For a neuroscientist, I suck at sleep.

It’s been a lifelong struggle, and it’s caused me a lot of anxiety.

When I sleep poorly, not only do I not function as well the next day, but I worry about my long-term brain health.

Sleep is foundational for learning and memory.

When sleep is impaired or insufficient, metabolic waste can accumulate in the brain, contributing to cognitive decline, and even Alzheimer’s disease.

So, bad sleep genuinely scares me, especially when it feels out of my control.

And I know I’m not alone.

Maybe you know the feeling. Do you?

And, of course, we’ve all heard that we should sleep around 8 hours a night.

It’s like the #1 Commandment of Sleep, right on the list above:

• “Thou shalt get morning sunlight”

• “Thou shalt keep your room cool and dark”

• “Thou shalt not use your phone in bed”

Or, even if you don’t adhere to the strict 8-hour rule, and are a bit more familiar with the sleep literature, the focus is almost always on how long you sleep. Not because it’s the most important variable, but because it’s the easiest one to measure.

For example, the biggest recent sleep headline was about a paper published in Nature that examined the relationship between self-reported sleep duration and 23 different biological aging clocks.

The healthiest agers slept between 6.4 and 7.8 hours per night.

Interesting… But even studies like that one, published in the world’s top journals, can sometimes obscure the more important question.

How do you sleep not longer, but better?

Here’s the deal: two people can each sleep 8 hours while getting dramatically different results.

In fact, it’s very possible one person can get more out of 6 hours of sleep than another person gets out of 8 or 9 hours of sleep.

I know it sounds unfair. But it’s also biology.

But once you understand that biology, you can leverage it…

Today, I’m going to flood you with practical, science-based, and overlooked strategies for improving sleep quality, even if you can’t always increase sleep duration.

There will definitely be some surprises along the way.

So, lock in: We’re about to go Deep.

And if you REMember what I’m about to each you, you’ll never think of sleep the same way again.

The rest of this letter is for StayCurious Metabolism Premium members.

In this premium deep dive, we’re going to tackle the big questions:

• Why do we sleep?

• What do the different stages of sleep do?

• How do you optimize the stages that matter most?

We’ll cover:

• Free behavioral tools

• Targeted supplements

• Experimental peptides

• Evidence-based light and sound treatments

I put this together so you can benefit from the lessons learned by an erratic, insomniac neuroscientist who has spent an unreasonable amount of time obsessing over the science of sleep.

My sincere hope is that the next 30-ish minutes you spend reading this article pay dividends every night for years to come.

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Some people believe saturated fat increases the risk of heart disease.

Others believe seed oils are the bane of human existence and should be completely eliminated.

Then there’s fiber, animal versus plant protein, omega-6 versus omega-3, intermittent fasting—the list goes on.

While I understand that the conflicting information is frustrating, what’s equally frustrating for me is how the underlying complexities are ignored or oversimplified.

That’s true not only in public discourse, but even within formal academic, medical, and dietetic training.

So in this deep dive, I’m setting an audacious goal: to arm you with more useful, accurate, and practical information than you’d get from completing an entire nutrition degree.

It sounds like a tall order. But I can deliver.

This is an extra-special letter for StayCurious Metabolism premium members, a 6,000 word manuscript that tackles the most consequential myths in nutrition for heart health.

• Saturated fat, including meat, dairy, and chocolate

• Eggs and dietary cholesterol and cholesterol homeostasis

• The complex and confusing science around seed oils

• Nuances around omega-6 fats that most people miss

• Fiber confusion and what really matters for gut health

• The paradox of salt and blood pressure

• The critical role of blood sugar in heart health

Throughout, I’ll give you practical guidance, deep mechanistic insight, and exactly the kind of information that lets you flex your inner nerd at your next dinner party, and maybe intimidate your local nutritionist.

Come find out why StayCurious Metabolism premium members call our community, “an oasis of nuance on the internet,” and, “the best investment I’ve ever made in my health.”

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And here’s why. Research shows that leg power predicts cognitive decline over a 10-year interval.

But that’s not all.

In a study of human twins, differences in leg power predicted not just long-term cognition, but actual brain volume measured by MRI.

What these findings strongly suggest is that your musculature, and particularly your leg muscles, are actively doing something to protect the brain.

And, at a biological level, this makes complete sense.

Because muscles are hormone factories!

During contraction, they release signaling molecules that travel throughout the body, including to the brain, where they can support neurogenesis and brain health.

Muscle also plays a central role in blood glucose regulation, insulin sensitivity, vascular health, and blood flow — all variables that directly or indirectly influence long-term brain function.

Nevertheless, the finding that even among genetically identical twins, leg power positively predicts cognition and brain size later in life should stop you in your tracks… and make you want to sprint to the squat rack.

In the rest of this letter, I’m going to break down the science, and explain exactly what you can do to leverage this perhaps unexpected relationship to preserve both muscle and cognition for the long haul.

Quick Roadmap:

• The Twin Study that made me rethink leg day

• Muscle-Brain Mechanisms: the biological pathways connecting your leg muscles to your brain

• Practical Muscle-Brain Protocols

  • Exercise recommendations

  • Fascinating molecules that may enhance your results

The Twin Study That Made Me Rethink Leg Day

First, it’s probably helpful to understand the research itself.

It had two parts.

In the first part, researchers followed 324 people between the ages of 43 and 73 over a 10-year period. Participants completed a battery of cognitive assessments known as the Cambridge Neuropsychological Test Automated Battery (CANTAB), at two time points spaced a decade apart.

In the second part, researchers studied sets of twins, assessing both leg power and brain structure using magnetic resonance imaging (MRI).

It’s also worth understanding how leg power was measured.

• Researchers assessed explosive leg power using a leg extension power rig.

• Subjects sat in a chair with their arms folded while one leg pressed explosively against a pedal until fully extended.

• Each participant performed three attempts, and the best result from the stronger leg was used in the final analysis.

This is similar to the leg extension machine at the gym, hence the thumbnail.

Stronger Legs Predicted Bigger Brains

So, what did the researchers find?

Leg explosive power independently predicted protection against age-related cognitive decline.

Importantly, this association remained significant even after adjusting for heart disease, diabetes, blood pressure, fasting glucose, smoking and alcohol habits, IQ, and socioeconomic status.

Quoting directly from the paper:

To put some numbers to the quote, an increase in leg explosive power of just 40 watts corresponded to the equivalent of being 3.3 years younger cognitively.

That alone is fascinating.

But let’s be honest — the twin data are the really jaw-dropping part.

Over the course of 12 years, twins who were stronger at baseline showed significantly less decline in both cognition and brain volume.

This pattern appeared across twin pairs, including identical twins.

Technically, the identical twin subgroup narrowly missed “statistical significance” because the sample size was smaller (identical twins are much rarer) but the pattern was remarkably clear, as you can see for yourself.

The stronger twin (light gray) consistently showed better preservation of cognitive performance over time than the weaker twin (dark gray).

• Here, the Y-axis represents the change in cognitive score over time.

• Anything above 0 indicates improved cognition, whereas anything below 0 indicates worsening cognition.

• So, remarkably, the stronger twins consistently showed improved cognition, while the weaker twins showed worsening cognition.

That’s not just a matter of slowed decline… it’s a complete directional reversal!

And the MRI findings paralleled the cognitive results.

The stronger twins had greater gray matter volume — the actual brain tissue involved in information processing, movement, memory, and emotion.

Simply put: the stronger twins literally preserved more brain tissue with aging.

This is the beginning of a remarkable story — one suggesting that muscle, and particularly large lower-body muscle groups, may play a major role in protecting the aging brain.

But of course, the next question is: How?

And the answer to that question is where the practical insights begin to unfold.

In the rest of this letter for StayCurious Metabolism Premium members, we’re going to dive into:

• How your muscles literally signal your brain to grow

• The positive feedback loops among exercise, blood sugar control, and brain health

• The relationship between vascular health and cognition

• Protocols: Exercise and supplemental compounds to support long-term brain health

If you’re someone who wants to see a squat as more than just a mechanical stimulus for muscle growth — someone who likes to see the awe, elegance, and hidden interconnectedness in biology — I’d love to invite you to join the StayCurious Metabolism community.

Come find out why it has become a top science newsletter on Substack globally, and why so many readers say their subscription has been one of the best investments they’ve made in their health journey.

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Imagine you could know only 7 measures about your health.

No full-body MRI. No 200-page blood panel.

Just 7 measurements that, together, tell you as much information as possible about your overall health.

Which 7 would you choose?

I was recently asked this question, and I loved it because it’s both intellectually difficult and incredibly practical. It forces you to separate signal from noise—to ask what actually matters. What can you use?

So that’s exactly what we’re going to do!

By the end of this letter, you’ll have a 7-point report card on your health.

More importantly, I promise you’ll understand each metric—perhaps even better than your average doctor. I think I can deliver on that provocative promise. At least, I can promise you’ll have information your doctor doesn’t.

And, most importantly, how you can improve those markers to increase your chances of living a longer, healthier, and hopefully happier life.

1) Waist-to-Hip Ratio

Forget the scale. And while we’re at it, let’s put BMI to bed.

Neither tells you what you really want to know.

Waist-to-hip ratio does.

Why?

Because it isn’t simply a measure of how much fat you carry. It’s a measure of where you carry it. And body fat is like real estate: Location, Location, Location!

Location matters.

Fat around your hips and thighs is relatively metabolically benign—and can even have some beneficial hormonal functions. (One more reason I’m not proud of my congenital pancake ass. Hey, don’t laugh! It’s a serious condition! I sincerely fear hard chairs.)

The fat you should worry about is visceral fat: the fat packed inside your abdominal cavity around your organs.

Visceral fat secretes inflammatory molecules, promotes insulin resistance, and disrupts metabolism throughout the body.

That’s why higher visceral fat is associated with cardiovascular disease, dementia, and premature death.

As a case in point, here’s a little doodle drawn from an earlier letter showing just a few of the ways visceral fat impairs brain health—consistent with recent 2026 research published by investigators at Harvard and other institutions, showing that higher levels of visceral fat are tightly linked to faster brain shrinkage and poorer long-term cognitive function.

Or take cardiovascular disease.

In one large study of more than 27,000 participants across 52 countries, researchers compared different measures of obesity—including body mass index (BMI) and waist-to-hip ratio—to determine which best predicted heart attack risk.

BMI showed only a modest association, and that relationship largely disappeared after accounting for waist-to-hip ratio.

Waist-to-hip ratio, by contrast, exhibited a striking dose-response relationship: as waist-to-hip ratio increased, so too did the risk of heart attack.

Individuals in the highest quintile of waist-to-hip ratio had a ~75% increase compared with those in the lowest quintile, even after adjusting for age, sex, geographic region, and smoking status.

The authors concluded:

But it gets even more interesting (and actionable) …

Visceral fat doesn’t just increase risk directly.

It also changes what other biomarkers mean.

Take Lp(a), one of the most feared cardiovascular risk factors.

Lp(a) is essentially an LDL-like particle with an extra protein attached—the apolipoprotein (a) tail—that makes it particularly sticky and more likely to contribute to plaque formation.

It’s also ~90% genetically determined.

Roughly one in four people has elevated Lp(a), and conventional wisdom says that if you’re one of them, there’s not much you can do. I’m in that group.

But I’m not worried because that’s not the full story.

Most of what we know about Lp(a) comes from populations that are metabolically unhealthy. And one of the hallmarks of metabolic dysfunction is—you guessed it—excess visceral fat.

So, researchers asked a simple question:

Does Lp(a) behave the same way in people with low vs. high weight-to-hip ratio?

In the rest of this letter for StayCurious Metabolism Premium members, we’ll dive into:

• The science behind each of these 7 metrics

• The optimal thresholds worth targeting

• Practical tools that can improve each number.

No matter where you are on your health journey, I promise you’ll find something here that’s valuable.

So, if you’re looking for nuanced, evidence-based health content, I’d love to have you join the community that’s made StayCurious Metabolism the world’s fastest-growing premium Science Substack.

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But over the past several years, one thing I’ve learned is that even the most fantastical claims occasionally contain a kernel of valuable truth.

So, when I hear people talking about the “Wolverine Stack,” named after the Marvel superhero famous for being nearly impossible to kill because he can regenerate damaged tissues and regrow parts of his body—my skepticism alarm goes off, just like yours probably does.

Honestly, fair enough.

After all, that kind of regeneration belongs in comic books. (Or perhaps in an axolotl).

But then I started to see examples of absolutely wild recovery stories.

A recent, shocking example comes from Dan Mace, the Chief Creative Officer of Beast Philanthropy.

If you don’t know, MrBeast is the world’s largest YouTuber by far. His main channel has nearly 500 million subscribers, and he’s one of the world’s youngest billionaires. Even now, he’s only 28.

Okay, but let me not reveal my jealousy any further. Back to Dan.

After suffering a severe facial injury, including a broken nose and fractured zygomatic bone, Dan tried the Wolverine Stack (BPC-157 + TB-500).

This is what happened.

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This recovery story is remarkable, even if it were just a one-off.

But it isn’t.

That was my first surprise.

My second surprise came when I started digging into the scientific literature.

What I found suggested that this wasn’t merely an anecdote or internet folklore. There were plausible biological mechanisms, a growing body of evidence, multiple studies published in top-tier journals like Nature, and even Phase 3 human trial data.

And that's where things start to get really interesting.

Today, I want to show you those data so we can separate fact from fiction.

Or, more accurately, uncover the fact hidden within the fiction.

Now, let me be clear about what I’m talking about here.

• The Wolverine Stack refers to a combination of two peptides: BPC-157 and thymosin beta-4 (T-β4)/TB-500.

• We’ve covered BPC-157 previously (HERE), so today most of our focus will be on T-β4/TB-500.

At the end, we’ll bring everything together and talk about the biological logic behind combining these two peptides.

Why So Popular?

Just a quick note on why this is becoming more popular: The simple answer is that pre-existing interest and experimentation in the biohacker community has been amplified by celebrity influence, including discussions from influencers like Joe Rogan and actors such as Matt Damon and Ben Affleck.

Sadly, I couldn’t find any commentary from Hugh Jackman on the Wolverine Stack, which feels like a missed opportunity given the name.

There is clearly substantial interest in these compounds. I’ve seen it echoed repeatedly in our own StayCurious community as well. Shout out to Michael!

Now, to be clear, I don’t use terms like influencer or biohacker as a pejorative.

Sometimes meaningful advances come from unexpected places, or from individuals willing to experiment on themselves long before the academic establishment takes notice. History is full of such examples.

But I won’t climb onto my soapbox about incentive structures in science. Let’s get to the meat of the matter.

Defining Our New Players: T-β4 & TB-500

So, let’s quickly define what T-β4 and TB-500 actually are.

T-β4 is the parent compound.

It’s a highly abundant small protein naturally found inside human cells and circulating throughout the body.

The primary role of T-β4 is to act as a reservoir for a protein called actin.

Actin is part of the cell’s internal skeleton, and one of the key structural proteins that cells use to rebuild their scaffolding and, importantly, to “crawl” from place to place.

To quickly distinguish between the two compounds:

• T-β4 is the parent compound.

• TB-500 is a synthetic fragment of T-β4, corresponding to the portion that binds actin.

In other words, TB-500 is a small functional chunk of T-β4. They’re technically different molecules, but because most of the research has been conducted on T-β4, I’ll primarily use that term going forward.

How T-β4 Helps Tissue Heal

Now, to understand why this matters, think of actin as a critical building block for tissue repair.

If actin is the raw material, T-β4 is essentially the storage warehouse.

When tissue is damaged, having a readily available reservoir of actin helps cells mobilize and rebuild.

Specifically, T-β4 promotes:

1. Cell migration, which is critical for tissue repair

2. The growth of new blood vessels (angiogenesis)

3. Survival pathways that keep cells alive

4. And it dampens excessive inflammatory signaling so the repair process isn’t overwhelmed by collateral damage.

Those are the boring mechanistic details.

Where does the science actually apply?

Quite impressively, all over the place.

• The earliest applications focused on skin wound healing.

• The strongest direct human evidence actually comes from the eye.

In one randomized, double-blind, placebo-controlled Phase 3 trial, treatment with T-β4 resulted in complete healing in 6/10 patients, compared with just 1/8 in the placebo group.

Patients also experienced significant improvements in comfort and disease severity, with no significant adverse effects reported.

It’s worth remembering that T-β4 is not some exotic synthetic molecule. It’s a naturally occurring repair signal that is already present throughout the body during development and adulthood. Of course, that doesn’t guarantee safety at higher doses.

But conceptually we’re amplifying an existing repair pathway rather than introducing something entirely foreign.

So, imagine my surprise when I started digging deeper into the literature on the peptides behind the Wolverine Stack and discovered, not just Phase 3 human trial data on eye applications, but even more interesting data on the heart

Specifically, a series of studies published in Nature found that T-β4 may help regenerate heart tissue after a heart attack!

The images are frankly hard to believe… until you see them with your own eyes.

Let’s take a look…

In the rest of today’s letter for StayCurious Metabolism Premium members, we’ll dive into:

• Evidence that T-β4 can repair the heart after a heart attack.

• The musculoskeletal applications that are making T-β4 popular among athletes

• The biological logic behind combining T-β4/TB-500 + BPC-157 in the “Wolverine Stack”

  • And I’ll finally answer the question many of you have been asking: “How can I access these tools safely?”

If you’re someone who enjoys investigating data with an open mind and is curious about the emerging frontier of human bioengineering, now is as good a time as any to join the StayCurious Metabolism community.

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But the story of visceral fat just took a fascinating turn.

A new 2026 study from an international team of researchers spanning Harvard, Israel, and Germany suggests that the more exposure you have to visceral fat over the course of your life, the faster your brain shrinks.

What makes this study particularly compelling is the methodology.

The Study in a Nutshell

The researchers drew from four previous lifestyle randomized controlled trials in which participants underwent:

• Visceral fat measurements

• Brain MRI scans and

• Cognitive testing

Collectively, this created a remarkably powerful dataset for examining the relationships among visceral fat, cognition, and actual brain structure.

Importantly, it also allowed the researchers to begin to tease apart a critical question: Does brain health improve because people lose weight in general, or because they specifically lose visceral fat?

I won’t starve you for the punchline...

Among participants who underwent brain MRI scans and visceral fat imaging, lower long-term visceral fat exposure was associated with slower brain atrophy.

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Notably, this relationship was not observed for subcutaneous fat, the type that sits beneath the skin and jiggles when you poke it.

And the association remained significant even after accounting for numerous potential confounders, including age, sex (the noun, not the verb), changes in BMI, adherence to the prescribed diets, and other relevant variables.

That’s a powerful finding.

However, for those of us who spend our days immersed in metabolism research, it may feel intuitive… even unsurprising.

But what is more surprising and more interesting is: How?

• If there is a causal relationship between visceral fat and brain shrinkage, what are the biological mechanisms?

• And how can we use those insights to preserve cognitive function, maintain mental sharpness as we age, and potentially reduce our risk of neurodegenerative diseases such as Alzheimer’s?

That’s exactly what we’re going to explore in today’s deep dive.

And I promise you’ll walk away with a practical insights and tools you may not have thought about before.

In the rest of this letter for StayCurious Metabolism Premium members, we’re going to dive into the mechanisms by which visceral fat talks to (and abuses) the brain.

We’ll also cover evidence-based strategies for reducing visceral fat, including:

• The #1 nutrient shown to reduce visceral fat without cutting calories

• A peptide backed by randomized controlled trials that can slash visceral fat like a hot knife through butter.

If you’re someone who enjoys exploring the frontier of metabolic health and practical ways to optimize your biology, come discover why StayCurious Metabolism is the fastest-growing premium science newsletter on Substack.

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Ulcers opened in my intestines.

Food became dangerous.

There was a real chance I could lose my colon entirely. I was diagnosed with inflammatory bowel disease.

And for years, my life revolved around pain, bathrooms, medications, fear, and this constant question: Why was my gut on fire?

Now, after a PhD in metabolism, after medical school, and far more importantly, after nearly a decade of experimenting on myself obsessively, I have answers.

And, I have tools.

But back then?

I had no idea what was happening to my body. And because of that, I suffered more than I could have imagined. (And I watch a lot of movies with torture scenes.)

So, I’ve spent a lot of time thinking about this question:

If I could go back to the moment of diagnosis, knowing what I know now: How would I put out the fire as fast as possible?

This letter will answer that question, not just for people with inflammatory bowel disease. But for anyone whose gut feels broken.

Because gut problems exist on a spectrum. And the truth is, most people are somewhere on it. But you don’t need to be.

Let me show you how.

Let me quickly lay out how this is gonna go.

• I’m going to start by outlining free foundational tools to support gut health — tools that you can implement immediately, even while reading this letter.

• Then we will turn to some dietary principles beyond just “cut out sugar and processed food,” which I hope is implicit.

• Finally, we will turn to the ultimate peptide stack for gut health. Nothing you need to inject, but powerful peptides nonetheless to help with multiple elements of gut healing.

Some of these tools will be free.

Some of them are, transparently, investments.

But if I may insert a personal quip, I’ve found that sometimes it’s worth investing in quality food and, yes, supplements…otherwise, you might end up spending over $2,000 out of pocket for a colonoscopy right after moving to the United Kingdom to do your PhD while living on a somewhat limited scholarship stipend… and then needing to eat sardines at 76 pence a can from Tesco market for months to make up the difference.

True story.

Free Foundational Tools for Gut Healing

Let’s begin with the freest and most accessible tool you have right now: breathing and stress reduction.

Now, if you’re closed-minded — like I admittedly was when I was first diagnosed — this probably sounds like a bunch of woo-woo fluff. It seems far-fetched to imagine that something as simple as chilling out could heal an inflamed gut.

But let me open your eyes to some astonishing science that begins with this hard fact:

You can directly feed your gut bacteria without eating.

How does this work?

• Well, you have glands in your gut, in particular, ones called Brunner’s glands, shown in green below.

• These secrete something called mucin, which nourishes beneficial gut bacteria and, at a very high level, helps build resilience in your gastrointestinal system.

The question then becomes: How do you influence Brunner’s glands?

Well, your gut is directly connected to your brain via something called the vagus nerve. And this nerve, as you may have guessed, is influenced by brain activity and your mental state.

So, in effect, there’s a direct, literal line going from your brain to glands in your gut that can feed or starve bacteria.

*Brunner’s glands are shown here with a green stain. The pathway on the right illustrates how stress reduction can activate the vagus nerve, stimulating mucin production by Brunner’s glands to support the microbiome and improve gut barrier function.

The consequences are tremendous.

For example, if you cut the vagus nerve, or negatively alter the input going through it to these glands, it can cause:

• Severe bloating

• Impairment of intestinal barrier function (“leaky gut”)

• And it can starve good gut bacteria

Quite literally, this is a direct pathway through which your mental state can heal or harm your gut.

*What you’re seeing here is what happens when Brunner’s glands are destroyed (BG-DTx). The result? Extreme bloating. The stomach blows up like a hot-air balloon.

Without getting too deep into the nitty-gritty — although if you want to dig through the 163 panels in the source paper, have at it — the punchline is this:

Stress-reduction activities help feed your gut and heal your gut lining, whereas chronic psychological stress most likely destabilizes and harms it.

The obvious caveat here is that much of the controlled experimental data was collected in animals. However, the exact same biological operating systems exists in humans.

So, I would literally bet my colon that these basic science findings translate to humans.

The question then becomes: how do you activate your vagus nerve in a way that helps nourish your gut?

In the rest of this letter for StayCurious Metabolism premium members, we dive into

• How to leverage your vagus nerve to heal your gut

• Dietary principles that matter most (hint: not fiber)

• The most powerful peptides for gut healing (no injections required).

  • As well as how to access prescription peptides from my peptide doctors

This is not the kind of knowledge I learned in medical school. It’s better. It’s the kind of knowledge I wish I’d had when my body was falling apart. Because if I had understood these mechanisms earlier, I genuinely think I could have avoided years of suffering.

So, if you want the full deep dive come find out why StayCurious Metabolism subscribers getting goosebumps and call these letters ‘life-changing.”

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It’s often called “Miracle-Grow for neurons” and frequently comes up in discussions about enhancing cognitive performance and protecting against dementia.

But what if I told you there’s a compound rumored to be 10 million times more powerful than BDNF?

That’s the buzz around Dihexa.

When I first heard these claims, I had my usual two-pronged reaction:

1. Skepticism

2. Curiosity

Any assertion that biological molecule ‘A’ is seven orders of magnitude more potent than biological molecule ‘B’ sounds far-fetched, especially when molecule ‘B’ (BDNF) is already so powerful.

But sometimes, buried in extreme claims, there’s a vein of useful truth, as is the case here.

Dihexa has gained traction in biohacking and research circles as a cognitive booster and potential anti-dementia therapeutic.

When I dug into the literature, I came away more optimistic than expected. Even if Dihexa won’t turn you into Doogie Howser overnight, the data suggests this is an orally bioavailable compound (it can be taken by mouth) and can cross into the brain where it enhances neural function and memory.

Today, we’ll explore the story of Dihexa.

From a Fragile Molecule to a Brain-Penetrant Drug

To truly understand Dihexa, we need to start with what this molecule is, and the challenges researchers had to overcome to create it.

That story begins with a natural compound called angiotensin IV.

For years, angiotensin IV has been known to enhance memory in animal models, making it an early candidate for treating dementia in humans.

But it has two major drawbacks:

1. It’s rapidly broken down by enzymes in the body, within minutes

2. Itdoesn’t easily cross the blood-brain barrier

So, researchers faced a clear challenge: could angiotensin IV be modified to overcome these limitations?

Ideally, they needed a compound that:

• Could be taken orally

• Remain stable in the body

• Reach the brain

• Enhance learning and memory

Dihexa is the result of that effort.

Let’s look briefly at some of the data.

What Happens When You Test It?

One of the first models used was the scopolamine-induced cognitive deficit model. Scopolamine blocks acetylcholine activity and, at high doses, produces Alzheimer’s-like symptoms in animals.

Researchers then test memory using tasks like the Morris water maze, where animals must learn and remember the location of a hidden escape platform in a pool of opaque water.

In these experiments, scopolamine impaired memory, as expected, i.e. animals took longer to find the platform.

But with increasing doses of Dihexa, performance improved, eventually restoring memory to normal, healthy levels.

Notably, Dihexa was administered orally, suggesting the compound remains active when consumed this way.

Researchers then tested Dihexa in older rats without drug-induced memory deficits.

These animals weren’t pre-selected for impairment, meaning any observed effect might actually underestimate the compound’s impact.

Even so, Dihexa improved learning and memory, again.

Dihexa Stimulates “Synaptogenesis” (Neuron Growth)

At the cellular level, the findings were just as intriguing.

Treated animals showed increased “synaptogenesis” —the formation of new connections between neurons, which is the biological foundation of learning and memory.

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In summary, this line of research led to the development of Dihexa, a modified version of a naturally occurring cognitive-enhancing compound.

It can be taken orally, remains stable in the body, crosses into the brain, promotes synaptogenesis, and improves learning and memory in animal models.

That’s promising, and undeniably interesting.

As the authors themselves put it:

For neuroscience writing, that’s about as close as it gets to a mic-drop moment.

So there’s promise here.

But we’ve just scratched the surface.

Dihexa works by triggering a signaling cascade that’s well characterized in neurons, activated by healthy brain insulin signaling and BDNF.

But Dihexa does it a bit differently...

In the rest of this letter for Stay Curious Metabolism Premium members, we dive into:

• How Dihexa actually works (and why it’s different)

• A critical evaluation of the “10 million times” claim

• What the human trial data shows & who’s most likely to benefit

• What people are experiencing in the real world

• My personal experience with Dihexa

• How to source and dose Dihexa

If you’re passionate, or even just curious, about the frontier of metabolism and brain health, and you want to join a community of genuinely curious people, now is as good a time as any.

Come see what makes StayCurious Metabolism such a special community, why it’s the fastest-growing premium letters on the platform, and a Top 2 Overall Bestseller in Science in its first year.

Get ready to stimulate those neurons…

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I know that’s a strange place to start but bear with me.

My mom makes the most incredible Chilean sea bass. It’s one of my favorite meals. The skin is thick, fatty, and perfectly crisped in a cast-iron skillet with ginger butter.

One day, craving that exact dish, I decided to make it myself.

Mistake.

To get the skin right, the cast iron needs to be screaming hot. So, I put the pan on the stove and waited. Then my phone rang. The call was important, and I stepped outside to get better reception. We got talking. I got distracted.

I forgot about the fish.

The next thing I knew, my home’s fire alarm was blaring.

I sprinted inside. In my haste, I’d left a dish towel draped too close to the stove. It had caught fire. I grabbed it, threw it into the sink, turned on the water, and watched the flames disappear.

Crisis averted. But if I’d been even a minute later, I might have lost the entire house.

Why am I starting there? Because the lesson isn’t just that I should leave the sea bass to my mother. It’s that prevention is everything.

Prevention is the difference between a secure home and a pile of ashes.

And it’s also the difference between a healthy brain and a demented one.

The First Smoke Detector for Alzheimer’s Disease (p-tau217)

For most of human history, we’ve been trying to fight Alzheimer’s disease without a smoke detector.

By the time symptoms appear, the fire has often been smoldering in the brain for decades. We’ve been forced to wait until smoke is pouring from the windows before realizing something is wrong.

But that era is ending.

A new blood biomarker called p-tau217 is giving us the ability to detect Alzheimer’s disease years before memory loss begins, potentially transforming how we diagnose, monitor, and eventually prevent one of humanity’s most feared diseases.

In other words, we’re finally getting a smoke detector for the brain.

(And boy, do I need it!)

To get to the heart of our story, we’ve been living in an era where Alzheimer’s disease has been diagnosed as a syndrome. In other words, you identify a collection of signs and symptoms, and if it walks and talks like Alzheimer’s disease, you conclude it probably is Alzheimer’s disease.

The problem?

By that point, the house is already burning down.

But that’s beginning to change.

Today, we have blood biomarkers that can detect Alzheimer’s pathology years before cognition starts to decline. There are several promising candidates, but perhaps the most revolutionary is called p-tau217, short for: phosphorylated tau at threonine 217.

p-tau217 is arguably the most important Alzheimer’s biomarker breakthrough of the past decade, bringing us closer to diagnosing Alzheimer’s disease with a simple blood test.

What Is p-tau217?

Tau is a normal protein found inside neurons. One of its jobs is to stabilize structures called microtubules, which function as part of the cell’s internal skeleton and transport network (1).

In Alzheimer’s disease, tau becomes abnormally modified through a process called phosphorylation, which is the addition of phosphate groups at specific locations on the protein.

Think of these as little molecular tags that alter the protein’s behavior and contribute to the disease process (2). One important site where this occurs is the 217^th amino acid in the protein, which happens to be the amino acid threonine 217… hence the name: p-tau217 (3).

As Alzheimer’s pathology develops, levels of p-tau217 rise dramatically (4).

Importantly, this signal doesn’t remain confined to the brain. Some of it spills over into the bloodstream, where it can be measured with a simple blood test (5).

The power of p-tau217 isn’t just that it’s measurable, it’s that it’s remarkably specific. Many brain biomarkers increase whenever the brain is injured. Stroke, concussion, multiple sclerosis, and other neurological conditions can all elevate various markers of brain damage.

But p-tau217 tracks much more closely with the biological processes driving Alzheimer’s disease itself.

That’s why p-tau217 is the sexy new smoke detector for Alzheimer’s disease.

It’s also far more accessible than traditional diagnostic tools.

Imagine going to your doctor for routine blood work—fasting glucose, cholesterol, triglycerides—and simply adding a p-tau217 test to the panel.

No PET scan. No spinal tap. No multi-thousand-dollar imaging study.

Just a blood draw.

• And despite its simplicity, p-tau217 predicts the presence of Alzheimer’s pathology with an accuracy exceeding 90% in many studies.

• Even more remarkably, it appears capable of detecting the disease process 10 to 20 years before dementia develops.

In terms of our kitchen-fire analogy, the dish towel has just begun to smolder.

The smoke detector is sounding. The house is still standing. And you can politely tell the person on the other end of the distracting phone call, “please excuse me for a moment while I avoid becoming homeless.”

And that’s precisely why the field is so excited!

p-tau217 represents a shift from symptom-based Alzheimer’s diagnosis to biology-based Alzheimer’s diagnosis.

We’re finally getting a smoke detector.

The next question, of course, is: what do you do with this information?

Imagine p-tau217 is available at your clinic tomorrow. Your doctor orders it. It comes back elevated.

No symptoms. No memory problems. No cognitive decline.

Just a smoke detector telling you there may be a fire starting somewhere in your brain.

So now what?

In the rest of this letter for StayCurious Metabolism premium members, we’ll explore:

• Transitioning from accurate diagnostics to prevention protocols

• An insider’s look into the future I’m trying to build for me and you

• An example protocol of how someone might begin acting on this information today

If you’re the kind of person who gets excited by the intersection of metabolism and emerging technology, consider joining the StayCurious Metabolism community and see why it has become one of the fastest-growing science newsletters on the platform.

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When GLP-1s for weight loss started becoming big and everyone was talking about how they would change obesity medicine, I was a strong skeptic.

This has happened before: medicine and big pharma tell a compelling story about a miracle drug — then years later we find out we didn’t have the whole story, and people ended up harmed, sometimes critically.

However, the more I read about GLP-1s and their newer evolutions, the more my opinion shifted.

In fact, my perspective has even leapfrogged from “these are being overhyped” to “maybe they’re not being hyped enough.”

Or more precisely, maybe the benefits people are hyping are only the tip of the iceberg.

Because the deeper I dug into the literature, the more I realized these drugs are acting on systems far beyond weight: the brain, addiction circuitry, cartilage, inflammation.

There are now data suggesting GLP-1 signaling might directly reduce both amyloid and tau pathology, the hallmarks of Alzheimer’s disease.

Then, I thought:

Maybe we’re not looking at just obesity drugs. Maybe everyone should be taking a GLP-1, if only at a low dose?

Or maybe I’m just drinking too much of the Kool-Aid and missing potential harms: muscle loss, bone health, blindness, things we haven’t discovered yet?

Today I’m going to demystify all of it for you, with rigor, and give you practical insights I guarantee you won’t find elsewhere: how different generations affect lipids and cholesterol differently, tools to potentially build muscle while on GLP-1s.

All of it.

My goal here is to make the definitive guide to GLP-1s: one that synthesizes insights gained from hundreds of research papers and years of study into one place.

*Note: I have no conflicts of interest with the pharmaceutical industry whatsoever.

This letter is a StayCurious Metabolism Premium special.

In it, I consolidate insights from dozens of prior letters, hundreds of studies, and years of research into one place.

Fair warning: this one’s a lot… >6,000 words… and likely to grow over time with your input. But I genuinely want this to become your one-stop shop for understanding GLP-1s, so pleasespend some time with it.

We cover:

• Muscle preservation, and even building muscle on GLP-1s

• Bone health, eye health, and other potential risks

• Different generations of GLP-1s and poly-agonists

• The new oral GLP-1, orforglipron

• Weight-independent benefits on the brain and joints

• Combination therapies designed to build muscle during fat loss (I have one in my fridge right now)

• Addiction and alcohol use disorder

• Preventing weight rebound after GLP-1 discontinuation

• What to do About “GLP-1 Resistance”

• And more

I realize I’m asking you to invest in this knowledge. But your subscription, which averages out to roughly 67 cents per premium letter, is what allows me to continue building StayCurious Metabolism into a long-term multimedia education platform dedicated to improving public understanding of metabolism and health.

And I take that responsibility seriously. If you join me, I’ll do everything I can to make it worth your while.

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“This work establishes that damage to aging proteins previously thought to be irreversible can be repaired.”

That’s the line from a new paper published 3 days ago in Nature Communications.

Bold words.

But they’re backed by data showing—for the first time ever—that age-related protein damage can be reversed.

Now, there are caveats. We haven’t found the Fountain of Youth just yet. But I’d be lying if I said this paper didn’t bring us one jump closer.

So, let’s do like CMLase to N^ε-carboxymethyl-lysine... and break this down. (That horribly nerdy joke—if it didn’t scare you away—will make sense in just a moment.)

First, though, I need to arm you with a little background.

And it starts with a simple question:

What Causes Aging?

The answer, of course, is many things.

1. But one of the foundational drivers of aging is damage to what’s known as the “extracellular matrix.” Think of it as the rebar in reinforced concrete—the scaffolding that holds your cells and tissues together so you don’t simply become a homogeneous blob.

2. The problem is that, over time, sugars attach to proteins within the extracellular matrix and begin to damage them.

3. You can think of it as a kind of biological rusting. And to be clear, these aren’t just passive biomarkers or innocent bystanders. They’re not merely correlated with aging—they actively drive it.

4. These modifications, known as “advanced glycation end products” (AGEs), activate several inflammatory pathways, including a receptor appropriately named RAGE. That signaling fuels chronic inflammation, creating a slippery slope toward aging.

This accumulated damage, produced by the normal metabolic processes that are almost impossible to avoid, leads to more oxidative stress, more mitochondrial dysfunction, and more inflammation, perpetuating a vicious cycle.

Organs age. They begin to fail. Eventually, we die.

Or, if you want another analogy:

Imagine your body is like a car. For years it runs beautifully. But every year, normal environmental conditions leave behind just a little more rust. At first, it’s cosmetic and doesn’t impact how your car runs. But then, the suspension weakens, the frame stiffens, and parts begin to fail, and the engine gradually conks out on you.

The rust doesn’t just tell you the car is old—it causes it to become old.

That’s what’s going on here, irreversible molecular rust.

Sugars slowly react with proteins throughout your body, permanently damaging the scaffolding that holds your tissues together.

And it’s worse that my car analogy suggests.

Because once that rust forms, it doesn’t just sit there. It sparks inflammation, oxidative stress, and mitochondrial dysfunction, accelerating even more damage.

So, here’s the main point and the big problem:

Once these advanced glycation end products form, they become embedded in our tissues. A slow poison. And they’ve long been thought to be irreversible.

Our bodies simply don’t have the molecular tools to remove them.

At least... not until now.

Building A First-of-its-Kind De-Rusting Protein

The researchers set out to build one—a molecular tool capable of de-rusting our organs, i.e. removing chemical modifications once thought to be permanent, modifications that are not only associated with aging but actually help drive it.

And if they can do that, it’s a big deal.

So, here’s exactly what they did, what they built... and what it means for you and me.

Among the many types of AGEs, one stands out as particularly abundant and particularly nasty: N^ε-carboxymethyl-lysine, or CML for short.

If you want help remembering CML, just think “Cellular Marshmallowization Layer.”

It’s not what it stands for, but it’s pretty much what’s going on.

CML is formed when sugars react with a particular amino acid, lysine (the “L” in CML), which is one of the basic building blocks of proteins. In the process, the positively charged lysine gets converted into a negatively charged “carboxymethyl” (the “CM”) group.

That charge flip alone is enough to distort structure and disrupt function.

But CML doesn’t stop there.

CML is also the primary trigger for RAGE (4, above)—the receptor I mentioned earlier—which activates NF-κB, one of the master switches of inflammation in the body.

For example, in the brain, CML accumulation has been linked to oxidative stress and mitochondrial damage in microglia, the immune cells of the central nervous system.

So CML is both structurally destructive and a signaling molecule that perpetuates chronic inflammation. A double threat.

And here’s the kicker: CML has historically been categorized as “chemically stable and irreversible.”

Once the CML modification is locked onto a protein?

Game over.

No known biological tool could undo it.

Until the researchers in this paper engineered one.

Now, for my nerdy joke to land: “CMLase” is the name of the enzyme they built.

*Nuance note: If you want some scientist vocabulary insider knowledge, the suffix -ase refers enzymes that break down “X,” where “X” is the prefix. So “lactase” breaks down “lactose” sugar. And my late dog with my sock would be a “sockase.” You get the idea.

CMLase removes the CML off proteins and restores the original structure and function.

Hence: “Let’s do like CMLase to CML... and break this down.”

I told you it would make sense. Whether it’s actually funny is a separate conversation I’m choosing not to have.

Anyway, this is effectively a reversal of molecular rusting.

How They Built It: Engineering a Molecular De-Ruster

Now, I want to back-up and answer the question: “how did they build it?”

Because the method is as important as the ‘end product.’ (Another horrible nerd joke. Did you catch it?)

• Observation: CML has a chemical structure that closely resembles the amino acid glycine. And there exists a well-known family of enzymes that chew up glycine.

• So they asked: Could we take one of those enzymes and force it to evolve to chew up CML instead?

Think of it like this:

• You have a key that opens Lock A (glycine).

• You need a key that opens Lock B (CML).

• Locks A and B look pretty similar—but not identical.

• So instead of building a new key from scratch, you start with the key you have and file down the edges until it fits the new lock.

That’s essentially what they did. But the “filing” involved screening over 500 million enzyme variants across five rounds of what’s called “directed evolution.”

Directed evolution deserves a brief detour because it’s a brilliant method—and one that won its inventor, Frances Arnold, the Nobel Prize in Chemistry in 2018.

The concept is simple: mimic natural evolution, but in the lab, at warp speed.

You take an enzyme. You introduce random mutations into its DNA. You screen millions of variants for the ones that work best.

Then you take the winners, mutate them again, and repeat.

Each round selects for better and better performance.

In this case, the researchers started with an enzyme from a heat-loving bacterium called Calidithermus roseus (CrGO). The enzyme had a tiny, barely detectable ability to act on CML when it was attached to a protein fragment.

From that faint whisper of activity, they amplified it through directed evolution into a full-blown CML-cleaving machine.

The final enzyme—CMLase—specifically chews up CML and restores the “unrusted” proteins.

Critically, it doesn’t touch other amino acids. And it doesn’t destroy the protein it’s repairing.

It’s not a molecular wrecking ball. It doesn’t demolish the building—it just scrapes off the rust.

It’s a precision tool.

Which raises the only question that actually matters: Did it work?

Not in a test tube. Not in theory.

In real human tissue.

In the rest of this letter, StayCurious Metabolism Premium members we dive into:

• The evidence from real human tissues—including lens proteins, arteries, and skin

• An honest discussion of what’s most exciting about this research, what hurdles remain before it reaches the clinic.

• High-yield strategies to reduce AGE formation that you can start using today.

If you’re ready to take your metabolic health education to the next level, I’d love to have you join the StayCurious Metabolism Premium community.

And unlike CML—if you don’t think you’re getting value—your subscription is completely reversible today. But based on community reviews and our retention rate, I think you’ll stick around.

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What if you didn’t need to sleep?

No, seriously!

A new article published in Nature Neuroscience explores a provocative possibility: what if we could replicate the restorative benefits of sleep without ever fully shutting down the brain?

Imagine staying awake for 24 hours a day without compromising memory, cognitive performance, or neurological health.

The trick would be to stop thinking about sleep as an all-or-nothing phenomenon.

Instead of turning off the entire brain at once, what if periods of restoration could occur locally, within specific neural circuits, while the rest of the brain remained awake and connected to the environment?

As strange as it sounds, evolution may already have provided a proof of concept.

Certain dolphins, seals, and bird species can engage in “unihemispheric sleep,” entering sleep in one hemisphere of the brain while the other remains awake, alert, and vigilant.

Which brings us to a bold and provocative question:

Is there a future in which humans no longer need to sleep at all?

That’s the question this paper forces us to confront.

And the answer is more plausible than I would have guessed.

What this paper does is demonstrate something that I believe is genuinely paradigm-shifting: The researchers showed that inducing sleep-like activity patterns in one hemisphere of an awake mouse’s brain produced the same molecular, electrophysiological, and even behavioral benefits as actual sleep—but only on that side of the brain.

The other hemisphere?

Completely unaffected.

Until it’s time to trade shifts.

Let me walk you through how they did it…

Why Sleep Exists: A “Brain Reset”

To understand why this paper matters, you need a bit of background.

During the day, as you learn, think, and experience the world, your brain’s synapses—the connections between neurons—get stronger. This is how learning works. But it comes at a cost: by the end of the day, your neural circuits are, in a sense, “saturated.”

Sleep exists, in large part, to “reset” those synaptic connections in the brain.

To prune back the noise while preserving the signal.

Or, by way of a reinforcing analogy…

Think of it like a whiteboard in a busy office. Throughout the day, people scribble notes, diagrams, and reminders all over it. By 5 p.m., it’s an unreadable mess (and some jerk has consumed the entire bottom corner scribbling nonsense about why Thor is the strongest avenger). Sleep is the janitor who comes in at night and selectively erases the clutter, ultimately keeping only what matters most.

This is called the “synaptic reset,” and it’s one of the main reasons why we sleep.

Now, the next key question:

What specific feature of sleep actually drives that synaptic reset?

The Rhythm of Sleep: “On” and “Off” Periods

During non-REM (NREM) sleep, which makes up roughly 80% of adult sleep, neurons don’t just go quiet. They do something far more interesting.

They oscillate.

Populations of cortical neurons rapidly alternate between two states:

• “On” periods: Bursts of intense, synchronized firing

• “Off” periods: Brief windows of near-total silence

It’s the neural signature underlying the slow waves you see on an EEG during deep sleep—those big, rolling, low-frequency waves that sleep researchers have studied for decades.

The strength and synchrony of these slow waves is slow-wave activity (SWA)

For our purposes, think of SWA as a biomarker sleep pressure.

SWA is highest when you’re most sleep-deprived, and it declines as you sleep.

Otherwise put, SWA is the brain’s built-in “tiredness meter.”

The big question has always been: Is this “on” and “off” oscillation just a marker of sleep doing its job? Like a thermometer reading a fever?

Or is it actually the mechanism—the thing that’s doing the work?

Is it correlation or causation?

This paper answers that question: Causation for sure!

And let me underscore what that means...

If you can mimic this pattern locally in the brain, then, in effect, you can begin to replicate the restorative functions of sleep without actually sleeping.

That sounds like science fiction.

But in the rest of this letter, I’m going to show you the data.

And it will blow your mind!

The rest of this letter is for StayCurious Metabolism Premium members.

This is one of those moments where I get to say: if you’re not already part of the premium community, this might be the time to make the leap!

If you’re a proper science nerd, what comes next is exactly the kind of thing that makes you fall even deeper in love with biology.

And, as much as I’d love to make all of my work freely available, the premium community helps fund many of my other projects and the broader mission of making metabolic health mainstream. So, if you have the means, membership is $8 per month and includes 12+ premium letters each month. That’s <67 cents per letter.

More importantly, it gives you access to a community that members routinely describe as an “oasis of nuance on the internet” and one of “the best investments I’ve made in my learning journey!”

Come find out why. I promise I’ll make it worth your while.

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Officially, it’s in clinical trials for diabetes.

Unofficially, it may represent something much bigger—a compound that reproduces some of the core metabolic effects of exercise itself.

If the early data continue to hold up, this could reshape how we think about treating insulin resistance, fatty liver, obesity, GLP-1s, and even exercise mimetics.

But before we get to the preclinical data and the human trials, I need to build a bit of biological foundation first.

AMPK: The Cell’s Fuel Gauge

The theory, and the challenges, begin with one of the body’s master metabolic regulators: AMPK.

AMPK functions as a kind of cellular fuel gauge.

During exercise, cells rapidly consume ATP—the body’s immediate energy currency.

As ATP levels fall, AMP levels rise, signaling that the cell is running low on available energy. In response, AMPK switches “on” and shifts the body away from energy storage and toward energy production.

If you want a cute mental image, it’s almost like AMPK flips “on” and the cell starts playing: “Burn, baby, burn—fat and carbs inferno!”

What? Too much? Sorry. Good song.

Anyway, the point is, AMPK activation leads to:

• Increased muscle glucose uptake

• Accelerated fat burning

• Increased energy expenditure

In theory, safely activating this pathway could mimic many of the metabolic effects of exercise.

It could lower blood sugar and improve insulin sensitivity—hence the “diabetes drug” framing.

However, it could also:

• Reduce fatty liver

• Increase calorie burn (more on that in a moment)

• Promote fat loss without muscle loss

So, for a long time, AMPK has been a highly desirable metabolic target.

But there’s been a challenge: manipulating AMPK safely has historically been difficult.

Activate it improperly, and you can end up pulling fuel into tissues without adequately burning it off—creating metabolic “traffic jams,” including excessive glycogen buildup in the heart. Not ideal. Highly efficient biceps are not much use if your heart has turned into that of a Sour Patch Kid.

But this new molecule, ATX-304, is different!

What is ATX-304?

At a high level, ATX-304 is an orally available “AMPK activator.”

Technically, it works by inhibiting the protein that naturally turns AMPK “off.” So it’s actually an inhibitor of an inhibitor. But to avoid confusing double negatives, we’ll simply refer to ATX-304 as an AMPK activator.

Of note, it’s not a peptide. It’s not injectable.

It’s a small molecule you can swallow in pill form with multifaceted effects on metabolism—including AMPK activation and apparent increases in energy expenditure.

In other words, it delivers a kind of metabolic one-two punch: pull fuel into cells, then burn it.

And that’s exactly what you’d want from an exercise mimetic.

So far, the data appear remarkably consistent with that hypothesis.

• In animals and early human trials: researchers are seeing improvements in glucose handling, insulin sensitivity, fatty liver, and body composition.

• In phase II human trials: patients with diabetes demonstrated improved blood sugar control, improved microvascular circulation, and reduced blood pressure.

But enough telling.

Let me show you the data.

And then we’ll talk about how people are already using ATX-304.

The Mouse Data

Let’s start with proof of concept in animals. Then we’ll move to humans.

Take a look at the graph below.

In this experiment, researchers started two groups of mice on an obesogenic high-sugar, high-fat diet.

However, one group also received ATX-304 (also called O304—because apparently they just wanted to confuse all of us).

• The group initially receiving ATX-304 is represented by black triangles.

• And you can see that, for the first 15 days, they gained essentially no weight despite the obesogenic diet.

But then comes the fun part!

The researchers flip-flopped the groups, now giving ATX-304 to the mice represented by the white triangles.

What happened?

A complete weight-inversion effect!

The animals that started taking ATX-304 rapidly lost weight, while the animals taken off of it gained weight.

Then, around day 56, the groups were switched again.

Like the ultimate weight yo-yo effect!

But that’s not even the best part…

Energy intake was higher in the groups losing weight at any given time point.

In other words, ATX-304 induced weight loss despite no reduction—and in some cases, even an increase—in food intake.

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What Happens to Energy Flow on ATX-304?

But if energy was being burned off:

• Where was it coming from?

• And where is it going?

Well, let’s consider some of the biological effects of AMPK:

• It increases the liberation of fat from fat cells (adipocytes)

• It supports beta-oxidation (the burning of fat in mitochondria)

• And it increases the uptake of glucose from the blood into muscle

This last aspect (glucose → muscle) deserves particular attention because of the mechanism involved.

• Normally, insulin triggers a signaling cascade in muscle cells.

• This causes GLUT4 glucose transporters to move from intracellular storage to the surface of the muscle cell.

• That, in turn, allows muscle to pull glucose out of the blood, improving blood sugar control and ultimately burning that glucose for energy.

All good.

However, in type 2 diabetes and insulin resistance more broadly, this signal becomes blunted.

Muscle cells no longer respond to insulin as effectively, leading to impaired glucose uptake and elevated blood sugar.

But there’s a metabolic back door.

There’s a way to partially circumvent this pathway that becomes activated during exercise and depends on, you guessed it, AMPK (red box).

AMPK activation—whether through exercise or ATX-304—allows muscle to pull glucose from the bloodstream without waiting for insulin’s permission.

It also improves insulin sensitivity, ultimately delivering a powerful metabolic one-two punch.

But that first effect (insulin-independent glucose update) is remarkable because it’s normally reserved for one physiological state: Exercise.

Except now, we can recreate it with ATX-304!

The animal data are remarkable.

The human data are encouraging.

But what people are reporting outside the clinical trials... that’s what really caught my attention…

In the rest of this letter for StayCurious Metabolism premium members, we will dive into how ATX-304:

• Improves glucose control

• Enhances exercise performance

• Reduces body fat while preserving muscle

Then we will turn to:

• The human clinical trial data

• How people are actually using it today

  • Real-world reports

  • Administration

  • Dosing & Access

If you want to join a community of curious people passionate about metabolic health, come see why StayCurious Metabolism is the fasting growing premium science newsletter on the platform, and why so many members call it the “best investment I’ve made in my healthy journey.”

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Legends surround it: that it can:

• Reverse wrinkles

• Accelerate healing

• Even protect against cancer

As I began researching GHK-Cu, I found it unusually difficult to separate fact from fiction.

But once you understand the mechanisms, the picture starts to come into focus.

You can begin to untangle the metabolic mystery and understand why this unusual copper peptide has exploded in popularity.

I’m going to walk through the data carefully.

I’ll explain the current state of the science and show you how GHK-Cu is being used in a way that is rigorous, nuanced, and hopefully understandable.

My goal here is not to oversimplify the science or exaggerate the claims, but to help you genuinely understand what’s known, what’s speculative, and why GHK-Cu has generated so much attention.

What is GHK-Cu?

To begin our journey, we first need to understand the foundational biology, which, frankly, I’ve never heard anyone publicly explain particularly well.

Let me see if I can do better.

GHK-Cu is a naturally occurring tripeptide-copper complex. That means it consists of three amino acids — represented by their single-letter abbreviations:

• G for glycine

• H for histidine

• K for lysine

• Combined with a copper (Cu) ion.

Hence, GHK-Cu.

Importantly, GHK-Cu is naturally produced by the body.

And GHK-Cu levels decline substantially with age: from roughly 200 ng/mL in your 20s to about 80 ng/mL by age 60.

Interestingly, this decline coincides with reduced skin density, impaired wound healing, and many of the features we associate with visible aging.

But is that merely an association, or is there something causal going on?

I’ll answer that question implicitly as we go.

Here’s a fact: GHK-Cu doesn’t simply bind a single receptor or activate one or two pathways.

Research suggests it systematically alters the expression of nearly a third of the human genome!

When it comes to aging biology, it appears to shift gene expression toward a more youthful state.

Now, I realize that sounds like a dramatic claim. But once you understand the mechanisms, it starts to make more sense.

Copper: The Double-Edged Sword of Aging Biology

Let’s begin with element copper itself.

Copper is absolutely essential for human biology.

It serves as the catalytic core of dozens of enzymes, including:

• Lysyl oxidase, which is critical for collagen cross-linking

• Superoxide dismutase, one of the body’s key antioxidant defenses

• Cytochrome c oxidase (a.k.a. Complex IV), a major component of mitochondrial energy production.

So copper is essential to life — but it’s also a double-edged sword.

Free copper ions are highly reactive.

They can drive the formation of free radicals that damage DNA, disrupt cell membranes, and contribute to cellular aging.

So, on one hand, inadequate copper is linked to dysfunction and aging; on the other, uncontrolled copper can itself accelerate damage.

That’s a bit of a biological pickle, isn’t it?

The body solves this copper problem by almost never allowing copper to float around freely.

Instead, copper is carefully escorted by molecular “chaperones.” And in this case, the GHK tripeptide acts as that chaperone.

Those three amino acids form a coordinated molecular cage (hence the thumbnail) that safely binds copper, allowing it to move through tissues and across cell membranes without causing oxidative damage.

Now let’s walk through what actually happens in the body after administration.

The Journey of GHK-Cu

Imagine you inject GHK-Cu beneath the skin.

Over the next 30 to 90 minutes, it begins diffusing into nearby small blood vessels called capillaries and connective tissue. Although blood levels decline relatively quickly, the compound binds to components of the extracellular matrix — essentially the structural scaffolding of the body — allowing tissue concentrations to remain elevated for 1 to 3 days.

At the cellular surface, GHK-Cu interacts with receptors that allow it to be internalized into small intracellular compartments.

Inside these compartments, the acidity is tuned almost perfectly to release the copper ion, which is then routed directly to copper-dependent enzymes.

This is the key moment: the “careful copper handoff,” first identified in a landmark paper in the journal Nature in 1980.

The Enzymatic Phase

The copper is transferred from its GHK carrier to be incorporated into enzymes like lysyl oxidase (collagen synthesis), superoxide dismutase (antioxidant defense), and cytochrome c oxidase (mitochondrial function), among others.

This handoff process is absolutely crucial.

It’s the key distinction between GHK-Cu and bulk copper supplementation.

• Free copper can generate damaging oxidative reactions.

• GHK-Cu, by contrast, appears to deliver copper precisely where it’s needed: directly to enzyme active sites in a tightly regulated manner.

Once delivered, the downstream effects begin.

• Lysyl oxidase activity increases, helping newly synthesized collagen and elastin become properly cross-linked into stable fibers.

• Superoxide dismutase activity rises, improving the cell’s ability to neutralize reactive oxygen species at their source.

• And mitochondrial cytochrome c oxidase (complex IV) function improves, potentially enhancing the efficiency of cellular energy production.

Double-Clicking on Copper in Mitochondrial Metabolism

Now, if the image below already freaks you out a little, that’s okay — you can skip ahead. But I do want to briefly double-click on why copper is so important to mitochondrial function.

What you’re looking at is the mitochondrial electron transport chain: a series of protein complexes embedded within the inner membrane of the mitochondria.

There are five major complexes, numbered I–V.

Complexes I - IV pass electrons between one another in a carefully controlled sequence.

As electrons move through the chain, the system pumps protons across the inner mitochondrial membrane, creating a proton gradient — essentially a stored form of electrochemical energy.

Complex V then uses that proton gradient, like water flowing through a turbine, to generate ATP energy.

Now focus specifically on Complex IV, a.k.a. cytochrome c oxidase, in gold.

This is the final complex in the chain responsible for both sustaining the proton gradient and converting oxygen into water during normal cellular respiration.

And critically, as you can see, copper sits right at the heart of this complex.

If Complex IV cannot function properly, the entire system begins to fail.

So yes — copper really is at the core of energy metabolism.

And if all of that went over your head, here’s the main point:

GHK-Cu appears to restore cells to a more youthful functional state.

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But the story continues.

The Gene Regulation Phase

GHK-Cu also appears to drive widespread changes in gene expression. Analyses, such as those using the Broad Institute’s Connectivity Map, suggest that thousands of genes are modulated under GHK-Cu exposure.

Among the pathways reportedly influenced are those involved in:

• DNA repair

• Antioxidant defenses

• Protein recycling

• Mitochondrial biogenesis

• Inflammation regulation

• Tissue remodeling

• Cancer suppression

Very few molecules appear to exert effects this broad in scope.

Some analyses suggest GHK-Cu may influence approximately 31.2% of the human genome.

So, really, GHK-Cu behaves less like a conventional drug or hormone, and more like a systems-level regulator — as though it places a hand on the master control panel of cellular physiology and biological aging.

That’s the theory.

Now, what are the consequences in animals and humans.

In the rest of this letter for StayCurious Metabolism premium members, I’m going to dive into the biological consequences of GHK-Cu in living organisms.

We’ll explore:

• Human data on topical applications of GHK-Cu

  • How to reduce wrinkles (controlled trial data)

  • Wound healing (controlled trial data)

• Promising studies using systemic (injectable) of GHK-Cu

• Real-world experiences people are reporting today

• Dosing protocols currently circulating in the community.

  • The product I recommend to family

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But they’re so much more than that.

They’re living, breathing, fluctuating, even dancing signaling networks that determine how your body generates energy at the most fundamental level, and even how you age.

In fact, if you look for the signature that distinguishes the longest-lived people — including a recent report on a woman who lived to 117 — what stands out in healthy aging is healthy mitochondria.

But the amazing thing about mitochondria is that, unlike a battery or an engine in a car, they can recover, heal, and renew themselves. And you can make them do this, starting today with free tools – but also, cutting-edge tools like performance enhancing mitochondrial peptides and hormones.

Which raises a deeper question:

Why do people lose energy as they age, and is that decline actually reversible?

In fact, when I gave myself one of these for a week, I felt like I’d been supercharged!

Today, we’re going to unpack tools to help you reset and upgrade your mitochondria to accomplish better health at a fundamental level: better energy, better aging, all of it.

We’re going to start with tools you can access immediately and then progress to some that are more experimental and at the frontier of human bioengineering.

Your Mitochondria Dance with the Sun

Let’s start at the beginning of your day: when you wake up and greet the sun. (Unless you live in Boston in the winter and spend several months of the year vitamin D-starved like Gollum.)

Jokes aside, exposure to morning sunlight does something very interesting: It kicks off a mitochondrial dance.

What do I mean by this?

Well, your mitochondria are not fixed, static little batteries. They ebb and flow. They fuse together and break apart in a dynamic process known as “fusion” and “fission.”

And this dance is critically important for maintaining mitochondrial function.

• When mitochondria fuse together, they effectively become more powerful and efficient.

• But breaking apart (fission) matters too: It helps segregate old and damaged mitochondrial components so they can be broken down and recycled for parts in a process known as “mitophagy.”

Imagine if the batteries in your phone could merge together into a super battery when demand increased, then split apart to repair themselves. That’s basically what’s happen in your body every day… trillions upon trillions of times.

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The balance between fusion and fission is dictated by light and circadian rhythm.

In fact, there was a fascinating paper out of Oxford last year — coincidentally from the exact same department where I did my PhD: the Department of Physiology, Anatomy, and Genetics — identifying this dance of mitochondrial fusion and fission as one of the drivers of sleep pressure.

Now, there are some experiments you simply cannot do in humans, and this is one of them.

But when researchers manipulate mitochondrial fusion and fission in animals, they can actually alter sleep drive itself.

It’s a bidirectional dance: light helps regulate mitochondrial dynamics, and mitochondrial dynamics help regulate sleep. By why does this really matter?

And where’s the actionable insight here?

In the rest of this letter for StayCurious Metabolism premium members, we’re going to dive into:

• The role of light in preserving mitochondrial health

• The foundational role of mitochondria in inflammatory disease

• A dietary pattern that boosts mitochondrial function and energy expenditure

• The peptides being explored for mitochondrial health and performance medicine

• What the future of mitochondrial medicine might look like.

If you’re a metabolism nerd, or aspiring to become one, come join a group of authentically curious people and lifelong learners dedicated to understanding how the body works and how to leverage those insights to optimize their health.

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It’s called tadalafil.

Most people know tadalafil as a treatment for erectile dysfunction, though it also carries FDA approval for conditions like benign prostatic hyperplasia and pulmonary arterial hypertension.

But a growing number of clinicians and researchers are now asking a much broader question:

What if tadalafil has meaningful effects on the heart, brain, blood vessels, exercise performance, and perhaps even mortality?

That question becomes easier to understand once you examine what tadalafil actually does.

Nick Note: And quickly, before we move on, I want to tease that, even if you’ve heard about tadalafil before, I’m also going to explain how to combine it with something else to enhance its potency and biological effects across body systems. This will be new knowledge for almost everyone. But let’s put a pin in that and build your foundational knowledge.

How Tadalafil Actually Works: PDE5 Inhibition

Tadalafil belongs to a class of medications known as PDE5 inhibitors.

To understand why that matters, we first need to understand how blood vessels relax and expand.

• The smooth muscle surrounding arteries controls how constricted or dilated those vessels are.

• When smooth muscle relaxes, arteries widen, blood flow improves, and tissues receive more oxygen and nutrients.

• One of the key signals responsible for this relaxation is a molecule called cyclic GMP, or cGMP.

In simple terms: cGMP → more smooth muscle relaxation → better blood flow.

Now, you need to know what causes cGMP to rise and fall.

• Rise: Nitric oxide stimulates the production of cGMP through an enzyme called soluble guanylate cyclase.

• Fall: Then there’s another enzyme, PDE5, that breaks cGMP down, effectively shutting off the signal.

This is where tadalafil enters the picture.

By inhibiting PDE5, tadalafil prevents the destruction of cGMP. The result is sustained smooth muscle relaxation, expanded blood vessels, and improved circulation.

Importantly, PDE5 is found throughout the body, including within blood vessels in your muscles, heart, and brain.

With this mechanism and wide enzyme (PDE5) distribution, it’s easier to see why tadalafil might have such a broad range of health effects.

All right. Foreplay over.

Let’s begin with tadalafil for cardiovascular health.

Tadalafil and Cardiovascular Health

Here, the literature is actually rather impressive—though admittedly, the strongest controlled human trial data come from men who already had some form of underlying cardiometabolic dysfunction.

For example, a 2005 study conducted in 32 men with elevated cardiovascular risk found that tadalafil improved a measure of blood vessel function, flow-mediated dilation, while also lowering levels of endothelin-1, a molecule associated with vascular dysfunction and constriction.

In this study, 32 patients were prescribed either tadalafil at 20 mg every other day or a placebo control.

Impressively, tadalafil more than doubled flow-mediated dilation.

That is no small effect.

Because flow-mediated dilation is not some obscure laboratory number, it is a clear functional measure of vascular health and endothelial performance.

And how it works, and how consistently it works, makes the findings even more difficult to ignore.

In the rest of this letter for StayCurious Metabolism premium members, we’ll dive into:

• How tadalafil affects blood vessel function

• A 50 million-person study on heart disease, dementia, and mortality

• The science behind tadalafil and neuroprotection

• How to stack tadalafil with a complementary molecules to amplify its effects

• Practical protocols, dosing strategies, and safety considerations

If you’re someone fascinated by the frontier of performance medicine and the deeper complexities of human physiology, now is a great time to join.

Find out why members say that StayCurious Metabolism has become not only one of the best investments they’ve made in their health, but also an exquisitely fun learning journey.

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It’s called KPV.

And it’s something I wish I’d had access to eight years ago.

Let me start by telling you something personal, and then we’ll get into the science.

The Gut Crisis That Changed My Life

I want to rewind about eight years, to the day of my college graduation.

You’d think this would be a celebratory time for me, as it is for most people. In fact, you might think I’d be especially excited, since I was the valedictorian at Dartmouth College and had the opportunity to stand at the stump and give an address to the entire community.

Now, in retrospect, I think my speech was sort of sh*tty, but not nearly the sh*ttiest thing about that day. And I mean that literally.

I had recently been diagnosed with inflammatory bowel disease, specifically ulcerative colitis, a condition in which the gut becomes so inflamed that ulcers open in the colon and begin spilling blood into the intestines.

And if you’ve never experienced that sensation, the blood can irritate the intestinal lining so intensely that it feels like there’s a fire inside you. The urge to go to the bathroom becomes cranked beyond what most people can imagine.

So, my experience that day was a kind of duality.

On the outside, I smiled and tried to express cheer and pride.

But on the inside, I was writhing because I knew there was a legitimate chance I would walk onto that stage, in front of 11,000 people, live and videotaped, and expel blood into my pants.

On that particular day, I got lucky. Nothing happened.

And I’ll fast-forward through the more gruesome parts of my illness and recovery and simply say this: it took me a long time to find something that worked. But the experience gave me a deep interest in innovative ways to heal the gut, because none of the conventional approaches had worked for me.

And today, I want to talk about one of those innovative approaches: a curious little peptide that has been studied for more than 40 years, particularly in the context of gut inflammation: KPV.

One more note before we begin:

KPV is one of several peptides that, as of May 2026, has been removed from the FDA’s Category 2 list, which restricts its preparation by compounding pharmacies.

As a result, it’s gaining increasing attention in the metabolic health community, particularly among people interested in gut health.

And there’s a good reason for that. Let’s talk about it.

What Is KPV?

First, it makes sense to describe what KPV is and how it’s thought to work in the gut.

The mechanism is quite fascinating.

KPV actually refers to the three single-letter amino acid codes that define the peptide, with a peptide simply being a short chain of amino acids.

• K stands for lysine

• P stands for proline

• V stands for valine

You’ll also see KPV referred to by other names in the literature, often derived from its parent compound: a larger peptide called alpha-MSH.

Now, there’s a bit of confusion in the metabolic health space because people sometimes assume KPV acts like alpha-MSH. It does not.

A simple way to think about it is this: KPV is a fragment of alpha-MSH that retains much of its anti-inflammatory activity, particularly in the gut, but it does not bind to the same receptors as alpha-MSH and does not drive skin pigmentation the way alpha-MSH itself, or analogs like melanotan II do.

For now, the key point is this: KPV is a small (three amino acid) peptide with potent anti-inflammatory effects.

So How Does KPV Work?

KPV appears to function inside cells by shutting down inflammatory pathways, including NF-kB: a powerful pro-inflammatory transcription factor that can enter the nucleus of the cell and activate inflammatory genes and cytokines such as TNF-alpha, IL-6, IL-1β, and others.

KPV also appears to suppress the ERK/p38 inflammatory signaling pathway.

Bottom line: at nanomolar concentrations, KPV dampens multiple inflammatory signaling cascades within cells.

But that raises the next question: How does KPV get inside the cells in the first place?

Many peptides work by binding to receptors on the outside of cells, which then trigger downstream effects. But KPV is different.

KPV sneaks directly into cells. And the mechanism by which it does this is both fascinating and highly specific.

It’s transported into cells by something called PEPT1 — a transporter expressed in the gut that essentially absorbs small tripeptides like KPV.

But it gets even more interesting, because KPV appears to have a kind of “self-targeting effect.”

KPV is Like an Anti-Inflammatory Smart Missile for Inflamed Gut Tissue

What do I mean by that?

KPV seems to preferentially home in on inflamed gut tissue, like a smart missile, which is exactly what you’d want from an anti-inflammatory compound.

Here’s how:

• The more inflamed intestinal tissue becomes, the more PEPT1 transporters it expresses.

• And the more PEPT1 that’s expressed, the more KPV gets transported into those inflamed cells.

• Ultimately, this delivers more anti-inflammatory signaling precisely where it’s needed most.

If you’ll indulge me in another analogy, and allow me to express my inner superhero nerd, I think of it almost like an anti-inflammatory Hulk.

Bruce Banner is usually physically unremarkable. But when a crisis emerges, the Hulk appears to deal with the threat. In a similar way, when gut tissue becomes inflamed, KPV is preferentially taken up into that inflamed tissue to help shut down the inflammatory response.

That’s the theory.

But does it actually work?

In the rest of this letter, for StayCurious Metabolism premium members, we will:

• See the effects of KPV on actual intestinal lining

• Explore the colon cancer connection

• Review real-world reports from people using KPV today

• Discuss KPV dosing protocols

• Explain exactly how KPV is being stacked with two other peptides for gut repair

If gut health is important to you — or if you simply want to join a community of deeply curious people passionate about metabolic health — now is a great time to discover why the newsletter is a Top 2 Overall Best-Seller in Science and why members call it an indispensable tool in their health journey.

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Or maybe it never worked all that well in the first place?

Those are not a hypothetical questions.

While GLP-1 drugs have helped millions of people lose weight, some people barely respond, some experience debilitating side effects, and many wonder whether the benefits will eventually fade.

So today we’re going to tackle the difficult questions:

Is GLP-1 resistance real?

And if it is, what can you actually do about it?

I’m going to give it to you straight—the good, the bad, and the ugly.

And while some of the data may put a frown on your face, we will ultimately end up in a place of optimism and armed with practical tools.

GLP-1s: A Metabolic Injustice?

Let’s begin with a scenario:

Imagine two people (persons A and B) start the exact same GLP-1 medication… at the same dose… at the same starting BMI… and on the exact same day.

Six months later:

• Person A has lost 60 pounds and feels fantastic.

• Person B has lost 8 pounds and is nauseated all the time.

What’s the difference?

Part of the answer may be written in their DNA.

There’s certainly evidence that the effectiveness of GLP-1s varies substantially from person to person. Other medications matter. Sex matters. Age matters. And increasingly, it looks like genetics matter as well.

One high-profile paper published a few months ago in Nature reported that genetic variants in the GLP-1 receptor and the receptor for another hormone, GIP, influenced both the effectiveness and side effects of GLP-1 medications.

• Some people lose a tremendous amount of weight with minimal side effects.

• Others may lose less weight and experience significant side effects.

There is, to some extent, a genetic roll of the dice.

If you look at many of the clinical trials, the average reduction in body weight with semaglutide is around 10–15%. But averages can be deceiving:

• Some people lose >25% of their body weight

• Other people lose <5% of their weight.

I’ve even seen people gain weight while on a high-dose of GLP-1. It happens.

And let me be clear: this isn’t necessarily just a matter of some people “eating through” the medication.

That’s just blaming the victim.

While this might sound pessimistic because, short of gene editing, your genes are largely set, it’s actually profoundly optimistic.

Because once you understand the biology, solutions begin to emerge.

• If you’re GLP-1 resistant, there are other levers you can pull.

• Or even if genetics aren’t your problem, what happens if the GLP-1 honeymoon period starts to fade. The drug seems to stop working? What do you do then?

That’s what we’re about to unpack.

In the rest of this letter for StayCurious Metabolism Premium members, we’ll dive into:

• Mechanisms behind GLP-1s, separating two distinct biological pathways

• Practical solutions if you’re truly “GLP-1 resistant”

• Insights and tools that can help if the benefits of a GLP-1 begin to fade

• Where this field is headed, why I’m so optimistic, and why you should be too

If you’re passionate about taking control of your health and learning about the frontier of metabolic science, I invite you to join us.

If you’re new to the StayCurious Metabolism community, what you’ll find is not shallow fringe thinking, but thoughtful analysis of the cutting edge, drawing from the newest and most interesting research published in journals like Cell, Science, Nature, Nature Metabolism, and The New England Journal of Medicine—all referenced are included in the letter.

And most importantly, you’ll join a community of genuinely curious people. To me, that’s what makes this community so special.

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I thought it was just an internet joke, but when I saw it in real life, the anger center of my brain lit up like a candle.

It was a plaque that said, “Don’t confuse your Google search with my medical degree.”

Now, before we go any further in this letter, which is going to be about why smart people believe dumb health ideas, I want to give you organically what rolled off my metaphorical tongue into a post I made after encountering that disturbing plaque:

“Don’t Confuse Your Prescription Pad with Critical Thinking” (Mini Rant)

I’m about to say what a lot of people and patients want to say, but might not have the words for.

Let’s start with an observation. I’m sure I’m not the only one who has noticed the pattern:

Some clinicians on [social media] increasingly seem to treat credentials, prescription authority, and clinical status as though they are arguments in and of themselves.

They mock “wellness influencers,” appeal to their ability to prescribe medications, or cheer on vulgar attacks against dissenters — all while conveniently sidestepping the actual data.

They know who they are.

And more importantly, you do too.

Here’s the uncomfortable reality:

Medicine is changing.

The era of tightly gatekept information and unquestioned authority is ending. Patients are becoming more informed. Younger physicians, researchers, and scientific communicators are more willing to challenge assumptions.

Science is becoming democratized.

And that is a good thing.

To be clear, clinical experience has value. But experience alone is not infallibility. It can sharpen judgment — or reinforce confirmation bias if it’s never challenged by data, humility, or self-reflection.

Having access to a prescription pad does not automatically make someone wise, rigorous, or intellectually honest.

Otherwise stated: don’t confuse authority over a prescription pad with critical thinking.

Thoughts?

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Anyway, that plaque clearly hit a nerve.

The reason why is simple.

Because, like many of you, I’ve been the patient, desperate for a partner, a guide — someone to walk with me through a hard medical journey.

Patients usually aren’t looking for a guru, but someone humble enough in their knowledge to question whether it’s their shortcoming that is leading to my suboptimal health outcome, rather than, when therapies fail, pointing the finger back at me, the patient.

This is a problem that is copy-and-pasted across society, where experts point the finger outward rather than looking inward, and perpetuate harmful ideas.

So, in this letter, I’m going to give you a peek behind the curtain. I’m going to give you examples of when, how, and why experts perpetuate stupidity — even outright lies, and even when they don’t realize that’s what they’re doing.

With that, let’s begin with one of the most common, and most sneaky, forces of all:

The Pseudo-Hierarchy of Evidence

The hierarchy of evidence is supposed to refer to how we weigh different forms of data.

• At the bottom are anecdotes: considered biased, weak, and generally not generalizable.

• At the top are randomized controlled trials, often treated as nearly infallible randomization is assumed to wash away confounders.

The issue is: this “hierarchy of evidence” can become a dangerous fallacy.

And sometimes, the data perceived as “highest quality” can become the most dangerous and misleading data of all.

I’ll give you an example that both I — and even one of the world’s most prominent plant-based nutrition scientists, Walter Willett — have described as a study that was “worse than useless because it was actively misleading.”

The study was published in Nature Medicine in 2021 by researchers at the NIH.

On paper, this study had nearly every bell and whistle imaginable.

It was a randomized controlled crossover trial in which participants consumed either an animal-based high-fat diet or a plant-based low-fat diet.

Participants were housed in a metabolic ward, meaning every calorie and food item could be monitored.

So, you had:

• a controlled human environment

• randomized interventions

• crossover design, i.e. each participant serving as his or her own control.

It was an expensive, taxpayer-funded study published in a prestigious scientific journal.

In other words, this was “top of the hierarchy” evidence, even if we forgive for a moment that the “animal-based low-carb ketogenic diet” looked like something you’d find at a Wendy’s and a gas station snack aisle.

Nevertheless, the result was immediately celebrated as proof that plant-based, low-fat diets suppress appetite better than low-carbohydrate diets.

There was just one massive problem.

The study was not merely flawed…

It was completely backward.

And remarkably, almost nobody noticed… for years.

Until we took a closer look.

In the rest of this letter for StayCurious Metabolism Premium members, I’m going to reveal some deeply uncomfortable truths about scientific culture, peer review, and the way medical narratives become cemented into “truth.”

We’ll walk through:

• How “the best” science can be the most misleading

• The prestige trap of peer review

• The permission structure for misinformation

• The mere exposure effect

• The economics of evidence-based medicine

• Questions every informed consumer should ask themselves

Each phenomenon will be illustrated through concrete real-world examples that will surprise you.

This is a different sort of letter — an insider’s look not into how to eat, sleep, or work out today, but into the larger forces that shape the advice we ultimately receive.

If you value nuance, intellectual honesty, and learning how to think more clearly about science and medicine, I think you’ll find this one both unique and worthwhile.

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In both ancient and modern societies, fasting has been practiced by billions of people and been used to treat diseases ranging from autoimmune and inflammatory disorders to neurological disorders, such as epilepsy.

But we still have a limited understanding of the adaptations humans undergo during a prolonged fast, and how these relate to chronic disease.

• So, what happens when you fast for one day, two days, three days, or even a full week?

• What changes occur across your metabolism, and different organ systems?

• And are there ways to capture some of these benefits without having to starve yourself for seven days?

  • In fact, is there a way to achieve some of the benefits of a 7-day fast in just 24 hours?

Today, we’re going to answer those questions.

(Hint: the answer to the last question is, “yes.”)

Let’s begin with a rather famous 2024 study published in the journal Nature Metabolism.

And to give credit where it’s due, the opening hook of this letter was actually modeled on the paper itself, which I thought the authors framed perfectly.

The study design was straightforward — and that’s part of what makes it so valuable.

The researchers recruited 12 healthy volunteers and put them through a 7-day water-only fast.

No food. No caloric beverages. Just water for an entire week.

These were healthy individuals whose average starting BMI was 25.4 kg/m².

As a little nuance, the study excluded anyone with body fat below 15% for women and 12% for men, which is quite lean, and was almost done for safety reasons.

And to the credit of the 12 participants, every single one completed the study, which is impressive. I think we need to give them some props.

Throughout the 7-day fast (days 0 – 7, below), and during a subsequent refeeding period (days 8 – 10, below), the researchers drew blood samples. But they didn’t just measure the usual suspects like glucose, insulin, and ketones…

They deployed a high-throughput proteomics platform capable of measuring 2,923 circulating proteins simultaneously.

Think of it this way: it’s a bit like fishing.

Often in science, we cast out a line looking for a specific protein, molecule, ketone body, or perhaps a hormone like insulin or ghrelin, and then reel it back in.

This technology is more like dragging a massive fishing net behind a trawling boat.

Instead of catching one or two targets, you pull up an enormous amount of biological signal that can then be studied.

As a result, the picture that emerged was far more complex, and far more fascinating, than anything that had been published before.

The way I want to approach this is by walking through the timeline: what happens on:

• Days 1–2

• Days 3–5

• Days 5–7

• The refeeding period.

Weight Loss: Lean Mass Loss Reversed vs Fat Loss Sustained

But before we get there, I know the question on a lot of people’s minds is: How much weight did they lose, and how much of that was body fat versus lean mass?

Over the seven-day fast, participants lost 5.7 kg (12.5 lbs; in panel b, above), equivalent to ~2 kg/m² BMI units.

Looking at the raw numbers, a large proportion of that loss appeared to be lean mass (3.6 kg) which sounds concerning at first.

But there’s an important caveat.

The technologies we use to measure lean mass aren’t necessarily measuring just muscle. They also capture tissues such as the liver, as well as factors like water content and glycogen stored within muscle, rather than just the functional contractile proteins that make up muscle tissue. (More HERE.)

As a result, it’s possible to see a substantial decline in measured “lean mass” during a fast, without that reflecting a meaningful loss of muscle.

Importantly, as the authors noted, the apparent loss of lean mass was “almost completely reversed” during the three-day refeeding period, “while the loss in fat mass (1.85 kg) was sustained.”

So, in short, even though measured lean mass decreased during the week-long fast, much of that either wasn’t muscle to begin with, or it rebounded very quickly. That’s reassuring. The fat that was lost, on the other hand, stayed lost.

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Now, let me walk you through the timeline.

And it gets better as we go…

Days 1–2: The Fuel Switch

During the first couple days, your body burns through its liver glycogen stores, driving a switch to fat burning, which requires an increase in the machinery responsible for fat metabolism.

The broad sweep of changes in the proteome the researchers observed aligned perfectly with this pattern.

Proteins involved in fat transport, fatty acid metabolism, and ketone production all surged during the first 48 hours.

There’s no surprise there; that’s fasting 101.

Nuance Note on PCSK9 and LDL-cholesterol

If you’d like to save a couple of minutes and aren’t particularly interested in cholesterol or lipids: feel free to skip ahead to the Day 3–5 section.

But I can’t resist mentioning one specific early change for the lipid nerds among us: PCSK9.

You may have heard of PCSK9 in the context of PCSK9 inhibitors, a class of cholesterol-lowering drugs that includes Repatha.

PCSK9 is a protein that promotes the breakdown of LDL receptors in the liver.

Since LDL receptors are responsible for clearing LDL particles from the bloodstream, more PCSK9 generally means fewer LDL receptors and higher circulating LDL cholesterol and ApoB levels.

PCSK9 inhibitors work by blocking this process.

In effect, they inhibit the inhibitor, leading to more LDL receptors, greater LDL clearance, and substantially lower LDL cholesterol levels.

Interestingly, fasting reduced circulating PCSK9 levels, starting within the first 48 hours, as you can see below.

Why?

One possibility relates to the massive increase in fat trafficking that occurs during fasting.

As the body transitions from burning glucose to burning stored fat, fuel must be continuously mobilized from fat cells, processed by the liver, and distributed to tissues throughout the body.

Efficient fuel movement requires both the export of fat via triglyceride-rich lipoproteins, such as VLDL, and the uptake of lipid components from circulating lipoproteins, including LDL particles.

From that perspective, lowering PCSK9—and thereby increasing LDL receptor activity—may help facilitate the movement and recycling of lipid fuel during fasting.

In other words, the body may temporarily increase its capacity to handle lipid traffic during a period when fat becomes the dominant energy source.

*As a nuance note on the nuance note (I know: “Oh boy...here Nick goes again…”), what actually happens to LDL and ApoB levels during fasting depends on several competing factors. You can have increased production of VLDL and LDL particles at the same time that you have increased clearance through inhibition of PCSK9 and higher LDL receptor activity. In other words, both sides of the equation are changing simultaneously. So don’t get too hung up on the cholesterol numbers themselves. The bigger picture is that fasting appears to dramatically increase fat fuel flux throughout the body, and many of these lipoprotein changes are probably part of that adaptation. Hopefully that makes sense. Don’t stress if it doesn’t.

The point is a broader theme of this study:

The changes observed during fasting appear to be coordinated adaptations working together to support a fundamentally different metabolic state.

Or, if I had to distill the last 500 words on the first two days of fasting into three words, they’d be: “burn fat now.”

Days 3–5: The Deep Remodeling Begins

But here’s where the story really gets interesting.

After the initial fuel switch, the researchers observed a massive second wave of protein changes that went far beyond energy metabolism—far larger than anything that happened in the first two days.

It’s like first two days are mostly about changing what the body burns. Day three is when the renovation crew shows up. Instead of merely swapping fuel tanks, the body begins rewiring systems throughout the building.

Proteins related to the immune system, inflammation, the brain, blood clotting, cellular stress responses, cardiovascular disease, all began shifting.

A total of 1,034 proteins changed significantly over the 7-day fast, and the majority didn’t really begin to shift until day 3.

We’re going to return to this “day-3 threshold” in a moment because it’s one of the most important findings of the paper.

But let’s complete our timeline…

Days 5–7: A New Metabolic Steady State

By the end of the week, many of the protein changes were approaching a new equilibrium.

The body wasn’t panicking.

It had settled into a reconfigured metabolic state that looked, at the protein expression level, fundamentally different from the original baseline state.

And, notably, some of these late-stage changes mapped onto proteins and pathways that have been independently linked to longevity, neuroprotection, and reduced risk of cardiovascular disease and autoimmune diseases.

Seriously. Think about this: more than one-third of all ~3,000 measure proteins changed significantly. And those specific changes provide remarkable insight into how fasting physiology actually works, and why it may matter in common diseases.

So, like an ATP synthase rotor spinning furiously in the inner mitochondrial membrane, that’s where we’re going to excitedly turn next!

The rest of this letter is for StayCurious Metabolism Premium members. We’ll dive into:

• The Day 3 Threshold: Why it matters, what changed, and what it tells us about the fasting literature.

• The Refeeding Surprise: What snapped back, what didn’t, and why that distinction matters.

• Practical Takeaways: Including how to hack a 7-day fast in just 24 hours, with a little metabolic demonstration conducted by yours truly.

If you’re someone who loves diving into the deepest corners of human metabolism and questioning nutritional dogma along the way, come join the fastest-growing community of metabolic health nerds on the platform and find out why so many members say becoming a premium subscriber was the best investment they’ve ever made in their health.

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