Does Most Chronic Disease Come Down to "Energy Flow?" | Greg Mushen & Josh Clemente

Greg Mushen is a technologist and systems thinker with over 20 years of experience building products in the tech industry. His most significant recent engineering project has been his own biology — after conventional medicine fell short and he experienced complications from mold exposure and chronic fatigue, Mushen applied his engineering background to debugging what he calls the most complex system in the universe: the human body. He taught himself to read primary literature, leveraged AI to validate statistical significance in studies, and began synthesizing broad research areas into systems models that explain chronic disease, metabolic health, and longevity. He writes about his findings on X as @GregMushen and on his Substack, Dark Lab.

In this conversation with Levels co-founder Josh Clemente, Mushen lays out his unified theory of metabolic health around a concept he calls flux — the capacity of biological systems to move energy substrates and signals efficiently under varying conditions. The conversation covers why insulin resistance is best understood as a flux problem rather than a blood sugar problem, what subsistence populations like the Hadza, Maasai, Chimane, Amish, and Pima teach us about physical activity thresholds and chronic disease, why walking may be the most underrated metabolic intervention, how lipid kinetics explains what most people get wrong about LDL and statins, and what Mushen's own personal health stack looks like.

"We think of insulin resistance and diabetes as a blood sugar problem, but it's not — at its root cause — a blood sugar problem. The blood sugar is a result of not having good insulin signaling in the first place." — Greg Mushen

Background: a medical family, a tech career, and a wake-up call

Josh Clemente: How did you get here? Tell us a little bit about yourself — what is "here" and what's the path that led you from your background to where we are right now, talking about the things we're talking about?

Greg Mushen: I think it kind of started at a very young age. I grew up in a medical family — my father was an MD, my mother was a nurse. So I was always really interested in medicine, always asking questions about the human body. He had this huge medical library and this amazing memory — he would be able to tell me, "Oh yeah, it's in this book, in this chapter, on this page," and he just remembered. So I always had this interest in medicine.

And then my dad was always — he was kind of like one of the OG biohackers, I would say, because he was always running experiments. I remember the first time I saw him taking a sample of his urine pH, and I was like, "What are you doing?" And he explained it. He was always doing these experiments.

I remember one time — it was in the '90s when people thought that just any kind of fat was the cause of cholesterol — and he had FH, familial hypercholesterolemia. So for a month he decided to remove all fat from his diet. And you might imagine how that went. From that, we had different conclusions. He concluded that there was nothing that could be done to lower cholesterol with diet. And I concluded that fat looks like it's really important, because he was jaundiced and had flaky skin and stuff like that. So that was kind of the intro to experimentation, I guess.

But I was always reading books on how things worked as a kid, teaching myself to program. I always had this interest in understanding and learning how things work. As I progressed in my tech career, I'd always had this interest in health and was always trying — I wouldn't say optimize, but just do as best I could. Was always reading books on it.

But I think things really changed about 10 years ago when I had a daughter. We got pregnant when I was 40 and I started doing some math, and I'm like, "Wow, I'm not going to have much time with her unless I really kind of clean things up and do the best I can." And what really hit me was I went to this wedding. There was a bride, she was in her 40s, and her dad wasn't there to walk her down the aisle. She actually stopped the wedding and talked about that a little bit, and that really hit me in a very big way — to think that unless I was as careful as I could be, I'd just be limiting the amount of time with my daughter. So that was really the impetus for getting to where I am now.

Josh Clemente: I love that intro and some of those anecdotes about your dad are incredible. It makes a lot of sense hearing that background, because the work that I see you do is just this incredible synthesis of lots of different areas into these mega threads. I'm really curious how you started your own process.

And I had my son — my first child — last year.

Greg Mushen: Oh, congratulations.

Josh Clemente: Thank you. And I feel it changing my perspective as well. It consolidates everything into reality.

Greg Mushen: Sure does. It changes your why in a big way.

Josh Clemente: It sounds like you had a bit of a health awakening in your 40s. Tell us about that — what did that look like, how did you achieve it, walk us through that whole health journey.

Greg Mushen: Well, I had always focused really highly on my health and fitness and everything like that. But during COVID, I think like a lot of people, I became a little bit more sedentary. And two things happened. One, I realized that I was almost 200 pounds — I stepped on the scale and it was 199. I was like, "There's no way I'm crossing that threshold unless it's muscle."

And then the second thing was I had been working on a project where I got exposed to mold, and that resulted in a lot of health issues because it was a pretty bad exposure. But one of those was just kind of almost crippling depression, which can be one of the common symptoms with that.

So my quality of life was really low and these two things happened around the same time. I remember sitting down and thinking, "How do I solve this? What are the lifestyle levers I can pull? I know what they are. I just need to prioritize them."

And this actually led into how I started posting, because I'd never really posted anywhere before. But during this process, I had asked ChatGPT how to get me addicted to running. And so I told one of my business partners the story. He was like, "That's so cool, you should post that on Twitter." And I was like, "Okay, yeah, that's a good idea." I ended up writing this thread — it was late on a Friday night — and I just went to bed and I woke up and all of a sudden my notifications were just blowing up. It had gone viral.

I remember I was at the park with my daughter and I saw that Greg Brockman had quote-tweeted it. But it wasn't necessarily the exposure that motivated me to do more of it. What I realized was I would get all these DMs like weeks later — "Oh my gosh, like you really inspired me and I want to let you know that I lost like 15 pounds, 20 pounds. It really changed my life." And so that's what motivated me to start posting more — just that it could have an impact on people.

Mold, copper, and learning to go deep

Josh Clemente: I want to make sure we really explore the mold story just a little bit deeper. Mold is one of those things that's kind of a little bit nebulous, honestly, in my opinion. There's a lot of talk of it but people don't really know how to think about it. Recently we've got some examples being talked about very widely, like Chris Williamson seems to have had a major exposure. And it is testable — it's showing up in the body. So I'd love to hear what testing did you do and how do you fix that problem?

Greg Mushen: So this is really one of those areas where it's good to see an expert, because there can be different ways of testing to try to determine if you have mold exposure, what kind of mold it is, and then depending on the specific type of mold, there might be specific treatments. And I'm not an expert in this area — I haven't gone deep in it because I just kind of fixed my problem acutely and forgot about it.

But what we did was there is a urine test — I can't remember the exact name of the company, I can look it up and add it to the show notes. I took that test and found that I was basically off the charts on one specific kind of mold, and there was medication that could be taken for that one. It was like an antifungal, so I took that to reduce it. But it really depends on how large your exposure is, what kind of mold it is, and whether it can be treated by medication. If so, which kind, or are there other ways to clear it just by removing exposure? Got to find an expert. They're actually kind of hard to find. There aren't too many people that really specialize in it. But if you find that you have it, seeking out somebody who really knows how to treat it is a good idea. It'll just accelerate the process.

Josh Clemente: What was the healing process like? Once you started the medication, did symptoms just sort of vanish? What was the time frame after which you said, "This is a solved problem"?

Greg Mushen: It was probably about three months. And there were some complications with it because the specific kind of mold I had — and this is actually right where we found it — but it can trigger activation of Epstein-Barr virus. And Epstein-Barr virus for those that don't know is just kind of like the latent version of mononucleosis, or mono. So when it reactivates, you kind of have the same symptoms of mono. And so I was just like tired all the time, like, "What the heck is going on?" And luckily my doctor knew to test that too. We found the EBV, and once we got both of those under control — probably over the course of about three months — I just felt like a brand new person.

Josh Clemente: Hopefully that gives some hope to people who maybe are feeling that sort of chronic fatigue. I'm in Austin, Texas, and it seems to be really really prevalent here.

Greg Mushen: Mold can show up in a lot of areas where you wouldn't expect. It's really common in Arizona of all places, and you'd be like, "It's so dry there, how could mold be a problem?" But it's really the AC, and what material is the house built from, and is that going to cause condensation, will that condensation cause mold. It can happen in a lot of places you wouldn't think.

Josh Clemente: It's actually not the climate, it's how the structures are built and whether they're built to manage the climate modification we do. This is an area that we're going to learn a ton more about over the next few years, and probably realize that a huge volume of chronic issues people are experiencing could be related — mold is such a broad genus, there's so much going on there. You can't really think of it as a single viral vector.

Josh Clemente: You mentioned that copper was low and copper can impact neurotransmitters — and fixing your copper level was a material decrease in the depression symptoms. That was a big moment for you.

Greg Mushen: It was a big moment because I realized — wow, if copper can have that big of an impact, what are all the other vitamins and minerals that I'm also short on that have a similar impact? So that's kind of where I started doing deep dives, going deep into all the vitamins and minerals and learning how they interacted together.

And then when we kind of exhausted all possibilities, my doctor said, "I had a mold issue when I was in Seattle and I had very similar symptoms to you. We've tested everything. What would you think about testing that?" So we tested, and sure enough it was basically off the charts on mold. We addressed that and it quickly fixed everything.

And mold wasn't really talked about a lot, and it wasn't something I had personally tracked, and that got me really interested in — what else am I missing? And I guess there's a third now that I think of it. I was in the process of doing a body transformation, and that kind of got me interested in fuel systems — how does the body choose which fuel to use, and how does that change under different conditions of caloric deficit, caloric surplus and things like that. That's what got me really interested in fuel and flux.

Josh Clemente: So that was where the rabbit hole fully opened.

Greg Mushen: Yeah, that's where it just went wide open.

The theory of flux: insulin resistance is a clearance problem

Josh Clemente: What are your current strongest held opinions? You talked about flux just briefly — tell me what are you thinking most about, what are your most excited areas of research right now?

Greg Mushen: I'll kind of start broadly. It's kind of two things that are closely related — longevity, which really is in a lot of ways how long can you ward off chronic disease, and then chronic disease by extension. And if you think about chronic disease, the most important lever in that is metabolic health. That has led me to do a lot of study in populations that don't have a lot of chronic disease, which would be a lot of the subsistence populations — or hunter-gatherers, even though not all subsistence populations are hunter-gatherers, but that's a common term people use.

And then also trying to figure out why, because I think that unfortunately disciplines in science don't have a tendency to really work together all that much. So you have the anthropologists that will study these populations but they may not be experts in exercise science or metabolic health in general, or they may not understand lipids. And what ends up happening there is you kind of have people reaching conclusions that may not survive scientific scrutiny, or you end up with paradoxes that people just throw up their hands and can't explain.

One really popular one is the Maasai. They're in Africa and they eat a lot of saturated fat — it can be up to like 100 grams per day — but they have very little heart disease. And there haven't been a lot of studies to determine why. Other populations that have very different diets also have lower heart disease or lower coronary artery calcification. There isn't a lot of bridging, and so you end up with a lot of people just throwing up their hands and calling it a paradox, or reaching conclusions that maybe just haven't gone through all the different mechanisms.

Josh Clemente: What I think you're doing is bridging the frustrations of so many people who will read these seemingly conflicting articles or research headlines. People have a certain specialty and they'll study a certain mechanism or phenomenon and publish from their perspective without the requisite information or without working to unify with other previously held positions. And so you end up with these situations like — eggs are good for you, eggs are bad for you. So people tear their hair out and say, "I don't know, I'm going to pay no more attention, I'm just going to do what works for me."

What you're doing well is synthesizing lots of information and explaining how things connect — putting forth maybe hypotheses, but in many cases clear explanations of how these different studies connect to one another and how a model emerges from them. So tell me — what is your number one theory of health and longevity right now?

Greg Mushen: If I were to boil it down to one thing, it is metabolic health. But I think the most important thing there is insulin resistance. For example — do you know what the number one risk factor for heart disease is? It's insulin resistance.

Josh Clemente: Can you tease that apart a little more? Would that be the number one risk factor for plaque formation?

Greg Mushen: This is where the nuance comes in. If you look at just risk factors on their own, insulin resistance is by far the number one thing for heart disease. And LDL is still definitely a risk factor, but if you're just looking at risk factors statically, it is much lower — that does not mean it's not important. Blood pressure is in there, obesity. But if you look at all of these things, one could come to a conclusion and say, okay, you need to treat insulin resistance number one, get your blood pressure down, get your weight down, and obviously treat your LDL. But what a lot of people are missing is that they're all part of the same system.

We have a tendency to silo these different symptoms and treat them differently, but they are all related. And this comes back to my theory of flux, which comes down to: what is your capacity to move energy substrate and signals through the system under varying conditions? That would be the basic definition. And they're all related to that.

Insulin resistance, for example — I'm going to trade a little bit of accuracy for being conceptual just so people can understand — insulin resistance is going to form in specific tissues when you have fat or ceramide accumulation. This can happen in all sorts of different tissues.

For example, it can happen in your liver. If you're eating in caloric excess, some of that is going to be turned into fat to be stored for later energy use. The first pool where that will go is your subcutaneous adipose tissue, or SAT. Once that store is full, it will move to VAT, or your visceral adipose tissue — that's the fat tissue closer to the organs. Once that is full, it connects to the liver via the portal vein and starts bathing your liver in fat. Fat will accumulate around your liver and that will impact insulin signaling. You can also have it in your muscle tissue, or peripheral tissue — when fat starts accumulating in your muscle tissue. When you have both of those, that's what we basically call diabetes.

But it's all part of the same system. And flux is the result of different things accumulating because they're not cleared fast enough. It's mostly fat accumulation for the chronic stuff, and that's mostly insulin resistance — fat in certain locations. But it's also dynamic.

We think of insulin resistance and diabetes as a blood sugar problem, but it's not — at its root cause — a blood sugar problem. The blood sugar is a result of not having good insulin signaling in the first place. But with glucose you have these other flux issues as well. We all know that if you have too much glucose hanging around for a long time, that's going to do all sorts of bad things. So there's this dynamic layer too — how do you clear glucose? And that can be mostly through movement.

Josh Clemente: What I really appreciate about this theory of flux is that it's a different articulation of things we've always heard — of course you want to prevent fat deposits from growing, people kind of take that at face value. But I think what's important is it's the capacity for the system to move substrate, to move fuel, to move nutrients efficiently through the system. And the movement is most important — flux is never going to be uniform. You're going to be changing constantly, whether we're sleeping, waking, exercising. There are all these different states. And the point, I think — help me articulate this — is that we need to be enforcing high-flux states where we are moving a lot through the system. We don't want to be in a low-flux circumstance. Is that what you would say?

Greg Mushen: Yeah, exactly right. And if you boil it down to a simple solution — I have some really interesting observations around this, and this is actually what led me to identify it. So when I was looking at and comparing all these hunter-gatherers, one common thing for them is to measure their energy utilization using doubly labeled water. They'll determine from that how much energy they're burning per day.

And you can look at a ratio of your total daily energy expenditure — how much energy you're burning on any given day — and you divide that by your base metabolic rate. Base metabolic rate is kind of like how much energy does your body need if you're lying in a hospital bed, just enough to keep critical systems active. Your idle rate. So if you divide TDEE by BMR, you're going to get what's called PAL — physical activity level.

Oddly enough, PAL is calculated for pretty much every subsistence population. And in their base state, when they are in their native environment, almost all of them have PAL values that cluster around two.

So this was my first observation. But then I was trying to understand why that would be the case and did a deep dive on some of those reasons. And then they would take these same people out of their populations and move them to the city. What would happen is their PAL would go down to around 1.6 or so. And once it reached that, all the chronic disease would start showing up again. They would start becoming insulin resistant, battling with obesity, their lipid values would go up, they'd have to go on lipid medication.

"They would take these same people out of their native populations and move them to the city. Their PAL would go down to around 1.6. And once it reached that, all the chronic disease would start showing up again — insulin resistance, obesity, lipid medication." — Greg Mushen

The Amish, the Maasai, the Chimane, and the Pima: natural experiments in flux

Greg Mushen: And then I found, just by pure luck and chance, two populations that are extremely interesting. The first one is the Amish. The Amish are really interesting because their diet is not too different from the standard American diet. They get like 20 grams of fiber. It's really high in saturated fat. I think they eat like 1.75 servings of cookies or pies per day. So you could think of it as kind of like the standard American diet, just without processed food. But they have really low rates of heart disease and really low rates of chronic disease — it's like a third of the general population. And the difference is that they walk about 18,000 steps per day, plus farm work and labor. So the PALs are really high.

But the interesting thing about a lot of these populations is you have this really natural split. In the Amish, there's this clearance gene — it's a 3500Q mutation and it impacts clearance. If you look at just that subset who has this gene that impacts lipid clearance, all of a sudden their lipids just go through the roof. They do have heart disease, high blood pressure, all of that.

And then another one that I think is really interesting for a different reason is the Pima. They were a population in Mexico, but when the Mexico border was redrawn, a portion of the population ended up in Arizona. Up until the mid-to-late '90s, the Pima who were living in Mexico started to modernize — they started eating a different diet, not moving as much. And it just so happens that studies comparing them were done literally like two years before this inflection point. So literally if we'd studied them two or three years later, all of that could have been missed. But if you just look at the differences in insulin resistance between those in the Mexican population versus those in the Arizona population, they're just wildly different. And there you can really isolate lifestyle and what's going on.

One thing that I found super interesting is that some of these subsistence populations still have insulin resistance, but it doesn't impact them. The Maasai have relatively high rates of hepatic insulin resistance — in the liver — but they're able to rescue it because their peripheral insulin resistance is preserved and they have high movement.

Josh Clemente: Sorry — peripheral insulin sensitivity is preserved?

Greg Mushen: Yeah, peripheral sensitivity is preserved. That's peripheral muscle. So even though their liver is producing glucose at levels that are higher than would be optimal, they're able to clear that glucose through movement. There's something called GLUT4 which is going to translocate. Conceptually, you could think of GLUT4 as almost like a vacuum — when there's muscle activation, it's going to vacuum all the glucose out of your blood and put it in your muscles. So even though they're hepatically insulin resistant, they don't have bad outcomes because they're clearing all of it.

Josh Clemente: So these are populations who are preserved from the health trends we've seen in all the developing nations — where chronic illness rates are all up and to the right. And what you're finding here is that the populations whose daily energy expenditure is about twice what their resting energy expenditure would be — TDEE divided by BMR of two or higher — it seems like there's this inflection point of positive health outcomes.

What is the Amish PAL on a consistent basis?

Greg Mushen: I couldn't find a doubly labeled water experiment with them — it would actually be a really great study for somebody to do. But I was able to back into it, and it's around two as well — like 1.92-ish. That's my estimate.

Josh Clemente: Makes sense. So somewhere between PAL values of 1.5 and 2, something bad happens. We end up no longer — and this is where your premise of flux comes in — when you hit a PAL of two, you're moving twice as much energy through the system. And that's only during waking hours, so you have twice as much energy expenditure compressed into whatever 16 hours you're awake.

The Maasai example is really fascinating because they have a diet of 100 grams of saturated fat, which is very high — I'm targeting like 20 grams right now. Maybe the conclusion is that that's leading to some visceral insulin resistance, but their muscles, which they're using continuously, can use blood sugar effectively with the GLUT4 transporters even though they're insulin resistant — because it's a non-insulin-dependent vector.

Greg Mushen: Right, you can consume glucose when your muscles are working. So they're sort of hacking the system a little bit because of their physical activity level.

Josh Clemente: So the conclusion — does it just come down to working out more? Like, we don't even have to eat better, just work out more and we can make up for it all?

Greg Mushen: Essentially, yes. In its most basic form, it seems to be yes. But it's one of those things where you don't want to get a PAL of over two for just a single day. It's PAL over two consistently over time. How many days in a row are you hitting PAL consistently over two? That's what's going to produce the outcome. And that somewhat limits how you can get there through exercise.

Josh Clemente: That's a really important point — this is a chronic lifestyle comparison, from early life through late life. And you must have case studies where these subsistence populations leave and go to cities and their health was tracked. We see this even with Blue Zones — Okinawans who have really amazing longevity, when they move to California, they end up with the same divergence in longevity. We see this constantly and it's obviously related to the amount of movement in all cases.

But I'm really curious how much we're hitting the problem from both ends — maintaining high movement is clearly important, but are we also making things worse by inducing peripheral and visceral insulin resistance through the ways we're eating? What are your takes on the nutrition side? If flux is the goal, how do we maximally support flux?

Saturated fat, clearance burden, and the Chimane

Greg Mushen: I think the best way to illustrate this is to compare and contrast two wildly diverging subsistence populations — the Maasai and the Chimane. The Maasai, as we talked about, 100 grams of saturated fat, walking up to 16 miles per day. And saturated fat is not per se bad. It's bad if you can't clear it all. It just makes clearance harder. It increases the clearance burden. That's all it's doing.

And a lot of people will have this question: does saturated fat cause heart disease? And they turn it into this binary, yes or no. And it's the wrong question to be asking, in my opinion. The better question is, are you meeting your clearance burden? Because you have the Maasai, and despite 100 grams of saturated fat and 16 miles of walking, they're still getting fatty streaks. It doesn't lead to outcomes and incidents — they're not getting heart attacks — but they're still getting fatty streaks.

The Chimane, on the other hand, have much lower movement compared to the Maasai — getting about 18,000 steps. And it's important to understand that they live in a very hilly jungle area, so it would not be the same as somebody doing 18,000 steps on flat land. But their diet is much lower in saturated fat, really low in fat in general. There was a study done with 700 participants — N equals 700 — with an age range of about 40 to 60 when you really start seeing accumulation of CAC, coronary artery calcification. And they have the lowest CAC scores ever recorded in any population.

So you can see the combination if you compare those two of what happens when you have a lower clearance burden and higher output, versus higher clearance burden and also higher output.

Josh Clemente: The conclusion sounds like the Maasai maybe have a saturated fat level that is beyond their ability to clear, because they are developing these fatty streaks. And that's not to say that saturated fat is a binary good or evil — nor is sugar or carbohydrates. The context has to be taken into account.

Greg Mushen: Exactly. And the reason I love comparing those two populations specifically is it really kind of isolates the interplay between diet and movement.

Flux vs. CICO: how they relate and where one falls short

Josh Clemente: How do you contrast your flux model with calories in, calories out? Because a lot of people are very aggravated by that model. How do you think about the differences?

Greg Mushen: So there are kind of two levels to this. The calorie in, calories out model is kind of based on the laws of conservation of energy, and it has been validated in metabolic ward studies so many times. As an energy model, it's really well proven. However, the problem is the way it's colloquially translated is "eat less and move more." And I think that's what people have the issue with — like, okay, that's not really telling me what to do. Of course everybody knows that. And then also it doesn't always solve the satiation problem. People are still hungry, still motivated to eat more. And there are certain diets where people will claim both of those things are solved — they eat certain things, it solves their satiation, therefore they feel like it's more effortless to lose weight. But then they conflate that with, "CICO is wrong."

So that's kind of the Gordian knot about CICO — it's correct as an energy model, mistranslated at the colloquial level, and it doesn't factor in things like satiation which impact it.

So how does flux differ? Flux will kind of describe — you'd apply flux at the energy level — that will determine if you're gaining or losing weight. But it's not just an energy model of are you gaining weight or losing weight. It's more: what energy is the appropriate fuel being selected for the appropriate context, and then given that fuel selection and your substrate burden, is all of that substrate being cleared, or is it being given a chance to accumulate and cause other problems?

So a really good example of this is lipids. It can be very simplified because for whatever reason, lipidology is very LDL-focused. And there's nothing really wrong with that, but it doesn't give people a good conceptual model to understand why. And then you get into these conditions where you have heart surgeons saying, "Well, most of the people I operate on have normal cholesterol." Well, of course they do — they're probably being operated on because they had an event. And that event is going to cause an acute reduction in lipids, and that's when you're measuring. But it doesn't mean their lipids have been high historically.

Josh Clemente: Can you explain that phenomenon? I don't think that's intuitive for most people.

Greg Mushen: Yeah. So when you have a heart attack — and let's say before the heart attack your LDL was 200, these are kind of fake numbers just to show the effect — if you have the heart attack and then measure LDL, that LDL is going to be way lower, maybe around 100. So it looks normal. Once people recover and go back to their regular lifestyle, it's going to go right back up to a steady state of 200.

And the thing about LDL is it's exposure over time. Total lifetime exposure. It's kind of like radiation — a little radiation isn't going to hurt you, but if you accumulate a huge amount of radiation exposure, that's going to be problematic. And LDL is the same way. The important thing is exposure over time.

And the way you measure that is what's called residence time — how long are the lipid pools staying around so you're getting exposed to it over time. So a good mental model is to think of it like a sink. You have the faucet, which is going to put water into the sink. You've got the basin, which is going to hold the water. And then you've got the drain, which is going to clear it. Any part of that system could impact residence time. Residence time would be how long the water is accumulating and sitting in the basin.

The faucet is what's called absolute secretion rate, or ASR. The drain is fractional clearance rate, or FCR. And residence time is basically one over FCR. ASR is going to basically be your clearance burden — how many lipids are you producing in the first place. And FCR is how many are you clearing. And this is how statins work. Statins work on both vectors. A lot of statins — not all of them, but the most popular ones — are HMG-CoA inhibitors. What that's going to do is limit ASR, or LDL production. And then it's also going to increase the number of LDLR, which is your LDL receptor. You can think of these as like little dumb waiters — they go up into the blood, lipid is put into the dumb waiter, and then they're taken down into the cell. So statins lower production and they increase clearance.

But there are other things that can increase clearance too. When you do any kind of movement, that's going to impact LDLR. And this is why, when you look at a lot of the subsistence populations, their LDL kind of clusters around 80 to 90 for pretty much all of them, no matter what they eat.

Josh Clemente: What is the physical movement doing — is it increasing the clearance rate or is it decreasing the production of lipids?

Greg Mushen: In a way, kind of both. But it's going to impact LDLR a little bit more. So you could think of movement in general as increasing your LDLR activation. But it will kind of operate on both.

Josh Clemente: So you're producing more receptors to pull that lipid particle down and out of the bloodstream — comparable to the GLUT4 that we were talking about with glucose.

Greg Mushen: Yes. It's very similar.

Josh Clemente: So right now we're sitting at our desks and we are producing lipid particles, we've got blood sugar flowing through us, and there's a certain flux in that system happening right now. And the goal is to get to a higher flux for as much of the day as possible on a consistent and recurrent basis in order to move these particles through the system sharper — improve the sensitivities across the board that drive flux — and overall that will, according to all the literature, lead to healthier outcomes, in this case insulin sensitivity. Is that a fair characterization?

Greg Mushen: Yeah, exactly. And some people may equate this to, "Gosh, I don't know if I can do that much movement." There's another way to think about it. The by far most harmful state in flux is being sedentary. In fact, there's this really interesting study where they took a population and put them into quartiles. If the only thing you did was move from the most sedentary quartile and you moved them just one quartile, it was like a 51% reduction in all-cause mortality.

So if you're going to do anything, just try not to be as sedentary — that would be the first stage. Even just doing a little bit of movement, standing up, doing some air squats — that's going to be by far the biggest bang for the buck.

Josh Clemente: And to build to a bit of a framework — I think that's first of all a staggering stat. And then I think there's a fivefold reduction in all-cause mortality to move from the lowest quartile to the highest quartile. Is that correct?

Greg Mushen: That's right, yeah, you remember right.

Josh Clemente: There is no other intervention, no drug that we know of that can achieve a 5x improvement in all-cause mortality.

Greg Mushen: That's right, not even close.

"If the only thing you did was move from the most sedentary quartile just one quartile, it was like a 51% reduction in all-cause mortality. There is no drug that we know of that can achieve a 5x improvement in all-cause mortality — not even close." — Greg Mushen

Why walking may be the most important exercise

Josh Clemente: People even kind of dunk on you as like "bought by big walking, big steps" — because you really hammer walking as maybe the best possible way to increase flux. That's a little bit confusing for some people. Like, wait a minute — aren't we trying to move the most nutrients through the system? How is walking going to achieve that? Bring me down the walking journey with you.

Greg Mushen: So I do love walking, but there's a specific reason why. I don't claim it's superior to everything else. I'm not saying don't run, only walk. But what's really interesting about exercise science is there are very few studies on mechanisms, and when they're completed they don't need to be replicated. And really what training is is a constrained optimization problem. The sole question for all training is: how do you maximize oxygen-driven transcription subject to the constraints of time, recovery, fuel availability and selection, and injury risk. That is all training is about.

But what ends up happening is most people — and this is why people have called me a walking grifter — is because it is a constrained optimization problem, what you're really looking at is an integral. How much oxygen-driven transcription has been done in the area under the curve? That is the key question. But training tends to look at the shape of the curve and mistakes that for the cause. And that's where you get into all these intensity debates, like, "No, you can't have a higher V2 max that would optimize longevity with just walking alone." And that's because from their perspective there aren't any studies of people doing 20,000 steps over time. But sometimes they can confuse that for not having any evidence, and the mechanisms aren't really studied or repeated.

Josh Clemente: Let's talk about what oxygen-driven transcription is and then what the adaptation is that takes longer with low intensity.

Greg Mushen: It's two adaptations. The central adaptation is more of a mechanical adaptation — conceptually, how much blood can you move through your left ventricle. The higher the intensity, the more the pressure, the more that variable is going to be impacted, and peripheral will also be impacted there too.

But the peripheral adaptation is more or less how many mitochondria do you have? So if you were to make a conceptual model of the two systems: on the peripheral side, it's like how many engines do you have that can contribute to oxidation — and it's mostly fat oxidation because it's going to be used at lower intensities. Then on the central side, it's like what's the size of your turbo booster on that same engine.

So two different adaptations. And the peripheral one — the reason why it takes more time in general is basically how many transcriptions can you do. What is the transcription activity of what's called PGC-1 alpha? The simple way to explain it is when you have more PGC-1 alpha activation, it's going to cause mitochondrial biogenesis — so it's going to create more engines. And because it is transcription-based, you could think of it as like a flywheel where every rotation is going to result in a transcription. And this is why PGC-1 alpha is so sensitive — it can be activated with something like ultrasound. Walking is certainly enough. But it's just going to turn that flywheel a lot slower.

HIIT, on the other side, is like spooling up that flywheel really fast. And then when you stop the stimulus, it's going to keep spinning — it's just going to decrease in rotations. So HIIT is going to be this huge spike in PGC-1 alpha activity and then a slow decay. It doesn't just spike and come down, it'll decay and keep going. Whereas if you're walking throughout the day, it's going to be all of these little spikes and the amplitude will be a lot lower, but the frequency will be higher.

But ultimately you're looking at the integral. And the integral — you can take any two activities regardless of their intensity, and if you match oxygen consumption, PGC-1 alpha transcription will be identical.

Josh Clemente: For those listening — my impression of V2 max optimization has been the sort of standard which is like a lot of high intensity. You've got to get out there and really kick it to get into fifth gear. And what you're saying is it's an area under the curve problem. Which our listeners will be fairly familiar with — think about that blood glucose curve. A big spike come straight down may hit a high absolute value but a low area under the curve. And your point is that you can have a huge monster spike that has a large area under the curve, or you can have smaller subtle perturbations which, although smaller individually, when added up hit the same area under the curve. And that ultimately is what determines the V2 max improvement.

What is the benefit of one versus the other? Why not, if you can compress it into a high-intensity interval session in 45 minutes, why would you choose the long low-and-slow approach?

Greg Mushen: This is where you really have to go back to the constrained optimization problem, and this is going to depend on your goals. Let's just compare walking 15,000 steps per day, every day, versus doing HIIT a couple times per week. The trade-off — if you're trying to maximize oxygen-driven transcription and the constraints are time, recovery, fuel selection, and injury risk:

On the HIIT side, you're going to have a lot lower time requirement. You're going to have higher recovery — and that includes CNS recovery, central nervous system, not just physical recovery. Fuel selection may not matter, but you're going to need more glucose. And injury risk relative to walking is going to be higher.

On the walking side, the trade-off is a lot more time, but your recovery is going to be almost nothing. As an example — in October I was out for a walk, I hit 10 miles, and I was like, "You know what, I'll just go for a marathon." So I walked 27 miles that day just on a whim. I was fasted, hadn't had anything to eat. And by the next day I was fully recovered. Walking has almost no recovery cost. Your fuel selection — you don't have to worry about it as much because with walking you can be fasted and do a marathon if you're trained. And injury risk is almost nothing.

So it depends almost entirely on how much time you have and what your other training goals are. If you're training to be fast, walking all the time is not going to be a good selection for you because you need that power, that high central adaptation. But if you're doing something like hardcore lifting, or let's say you have really high cognitive demands because you're CEO of a fast-growing startup — it may be that doing a ton of HIIT primarily for the purpose of increasing V2 max for health, that might be enough to tip you over and impact your performance at work or in the weight room.

So it's really all a big trade-off under those constraints and what your goals are.

Josh Clemente: I think this is really important to stress — I've always thought some movement is better than none, but to reframe it as, you actually can achieve V2 max improvements with this much more achievable modality of exercise. I've started to take this to heart. Now, for example, if I have to take a bunch of meetings, I'll do them from my phone and I'll be walking during them. I used to think there's no way that can move the needle, so I'll just be at my desk. But understanding that there is an area under the curve element here — which makes intuitive sense, but a lot of people struggle to believe it's going to achieve anything because you're not sweating and wanting to throw up on the floor afterwards, it feels like you didn't work hard. But that you can still achieve that outcome is really important.

And we stress this a lot with Levels. You can see the mobilization of GLUT4 — eat a high-carb meal, be stationary, sit on the couch, go to sleep, see how your blood sugar responds. Then do the same thing and instead walk for 30 to 40 minutes afterward. The area under the curve of that blood sugar reduction is amazing.

Greg Mushen: Back to your point about those glucose curves — what's so amazing is a lot of people don't realize how impactful this is. There was this one study — one of my favorites. They compared, for type 2 diabetics, metformin versus a 50-minute postprandial walk. And the 50-minute postprandial walk outperformed metformin alone.

Josh Clemente: Yeah, it's one of the most robust findings I think in our data set — when people are active following a meal, not intensely active, just taking walks, we see substantially improved blood sugar control.

Greg Mushen: Taking walks during meetings is just a cheat code.

Josh Clemente: In my own personal life, high-intensity training has always been kind of part of my life. I was a CrossFit trainer. I loved it. It was super competitive, I love the feeling of just kind of going 100%.

But later, as I started to get further in my career, there's this base level of stress that rises. And whether I can handle stress fairly well, I think, my cortisol when I measure it is high, and there's some epinephrine going on too. And so I'm exposed to all these other stressors that have complications in my life. And when you look at the stress and inflammation that a high-intensity interval training session induces, it kind of gets to a point where I can't sustain that. My body — like you're saying, it's recovery — and it does 100% affect my ability to show up for my family, to show up at work for days afterward. Like if I do a 150% session in order to try to create an adaptation, I'm going to take away from the next two days of output at work. And so this is the sustainable approach to V2 max optimization.

Greg Mushen: I think that's a great way to put it. And then injury risk is a big one too, because if you compare running to walking, there's on average about one injury per 750 miles with running, and I think it takes like a month or two to recover from most walking injuries. So the higher the intensity, the higher the injury risk. If you can lower that, you kind of end up in a situation where you net out for certain low volumes of running.

Josh Clemente: I've also experienced that myself. And it's a mixed modality. You can do a lot of this stuff. We've heard a ton about zone two. Walking is maybe a zone one, and you can fit it in everywhere. Lately there's been this whole rocking thing that goes right along with walking — add a little weight, make it maybe a little bit more of a resistance exercise. But I do think that people are really adopting in a big way this understanding or belief that we don't have to go into a box of fluorescent lights and grind at 110% in order to create health adaptation. And I think that unifying it with flux theories and the underlying mechanisms is what I'm most excited about. It's not just a tagline that "all movement matters" — instead, to really back that up with evidence is what I think is most important.

What Greg has changed his mind on

Josh Clemente: I'm curious what you've changed your mind on. Is there anything you firmly believed a few years ago that you've changed your mind on?

Greg Mushen: There are a lot. I would say the one thing I really changed my mind on was plant versus animal protein. I used to be of the opinion that animal protein was superior — and it is in some ways, I'm not going to say they're equivalent. But what research is showing now is that given enough protein, whether it's plant or animal, that's going to be sufficient.

The way I found that out was actually kind of funny. I got into this argument on Twitter with someone named Veganella, and she was telling me I was wrong. So we were having this debate and she looped in Stuart Phillips. He probably knows more about protein than anyone else. Stuart came in and actually corrected me and showed me two studies. He was like, "Yeah, I used to think that too, but here's what changed my mind." I read both of those studies and changed my mind on that. Due to a debate on X.

Josh Clemente: What is it about — help us understand — is it the amino acid profiles that are not as important as we thought? How is it that we could be wrong about this?

Greg Mushen: It comes down to this protein digestibility index — how well can your body assimilate these amino acids. When you look at all the animal side, it's really really high. It's lower for plants. I think the highest is whey protein — on a scale of 100, that's like 100. Eggs are next. Beef is pretty high too. And then when you go down to some of the plants like beans, they're a lot lower, like in the 70s or maybe even the 50s.

There's a reason behind that. A lot of these plant-based proteins — two things. One, a lot of them are low in leucine. Leucine is the amino acid that's necessary to stimulate muscle protein synthesis. It's not like plants are devoid of leucine, you just need a lot more of it to achieve the same effect. And it's going to be like 1.6 grams of protein per kilogram of body weight. If you kind of hit that level, whether it's plant or animal, you'll do fine.

And then the second thing is you have a lot of these plant protein powders. And what's interesting is that due to the processing, they remove the stuff that inhibits amino acid digestion. So a lot of those plant-based protein powders are on par with whey protein.

Josh Clemente: What you said there about quantity being a really big factor — the rule of thumb has been moving towards something like maybe even as high as a gram per pound of body weight, which would be 2.2 grams per kilogram. So at that level, it sounds like you're above a threshold where you're getting sufficient quantities of these amino acids to stimulate muscle protein synthesis. So for people who want to have a wider selection, that's really cool to hear.

Greg Mushen: And one more thing on that — it's important to call out the limitations of the literature. The 1.6 grams number — the population that's studied on is mostly younger people. So if you're older, you need more protein. If you're older, you might want to err on the side of one gram per pound of body weight. It's an even more challenging problem because I find that as people get older and lose a little bit of lean body mass, their appetite reduces and it becomes even harder to keep up. So I think people should in general keep that super high protein threshold.

There's so much satiety benefit. The benefits to lean mass retention are so high. Targeting one gram per pound of target body weight — so if you want to gain some muscle mass, add those five pounds into your daily allowance and really shoot for it. Protein supplementation is one of the most underutilized levers people have at their disposal.

Fiber: the environmental sensor of the gut

Josh Clemente: Let's talk about fiber. What is your current approach to fiber and why does it matter?

Greg Mushen: It's kind of funny — we probably shouldn't call fiber "fiber" because I think that's where a lot of the confusion comes from. When people think about fiber, they tend to think about insoluble fiber — basically just as this thing that's going to help their throughput a little bit more. But that's not the primary purpose. And not to say that a little of that isn't good, because it is. But what's more important is short-chain fatty acid signaling.

This is my personal belief, but I believe that our microbiome and our gut kind of works as an environmental sensor. One of the reasons it's there is to determine what is the energy state of our environment — are we in a state of bountiful energy or are we in a state where food might be scarce? And it's going to make adaptations really quickly based on short-chain fatty acids for that signaling. And it can happen in like five days — it happens so fast, which I think kind of lends evidence to this environmental and food sensor idea.

But when you don't get enough short-chain fatty acids and the right kinds, what's going to end up happening is your body is going to not inhibit what's called HDAC. And HDAC controls a couple things, but one thing it controls is how tight your junctions in your gut are. If HDAC isn't inhibited through short-chain fatty acids, the tight junctions in your gut lining are going to start loosening. And I think one of the reasons why is so that it can then generate short-chain fatty acids from the mucin in the gut lining. By loosening it, it just makes it easier to access that mucin, which it can then ferment into short-chain fatty acids.

So that's kind of the first thing — gut lining. And that can add to leaky gut issues. And then the second thing is it's going to modulate your insulin sensitivity. In a low-fiber environment, I think the signal your body is getting is, "Wow, we're really short on glucose here, because there aren't too many plants around, which is what has it." So it's going to make the body more sensitive to glucose so you can better utilize the glucose that's there.

Another thing it will impact is satiety. It will impact GLP-1 production — that's where GLP-1 and PYY are initially signaled in the gut. And I think the reason why is in a low-fiber state, in a state of like food scarcity, your body probably wants to be a little bit hungrier, so you're more motivated to find food, or if you find some you'll eat it.

And then speaking of the rotting carcass — it's also going to increase inflammation. And I think that's a response to things like that because in food scarcity you don't have the choice of what food you're going to eat and you might need some extra protection against the foods you find.

Josh Clemente: It's going to increase inflammatory action as an immune response — or preparation, essentially.

Greg Mushen: That's right.

Josh Clemente: Fascinating.

Greg Mushen: And then the last thing is that because you're mostly fermenting amino acids, there are going to be a lot of byproducts of that that aren't really that great. There's this one — I can't remember the name of it right now — but it's one that increases insulin resistance over time and can modulate LDL and things like that.

So that's why I think fiber is important. There are really only two ways to get short-chain fatty acids into your gut. The first way is to eat foods that will ferment into short-chain fatty acids. The second way is to inject them. And if you're not injecting them, your only possible option is to ferment them by eating them.

Greg's personal health stack

Josh Clemente: I want to end on your personal health stack. Walk us through what's in there — supplements, macronutrient targets, any other techniques you're using to modify and improve metabolic health and longevity.

Greg Mushen: I'll kind of start with three areas. So exercise: I try to hit about 15,000 steps per day on average. I just love that time — it's my favorite time of the day, when I'm out there walking. Secondly is resistance exercise — four or five times a week. I try to hit five every week, but some weeks I can only hit four.

For diet, my caloric target is around 2,600 calories. I try to get one gram per pound of body weight in protein — so like 185 to 190 grams. The rest is split up between carbs and fat and I don't worry about it too much, but there are certain fats I try to get less of, which is saturated — that's just because of my genetics. And then I try to get more monounsaturated and omega-3s. That's kind of the macro side.

And then the micro side, I just try to hit all of my micronutrient targets every day. One part of the supplement system is really to make up for those micronutrient gaps. And then the other part of the supplement system is really just there to address things that are easier to address through either pharma or other compounds.

One that I love is tadalafil. It's a PDE5 inhibitor, and it'll help with vasodilation. I take it off-label for that. A lot of people know of it for erectile dysfunction, but the reason why it's so effective with that is just because of how effective it is at increasing blood flow. It's really there as a cardiovascular preventive measure — to keep your blood vessels supple. You don't want them getting stiff. And the way you can do that is through lots of movement, and then through inhibiting PDE5. As you age, you're producing more PDE5 and probably less nitric oxide. So it's really countering both of those things — the sheer stress on the wall from movement, and then inhibiting PDE5.

And then potassium is another big one, for the same reason — supple veins. And that's really about it. It's a really simple stack.

Josh Clemente: Tadalafil, potassium — do you supplement fiber?

Greg Mushen: Yeah, I made my own fiber mixture. So I dehydrated green plantains — a tablespoon or two of that. Some soluble corn fiber. It has some psyllium husk in there, some wheat germ, and some oat bran.

Josh Clemente: I'm going to have to get more creative. I'm just taking psyllium by the scoop — about 15 grams of psyllium in the morning. What's your daily fiber target?

Greg Mushen: I try to get between 60 and 80 grams total.

Josh Clemente: That's a lot. That's awesome.

Greg Mushen: And it really comes down to what are the ratios of short-chain fatty acids that you want and the quantity. That's why I designed the fiber supplement the way I did — to make sure it could get to the right places in the colon and in the right ratios.

Josh Clemente: So how can people follow along with both your lifestyle and what you're digging into on the bigger picture of health?

Greg Mushen: On X I'm just my name — Greg Mushen, G-M-U-S-H-E-N. And then Dark Lab on Substack.

"There are really only two ways to get short-chain fatty acids into your gut — eat foods that will ferment into them, or inject them. And if you're not injecting them, your only possible option is to ferment them by eating them." — Greg Mushen