The Molecular Choreography of Exercise: One of the Most Beautiful...
Nick Norwitz MD PhD@nicknorwitz
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Sep 16, 2025
~6 min read
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The Molecular Choreography of Exercise: One of the Most Beautiful Studies Ever Written 💪🫀😍
1/10) After the excellent response to the Four Causes of Diabetes Interview, I’m thrilled that Professor Michael Snyder @TheSnyderLab @Stanford will be joining me for a series of interview on Aging, Multi-Omics and Personalized Medicine.
One paper I NEED (and definitely will) discuss with him ranks as my all-time favorite in exercise science: The Molecular Choreography of Acute Exercise, published in Cell.
🔗Today’s Newsletter (linked at the end) is my love letter to this incredible study!
My purpose in the letter isn’t to make sure you understand every technical detail. Rather, I want you to catch a glimpse of the awe and artistry that lives within this science. But don’t worry, you will still walk away with practical scientific insights.
We will:
👉Discuss the simple elegance of its methodology.
👉Walk through some of the fascinating signals in the data and explore their real-world meaning.
🚨And I will show you what may be one of the simplest yet most stunning' graphs in all of exercise metabolism literature—and explain what it means for you every time you step into the gym. (I know… that’s a big promise. But I will pay it off!)
Cc @hubermanlab @BenBikmanPhD @AKoutnik @drgabriellelyon @BiggestComeback and anyone interested in exercise or metabolic health
1/10) After the excellent response to the Four Causes of Diabetes Interview, I’m thrilled that Professor Michael Snyder @TheSnyderLab @Stanford will be joining me for a series of interview on Aging, Multi-Omics and Personalized Medicine.
One paper I NEED (and definitely will) discuss with him ranks as my all-time favorite in exercise science: The Molecular Choreography of Acute Exercise, published in Cell.
🔗Today’s Newsletter (linked at the end) is my love letter to this incredible study!
My purpose in the letter isn’t to make sure you understand every technical detail. Rather, I want you to catch a glimpse of the awe and artistry that lives within this science. But don’t worry, you will still walk away with practical scientific insights.
We will:
👉Discuss the simple elegance of its methodology.
👉Walk through some of the fascinating signals in the data and explore their real-world meaning.
🚨And I will show you what may be one of the simplest yet most stunning' graphs in all of exercise metabolism literature—and explain what it means for you every time you step into the gym. (I know… that’s a big promise. But I will pay it off!)
Cc @hubermanlab @BenBikmanPhD @AKoutnik @drgabriellelyon @BiggestComeback and anyone interested in exercise or metabolic health
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1b/10) Before we continue with this monster of a thread, here's the link to the full letter. I think you'll find it worth your time: staycuriousmetabolism.substack.com/p/the-art-of-a…
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2/10) The Study Design: Simple and Elegant
The design was deceptively simple yet brilliantly structured. Thirty-six participants, aged 40 - 75, with a wide range of metabolic profiles—about half insulin-sensitive and half insulin-resistant—completed an exercise protocol. Researchers collected biological samples before exercise and at multiple time points thereafter. These samples were used to build each participant’s “longitudinal multiomic” profile.
“Multi-omic” refers to capturing many different layers of biology: the microbiome, proteome, transcriptome, lipidome, metabolome, and so on. “Longitudinal” means repeated sampling over time. In effect, the researchers created a high-resolution video of how each individual’s metabolism shifted in response to exercise.
To ensure the changes weren’t just random fluctuations, a subset of participants served as controls. This confirmed that the signals truly reflected exercise-induced effects.
*Nuance Note: The exercise protocol itself followed a ‘ramp protocol,’ meaning the effort started easy and then gradually became harder—like jogging up a hill that gets steeper and steeper. The pace of this “ramp” was adjusted to each person’s cardiovascular fitness, so the challenge was matched to their ability. The goal was for each test to last about 8–12 minutes, long enough to push each body to its (safe) limit.
The design was deceptively simple yet brilliantly structured. Thirty-six participants, aged 40 - 75, with a wide range of metabolic profiles—about half insulin-sensitive and half insulin-resistant—completed an exercise protocol. Researchers collected biological samples before exercise and at multiple time points thereafter. These samples were used to build each participant’s “longitudinal multiomic” profile.
“Multi-omic” refers to capturing many different layers of biology: the microbiome, proteome, transcriptome, lipidome, metabolome, and so on. “Longitudinal” means repeated sampling over time. In effect, the researchers created a high-resolution video of how each individual’s metabolism shifted in response to exercise.
To ensure the changes weren’t just random fluctuations, a subset of participants served as controls. This confirmed that the signals truly reflected exercise-induced effects.
*Nuance Note: The exercise protocol itself followed a ‘ramp protocol,’ meaning the effort started easy and then gradually became harder—like jogging up a hill that gets steeper and steeper. The pace of this “ramp” was adjusted to each person’s cardiovascular fitness, so the challenge was matched to their ability. The goal was for each test to last about 8–12 minutes, long enough to push each body to its (safe) limit.
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3/10) Four Patterns of Change
The data revealed four main clusters of response:
👉Cluster One: Markers that increased rapidly with exercise and returned to baseline.
👉Cluster Two: Markers that increased slowly after exercise.
👉Cluster Three: Markers that decreased sharply, then recovered.
👉Cluster Four: Markers that decreased for a prolonged period into recovery.
The data revealed four main clusters of response:
👉Cluster One: Markers that increased rapidly with exercise and returned to baseline.
👉Cluster Two: Markers that increased slowly after exercise.
👉Cluster Three: Markers that decreased sharply, then recovered.
👉Cluster Four: Markers that decreased for a prolonged period into recovery.
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4/10) The natural next questions are:
👉Which markers belonged to which clusters?
👉How did these patterns differ depending on whether someone was metabolically healthy or insulin resistant?
👉Which markers belonged to which clusters?
👉How did these patterns differ depending on whether someone was metabolically healthy or insulin resistant?
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5/10) Cluster 1: Sharp Spike 📈📉
Cluster 1 was enriched with molecules tied to oxidative stress and inflammation. Let’s single out an example: myeloperoxidase (MPO). This enzyme, produced by immune cells and other tissues (like fat), generates oxidative stress. In a chronic setting, that’s problematic—it can oxidize lipids, interfere with hormone signaling, and broadly undermine health.
🚨But here’s the key: In this study, MPO sat in Cluster 1, which means it spiked sharply with exercise, then quickly returned to baseline. That pattern is normal—and healthy. The important distinction is between a brief, beneficial rise versus a prolonged, harmful elevation.
Cluster 1 was enriched with molecules tied to oxidative stress and inflammation. Let’s single out an example: myeloperoxidase (MPO). This enzyme, produced by immune cells and other tissues (like fat), generates oxidative stress. In a chronic setting, that’s problematic—it can oxidize lipids, interfere with hormone signaling, and broadly undermine health.
🚨But here’s the key: In this study, MPO sat in Cluster 1, which means it spiked sharply with exercise, then quickly returned to baseline. That pattern is normal—and healthy. The important distinction is between a brief, beneficial rise versus a prolonged, harmful elevation.
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6/10) By way of analogy, think of it like a stove. You turn on your stove to cook—that’s functional, helpful, and healthy (assuming you’re not making cornflake French toast). But if you left your stove on 24/7, it would become unhealthy and harmful. Toxic gases could build up, or worse, the ongoing fire could burn your house down.
It’s the same with oxidative stress enzymes and inflammatory signaling molecules after exercise: In short bursts, they serve important signaling roles that help your body adapt and your muscles grow stronger. But if they’re chronically elevated, they can cause trouble—eventually burning down your metabolic house.
It’s the same with oxidative stress enzymes and inflammatory signaling molecules after exercise: In short bursts, they serve important signaling roles that help your body adapt and your muscles grow stronger. But if they’re chronically elevated, they can cause trouble—eventually burning down your metabolic house.
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7/10) A “Fitness Inflammatory Signature” 🔥
The researchers went on to examine biomolecular signatures of fitness, focusing on biomarkers tied to peak oxygen consumption (VO₂ max), one of the strongest predictors of longevity.
What they found was a pro-inflammatory signature at 15 minutes post-exercise—driven by Cluster 1–type changes—was positively associated with peak VO₂. They dubbed this the “fitness inflammatory signature.”
In other words, a sharp, acute inflammatory spike with exercise was not a marker of damage, but rather a hallmark of being fit and healthy.
🔥The fitness inflammatory signature wasn’t random noise; it was a coordinated pattern.
Although many molecules were involved, the researchers found that one stood out as a key driver: interleukin-5 (IL-5). This single signaling molecule appeared to ignite a broad, integrated cascade of responses across the body. This figure from the paper makes this clear: an IL-5 spike just two minutes after exercise set off a complex network of downstream adaptations.
The researchers went on to examine biomolecular signatures of fitness, focusing on biomarkers tied to peak oxygen consumption (VO₂ max), one of the strongest predictors of longevity.
What they found was a pro-inflammatory signature at 15 minutes post-exercise—driven by Cluster 1–type changes—was positively associated with peak VO₂. They dubbed this the “fitness inflammatory signature.”
In other words, a sharp, acute inflammatory spike with exercise was not a marker of damage, but rather a hallmark of being fit and healthy.
🔥The fitness inflammatory signature wasn’t random noise; it was a coordinated pattern.
Although many molecules were involved, the researchers found that one stood out as a key driver: interleukin-5 (IL-5). This single signaling molecule appeared to ignite a broad, integrated cascade of responses across the body. This figure from the paper makes this clear: an IL-5 spike just two minutes after exercise set off a complex network of downstream adaptations.
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8/10) 🚨The takeaway? Brief, acute inflammatory signals are not harmful—they’re essential. They act as the spark that triggers systemic adaptation, strengthening the entire organism. Far from being dangerous, this “fitness inflammatory signature” is a marker of resilience and health.
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9/10) Cluster 2: Slower to Rise 🐢📈
Cluster 2 metabolites rose more slowly, and many were tied to carbohydrate metabolism.
A clear example was the stress hormone cortisol, which stimulates the liver to make new glucose—a process called gluconeogenesis—and thus raises circulating blood sugar.
Unsurprisingly, higher glucose levels were positively associated with higher insulin levels. That makes adaptive sense: insulin’s job is to drive nutrients into tissues where they’re needed.
👀But here’s the teaser: exercise-induced insulin responses aren’t the same for everyone: People who are metabolically healthy tend to have a modest insulin rise. Those who are more insulin resistant, however, often experience a much larger spike.
Why? Because their muscles are sluggish in responding to insulin’s signal, so the body compensates by producing more.
The result can be a more maladaptive hormonal milieu—with elevated stress hormones and insulin, alongside lower levels of other potentially beneficial signals. And that imbalance sets the stage for what we are going to discuss next…
Cluster 2 metabolites rose more slowly, and many were tied to carbohydrate metabolism.
A clear example was the stress hormone cortisol, which stimulates the liver to make new glucose—a process called gluconeogenesis—and thus raises circulating blood sugar.
Unsurprisingly, higher glucose levels were positively associated with higher insulin levels. That makes adaptive sense: insulin’s job is to drive nutrients into tissues where they’re needed.
👀But here’s the teaser: exercise-induced insulin responses aren’t the same for everyone: People who are metabolically healthy tend to have a modest insulin rise. Those who are more insulin resistant, however, often experience a much larger spike.
Why? Because their muscles are sluggish in responding to insulin’s signal, so the body compensates by producing more.
The result can be a more maladaptive hormonal milieu—with elevated stress hormones and insulin, alongside lower levels of other potentially beneficial signals. And that imbalance sets the stage for what we are going to discuss next…
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10/10) We’ve only just begun! In the rest of the letter (HERE: staycuriousmetabolism.substack.com/p/the-art-of-a…) we discuss
👉Clusters 3 & 4 – The hormones that drop, bounce, and stay down
👉Hunger & Exercise – Why some people feel hungrier after a workout
👉Fats in Motion – How saturated vs. polyunsaturated fats behave differently
👉Fitness Predictors – Molecules that reveal aerobic health
🚨The Graph You’ll Never Forget – The simplest, most stunning insight in exercise science
👉Clusters 3 & 4 – The hormones that drop, bounce, and stay down
👉Hunger & Exercise – Why some people feel hungrier after a workout
👉Fats in Motion – How saturated vs. polyunsaturated fats behave differently
👉Fitness Predictors – Molecules that reveal aerobic health
🚨The Graph You’ll Never Forget – The simplest, most stunning insight in exercise science
