Mushen’s Theory of Clearance Symmetry

Metabolic health isn’t about what you eat or how much you move. It’s about how efficiently you clear what you take in.

When flux slows, energy accumulates, and that accumulation produces maladaptive responses and negative feedback loops. Glucose Dysregulation is impaired carbon flux

In a healthy system, glucose moves dynamically through states:

Dietary intake -> blood -> tissues -> mitochondria -> CO2 + H20

Key steps:

Uptake: GLUT transporters

Processing: glycolysis, pyruvate oxidation, TCA cycle

Clearance: oxidation or conversion to glycogen/lactate

Longevity is a game of avoiding chronic disease for as long as possible. The more diseases you accumulate over time, the shorter you will live.

Subsistence populations are largely free of chronic disease, and despite wildly different diets, there’s one metric they share 👇 Most chronic diseases are flux issues. If our inputs exceed our outputs, that’s when we start developing disease.

Deconstructing CICO vs CIM: What Actually Drives Sustainable Fat Loss

Nearly every chronic disease traces back to poor metabolic health.

But when it comes to fat loss, two camps dominate: CICO vs CIM.

Which model actually holds up, and what’s sustainable long term? 👇 First is the CICO camp. This is the energy balance model.

If energy balance is negative, you will lose weight.

If energy balance is positive, you will gain weight.

This is empirically true, and I’ve outlined the entire model here:

https://twitter.com/gregmushen/status/1982661812454850956

Do low carb diets increase energy expenditure or fat loss independent of calories?

This is the central prediction of the carbohydrate-insulin model.

Lower insulin -> greater fat oxidation -> more fat loss.

But does it work in practice? 👇 Kevin Hall and Juen Guo analyzed 32 controlled feeding studies (563 participants) testing how carb-to-fat ratio affects body energy change when total calories and protein are the same.

Deconstructing CICO

Many people say that “CICO is oversimplified”

But it’s one of the most misunderstood concepts in nutrition.

Here is how energy balance actually works, and how macros can change what you lose, not how much 👇 CICO is based on the first law of thermodynamics. That energy can neither be created nor destroyed.

Some say that this law only applies to closed systems. That is not true.

Very interesting paper. For the past 6-7 years, there has been talk of a constrained energy model, where calories don’t scale linearly with physical activity. But this paper says the opposite. Why the conflicting data? 👇

https://twitter.com/nick_krontiris/status/1980908560218304540

First, some background. In 2016, Pontzer et al. studied subsistence populations.

When weight matched with sedentary westerners, they appeared to have the same TEE, despite the vast difference in movement (~17k steps versus mostly sedentary).

One of the most confusing things about cholesterol is that it’s a dynamic system attempting to reach equilibrium.

The measures we use are snapshots of parts of the system.

Furthermore, at times, only parts of the system are talked about.

This leads to confusion 👇 Yes, LDL is causal. Given enough circulating LDL which contains ApoB, and enough time, ApoB will get trapped in the endothelia.

This is the initiating event for atherosclerosis.

Nothing else needed. Inflammation is not needed.

Only circulating LDL and time.

Is the ideal cholesterol 200?

This graph has been making the rounds on social media. It was from a Korean study with 12.8m people.

But is has some serious flaws, and the true ideal cholesterol is much lower 👇 Problem #1 Reverse Causation

Certain diseases cause cholesterol to be lower: chronic inflammation, cachexia, liver dysfunction, frailty, and certain kinds of cancer.

So if someone enters the study, and they have one of these conditions, they are already unhealthy.

Vascular stiffness is a causal factor in age related decline. It can impact everything from heart/kidney, and even cognitive decline.

We used to think it was an inevitable part of aging, but now we know it’s not.

Here is how you can prevent it and become a SUPERNOVA 🧵 Vascular stiffness is one of the biggest risk factors as we age.

- Cardiovascular morbidity
- Hypertension
- Chronic kidney disease
- Cognitive decline and dementia
- Stroke
- Elevated risk of diabetes

So being able to reduce risk by lowering vascular stiffness lower risk.

Most modern diets don’t deliver enough slow, distal fermentables.

That means the proximal colon burns out early, leaving the distal colon fiber starved.

The result is proteolysis, odor, inflammation, permeable gut, weak GLP-1/PYY signaling.

Here’s how I’m fixing this 👇 The design hypothesis

If you deliver a large RS2 payload plus carriers to slow access, it should:

- Survive the proximal colon
- Reach the distal colon
- Bias toward butyrate production
- Trigger sustained GLP-1/PYY via FFAR2/3 signaling in distal L cells

Potassium IMO is the #2 nutrient (protein being #1)

Our bodies require structure (protein) and charge (potassium/sodium).

A battery operates on a gradient. One side is positive, one side is negative. That difference, or gradient is energy potential. Cells are like little batteries, and need a gradient for energy. Inside the cell = potassium. Outside = sodium.

We have a “charger” called the sodium/potassium pump, which constantly moves sodium out and potassium in (3 Na out for every 2 K in).

Why Exercise Doesn’t Replace Walking

Many people think that intensity can replace walking. And they are right to a degree. It does on the aerobic side.

But there are things it doesn’t replace: lipid clearance, and vascular remodeling. 🧵 To make this model conceptually simple, imagine you have a sink.

- Basin = your blood plasma
- Water in the sink = ApoB containing lipoproteins (VLDL, LDL, remnants)

Clearance is the drain. If the water stays in the sink too long, it gets stagnant.

So it needs to be drained.

Over the past few days, I’ve had many discussions with athletes and physiologists who claim that you can’t get a high VO2max from just walking.

Here is what I think they are missing 🧵 Most exercise physiology is based on training data and observation.

Therefore the studies on exercise are designed as interventions that are themselves based on those observations.

VO2Max - How Walking Can Create an Elite VO2Max

Many people think that the only way to raise VO2Max is by doing HIIT.

But you can achieve a high VO2Max just with walking.

Walking is arguably the superior way to build it 🧵 In 2001, there was a landmark paper published. They took a VO2Max measurement at baseline and tracked the cohort for 10.7 years.

What they found was an inverse correlation between VO2max and all cause mortality.

Many people report their health improving after removing fiber.

Why is this, and are they really improving their long term health?

Is this proof that fiber is “non-essential”?

Short answer: no
Long answer: 🧵 You could think of our microbiome as a fermentation vessel.

The fermentation feeds the 10^13 organisms living in your gut.

We have 3x10^13 human cells.

In that sense, we are at least as much microbe as we are human.

Why Don’t Hunter Gatherers Have Heart Disease? (Part 10)

We know what happens when you move subsistence populations to the city. They start developing disease.

But what happens when you move them back? 🧵 In the 70’s and early 80’s, health surveys in remote Aboriginal villages showed a disturbing trend:

- T2D was exploding in prevalence
- The onset was very rapid, occurring within a decade or two of lifestyle change

Why Don’t Hunter Gatherers Have Heart Disease? (Part 9)

In parts six we evaluated several groups with hepatic insulin resistance.

In part seven, we evaluated how this could happen with VAT being the likely culprit.

But what is VAT and how does it lead to insulin resistance?🧵 What are SAT and VAT?

SAT = subcutaneous adipose tissue
VAT = visceral adipose tissue

SAT (also SCAT) is the primary, low risk storage depot. It has the ability to expand but expansion is limited (hypertrophy, fibrosis, inflammation), then it starts spilling over into VAT.

Why Don’t Hunter Gatherers Have Heart Disease? (Part 8)

We have learned a lot in this series. Before going further, let’s build a model for what we are seeing.

The model will help explain why hunter gatherers aren’t getting chronic disease

Could this be a unified theory? 🧵 Before we start, it’s important to realize that all models are wrong, but some are useful.

Science has many examples of wrong but useful models. Bohr’s model is a good example of this. It was wrong, but led to quantum mechanics.

So our goal is to be wrong but useful.

Why Don’t Hunter Gathers Have Heart Disease? (Part 6c)

The Maasai taught us the case:

Hepatic dominant IR can be low risk until urbanization pushes it to multi-axis

Can the Pima prove the law?

What happens when you hold genes constant, but change lifestyle? 🧵 First, a little background about the Pima. This may seem like a bit of a detour, but it provides important context for how we ended up with such a perfect natural experiment…

Why Don’t Hunter Gathers Have Heart Disease? (Part 5)

Hunter gatherers have VO2max > 50

VO2max is strongly correlated with longevity.

So raise VO2Max fast with HIIT and you should be able to skip the walking, right?

Not so fast🧵 VO2Max Correlation is from Population Data

In 2001, there was a landmark paper published. They took a VO2Max measurement at baseline and tracked the cohort for 10.7 years.

What they found was an inverse correlation between VO2max and all cause mortality.

But there’s a problem

Why Don’t Hunter Gathers Have Heart Disease? (Part 4)

Hunter gatherers walk between 15-20k steps a day.

In a modern society, that takes a lot of time. Surely running for an hour would replace that, right?

No. This is why we see endurance athletes with heart disease 🧵 Cardiorespiratory fitness (CRF) cuts all cause mortality and CVD risk. Every extra MET of CRF reduces risk by 13%