Guest Episode
May 6, 2024

Dr. Casey Means: Transform Your Health by Improving Metabolism, Hormone & Blood Sugar Regulation

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In this episode, my guest is Dr. Casey Means, MD, a physician trained at Stanford University School of Medicine, an expert on metabolic health and the author of the book, Good Energy. We discuss how to leverage nutrition, exercise and environmental factors to enhance your metabolic health by improving mitochondrial function, hormone and blood sugar regulation.

We also explore how fasting, deliberate cold exposure and spending time in nature can impact metabolic health, how to control food cravings and how to assess your metabolic health using blood testing, continuous glucose monitors and other tools.

Metabolic dysfunction is a leading cause of chronic disease, obesity and reduced lifespan around the world. Conversely, improving your mitochondrial and metabolic health can positively affect your health span and longevity.

Listeners of this episode will learn low- and zero-cost tools to improve their metabolic health, physical and mental well-being, body composition and target the root cause of various common diseases.


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About this Guest

Dr. Casey Means

Dr. Casey Means is a clinician who trained at Stanford University School of Medicine, an expert on metabolic health and the author of the book, "Good Energy."

  • 00:00:00 Dr. Casey Means
  • 00:02:18 Sponsors: Maui Nui, Eight Sleep & AeroPress
  • 00:06:32 Metabolism, Metabolic Dysfunction, Medicinal Blindspot
  • 00:14:17 Trifecta of Bad Energy
  • 00:24:02 Western Living, United States, Specialization & Medicine
  • 00:27:57 Insulin Resistance, Tool: Mitochondrial Capacity & Exercise
  • 00:33:33 Sponsor: AG1
  • 00:35:03 Tools: Walking & Glucose; Frequent Movement
  • 00:44:25 Tools: Exercises to Improve Mitochondrial Capacity; Desk Treadmill
  • 00:51:18 Soleus Push-Ups & Fidgeting, Non-Exercise Activity Thermogenesis (NEAT)
  • 00:57:14 Sponsor: InsideTracker
  • 00:58:21 Tool: Blood Test Biomarkers, Vital Signs & Mitochondrial Function
  • 01:11:16 Navigate Medical System & Blood Tests, Consumer Lab Testing
  • 01:16:46 Tool: Environmental Factors; Food, Life as a Process
  • 01:21:58 Tool: Ultra-Processed vs. Real Food, Obesity, Soil & Micronutrients
  • 01:32:03 Ultra-Processed Foods: Brain & Cellular Confusion
  • 01:39:10 Tools: Control Cravings, GLP-1 Production, Microbiome Support
  • 01:51:42 Ozempic, GLP-1 Analogs; Root Cause & Medicine
  • 02:00:54 Tool: Deliberate Cold & Heat Exposure, Brown Fat
  • 02:07:27 Tool: Intermittent Fasting & Metabolic Flexibility; Insulin Sensitivity
  • 02:17:03 Tool: Continuous Glucose Monitors (CGMs) & Awareness, Glucose Spikes
  • 02:24:34 Tool: CGMs, Glycemic Variability, Dawn Effect, Individuality
  • 02:33:10 Sleep; Continuous Monitoring & Biomarkers
  • 02:37:39 Mindset & Safety, Stress & Cell Danger Response
  • 02:44:04 Tool: Being in Nature, Sunlight, Fear
  • 02:54:44 Zero-Cost Support, Spotify & Apple Reviews, Sponsors, YouTube Feedback, Social Media, Neural Network Newsletter

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This transcript version is not in its final form and will be updated.

Andrew Huberman: Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Doctor Casey means. Doctor Casey means did her undergraduate degree at Stanford University and her medical degree at Stanford University School of Medicine. She is one of the world's foremost experts in metabolic health. Today we discuss how metabolic function and dysfunction impacts our health. In particular, we discuss mitochondria, which are involved in energy production within our cells, and the various things that we can each and all do to ensure proper mitochondrial function, which is essential not just for things like body composition and physical and mental energy, but also our ability to regulate hormones, blood sugar and much more. We discuss how exercise, even simple exercise like walking as well as sleep, as well as more vigorous exercise, and in particular, nutrition, including the types of foods we eat, the timing of food intake, and the sources and quality of those foods impact our mitochondria and other aspects of metabolic function. We also discuss how particular micronutrients within specific foods can directly impact mitochondrial and metabolic health. Doctor means explains how mitochondria, inflammation and reactive oxygen species, which are the byproducts of metabolism in our cells, can combine to create conditions of obesity, as well as ways that we can manage those things, or even reverse motivation, mitochondrial inflammation and reactive oxygen species dysfunction in order to reverse obesity, reverse diabetes, and enhance our health in myriad ways. By the end of today's discussion, you'll have a clear picture of the cellular processes that occur in the brain and body that underlie metabolic disease and metabolic health. And most importantly, you'll have a very clear picture of the actionable items that we can each and all carry out every day and every week in order to ensure metabolic health, proper mitochondrial function, and indeed that can also impact body body composition and overall feelings of well being. I would also like to share that Doctor Casey means has a terrific new book coming out. I know it's terrific because I've read it. It is entitled good the surprising connection between metabolism and limitless health. If you're interested in the book, we provided a link to the book in the show. Note captions 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, I'd like to thank the sponsors of today's podcast. Our first sponsor is Maui Nui Venison. Maui Nui Venison is the most nutrient dense and delicious red meat available. I've spoken before on this podcast and with several expert guests on this podcast about the fact that most of us should be seeking to get about 1 gram of quality protein per pound of body weight every day. Not only does that protein provide critical building blocks for things like muscle repair and synthesis, but also for overall metabolism and health. Eating enough quality protein each day is also a terrific way to stave off hunger. One of the key things, however, is to make sure that you're getting enough quality protein without ingesting excess calories. Maui nui venison has an extremely high quality protein per calorie ratio, such that getting 1 gram of protein per pound of body weight is both easy and doesn't cause you to ingest an excess of calories. Also, maui nui venison is absolutely delicious. They have venison steaks, they have ground venison and they have venison bone broth. I personally like all of those. In fact, I probably eat a maui nui venison burger pretty much every day, and occasionally I'll swap that for a maui nui steak. And if you're really on the go, they have maui nui venison jerky which has 10 grams of protein per stick at just 55 calories. If you'd like to try maui nui venison, you can go to maui huberman to get 20% off your first order. Again, that's Maui nui Huberman Today's episode is also brought to us by eight sleep. Eight sleep makes smart mattress covers with cooling, heating and sleep tracking capacity. Now, I've spoken many times before on this podcast about the critical need to get sleep, both enough sleep and enough quality sleep. When we do that, everything, our mental health, our physical health, performance in any sports or school, etcetera, all get better. And when we're not sleeping well or enough, all those things suffer. One of the key things to getting a great night's sleep is that your body temperature actually has to drop by about one to three degrees in order to fall and stay deeply asleep. And in order to wake up feeling refreshed, your body temperature actually has to increase by about one to three degrees. One of the best ways to ensure that happens is to control the temperature of your sleeping environment. And with eight sleep, it makes it very easy to do that. You program in the temperature that you want at the beginning, middle, and end of the night. You can even divide the temperature for two different people. If you have two different people sleeping in the bed and it tracks your sleep, it tells you how much slow wave sleep and rapid eye movement sleep you're getting. It really helps you dial in the correct parameters to get the best possible night's sleep for you. I've been sleeping on an eight sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better. If you'd like to try eight sleep, you can can go to eight huberman and save $150 off their pod. Three cover eight sleep currently ships in the USA, Canada, UK, select countries in the EU, and Australia. Again, that's Huberman Today's episode is also brought to us by Aeropress. Aeropress is like a french press, but a french press that always brews the perfect cup of coffee, meaning no bitterness and excellent taste. Aeropress achieves this because it uses a very short contact time between the hot water and the coffee. And that short contact time also means that you can brew an excellent cup of coffee very quickly. The whole thing takes only about three minutes. I started using an aeropress over ten years ago, and I learned about it from a guy named Alan Adler, who's a former Stanford engineer who's also an inventor. He developed things like the Aerobi Frisbee. In any event, I'm a big fan of Adler inventions, and when I heard he developed a coffee maker, the aeropress, I tried it and I found that indeed, it makes the best possible tasting cup of coffee. It's also extremely small and portable, so I started using it in the laboratory when I travel on the road and also at home. And I'm not alone in my love of the aeropress coffee maker. With over 55,005 star reviews, Aeropress is the best reviewed coffee press in the world. If you'd like to try aeropress, you can go to huberman to get 20% off. Aeropress currently ships in the USA, Canada, and to over 60 other countries around the world. Again, that's huberman and now for my discussion with Doctor Casey means. Doctor Casey means, welcome.

Casey Means: Doctor Andrew Huberman. Thank you so much for having me.

Andrew Huberman: Really excited to talk to you today about all things health. One of the things I love so much about your work is that you really give people a sense of agency through knowledge and actionable tools, which is very near and dear to my mission and my heart. But to kick things off, let's talk about metabolic function and dysfunction. I think most people hear the word metabolism and they think, okay, the burning of energy. Maybe they think about ATP. Maybe they think about calories in, calories out, that sort of thing. But what are we talking about when we're talking about metabolic function and dysfunction? Because these are really important concepts for everyone to understand.

Casey Means: Yeah, I think you're exactly right. I think that when we hear the word metabolism, the first thing that comes to most people's minds is my weight. Do I have a fast metabolism, or do I have a slow metabolism or something like basal metabolic rate? And I think what's really important for people to realize is that metabolism is actually the foundation of all health. It is the core foundational pathway that drives all other aspects of health. And it's also the core foundational pathway that's truly getting crushed in the modern american world and underlying nine of the ten leading causes of death in the United States today. It's really quite relevant to everyone. And the spectrum of metabolic rooted disease is vast and actually really relevant to most Americans. The latest research from American College of Cardiology suggests that 93% of american adults have suboptimal metabolism. And we can go into what that means. But fundamentally, when we're talking about metabolism, we're talking about how we convert food energy to human energy. So we take in a astonishing 70 metric tons or so of food in our lifetime, and that is potential energy. It's energy from the environment that's outside of us that, through our metabolic pathways, gets converted to a currency of energy that can then be used to pay for essentially every chemical reaction inside our body. And the bubbling up of all of those chemical reactions is our lives. And so when metabolism is not working properly, it's essentially creating underpowered cells. And like any city or factory or machine, not having adequate power will lead to dysfunction. And the reason that the metabolic spectrum of disease is so vast is because we have over 200 cell types in the body. And underpowering in different cell types is going to look like different symptoms. Because underpowering in a astrocyte is going to look different than underpowering an ovarian theca cell or an endothelial cell. It's going to look different. But the core foundational process that is dysfunctional can actually be the same. And I think the biggest blind spot in western healthcare and actually the reason that health outcomes are actually getting worse every year in the United States is because fundamentally, we are ignoring metabolic health and metabolic dysfunction. We are laser focused on the downstream symptoms that result from metabolic dysfunction in different cell types. And we spend all of our energy focusing on those symptoms, playing whack a mole with them, and really ignoring that underlying foundational root cause of metabolic function. And what's so fascinating to me and what I saw in the healthcare system as like a super sub specialist, as an ENT surgeon, is that the more we specialize in healthcare, we have over 100 specialties now that we've just invented in the healthcare system, the more we specialize in healthcare, the sicker we're actually getting. So the more we do technological innovation in all these different specialties, the sicker we're getting. And I think the real nugget there that everyone really needs to understand is we've bought into a system where we value specialization, and this is the game in western medicine. But while we've done that, what has happened is we have the worst chronic disease epidemic and the lowest life expectancy of any high income country in the world. And the reason is because in that specialization, we're focused on the downstream manifestation of underpowering of cells, the cell specific symptoms, and not the metabolic function itself. So really, our chronic disease epidemic in this country, it is a metabolic dysfunction epidemic, an underpowering epidemic. And that is the biggest blind spot in healthcare. And I think a focus on metabolic function as the center of our healthcare system. It's a completely new paradigm for health that is urgently, and I cannot overstate enough, it's urgently needed. We know we're not in the right paradigm right now when we have 100 isolated specialties, and yet 85% to 90% of the conditions in those specialties, if you go to the science and look at the real physiology, is metabolic dysfunction. So that's kind of the landscape of what metabolic dysfunction is and how it's kind of creating a big blind spot in the healthcare system that really represents an outdated way of categorizing disease that unfortunately is killing us, I would say.

Andrew Huberman: Yeah, thank you for that. I have several reflections and a question. First off, the analogy that comes to mind is an assembly line that's constructing, let's say, an automobile. And it sounds like 80% to 90% of the automobiles that are coming off that assembly line are not working well. Tires aren't aligned, engines isn't working well, transmission isn't working. There's a bunch of issues, and no factory, no car manufacturer would tolerate that, nor would the customers. But we're tolerating that in ourselves. It sounds like many people are. And then accepting the fact that then a bunch of other businesses are going to crop up, like the business that aligns the tires, the business that goes and repairs the pistons. And essentially, when you talk about these multi specialties that have evolved in the medical care system, they provide an opportunity to go and fix the problems, or try and ameliorate the problems. But really, what we need to do to make this analogy much briefer than it otherwise would be, is just to go further up the assembly line, figure out whether or not the hardware is correct, the software is correct, and where the hardware and software are becoming deficient. In this analogy, where we are the automobile that's essentially coming off the conveyor, broken. And the good news is, and I know this because I've read your book and because I follow your work very closely, the good news is that we, each and all, can take matters to some extent, into our own hands, collaborate with healthcare providers, and repair metabolic dysfunction, essentially make us metabolically functional. So the question, therefore, is, I think most people, when they hear metabolism, they think energy. And when we hear energy, we think ATP sometimes. But typically, people think about mitochondria, the powerhouse of the cell, so to speak. So you've talked about the trifecta, or the big three, mitochondria, inflammation and oxidative stress, as three critical factors underlying metabolic dysfunction. And I'm presuming those are also the avenues to address in order to create metabolic function. Because ultimately, what we want, of course, is an optimistic picture that we can actually take some control, that we have some agency in all of this, which I believe we do. So if you would, could you get us all on the same page about what are mitochondria and what do they do? Why are they so important? Then we can turn to inflammation and oxidative stress.

Casey Means: Yes, absolutely. The mitochondria are the structure within the cells. We have 40 trillion cells, and each cell might have a handful or many thousand mitochondria. And they are the magical part of the cell that does that conversion process of food breaking down and then converting to energy, translating it to a currency of energy our body can recognize. And so currently, what's happening is that our environment, the environment that our cells exist in, across every single facet of our life over the past 50 to 75 years, has changed rapidly. You look at how our food system has changed from whole real food and good soil to industrial food. Our sleep habits have changed. We're sleeping less. It's very fragmented. Our movement patterns have changed. We're sitting 80% of the waking day. Our time in nature has changed. We actually are indoors as Americans, 93% of a 24 hours period. So that totally changes our relationship with light. We have 80,000 synthetic toxins in our food, water, air, personal care products, home care products. We live a thermoneutral existence now with our thermostats. There's no real swings in temperature, unless you're intentionally trying to. And then our emotional health is very different. We are very much exposed to low grade chronic stress triggers. So across food, sleep, movement, emotional health, toxins, light, and temperature, things are not what they once were. And it's changed in the blink of an eye. I mean, the light bulb was created in 1806. This is like 0.04% of human history that we've even had artificial light. So things have changed. And the unique thing about all of these changes in our environment is that each one of those pillars, each of those changes in our environment, synergistically directly hurts the mitochondria through different mechanisms. The chronic low grade stress, the sitting, the ultra processed, nutrient devoid food, even the blue light at nighttime. All of it, through different core biologic mechanisms, synergistically hits this part of the cell, the mitochondria. So we have the food coming in, but we're not doing a good job of converting it to an energy form we can use. So we have these underpowered dysfunctional cells because of mitochondrial dysfunction caused by our environment. And, of course, what happens if you've got energy substrate that you can't process? It's going to be stored. And that's, of course, why we have an obesity and obesity overweight epidemic that's affecting close to 80% of american people.

Andrew Huberman: It's so wild.

Casey Means: It's just, we talk about obesity like it's the problem. Obesity is one branch of a tree that's rooted in this mitochondrial dysfunction that's caused by our environment. And just to back up a little bit, to just sort of share kind of, maybe, like, how I sort of started thinking about that. You know, I had trained as an ENT surgeon, and I was at Stanford Medical School, and I was so fascinated by this idea of, like, the way that we're defining the diseases we're treating in a specialty. Like ENT is like, I saw sinusitis day in and day out, and we'd have these patients on the table that we'd be literally drilling into their skulls to suck out sinus pus. And that's, like, the treatment for sinusitis. And the way we diagnose the patients is we say, like, okay, this patient has sinusitis if they have facial pressure, purulent pus, you know, nasal discharge, nasal obstruction, and low sense of smell. So if they have these symptoms, then they have this disease. But when you actually go to the science and you actually go to the studies of, like, what is actually happening to create this, what you find is a lot of papers about mitochondrial dysfunction, because sinusitis is in a chronic inflammatory condition where the cells are essentially sensing some threat, and then they mount this immune response that creates swelling, and then you get pus buildup. But we confuse the pus buildup with the disease, which is actually happening inside the cells. You start looking at Pubmed as a clinician, through a slightly different lens of, like, what's actually happening in the cells. And what you find for almost every chronic disease we're seeing in the US is that you will find a lot of papers on how the mitochondria are dysfunctional, lower ATP generation in a lot of these cell types, and then what does that do? And this gets to your question about chronic inflammation and oxidative stress. Well, when you've got that dysfunctional mitochondria, let's say, in a nasal mucosal tissue, that is a cell that can't do its job, that is a cell that's underpowered. And what could be more threatening to the body than a cell that can't do its job? Interestingly, those cells will initiate a whole process, which is called the cell danger response. It's work that's been done by Robert Naviou at UCSD, where basically they understand the mitochondria is not working properly. This is, of course, caused by the environment, and they will actually release extracellular ATP, which is not really supposed to go outside of the cell. And that creates a massive innate immune response saying, like, I'm underpowered, I need help. My mitochondria is broken. This is the cell releases ATP outside of the cell. Usually the concentration of ATP is a million times higher inside the cell, so releases it almost as a neurotransmitter, a pure genic neurotransmitter, neurotransmitter that massively activates the immune system to come and help. But the immune system comes and is like, not much we can do for you here, because the problem is not something that the immune system can help with, like grabbing a bacteria and lysing it, or, you know, taking care of some cells infected with a virus. The problem is outside the body, it's the environment. So you end up getting this tornado of dysfunction, of mitochondrial dysfunction caused by the environment, leading to the cell danger response, which leads to innate immunity. And then on top of this, you get the oxidative stress, which is the third piece of the trifecta, which is essentially these mitochondria trying so hard to do their work, but they're not working properly. So they create damaging metabolic byproducts called oxidative stress free radicals that cause more damage. So this is happening in the nose, it's happening all over the american body because of our environment. So you've got these tornadoes of interrelated physiology of mitochondrial dysfunction, chronic inflammation, oxidative stress, which, if you start going to the research as a clinician who's focused on symptoms and confusing those for the disease, and look at what's the pathophysiology of arthritis, what's the pathophysiology of Alzheimer's dementia? What's the pathophysiology of type two diabetes, obesity, fat or fatty liver disease, polycystic ovarian syndrome, erectile dysfunction. It all traces back to this trifecta that no medication or surgery, you obviously can't operate on oxidative stress. You can operate on the downstream symptoms. So that's the real secret that I really feel like we need to reorient the healthcare system around. Since 90% of healthcare costs go towards treating the downstream symptoms of these. And for every marginal dollar we're spending on treating symptoms, we're getting, the rates are going up because they're doing nothing to actually affect that trifecta. But to really make it simple, I like to think of this trifecta of what I call trifecta of bad energy trifecta. Underlying metabolic dysfunction of chronic inflammation. Mitochondrial dysfunction, oxidative stress, as chronic inflammation is biochemical fear. It's response to a threat. Mitochondrial dysfunction is kind of like rolling blackouts. It's not enough power. And the oxidative stress is like wildfires. So it's kind of what's funny to me a little bit is like what's happening inside the cell is almost like what's happening in our society. It's like, this is like living in California. It's like blackouts, fire, fear, and that's literally what's happening inside our cell because of the environment. And again, the optimistic news that you alluded to is that we actually have tons of tools and tests that can actually help us understand our level of metabolic health and even give us hints about inflammation, oxidative stress, and mitochondrial dysfunction. And it's very easy to improve if we know what we're actually focused on.

Andrew Huberman: Well, that's reassuring. And we're definitely going to go there. I appreciate the analogy to living in California. I've lived here my entire life. I have been outside of California. But perhaps the only thing you left out besides rolling blackouts, fires. And what was the other one?

Casey Means: Fear.

Andrew Huberman: And fear is high taxes. The taxes are the health debt on the body. So in any case, not to be too dark and pessimistic, well, that's the healthcare cost. I maintain great hope and still a lot of love for California. It's pretty great. It's got its great aspects and it's not so great aspects. And I can say that as a lifelong California resident, there are other wonderful places to live. A couple of questions. First of all, about places to live you've been talking a lot about in the United States. Are some of the same issues with metabolic dysfunction occurring outside of the United States? I would imagine so, yeah.

Casey Means: Any country where we've exported the standard american diet and some of the other norms of western living are starting to see the same rates of chronic disease. But it is worth not mincing words here. Of all high income countries in the world, the United States has the worst chronic disease rates and the lowest life expectancy. And our life expectancy is going down. And we spend about twice as much on health care than the second highest spending country in the world. So we are abjectly failing. And that failure is predicated in our cult of siloing conditions into different, you know, different specialties. And not focusing on this root cause. And I want to just be super clear, like, there's a war being fought right now to get us to believe that siloing is the way, because as you alluded to, siloing is profitable. If you can convince doctors and people that their ten different symptoms are separate things, then they're going to ten different specialist office. Meanwhile, 75% of american adults are overweight and obese, some of the highest in the world. A full 50% of american adults now have pre diabetes and type two diabetes. 50% 30% of teens have prediabetes. 40% of Americans have a mental health diagnosis. Cancer is set to reach 2 million cases this year in 2024, highest ever in recorded history. Alzheimer's is going up. Fatty liver disease is affecting 40% of adults, 18% of teens. Autoimmune disease is skyrocketing. Infertility is going up at huge rates. All these things are going up all at once in the US and yes, in many of the other countries that are eating our diet and there's no sign of it slowing down. And so that's really, if you look at the research through this different lens, you'll find that all of those diseases trace back to metabolic dysfunction caused by our environment that no shot pill or surgery can really address unless we unpack the environmental piece.

Andrew Huberman: Scary picture. I'm glad to hear that. But hopefully we can fix it. Exactly. I'm glad that you are creating solutions. And I should say, and just remind people I said this in my introduction, but you're talking about siloed medical care. You're talking about the kind of standard medical system. But let's not forget I happen to be a faculty at Stanford. You did your medical training at Stanford. You are a medical doctor. You have MD and are highly trained. You were an ent, your nose and throat doctor. If anyone would be familiar with the industry and the practice and the educational system around this, it's you. So you're not speaking outside your balliwick. So before we pivot to solutions, I know people are eager to hear solutions, but in order to understand how to best apply those solutions, I do think it's worth drilling into some of the issues here just a little bit more. You talked about underpowered cells.

Casey Means: Yeah.

Andrew Huberman: You've also alluded to the fact that most people are consuming enough, and probably excess amounts of caloric energy. So is it the lack of mitochondria or mitochondrial dysfunction that's at the root of the problem? The analogy I come up with is you've got a power plant that can convert incoming power line to power that can be distributed to a community. The community, in this analogy, being the organs and cells of the body. There's plenty of potential energy, but there's something about the power plant that is inefficient or dysfunctional. There are shorts, there are circuitry that's just not working, such that the energy that the community can benefit from, the cells and organs of the body, is just not there. So it's not a lack of input, it's a lack of conversion and output. And the consequence of this we see in the form of excess adipose tissue and all the downstream effects. It's not just aesthetic, it's really all the downstream effects of visceral fat, subcutaneous fat, etcetera. What is it that would improve access to energy and energy utilization in cells? Is it simply a matter of getting the mitochondria to function better? Or is it that one can actually create more mitochondria?

Casey Means: This is the key question for how we can get healthy. And it's really about creating capacity in the body to turn more potential energy to usable energy, as opposed to taking that potential energy and shunting it to a storage form. It's all just like, I think about everything visually, and I'm like, you got the circular cell from high school biology textbook. Inside are all the little mitochondria with the squiggly lines inside, and it's just like there's xs through those mitochondria. So instead of after glycolysis and you've got the pyruvate, instead of going through the mitochondria, it's being shuttled into something else. And, I mean, this is fundamentally the cause of insulin resistance, because when the body senses that the mitochondria can't do that conversion process, the cell basically says, because I can't convert this, I don't have the capacity to convert it to usable energy. I'm going to take the substrates and I need to block them. I mean, you've got to turn them to basically a storage form, which inside the cell could be toxic fats like ceramides and diacylglycerol. And I'm also going to block the cell from taking any more substrates because I can't do anything with them. That is fundamentally a root of insulin resistance. So the body says, okay, we're going to block the ability of the insulin receptor to transduce its intracellular signaling pathway. We're going to block it. And when that insulin binds, we're not actually going to allow for glucose to come in. So essentially, insulin resistance is the cell compensating for the mitochondria being broken and telling the insulin receptor that it, you know, that it's not going to be functional. And so you don't get the glute for, you don't get the glute receptors on the cell membrane to allow the glucose to come in. So that's, that's insulin resistance. Again, we talk about that as the problem, but the problem is actually inside the cell leading to that. So that's why just giving someone insulin isn't necessarily the answer. We have to increase mitochondrial capacity to let the flow happen through it to energy, which then trickles up into relieving a lot of these problems. So, to answer your question, what we really want to do to increase our metabolic capacity from a first principles perspective, it's we need to make more mitochondria. We need to get each mitochondria to be more functional, and we need to have each more functional mitochondria, processing more energy substrates. It's really that simple. And the beauty is, we can do all of those things. If you actually break down what those three things mean. It means promoting mitophagy, the recycling of old mitochondria to new mitochondria. It means promoting mitochondrial biogenesis. It means increasing the oxidative capacity of our individual mitochondria. It means improving mitochondrial fusion, which is actually when mitochondria come together to form long chains of mitochondria that are more efficient. So there's, like, a lot of technicality to like what it means to print more mitochondria, have them each be more efficient, and have each one do more work. But that's really what we want to do. And that's when it just kind of gets into the simple habits. Like, there's simple things we can do for each of those things. From mitophagy, we can focus on various types of endurance exercise and high intensity interval exercise. There's compounds like urolithin a that promote mitophagy. When we talk about improving our oxidative capacity, this is things like the sprint workouts. We want to build more mitochondria. This is resistance training, literally telling the body to make more. But first principles, it's, how do we get more of these working better, doing more work every day? And then we think about, you know, you look at the data on walking, and it's like, people who walk more than 7000 steps a day have a 50% to 65% lower chance of dying in ten year follow ups. And it's like, yeah, because walking is literally a glucose disposal signal. So you're just simply asking, it's not a great biogenesis signal, it's not a great mitophagy signal, but it's a great disposal. So, if you're doing lifestyle habits that do one of those three things, which we can, of course, go into more, you're improving the cell's capacity to do that conversion process better.

Andrew Huberman: I'd like to take a brief break and acknowledge our sponsor, ag one. By now, most of you have heard me tell my story about how I've been taking ag one once or twice a day, every day, since 2012. And indeed, that's true. I started taking ag one, and I still take ag one once or twice a day, because it gives me vitamins and minerals that I might not be getting enough of from whole foods that I eat, as well as adaptogens and micronutrients, and those adaptogens and micronutrients are really critical because even though I strive to eat most of my foods from unprocessed or minimally processed whole foods, it's often hard to do so, especially when I'm traveling and especially when I'm busy. So by drinking a packet of ag one in the morning, and oftentimes also again in the afternoon or evening, I'm ensuring that I'm getting everything I need. I'm covering all of my foundational nutritional needs. And I, like so many other people that take ag one regularly, just report feeling better. And that shouldn't be surprising because it supports gut health. And of course, gut health supports immune system health and brain health. And it's supporting a ton of different cellular and organ processes that all interact with one another. So while certain supplements are really directed towards one specific outcome, like sleeping better or being more alert, ag one really is foundational nutritional support. It's really designed to support all of the systems of your brain and body that relate to mental health and physical health. If you'd like to try ag one, you can go to huberman to claim a special offer. They'll give you five free travel packs with your order, plus a year's supply of vitamin D. Three, k, two. Again, that's drinkag Huberman there's a lot of great science and a lot of great stuff related to testing and assessment of one's metabolic health that we should get into and will get into. But since we touched on lifestyle, and because we've been talking about the sort of dysfunctional dark side for a bit, maybe we could just touch on some of the lifestyle factors that you just mentioned. Because I do think it's important that people really start to feel into their sense of agency. And here we're talking about things that are relatively low time investment, certainly don't have much financial cost in the sense that they could be done in gyms and with fancy equipment, but they require that. Again, I want to point out that these are not strict prescriptives, but if you had a magic wand and because you are interested in the health of humans, let's talk about a few of these things that can improve glucose disposal and mitochondrial function, mitophagy, the removal of dead or dysfunctional mitochondria so they can be replaced. Let's talk about the walking one first. You said 7000 steps a day. I don't track my steps. What are we really talking about there? We're talking about taking the stairs and trying to walk as much as possible. Maybe we were going to just give a really crude prescription. You're a doctor, so you can prescribe things. What would you tell people to do? How many short walks per day? Is it three? Is it five? What are we talking?

Casey Means: I would say at least three. I would say aiming for more than that is good, though. So to sort of just give a sense of the picture of walking, if walking were a pill, it would be the most impactful pill weve ever had in all of modern medicine. There was a paper in JAMA 6300. Participants followed for ten to eleven years, and the people who simply walked 7000 steps per day, compared to less than that, had in up to 70% lower risk of all cause mortality in the follow up period. So not causality, but it's pretty incredible. They've done follow up research with slightly different numbers showing. Again, though, like many thousands of people in the study followed for about ten years, 8000 to 12,000 steps per day was associated with 50% to 65% lower all cause mortality. And this has been played out in many studies showing about a 50% reduction in Alzheimer's, dementia, obesity, type two diabetes, depression, cancer, gastric reflux, just all across the board. And I think the key thing is that it's not about the steps, it's about the fact that muscle contraction is medicine. When we contract our muscles, even in a very, like, low grade way, like walking or doing a couple air squats, you know, we're activating ampk and we are essentially causing that cell to have a stimulus to push glucose channels to the cell membrane. Most of the time, the glucose channels are like in vesicles, in little bags inside the cells. They're not on the cell membrane. So of course that's going to keep the glucose in your bloodstream not being processed by the mitochondria. So when we think about steps, it's a proxy metric for just moving more throughout the day. So let's take two people, you have a person who's walking for one to two minutes every 30 minutes throughout the day. Maybe they're exercising at the end of the day or the beginning of the day, maybe they're not. That person is stimulating glucose channels to be at the membrane all day. Now let's take another person who works out really hard for 1 hour in the beginning or the end of the day. They feel great about it, they've checked that off their box, but they're sitting the entire rest of the day. Yes, they have gotten the benefits from the exercise, but for a lot of that day, those glucose channels are inside the cell, not doing the work they could be doing. So I think about these little teeny short walking breaks or push up breaks or air squat breaks every 30 minutes or so throughout the day, as me essentially inside the cell, pushing the glucose channels, the cell membrane, to make them constitutively active. It's totally different physiology, and it's so easy. So it's not about the steps, it's about muscle contraction regularly throughout the day. And this has been shown out in actually more clinical research, which has taken. There's been several studies, two that I think are fascinating, where they basically took two groups and they said, okay, we're going to have you walk 20 minutes before each meal, three times a day, 20 minutes after each meal. So that's also three times a day, or for like two minutes every 30 minutes throughout the day.

Andrew Huberman: So these are three separate groups.

Casey Means: Three separate groups.

Andrew Huberman: Either 20 minutes before, either 20 minutes.

Casey Means: After, or two to three minutes every 30 minutes.

Andrew Huberman: Okay.

Casey Means: All added up to 60 minutes of walking or light jogging a day. I'm kind of paraphrasing two different studies that showed the same thing. One was jogging, one was walking, but it was basically chunks versus short walks every 30 minutes throughout the waking day. The groups that do the short movement regularly throughout the day, even though the total time is the same across all the groups, have significantly lower 24 hours glucose level averages, 24 hours insulin level averages. They are metabolically healthier. And I believe, and the research mechanistically has shown that it's because we're constitutively putting this, that these channels of the membrane, to take up the substrate, use the substrate. So this is not in to replace exercise, but I think it's a reframe. I think the concept of exercise is something we're really very wedded to in our western culture. And you look at more like the blue zones and the centenarians, and it's like they're kind of moving, is built into their everyday life. So we've taken movement out of our everyday life as these knowledge workers, as we've been industrialized. And then we think that exercise replaces that all day movement, but biochemically it does not. So I think a big part of kind of digging ourselves out of this chronic disease mess and creating capacity for mitochondria is finding ways to take a lot of the activities we do now seated, and just find a way to do more of them moving, standing or walking. Or if that's tough, you really need to sit at your desk all day. Then every 30 minutes, taking two minutes to do some just light movement, flex those muscles, get the glucose channels of the membrane, get the mitochondria active. So, and I think another fascinating stat is like, our gym memberships in the US have doubled since the year 2000, and obesity has gone up in the same period. So there's some mismatch between our obsession with exercise and our actual outcomes that we're seeing. And I think it's that we have not actually rebuilt constitutive movement into our daily lives.

Andrew Huberman: Very interesting. Cause I think a lot of people are now working out, so to speak, doing resistance training, which I think is terrific.

Casey Means: Terrific.

Andrew Huberman: Used to be such, you know, so restricted to niche subculture stuff like bodybuilding, preseason football, military, etcetera. And now it's more ubiquitous for everybody, men, women, young, old. That's terrific. Same thing with things like yoga and cardiovascular training. I mean, I like to study the history of exercise culture, and it wasn't, but in the sixties when, you know, jogging was considered kind of like, whoa, that's like a really esoteric niche culture thing. So lots changed. I love the prescriptives you gave, because it's just very straightforward. A couple of short walks, it just makes so much sense. And I love the visual, and I hope people will really hold it in mind. So I'll reiterate it. The translocation of these energy utilization stores vesicles, as you call them, these little packets from the center of the cell out to the cell surface, where then they can be involved, excuse me, in metabolic processes and the utilization of energy in ways that otherwise they wouldn't, and glucose disposal being a big part of this. So I have heard that a short walk after a meal will reduce blood glucose in a way that's really dramatic.

Casey Means: Huge amount, 30, 35%. Just taking a walk around the block after meal, that's definitely a prescription I think everyone should do, because the research is so strong on it. Is that building in simply a ten minute walk around the block, or a dance party in the kitchen? Moving your muscles for ten minutes after a meal can drastically reduce your glucose response. Cause you're just bringing all those channels to the membrane, you're taking up the glucose, you're using it. It's a whole different physiology than sitting on the couch after a meal. That's very high impact, it's high leverage if it's after a meal. So highly recommend that. And the levels, data and clinical data has shown that out time and time again.

Andrew Huberman: Whenever I go to a city like New York, when I am forced to walk more, I always just feel so much better. We also know that the optic flow that one experiences with walking has some interesting effects on the limbic pathways and quieting of some of the anxiety and stress related pathways. This links up with things like EMDR, although there are factors that are separate from EMDR. Basically moving through space, not outer space, but walking through space with optic flow has a certain anxiety reduction function in the brain, which. Beautiful data there, in my opinion. Okay, so that touches on walking. You did mention higher intensity exercise. So let's keep it within the cardiovascular realm for now. So getting heart rate way, way up, getting breathing hard for some minutes each week, maybe a couple times per week, seems that's a good way to increase mitochondrial function and mitochondrial number. Is that right?

Casey Means: Yeah. So you take sort of each type of exercise. We've got walking, we've got resistance training, we've got high intensity interval training, we've got endurance training, and then we've got sort of more like zone two. So we've got these different flavors of how we get our heart rate up, how we get the blood flowing, what we signal to the cells. And each one actually has like a slightly different impact on the mitochondria. When we think about biogenesis, we're thinking mostly like endurance exercise and really more of that zone two. And like, that is really going to be a stimulus inside the cell to print more mitochondria. When we think about improving mitochondrial fusion, high intensity interval training is really, really good for that. When we think about resistance training, it's like, that's like muscle hypertrophy. We're going to be creating more muscle cells and we need more mitochondria for those. So each one has kind of a different impact. And I think this is where, honestly, I think the regular guidelines that we have, even by our government, you know, actually make a lot of sense. It's like work every major muscle group three times a week in a resistance type training, and then work to get 75 to 150 minutes of moderate strenuous activity. So 75 minutes of strenuous activity, or 150 minutes per week of moderate activity. So that actually makes a lot of sense. 80% of Americans are not meeting those very basic guidelines, and 20% of Americans don't get any physical activity, really at all. Activity for the average American is 3000 to 4000 steps per day, which is less than 2 miles. So we are not even close to even meeting the basic recommendations that are out there. But I think those are pretty reasonable resistance training two to three times a week, most major muscle groups and working to, you know, get the, get the heart rate up moderate level for 150 minutes a week or strenuous for 75 minutes a week. Those are going together to be potent stimuli for biogenesis, mitophagy, mitochondrial fusion for increasing antioxidant enzymes that are going to protect the mitochondria from that oxidative stress. And the one that's just actually not in there in the basic recommendations for Americans is the walking. And I would just absolutely add to that at least 7000 steps per day based on what the data is showing, which honestly would probably take less than an hour total to do. If you break it up throughout the day it's just a few minutes a day. So that right there are going to be like a big multifaceted set of signals for increasing mitochondrial capacity in different ways.

Andrew Huberman: Terrific. What are your thoughts on under the desk treadmilling? I dont own one of these and I try and get walks and I definitely do my three resistance training sessions per week. Different muscle groups on different days. So it ends up being each muscle group is hit directly once and indirectly a second time. But I like to do a long hike once on the weekend run in the middle of the week thats 30 maybe 35 minutes and then some vo two max really short workout. Twelve minutes total. Where basically im just going for the feeling that my heart is going to jump out of my chest and I'm going to die from gas. But luckily thus far I haven't died. Nonetheless, the total time commitment isn't that great but I find that I'm at a desk a lot and I have a standing desk. Is it wise to get a treadmill to treadmill under the desk? Seems like it would be one of the best things one could do.

Casey Means: I'm a massive fan of under treadmill desks because genuinely I believe that if we move more of our daily activities that we're doing seated indoors to outdoors moving, it would radically change the health of the United States with real physiology underneath it. So there's actually been research on underdesk standing desks. That is pretty interesting. Small studies but they took a handful of people, I think it was around ten, in a workplace environment and they had them use under desk treadmills for two and a half hours per day during the workday. So not a lot at very so speeds for two weeks and people lost on average 2.6 pounds of fat and put on 2.2 pounds of lean mass. Wild in a very short period of time. The study makes a somewhat wild claim that if this were extrapolated to a year, we anticipate that we could see a loss of 44 to 66 pounds.

Andrew Huberman: Assuming it's linear progression.

Casey Means: Exactly.

Andrew Huberman: Which is not. Which is not the case, folks.

Casey Means: But that's why I'm saying it was a pretty. But that was there in the discussion. But I think that short period is quite interesting. So that's pretty significant. And that's just for two and a half hours a day. So I think now that they're about $150 on Amazon, these under desk treadmills, I think for anyone who's a knowledge worker, it's a good thing to have at your house. And the way I use it is like I basically just force myself to start my day on the treadmill desk and I say to myself, if I don't like it after five minutes, I'll sit down if I need to sit, but I'll start and just see how it feels. And then an hour goes by and I've forgotten I'm even on it.

Andrew Huberman: Is that right? So you're able to work without thinking about having to treadmill.

Casey Means: I am putting it at such a slow speed, I think I'm usually walking at like 1 mean, it's very, very glacially slow. I do put my oura ring on my second toe when I do this because otherwise it doesn't count my steps. Because if your hands are at your desk, it won't count your steps because.

Andrew Huberman: The oura ring's measuring hand accelerometry.

Casey Means: Yeah, but it's incredible how even at a 1.0 1 mph speed, after two to 3 hours you're easily gonna get six, seven, 8000 steps and then throw in a couple other short walks throughout the day and you're getting there easily. So it's just a great way to build back in what modernity took away. And that unfortunately is unavoidable that regular movement for good physiology. So I'm a big fan of them and the data suggests that for a couple hours a day they can actually have an impact on body composition, which I think is a great easy, inexpensive thing for people to do. But if you don't want to buy one, just set those timers and build in the walks throughout the day outside.

Andrew Huberman: Terrific. Yeah, I'm a fan of getting walks when I can. I also, I wonder your thoughts on. There was a study, I'm not sure if you're familiar with it, published at the University of Houston, where they looked at what they called soleus push ups, which all the gym goers are going to roll their eyes. Imagine sitting down and pressing your toe against the ground and raising your heel. So kind of like seated calf raise, but no weight, right under the desk. And this study had some remarkable claims and conclusions, which included, as I recall, that the activation of this muscle, the soleus, which makes up about 1% of the body's total musculature, involved. It caused rather a disproportionate use of blood glucose. So it mobilized blood glucose in a good way. And the idea was, if people would, it's not just bouncing your knee, but would actively push their toes against the ground and raise their heels as they were seated and doing work, that somehow there would be a positive effect on metabolism and blood glucose utilization. I talked a little bit about this on social media and a few other podcasts, and it was interesting to see the sort of attacks that I got. People really didn't like the idea that this was any different than so called neat non exercise in activated thermogenesis. So it's known that people that fidget a lot or move around a lot burn a lot of calories. This actually goes back to some really beautiful work several decades or more ago from Rothwell and Stock, who talked about the fact that animals and people who fidget a lot burn a lot of energy. They tend to be thinner, they tend to have lower adipose tissue stores, and it's because they're just burning a lot more calories. And this is actually what people who suffer from anorexia, which is, by the way, the most deadly of the psychiatric conditions. So we're talking about true anorexia, are encouraged not to do, because they either do it spontaneously, or they learn that it's a very efficient way to burn calories, and that's not what they need. But many people do need to burn more calories. So, bouncing the knee, that thing that drives everybody crazy if you're not the one doing it. Soleus pushups. What are your thoughts about this in that study? We don't have to pick it apart in detail, but I thought it was kind of interesting. It's all coming back to just moving the body as much as possible during the day. Contracting muscles, contracting muscles.

Casey Means: Contracting muscles. It's medicine. I find the concept of neat just endlessly fascinating, because we kind of come up with this term non exercise activity thermogenesis, and the data is really good about it. It basically shows that this is a prime potential intervention for the obesity epidemic. And it all goes back to the cell. It's essentially a stimulus that's telling the body to stay metabolically active as opposed to keeping all those metabolic pathways, you know, dormant during the day. And I think that it is funny, though, that we have these acronyms for basically, like, this is just the way life was 100 years ago. If you look at the 18 hundreds, almost 100% of Americans lived on a farm, basically, like pre industrialization, pre urbanization. Most Americans, not 100%, but close lived. They grew some of their own food. They lived either on a farm or had a large garden. Now that number is less than 1%. So, like, movement was just built into everything we did. And you think from there, like, what has happened? Like, we were outside, we were moving. Our activities of daily living involved movement. And if you just take the grocery example, then it moved to, like, okay, maybe farmers markets and sort of like, you know, outdoor open air markets. Then it's supermarkets, then it's. Now it's literally buying food online with the click of the button. And now some people aren't even doing that. They're literally on the food delivered to them with Uber Eats. So at every level, we've taken away movement from everyday life, and now we have sort of an acronym to bring it back in. But really, it's about just giving the body stimuli that the cells have been entrained to expect throughout all of human history and building the back into our modern life. So I think neatly, it's incredibly important, and I think it also brings up this point that is so critical, which is, like, I really think our way out of this chronic disease epidemic, and even for people who are listening, don't have a chronic disease. Any real chronic symptoms we're dealing with. And just the fact that we're not feeling as good as we could. The way out is pretty simple. It's some of these basic things like walking more throughout the day, moving more throughout the day, getting outside, you know, eating clean, unpoisoned food. A lot of these things that have the best data are so simple. And I think it's, like, really important to just always remember, like, the game and the industry. It's all about how complex can we make it, like, specialization, talking about some of the minutiae. But, like, at the end of the day, all the simple habits that we know are healthy fundamentally improve cellular biology. And some of these things, like the neat, the walking, it's emblematic of the fact that some of the simplest solutions are the ones that are by far the most effective. And I think the biggest misconception in healthcare right now is that the way out and the way to get really back to true incredible health is complicated. Like, it's really not that complicated. We've got to move more throughout the day. That's one of them. You know, on each pillar that we touched on earlier, food, sleep, all of this, you know, when we talk about the simple habits that we know work, the reason they work is because they all positively impact the mitochondria. They positively impact oxidative stress, they positively impact inflammation. So, yeah, I love it.

Andrew Huberman: I love simple solutions that hit multiple cellular pathways that can make everybody healthier. I'd like to just take a quick break and acknowledge one of our sponsors, Insidetracker. Insidetracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. Now, I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact our immediate and long term health can only be addressed, that is, can only be measured with a quality blood test. Now, one issue with many blood tests out there is that you get information back about lipid levels, hormone levels, metabolic factors, etcetera, but you don't know what to do with that information. With Insidetracker, they make it very easy to understand your levels and what they mean and specific actionable items that you can undertake in order to bring those levels into the ranges that are optimal for you. InsideTracker also offers InsideTracker Pro, which enables coaches and health professionals to provide premium and personalized services by leveraging Insidetracker's analysis and recommendations with their clients. If you'd like to try inside tracker, you can go to huberman and you'll get 20% off any of Insidetracker's plans. Again, that's huberman I'd like to talk about assessment, blood tests in particular. I remember in college, I was just very curious about blood testing, and I had read a little bit about it, but it was really hard to access. I actually went to the student health center and said, can I just get my lipids measured, some hormone stuff measured? I was in great health. I want to do that. And they're like, no, what's the issue? Why would you do that? Now it's very easy to find places that will do blood tests, but there is some cost often. And nowadays, thanks to your efforts, your innovative and engineering efforts, and the efforts of others, there are ways to measure what's in your blood, blood glucose in particular, with continuous monitoring and with snapshot monitoring. So, let's talk about blood tests. What do you think are the three to five things that basically everybody, if they can, should know about what's circulating in their blood? I'm imagining LDL, hdl, this kind of thing, I guess. Apob is a big favorite of our friend Peter Attia. Fasting blood glucose, continuous blood glucose, post meal, et cetera. Just kind of evaluating how exercise, food, et cetera, impacts blood glucose. And then I'll leave the other categories open, because my point here is not to answer the question, but that's what comes to mind.

Casey Means: You've got the big ones. So this is key, is that every single person listening, I hope after this episode, will go to their health record or send their doctor a message and at least get the following test. And the first seven that I'll mention are very basic, and people might take umbrage to them, because obviously, there's a lot of debate about, like, what's everyone's favorite lab tests. But I think about it as, like, what are the basics that everyone should know? And then what's, like, the next tier up that are easy to access and are cheap? That'll give you a lot more richness, but which you still might have to kind of fight your doctor for. So the first few that you will not have to fight your doctor for and are often free on an annual physical and literally define metabolic syndrome, are fasting glucose, fasting triglycerides, hdl cholesterol, hemoglobin, a one c, total cholesterol, waist circumference, and blood pressure.

Andrew Huberman: Okay, sorry, I hate to interrupt, and my audience hates it even more, but I'm gonna just. Could you just explain what each of those is and what it corresponds to?

Casey Means: Yes.

Andrew Huberman: Great. Thank you.

Casey Means: And I will say, first of all, the reason I'm choosing these, it's not even my own choice, really. It's two reasons. One is that the two studies over the past five years that have shown us, in large populations, that the vast majority of american adults are metabolically dysfunctional use those biomarkers. So I think because of that, it's important to know them. And the two studies that I'm referring to are one from UNC in 2018, which showed that based on those biomarkers, 88% of american adults have suboptimal metabolism. And then a follow up study from the Journal of the American College of Cardiology from last year showed that that number has gone to 93.2% of american adults are suboptimal in their metabolism. And these are the metrics that they use, and they're very basic. If you had to pay out of pocket, they would be less than $100. So let's talk through them. Why they're great is because together, they give you kind of like a tapestry of what's actually happening inside the cell. If you choose to look at them that way, if you read the tea leaves of them, the doctors often, if they see all these lab tests, it'll be in an electronic health record. We've all been through this experience. They'll come up on the screen and there will either be, like a green, orange, or red color next to it. Like, it's high, it's low, it's borderline. And the doctor will basically, it's very algorithmic. Oh, you know, your ldl is high. We need to bring it down. Oh, your glucose is high. We need to bring it down. Oh, your blood pressure's high. We need to bring it down. But what I'm inviting people to do is understand a little bit about each test and then read the tea leaves of what it's telling us about our mitochondria. So let's start with fasting glucose. So, fasting glucose, when you look at these studies that I'm referring to, they call optimal. Less than 100. So to define whether you were in that 88 or 93%, you had to essentially be in their optimal range for all biomarkers not on medication. So I'll quickly run through what their ranges were. My ranges for optimal are tighter than these, but fasting glucose, less than 100. Triglycerides less than 150. Hdl above 40 for men or 50 for women. Hemoglobin one c, less than 5.7%. Total cholesterol to hdl ratio less than 3.5 to one. Waist circumference less than 35 inches for women or 40 inches for men, and blood pressure less than 120 over 80. If those things were in those ranges and you weren't on medication for blood sugar or blood pressure or whatnot, you were considered optimally, metabolically healthy. That's now 6.8% of Americans. All of these biomarkers are easy to change in one to two months, I would say, with simple lifestyle habits.

Andrew Huberman: Could you remind us what hemoglobin a one c is? I think most people are familiar with hdl cholesterol being the quote unquote good cholesterol and ldl being the bad cholesterol. And as I say that, I know I'm going to get dogpile.

Casey Means: Yeah. Oh, totally.

Andrew Huberman: I'm not sure that I adhere to that. I'm not sure. I don't adhere to that. I'm not sure about a lot of things, but I am sure that most people think of them that way. So just to stay functional here, we'll frame it that way for now. With the caveat that that might not be the whole story. Isn't the whole story, but triglycerides, fat in the blood, fatty stuff.

Casey Means: But so, key to understand about the triglycerides, it's not. We don't want to confuse triglycerides with eating more fat. Triglycerides are a storage form of excess carbohydrates in the blood. This is why it can tell us something about, and I know you and Rob Lustig talked about this at length, but it's.

Andrew Huberman: And Lane.

Casey Means: Norton and Lane. Yeah, yeah.

Andrew Huberman: I mean, one of the things that's really tricky, gosh, is that the language around nutrition and health is complicated because people hear the word fat, they think body fat, right? But then they also think the macronutrient fat. We just need more words to better parse totally the reality. In biology, we call the two major groups of. Of people lumpers and splitters. Lumpers like to lump everything together. It oversimplifies and complicates. Splitters like to split everything, give a name for everything, individual name for everything. It complicates. And so there's a middle ground, right? There's a land of reasonable people and nomenclature. And unfortunately, that does not exist on the Internet, nor does it exist in any one specific subfield of medicine or science. I mean, so much of the confusion out in the world is because of a lack of adequate language in order to explain, okay, so the triglycerides are a reflection of excess carbohydrate intake.

Casey Means: And how it's helping us with that tapestry of understanding the trifecta of bad energy is that if you think about it, let's just go back to that cell and that poor mitochondria that's being absolutely decimated by our environment and its capacity is low. Okay, so that mitochondria is like, I can't process glucose or fatty acids to ATP very well, so I'm going to block their entry into the cell. So now you've got glucose rising in the bloodstream. So, okay, fasting glucose. That was one of our biomarkers. If that's going up, that is a little bit of that tapestry of maybe something's going on inside the cell that's blocking the entry into the cell. So it's rising the bloodstream. Okay, well, where's all that? The body does not want lots of glucose floating around in the bloodstream because it can literally independently cause endothelial dysfunction, which is basically blood vessel problems. It can cause oxidative stress in the bloodstream. It can cause glycation, which is sugar, literally just sticking to things. The body doesn't want that glucose high in the bloodstream, so it converts it to triglycerides to be stored in a storage form of energy. That's a key point that I think is helpful to understand, is that the body, it's always trying to, like, kind of keep things in the right range so it'll convert things. So then triglycerides, a picture in your blood of glucose being high and triglycerides being high is very much should signal to everyone when they look at their labs that there's probably something going on inside the cell that's blocking the cell from being able to use and process. It's a sign of mitochondrial dysfunction and chronic over nutrition. Too much substrate, not enough processing. Glucose is going to go up. Triglycerides are going to go up. So then if you kind of squint and read the tea leaves, it's like, huh, I think metabolic dysfunction. And what's fascinating is that the travesty in our healthcare system is that a patient might go into the doctor and their fasting glucose is 99, one point under what we'd consider the normal range. And their triglycerides are 149, one point under what we'd consider the normal range. From these things that doctor might say to that patient, you're totally fine. Both glucose and triglycerides are normal, but that's just really problematic because they're on the upper end of normal for both of those. And so really what that would say to me, as someone thinking about the mitochondria is like, this person is definitely metabolically dysfunctional. They're on the highest end of normal for both triglycerides and glucose. There's something. There's definitely insulin resistance going on here. I would much rather see that glucose at 73 and that triglyceride at 50, which to me would say, oh, this cell is processing through energy great. And things are moving through, and we're not backing up in the bloodstream. We're not converting to triglycerides. So that's where really optimal ranges get in. But so that's. So that's glucose and triglycerides. Why, if those are starting to creep up, it's a sign that something is happening metabolically. And then when we look at some of the other biomarkers. So hemoglobin a one c, is really. So that's a marker that's looking at how many of the hemoglobin molecules that are in the red blood cells that carry oxygen, how many of those hemoglobin molecules have sugar stuck to them, and that's glycation. So you're looking at glycated hemoglobin, and you can imagine that if the concentration of glucose is higher over time, more glucose is going to stick to red blood cells, and that's going to create a higher percentage of glycated hemoglobin. So that's why that lab is represented as a. So less than 5.7 is what we want.

Andrew Huberman: You want those cells nice and smooth.

Casey Means: And slippery smooth, no sugar stuck to them, causing dysfunction. And because blood cells last for about nine to 120 days, hemoglobin a one c, is giving us a basically a snapshot of average blood sugar levels over nine to 120 days. And if that average is higher, again, probably a sign that cells are rejecting glucose from the cell and it's causing a rise in the bloodstream. And then just talking about one other biomarker in that that we talked about, which was blood pressure, people might say, well, how does blood pressure relate to, like, what's going on inside the cell, you know, in the mitochondria and whatnot? And a really, the fascinating link is that when that cell becomes insulin resistance, which, again, is a compensatory mechanism for mitochondrial dysfunction, the insulin is gonna rise in the blood because the body's insulin resistant. So the body's gonna churn out more insulin to try and overcome the insulin block to drive the sugar into the cells. So insulin levels rise. Well, insulin is one of the key activators of nitric oxide, which is the molecule in the blood that dilates and relaxes blood vessels. And so when we become insulin resistant and we're not responding to that insulin signal, we end up getting less nitric oxide activity. So this is how kind of looking at even these very basic, very cheap biomarkers. So the lens of basic cellular physiology, we can start to see, man, my body might be, like, underpowered. I might have a mitochondrial issue here. So that's a few of those tests that we really want to shoot for.

Andrew Huberman: Terrific. And thanks for bringing up blood pressure again. It sort of comes across to many people as old school. Right? But when Attia was here, one of the several times he was here, he really pushed on blood pressure, such a key metric, right? I mean, obviously, if blood pressure is high, you're getting less nitric oxide through whatever means here. Vessels and capillaries are constricted, cells aren't able to use the energy that's coming in. There's excess energy, there's buildup of metabolic waste. There's all this stuff. And now we can start to see the picture and starting to emerge. And as you mentioned briefly, these markers can be put into healthy range or maybe even fantastic range in a very short period of time. So we'll talk about how to go about that in terms of getting a basic blood test. You're a physician. What's the secret code? I'll give away, one that a former guest who's also an MD shared, which is oftentimes, if you ask your physician for a blood test, they will say, well, unless there's a particular need or you're struggling with something, they won't give it to you. But if you have a shift from baseline in a symptom or in a number that can help, all the physicians are going to come after me now, I guess with stethoscopes, I'm willing to stand my ground. If you want a blood test, it's often useful to mention that there's been some market shift. You want to be honest, but some market shift in sleep, in lifestyle, in how you feel standing up, sitting down. I'm not trying to lace people's minds with ideas, create narratives here, but oftentimes where physicians are resistant, they'll be more amenable if they understand that, hey, like, something's changing and the patient's saying something's changing, it actually would be irresponsible of them to not give the blood test. So there you go. Bring it on, mds.

Casey Means: Yeah. Truly. And I think the nice thing about these, again, very basic tests, and there are so many other tests that I talk about in my book and that you've talked about on your podcast, apOb, uric acid, fasting insulin, homa, iron, HSCRP, liver function test, GGT, all these other tests that are great, that can really tell us more about mitochondrial dysfunction, oxidative stress, chronic inflammation. But the ones I'm mentioning are the ones that you will not have to fight with your doctor about. Like, everything I just mentioned, like, the doctor should order on an annual physical, and it's really about us learning to actually, like, read the tea leaves of what they're saying and not look at them in this algorithmic way, but, like, how together, if they're creeping up, or if many of them are a little bit high, like, we need to focus all of our energy on improving mitochondrial capacity, basically, and. And bring those numbers down, which we can do very, very quickly. Once you start getting the mitochondria moving through more of those substrates, a lot of them will just naturally come down. Now, in the book, I give scripts to literally talk to your doctor with because you are going to get pushback often, if you ask for a fasting insulin, I would say probably. I mean, even though doctors are waking up a little bit, like, maybe 85% of people are going to have their doctors say they won't order that for them. So I actually think there's a huge benefit. I hate to say it, but, like, going outside the system, this is where I think innovation has been valuable. There's a lot of, like, amazing companies doing direct to consumer lab testing, so you can basically avoid the hassle. And some of them are very affordable. There's function. Health is a company that's doing 110 biomarkers, including all the key metabolic biomarkers, for less than $500. And they'll do it twice a year, so you don't ever have to. And then they do interpretations. Inside tracker next health levels is doing labs. And so there's a lot of this springing up because I think people are sick of fighting with their doctors to get a crumb of information about their health. And we should probably be testing these, I would say, three to four times a year. And the beauty is that I think a lot of what keeps people down in the health world is that they're confused about what to do. There's a lot of noise. There's a lot of different strategies. Do I do paleo? Keto, carnivore. Vegan. Mediterranean? Do I do hit or zone two or eccentric? It's like there's so much noise. And the beauty with having a plan for understanding your biomarkers regularly is that you can cut through all the noise, try a strategy, see where you stand, retests in a few months, and see if you're moving in the right direction.

Andrew Huberman: I'm a scientist.

Casey Means: You don't have to trust your doctor. You don't have to trust me. You don't have to trust anyone. You can literally trust your own labs. And I say to people, like, if your labs are optimal and the ranges I just mentioned are not optimal, like, we want to actually get to better than all of those. If you want to be optimal, if your. If your key metabolic biomarkers are optimal, if you feel absolutely freaking incredible and you have no symptoms, then you're probably doing the right strategy, whatever that is. Vegan, keto, whatever, like, and exercise and your lifestyle, because that is showing that your cells are fundamentally working properly. So I think that's just a really empowering message. Now, there's phenomenal companies that are cropping up to basically help allow people to do this on their own schedule, which I think is really the future of health and actually will help lessen, I think, some of the intensity of the diet wars. You know, because it's like people can just say, like, I trust my strategy. I know I'm doing what's right for me because, like, look at all my biomarkers and I feel great, you know?

Andrew Huberman: So, yeah, what used to be the before and after pre diet exercise, post diet exercise photos on social media are now starting to also include numbers, which is kind of interesting. I mean, obviously these aren't randomized controlled trials, but it's cool to see people posting their numbers of things that are not just related to aesthetics or body weight, but are related to health metrics. It's fun. I think it speaks to a more scientific, or at least a more quantitative approach to things. And I think it's inspiring for people. Thanks for putting those scripts in the book that people can refer to. Let's say that I go in for these blood tests, I do the basic seven, and I find that my fasting glucose is a little high, my triglycerides are a little high, my ldl is a little high. Maybe a few other things are okay. So I'm kind of in the, you know, not in the red zone, but I'm in the, like, you should probably pay attention to these things. What are some of the things that one can do in order to try and move those needles in the right direction? I know we talked about walking and movement before. What are a few others? And maybe we could start to touch into nutrition a little bit, and then we'll pivot to insulin and blood glucose.

Casey Means: I think on the highest level, it's about running through what are the science based things that we know in our environment can lead to metabolic dysfunction and take honest stock of how those factors are playing out in your life and then choose a few to start moving in a different direction. So the ones that I think are ones that we can really control and that are, we know based on the science, are impacting our mitochondrial metabolic health is the food, the sleep, the movement, the emotional health, the toxins, our relationship with light and our relationship with temperature. And your journey to optimal metabolic health might be totally different from mine because I might really need to focus on the food and the sleep and the emotional health, and you might really need to focus on the toxins and the light and the movement. And so it's a lot of it is actually taking stock on where the levers are in your own life, where are you crushing it? And where is there a lot of room for improvement? So step one is knowing, like, that those are the things. Those are the things in our environment that we need to basically improve to give ourselves the best capacity. And then, of course, checking your biomarkers to make sure your interventions are working. But food, I think, is one that is, like, totally unavoidable of those pillars, those seven pillars. Food is one that most of us are getting wrong and that we really, actually have to get right to improve our metabolic health for a lot of reasons. I mean, our bodies are basically 100% molecularly made from food.

Andrew Huberman: That's so wild.

Casey Means: It's so wild.

Andrew Huberman: Every time I think about that, it kind of blows my mind.

Casey Means: Like, babies are 3d printed from food, basically, inside a woman's body. It's wild to me. And then what's so cool about the body, what brings me just immense awe every day, is that we have this conception in our western world that the body is like a thing that we're with throughout our life. Cause we kind of look the same and we age slowly. So it's like Casey is a thing and Andrew is a thing, but the body is actually a process. The body. And there's this amazing taoist statement, like, life is a process, not an entity.

Andrew Huberman: I love that. I'm sorry to interrupt. I'm just. I always wish that if people could understand that with biology and health, understanding the nouns and the names is important. But it's verbs. It's verbs, verbs, verbs. If you understand that things are processes, or processes, depending on who you are and where you live in the world, it all becomes so much more tractable.

Casey Means: Yes. And it's so much more hopeful, because if I'm a process, if you're a process, then every day we're eating, we are changing the process. Whereas if you think you're a thing, then there's no hope. Because I'm just. I'm Casey, and that's who I am. And I have this disease, you know? And I think so much in our language, actually, of healthcare, both our western sort of de spiritualized nature. We don't really have a lot of curiosity with process. But even the ideas, the way we talk about disease, I have diabetes, and we don't even talk about diabetes cures, which now a lot of people are curing their diabetes. We call it remission. It's this thing that's a part of you. And I just love this idea of we're evolving every day. And food is so important because, again, we take in 70 metric tons of food in that lifetime, two to three pounds per day, one metric ton per year on average. And that is like the printer ink, that's the 3d printer ink to create tomorrow's version of ourself, which is molecularly different than the casey of today. That's a hopeful message, because if we can give the body food, which, you know, I think we, again, our conception of food, I think, is very limited. Food is the molecular building blocks of the body. It is the cell signaling, functional molecules that tell our cells what to do. They act as transcription factors, epigenetic modifiers, cell signaling pathway intermediates, and it's also, of course, the substrate to change what the microbiome does and the composition of the microbiome, which is basically a pharmacy inside our bodies to create different molecules that can affect our health. So food is certainly a calorie, is a calorie from the concept of thermodynamics, but from the concept of molecular information. It has three massively important parts that are unavoidable for creating cellular health. So I would just say that that is the pillar that we can be happy to drill into of, like, what do we really do to, you know, build as much metabolic health as possible?

Andrew Huberman: Yeah, I want to focus now, if you're willing, on food, not just macronutrients, proteins, fats, and carbohydrates, not just calories, although that as well, but things like timing, things like fasting and micronutrients, which I think is a highly underexplored topic. So, with respect to food, gosh, I feel like we've all been exposed to pretty much every variation of, you know, it's all calories in, calories out. And by the way, I believe in the laws of thermodynamics. So, yes, total caloric load matters. Total energy expenditure matters, without question, within the framework of not consuming excess calories, there's a lot to explore. However, I can just say for myself, for what it's worth, I'm not very hungry until 11:00 a.m. noon, or one. I'm okay not eating until then. And just water, electrolytes and caffeine does me just fine, I can exercise, et cetera. But once I start eating, I really enjoy eating. And I mostly like the proteins. I like meat and fish and eggs, and I like cheese and vegetables and carbohydrates and fruit and all of it. I like all the stuff. And I tend to like single or few ingredient foods. I just naturally do. So I've been lucky in that way. But I know a lot of people like sandwiches, processed foods, things that are combinations of ingredients. What do we know about kind of. I don't want to say optimal, but if one, we're going to explore different ways of eating for sake of adjusting these biomarkers in the right direction and improving metabolic health. Is there kind of a generic jumping off point? Would most people, for instance, be wise to cut back on the total number of sugars, or the total amount of sugar, rather perhaps reduce the amount of carbohydrate and replace it with some lean, quality protein? I mean, are there generalizations that we can make, or is it really all just about not getting excessive calories and trying to get those calories from the most nutrient rich sources?

Casey Means: Well, just drilling in on two things you just said there. So one thing you said that was interesting was that you're lucky that you like all of those foods. And then the second thing was, is it just about not getting excess calories? But I think what's interesting about both of those is that I would argue that the reason you like those foods is because you have given your body enough whole, real foods that now everything in your biology, neurobiologically, your reward circuitry, your microbiome, your satiety, hormone threshold, all of these are now basically creating a situation in which you like those foods. And then the caloric thing fits into that. Because the reason we're eating excess calories, the reason chronic nutrition is happening, and the reason we are quite literally in the United States, eating ourselves to death for the first time in human history, is because we're not eating real food and we're eating 60% to 75% of our calories of ultra processed, nutrient depleted foods that fundamentally don't give our cells what they need. And a real premise that I think is so important to realize is that our cells are brilliant. And if the cells aren't getting what they actually need to function properly, they will drive you to eat until they get their needs met. Unfortunately, because the ultra processed food is designed to be highly addictive and it's devoid of what the cells actually need for good function, we end up eating ourselves into a grave and now almost 80% of Americans are overweight or obese. Close to 50% of the country is obese. We literally gloss over this as a culture. It has become so normal in such a short amount of time. But I always think about the fact that, like, there are really no other animal species in the world that have obesity and chronic disease epidemics, and they don't have social media, they don't have experts, they don't have pubmed, they don't have the FDA, they don't have the USDA, they don't have any of it. And they have somehow figured out a way to stay at a healthy weight and to not get heart disease. And it's because they're eating real food that meets the needs of their cells. And so I think to just boil that down, the root cause of the problem is that we have a toxic food supply that's no longer filled with the molecular information that our body needs to know to be satiated and to function properly. And so through the complex biology of satiety hormones and neurobiology and microbiome function, we are driven to eat so, so, so much more. So truly, the jumping off point for anyone on the quest to better health is to eat as much real unprocessed food from good soil as possible. And really of any dietary philosophy they want. Truly, I think if someone's eating real unprocessed food from good soil, who is, you know, plant based or who is keto, they are going to have such a higher chance of meeting their body's actual fundamental needs. And the good thing about biomarker testing is they can track for themselves if they are having good cellular function with that strategy. There's been studies that have panned this out. You know, we know that the more ultra processed food you eat, the higher risk of obviously obesity, but also chronic diseases are. But then of course, there's an amazing study from Kevin hall just recently where he basically locked people up at the NIH and for two weeks he had them eat ultra processed food. And for two weeks he had them eat real food. And people ate 7000 more calories in the two week period when they were eating ultra processed food versus than unprocessed.

Andrew Huberman: Food, they were locked at the NIH. I've been to nih quite a bit. It's great for a day job or a day visit. I don't know that I want to be locked there. That sounds like the Stanford prisoner experiment.

Casey Means: I say this tongue in cheek and with such admiration for what he had to do, but I think it's so amusing that we have this totally franken food toxic food system that's largely ultra process. And it took amazing Kevin hall to basically do an NIH funded study where people, what I say by locked is that they were inpatients at the NIH and every had ad lib, unlimited access to food during each of those two week interventions. So it was two weeks of ultra processed food, two weeks of unprocessed or minimally processed food, and they could eat whatever they wanted, as much as they wanted in both groups. And then they would weigh every single bite that was left on their trays. They knew exactly, exactly how many calories they ate. And literally just giving people this ultra processed food, which is devoid of what our bodies need and therefore will drive people to eat more. They ate 500 calories more per day for a total of 7000 calories more in that two weeks. And they gained about two pounds and then lost two pounds in the unprocessed group, which makes sense, of course, because a pound is about 3500 calories. And so we have to do these kind of crazy studies just to prove what we kind of know is true, which is that this ultra processed food environment that's cropped up for the past 50 years is an experiment that has failed. It has failed. You know, close to 45% of kids are overweight or obese now. Like, it's not working. And that really is the root cause. So I think a lot of food is about quality and how do we actually really meet the needs of the cells so that our satiety hormones get secreted and we naturally stop eating. Because just telling people eat less calories, but eat whatever you want, that just doesn't work. We have to inspire the body to not want to eat excess calories, which we do by stimulating satiety hormones, you know, helping the microbiome support that process, and then change our reward circuitry, which is done with nutrient rich, the most nutrient rich food we can possibly get. And that's why I mentioned the soil, because our food is drastically depleted of nutrients. So when we look at that 70 metro tons of food reading in the lifetime, it's just fascinating. That's, that's the information for our body, what it's going to be built from, how it's going to function. Well, right now, 60% to 75% is ultra processed. So we slash the value because the ultra processing just like slashes the nutrients. We slash the value of that 70 metric tons. And then we have crappy soil because our industrial agriculture system, which means the food in some cases has 70% less of key micronutrients in it. So that 70 metric tons, what's actually useful for our body, becomes so much smaller. So what we want to do is basically expand the value of that substrate we're putting in the body. And that means real food, unprocessed from good soil, meet the needs of the cells naturally, don't be hungry, maintain a healthy weight. And, you know, something I talk about is that we could, I mean, we could talk about nutrition, the biochemistry of nutrition all day. But in my review of sort of the biology and the biochemistry, like, there's five main things I think we can strive for in our food that can really help meet the needs of our cells. And when it really comes, there are obviously more things our body needs. But if we strive for these five things, we will ultimately, I think, eat a really healthy diet. And that is fiber, omega three s, adequate healthy protein, a good amount of probiotics and high antioxidant sources. And if we build our diet around knowing a few things in each of those categories that we really love, and stock our kitchen with it and make our meals, a mixing and matching of each of those components, and we get a good amount of those, we will give the body a lot of what it needs to have mitochondrial health, reduce chronic inflammation, reduce oxidative stress.

Andrew Huberman: It's interesting for me to take a step back from nutrition as it's typically presented, and think about the brain, the hypothalamic circuitry that drives hunger and satiety and things like that, and to map that onto what I've heard and I believe to be true, based on my view of the literature, which is that we are largely, meaning these circuits in the brain make us largely amino acid foraging machines, because we need those amino acids in order to carry out metabolic processes and reconstruct any tissues that need repair and recovery, not just from exercise, but just daily turnover, removal of waste, et cetera. So we're foraging for amino acids unconsciously, we're foraging for micronutrients. And of course we need macronutrients. We need enough energy from proteins, fats and carbohydrates, or some either combination of the three. I feel like I'm sort of in the dying category of omnivores. I'm not meat based and I'm not plant based omnivores. I think most people are omnivores, actually, but omnivores aren't discussed quite as much as the other categories, at least not on social media, but that we think of ourselves as getting hungry and wanting to eat. And I think eating the foods, some of them that I listed off before, like meat and fish and eggs and vegetables and fruits. And some I do like starches, like rice, oatmeal, some pastas, some sourdough breads and things. I love butter. Who doesn't love butter? Of course, none of that stuff in excess olive oil. But if one looks at kind of that buffet of options, you realize you can get some high quality amino acids, you can get some high quality lipids. You probably want to get more of them from olive oil than from butter. But you can get the micronutrients you need, provided those food sources are healthy. Now, contrast that with a highly processed diet, or even a minimally processed diet, and you can get the taste, you can get the macronutrients, you can get the calories, but you don't, meaning the brain doesn't really have a sense of it can't directly map taste, calories, micronutrients onto one another. And so you can imagine that the neural circuits, and here is a little bit of hypothesizing conjecture, but that the neural circuits responsible for hunger and satiety would get immensely confused by what's in a highly processed food. A Snickers bar, if you like sweets, tastes pretty good, but it's unclear what's in it except sugar. Except it's got a certain snickers bar taste. Right? But if the circuits of the brain are really trying to drive us to get amino acids and micronutrients for bodily health and repair, well, then highly processed and even moderately processed food has just got to be pure confusion. Sorry to go long here, but it reminds me of an idea I had once where imagine if you took a pill that greatly increased the level of dopamine, norepinephrine, acetylcholine, and serotonin all at once, that's polypharmacology. And it might make you feel a certain way, maybe good, maybe bad. And then afterwards, you'd probably have a bit of a crash as the drug wore off. No doubt you would. But let's say you wanted more of that feeling. You wouldn't really know what to go look for because you don't know what was in it, because it's polypharmacology. So I feel like highly processed food is polypharmacology. Whereas when you are eating foods that create a more pure experience of micronutrients, amino acid content, calories, and taste, those four things map to one another, that intuitively we can start to understand, oh, I like this food, and it's good for me. And this is enough of it, right? I don't know anyone of reasonable size that eats, like, four rib eye steaks. You know, they eat one. I mean, I'm sure there's some freaks out there that do that, but one even small piece of quality meat is very satiating.

Casey Means: Yeah. You will self regulate, because the body, like every other animal in the world, is exquisitely designed to regulate hunger. On a very intuitive level, if we eat natural food, it's, you know, it's. I think it's almost ridiculous to talk about calories and isolation, because the reason we're eating more calories is because we're eating ultra processed food. And so. But I love what you just said, andrew, about the brain and the polypharmacy. I think that literally is. I've never heard that said. And I think it's like, processed food is like polypharmacy of food. It is the definition of processed food, which I know you talked about with rob Lustig. The Nova four criteria is, literally, it's breaking down foods into these constituent parts that were never meant to be separated from each other. Like the endosperm of a wheat kernel separate from the bran and the germ. And then take that, and like a little science experiment, pair it up with all these other individual components and synthetic chemicals that are made in a factory and put them together to create this thing that the body. I truly think our insatiable hunger, again, we're eating ourselves to death in the United States. That's the reality. Our insatiable hunger and our chronic disease epidemic fundamentally is a lot of it's mass cellular confusion. And when you think about what chronic inflammation is, chronic inflammation is biochemical fear on the cellular level. Well, when you put this stuff into the body that it's never seen before, obviously that's gonna generate some confusion. And, you know, you could trace that back to what that really means with leaky gut and, you know, all the sorts of the real physiology of that. But there's a wonderful book that is called the end of cravings by Mark Schatzer. He also wrote the Dorito effect, but he talks a little bit about what you're talking about is this ideal that processed food is actually the ultimate sort of food based variable reward. So in the way that it like, things that, I mean, I'm speaking expert here, but things that the body can't predict what the outcome is gonna be are gonna kind of get you in that dopamine motivation pathway. And that's actually what processed food is doing, is it's every time we eat a different. We think we're eating a tortilla, but it's like completely different than all the other weird tortillas, ultra processed tortillas on the shelf. So every time we eat tortilla and our brain is this incredible prediction machine, and as it's coming towards our mouth, we're predicting what the load is going to be, but we have no idea. Is it a coke zero? Is it a Diet Coke with aspartame? Is it a regular coke? It all tastes the same, but the nutrients that our gut are totally different. So we end up actually triggering the motivation pathways because of processed food representing a variable reward. Whereas every time you eat a rib eye, your body's pretty much getting a similar thing each time. And so the prediction matching is going to be more conducive to getting off the motivation treadmill for more, which I think is so fascinating. But I think backing up a little bit, one concept I have for food that really helps me is really thinking about the body's always trying to help me be satiated and trying to help reduce my cravings. I literally just have to give the body what it needs. I have to stimulate the body in a way that it will serve me in giving me satiety hormones to basically regulate my hunger. And again with visuals, I think it's so helpful. I think about these cells lining our small intestine that literally have nutrient sensors and literal receptors on the cell membrane in the luminal side of the gut that's facing all the food that are just sitting there, like, waiting to bind with these things in our food, that will stimulate the cell to make the satiety hormone that, poof, effortly makes us not hungry, gets rid of that grip of attachment to cravings that all of us are so plagued by. And I think we have this intense conversation happening in society right now about GLP one analogs and ozempic and manjara and all these things. But, like, you know, we rarely talk about the fact that, like, we have nutrient sensing cells of the gut, the l cells of the gut that when stimulated appropriately, will make GLP one and when stimulated the way they want to be, will secrete hoards of GLP one for us. And so how do we actually think about just literally giving the body what it needs to stimulate society? Hormones and the processed foods aren't giving us those things, you know, the things that are going to stimulate those cells well, the things that will. I mean, this is kind of fascinating, if you don't mind going down a little road.

Andrew Huberman: Nope.

Casey Means: Talking about. Yeah, please. With the GLP one conversation, I feel like so missing from the conversation is the idea that, like, from a first principles perspective, there's three ways our body could make more glp one. We make more cells that make it l cells of the gut. Each of those cells makes more glp one. And importantly, we can also inhibit the inactivator of glp one, which is an enzyme called dpp four. So glp one actually gets rapidly degraded by dpp four in the body. So if we can figure out how to inhibit dpp four, we can raise our glp one levels.

Andrew Huberman: What is dpp four?

Casey Means: It's an enzyme that breaks down glp one.

Andrew Huberman: Thanks for having me. I think you said that, and I missed it. I apologize.

Casey Means: So fascinating. And so, how often have you seen in the headlines, oh, here's some strategies to inhibit your dpp four, never. Because ozempic is on track to be the highest grossing med in human history. And just like we talked about in the beginning of the episode, the whole industry, this $4 trillion healthcare industry, is desperate for us to not understand how to do the things that drugs could do for us. So when we look at those three first principles, approaches of how do we make more l cells, get them to produce more glp one from each l cell, and then inhibit the breakdown through the. The inhibition of dpp four. For the first one, we know that short chain fatty acids, which, of course, are the byproduct of microbial fermentation of fiber in the diet, stimulates the differentiation of more l cells in the gut. So, more short chain fatty acids, more.

Andrew Huberman: L cells, can we translate that into support the gut microbiome?

Casey Means: Eat more fiber.

Andrew Huberman: Eat more fiber. And we had Justin Sonnenberg from Stanford on a world expert in gut microbiome, and he was a big proponent of, based on work he's done with Chris Gardner and others at Stanford. So happens, of ingesting one to three servings of low sugar fermented foods each day, things like sauerkraut, kimchi. Again, low sugar varieties, probably best kombucha. Yeah, maybe not. You said not kombucha.

Casey Means: Yeah, because that's going to be like the highest sugar of the fermented foods, which people often go to, but often costly, too.

Andrew Huberman: And pretty costly. The sauerkraut. You can actually make your own sauerkraut. Tim Ferriss had a great recipe for this in the four hour, chef, you have to be careful because you can create some unhealthy ferment. You have to do it the way he describes. So check out the recipe. It's online. Or you can buy sauerkraut and the brines. Drinking the brine off the sauerkraut or off seems to be good for the gut.

Casey Means: That's such a great point, which is that ultimately we want the short chain fatty acids, which is the, the medicine that the microbiome are making for us through the microbial fermentation process. And we can basically do that in three ways. One is we can eat more fiber, which is prebiotics. We can also eat more polyphenols, because we're now learning that the microbiome actually processes they ferment polyphenols from our, which is basically, you'll find those in colorful fruits and vegetables, spices, teas, cocoa, things like that. So, fermentation of polyphenols and fiber to short chain fatty acids, which then we absorb, um, and then, like you just said, in a fermented food, the bacteria in that food will be making short chain fatty acids by fermenting the food in there. And then if we drink that, we're getting the short chain fatty acids directly. So that's the kimchi, sauerkraut, uh, greek yogurt, kvas, which I'm obsessed with, which is like, low sugar kombucha. It's like, made with fermenting beets, basically.

Andrew Huberman: It's good stuff.

Casey Means: It's such good stuff. Miso natto. So that's one that has been shown to differentiate more l cells in the gut. We also know that people with type two diabetes have much fewer l cells in the gut. And it's hard to know what the causality is there. But I think a safe assumption is, like, if we keep our blood sugar under better control and sort of stay out of that diabetic range, it probably lends itself. I don't know what the chicken and the egg is there, but blood sugar stability, more l cell differentiation, and then actually ginseng has been shown to improve l cell differentiation. So that's just sort of one set of things. And I don't think the dose on ginseng has been settled, but very high antioxidant component plant. When we look at actually stimulating more glp one, you've talked about yerba mate, I think, having like, a, a mild effect on glp one. But there's actually a lot of other things in the literature. Protein, of course, very potently stimulates these nutrient receptor cells and specifically like valine and glutamine seem to have a potent stimulatory effect on glp. One. Interesting. So you're gonna find that in like meat and turkey and eggs and things like that.

Andrew Huberman: What are your thoughts on supplementing l glutamine? It's controversial. I know that some people do it in an effort to relieve leaky gut, but there aren't any randomized controlled trials for that. So depending on one stance on what's required for kind of a threshold for adopting something, some people say that's crazy. Other people really swear by supplementing l glutamine. Maybe it's through this route of increasing l cells that some of the gut relief might exist. I guess we'd have to explore it. So that's speculative, folks. So this is interesting. These are ways to increase the cells that then make glp one. So fiber, prebiotic, probiotic fiber and fermented.

Casey Means: Antioxidants, lowering blood sugar, ginseng. So those are kind of the l cell ones. The actual secretion of more glp one, one of the most potent ones. And the study that looks at this like the bar graphs are very clearly statistically significant. Lots of asterisks is actually thylakoids.

Andrew Huberman: Thylakoids. Tell me more about thylakoids.

Casey Means: Thylakoids are so fascinating. Thylakoids are actually a structure in plants that are part of the chloroplasts. So you know, chloroplasts. And this also is fascinating because chloroplasts are basically the plant version of mitochondria, essentially. And thylakoids are a molecule in the chloroplast. And there's actually been research that shows that when you eat about 100 grams of spinach, which gives you 5 grams of straight thylakoid over twelve weeks daily, it led to a significant increase in glp one. And again, I don't remember the exact, it was two or three fold higher secretion. So this is in part. So that's a direct stimulatory effect of the l cells. And so this equates to 3.5oz of spinach a day, which is like nothing. So just getting raw spinach or cooked spinach. I actually, I don't think it actually, it might have said in the methods, but I would imagine raw, because you want to get those undenatured thylakoids in the gut. So just kind of another. And actually thylakoids do a lot of other interesting stuff. They inhibit lipase in the gut and so actually help more fat get down to the distal small bowel and promote satiety. So this is one of the reasons why you talk about, oh, the people who eat all these healthy foods and greens, they're less hungry. It's like it's biochemistry. Like, there's stuff happening in there that is making the hunger signals go down through things like inhibiting lipase, improving glp, one secretion. So other things for GLP, one secretion, the thylakoids, also fibers been shown, specific amino acids. So high protein foods, things that involve a lot of valine and glutamine, green tea, and specifically the eclipse ECGC, that is one of the compounds in green tea that's been shown to stimulate GLP. One, curcumin. So there's several things that are all in that, like whole food, you know, basically things you would associate with a healthy diet. But we actually know they stimulate GLP one. So, you know, those are all things I try to include in my diet. And the last one is inhibition of DPP four. And that one, there's just actually, when you look at the research, there's some kind of random foods that tend to inhibit dpP. Four black beans, mexican oregano, other forms of oregano, rosemary, guava. And I wrote this one down because it's a word I hadn't seen very much before I started digging into this. But muricitin, which is found in berries, cranberries and peppers and swiss chard. So all that is to say, ultimately, many of us are gripped by cravings. And the idea of just sort of not being constantly driven to eat more, which I would argue that about 80% of Americans are, feels really hard to overcome. But a lot of it is literally just communicating to your cells in a clear way through food to help you be satiated. And the science can show us how to do this. And a lot of it comes down to eating, essentially what you were talking about, how you eat omnivorous protein, healthy sources with nutrient density, and lots of colorful fruits, vegetables, spices, herbs, things like that.

Andrew Huberman: Yeah, it's interesting. Again, these aren't randomized controlled trials, nor are they peer reviewed studies. But I have a few friends who I've known for most of my life who really struggled with their weight, carried a lot of excess weight, and were starting to suffer health issues in their, even their thirties. But in their forties, I'm 48, so they're my peers, and so they're about that age range. And they've all done extremely well, meaning they lost a tremendous amount of body fat, are terrifically healthy. Now, by way of basically restricting their food intake to proteins. So fish and meat, eggs, fruits and vegetables, they basically just cut out starches. But I don't think it was the starches per se. I think it was the satiety that comes from eating high quality protein, fruits and vegetables and from limiting the number of highly processed foods. And actually, the toughest thing for all of them was to stop asking me or themselves, rather, like, can I include this condiment, this, this. And what's interesting is all of them now seem to really enjoy eating foods in their more pure form. And I'm not somebody that, like, pushes this on. My friends, they just come to me and say, like, how do I lose 50 pounds without having to exercise it all off? You know, as the only source of weight loss? They all exercise as well, but it's just so daunting to try and lose, you know, 2030, 40 pounds and to do so quickly and then to keep it off because they've all had the experience of going on a diet and then exercising a lot. The point here is that I really think there's something powerful about that relationship between taste, macronutrient value, micronutrient value, and satiety. I think there's really those powerful associations because the brain is such an associative machine. One thing that I should have said before, and I know most people are familiar with Ozempic and its commercial names are, I forget what the Ozempic is.

Casey Means: The commercial name, and Munjaro and Wagovi.

Andrew Huberman: Got it, is that GLP one acts more or less as an appetite suppressant? Powerful appetite suppressant. So many millions of people are now taking GLP one analogs, is that right?

Casey Means: I think there were over 20 million prescriptions in the United States last year.

Andrew Huberman: Is it expensive?

Casey Means: It's $20,000 per year.

Andrew Huberman: Does insurance cover it?

Casey Means: Typically right now insurance is covering it for indications, but there is a all out assault from the pharmaceutical industry to essentially classify obesity as a genetic disease and a chronic disease in order to be able to feed this medication more into the insurance pathway and essentially get more taxpayer dollars to pay for this medication. And it is extremely expensive, and it's on track to be the highest grossing medication in human history because it's now being recommended for people with obesity, type two diabetes. And then the American Academy of Pediatrics recently has talked about giving this to children as young as twelve as part of the first line for overweight. And I think really, it's such a travesty. Based on the conversation, we've had, because what ozempic does not do in any way, shape, or form is impact the toxic environment that we're living in that's hurting our mitochondria. Losing weight is different than improving mitochondrial function. And mitochondrial dysfunction is the root cause of basically every chronic illness and symptom that's torturing american lives today. And so in many ways, it represents the ultimate band aid for an environment that is not changing. And when you think about what we could do with $20,000 per year, and it's a weekly injection, so people will say, well, per person, and it's a medication that is intended to be taken for life, because when people come off this medication, many people are gaining back all of the weight or even more weight afterwards. And then there's been conversations, Peter Attia has waited on this, about loss in lean mass. Part of the weight loss is disproportionately muscle. And so there's a lot of concerns about it above and beyond its ability to lower the number on the scale that we should all be very alert to. Because the reality is that the 40 trillion cells in our body are in an environment in the western world right now that is not conducive to core biologic functioning. And there is obviously no shot that can mitigate the multi front assault on our biology that ultimately generates a body that's immensely profitable for those hundred specialties of healthcare. So, you know, we're living in this matrix and this game of, you know, a devil's bargain between a $4 trillion healthcare and pharmaceutical industry and a $6 trillion processed food industry that all want us to think that, you know, the answer is found in a shot. And we don't need to change anything about our lifestyle. But of course, you know, these simple habits that we're talking about, eating real food, moving, walking, et cetera, getting out in the sunlight rapidly can increase our mitochondrial capacity. And, you know, are just the most disruptive thing that we can do, you know, in our culture today is. Is learn about metabolic health and improve it. And it's just interesting to see what's happening in the media with sort of the assault against these empowering habits and vary in favor of a medication like ozempic. And then when you trace, unfortunately, incentives, there a huge percentage of these outlets that cover ozempic as a miracle drug. Their bills are paid by pharma. 60% of mainstream media advertising budget is pharmacy. I just say that because I think it's a scandal that we give so much airtime to these medications and not two simple metabolic habits that can make us feel so incredible and really change our core biology.

Andrew Huberman: So walking, exercise, eating minimally processed or non processed foods. You also mentioned temperature. Yeah, very, very interested in that. But before we go a little bit further down the path of what one can do in terms of having agency over their metabolic health, I just feel obligated to just entertain the possibility. Presumably somebody who's really struggled with their weight a long time, maybe because of excess cravings, challenges in regulating their appetite or whatever. We don't know what the reasons are. Maybe they injured their knee and they can't exercise. I mean, this happens, at least not yet. Take a GLP analog like Ozempic. Loses some weight, probably loses some muscle also. One would hope that that would give them the sense of, okay, now I can move my body better, I'll start exercising, eating better as well. I think that I have to imagine that there's a middle case condition where people are not just relying on pharmaceuticals and not just relying on behavioral routes to improve metabolic health. Can do both, right? I mean, and one would hope they are, if they're already taking these meds. Or is it the case that when people have a pill or an injection or a potion that gives them the effect that they want, that they just remain sedentary?

Casey Means: I think we have to look at history here. I mean, first of all, there have been other weight loss medications throughout history that you've talked about in the podcast, like the fenfen. And then there was another one, I think even before that, that made people, their temperature go up. That you can.

Andrew Huberman: Yeah. So the two, these are. I used to work on thermal regulation as an undergraduate. Fen Phen was eventually banned because it caused some cardiac issues. I believe it was a stimulant, fenfluramine. Sorry, it's not fenfluramine alone. It's a combination of things. That's why it's called fen Phen. And then dinitrophenol, which was based on the observation that workers in ammunition factories were being exposed to this stuff and losing a lot of body fat and weight. It actually made its way into the sports community. It's highly deadly. Highly deadly. Just don't even. Don't even look it up. It's highly deadly because the moment people start looking it up, they start thinking about dabbling. The way the Internet is now, dinitrophenol. And I think it has to do with sort of processing of mitochondria. I think this is happening in the electron chains in mitochondria. So anyway, free electron. Look it up.

Casey Means: Excuse me.

Andrew Huberman: The bottom line here is that there have been plenty of drugs, mostly stimulants, used to help people lose weight or that have acted directly on the mitochondria. It has not worked out well historically, it just hasn't.

Casey Means: And I think that I'm not just gonna lump. It's a different mechanism, so I don't wanna lump it in with past weight loss drugs. However, if you look at the trends throughout history, the medicalization and pharmacology towards chronic issues has been an abject failure. I don't know of, and I'm sure people can correct in the comments, but of a single chronic condition for which the explosion of the pill to treat and manage that condition has lessened the rates of that condition. The more SSRI's you prescribe, the more depression we have, the more metformin we prescribe, the more type two diabetes rates are going up, the more ozempic is being prescribed. Obesity is going up. You know, this is on Wall street, they're not. This is on track to be a blockbuster drug, and they're not assuming the rates of obesity are going to go down. That wouldn't actually make sense for the business model. Model. I mean, these are being talked about at the JP Morgan healthcare conferences. Do you think they're thinking that this is gonna plummet? No. Like, there are, I can't think of very many chronic conditions for which the explosion of the medication has reduced the frequency of the disease. That's really something to think about. And the reason is, because of exactly what we started this conversation with, they're not actually truly impacting or healing the root cause physiology. In some cases, they're worsening that root cause physiology. Like they are inducing oxidative stress. They may help with the symptomatic management, but not actually reducing that trifecta that we talked about in the beginning. And so why do we have reason to believe that medicalizing obesity and not actually getting at the root cause, which has to be impacted by multimodal gentle nudges in our daily life habits and environment, that that's actually gonna reduce the rates of the condition?

Andrew Huberman: So, no, that's very helpful. Okay, so I'll then return to the other question about temperature. What are some things that can do with temperature? And by the way, as I do this, I can't resist any longer. Casey. Doctor means brought me this jar of blueberries. People that know me know that I'm a drive by blueberry eater. So if there's blueberries out on a table I'm gonna take some. I've never eaten during a podcast, but I'm going to now, so I'll try and chew quietly. Do you want some?

Casey Means: Sure.

Andrew Huberman: I love blueberries, and no, I don't eat them one by one, but I'm going to try and eat them quietly. So we'll keep them here in the middle for the time being, and I'm going to eat them by the handful just because I got hungry. And you mentioned berries earlier, and it triggered a neural circuit for me. So what about temperature? People that know me, or even that, just listen to the podcast, know that I like the cold shower thing, cold plunge thing. I don't do it every day. I don't do it after resistance training workouts for at least 6 hours, and mostly keep it on days separate from the resistance training, because there are some data that can inhibit hypertrophy and strength adaptations. But I like it. I like it. It feels good. I feel great afterwards for many hours. And I believe there are some health effects. And I'm willing to weather the storm of naysayers, because more and more data keep emerging that that's the case. Not all the data are spectacular. One paper on this actually was just retracted. We need to do an update to an episode to. It's not work from my lab, but I still think that there's a lot of really terrific work on deliberate cold exposure. What's the deal with temperature and mitochondria?

Casey Means: So, no one has basically described this better than you, I feel like, on your platform. But I think about it very, very simply. Throughout human history, humans have really, in so many different parts of the world, been exposed to hugely fluctuating temperatures. Like if you look at the Sahara desert or like a regular day in Colorado, it's like you can go from, let's talk about Sahara desert. You can go from 30 degrees to 110 degrees in the span of one day. And even the concept of indoors is a relatively new concept in human history. Four walls, insulation, then central heating and cooling. That's like the last 50, 75 years in most homes. And so this idea, our cells have evolved to respond to big swings in temperature that very recently we have totally pulled away. And I think that when I think about the mitochondria and increasing their capacity, I'm thinking about, well, how do I use different energetic signals in my environment to essentially get the mitochondria to do better work? And we can think about all the different types of energy that we're exposed to, solar energy, thermal energy, acoustic energy, mechanical energy, you know, food energy, like there's, there's. That's basically what our environment is, right? And thermal energy is a big one of those. We can speak to our mitochondria with the language of thermal energy and say, hey, it's cold outside, we need you to print more of yourselves or work harder such that we can create heat inside the body to respond to this stimulus. And so that's kind of the framing that I use for it. And, like, you know, this data is hard to know if it's totally accurate, but, like, our population is cooling and some, I think it was data Stanford, actually, that was showing that, like, our temperature has gone down like 2% or something like that in the last hundred years. And that fundamentally is mitochondria not working as well as they should. Research has shown we're making less ATP in a lot of our cells, and that's a function of mitochondrial dysfunction. One fun fact, I don't know if you knew this, but the body makes about 88 pounds of ATP per day for the average American. So we're constantly making it and we're constantly recycling it in this, basically, make it, use it, make it, use it, make it so fast that we essentially don't change our weight. And of course, as it's being broken down ATP to adp, we release heat. And so I just think of cold as like, one of the tools in our tool belt to talk to the mitochondria to say, make more heat. And in a world in which our mitochondria under siege, I think it's a valuable, often very inexpensive one that can. We can use. Of course, it does not supplement or replace food, sleep, exercise, but I think it can be a very valuable tool to stimulate, you know, through that signal to basically make more heat. And we know, of course it can help, and the data is mixed. But increased brown fat, which is mitochondrial dense fat, and have it do more work and whatnot. So ultimately, brown fat is mitochondrial dense fat, and we want to help promote that. So that's how I use cold. And then on the heat side, just fascinating how that's kind of acting to help metabolic health through the activation of the heat stock proteins, some of which have the ability to upregulate antioxidant defense systems and quell some of that wildfire that we talked about that can hurt our mitochondria. So I put them lesser on my list, but, you know, cause we just can't. We can't avoid the food and, you know, the sleep and the movement. But I think it's a great tool that we can use.

Andrew Huberman: I love it. I will just point out that the reason the brown fat is brown at all is because of the density of mitochondria. Literally brown down the microscope. This is not the kind of fat that is subcutaneous, although it sits around the scapula, neck, upper back. There's other pockets of it on the body, too. And such an interesting tissue. Yeah. I don't know why deliberate cold exposure is so controversial. I think it's because people who don't like it, and frankly, no one likes getting in it. The best part is getting out and how you feel afterwards. But I think nothing grates on people like deliberate cold exposure if they don't like deliberate cold exposure, and there's no requirement for it, I think it's a very interesting stimulus. And I think there's also a very interesting relationship between light and temperature, because in most areas of the world, as days get longer, meaning more sunlight available, temperatures go up, and nowadays, we can really divorce ourselves from all this day lengthening and shortening temperature fluctuations. Which is not to say that we should all be running around in a minimal amount of clothing outdoors, but there's just such beautiful data from Doctor Susanna Soberg's work showing, for instance, that deliberate cold exposure then leads to one feeling more comfortable at cold temperatures because you become essentially more of a furnace, more brown fat. Anyway, we could go on and on, but I think it's yet another lever of autonomy in terms of taking control of one's health. As you said, not as critical as food intake and quality, amount and maybe timing as well. Speaking of timing, what are your thoughts on fasting? And then, of course, movement and exercise?

Casey Means: The way I conceptualize the idea of fasting, obviously, this is one where we need more words. Right. Because the word fasting is so limited. There's so many different parts of this.

Andrew Huberman: But skipping breakfast, for me, would be that, or skipping dinner. Sometimes I'll skip dinner, sometimes I'll skip breakfast.

Casey Means: Right. I think that some of the most interesting data that I've seen has been about if we reasonably compress, are eating into daytime hours during the part of the diurnal cycle when we are supposed to be eating. So essentially matching our chronobiology with our behavior, which, you know, we are diurnal organisms, so we kind of need to respect that. Like, when we do that and we compress it in a moderate way, our metabolic health is better. And so some of the studies that have looked at this one that was interesting was, and I think very hopeful for people is that if you take all the food, all the calories that you're going to eat, and eat them in a six hour window versus a twelve hour window, totally same amount of calories, exact same food. This is a controlled experiment. People who eat the same amount of calories in a six hour period are going to have much lower, statistically significantly lower glucose, 24 hours glucose and insulin levels compared to people who just space it out over the course of a twelve hour period. And it makes sense because if you're spacing that food out over the course of 12 hours, that is a different biochemical milieu in your body throughout the day. It's kind of similar to the walking. You know, it's like you are then stimulating insulin several more times. You are exposing the bloodstream to insulin and glucose just more throughout the day and giving the bloodstream less of an opportunity to sort of be clear from that glucose and that insulin. And so compressing our eating window seems to be helpful for metabolic health. And it's a bang for your buck, right? Like you can eat the same amount of food, you just have to eat in a shorter period of time. So for people who want to eat, you know, a lot, maybe just consider compressing it into daytime hours. Six to eight hour window.

Andrew Huberman: Yeah. For me, six is tough.

Casey Means: Six is tough.

Andrew Huberman: The one meal per day thing is tough. I have friends like Lex Friedman that do the one meal per day. I end up eating so much food at that meal that I experience a lot of mechanical distress as typically later in the day. I think an eight to ten hour window has worked well for me most days. I know as soon as we talk about intermittent fasting or time restricted feeding, same thing, which is what we're talking about right now. I'm sure somebody's going to call up the. There's been a study that's been circulating about a massive increase in cardiovascular risk in people doing intermittent fasting. In particular, the six hour feeding window. I just want to point out, worst study as far as I know, I could be wrong, but as far as I know, that study is still in abstract form. It's not yet peer reviewed. It's like the fact that studies that haven't been peer reviewed aren't even close to being peer reviewed are being put out there as news stories is really problematic. Because I can tell you as somebody who sat on the editorial boards of many journals for many years, I still sit on a few, reviewed countless papers I've submitted and had to deal with reviews on countless papers. The fact of the matter is, like, until the reviews are done, the revisions are made. Like, that paper may never see the light of day, and it may end up in a journal that is barely worthy of a placemat. It might end up in a high tier, high quality journal, but it might not. So just because there was, quote unquote, a study done means very little, but it means especially little, maybe nothing, until it's peer reviewed.

Casey Means: Absolutely. And the methods were very poor in that study. It was a recall based study, I think, for two days of recall of people's diets, which is notoriously very bad in terms of accuracy. So, yeah, and I think I'm not in any way suggesting that a six hour window is the optimal window. I'm just sharing the data that suggests that compressing the window seems to have a favorable effect. And I certainly don't do 6 hours. But I think when you look at what the average American is doing, which is the average American has eleven eating events per day, and 50% of Americans eat over a 15 hours window per day. I can recall those because I remember when I was writing the book, I was like, that's a long time, 15 hours and eleven events. And every time you're doing that, you're going to be stimulating this glucose rise in the bloodstream, exposing the blood vessels to that glucose. You're going to be turning on all the pathways with insulin to basically store it, or, you know, and it's. So it's. It's strain for the body. And so I think giving the body times intentionally to allow insulin to come down and to allow glucose to come down, what that does is it generates metabolic flexibility. It gives our body an opportunity to have space to use accessible glucose and then convert into using stored fat. But be. And that ultimately, is metabolic flexibility. The ability for the body, giving the body opportunities to use glucose, but then have times when there's not high glucose and insulin around to actually get into the fat stores. And I think one of the reasons why we have such a massive overweight and obesity rates in the country is because with the culture of eating right now, eleven eating events per day, eating over the course of 15 hours per day, I would imagine the average american body is rarely, if ever, tapping into their fat stores for energy in a meaningful way, because we always have glucose available to the body. If you think about, again, the stats about ultra processed food, about 70% of the items on the shelves in the grocery store are ultra processed food. And those ultra processed foods are built on refined added sugars. And refined added grains. So we're just, we very rarely give the body the opportunity to rest and move into fat burning. And that's where compressing the eating window can be valuable. Obviously, people have talked about this before, but fasting can be a stressor for the body, especially if your body's not used to using fat for energy. And so it's something to ease into and go slow. But I think if you're slowing down enough to really hear what your body's signal are saying, you can kind of know whether I think your fasting is working for you or not. I can tell if I've got too many other things going on. I haven't slept well, a lot of stress. I can tell that fasting is kind of making me jittery and not feel good versus if I'm really, if I have good capacity, I can feel that it's actually making, making me feel really incredible. And so tune in with your body, obviously, and, you know, you can check your biomarkers if you have a CGM on, you can see what's happening in your glucose. If you have a ketone monitor, you can see what's happening to your ketones and really actually track, which I think makes fasting actually even, even more fun. I'll mention one other piece of data that I think is actually really kind of fun as well, with timing of eating. There was a study that looked at people who ate the exact same meal at 09:30 a.m. or 08:30 p.m. so basically after dark, essentially in the part of the diurnal phase when we probably shouldn't be eating, versus early in the morning 930. And the glucose and insulin responses for the same meal at 08:30 p.m. were significantly higher than when eating at 09:30 a.m. and so again, bang for your buck. It appears that eating in that earlier part of the day, when we're active and our chronobiology is set up for metabolism and activity, we have a lower glucose and insulin response. There's also some evidence that melatonin, which is secreted as we get closer to sleep, has somewhat of an effect on impairing our insulin sensitivity transiently. And so we may actually just be not absorbing the glucose from those meals effectively later at night. So I tend to move a little bit more low carb, I would say, throughout the day, based on that data and what I've seen on my continuous glucose monitor, basically just higher spikes for the same meal later in the day. So why not just kind of move it up earlier.

Andrew Huberman: Very interesting. Something I'll definitely try. I tend to push my carbohydrates to a little bit later in the day for sake of sleep, unless, of course, I've done resistance training, which I aim to do three times a week. And post resistance training, I try and get some starchy carbohydrate in me just to replenish glycogen, and that's then tends to reduce my carbohydrate craving later in the day. I love bread and butter, bread and olive oil pastas. And the other day, I found this argentine place, and I love the steaks there, but they had gnocchi that it took everything I had, every neural circuit that releases gaba inhibition to my brain. To not order three of those orders, it was so good.

Casey Means: But you can walk after the gnocchi.

Andrew Huberman: Oh, yeah, sure. I'll allow myself to do those things. I'm not super restricted, but again, I tend to eat high quality foods. By the way, these blueberries are amazing. Then you figure out where you got those, because they're just tangy enough. I'm doing everything I can to just not take the jar and funnel them into my mouth. Yeah, I think if we're looking at blood sugar, blood glucose and insulin, and as long as we're talking about that, I did use a levels tracker, and full disclosure, they're a sponsor of the podcast regularly. I learned a ton. I'll tell you what I learned. I learned that indeed, my blood sugar goes up after I eat that. Certain foods, although the foods that did this surprise me, certain foods tend to spike my blood sugar quite a bit. Grapes. That shouldn't be surprising. Food order was very powerful for me. I know that the data on food order are a little bit mixed, and it's controversial, but I like to eat like the French. I like some soup. Then I like my entree. I like the salad at the end. That turned out to have the steadiest and lowest rise in blood glucose for me. And then across time, I also found that I love hot sauna. I go so hot with the sauna that I've been accused by Rogan and other people. I'm gonna turn myself into a brisket. But after the sauna, my blood sugar spikes, presumably because I'm a bit dehydrated and it's the concentration of blood glucose. Is that possible? Does that make sense?

Casey Means: It does make sense, but also the heat can affect the accuracy of the sensor itself.

Andrew Huberman: Ah, okay, so that could be it, too. But, yeah, basically, what it allowed me to do is make a few adjustments in terms of foods that I eliminated, or eat less of food ordering within a meal. And I find that I'm very susceptible to, if I don't include enough fat, dietary fat, in the meal, then my blood glucose spikes, even if it's just like tuna. Right. But by including olive oil and other things, it really blunts it. And of course, here we're doing correlative anecdote data. But for me, I felt far better when I included a bit more fat. And when the food order was adjusted the way I mentioned before, always including a little bit of fiber, really helped. And that makes sense, right? Slow the absorption of the food, presumably. So I found that it was a very valuable experiment for me. Again, this isn't an advertisement. It just so happens I did this and really benefited from it. What are some other things that one can learn from continuous monitoring of blood glucose? What are some things to watch for that might signal a problem? And what are some fun things that one could do to explore and experiment? Because I like to explore and experiment.

Casey Means: Yeah, well, I mean, a lot of the things that you just naturally learned are the things that have been shown in data. And like you said, some of this data, it's like small studies, small groups of people. But, for instance, adding fat and fiber to meals has a significant and repeatable impact in populations on lowering glucose response. Fat probably in some part due to slowing gastric emptying and actually slowing the digestion process. So the rise in the bloodstream stream is going to slow down and then fiber, both for that reason, but also because fiber can, in a sense, create like a mesh, sort of blocking the absorption of some of the glucose that's in the meal. So literally kind of actually preventing you from absorbing all of the carbs. And we've actually seen that in the levels data set that the more fiber people include with their meals, we see essentially a direct relationship with lowering of their glucose excursions, which is really exciting because fiber is something that you can add to meals very easily. I put basil seeds, chia seeds, hemp seeds, flax seeds on a lot of my food at this point, because it's essentially a little bit of fat, a lot of fiber, and it's kind of just helps you kind of get more from your meal. So what you can learn. So I think, step one, the way I think about a glucose monitor, first of all, I'll say the purpose of the glucose monitor is not to have to game the system and get flat glucose. The purpose of the glucose monitor is curiosity. It's to start to understand how it's essentially an MRI for how all of our different dietary and lifestyle strategies are creating this readout of glucose in our body, which I think can be really interesting, and in a world where so many cards are stacked against us with diet and lifestyle, and where there's a lot of confusion about what's right for us, that can be, like, very helpful in actually reducing the confusion and the cognitive load of our choices. We know that keeping your blood sugar through the course of a lifetime in a low and healthy range. So I don't mean up and down spikes during the day, but keeping your blood sugar healthy throughout the course of your lifetime is probably the best thing we can do for longevity, staying insulin sensitive, staying out of the diabetic range. And so one thing that the glucose monitor does for us is just give us more awareness and agency into, like, what the trends of our glucose are over time, as opposed to a literally one data point snapshot once a year in the doctor's office, which is what the majority of us are used to. I really love the idea that people who are able to wear glucose monitors every now and again, maybe once a year, or maybe more than once a a year, they know what their glucose is, and so they're never going to walk into a doctor's office and have a bomb dropped on them about prediabetes or type two diabetes, because you have the data, which is ultimately, I hope, the world that we can move towards for a lot of biomarkers. So you can see trends over time, which I think is very valuable. One thing that's fascinating in terms of early prediction of metabolic disease, is that you can see how long it takes your glucose to come down after a meal. So in a normal, healthy, insulin sensitive body, even if the glucose goes way up, it should come way down very quickly. Cause the insulin is binding to insulin receptors and the glucose is getting taken up and it'll lower what is quickly.

Andrew Huberman: Over the course of it should be.

Casey Means: Down by 2 hours. But from what I've actually seen in our, like most insulin sensitive people, and also in research that looks at young, healthy populations, you should basically be spiking and coming down, spike about 45 minutes and come down hour and a half, 90 minutes to 2 hours.

Andrew Huberman: But if this is after. Sorry, after last bite.

Casey Means: After last bite, although it's hard to kind of exactly know, but, yeah, meal is over, I would say about 45 minutes to go up to the peak and then start coming down very quickly. Now if you start to see that glucose is going up and then trailing very slowly back down to normal, maybe taking more than 2 hours, 3 hours, that is going to be one of those early indicators of potential insulin resistance. Your body's not clearing the glucose, but that's not a metric that we use in standard practice at all. And I've actually seen myself very insulin sensitive. My insulin is like 2.5, and, you know, if I don't sleep and I am stressed and I have been sitting, my glucose will take way longer to come down. I have become transiently insulin resistant. So I think that's just fascinating to see. See that? So, looking what that ultimately, the metric that we call that is area under the curve. You want a low area under the curve, AUC, after a glucose spike. So you want to spike and come down quickly. That's going to. If you shade the area under the curve, it's a small amount. If you go up and then trail off for two to 3 hours, um, that's going to be a lot of shading under that curve. And high AUC is associated with insulin resistance. Basically. Another thing that you can see is essentially glycemic variability. And glycemic variability. GV is a metric of how spiky your curves are. Fasting paper out of Michael Schneider's lab at Stanford in 2018, called glucotypes, reveal new patterns of glucose dysregulation. Totally landmark study, but basically they put continuous glucose monitors on non diabetic individuals who, by standard criteria of diabetes, do not have diabetes. And he showed that on a CGM, a continuous glucose monitor, you have these low variability people that are pretty much flat throughout the day with little teeny rolling hills after their meals. You have moderately spiky people, and then you have very spiky people who are going up, down, up, down, up, down, up, down. When you correlate those different patterns of glycemic variability in non diabetic people, you find that the spikier they are, the worse their biomarkers are, metabolically across the board, insulin, triglycerides, et cetera. So basically, they're showing signs through variability of underlying dysfunction that you would never know from a standard test. Those are the people who I imagine are probably gonna go on to develop diseases, and yet, based on standard criteria, their doctor's telling them that they're fine, that they're all the same. So he also showed in that study that non diabetic individuals, when you have a CGM on, are going into the diabetic range and the pre diabetic range, a fairly significant amount. And we would never know that if you weren't, um, if you weren't actually tracking, like, a movie of the glucose. So that's so glycemic variability, um, area under the curve. Those are two things. Another really interesting thing you can know from a CGM is dawn effect. So dawn effect is basically a term in the literature for how high your glucose rises right when you wake up in the morning. I don't know if you noticed this when you were wearing a CGM, but some people noticed that the second they wake up, their glucose jumps up. 510, 2030 points. What's happening here is that the cortisol awakening response to actually get you to wake up and get out of bed, that cortisol can cause you to dump a bunch of glucose from your liver, because it's basically saying stress hormone, cortisol, we got to get up. We need glucose to fuel the muscles. Let's dump a little glucose so it's normal. But what the research shows is that magnitude of dawn effect is correlated with insulin resistance. So the more the dawn effect you're getting, I think it can signal maybe the more stress you're under, the more cortisol you have floating around, how big your cortisol awakening response is. But also, if you imagine if you're dumping all that glucose from your liver and your cells aren't taking it up well because you're insulin resistant, that response, that dawn effect is going to be higher. So I don't have the numbers right in front of me, but typically, I would want to see a dawn effect, I think of, like, less than ten points. So you wake up and you may very well see a rise. This is absence of any food yet, and you do not want to see that going up 20, 30, 40 points. Some people see a little bump, again with caffeine in the morning because it's more cortisol. And so that's another thing that standard stuff would never tell you. So those are kind of some of the looking at early predictors of metabolic dysfunction. More of the fun stuff is, like, actually just figuring out, like, how is food affecting your body? And this is where people really enjoy it and, like, figure out, like, oh, my God, this food that I thought was healthy is actually not serving me. And actually a lot of people, I think, who are trying to make healthy choices. My boyfriend, when we started dating, he started using levels. His healthy snack, he worked in Venice, would be to go to moon juice and get, oh, gosh, I don't want to throw moon juice under the bus here, but he would.

Andrew Huberman: They have some tasty stuff.

Casey Means: They do. But he would get this green juice that was sweetened with dates, and it was like dollar nine. And this is like, the healthy choice. And he saw the second he put on levels that it was causing a huge spike, like 50, 60, 70 points. And then he was crashing, and he was actually trying to make a good decision. So now he's swapped his snacks out for more, like, grass fed cheese and some flax crackers and maybe a venison stick or something like grab and go stuff that isn't spiking his glucose. But I think it can help people figure out which foods are doing what I want them to do and which maybe aren't. And same thing happened for so many of our members with oatmeal. Unfortunately, oatmeal, instant oatmeal, is one of the biggest spikers in our data set for breakfast. And a lot of people are making that choice because they think it's heart healthy. And in many people, it's actually causing a big glucose excursion and crash. And then in some other people, it's not. And so it's really helping with, what are the sneaky spikers? Where's the biochemical individuality? And there was a phenomenal paper out of Israel that from cell about seven years ago called personalized nutrition. By prediction of glycemic responses, it made big waves, but it basically showed that you and I could eat the same handful of blueberries and have totally different glycemic responses. So the idea of glycemic index as, like, a certain amount of food with a certain amount of glucose causes a certain glucose rise, it kind of debunked that. And that matters because repeated, sustained glycemic variability over time is not good for our health. We want to choose the foods or balance the foods that are going to keep us relatively more stable. So that's very helpful, just understanding your personal response to food. And then what are the lifestyle strategies you can use? Sleeping better, walking after meals, more resistance training, cold, plunging breath work that can actually serve to modulate the food environment to actually reduce the glucose spikes. And people find that all of those things can positively impact glucose spikes, especially the walks after the meals. But it's been fascinating to see a lot of women, especially like menopausal women in our community, who find that their glucose patterns are getting worse because estrogen's dropping, and that's gonna, you know, really take a hit on insulin sensitivity. They start resistance training, glucose comes kind of right back down. So because of the monitor, they can feel more confident in the intervention they've chose to do to help with metabolism, and that kind of creates a virtuous cycle. So, um. So those are some of the big things.

Andrew Huberman: Those are big.

Casey Means: Can I mention one more? I could obviously talk about this all day. I think it's fascinating. But this is just one more that I think is fascinating, because this was a paper in nature from last year that talked about, and this might actually be one of the most valuable things to people, which is that, again, talking about cravings. We all want to get off the craving grip. This paper in nature showed that essentially, when people spike their glucose with high carb, high starchy foods, they'll often have a big crash afterwards. And the reason for that is because a big spike leads to a lot of insulin secretion, and then you soak up all the glucose and sometimes you can actually go below your baseline. So a small spike usually won't lead to a crash, but a big spike often will. That's called reactive hypoglycemia. Postprandial hypoglycemia. A lot of people think they're dealing with hypoglycemia, when in fact, what they're really dealing with is that they're spiking their glucose too high and then they're crashing.

Andrew Huberman: I see.

Casey Means: And the paper showed that the extent of post meal dips, the crash after the spike, was predictive of 24 hours energy intake and cravings for carbohydrates. And this makes sense, if you crash low, that is a signal to your body. We have to get our glucose back up and it will drive you to eat high energy foods, carbohydrate rich foods and cravings. So one of the best things we can do to, I believe from my personal experience, from members experience and with some data to support this, is that one of the adjuncts we can use to monitor our. To manage our cravings is actually to, like, lower the extent of our spikes so that we crash less. And so that was a fascinating study looking at CGM data.

Andrew Huberman: That's interesting. So the CGMs can reveal things not just in the immediate meal period, but can relate to sort of downstream consequences. Yeah. Again, I found it to be tremendously useful. I'm so glad you mentioned sleep, by the way. I'm going to resist the temptation to rattle off 20 studies showing that, oh, God. Even having too much bright light in a room while one is sleeping at night, even dim light, which is I don't want to scare people into thinking they have to sleep in complete darkness, although an eye mask can be great, can alter morning blood glucose levels. I believe it was adults and kids as well. It was a study in proceedings in the National Academy of Sciences. I have to go back and check if it included kids, but pretty striking. And then there's something very clear about the fact that when people get the early night sleep of four to 5 hours, but then don't get the rem dominating last hour or two of sleep in the morning, that resting blood glucose is altered. It's so interesting to think about what's going on in sleep. There's at least one paper that I'm aware of where they had people breathing into a tube during sleep to measure what sorts of metabolism they were undergoing. And it's interesting, during a full night's sleep, all of us seem to transition between different forms of metabolism. I'll send you this paper, it's really cool and I'll put a link to it in the show note caption such that at one portion of the night we're relying more on, let's just call it sugars for sake of simplicity. Other times we're more ketone dominant. Market shifts in metabolism throughout the night. It's almost like the brain and body cycle through all the different modes of metabolism throughout the night, and then almost like a rehearsal of the metabolic pathways, if, you know, we can anthropomorphize a bit here. But then if sleep is truncated, it clearly has an effect on daytime fuel regulation. Just so. Interesting. So getting sufficient sleep, getting quality sleep is absolutely key. There's a lot for people to pay attention to, but you've given us a lot of tractable avenues for people to do that that are mostly behavioral. There's a few don'ts, but mostly some do's. We haven't mentioned that you don't need to even perhaps belong to a gym. And with the cold exposure thing, I always say if anything, it'll save you money on the heating bill. There's a literally potential negative cost there. I think levels and other cgms are really interesting and valuable to experiment with. What sorts of other stuff is going to soon be monitored in our blood? Because, for instance, I would love to know continuous hormone levels, lipid levels, blood sugar levels. I mean, are we moving past just blood glucose? And are there soon to be other things in these monitors? So that when we. And by the way, if you haven't used this, it's really cool. You just take your phone, you scan it over the sensor, and then it basically gives you a chart graph of what's going on in your bloodstream.

Casey Means: And now they're all the latest gen of each of them are all Bluetooth now. So no more scanning, which is kind of nice. And the answer is yes. There are several different analytes that we're going to be able to track. And Abbott, which is one of the three main manufacturers of cgMs, has announced that they have a new product called the Lingo, which is going to actually be able to measure ketones, lactate and alcohol continuously, which is pretty interesting from a metabolic, comprehensive metabolic standpoint. Different sensors for each, not all in one. So I think we'll have to polka dot ourselves if we're tracking all those things. And then Dexcom, which is the other main company that makes cgms, has just announced that they're coming out with an over the counter, non prescription version of a CGM called the Stella later this year. So there's exciting things happening in the industry, and I really do think continuous monitoring, it's gonna expand to a lot of these other things that you're talking about, hormones, et cetera. And, I mean, it really needs to. I think that snapshots of dynamic system are just never gonna really be able to give us a full picture on what's going on. And what we really wanna be able to do to dig our way out of this healthcare crisis, I think, is empowerment individually and understanding how this rapidly changing environment is affecting our own biology so we can make the targeted choices to hopefully change the environment to be more conducive to cellular health. And continuous monitoring is a closed loop biofeedback that can help us with that decision making and essentially predict failure of the system, rather than wait for failure of the system before we do something about it. So, yeah, I think lots coming down the pipeline.

Andrew Huberman: Love it.

Casey Means: Yeah.

Andrew Huberman: Let's talk a little bit about mindset. This is a really interesting topic that you include in your book. We've had guests come on and talk about growth mindset. Stress can be enhancing mindset. I'm big on mindset because I'm interested in how our cognitive reframing or cognitive framing can just change the way our biology works, and vice versa, of course. But you talk about mindset in a certain context. And one of the favorite passages around that that I really enjoyed was the relationship between kind of like trying to control everything and nature, you know, and how getting into nature itself can be valuable for us. So maybe touch a little bit on mindset, if you will. And what are your thoughts on nature literally getting out of doors?

Casey Means: Yeah. So I think that mindset, and more broadly than mindset, I think psychology and our relationship specifically with fear and control, I think they're probably the most under recognized thing that is impacting the metabolic health crisis, the chronic disease epidemic. There has been data that's looked into this. We know that there's studies showing that loneliness impacts mitochondrial function and that loneliness is a risk factor and stress is a risk factor in these things. And something really fascinating, actually, with the CGM data, is that many people who wear a CGM, I don't know if you saw this, but when you feel stressed, it actually has a diabetogenic effect. It literally causes our blood sugar to go up when we feel stress. And that can be a fascinating unlock for people to realize. I kind of feel like I'm okay right now, but my body is telling me something different. It's telling me that biochemically, I'm actually releasing energy stores from my liver glucose to fight some threat that I wasn't really aware of. So we definitely understand there's this link here, but it's certainly not made its way into clinical practice. So the way I think about it is that what we know about the cells, and especially the mitochondria, is that the mitochondria are more than the powerhouses of the cell. They actually are, are a part of the cell that is constantly tracking resources and threats and are basically modulating energy resources based on that. And the threats can be anything. They can be a virus, they can be. And this is all coordinated through this thing called the cell danger response. It can be a virus, it can be a toxin in the environment. It can be lack of micronutrients for the electron transport chain that it needs to do its function. It can also be psychological threats, because, of course, our psychological milieu translates through nerves and hormones and neurotransmitters and our microbiome to affect our cellular biology throughout our whole body. Our cells hear every single thought that we're thinking through biochemistry. And when a cell and a mitochondria are getting the message that there is a threat or something to be afraid of, they are going to change metabolic function towards defense. Alarm, threat response, and away from repair, homeostasis building, essentially thriving. And I think what's really maybe the most unnatural thing about our modern world. The food, of course, is unnatural, 70% is ultra processed. But we also have this device in our hands, literally with us all the time. Streaming fear inducing media into our brains and eyeballs every waking moment of the day, if we let it. So we're glued to our screens and our devices, and right now, essentially, the traumas and fears of 8 billion people all over an entire globe are now ours to process. And our cells and our mitochondria, there is no escaping it. They are going to respond to that. And so I think a big part of the metabolic health conversation is how do we create a sense of safety in our bodies, no matter what is happening outside of our bodies? And this can come down to every person's journey will be different for this, because the things that cause a sense of threat or fear for any two people are going to be different. And I think some of the main categories is one unresolved childhood trauma, like, something that I think is getting a lot more talked about these days, but, like, what's embedded in our nervous system, these limiting beliefs and memories that are really wired, that create a sense of hyper vigilance in us, sort of all the time. What's coming in through our devices, our phones, our computers, the media that we're exposed to, that's constantly giving a fear signal. And I think on a broader level, a big western one that we don't talk about is literally like existential fear of mortality. We have a very despiritualized, very uniquely death fearing culture. Like you look at other cultures, eastern, indigenous, the stoics, they all had intense curiosity about death. We talk about the cycles of life. There's this real engagement with it that we are so afraid of in the western system, to the extent that our entire healthcare system actually, I think, you know, we've built it around, like, we're not gonna.

Andrew Huberman: We're.

Casey Means: We're not gonna help you thrive. We're just gonna do whatever we can to make sure you don't die. Like, that's. It's built in everywhere. And so we've got the devices, we've got the childhood trauma, we've got the fear of mortality. We have a very poor system of mental health care in the culture. And I think that through all these things, Americans are getting crushed, mindset and psychology wise. And that is a big, big trigger of our mitochondria, essentially diverting resources towards defense, threat, and alarm, rather than homeostasis, building repair. So, again, it comes back to taking really honest stock of what are the true fear triggers in our lives, across those and others, and creating a sense of safety in our minds and bodies, no matter what the external world looks like, which may mean, putting boundaries up to the media, doing the therapy, doing the different modalities. What I believe and I talk about in the book, getting back to the question about nature, is one of the best things that we can do is actually literally just go outside. And it sounds so simple, but one of the most astonishing stats I literally found in researching this entire book was that the average American is spending 93.7% of their time indoors.

Andrew Huberman: Wild.

Casey Means: 93.7. That's in a car or in a building. So we are locked in these cages, staring at fear inducing media. And our mitochondria are like, what? Like, I don't know where to channel my energy. It's just. It's short circuiting. I think so many things happen when we go outside, as, you know. I mean, even what the vision system is doing to our anxiety levels. We are getting sunlight, which, of course, for, you know, complex reasons, is very helpful for our metabolic health. Separately, in trains, our chronobiology and light from the sun is an incredible regulator of our mitochondrial function. But also, it's our best teacher. When we're out in nature and we really look at how beautiful the world is and the cycles of nature, we see the cycles of the seasons, and we see the awe of the sun and the trees and just this. All this alchemy that's happening outside of us. We see spring to summer to fall to winter. We see the tides moving in and out. Everything's in phases. And I think when we reflect and meditate on all the cycles and the polarities in nature, night and day, cold and hot, new moon, quarter moon, full moon, all these things, it's actually. It entrenches on a subconscious and conscious level that there is a fundamental harmony and pattern to the world we're living in that is bigger than us, and that is fundamentally good and beautiful. And we are locked inside of the four walls of our house, I think we get very scared, we get very controllable. And the system wants it that way, because when we are scared and when we are existentially afraid, we will literally do anything, we will buy anything, do anything, watch anything that will in some way ameliorate that pain that we're feeling. And we will take any pill, we'll get any surgery, anything that makes us feel like we're controlling this seemingly out of control situation. And that's what drives us into all the dopamine loops, you know, the social media, the processed food, the porn, the gambling, the alcohol, all of it. It's all to ameliorate. I think ultimately fear. And I think, yeah, I think by actually really just spending a lot more time trying to get that 93.7% down to, like, 50%, spend as much time as you can outside. We know that people who spend more time outside are metabolically healthier. And I think it's from pleiotropic reasons. But I think one of it is that it is the ultimate convincing of abundance and fundamental abundance in our world, and of awe, which I think is really the antidote to fear. And that has a profoundly soothing effect on our psychology and the sense of scarcity that drives a lot of the decisions that actually make us unhealthy. It's fundamentally rooted in scarcity. And I think also when we realize we are part of nature, again, going back to that taoist statement, we're a process, not an entity, realizing, like, you know, all the trees around us, and we take that walk, even in a city, we see all the trees, all those plants, all those leaves are making the oxygen, that process that literally let us do oxy phosphorylation, and that sun and that leaf on the tree. The sun's energy is literally being stored in the carbon carbon bonds that the plants are generating in photosynthesis. That ultimately all metabolism is. Is unlocking the potential energy stored from the sun to create the human energy that lets us love and move and live and think, do all the things we love to do. And then it just becomes so obvious. Like, of course we have to, like, eat real food, and of course, we have to not poison our soil with pesticides. And of course, we have to, like, you know, care about the environment, and we have to get outside and move, and we have to be in the sunlight during the day, because we are the environment. We are a process that's constantly in dynamic conversation with it. And I think a lot of people will find that their health gets a lot better if they spend radically more time outdoors. And I think a lot of people might say, well, I can't. I work on a computer. And I'm like, you know, Rome is burning. Like, we're sick as hell right now. We need to get creative. Like, move your computer outside, take a walking meeting, open your mail outdoors, chop your vegetables on your balcony at your apartment. Like, we have to find a way to connect back with our source, understand that the world is abundant and harmonious, re entrench the belief in our connection with nature, and then let all of our dietary and lifestyle strategies stem from that sense of gratitude and awe. And that will lead us right where we need to go, which is a really, I think, joyful experience of our health journey that's rooted fundamentally in connection, rather than us being siloed from all of this, which, going back to the end of the conversation, that's fundamentally what's wrong with the healthcare system. It silos, and we have siloed ourself from all of the life giving things in our environment. And that has ultimately led us to be very, very, very sick. And we just. I think we gotta go back outside. So that's one of the things. But there's many other things we can do to change those. Our relationship with fear, but we can't change the world as a whole, but we can change what happens inside our body in terms of how we respond to it. And for our mitochondria's sake, we have to. We have to create a sense of safety in our bodies for our mitochondria to do the work we need them to do for health.

Andrew Huberman: I love it, and I love it for many reasons. I think. I know. It was my friend and former guest on this podcast, Rick Rubin, who several times, early in our friendship, he said, back to nature, the only truth. And I asked him what he meant by that, because Rick can be a little bit cryptic sometimes. Not always, but sometimes. And what he was saying is, it's a real thing. You can immediately feel the connectedness between the human experience and life of other types, plants, animals, sunlight, the circadian rhythms, and the rhythms of light and dark, because they impact us so powerfully. I mean, if there were ever a force in the world that impacts how we feel, it's the circadian rhythm. It's the rising and setting of the sun. It's on the impact of light and dark. And then all the other things that you talked about today, I can't help but reflect on kind of your take on kind of what a lot of not all, but a lot of modern society attempts to do. It attempts to do a lot of good things, too. I believe. I'm a believer in technology, but that it, if I were to translate, it sounded like what you were saying is that it gives us a sense of loss of control by instilling fear like we don't have control. And then there are a number of, let's just call them programs in the world that then sell back the illusion of some sense of agency, little by little, temporary agency, and then puts you back into the cycle. And there's something about going into nature which just removes one from all of that, at least temporarily, gives you a more basic understanding of the relationship to self and things around us. Even just looking, being able to see it to a distance we know is powerful for the brain, reducing anxiety. We know being outdoors for 2 hours or more per day reduces myopia, nearsightedness. This is independent of all the other effects of. Of circadian rhythms, et cetera. Anyway, and on and on. So I second and third, and hear, hear all the statements you made before. I also just have to say I really appreciate how you are able to tackle the cellular biology, the molecular biology, the macroscopic things that we can all do. Walking, resistance training, cold exposure, sleep, high intensity interval training, and make a case for each and all of those as it relates to the underlying biochemistry. And weave all that together in a way that then you beautifully wrapped into this idea of connecting to nature and not divorcing ourselves from modern life, but really looking at the ways in which certain components of modern life are really making us sick. Not just the behaviors, not just the do's and the don'ts, that it's kind of imparting on us, but also kind of the psychology around it. That it is quietly but powerfully oppressive is the message that I'm getting and that we have to take a stand against it. And the way to take a stand against it is to do what are very basic and fairly easy to access things, making better choices about food, timing, quality, amount, exercise, and on and on. So I'm running long in my response to your much more eloquent description of mindset. But what I want to say is, on behalf of myself and everyone listening, I so appreciate. We appreciate the work that you're doing to be a medical doctor specialized in one of these silos, and then to take a step out and say, nope, not me, I'm going to do what I see as best for the greater good in terms of giving people tools, giving people a sense of agency and autonomy to take control of their health. This is in some ways a heretical idea, but luckily, the numbers of folks like you are growing and you're a real leader in this field by example and by the incredible work you're doing with technology and information sharing. Love, love the book. I did go through it front to back. I haven't tried the recipes yet, but thank you for bringing the blueberries. I'll try the recipes, at least one of them. And I just want to thank you for sharing what you do, for continuing to do what you do. We need it and we appreciate it. So thank you.

Casey Means: Thank you.

Andrew Huberman: Thank you for joining me for today's discussion about metabolic function with Doctor Casey means 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 subscribe to the podcast on both Spotify and Apple. And on both Spotify and Apple. You can leave us up to a five star review. Please 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 topics or guests that you'd like me to consider for the Huberman Lab podcast, please put those in the comment section on YouTube. I do read all the comments if you're not already following me. On social media I am Huberman Lab on all social media platforms. So that's Instagram, Facebook, X threads, and LinkedIn. And on all those platforms I discuss science and science related tools, some of which overlaps with the content of the Huberman Lab podcast, but much of which is distinct from the content on the Huberman Lab podcast. Again, that's Huberman Lab on all social media channels. If you haven't already subscribed to our neural network newsletter, our neural network newsletter is a zero cost monthly newsletter that includes podcast summaries as well as protocols in the form of brief one to three page PDF's that cover everything from learning and neuroplasticity or how to improve your sleep, optimizing dopamine, deliberate cold exposure, deliberate heat exposure. There's a foundational fitness protocol, all available, completely zero cost. You simply go to comma, go to the menu tab, scroll down to newsletter, and enter your email. And I should mention that we do not share your email with anybody. Thank you for joining me for today's discussion about metabolic health with Doctor Casey means. And last, but certainly not least, thank you for your interest in science.

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