I was like flabbergasted, you know? Was it a coincidence? What the heck was that? Why is closing that little hole so important, right? So that's what got me involved in understanding these gut hormones, honestly. Because we were able to now, if I learned about the gut hormones and why we saw this treatment effect, we could potentially manipulate them to get, to get better results, right? So that was the beginning of it for me.

• 1:44:26Speaker 00

  And there was, shortly after that, one of my friends and colleagues actually did some animal work. He had a rat model and they're called GK rats. And they're rats with diabetes that don't have obesity, okay? And they were a great model for this because you didn't want weight loss to confound things. And so he did two surgeries of foregotten hind gut method, right? So the one surgery, he basically excluded the foregut. So he excluded the duodenum and the very first part of the jejunum, okay? And he did, he did a little bypass surgery there. So no food could get in the duodenum. Went from the stomach and it went to the, the very first part of the duodenum and then boom, down into the jejunum, not touching that foregut, not touching that bowel. The other one, he did a gastrojejunal anesthetosis.

• 1:45:09Speaker 00

  So stomach, too small bowel, but he left the rest open. So food could go either way. He'd go into the duodenum like it normally would in the foregut or go to the hind gut, dropping down into the distal bowel. What he found was, these were diabetic rats. He did glucose tolerance tests on them and he found that the ones that had the exclusion, their diabetes got much, much better. The ones that didn't have exclusion didn't get better at all, even though you were dumping stuff into the distal gut. Very interesting. So he thought there was something very important about foregut exclusion and he hypothesized there was something called an anti-ancritin in that bowel that would maybe protect against hypoglycemia, but there was something in there that if you exclude it, you got a better treatment effect.

• 1:45:51Speaker 00

  So that was, you know, my fistula work and then his, his very interesting animal work got us going down that path. And it kind of fed well into something that actually was done in the 1980s that, that was from a continuation of that work that Sherlock had done looking at ancratines and it was a famous publication by NOK. And what he did is he looked at the same, the same study that Sherlock did in London, where they were giving glucose to look at the insulin response. But he did it in diabetics and he did it in a normal population, normal, healthy population. The normal population had that exact same ancratin response where you gave a certain amount of glucose intravenously, little spike, same amount of glucose orally, big spike. Diabetics didn't do that.

• 1:46:34Speaker 00

  And they'd already tied it maybe to GLP-1 and maybe in the, in the, in the bowel. So very exciting. So maybe by excluding this foregut, you're playing a role, you're having something to do with that, or maybe not. So that was the beginning of trying to understand the procedures for me. And with that, I then did another study where I closed those fistulas, right? And, and where we closed the fistulas, 60% of people had resolution of their diabetes. If we didn't close it, no one got resolution of diabetes. So, okay, that's a good thing. So we learned there's some important element to, to foregut exclusion. Then there's various device companies that start getting involved in the space because there's this, there's this information out there that excluding the foregut might be important. And a company comes up with the idea of putting a liner endoscopically.

• 1:47:19Speaker 00

  So it's like a little sleeve. You anchor it, has a little stent that springs open, you anchor it in the first part of the small bowel, it covers the duodenum, protects it. It's an implant, so it has to come out, right? At some point in time, maybe a year later. But it was very interesting because I was, I was part of those, those clinical trials. And we found you had a one point in diabetics, you have a one point drop in A1C. That's fantastic. And you lose weight, about seven, 7%, total weight loss. So clearly it's doing something and it's, it's important. The problem is, it's an implant, it's got to come out, but it's exploiting this mechanism potentially.

• 1:47:51Andrew D. Huberman?

  So you're essentially cinching down this compartment of the gutter? You're creating more compartmentalization along the tube?

• 1:47:59Speaker 00

  You have the duodenum, right? And then there's a liner that you place in it. So this is like a stent, so it springs open and holds its form inside it. And then it's a sleeve that kind of goes down. So you can still get all your secretions that go on the outside of the sleeve and track down, but it's right after the pylorus, the outlet of the stomach. So all the food's going in the tube. So the food is inside the sleeve, the digestive enzymes are outside the sleeve and they don't mix for a few feet down. So that's very interesting and it worked. The problem is, it's still in clinical trials, been around for a while, but it's an implant. So it's just like taking a drug, eventually it has to come out. But then there was a, there was a brilliant idea that came about from one of my colleagues at the Brigham. And he's a cardiologist, right? And he knew I was trying to do something that was, so I traveled to Brazil, right?

• 1:48:44Speaker 00

  And I was doing surgery, endoscopic procedures in Brazil and there was a doctor in a room nearby. And that doctor was doing a very novel experimental surgery called ileal interposition. And what he was doing, and this was a lean diabetic, so they, they weren't suffering from, from obesity, they had type 2 diabetes. And he was taking this, the small bowel, the distal small bowel, kind of the opposite a little bit of what Rubino had done. Took the distal small bowel and he moved it up, kept it on his mesenterian blood flow. He resected it out of the, out of the, out of the distal small bowel near the colon and he moved it up and he put it near the duodenum. And his idea was, you know, the concept was that GLP-1 was denser in that part of the bowel and it was also denser, you know, down lower. And if you moved that up higher, you'd get a more immediate ancratin effect from GLP-1.

• 1:49:29Speaker 00

  So you'd hit GIP and then immediately GLP-1 and you'd have this amazing effect. And he did, it was incredible, right? These people, their diabetes went away and they didn't lose any weight because he didn't actually have any blind areas. The food, he didn't change anything, there's no restriction, there's no absorptive change, you just moved that part of the bowel up. That was phenomenal. So I was trying to do that endoscopically by harvesting tissue from the ileum via colonoscopy, creating stem cells and then injecting it in the foregut and getting them to take and hopefully getting an ancratin effect. That wasn't successful. But one of my colleagues is a cardiologist and he actually said, why don't you just burn the duodenum, you know, ablate the duodenum. There are different ways you could do it. You could do it with steam, hot water, et cetera.

• 1:50:12Speaker 00

  Just ablate it and see if you can reset those stem cells because the duodenum is sick. Okay? And this is very interesting research that proved the duodenum is sick, we should probably talk about. But, you know, the duodenum is sick, if you can reset the duodenum, it might work. And I said, why don't you do it? And he did and he started a company and it's been great. So, and that, that is something that we're studying more and more of. And now you don't have a sleeve in place, you don't reroute any bowel, you just ablate the duodenum, okay? And what happens is your A1C drops by over a point. You don't lose a lot of weight by just ablating the duodenum, right? But your A1C corrects and it's a potential, a potential treatment for diabetes. They've also done some studies. I don't believe these are published yet, but I think they're showing that when someone comes off of GLP-1, if you use this treatment, it keeps them from regaining their weight.

• 1:50:54Speaker 00

  So you can take a GLP-1 and then have your duodenum kind of reset, if you will, the stem cells come back and you've maybe healed those tight junctions and other problems that you're having, so.

• 1:51:05Andrew D. Huberman?

  So it regenerates?

• 1:51:06Speaker 00

  It regenerates, yeah. It comes back more healthy and more normal. And the rationale for that comes from a lot of very good research, right? So there were studies that showed in mice that if you feed mice, you overfeed them in an overfeeding study and you have a control group, you don't overfeed. When you take them to necropsy and you look at their, their bowels, the bowels in the, the overfed mice are longer, they're heavier, the villi are longer, they've adapted, they've adapted it, upregulated the ability to absorb calories. And then these studies have been repeated in humans where people getting gastric bypass, they're already going to be doing surgery on them, so they resect part of their small bowel. And someone getting cancer surgery is a control patient, they resect their small bowel and they look at the differences. And there's extreme differences, right?

• 1:51:51Speaker 00

  The villi are longer, it's thicker, there's more inflammation in people with obesity or type 2 diabetes, a lot more inflammatory cells. The natural killer cells are up eightfold. Macrophages up 1.5 fold in these studies, right? So you have more inflammatory activity going on in these patients. The only thing that's different is really obesity, right? Additionally, if you look at those patients and you, you do immunostating for like zonulin oclutin, like tight junction proteins, scaffolding proteins and proteins, you'll see that those are much lower and they're disorganized.

• 1:52:21Andrew D. Huberman?

  Two questions. So if I understand correctly, if people overeat, the villi, like basically the little finger like protrusions inside the gut that can sense things but also collect nutrients, right? They're growing to adapt to the elevated levels of calories. And so then essentially you've changed the digestive tract in a way that yes, they can make more use of, of those calories, but that also creates a more pro-inflammatory environment. Do I have that?

• 1:52:48Speaker 00

  That's absolutely correct. And also because they're changing in configuration and you're using that energy, the cells are using energy to do other things, your tight junctions are deprioritized.

• 1:52:58Andrew D. Huberman?

  Okay, right. So then there's this secondary or parallel effect of the, the tight junctions. We haven't really talked too much about tight junctions here, but I'm not, by no means an expert, but I'm familiar with them from the blood-brain barrier. They get like, cells need to stick together and some tissues, you want things sticky but not too sticky. Some tissues you want really sticky. And my understanding is that, that tight, as the name suggests, tight junctions, the goal is to keep stuff inside the gut, not let bacteria out. Is leaky gut a real thing or is leaky gut, because I've heard it's sort of like chronic fatigue syndrome, that a lot of the standard medical community, they hear a chronic fatigue syndrome and they go, okay, that was made up by people in the Bay Area. I'm only half kidding here, I'm from the Bay Area.

• 1:53:43Andrew D. Huberman?

  But that's how a lot of physicians react online to this phrase, leaky gut. But we've had a fair number of people come on here and talk about tight junction deficits, bacteria getting out of the gut, this isn't good for the body, inflammation going up, bacteria circulating places they shouldn't be is not good. So is leaky gut real?

• 1:54:06Speaker 00

  Well, increased gut permeability is 100% real.

• 1:54:10Andrew D. Huberman?

  But that's, I mean, I'm not pushing back on you. That sounds like, like, that sounds like a different language for leaky gut.

• 1:54:15Speaker 00

  Yeah, so it is.

• 1:54:16Andrew D. Huberman?

  So why, so why is this phrase, leaky gut, so, no pun intended, so irritating to the medical community?

• 1:54:22Speaker 00

  So I think if you say leaky gut, it could have other connotations that you don't know what it means to the person. Someone might think that leaky gut means that is responsible for a certain constellation of symptoms potentially.

• 1:54:34Andrew D. Huberman?

  Like irritable bowel or Alzheimer's, like they can take a leak?

• 1:54:38Speaker 00

  Yeah, yeah, because, because you see in, in lay literature, right? In other literature, they say leaky gut is associated with XYZ, right? And it's not clear that, that, that phrase, leaky gut is, is, is really talking the same thing I'm talking about. Now, is leaky gut the same thing? Yes, I'm still talking about leaky gut in a sense, right? But the danger is calling something leaky gut when people already might have a definition for leaky gut in mind, like it's responsible for, for all these other problems, right? But let me tell you what leaky gut is to me or what increased gut permeability is. And I'll tell you that it's very real and it is actually tied to metabolic illness. We can start with a study that used small bowel biopsies, right? And this was recent, just last year.

• 1:55:20Speaker 00

  And they did small bowel biopsies and then they, they actually were able to, from the stem cells, grow little organoids, right? And then organoids are like three dimensional cultures that they, they behave as they should. As this, the cells kind of populate out of there, they take their normal form and structure. And they had a control group and they had a group with MASH, obesity in MASH, right? So, which is a metabolicly associated steatohepatitis. So these two groups, they looked at the organoids and they found that the tight junctions were far less well-developed and more disorganized in the MASH patients compared to the control patients. Additionally, they did transcriptomics on it and they found that they weren't even producing, you know, the, the proteins, they weren't even making the RNA to produce the,

• 1:56:05Speaker 00

  the tight junction proteins. So clearly at transcriptional level, they were down-regulating the, the, the tight junction proteins. So with immunohistochemical staining and then transcriptomics, they found that the tight junctions just weren't functioning as they should in people with MASH. So if you don't have tight junctions, it stands to reason you might have, quote unquote, leaky gut. So another group actually looked at something similar, right? They had same population, patients with MASH, and they actually studied. They can, there's different tests you can do to look for a leaky gut. You can give something that's very small, but it should not get through those tight junctions, right? There are different tracers you can use. 51 chromium EDA is one that they use. And that's one that was used in this study. And so they give it, it's not supposed to get into the bloodstream.

• 1:56:51Speaker 00

  And patients with MASH zipped right in, much higher levels than they should be. And in patients without MASH, it wasn't getting in. Additionally, in patients with celiac disease that was treated, it wasn't getting in. But in patients with fatty liver disease, it was getting in. And it's probably playing a role, right? So if you think about it, the gut, the first place it goes is the liver. There's a portal circulation and the gut goes to that portal circulation. Everything that goes through there has to stop by the liver, with the exception of fat. Fat gets into the lymphatics and dumps out of the thoracic duct. It doesn't have to actually go to the liver. So if you have bacterial products, LPS, lipopolysaccharide, it's a portion of gram-negative bacterials cell membrane, right? If that gets through these tight junctions, it causes all sorts of problems.

• 1:57:35Speaker 00

  It is going directly, they're inflammatory. They interact with tolyrecepta 4 and, you know, that goes, you know, it starts all sorts of inflammatory cascades. So goes via NF cap B signaling, et cetera. That can be problematic. Another group proved that was problematic, but actually, this was done at Duke. They actually took LPS and they injected it into healthy people. And they found that their inflammatory markers went through the roof and they found all sorts of other problems out, including they did clamp studies in these patients, they found it induced insulin resistance. So yes, I think leaky gut can be involved in all this stuff. And that gets back to our very early discussion about fiber and about, you know, fermented beverages and how important it is to keep your microbiome healthy.

• 1:58:18Speaker 00

  Because that microbiome and that butyrate is critical to producing healthy enterocytes. That's first and foremost, right? As well as healthy tight junctions, a healthy mucin layer. All the, and actually it also works together. Butyrate and the microbes and the byproducts of the microbes work with your immune system, your innate immune system. And it tells them what to recognize and what not to recognize, which is just as important because your bowel is full of bacteria, right? So absolutely very important. And you do see where this increased gut permeability is associated hardcore, good science evidence with real illness. So absolutely is a problem. It's just I don't want to blame it for everything.

• 1:58:57Andrew D. Huberman?

  Right, right. I get it. I think that the, you know, earlier we were talking about CGMs and there's sort of a, kind of a common theme here, which is the general public now, because of online health information, good and bad, is starting to create their own nomenclature. And I could see why that would scare physicians. But I think that a more symbiotic relationship between like the public's, like, knowledge of their own data, questions about like, maybe it's leaky gut, you know? And being able to approach their physician with these things in mind and still acknowledging that the physician is the physician, right? Could be really helpful. I have a couple of questions that feel free to pass if these aren't meaningful.

• 1:59:39Andrew D. Huberman?

  I get a lot of questions about artificial sweeteners and negative effects on the gut microbiome. Seems like they're marginal to zero effect on insulin and resting blood glucose from artificial slash low calorie sweeteners in a way that like would lead people to say these are bad. There's no reason to run out and use them if you don't want to. But the weight loss data say people who drink diet sodas instead of water actually lose more weight. I've seen those data. But this is not an incentive for people to start drinking diet sodas. It sounds like, you know, saccharin and Splenda are probably worse for you than stevia and aspartame. Like where are you at with these things in terms of their potential negative effects? And if you know of any positive effects, I'd be curious.

• 2:00:21Speaker 00

  I think they're better than high fructose corn syrup for sure, right? I mean, that I think we should be treating like alcohol, right? Yeah, I think fructose in fruit is fine. I'm not worried about fructose in fruit, fructose in general, because it comes with a matrix around it. It's not, it's not like a rush of fructose into your liver. But fructose can only be processed by the liver, right? And so it's busy as it is. Now it's got to take the burden out of, you know, a beverage which is absorbed very rapidly, goes directly to the liver and it has to be, has to be dealt with. And, you know, it gets trapped in the liver very quickly and it's the only place that can really process it. So I think that fructose is something to watch. Again, not if it's in fruit, even in juices, it can be kind of, juices are processed fruit, right?

• 2:01:05Speaker 00

  So it's similar, it's just minimally processed stuff is better. I think the problem with sweeteners, artificial sweeteners, is they come in foods that are, that are highly processed as it is, right? And you can't separate the two. I think that's for a while why people were so down on polyunsaturated fats, right? Because they'll come in a bar full of a bunch of other stuff that's not good for you. So well, I guess the polyunsaturated fats are also bad for you in some way, right? That was like a more recent phenomenon. Well, no, the food that it's in is bad for you, but the polyunsaturated fat has been shown to reduce health and has health benefits.

• 2:01:41Andrew D. Huberman?

  The word essentially, translation for people, like seed oils, basically.

• 2:01:44Speaker 00

  Yeah, seed oils.

• 2:01:45Andrew D. Huberman?

  Yeah, there's some still debate about whether or not the processing of them can make them worse. But yeah, it's, it's hard to, well, I don't know. Do you see this recent avocado oil thing out of UC Davis? This is wild. UC Davis went and analyzed like all these avocado oil containing products that are supposedly like healthier. You know how much avocado oil these products contain?

• 2:02:08Speaker 00

  Oh no.

• 2:02:09Andrew D. Huberman?

  And the pushback has been that maybe they're looking at the wrong metabolites of avocados. I don't know how this is going to play out, but if it, this could, this could potentially do more damage to the, I just call it the non olive oil community, right? Because in my mind, like the safest thing is to just use olive oil, a little bit of butter here and there, right? Like, okay, no one debates olive oil. It's kind of wild. No one debates, everyone knows it's good for you, no one thinks it's bad for you. But this seed oil lard thing, they go back and forth and it's kind of like professional wrestling. I feel like it's all kind of made up for entertainment, but both sides are really adamant. It's just kind of stupid. Olive oil butter, right? Or you're the physician, tell me, am I thinking about this wrong?

• 2:02:50Speaker 00

  I do the same, no. Olive oil is the best, obviously, then small amounts of butter. I don't think, you know, lard is bad in small amounts. I think the problem is overall amount of saturated fat, right? But polyunsaturated fats have a lot of proof that they're very safe. Where you get into problems is if you have a big container of it, a huge container, they're not going to use it in a reasonable amount of time and it's sitting in the sun or something and you get oxid, you know, it oxidizes. That's a problem. You don't want to take an oxidized oil into your body, right? Or you're deep frying with it and you're frying over and over again, you start generating trans fats. That's a different story. But in general, I think, you know, I think they're fine. And I don't even think you need this omega 3 to omega 6 ratio people used to worry about, right? I think you need a certain minimal amount of omega 3s, right? You know, if you eat fish once in a while, you're getting all you need.

• 2:03:34Andrew D. Huberman?

  Do you strive to get like some fatty fish in your diet?

• 2:03:36Speaker 00

  I do, yeah. I love, I love fatty fish. It's, it's good for you. I try to do a couple of times a week.

• 2:03:40Andrew D. Huberman?

  I take LaVaza, a high dose omega 3 pharmaceutical, because I don't want the mercury. It's clean of mercury. I don't know, my blood markers are where I want them to be. But I'm, I'm curious, what's your read of the data on omega 3s for metabolic health and cardiovascular?

• 2:03:55Speaker 00

  It's mixed. I mean, it's probably better for Alzheimer's, right? If someone's starting to show signs of Alzheimer's, I think it's, it's better for, you know, for that, the data. I think the problem is universally supplementing is not necessarily the way to go. You want to find a deficit and then supplement, right? So even with the vitamin D, you know, most people probably are deficient, so they benefit from it. But there's no point in really doing it unless you're deficient for most things. And I think with omega 3s, it's similar. You want to get your daily allowance, if you will. And again, if, if you're a vegetarian, you can do it from algae, the original source. The fish are just consolidating, right? So, you know, you don't have to eat the fish, but that or get in some kind of, you know, supplement form.

• 2:04:34Andrew D. Huberman?

  You heard it here from Chris Tomes, and fish are just consolidated algae. I'm just kidding, I put those words in your mouth. I love that. For all the people who are like, no, you can't get omega 3s from non-animal sources. I mean, I think you put it beautifully. I don't like eating fish, so I take the LaVaza.

• 2:04:49Speaker 00

  Yeah.

• 2:04:49Andrew D. Huberman?

  I don't like, I don't like, but I'm on the East Coast. You guys tend to have better seafood.

• 2:04:53Speaker 00

  It's delicious in Boston.

• 2:04:54Andrew D. Huberman?

  Yeah, I know, I gotta, but it's too cold out there. Then you gotta take vitamin D out here, you don't, I'm just kidding. What else do you recommend to your patients as they start to move away from obesity? So obviously fiber, some fermented foods. It sounds like resistance training might be in the list, given that they're, they're at risk of re becoming thin but more jelly tissue than lean mass. Do you prescribe resistance training?

• 2:05:26Speaker 00

  Absolutely. So all my patients, I ask them to do resistance training, even, you know, before they start losing weight, before they go through a procedure, it's essential. Zone 2 cardio is great, right? It's good for fat burning. You're in that zone where you're burning fat and, you know, not carbs as much, right? HIIT is great. So high intensity interval training is great for mobilizing visceral fat. Because your visceral fat, we haven't talked a whole lot about it, but it has beta adrenergic receptors on it. It also has gonadotropin hormone receptors on it as well. So it's responsive to, to stress, like acute stress. So it will mobilize when you're going, you know, through the stress of, of, you know, high intensity interval training. So it'll mobilize, it won't be burned right away, right?

• 2:06:09Speaker 00

  Because you're burning carbs at the time, you're burning your, your liver glycogen and, and your muscle glycogen, you're burning that. But you mobilize the fat at least, and that's kind of what it's designed for. That's why you have some visceral fat there.

• 2:06:21Speaker 00

  So I included, I try to have them do those things. HIIT, a little zone 2, and then resistance training. I think those are the most important things long-term.

• 2:06:27Andrew D. Huberman?

  Do they do it?

• 2:06:28Speaker 00

  This is very interesting. So I think they try. And depending on how they lost the weight determines if it's effective, right? So it's theory of set point, right? Which is something that's very important, back to, back to metabolic health. So it's not a point necessarily, it's a defended range, if you will, right? So you have this defended range of what you think your weight's supposed to be. And that's set by a variety of things, leptin is part of it, right? And your thyroid hormones and whatnot, and you think you're supposed to be a certain weight. And then what you do is you do a crash diet, you lose a bunch of weight. Like The Biggest Loser was a great example of this, right? You lose a bunch of weight. So now you're fighting several factors, right? So one factor is your body's smaller, so it burns less weight, okay?

• 2:07:10Speaker 00

  So you have to eat less to just maintain the same weight you're at now, this lower weight. That's a bit of a problem. You down-regulate your gut hormones, we talked about a bunch of gut hormones. You're producing less GLP-1, you're producing less PYY. You're producing, GIP is here, not here, neither here nor there, a little less CCK. So your satiety hormones are being produced less. Your ghrelin goes through the roof. If you do this with diet and exercise, your ghrelin goes through the roof, right? So that, in addition to the fact that your muscles become more efficient, I think it becomes 25% more efficient in doing a similar task, they're going to burn less fuel to do the same task. It's amazing, right? Your kind of non-exercise energy expenditure, right?

• 2:07:50Speaker 00

  So just kind of daily activity, your basal metabolic rate as well, they all kind of go down. So you're burning less calories at rest. So we've shown this study, study after study. So your whole body is fighting you, okay? It wants to go back to that weight, whatever it thought it was supposed to be at. The Biggest Loser was a great, there was that kind of an NIH follow-up study to that, and they found that they were burning 500 fewer calories per day after that. So, and there's other studies that have shown this as well, if you lose weight that way. So that's why it's so important, GLP-1's helped fight part of that, right? You're replacing the GLP-1, that's, you're not addressing the ghrelin or other things. So time will tell if we can have long-term weight loss, but it does, it does. So ghrelin isn't the whole story, right?

• 2:08:31Speaker 00

  So like with our procedures, so we're addressing these very targeted with procedures. And one bridge into that is, is the ESG procedure. So this is the procedure I developed in 2012. So you go in through the mouth, someone's sleeping, obviously, with a little scope, and you fold the stomach on itself. Now, the goal of that was to do two things, you know? That one was to augment the stress receptors. So it's a smaller pocket, so when food hits that, the stomach stretches quicker. And you have the vagal afferens now that go up to the nodos ganglia, and then, you know, NTS, and then boom into the hypothalamic areas.

• 2:09:06Andrew D. Huberman?

  As you tell the brain, we're full.

• 2:09:08Speaker 00

  Yeah, exactly. We're full, right? Stretch, fast, boom. So when you stretch, you get that signal, boom, and you're full. That's part of it, right? That's phenomenal. The other part of it is you suppress ghrelin, because food stays in the stomach longer, right? And so it's suppressing ghrelin. So it's doing two different things. Now, when those people lose weight, they don't have to worry about their ghrelin going up, because it's been suppressed. So it's easier to keep the weight off for 10 years or longer, because you're not fighting that part, you know, of the countermeasures that the body will do to defend this potential, you know, potential range. We're not doing anything with that necessarily to GLP-1 and other, and other gut hormones, but you'll see, it actually, you have ways of dealing with this. So how do you augment weight loss? You have all these different targets, right?

• 2:09:52Speaker 00

  So one thing we're doing now is we talked about how ghrelin resides in the fundus. Now, in addition to that ESG where we tighten the stomach, someone developed an idea, I think they were in Germany, where you can actually ablate those fundal ghrelin cells. Because they live in the mucosal layers, you can get to them. So you can, they use argon plasma coagulation, there's different ways to ablate it. You just kind of spray this over the fundus, and it kills off the ghrelin-producing cells. They grow back, and there's not much of them, right? So now all of a sudden, you can suppress ghrelin as well. So the weight loss goes from about 18% with the ESG alone in a top center, goes up to way over 20%, maybe 25% if you start ablate the ghrelin.

• 2:10:27Andrew D. Huberman?

  Are there drugs that just inhibit ghrelin?

• 2:10:29Speaker 00

  No, not effectively, yeah. So, and then you add to it, right? So now if you've delayed gastric emptying, your CCK's not spiking as much as it was, et cetera. So, but you're not getting, which is a subtle countermeasure potentially, right? It will still spike, but GLP-1's an issue. So now what if you combine that with a small bowel procedure, right? And there are different small bowel procedures that we've come up with. Using magnetic anastomosis is one we published about 10 years ago, we did it in the Czech Republic, we used endoscopes. It was a hard way to do it, we went from below, a colonoscopy, my partner did that. I went from above, it released these two magnets, and we connected the jejunum, the first part of the jejunum, to the lower part of the ileum.

• 2:11:07Andrew D. Huberman?

  We should probably tell people what an anastomosis is, basically, when you connect two tubes.

• 2:11:11Speaker 00

  Exactly.

• 2:11:12Andrew D. Huberman?

  Is that right? You're basically just, so you're basically like ligating a tube.

• 2:11:15Speaker 00

  Yep.

• 2:11:16Andrew D. Huberman?

  Right now here, we're using more nomenclature. You're bridging two tubes.

• 2:11:19Speaker 00

  Bridging them, right, yeah. And they did it originally with sutures, you cut a hole and you suture the tubes together, and then they did staplers, and staplers they do it. But they're big and bulking and hard to position. So, so our lab developed magnets, right? And these are ring magnets. So they come out, they're magnets encased in nitinol, so they can take a certain shape. So you put them through a tube, in this case, it's an endoscope, you could put them through a laparoscope, or whatever else you want to put it through. And they come out, and they form a ring, right? So we went from the top endoscope, we formed a ring in the jejunum, in the bottom, we formed one in the ileum, way downstream. And then we had an anastomosis that would allow the food to directly pass there. And what we found is you get these big spikes in GLP-1. So now what people are doing, I'm conflicted and can't do this part of the procedure,

• 2:12:02Speaker 00

  but what they're doing is, they're doing that anastomosis, and they're doing a suturing procedure endoscopically. And together, you're really replicating a full gastric bypass, you're having a GLP-1 hindgut spikes, you're getting that sense of restriction in the vagal afferent signaling, you're getting, you know, ghrelin to be suppressed, and you're getting really amazing weight loss. So what we can do now is take a procedure that was really big, it started off as a big, open procedure, it had certain risks to it, we didn't know how it was working, and it did a bunch of different things. And we're targeting different aspects of it. And the goal moving forward is to even be more precise, and find out what someone's going to be more responsive to, and then just do the least you need to do. Maybe they just have ghrelin that's driving them, just to ablate the ghrelin, right? Maybe they need something more.

• 2:12:45Speaker 00

  And people are actively studying that. They're studying the phenotyping of obesity, it's quite exciting.

• 2:12:51Andrew D. Huberman?

  I'm sensing another theme here. This procedure that you co-developed or developed?

• 2:12:57Speaker 00

  Which one?

• 2:12:58Andrew D. Huberman?

  This bridging of...

• 2:13:00Speaker 00

  So is my lab, so yeah, it's my lab, I'm the PI, but I have a whole team, obviously, yeah.

• 2:13:04Andrew D. Huberman?

  Yeah, so it's increasing GLP, but I'm guessing it's not increasing it thousands-fold, like a GLP drug would. It's got some other positive consequences that help cure the obesity. I'm kind of sensing a theme here, right? Like, we have this, these drugs, like Ozempic, Monjaro, et cetera, that blasted GLPs through the roof, helped a lot of people that need help, but there were a lot of side effect issues. Then along comes this other drug, Retatrutide, which is like, okay, well, let's increase GLP, but let's also kind of bump up the GIP system a nudge or two. Let's also bump up the glucagon system, and low me whole, we get a much better effect, muscle sparing, and actually better weight loss.

• 2:13:47Andrew D. Huberman?

  So kind of a, perhaps a lesson to us, that like, you don't really want to push really hard on one lever in biology, or take any one thing out with, maybe the more combinatorial approach is the better approach. I'm speculating here, but there seems to be a, you know, parallel theme.

• 2:14:04Speaker 00

  Oh, definitely. I think that you can mitigate risk by doing that, by not giving too much of one thing. And I think it's hitting, again, using multiple levers is definitely a way to get a treatment effect without exposing the body to potentially the harms of going too, too big on one thing. So that'd be the argument for these kind of multimodal approaches. And then you can also combine these procedures with the drugs, right? So you do an endoscopic procedure, like tighten, tighten the stomach, and then give a drug, and see if you get much more weight loss.

• 2:14:34Andrew D. Huberman?

  Or at a lower dose and get this.

• 2:14:36Speaker 00

  Lower dose, right?

• 2:14:37Andrew D. Huberman?

  Yeah, this was, what, years ago on this podcast, we looked at the whole ADHD thing, and the effects of these drugs on ADHD, and, you know, like, parents who get a great effect of a, of a, you know, an Adderall or a Viva Ants for their kid that couldn't focus. It's, I have friends with a kid like this, and, you know, they're just like, it's remarkable, but they're worried about the reduced growth effects, they're worried about the sleep effects, and, you know, so they're in this trade-off. And that's where I think, it's not always an either or, we forget, it could be, well, maybe this child could get by with a lower dose of medicine, if they're also doing some things behaviorally, if they're also doing some things with nutrition, et cetera. Obviously, the constellation of things will differ, but we don't often think like that.

• 2:15:20Andrew D. Huberman?

  Americans want the drug that fixes the problem. We love that. And then we get all pissed off when we're like, we had a generation of kids raised on amphetamines. It's like, maybe kids just drink a little amphetamines, and more exercise, right? And so it's gratifying to hear that you're doing these multi-pronged approaches, and that you do recommend exercise, including resistance training, right?

• 2:15:44Speaker 00

  And, you know, they do all these studies that show diet and exercise alone don't work because of the set point. Like, Look Ahead was a great study, right?

• 2:15:51Andrew D. Huberman?

  But that's running, right? It's like treadmill.

• 2:15:53Speaker 00

  Look Ahead, yeah, it was a lot of that, and it was a lot of just diet, heavy diet, too. And they found they got like a 6% total weight loss or something like that, about 10 years, and no improvement in heart disease and stuff like that, right? So and there's other studies that show it's hard to do it alone, just like The Biggest Loser version, and there's several other versions of that, where it's hard to do it alone because you're not addressing the countermeasures the body throw at you, right? The body throws at you. But that doesn't mean it's irrelevant, right? So when you do a procedure, like, say, gastric bypass surgery, right? Or you go on a GLP-1, you've still got to fix the fundamentals that got you in the problem to begin with, right? You need to start getting more fiber, you need to, you know, have a better diet, you know, try to avoid the insulin spikes, do what you can to treat those things, you got to start moving, you got to start exercising.

• 2:16:37Speaker 00

  Otherwise, it's going to fail, the treatments will fail. The endoscopic procedures, the surgeries, the medicines will fail unless you really address those underlying problems. So even though alone, they don't do it, because the body has adapted, they're still important to the ultimate treatment.

• 2:16:51Andrew D. Huberman?

  So given where things are at now, the treatments that you and colleagues have developed, and when I say colleagues, I mean people within your laboratory and clinic, but, you know, clearly is like an international thing going on, trying to solve these issues. Where are things headed next? You mentioned AI, what's the potential role of other technologies to improve health and outcomes?

• 2:17:15Speaker 00

  Well, I think one thing that's very exciting is gene therapy, right? So we talked about GLP-1s, and how it's mega-dosing, superphysiologic, it's not nutrient-responsive.

• 2:17:28Speaker 00

  There's a new, a company working on a new approach, which is a gene therapy. And I was involved in the very early work for this. And basically what they're doing is they've, they've developed a viral vector, right, that has the gene for GLP-1 in it. And they're using the promoter for the beta cell insulin gene, right? So basically, when a patient would secrete insulin in a nutrient responsive way, they're simultaneously secreting GLP-1.

• 2:17:59Andrew D. Huberman?

  These viral vectors are, they're a beautiful tool of biology, where you can put some genetic cargo into a virus that doesn't cause any problems, but allows for stable expression of, and the production of certain proteins in the cell. So how are you getting into the pancreas? Are you injecting it through the skin?

• 2:18:18Speaker 00

  Correct. No. So we are actually using endoscopic ultrasound. So that same device we developed to actually, you know, bypass the pancreas, we're now using something similar to actually treat. And you can, you can ablate tumors with energy as well. People are using electroporation to cause apoptosis. They're using thermal means, but you can also inject something, fine needle injection, right? So, and we're injecting the, the viruses basically into the tail of the pancreas. Now, you wouldn't want to just take this intravenously because it can end up in other tissue, right? We've done a lot of work to make sure those things stay in the tail of the pancreas too, right? We've done a lot of animal studies where we've injected it and we make sure, we use, you know, green fluorescent protein, make sure it doesn't end up in areas it's not supposed to be.

• 2:18:58Andrew D. Huberman?

  This, so we're getting technical here, but is there a pancreas specific promoter? Translation, this would allow, even if something got out, it could, I mean, it wouldn't get expressed elsewhere. Is there a way to make it only expressed by pancreatic islets?

• 2:19:11Speaker 00

  Yeah, very, very close. Yeah. But it's still, you just don't want it getting anywhere else, anywhere. But it, the only place it becomes active is in the beta cells. It doesn't become active in the alpha cells, right, of the pancreas, right? So it really is just active in beta cells. And, and again, you, you secrete insulin into these little vesicles, right? And so you're secreting GLP-1 into those same vesicles. So then when you have your meal, the vesicles release GLP-1 and insulin together.

• 2:19:32Andrew D. Huberman?

  Well, that's clever.

• 2:19:33Speaker 00

  Nutrient responsive.

• 2:19:34Andrew D. Huberman?

  You're making the drug. I mean, we were already making the drug, but now you're making it at elevated rate.

• 2:19:38Speaker 00

  Not only that, you're not making it in the L cells, where it has to go all the way up through, go to the liver, go around, do its thing, right? You're making it at the place where it's needed, right at the pancreas. So it has an autocrine function, paracrine, you know, and it can, and it's, it's much faster.

• 2:19:52Andrew D. Huberman?

  How often are these cells turned over? Cause it, you know, if it were brain, no problem, because brain cells don't turn over. But how often does pancreas turn over?

• 2:20:00Speaker 00

  Very important. Why you can't do it in the bowels? Because they're not terminally differentiated, right? You're turning over your whole bowel every five days or whatever. Pancreas is terminally differentiated, so they're not going to be changing. So it's a, it's a permanent, the episomal DNA stays in there. It doesn't integrate into the host DNA, stays next to it, transcribed with it, process. But they're, they're, they're not gonna, you know, not gonna have to turn over.

• 2:20:23Andrew D. Huberman?

  I feel like there's, here's another theme emerging. Like we're hearing about drugs that you can get one injection to permanently lower your LDL. We're now hearing about gene therapy to chronically elevate GLP at exactly the place and time that you want in order to offset excess calorie consumption and obesity. I mean, is this what we're gonna see? Like instead of people taking drugs, they're gonna take a one-time injection?

• 2:20:47Speaker 00

  That's what I'm hoping, right? It's very exciting. They actually just entered clinical trials in, I think, the Netherlands. So it's very exciting. So we'll see how that goes. But it looks like it'd be very promising, right? So one-time GLP-1 injection, that could be nice. Additionally, you could use it to augment other therapies. You can use it to augment the gastric procedure, the small bowel procedures. It might be another tool in your armamentarium. It might be more use for diabetes than it is for weight loss. We don't know, right? So it's so early right now, but it's certainly very encouraging.

• 2:21:16Andrew D. Huberman?

  Really glad you're doing this work because I'm aware of a few conditions, but they're rare, fortunately, but they're not exceedingly rare where hyperphagia is an issue. Prader-Willi syndrome and other syndromes where these kids just can't stop eating because they, the lack of hypothalamic signals. And I don't know, my read is that the traditional GLP drugs are, are not really working there. This would be amazing.

• 2:21:39Speaker 00

  And I mean, in rodent models, it's phenomenal because we did these trials where you randomized mice to get semaglutide, high dose semaglutide, much higher than you get for a human, and then the transgene, right? And both groups lose weight, transgene lose a little more, then they stop losing. So they don't keep losing weight forever, right, which is good. And then you took the group on semaglutide and you randomized them further to get nothing or to get the transgene. They get the transgene and they go back right down to the same settling point, which is great. And the ones that were randomized to nothing, put all their weight back on. Phenomenal, right? So it seems to be getting really good results from a weight loss standpoint as well.

• 2:22:13Andrew D. Huberman?

  I don't want to take too much more of your time, but if you're willing, if we could just briefly talk about you for a second. We won't go into deep layers. That's not the purpose here. But you're an interesting person, whether you realize it or not, I hope you do. Because it occurs to me that you, you had certain solutions in hand, but you decided to make, search for better solutions. So I'm just curious, like, was that always, are you, have you always been a tool builder? Like in medical school and residency or even prior, like high school? Are you, are you the person who like sees like, okay, like the reason you have to keep, I'm dating myself here, like, like fix the antenna on the TV is because actually the antenna sucks. Let's, let's do something to the antenna. Were you that kid?

• 2:22:55Speaker 00

  Yeah, my, my mother would attest to that, unfortunately. I, I took my motorcycle apart in high school, couldn't get it back together. I had to have it flatbed away and fixed. And I fixed, I fixed some parts of my car that ended up bursting into flames. So I'm much better at dealing with, with patients than with.

• 2:23:11Andrew D. Huberman?

  Thank goodness. Could have been the other direction, right?

• 2:23:14Speaker 00

  Exactly. So no, I always, I always would tinker with things for sure. And I needed to do things with my hands. So that's why in medical school, I couldn't be kind of a general internist. I think I needed to, I needed to solve problems with my hands. And I think that's the feeling to me is to, I don't, I don't like managing a slow demise, right? And I felt like internal medicine, we were giving people a reason to, to continue with their current life, right? And instead of addressing problems, like their blood pressure is high. Well, instead of finding a way to really help them address that, it's, well, take this medicine. Your LDL is high. Instead of finding a way to address it, you give them a medicine. And you see what that gets us into, these situations where we treat HD, we treat a high LDL,

• 2:23:58Speaker 00

  APOB really effectively, but we're not, we reduce mortality from that specific thing. But we took our eye off the ball and fatty liver is up and diabetes is up and people are still dying in greater numbers, right? So I feel like we need to address the underlying problem and that's very important. But aside from that, I just liked doing things with my hands. And I think that was a large part why I was going to go into cardiology or go into interventional gastro.

• 2:24:22Andrew D. Huberman?

  So grateful that you're a tinkerer. It's a unique thing to find these qualities and expertise woven into the same person. The fact that you clearly have immense compassion for your patients and that you're willing to come here and share information publicly. You have many, many important roles in your daily life. So the fact that you take the time out of your schedule to educate the public is, I and everyone listening have immense gratitude for that. And that you're thinking about what could be done better. That's like the ultimate quality, in my opinion, of a, of an excellent physician or scientist or engineer. But when it comes to physicians and the general public, we need people who are thinking about how things, yes, there are some solutions for some people, but we need to broaden the, the treatments to help many more people.

• 2:25:05Andrew D. Huberman?

  So I'm just very grateful to you and, and thanks for coming here today and sharing this info.

• 2:25:09Speaker 00

  Well, thanks so much for having me. Very kind. It's definitely always a team effort, as you know, right? As, as well as anyone, everything is a, is a, is a team effort. And I think innovation is never the result of one person's, you know, work. It's, it's, it's a whole group. And I've been very fortunate to be surrounded by a bunch of amazing people that help, help us move things forward, so.

• 2:25:27Andrew D. Huberman?

  Well, throughout today's discussion, your reflex to give proper attribution is more a testament to what, what you just said. It's not lost on me when, and, and nor people listening. People who give credit where credit's due, it says a lot about them. So thank you. Come back again, maybe in a couple of years when you've solved everything or are close to it. Just joking. I'm sure you guys are making tremendous strides, but these things take time. Once again, thank you very much. This was very, very informative and has enriched my thinking a tremendous amount. I'm sure everyone listening as well.

• 2:25:57Speaker 00

  Thank you.

• 2:25:58Andrew D. Huberman?

  Thank you for joining me for today's discussion with Dr. Chris Thompson. To learn more about his work, please see the links in the show note caption. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please follow the podcast by clicking the follow button on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five star review. And you can now leave us comments at both Spotify and Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. If you have questions for me or comments about the podcast or guests or topics that you'd like me to consider for the Huberman Lab podcast, please put those in the comments section on YouTube. I do read all the comments.

• 2:26:40Andrew D. Huberman?

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• 2:27:24Andrew D. Huberman?

  All of that is available completely zero cost. You simply go to hubermanlab.com, go to the menu tab in the top right corner, scroll down to newsletter and enter your email. And I should emphasize that we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Chris Thompson. And last, but certainly not least, thank you for your interest in science.