The paper reports that a compound found in aged garlic may protect both the brain and skeletal muscle from age-related decline.

As far-fetched as that sounds, the data are surprisingly strong.

There are even human clinical evidence supporting the idea that this compound could has anti-aging potential.

Quoting the researchers: [our] findings raise “an interesting possibility of S1PC as a nutraceutical anti-aging compound.”

Now, I just dropped the compound’s name in there without much fanfare because, admittedly, it’s not nearly as sexy as the results: S1-propionyl-L-cysteine (S1PC).

What is S1PC?

S1PC is a sulfur-containing compound identified in aged garlic extract.

It’s been attracting increasing scientific attention for years, with studies suggesting a variety of beneficial effects, including enhancing fat metabolism and potentially ameliorating atherosclerosis through its anti-inflammatory activity.

But in this study, researchers uncovered a new connection between S1PC and a molecule we’ve discussed before, one that sits at the very heart of human energy metabolism: NAD⁺.

You can think of NAD⁺ as one of the body’s master energy molecules.

It shuttles energy from the food we eat into the mitochondria, where it is transformed into ATP—the fuel that powers nearly everything your cells do. More broadly, NAD⁺ is involved in DNA repair, cellular resilience, and many of the processes that keep us alive and functioning.

Put simply: no NAD⁺, no life.

The Stakes, The Question, And the Signal

So, we understand the stakes: We’re talking about a dietary compound that appears to influence one of the most fundamental cellular processes involved in aging—one with direct implications for both muscle and brain health.

The big question then is: how could a single, awkwardly named molecule found in aged garlic possibly connect all these seemingly different systems?

The answer lies in a “signal” called NAMPT.

Now, technically, NAMPT is an enzyme.

Its primary job is to help synthesize NAD⁺, which, again, is one of the most important molecules in cellular metabolism.

By supporting NAD⁺ production, NAMPT helps maintain mitochondrial energy generation, DNA repair, cellular resilience, and many of the processes we associate with healthy aging in tissues ranging from muscle to brain.

But in this story, NAMPT isn’t acting like a typical enzyme that’s made inside a cell, does its job, and eventually gets chopped up for parts and recycled.

Instead, it’s acting more like a signal.

That’s because NAMPT can be packaged into tiny membrane-bound spheres called extracellular vesicles and released from one tissue to communicate with another.

In this case, S1PC is causing fat cells specifically to act like a broadcasting station, secreting these microscopic packets containing NAMPT into circulation where they travel throughout the body.

When NAMPT is packaged into these extracellular vesicles, we call it “eNAMPT.”

So, to quickly recap the jargon (and I know you’re smart enough to keep up) our two main players are:

• S1PC = compound derived from aged garlic extract

• eNAMPT = an enzyme packaged into tiny vesicles that are secreted by fat cells.

The key idea is that S1PC stimulates the release of eNAMPT from fat cells, setting off a signaling cascade that ultimately influences NAD⁺ levels, brain function, and muscle metabolism throughout the body.

In fact, previous work has shown that:

• Levels of eNAMPT decrease in humans with age (left)

• Treating animals with eNAMPT increases NAD⁺ levels in the brain, improves physical activity, and even extends lifespan by ~10% (right).

So, when I tell you that S1PC from aged garlic appears to crank up the release of these NAMPT-containing vesicles, I know it can sound like a lot of biochemical word salad.

But hopefully you can now appreciate why this finding is worth paying attention to.

If these vesicles truly serve as a body-wide delivery system for maintaining NAD⁺ and cellular function, then increasing their production could have implications that reach far beyond any single organ.

And, by extension, it no longer seems far-fetched to think a compound in garlic might just help slow aging in muscles and the brain.

Let’s get into it…

S1PC Boosts Circulating eNAMPT… Fast

The researchers started with a simple question: Can S1PC increase circulating eNAMPT levels?

They fed young S1PC (5 mg/kg) and tracked what happened in the blood.

The answer was unambiguous — and surprisingly fast.

Within 15–30 minutes, circulating eNAMPT levels rose significantly. There was then a second peak at around 300 minutes.

Now, here’s where it gets really interesting.

The researchers then measured where S1PC actually went in the body. They tracked its distribution in the blood, in fat tissue, in muscle, and in the brain.

S1PC levels peaked in both blood and fat tissue at just 15 minutes.

In other words, S1PC is quickly absorbed, rushes to fat tissue, and triggers eNAMPT secretion almost immediately.

And the downstream consequence?

Brain NAD⁺ levels were significantly enhanced at 15 and 30 minutes after S1PC administration.

So: Garlic compound in → eNAMPT up → brain NAD⁺ up. Within minutes.

That’s interesting.

But here’s the question that matters: Is this just a biochemical curiosity—or does it actually change the biology of aging?

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

• The experimental evidence for S1PC and aging

• A fascinating circuit linking fat, brain, and muscle

• Protocols and practical takeaways, including:

  • How to source and dose S1PC

  • How to combine S1PC combined with other synergistic supplements.

If you’re someone who enjoys exploring the frontier of metabolic health and longevity science, join a community of genuinely curious people and discover what makes #StayCurious special.

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Last week, I hit a bench press personal best.

And this month, my focus and productivity have been at their peak.

Why?

I tried something recently that really kicked me into a new gear.

It’s called 5-Amino-1MQ.

And don’t let the boring name scare you off. It’s a small-molecule bioregulator being explored at the frontier of metabolic health and bio-optimization.

And let me just say, when I dug into the literature, I got genuinely excited.

In preclinical studies, 5-Amino-1MQ has been shown to:

• Improve grip strength by up to 40%

• Increase muscle cross-sectional area

• Boost muscular endurance

• Activate muscle stem cells

• Reduce fat mass

• Protect against diet-induced obesity

There’s even emerging evidence suggesting potential roles in:

• Cardiovascular disease

• Alzheimer’s disease

• Parkinson’s disease

Now, I do want to be clear about where the science stands. At present, there are no randomized controlled trials in humans. This is all based on animal models and what we understand about underlying physiology.

I don’t say that to discredit what I’m about to share with you. Quite the opposite: I aim to highlight just how novel and underexplored this space is.

Because while conventional medicine tends to rely on a strict hierarchy of evidence, I think that can sometimes be a bit… well… sluggish.

Sometimes, the most powerful tools are right in front of us, and conventional practice just hasn’t caught up.

5-Amino-1MQ might be one such underutilized tool.

At least, I think so. Let’s see if I can convince you.

NNMT: The Metabolic “Leak” That Needs Fixing

Now, to understand why this might matter, we need to zoom in on an underappreciated problem in human metabolism.

There’s an enzyme called NNMT. And, in a lot of ways, it behaves like a “metabolic leak.”

Here’s what I mean.

NNMT catalyzes a reaction where it takes methyl groups from the body’s universal methyl donor (SAM) and transfers them onto vitamin B3, producing what is essentially a metabolic dead end.

Now, that might sound harmless. But it’s not.

This reaction is wasteful in 2 really important ways.

1. First, it drains from your NAD⁺ system, one of the central engines of cellular energy production.

   If you recall, we’ve talked about NAD⁺ before in the context of Alzheimer’s disease. As a refresher, NAD⁺ shuttles electrons into the mitochondria to generate energy. It is essential for virtually every organ system in the body.

   And importantly, NAD⁺ levels decline with age and metabolic disease.

2. Second, NNMT depletes that universal methyl donor, SAM, which is essential for DNA methylation, neurotransmitter production, and other indispensable biological processes.

So instead of supporting metabolism, NNMT is effectively siphoning off key resources your cells need to function.

Otherwise stated, instead of helping your body run better, this NNMT pathway is quietly draining the tank.

And here’s where it gets more interesting…

NNMT is hyperactive in conditions like obesity & type 2 diabetes, Alzheimer’s & Parkinson’s disease, aging in general.

Which means in those disease states, and aging, this “metabolic leak” gets worse.

NNMT is more active.

Cells lose efficiency faster.

Function declines faster.

The system starts to spiral.

Enter: 5-Amino-1MQ

What it does is actually pretty simple.

5-Amino-1MQ binds to and inhibits NNMT, and shuts that leak down!

And by doing that, it helps preserve NAD⁺ (key energy carrying molecule), SAM (universal methyl donor), and the downstream processes that depend on them.

So instead of bleeding metabolic resources, your cells can start reallocating them toward energy production, repair, and maintenance.

So that’s the background biology.

And viewed through this lens, it’s not totally far-fetched to imagine how 5-Amino-1MQ could improve energy metabolism in muscles, the heart, and the brain, potentially impacting obesity, insulin sensitivity, cardiovascular disease, and cognitive function.

But that’s the theory.

When researchers actually tried to shut this “leak” off… the results weren’t subtle.

In the rest of this article for StayCurious Metabolism premium members, we’ll break down some pivotal studies, and dive into how 5-Amino-1MQ impacts:

• Muscle strength and recovery

• Cardiovascular health

• Alzheimer’s and Parkinson’s disease

Then we’ll get into the practicals:

• How to access it, how to dose it, and exactly what I’m doing.

If you want to join a community of genuinely curious people operating at the frontier of bio-optimization, come find out why StayCurious Metabolism is one of the top best-selling science newsletters on Substack.

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But there is a curious observation that, honestly, humbles my entire field.

When you look at some of the longest-lived and healthiest people in the world, they typically aren’t united by any one diet, supplement regimen, or rigorous daily exercise routine.

(Sorry. I know you’re disappointed to know treadmills aren’t the secret to living to 120.)

Instead, what unites the people with the longest lifespans and health spans are strong social connections and a deep sense of purpose.

If there is a single word that best captures what many of these individuals have in common, it may be this: gratitude.

Quick Roadmap

So today, we’re going to talk about gratitude.

• We’ll begin at a high level, speaking to what the human studies show.

• Then we will delve deeper to discuss the biological mechanisms that connect gratitude to health.

• Finally, we’ll zoom back out to explore how we each might cultivate a meaningful gratitude practice that actually works.

And if I’m being completely transparent, I’m writing this letter for me.

In many ways, this is a selfish exercise. (In fact, I’ll show you later as I deploy one of these practices in this very writing exercise. Let’s put a pin in that for now.)

But I see no reason not to put these thoughts down in black and white for you to consider, share if they prove useful to you or someone you love, or critique if you have additional perspectives.

So, without further ado, let’s discuss gratitude.

The Gratitude Data: What Human Studies Show

The foundational work in this spa`ce comes from psychologists Robert Emmons and Michael McCullough, who published a series of studies in the Journal of Personality and Social Psychology back in 2003.

The experimental design was disarmingly simple.

Participants were randomly assigned to one of three conditions where they were asked to write about:

• Gratitude: One group was asked to write about things they were grateful for each week.

• Hassles: Another group wrote about things that irritated or hassled them.

• Neutral: A third group wrote about neutral life events.

After ten weeks, the gratitude group reported higher levels of optimism and life satisfaction.

They also exercised more and made fewer visits to a physician.

So maybe it’s not an apple a day that keeps the doctor away. Maybe it’s remembering how fortunate you are to have the apple in the first place.

Now, before the skeptic in you (and me) dismisses this as feel-good psychology, let me point out something important: this was a randomized trial. The independent variable that changed was what people chose to focus their attention on.

Writing a few sentences about what you’re thankful for.

That’s it.

That was the intervention. (I’ll reveal more specifics below.)

And yet, it changed behavior, perception, and even healthcare utilization.

Still, I understand if you’re thinking: Okay, people felt better and maybe exercised a bit more. That’s nice… but I need more biology.

Fair enough. Mt too. Let’s keep going.

Gratitude and the Heart

A study published in 2015 examined gratitude in patients with heart failure.

The researchers assessed each patient’s baseline level of dispositional gratitude, i.e. how naturally grateful they tended to be, and then looked at what correlated with it.

Quoting from the paper:

That last point is critical.

We’re no longer talking about subjective well-being. We’re talking about a measurable, objective marker of systemic inflammation (C-reactive protein, CRP).

But it gets better.

In a follow-up study published in 2016 by Redwine et al., heart failure patients were randomized to either an 8-week gratitude journaling intervention or a control group.

The gratitude group showed:

• Reductions in inflammatory markers (a composite of CRP, IL-6, and TNF-α)

• Improvements in heart rate variability (HRV), a measure of parasympathetic nervous system tone that reflects the body’s capacity to rest, recover, and adapt to stress.

Let me say that plainly: Writing about what you’re grateful for improved the measurable function of the autonomic nervous system in patients with heart disease.

(And, yes, I also see the humor in the first author’s name being “Redwine.”)

Gratitude and Sleep

Now, since we mentioned “gratitude was associated with better sleep,” let’s talk more about sleep.

A study published on a group of over 400 men and women ranging in age from 18 to 68 found that gratitude predicted better sleep quality.

Notably, the focus of this study was “pre-sleep cognitions,” i.e. what people thought about while lying in bed at night.

Quoting from the study:

In other words: those who fall asleep thinking more positive, less anxious thoughts, reported:

• Faster time to fall sleep

• Better sleep quality

• Longer sleep times

• Less daytime dysfunction

If that sounds trivially obvious, it is. But that doesn’t make it less important.

Or consider the implication from the other direction: rumination is a predictor (and likely causal drivers) of insomnia.

Now, I don’t say this because knowing this will make the habit disappear. I am a ruminator. I know the feeling all too well. However, I do think there is utility in being aware of this relationship, not to encourage you to chastise yourself when you next ruminate in bed… but to, hopefully, gently nudge you (and me) to healthier mental habits over time.

Or the pithy version:

Gratitude may be a cognitive antidote to rumination.

No, up to this point, we’ve talked about what gratitude appears to do.

But the more interesting question is how gratitude is actually changing your biology…

And then, how those insights can be leveraged to improve your biology.

The answer involves your vagus nerve, your microbiome, your stress hormones, and even your mitochondria.

In the rest of this letter for StayCurious Metabolism Premium members, we’re going to answer that question: How? We’ll dive into mechanisms:

• Your neuroendocrine stress axis

• Vagal tone & cardiovascular health

• The microbiome & gut health

• Chronic inflammation & mitochondrial function

Then we’ll bring it all home with 3 evidence-based gratitude practices you can implement in as little as 30 minutes per week.

If you haven’t yet joined as a Premium member, I hope you’ll consider doing so. I’ll do everything in my power to make sure you’re grateful that you did.

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If I had to pick the top buzzwords in health and medicine right now, those might be it.

And where they overlap—muscle-building peptides—you run into a dense thicket of multisyllabic names and acronyms that can make even a literary PhD’s head spin: CJC-1295, Ipamorelin, Sermorelin, Tesamorelin, MK-677, Follistatin-344, ACE-031, IGF-1, hGH, and on and on.

So today, the objective is simple: demystify the space.

Author’s Note: The structure of this letter is going to be a bit different from our usual, more narrative style at StayCurious Metabolism.

• Normally, I like to walk you through the story of the science. But every now and then, it’s worth stepping back and just clarifying the landscape.

• That’s what this is. It will be a bit drier, but hopefully serve as a good resource for what these compounds are, how they work, and how people are using them.

And I’ll be very, very, very, very, very (did I say “very” enough?) clear: this is not prescriptive.

Some of these compounds are FDA-approved, many are not. And even the ones that are approved are typically indicated for very specific conditions.

The purpose here isn’t to say, “Go use these.” It’s to acknowledge a trend and provide context.

Medicine is moving toward bio-optimization and “performance medicine.” And peptides are increasingly part of that conversation, largely because they’re becoming more accessible and of greater public interest.

That puts me in an interesting position.

The Information vs Abstinence Problem

I could take the conventional route and say: don’t even look at these until every box is checked and every approval is in place. Alternatively, I can offer straightforward, good-faith education. Because the reality is, some of you are going to explore this territory regardless.

To me, sticking our heads in the sand and ignoring this conversation is like preaching abstinence as the only form of contraception on a college campus—largely ineffective.

So let’s be honest: people are going to “use peptides.” And as with sex, the better approach is education, information, and consent—and if someone says “no,” respect it… then maybe ask which nitric oxide–boosting peptide they were referring to.

Leave a comment

(Okay, I do need to have at least a little fun with you.)

With that out in the open, let’s spend a few minutes demystifying this space.

The Hormonal Axis: How Muscle Growth Is Actually Regulated

Before we get into naming and bucketing these compounds, it’s worth grounding ourselves in the hormonal axis they act on.

Start with four key players:

1. Brain

2. Pituitary

3. Liver

4. Muscle

The brain releases growth hormone–releasing hormone (GHRH), which does exactly what it sounds like—it signals the pituitary to release growth hormone (GH).

Importantly, GH isn’t secreted in a steady drip.

It’s pulsatile, released in waves, with peaks and troughs that tend to crest at night.

That rhythm matters.

It’s tied not just to muscle repair and growth, but also to sleep itself. There’s a reciprocal relationship, and we’ll come back to it, because some of these compounds are used as much for sleep as they are for physique.

From there, growth hormone travels to the liver, which in turn produces another key hormone: IGF-1 (insulin-like growth factor 1). IGF-1 promotes muscle protein synthesis, supports tissue repair, and plays a central role in hypertrophy.

It also influences bone density, helps regulate metabolism, and contributes to cell growth and regeneration more broadly.

Then, there’s the muscle itself. The muscle has built-in brakes for muscle growth. This might seem counterintuitive, but evolutionarily, it makes a lot of sense.

Muscle is energetically expensive, so from an evolutionary perspective, you don’t want to hold on to more than you need. If you zoom back 10,000 years, and you were a 350-pound hulk with a basal metabolic rate of 8,000 calories, you’d be slow to move around, require immense amounts of food, and you’d quickly starve to death.

We’ve talked about these brakes before (HERE and HERE), but in brief, there are muscle-break receptors that bind various hormones in the blood.

The one of greatest interest is called myostatin.

• The suffix -statin is derived from the Latin, stare, which means to “stand still” or “stop.”

• The prefix myo- refers to muscle, so myostatin means literally “stop muscle.”

You can think of myostatin as the brakes on muscle growth.

Quick Summary

• The brain releases growth hormone–releasing hormone (GHRH) → signals the pituitary to release growth hormone (GH) → signals the liver to produce IGF-1.

• And then, at the level of the muscle itself, you have a built-in braking system, largely driven by myostatin, that modulates how far that growth signal can go.

The image above is a sketch of the system.

But here’s the real question: once you understand this pathway, where exactly do these peptides intervene—and which ones are actually worth your attention?

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

• How each of these peptides and bioregulators actually work

• Their real-world benefits, risks, and how people are using them

• What’s approved, for what indication—and what’s not

Consider this your no-BS guide to what’s real, what matters—and what’s coming.

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Nick: “[Mom], are you take glucosamine [for your joints]? If so, stop…”

Mom: “Yes, I am. Will Stop.”

You’ll notice the introduction to this letter is different.

I’m not burying the lede, and the tone is one of caution and a bit of negativity.

However, in this case, I think it’s justified.

Whether you know what glucosamine is or not, these data should be interesting to you and will help build towards points that are important when thinking about your long-term brain health.

Glucosamine is a naturally occurring amino sugar and a building block of cartilage.

And, it’s commonly taken over the counter as a dietary supplement to support joint health. It’s typically considered a good thing. Otherwise, my mother—who is at genetic risk for Alzheimer’s disease by virtue of being an ApoE4 carrier—wouldn’t be taking it.

But our risk-benefit analysis just changed, and I’m telling her to stop taking it.

Let me explain why, based on these new data, and then we’ll expand the discussion to cover some broader, important points.

A New Alzheimer’s Risk Factor Hiding in Your Medicine Cabinet

The paper in question was published less than 48 hours ago as I write this—specifically at 4:40 a.m. on June 11—in Nature Metabolism.

*Nick Note 1: Yes, I do appreciate the irony of writing this at 4:40 a.m.

*Nick Note 2: I’m sorry you’re getting this a full week after publication (gasp!). I had to step away for two of my best friends’ engagement parties and weddings. And candidly, I didn’t want to stack too many brain health–themed letters on top of one another.

Anyway, the paper.

It begins with the finding that:

Okay, now we need to explain that term: “hyperglycosylation.”

Glycosylation refers to adding sugar molecules to proteins, much like phosphorylation, methylation, and other post-translational modifications.

This is a process called post-translational modification, where molecules are added to proteins to change their function.

In the brain, glycosylation sits at the intersection of energy metabolism and protein function. It’s not a bad thing—in fact, it’s essential—but it needs to remain in the Goldilocks zone. Too little or too much can cause problems.

The researchers observed that in the Alzheimer’s brain, there is hyperglycosylation, meaning excessive glycosylation.

They found this pattern in both animal models and humans.

For example, when they used new technology to examine glycosylation in Alzheimer’s brains versus healthy controls, glycosylation was dramatically increased in the Alzheimer’s samples—by as much as 10- to 20-fold in some regions—a finding that was validated in a second cohort.

But I actually want to show you some of the data.

• On the left, you have a heat map showing the degree of glycosylation mapped across the brain, including both the gray matter—which contains neurons and cell bodies—and the white matter, which includes structures such as axon tracts.

  • The left two columns represent gray matter, and the right two columns represent white matter.

  • At the top (and boxed in red) Alzheimer’s disease (AD) brains versus healthy brains.

What I want to point out is that red indicates higher glycosylation, and clearly, across the brain, the Alzheimer’s samples show more glycosylation.

You can also see this even more clearly in the brain images (on the right), where there is substantially greater glycosylation in the Alzheimer’s brains than in the normal brains.

There is a very clear pattern: There is increased brain glycosylation in the human Alzheimer’s brain.

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The question then becomes: Is it causal?

And the answer appears to be: Yes.

But before we get to causality, let me reinforce that this pattern continues to hold across multiple analyses.

For example, when you examine human brains and compare glycosylation levels across the stages of Alzheimer’s disease—the so-called Braak stages, which range from 0 to 6—you see that hyperglycosylation increases as Braak stage increases (follow the red arrows).

• At Braak stage 0, which essentially represents no Alzheimer’s disease, glycosylation levels are very low.

• At Braak stages 1–2, they are higher.

• At stages 3–4, they are higher still.

• And at stages 5–6, they are higher still.

So, at a minimum, human brain data consistently show that hyperglycosylation is associated with Alzheimer’s disease and becomes more pronounced as the disease progresses.

What’s more, the hyperglycosylation tends to be concentrated in the regions most affected by Alzheimer’s disease, including the cortex, hippocampus, and thalamus—regions involved in memory and cognition and well known to be impacted by the disease.

At the very least, we’re beginning to see a conspicuous pattern.

But now we’ll turn to causality ,and to the factors that worsen hyperglycosylation and potentially increase the risk of Alzheimer’s disease.

Hyperglycosylation: From Correlation to Causation

Now, I want you to put your scientist hat on for a moment:

Given this pattern, how would you prove causality, i.e. that hyperglycosylation contributes to Alzheimer’s disease rather than just being correlated with it?

The best way would be to inhibit and activate hyperglycosylation processes. We would predict that inhibition protects against Alzheimer’s, whereas further activation makes it worse.

That’s how you test causality, and that’s exactly what researchers did in mice, because you can’t ethically, or practically, do these experiments in humans.

In mice, they used genetic modification and chemical inhibitors to block enzymes involved in glycosylation. When they did this in multiple mouse models of Alzheimer’s disease, including the 5xFAD and PS19 mice, they found significant improvements in memory compared with control mice.

Simply put: blocking excessive glycosylation improved Alzheimer’s

But what about accelerating glycosylation?

Well, here’s where the rubber hits the road, and things get very practical for humans.

The common supplement glucosamine, which is often used for joint health at around 1,500 to 2,500 mg per day, readily crosses the blood-brain barrier and is known to incorporate into brain glycans, meaning that, at least in theory, it can make hyperglycosylation worse.

The researchers found, starting in animals, that glucosamine supplementation significantly increased glycosylation across the brain, and they found that this made memory worse in Alzheimer’s models.

Okay, so we’re starting to build up a concerning and cautionary picture.

So, the obvious question becomes: does glucosamine merely affect biomarkers in mice, or is it actually associated with faster progression of Alzheimer’s disease in real patients?

The answer came from a dataset of roughly 50,000 individuals—and it forced me to text my mother to prompt her to change her supplement regimen.

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

• More human data, focusing on one shocking graph

• A series of evidence-based “do’s and don’ts” to protect your brain health

My goal is not only to make this a cautionary tale about new data, but also to give you high-yield, accessible tools you can start implementing today.

If you want to join a community of people passionate about the complexities of biology and health, come find out why StayCurious Metabolism is the fastest-growing premium science newsletter on the platform.

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It’s a deceptively complicated question.

And whether you have IBS, IBD, celiac disease, or another functional gastrointestinal disorder, chances are you’ve experienced bloating once or twice… or more.

But again, I ask: what causes it?

There isn’t a single straightforward answer, but one contributing factor is something called leaky gut.

“Leaky gut” sounds a bit woo-woo, but it’s simply another term for a very real physiological phenomenon: increased intestinal permeability.

And before we go further, let me emphasize something important: the implications here may extend far beyond bloating.

Emerging research is exploring whether intestinal permeability could also contribute to:

• Autoimmune disease (type 1 diabetes, rheumatoid arthritis)

• Chronic inflammation

• Even long COVID, MIS-C, and post-viral syndromes

And yes — in this letter, we’re going to touch on all of it. I promise.

But first, consider something simple: your gastrointestinal tract is effectively exposed to the outside world.

It must serve as a barrier between harmful inflammatory substances in your environment — including those you consume and those produced by microbes in your gut — and the inside of your body.

To accomplish this, intestinal cells are held together by a series of proteins called tight junctions.

Think of them as the mortar between bricks.

If these tight junctions become compromised, inflammatory compounds can pass into the body and trigger immune reactions.

This can contribute not only to bloating, but also to autoimmune and inflammatory conditions such as celiac disease, inflammatory bowel disease, type 1 diabetes, and more.

The issue here isn’t just gastrointestinal discomfort — the implications can be far broader.

Today, we’re going to explore leaky gut and bloating through the lens of a fascinating compound: a peptide called larazotide.

To be clear, this isn’t some esoteric wellness supplement.

Larazotide acts directly on tight junctions in the gut and has been studied in multiple randomized controlled trials.

There are even ongoing trials at Harvard and elsewhere investigating its use in inflammatory conditions such as long-COVID.

So, while the science is far from definitive, there appears to be something legitimate happening here that deserves attention.

Or perhaps I shouldn’t be presumptuous… I hope it deserves your attention, and that you’ll continue reading.

With that, let’s begin.

What Is Larazotide?

Larazotide is a small peptide derived, somewhat surprisingly, from cholera toxin.

Don’t freak out!

That doesn’t mean it’s toxic; it simply refers to its origin.

Larazotide functions as a zonulin receptor antagonist. Ugh…more jargon, I know. Here’s the simpler explanation:

• A protein called zonulin is secreted by the cells lining your gut in response to gluten, bacteria, and other inflammatory triggers.

• Zonulin binds to its receptors in the intestinal lining and signals tight junctions to open, increasing intestinal permeability, i.e. or “leaky gut.”

It’s essentially your body lowering the drawbridge.

Unfortunately, that can allow unwanted invaders in.

Larazotide works by binding to the zonulin receptor so zonulin itself cannot.

That’s why it’s called a “zonulin receptor antagonist”— it antagonizes the function of zonulin at its receptor.

In other words, it helps keep the drawbridges of the gut raised, preventing substances such as bacteria, lipopolysaccharides (endotoxins), and other inflammatory compounds from entering the body.

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Yes, this may improve bloating.

But that’s likely only the tip of the iceberg. The broader theory is that strengthening intestinal barrier function may help prevent inflammatory reactions throughout the body.

At least, that’s the hypothesis.

But here’s where things get genuinely interesting: this isn’t just theoretical biology anymore.

Larazotide has now been tested in multiple randomized controlled human trials.

And the results were compelling enough that researchers are now exploring its use not only for leaky guy, but autoimmune disorders and even long COVID.

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

• Human randomized controlled trial data

• Links between intestinal permeability, autoimmune disease, and long COVID

• What people are experiencing in the real-world with larazotide

• My personal “fiber challenge” experiment

• Practical dosing and sourcing considerations

• How to stack larazotide with another gut-health peptide

If you’ve ever struggled with bloating, IBS, IBD, food sensitivities, autoimmune symptoms, or post-viral inflammation, I think you’ll find this fascinating.

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This is due to the fact that I carry two copies of the Alzheimer’s risk variant ApoE4, which is thought to increase my risk of developing Alzheimer’s disease by roughly 10- to 15-fold.

As a result, I leave no stone unturned when evaluating interventions that might help prevent it.

And one of the most interesting, provocative, and promising possibilities to cross my radar recently has been GLP-1 drugs.

Yes, the same blockbuster weight-loss medications you hear about in the news practically every day.

But the truth is, these aren’t just weight-loss drugs.

Weight is the metric our society fixates on, so it takes center stage.

But these compounds are potent biomodulators that do far more than reduce body weight. In fact, you could argue that weight loss is simply one downstream effect of their broader impact on human metabolism.

We’ve touched on this in prior letters, but today I want to zoom in on one specific domain: the potential role of GLP-1s in preventing Alzheimer’s disease.

To do that, we’ll draw from a new systematic review of the literature focused on this exact question.

Quick Roadmap

• Biological background you need to understand Alzheimer’s pathogenesis.

• Results from the new systematic review

• How GLP-1s interact with those processes, independent of weight loss.

• Other high-yield accessible options that I use to protect my brain.

Biological Background: Alzheimer’s Pathologies and Enzymes

Let’s get into some biological background. I’ll do my best to keep this from getting too dry, but stick with me, because this part matters.

I want to focus on two key pathological hallmarks of Alzheimer’s disease—Aβ and neurofibrillary tau tangles—and two key enzymes that drive them: BACE and GSK3β.

Two Pathological Hallmarks: Aβ and neurofibrillary tau tangles

When I say, “pathological hallmarks,” I mean this is what you tend to see when you look at the brains of patients with Alzheimer’s.

• Aβ starts as toxic protein fragments and later develops into larger plaques— sticky aggregates outside of neurons.

• Tau tangles, by contrast, form inside neurons. Tau itself is normally a functional protein. It helps stabilize microtubules, which you can think of as part of the cell’s internal skeleton. But when tau becomes excessively tagged with phosphate groups, it detaches from that structure and begins to clump together, forming tangles that essentially choke the neuron from the inside out.

A simplified way to think about this is that Aβ fragments, which come from a larger precursor protein, may facilitate or accelerate the formation and spread of these tau tangles.

*Nuance note: the plaques themselves may be less directly toxic than smaller Aβ fragments, and may serve more as a marker that these fragments are present and causing damage. That’s part of the reason why therapies that simply remove plaques haven’t been as effective as we might have hoped.

But let’s be clear, this isn’t a simple, one-directional pathway.

Biology rarely is. It’s more of a web. Aβ may contribute to tau tangles, but tau tangles can also feedback and promote more amyloid production. And both processes are intertwined with broader metabolic dysfunction, especially insulin resistance and inflammation.

I’m sorry if that’s confusing. But I don’t want to present to you a web and pretend it’s a single straight string.

Now, let’s talk about the two enzymes, and then tie the mechanistic picture together.

Two Enzymes: BACE and GSK3β

BACE is involved in processing a protein called the “amyloid precursor protein.”

This protein can be broken down in one of two ways.

• One pathway is relatively benign, even protective.

• The other generates Aβ, the fragments that go on to form plaques.

BACE initiates this second amyloidogenic (toxic) pathway, ultimately leading to the formation of Aβ.

So, in simple terms: BACE promotes Aβ formation.

Then we have GSK3β. This enzyme is also known as “tau kinase 1,” which is actually a more helpful name. Kinases are enzymes that add phosphate groups to proteins, and tau kinase 1 (GSK3β) does this to tau.

That phosphorylation is what causes tau to detach, misfold, and ultimately form those toxic tau neurofibrillary tangles.

So again, simplified:

• BACE → Aβ

• GSK3β → tau tangles

The New Systematic Review: Preclinical and Clinical Trials

Now let’s talk about this new systematic review.

The researchers searched three major scientific databases (PubMed, Embase, and the Cochrane Library) and ultimately identified 32 studies of interest. Most were preclinical, meaning conducted in cells, rodents, or non-human primates, although there were two clinical trials.

Across the preclinical studies, the results were rather consistent.

• 22/30 showed a decrease in Aβ

• 19/30 showed a decrease in tau tangles

The authors summarize it plainly:

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That’s a strong claim. And, in my view, generally supported.

That said, we can only go so far with preclinical studies.

What happens in humans?

Of the two clinical studies included, the results were unimpressive.

One was a 26-week randomized, double-blind, placebo-controlled trial in 38 patients with Alzheimer’s disease. The other was an 18-month randomized, double-blind, placebo-controlled trial in individuals with mild cognitive impairment or early dementia.

Overall, there wasn’t much of an effect on Aβ or tau, at least based on the measurement tools available. And to be clear, in living humans, we’re not staining brain tissue directly like we do in animal models. (Typically, clinical trial ethics boards don’t approve trials when the methodology section reads, “decapitation.”) Instead, we rely on advanced imaging techniques like PET scans, which are inherently less precise.

That said, there were small signals.

For example, one study showed decreases in Aβ within extracellular vesicles, which are essentially tiny packages released by neurons that circulate in the bloodstream. But overall, the results were modest.

Why The Gap?

Why do the preclinical studies look so promising, while the clinical trials seem underwhelming?

The answer is simple: timing.

Most human trials enroll patients who already have cognitive decline: at least mild cognitive impairment, if not full-blown Alzheimer’s disease. By that point, the pathology is well underway.

I think of it like a boulder rolling down a hill. Alzheimer’s disease begins decades before symptoms appear. By the time cognitive decline is noticeable, that boulder has already picked up momentum.

The most effective strategy isn’t to stop the boulder at the bottom, it’s to prevent it from rolling in the first place.

So, if you think of GLP-1 receptor agonists as putting up a protective fence, they may be highly effective when the boulder is still sitting quietly at the top of the hill. But a small fence at the base won’t do much once a two-ton boulder is already in motion. It’ll go straight through it.

And this highlights a real challenge in medicine.

We tend to think in terms of a hierarchy of evidence, with randomized, double-blind clinical trials at the top. That’s the “gold standard.” But in some cases, that standard is simply not feasible.

It’s not realistic to enroll thousands of healthy individuals, control all variables, and follow them for 20 or 30 years in a blinded trial.

So, put simply, I do think there’s real potential here for GLP-1s in neuroprotection.

And I don’t think we should expect that potential to show up cleanly in the clinical trials we currently have. Negative results in this context don’t necessarily mean absence of a biological effect, especially if the intervention needs to happen early.

So, if the clinical trials don’t show benefit… but the preclinical data strongly suggest it… what exactly is going on?

And how can we leverage new knowledge and new tools for effective, long-term strategies for Alzheimer’s prevention?

In the rest of this letter for StayCurious Metabolism Premium members, we resolve the intellectual tension and dive deep into:

• Promising signals in the human data

• How GLP-1s might protect the brain (4 mechanisms)

• Minimal effective dosing

• High-yield accessible tools for brain health, including:

  • My favorite form of omega-3

  • My favorite element for neuroprotection

  • Boosting brain energy with NAD

  • The cholesterol drug that people misunderstand

Come find out why StayCurious Metabolism is a Top Overall Bestseller in Science, and why members rave it’s the best investment they’ve made in their health.

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It’s called retatrutide.

We’ve discussed it before.

Briefly, in the published trials people are losing a quarter of their body weight, like a snake shedding its skin, or like they just flew through a 20 second body recomposition movie montage.

The power of this compound is insane, outperforming all other weight loss drugs, by a wide margin.

It seems to be constantly in the news.

In fact, I'm releasing this letter a little earlier than planned because, just yesterday, a series of major headlines dropped reporting that pharmaceutical stocks surged after this next-generation weight-loss drug posted record-breaking results, with participants losing 28.3% of their body weight over 80 weeks.

(To be clear: I have no financial or other conflict of interest with Eli Lilly or any pharmaceutical company.)

So, I tried it.

Wait… Pause!

I know exactly what you’re thinking. Nick, you’re skinny as heck.

Why would you try a weight loss drug?

Are you crazy?

Well, probably a little. But that’s beside the point, and perhaps even why some of you like me.

Here’s why I felt compelled to try it:

In addition to being a highly credentialed professional guinea pig, I was hearing rumors about this specific drug that didn’t quite add up.

There were two main paradoxes bothering my brain:

• First, some people taking it and actually getting hungrier

• Second, people were claiming they were shedding body fat without losing muscle.

And frankly, that piqued my curiosity enough to feel a compulsion to dabble, not for my health but at the risk of my health—just to see what the hype was about.

I logged my personal experience: the good, bad, and ugly.

And I collected 127 biomarkers to see what was changing under the hood over the course of 4 weeks.

What happened to me was not what I expected.

But I can tell you this upfront: it’s not like any other weight loss drug on the market.

Why Reta Is Different?

Retatrutide—sometimes called “Reta,” or informally “GLP-3”—is the next evolution in a class of weight loss drugs known as GLP-1 receptor agonists.

The first generation—think the original iPhone—was drugs like Ozempic and Wegovy. These target the GLP-1 receptor, which, in simple terms, makes you less hungry.

There are other effects we’ll get into, but at a high level: GLP-1 = less hunger.

Then came the second generation, think the next iPhone upgrade. This was tirzepatide—or perhaps you’ve heard of Mounjaro and Zepbound. These hit two pathways: GLP-1, plus another hormone called GIP, which plays a role in how your body handles and partitions fuel.

So now you have: less hunger (GLP-1), plus improvements in how your body uses energy (GIP).

And then comes retatrutide, yet the next iPhone upgrade!

This adds a third mechanism: activation of the glucagon receptor. Which, at a high level, increases energy expenditure.

So now it’s not just that you’re eating less, you are also burning more.

And that’s part of why people report things like an elevated heart rate. In my case, my resting heart rate went from around 40 beats per minute to about 65. A pretty dramatic shift. I’ll talk about the biological relevance of this later.

So zooming out: retatrutide is hitting three different hormonal pathways—reducing appetite (GLP-1), altering how your body uses fuel (GIP), and increasing energy expenditure (glucagon).

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And as a quick side bar, I use the iPhone analogy because I find it a bit funny how these compounds are being marketed. Reta is often called “GLP-3,” even though there is no such thing. But it’s clearly a play on the original GLP-1s.

This honestly makes me think, “what will GLP-17 Pro look like?” But that’s a story for later.

The Two Big Reta Paradoxes

Retatrutide Making Some People Hungier?

Now, you’d think—because this is a weight loss drug—it would make you less hungry.

And for many people, it does. It crushes appetite. But that’s not the whole story.

I kept hearing something strange. From friends, from scientists, and people I trust.

But they were reporting the opposite. They were getting hungrier. Which doesn’t make sense. They were still losing weight. But their initial response was increased appetite.

And that alone was enough to make me curious. Because as counterintuitive as it sounds… There actually is a mechanistic explanation for it. We’ll get to that.

But that wasn’t the only thing.

“Retatrutide Might be Muscle Sparing”

There was a second rumor floating around: that retatrutide could drive fat loss, without loss of muscle mass.

This was such a powerful article of common knowledge that even famous scientists (e.g. Andrew Huberman) were suggesting “retatrutide might be muscle sparing,” on TV.

This, if true, would be very different from earlier drugs in this class, where roughly 25 to 40% of the weight lost tends to come from lean mass.

But here’s the thing: The actual human data on retatrutide doesn’t really support that.

In the main body composition studies, especially at higher doses, around 38% of the weight lost is still lean mass.

So now you have two paradoxes:

1. People getting hungrier… while still losing weight.

2. And people seemingly preserving muscle… despite clinical data suggesting otherwise.

So, what’s actually happening here?

I thought these claims sounded exaggerated too… until I tried retatrutide myself and tracked 127 biomarkers.

I'm not overselling it to say that some of the results surprised me and revealed truths about retatrutide that nobody else has talked about.

So that's what we're going to get into…

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

• My Experiment

  • Personal experience

  • Biomarkers

• Resolving the Retatrutide Paradoxes

  • Why some people get hungrier while others lose their appetite

  • Why some preserve muscle while others lose it

• We will address the trillion-dollar question: Should you?

If you’re passionate about metabolic health, nuanced science, or the future of human optimization, join a community of deeply curious people exploring these questions together, and find out what makes the StayCurious community so special.

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But my brain is apparently missing the waste disposal part!

(Maybe that’s why it’s packed with completely random animal facts.)

Jokes aside, all of our brains are, for the most part, missing the conventional lymphatic system.

The brain is so densely packed with blood vessels, neurons, and support cells that there simply isn’t room for the lymphatic vessels found throughout the rest of the body.

That raises an interesting paradox.

The brain is one of the most metabolically active organs in the body. It consumes enormous amounts of energy and generates plenty of metabolic waste.

So how is it supposed to get rid of that waste if it lacks the disposal system the rest of the body uses?

How is your brain supposed to clean itself?

Enter the “glymphatic system.”

The name comes from a combination of lymphatic—the waste removal system used elsewhere in the body—and glia, the support cells of the brain that play a central role in this process.

The glymphatic system is unique.

Rather than being a network of dedicated vessels like the lymphatic system, it’s a series of appearing and disappearing channels that become especially active while we sleep.

*Nuance note: Technically there are some meningeal lymphatics at the skull base, but for the most part the brain lacks a dominant conventional lymphatic system.

How Does the Glymphatic System Work?

When you’re asleep, your brain’s energy demands decrease.

As a result, it doesn’t require quite as much blood flow to deliver oxygen and nutrients.

The blood vessels are able to constrict slightly, creating more space around them.

That space forms glymphatic channels through which cerebrospinal fluid can be pumped, helping wash away debris that accumulated over the course of the day.

Glymphatic flow is essentially a shower for your brain.

And if your brain doesn’t get that shower, waste begins to accumulate.

Over time, impaired waste clearance is thought to contribute to metabolic dysfunction in the brain and play a role in cognitive decline.

What I’m really saying is that an effective glymphatic system is absolutely essential for maintaining brain health over the long haul.

That’s why today’s letter is devoted to explaining how to optimize glymphatic function.

Laying the Foundation: Stages of Sleep

I want to talk about deep sleep. But before we do that, we need to cover the different stages of sleep, so you have the proper frame of reference for what we’re about to discuss.

Stages of sleep:

• Stage 1: Falling asleep.

• Stage 2: Stable, foundational sleep.

• Stage 3/4 (Deep Sleep): Physical restoration and brain cleanup.

• REM Sleep: Mental restoration, learning, and emotional processing.

As simply as I can put it: deep sleep is the brain’s maintenance phase.

It’s when glymphatic clearance is at its highest, helping wash away metabolic waste that accumulates throughout the day. Deep sleep is also critical for physical recovery, immune function, and hormone regulation.

By contrast, REM sleep is the brain’s integration phase.

REM is incredibly important—you don’t want to lose REM sleep. During REM, the brain is highly active, which means glymphatic clearance is generally not as robust as it is during deep sleep. Instead, REM is when the brain processes emotions, strengthens learning, integrates memories, and supports creative problem-solving.

So, put simply, deep sleep helps clean and repair the brain, while REM sleep helps organize and optimize its performance.

You need both.

You don’t necessarily want to trade one for the other.

In general, the more of your total sleep time that is spent in deep sleep and REM sleep combined, the better.

Today we’ll talk about how to improve deep sleep and, thereby, glymphatic function.

But that’s not all.

We’ll then expand the discussion to cover additional tools: evidence-based supplements, peptides, sleep posture, and even some strange light and sound therapies supported by research published in top scientific journals.

Together, these interventions may further enhance glymphatic efficiency to clean and preserve your brain.

Get ready.

This one goes deep. (Get it?)

Today’s StayCurious Metabolism letter, a special request directly from a member of our community, is all about how to optimize the brain’s waste removal system and glymphatic clearance. We’ll dive into:

• Evidence-based tools for improving deep sleep

  • Foundational lifestyle interventions

  • Accessible supplements and experimental peptides

• The best sleeping position for glymphatic clearance

• Light and sound therapies that enhance glymphatic function, drawing on research from some of the top scientific journals in the world.

If you’re passionate not only about optimizing your health, but also about exploring the complex biology within each and every one of us, now is as good a time as any to join the StayCurious Metabolism premium community and discover why members call it the best bang for their buck they’ve ever spent on their health journey.

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As far as esoteric holidays go, I think this is a great one to acknowledge.

And, on a personal note, now that I am finally settling down in a place where I can have a pet, I’m actually looking to adopt a dog myself.

So, in celebration, I thought I’d blend dogs with health—specifically heart health—in a way that’s hopefully both informative and entertaining.

Let’s talk DOGMATIC: a hypothetical randomized controlled trial.

Oh, and at the end, if you have any tips on adopting a dog, recommendations for breeds, or just want to brag about your dog, I’d genuinely love to hear.

DOGMATIC: A Dogs vs. Statins Randomized Controlled Trial

Question:

What if puppies are a better prescription for cardiovascular and overall health than statins?

It’s a provocative proposal.

But that’s the point.

When examined thoughtfully, provocative questions can teach us more than the most agreeable truths. And today, we’re going to dissect this one, alongside man’s best friend.

Think of it as a hypothetical randomized controlled trial — the framework we’ll use to explore today’s topic. Yes, the cover image is cute and clickable. But what’s inside might just have you thinking about dogs as medicine.

“Lower is Better” Dogmatism in Medicine

Let’s start with the inspiration for this letter. If you’ve been following me for a while, you know I have a sore spot for cardiology’s hyperfixation on LDL cholesterol and, by extension, ApoB-containing lipoproteins.

The entire conversation about cardiovascular risk management tends to boil down to three words, “lower is better.”

And let me not mince words on my opinion: this is not just a scientifically offensive oversimplification; it is a dangerous oversimplification.

“Lower is better” is meant to refer to the idea that lower levels of LDL cholesterol and ApoB-containing lipoprotein particles are better for a patient’s risk management.

Of course, the real questions any thoughtful mind should be asking now are:

• Better for what?

• And at what cost?

In terms of “better for what,” we’re not talking overall health, but cardiovascular disease specifically. And even then, the waters are choppy. How much better in any given individual? Would treating LDL cholesterol lower reduce risk by 10%, 1%, 0.00001%? Magnitude of benefit matters because magnitude of risk matters.

And that’s the other side of the equation. How do you get LDL cholesterol and ApoB lower? And what is the cost of treatment?

Many of these are underappreciated and underacknowledged.

The symptoms that often get the most focus, like muscle pain and exercise intolerance with statins, are barely the tip of the iceberg.

Then there are biochemical effects whose clinical consequences we don’t fully appreciate because nobody’s taking the time to inquire seriously. What is the effect of long-term suppression of GLP-1 with atorvastatin? What about impacts on mitochondrial health?

The list goes on, but the point I’m making is simple and clear: Medicine is hyperfocused on the LDL story, a story whose repeated telling has been entirely inadequate to truly improve the burden of cardiovascular disease.

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Other than some advancements made in emergency medicine, we’ve basically been stalled for half a century on stemming the tide of cardiovascular disease. And when you come to think about how many billions of dollars have been invested into this research space, is a truly embarrassing failure of science and medicine.

So, is it so profound to imagine we might be barking up the wrong tree?

Now, before we really begin, let me pull some quotes from the internet from actual cardiologists and lipidologists to show you I’m not blowing smoke. Beyond, “Lower is better,” we have:

• “Statin deniers, read it and weep.”

• “It’s the cholesterol, stupid.”

• “ApoB is lie rally the whole problem”

• “LDL causes heart disease. People don’t need more nuance. It’s just confusing.”

• “Accept the science.”

I don’t know about you, but when I read those words, I think things like: “wow, ‘accept the science’ … that’s the least scientific thing I’ve ever heard.”

So now, with that framework in mind, let’s turn to our thought exercise and prove the puppies put the “p” in p-value.

Dog Ownership is Associated with Improved Mortality and Cardiovascular Disease Risk

A systematic review and meta-analysis examined dog ownership and mortality.

Dog ownership was associated with a 24% reduction in all-cause mortality.

And in individuals with prior coronary events? That number jumped to 65%. Cardiovascular mortality was reduced by 31%.

Which raises an uncomfortable question: How do dogs compare to statins for overall health and cardiovascular health?

For StayCurious Premium members, we’ll conduct the DOGMATIC trial, a deliberately absurd but well-reasoned comparison between pharmaceuticals and pooches.

If “accept the science” is enough for you, feel free to stop here. If you’d rather interrogate it, let’s continue. We will discuss:

• The relative benefits of dogs vs statin on all-cause and cardiovascular mortality

• The mechanisms by which dog can improve cardiovascular health

• How to cultivate critical thinking, not conspiracy theories

• How to evaluate the hierarchy of evidence from a broad, rationale perspective.

If critical thinking (and some fun along the way) sounds appealing to you, join a community of people who appreciate nuance, even and especially when it pushes some buttons.

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Now, I understand why you might be skeptical, or even afraid to hope that something like this is possible.

But the data from both humans and monkeys suggests that it very much is possible… and maybe even around the corner.

But that may provoke a second layer of skepticism: even if it’s possible, is it actually desirable?

After all, in nature and medicine, there’s rarely a free lunch. I’ll absolutely address that concern, along with the limitations of the data, as we move through this scientific story together.

But first, I want to plant a seed in your mind.

Our bodies were shaped by evolution to meet the demands of a very different environment, one defined by the constant risk of food scarcity and starvation. As a result, we did not evolve to easily pack on muscle while shedding fat.

In fact, evolution favored the opposite.

• Body fat was evolutionary security. Energy insurance.

• Muscle, at least beyond what was necessary, was energetically expensive. From a survival standpoint, you don’t want more of it than you truly need.

Obviously, our priorities have changed.

Now, I won’t presume to speak for you; but speaking for myself, I’d love to gain 20 pounds of muscle while losing the little body fat I have left, especially if doing so actually improved my health as well.

In today’s letter, I want to give you a glimpse of the future: a future in which we unlock a few deeper secrets of metabolism and begin to realize a new era of human bioengineering.

And, I promise, that future may be much closer than you think.

Roadmap

As a quick roadmap to the rest of this letter:

• Biological pathways: Activin A and Myostatin

• Preclinical data: Muscles, Monkeys, and mABs

• Human data: Results of a double-blind, controlled trial.

• Present practicals & protocols: options available today that can help you optimize body composition and physical performance

Biological Pathways

Let’s return to the idea that, evolutionarily, muscle is expensive.

While our bodies do have systems that can build muscle quite rapidly, they’re often held in check by a “brake,” or “breaks.”

If you pause to think about it, that’s not so surprising.

Consider other animals, like a tiger or a gorilla. With relatively little effort, they can put on maintain immense amounts of muscle.

The reality is that we, too, have far greater potential for muscle growth than most of us realize. It’s just chronically restrained to prevent us from burning too many calories.

I know…ironic.

And, as with most things in biology, evolution tends to build in redundancy to ensure robustness.

So instead of relying on a single mechanism, our bodies use multiple overlapping systems to suppress excessive muscle growth. In this case, that includes several circulating molecules that act as muscle growth “breaks.”

Two of the most important are myostatin and activin A.

Interestingly, they bind to similar receptors.

The logic, then, is straightforward: while blocking either one of these molecules can enhance muscle growth by releasing the brake, blocking both simultaneously may provide a greater capacity for muscle building.

In theory, this should unlock a level of muscle growth most humans have never experienced.

But what actually happens when you test this, in monkeys and in humans?

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

• The biology behind these muscle-building therapies

• What happens when you combine them with GLP-1 weight loss drugs

• What we know about safety and side effects.

Then we get practical. I’ll walk you through strategies you can use today, including:

• A nutritional intervention proven in a multiple randomized controlled trial to blast visceral fat

• A weird way to potentially increase energy expenditure through thermogenesis (heat production)

• A mitochondrial hormone that might be the closest we’ve ever come to a true exercise mimetic.

If you’re someone who values nuanced science and wants to stay on the cutting edge of metabolic health, this is exactly what we do inside StayCurious Metabolism. Find out why members consistently call it the best investment they’ve made in their health.

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It felt like the paper itself had just walked out of the room after dropping an intellectual mic.

Here’s the punchline:

The thymus—a largely overlooked organ that sits behind your breastbone, just above your heart—may be one of the most important organs for human longevity. In fact, individuals with healthier thymic function had roughly a 50% lower risk of death.

You read that right: a 50% lower risk of death.

Now, what surprised me wasn’t the topic: longevity, life and death. It wasn’t even the magnitude of the effect.

It was the organ.

The thymus.

And I’m willing to bet most of you don’t even know what that is. And if you do, you probably think of it as irrelevant in adulthood, basically the appendix of your chest.

It’s just… there.

That’s certainly what we’re taught in medical school.

When you’re young, the thymus plays a critical role early in life. It helps generate “T cells”—key players in your adaptive immune system—essentially training your body to recognize and eliminate threats.

In that sense, it sets your immune system up for life.

But then, as we’re taught, it fades. It shrinks. It turns into fat through a process called “thymic involution.”

By adulthood, the assumption is that the job is done. You’ve got the immune repertoire you’re going to have, and it just slowly runs the clock out.

But this new paper flips that entire paradigm on its head.

It shows that the rate at which your thymus ages varies dramatically between individuals, and that slower thymic aging is strongly associated with lower overall mortality, lower cancer mortality, and lower cardiovascular mortality.

In other words: An organ that wouldn’t normally even qualify as a side character in the story of longevity… might actually be the main character.

And the best part?

There are an increasing number of ways you can take action to slow, or even reverse, thymic aging.

Let’s get into the data.

Thymic Aging Predicts Mortality

First, what did the researchers behind this study actually do?

In brief, they analyzed data from two large, independent cohorts: the National Lung Screening Trial, with 25,031 participants, and the Framingham Heart Study, with 2,581 participants.

These are deeply characterized populations, meaning there’s a wealth of existing health data that can be linked to thymic health.

Now, how do you even measure the health of the thymus?

Well, as we discussed, the thymus undergoes a process called “thymic involution;” it essentially turns into fat with age. And that’s something you can actually see on imaging, like a CT scan.

What you’re looking at below is a cross-section of the chest, it’s like slicing the body like a loaf of bread using an advanced X-ray. The area outlined in orange is the thymus.

The key detail:

• White represents a healthy, “high”-functioning thymus (left)

• Black represents fatty involuted, “low” -functioning thymus (right)

Using this, the researchers grouped people into three categories:

• The bottom 25% → low thymic health (left)

• The middle 50% → average thymic health (middle)

• The top 25% → high thymic health (right)

Then they asked a simple but powerful question:

How does this relate to survival?

They followed participants for 12 years and looked at all-cause mortality, i.e. death from any cause.

Here’s what they found:

In the National Lung Screening Trial, individuals with high thymic health had a 51% lower risk of death compared to those with low thymic health.

*These are survival curves. The Y-axis is % of surviving participants. Thus, the steeper the slope, the more death occurred in that group. Individuals with “high” thymic health (red) died the least, followed by “average” thymic health (orange), followed by low thymic health (blue). The mortality risk for high vs low thymic health is 0.49, or a 51% risk reduction for death.

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That alone is striking.

They then adjusted for confounding variables, factors including age, past and existing disease, and even repeated the analysis in a healthier subgroup, excluding people with cancer and major comorbidities. And the result held strong.

Thymic health remained independently associated with better outcomes, even after controlling for age and disease burden.

Similar results were reported for the Framingham Heart Study cohort.

And, as we will see for cardiovascular disease and cancer—again and again—the pattern held: Better thymic health was associated with better outcomes. We’re not talking about small differences either—we’re talking about reductions on the order of ~40–50%, or more.

The magnitude of these effects, and what they imply about how and why we age, are where this really starts to get uncomfortable.

Because once you see the numbers… it becomes very hard to ignore what this organ might actually be doing, and how we might be able to easily intervene to slow aging.

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

• The thymus, cancer, and cardiovascular disease

• How the thymus shapes the aging process

• Evidence that thymic aging can be reversed

• Tools available now and those on the horizon

If what you’ve seen so far has surprised you, it only gets more interesting from here.

Join a community of deeply curious thinkers who are willing to question assumptions, follow the data, and explore the edge of what’s possible in human metabolic health.

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It’s become almost mythical for its supposed ability to accelerate healing across the body: from gastrointestinal disorders like inflammatory bowel disease—which is personally relevant to me—to tendon, ligament, and muscle injuries.

But there’s tension here, both scientifically and culturally.

On one side, you have people actually using this compound and reporting remarkable recoveries. Perhaps the most famous example is podcaster Joe Rogan, who has spoken emphatically about how BPC-157 helped him recover from injuries that should have sidelined him.

On the other side, there’s significant pushback from the scientific establishment. In an interview for STAT News, Dr. Flynn McGuire at the University of Utah, for example, said: “The amount of hype to evidence is so skewed, it’s crazy,” and that BPC-157 “Should not be used by humans.”

At the same time, other physicians and researchers see things differently, and are prescribing BPC-157 for a wide variety of illnesses and injuries: ulcerative colitis, orthopedic injuries, and even mental health.

So, the obvious question becomes: Is BPC-157 legitimate science that could genuinely help people today, or is it bro-science hype bolstering a dangerous wellness fad?

As usual, the truth lies somewhere in the middle; however, and despite having cut my teeth in traditional academic institutions, I find myself in the unusual position of siding, at least in part, with the people the academic elite often dismiss as “wellness influencers.”

And today, I explain why.

We’re going to explore the science, the stories, and the deeper question of how scientific knowledge is actually generated and sometimes constrained.

Yes, you’ll learn about BPC-157, its mechanisms, and its use cases.

But if I do my job well, you’ll also walk away with a broader appreciation for how these conversations should be had in the first place.

What is BPC-157?

Let’s first discuss what BPC-157 actually is, and how it works.

BPC-157 stands for Body Protection Compound-157.

It’s a 15-amino-acid peptide originally derived from a protective protein naturally found in human gastric juices, and it has been studied for more than 30 years by multiple independent research groups—most notably teams in Croatia and Taiwan.

Just to clarify its regulatory status: BPC-157 is often sold in injectable and oral forms for off-label clinical use and is produced by some compounding pharmacies.

Visual Proof BPC-157 Does Actually Work

Real quick, before we go deeper into how BPC-157 works, let me first show you a striking example suggesting that it does work.

This is an extreme model: a full transection of the quadriceps muscle in a rat.

Imagine putting your right leg in a guillotine and pulling the cord. Slice. Ouch!

“C” is the control group and “B” is the BPC-157-treated group.

I want to draw your attention to the red arrows showing healing at 14 days on the left and 28 days on the right.

What you can clearly see is that the muscle heals dramatically faster with BPC-157 treatment.

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By 72 days, the BPC-157 group showed consistent improvements across essentially every healing parameter: mechanical strength, functional recovery, macroscopic appearance, and microscopic tissue architecture.

In fact, the injured muscle eventually approached the structure and function of normal, non-injured tissue.

Meanwhile, the control animals continued to show incomplete healing, with persistent gaps filled by fatty tissue and weaker, less organized collagen fibers.

Put simply: without BPC-157, the muscle fibers struggled to reconnect across the injury gap. With the BPC-157 boost, they succeeded.

And yes, this was done in rats, not humans. But we are not that biologically different.

Mammalian wound-healing pathways are deeply conserved, which is precisely why animal models are used in biomedical science in the first place.

Findings like this are remarkable. You can see it with your own eyes!

And with that as framing, is it far-fetched to imagine the BPC-157 recovery stories of the “wellness influencers” harbor some truth (citation: Rogan et al?).

But the really interesting question is why BPC-157 seems capable of accelerating healing across so many completely different tissues and organs.

That’s where we’re going next.

In the rest of this letter—available to StayCurious Metabolism Premium members—we’ll dive into:

• How BPC-157 is works

• The honest state of the evidence (human and animal data)

• How people are dosing and using BPC-157

If you’re someone who has suffered from sports injuries, joint problems, IBD or IBS, I think you you’ll find what follows both fascinating and high yield! Come see what makes StayCurious Metabolism so special.

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You can increase your attractiveness to the opposite sex with light.

I know that sounds insane.

It sounds far-fetched. Honestly, that was my reaction too — until I started digging into the data we’re about to break down today.

I’m going to walk you through something that is both deeply surprising and surprisingly well-supported—how exposure to specific wavelengths of light can:

• Increase testosterone in men

  • Including how you can boost your testosterone in a week for free

• Increase the physical attractiveness of women to their partners

• And alter reproductive biology in ways that sound almost too strange to be real—until you understand the data.

This is one of those stories where my goal is to take you from where you are right now, probably:“There’s no way this is true.”

To a place of, “Oh my God… this actually makes a lot of sense!”

So, put your skepticism in a dark box for the next few minutes—and let’s turn on the light.

Light is Our Oldest Biological Partner

Here’s a mental image to hold onto as we begin:

Imagine two identical people—same genetics, same personality, same appearance.

The only difference?

One is exposed to a different light environment. And, as a result, they become more attractive.

More desirable. More compelling. More… chosen.

At a high level, part of the reason this sounds so implausible is because we don’t think of light the way we think of nutrients.

Vitamins, minerals—those feel tangible, ingestible, real.

Light feels ephemeral. But that distinction is, in many ways, itself an optical illusion.

Light has been shaping our biology since the very beginning—it is our oldest biological partner.

And modern research is beginning to show that it interacts with our metabolism at the deepest levels.

For example, mitochondria—the powerhouse of the cell—undergo cycles of fusion and fission that influence metabolic efficiency; and these cycles are directly governed by light.

And we can look through a human evolutionary lens.

Evolution Timed Reproduction to the Sun

If you were designing a species through natural selection, you’d want reproduction to be timed for maximum survival.

Conception wouldn’t be random: it would align with environmental conditions that optimize the chances that offspring thrive.

And in fact, we see exactly these patterns.

• Across much of Europe, births peak in April and May.

• Do the math, and that places conception in July and August, when sunlight exposure is highest… and when male testosterone levels do, in fact, peak.

Start connecting the dots and a picture emerges:

Light influences hormones → hormones influence reproductive behavior → and the timing of both shapes outcomes that matter for survival.

Of course, modern life has dramatically altered our light environment—but those underlying biological programs haven’t disappeared. They’re still running.

And if you understand them, you can begin to leverage them.

You can, in a very real sense, use light to create what my generation would call a “glow up”—enhancing not just how you feel, but how you’re perceived by others.

Old Knowledge, New Research

Let’s start with some old data.

Exposure to specific wavelengths of light—particularly UV—has been known to alter sex hormones since the late 1930s, when researchers first showed that this component of sunlight could increase testosterone in men.

At the time, the mechanism—and certainly the behavioral consequences—weren’t well understood.

Skin is an Endocrine Organ

But what has been clear for decades is that the skin isn’t just a passive barrier. Skin is an active endocrine organ, capable of producing and releasing hormones, including vitamin D, certain peptides (yes, I said peptides), and beta-endorphin.

Many of these signals can even reach the brain’s hypothalamus and influence downstream hormonal cascades.

So, the question becomes: why—and what does this actually do?

This is where the story gets interesting, starting with a paper published in Cell Reports in 2021 by researcher in Israel. And while we’ll get to some compelling human data, we need to start with animal models, because that’s where mechanism comes into focus.

Light Changes Behavior in the Opposite Sex

In one set of experiments, researchers exposed mice to full-body UVB radiation at a dose of 50 mJ/cm². (We’ll talk about human-relevant doses later.)

The results were not subtle.

For example, when female mice were exposed to UVB triggered noticeable behavioral changes in males, almost like mind control.

This is a StayCurious Metabolism premium special. Inside, we go into the data showing how specific wavelengths of light can:

• Alter your hormones in measurable ways

  • For men: how you can boost your testosterone in a week for free

• Increase attractiveness to the opposite sex—emotionally and physically

  • For women: How to increase your partner’s “Obsessive thoughts [about her]”

• Activate a powerful skin–brain–gonadal axis involving an unexpected player

• The minimal effective dose of sunlight you need to get sexier

By the end, you won’t just understand these data, you’ll feel it: a mix of awe, respect for biology. And you may just find you feel more confident as well.

Come find out why StayCurious Metabolism is a Top 2 Best-selling in Science and why users say a premium subscription is the best value investment they’ve ever made in their health journey.

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And it’s breaking headlines.

Now, I realize that sentence, and the associated headlines, are going to provoke two polar-opposite reactions.

• On one hand, we have those pronouncing: “We are curing heart disease with one shot!”

• On the other, we have those warning: “This is ridiculous. Why would you lower LDL cholesterol with gene therapy? This is pure idiocy.”

Everyone seems to have an opinion.

But everyone also seems to be missing the real story here…

Because there is a breakthrough here worth being excited about. But it’s not what you think.

So, today, I want to dig into this landmark paper and reveal to you why I had a grin stretched ear-to-ear while reading it.

The Real Science Behind the “Cure Heart Disease” Headlines

Okay, first let me quickly explain what this paper was — and what it wasn’t.

• It was not a signed-and-sealed approval making gene therapy the new standard of care for LDL lowering.

• It was a Phase 1 open-label trial testing a new technology called VERVE-102, developed by Verve Therapeutics (part of Eli Lilly). Specifically, it tested a CRISPR-Cas9-based gene-editing therapy designed to lower PCSK9 levels specifically in the liver.

Okay… let’s unpack that gobbledygook, because what’s happening biologically is more precise than most people realize.

The goal here was not to gene-edit an entire human being indiscriminately. Rather, this was a highly targeted therapeutic approach aimed specifically at the liver.

The VERVE-102 system contains:

• A gene base editor, termed adenine base editor (ABE; red), which changes essentially one “letter” (adenine) in the gene coding for the PCSK9 protein

• A guide RNA (blue), which acts like a homing device to direct the editor to the correct place in the genome.

Ironically, that’s the easy part.

The difficult part — and historically the biggest barrier in human gene-editing therapies — is getting the entire editing complex to the right tissue and organs in the body.

And this is where the story gets more interesting.

They solved that delivery problem using a lipid nanoparticle containing N-acetylgalactosamine (GalNAc; pink, above), which enables entry into liver cells by binding to a receptor called the asialoglycoprotein receptor (red circle, below).

Another way to think about it is this:

• Gene editor = the letter

• Lipid nanoparticle = the envelope

• GalNAc = the stamp that tells the body to deliver the package to the liver.

Additionally, the researchers didn’t select random participants.

They specifically enrolled people with premature cardiovascular disease, most of whom also had familial hypercholesterolemia: a genetic condition that impairs the clearance of cholesterol-containing particles like LDL.

And to be completely clear about my opinion: I think this is exactly the right population in which to test this technology.

These are highly vulnerable individuals, many with a strong genetic predisposition to disease, where the therapy is essentially attempting to correct a biologically rooted defect, at least in the 83% with familial hypercholesterolemia.

Does that all make sense?

One Injection, 62% Lower LDL

Now, the headline result was, of course, that a single administration was highly effective at lowering LDL cholesterol.

Specifically, at the highest dose (1 mg/kg, administered to seven participants) the average percent change in LDL cholesterol was 62% (dark blue).

And this reduction was largely maintained over time.

So, you can see where people got the idea that a single injection could protect people from cardiovascular disease for life.

Obviously, that requires extrapolation, even on the durability of the treatment. For the most part, they only looked at a maximum 1-year timeframe. But you can see where the headlines and hype came from.

Additionally, I’ll be very clear about this: this study reported no improvements in cardiovascular or health outcomes.

They were looking at biomarkers.

And because this was a Phase 1 trial, it was primarily a safety trial, not a trial designed to assess cardiovascular outcomes.

Now, if you want my speculation: cardiovascular risk, yes.

Overall health? It probably depends on the population.

If we’re talking about metabolically healthy people with high LDL and ApoB, I think it would be borderline insane to administer this therapy today.

This is not the next evolution of peptides for your average biohacker bro… although if tomorrow I saw a YouTube video by Bryan Johnson entitled, “I Verved My Liver,” I wouldn’t be entirely surprised.

Sorry… a little inside baseball there. Just a light-hearted joke!

But Was It Safe?

However, what about safety? That was the main objective of the trial.

Well, on balance, there were very few meaningful adverse events reported.

• Transient infusion-related reactions occurred, but they were not severe.

• There was a small bump in a liver marker called ALT early in the post-dose period, but that largely resolved.

• There was only one serious adverse event: a condition called aspiration pneumonitis. But this occurred in someone with a history of gastroesophageal reflux, and the adverse event was not considered related to the treatment.

So, was it safe? Based on the reported data, it appears so.

Furthermore, something I found reassuring was that the delivery system (the GalNAc lipid nanoparticle) cleared from the body very quickly. Its half-life was less than 20 hours. So, within a couple of days, the delivery system was basically gone.

In other words, if we go back to our letter-and-envelope analogy, the envelope was pretty much shredded and discarded, with very little debris left within a couple of days.

All else being equal, that’s probably a good thing.

The TL;DR is:

The injection was effective at delivering the gene-editing system where it was supposed to go — to the liver — making a modification and then clearing out.

Additionally, prior evidence suggests very little distribution of the gene-editing technology across other organs, like the adrenal glands and spleen.

And, importantly, at least in a mouse model, there was no transmission to the next generation.

So, we’re not editing the human germline here.

Taken together, my honest assessment is that:

This technology appears rather specific and generally safe in the acute sense for targeting PCSK9 in the liver and lowering LDL cholesterol in patients with genetic familial hypercholesterolemia or premature cardiovascular disease.

Why This Is Different Than a Statin

But now I should probably delve a little deeper into the downstream effects of this medication, i.e. how it lowers LDL.

And I want to parse the difference between this technology and something like a statin.

• Statins inhibit an enzyme involved in cholesterol synthesis. So, your body makes less cholesterol in the liver and elsewhere. (A downstream consequence, in fairness, is that LDL receptors are also unregulated.)

Here, we’re doing something mechanistically different.

• The PCSK9 protein promotes the destruction of LDL receptors, which are important for clearing particles out of the bloodstream faster.

Physiologically, I think this is a better approach, caveating that this is my opinion.

And I’ve gone on the record before saying that, if I had to choose between taking a statin and a PCSK9 inhibitor, I would take the PCSK9 inhibitor.

So, if you want an honest, non-hyped assessment of this literature (again), here it is:

This was a breakthrough proof-of-concept safety trial demonstrating that targeted delivery of gene-editing technology to the liver can successfully make a specific genetic modification.

In other words, the technology works.

And as far as we can tell from this early-stage trial, it also appears reasonably safe.

Technologically speaking, I do consider that a genuine breakthrough.

But in my opinion, the headlines actually understate what’s truly exciting here.

Because the real breakthrough is not simply: “We can lower LDL cholesterol with one injection.”

The real breakthrough is that we are beginning to demonstrate the ability to deliver highly targeted gene-editing machinery to a specific organ, make a precise modification, achieve a desired physiological effect, and then have the delivery system rapidly clear from the body.

That is a therapeutic paradigm shift.

And that’s what I want to spend the rest of this letter talking about, because this isn’t the end of the discussion. It’s the beginning…

In the rest of this letter for StayCurious Metabolism Premium members, we will delve into:

• How the technology could become a springboard for far greater innovations, including Alzheimer’s prevention

• Obstacles that still remain in pursuing these advancements (and ways we could get into the brain)

• The unusual way I lowered my LDL and ApoB by 71% (no statin, PCSK9 inhibitor, gene therapy, or Oreos)

• The ethics, and why “playing God” is often framed incorrectly

If you’re someone who appreciates nuanced science and a truly open-minded exploration of the frontier of metabolic health, rather than influencers simply pandering to dogma, then this is the community for you. And I’d love to welcome you into it.

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Now, forgive the authoritative opening tone, but I want to get you laser focused on what this letter is going to be about: This is a high-yield synthesis of my supplement and medication protocol for Alzheimer’s prevention.

My Aim is Simple:

• Summarize what I do to protect my brain and why in a manner that is as concise as possibly while maintaining nuance.

• Throughout, I’ll back every statement with links out to deep dives from our archives for those who want to scrutinize the mechanisms and evidence behind each decision.

No fluff. No hedging. Let’s get straight to it.

This letter is a special for StayCurious Metabolism Premium subscribers. It’s the kind of rigorous, forward-thinking, nuanced yet accessible analysis our members have come to expect.

If you’re ready to go beyond surface-level summaries and into truly actionable science, join the premium community and see why so many subscribers call it the best investment they’ve ever made in their health.

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But that’s not the interesting part.

What is interesting is that this same molecule might have implications for some of the most common and burdensome chronic diseases on the planet, from heart disease to diabetes and even to Alzheimer’s and Parkinson’s disease.

This is certainly a peptide I might consider including in my health routine.

But not before first diving into the scientific literature. And when I did, I was struck by genuine optimism.

This is a very peculiar biomolecule that appears generally safe, with a wide variety of potential use cases. Maybe that’s not surprising since it helps shore up the foundational hub of metabolism in our bodies: the mitochondria.

Now, you might have noticed I haven’t told you what this molecule is yet.

That’s because its name sucks.

Science isn’t always great at marketing, so brace yourself.

It actually goes by many names: SS-31, elamipretide, Bendavia, MTP-131, Forzinity—even D-Arg-Dmt-Lys-Phe-NH₂.

Gosh! This molecule has more names than a Game of Thrones character.

Seriously, we could call it: “SS-31 of the Inner Membrane, First of Its Name, Binder of Cardiolipin, Keeper of the Electron Chain, Defender Against Oxidative Chaos, Restorer of Cellular Power”

But on the internet, it’s most commonly referred to as SS-31. So, that’s what we’ll call it.

Today, I’m going to tell you:

• How SS-31 works.

• How it’s being used today.

• What conditions it might soon be used to treat.

• What’s next in the universe of mitochondrial medicine.

• How I’m sourcing my peptides.

What You Need to Know About Mitochondria

I want to begin with some basic biology—the background you need to understand this.

Specifically, let’s talk about mitochondrial structure.

Mitochondria, as you probably know, generate energy for your body. But they’re also communication and signaling hubs. Physically, they look like little beans and have two membranes. The inner membrane is folded into structures called cristae—and these are absolutely critical.

I like to think of the folds in the inner mitochondrial membrane kind of like the folds in your brain… and you don’t want to be a smooth brain.

These folds increase surface area and, more important to our discussion, allow different components of the membrane to interact with each other.

And that idea of interaction is key.

For efficient energy production, you need specific components to link together. When that process breaks down, energy production fails. And when energy production fails, organ systems begin to fail.

Now, there’s a critical component here: a lipid called cardiolipin.

Cardiolipin helps give the inner membrane its structure and those elegant folds.

More specifically, it promotes the curvature of the inner mitochondrial membrane to optimize energy production through what’s known as the electron transport chain, a series of complexes (I, II, III, IV, and V) that pass electrons along to ultimately generate the energy that keeps us alive.

So that’s your biology background.

SS-31: A Mitochondrial Targeting Peptide that Stabilized Mitochondria

Now, where does SS-31 come in?

SS-31 is a peptide that uniquely localizes to the mitochondrial inner membrane and binds to cardiolipin. In doing so, it helps recruit and stabilize other proteins and enzymes involved in energy production.

And I really want to emphasize how unique this is.

To have a peptide that can travel throughout the body, enter cells, home directly to mitochondria, and then stabilize these energy-producing “supercomplexes” (these assemblies of enzymes embedded in the membrane), that’s pretty remarkable.

FDA Approval for SS-31

But now let’s return to the recent FDA approval in this rare mitochondrial condition before broadening the discussion to more common chronic metabolic diseases.

The disease in question is called Barth syndrome.

It’s a 1 in a million genetic disease linked to a gene on the X chromosome, so it primarily affects males. At its core, it’s a disorder of mitochondrial cardiolipin metabolism.

In many ways, it’s human proof that if you don’t have sufficient functional cardiolipin, your mitochondria fail.

Barth syndrome is characterized by problems with the heart, skeletal muscle dysfunction, growth abnormalities, and a host of other complications, with many children requiring heart transplants by their teenage years.

So, researchers conducted a randomized, double-blind, placebo-controlled trial lasting 28 weeks, followed by a 168-week extension period.

The primary endpoint was safety and tolerability of SS-31, with secondary endpoints focused on functional outcomes, including fatigue scores and the six-minute walk test.

To cut to the chase: the SS-31 peptide was found to be safe, and it led to significant improvements in physical function, including fatigue and performance on the 6-minute walk test.

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The 6-minute walk test is exactly what it sounds like: it measures how far a person can walk on a flat, hard surface in six minutes, serving as a proxy for functional aerobic capacity and endurance.

In general, an improvement of 25 to 35 meters is considered clinically meaningful.

In this trial, SS-31 led to a 96.1-meter improvement.

That’s a substantial signal, and clear evidence of improved physical function in patients with this mitochondrial disease. These benefits extended to fatigue scores, muscle strength, and other functional measures.

In short, this simple peptide, by helping to partially restore mitochondrial function, improved global physical performance, as well as signs and symptoms, in boys with Barth syndrome.

But there’s roughly a 0.0001% chance you have Barth syndrome.

So, you’re probably wondering whether SS-31 has any relevance for you or me?

The honest answer is SS-31 almost certainly matters for far more than the condition it was approved to treat.

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

• Potential use cases for SS-31

  • Heart disease

  • Diabetes & diabetic complications

  • Alzheimer’s & Parkinson’s disease

• The future of mitochondrial medicine, including mitochondrial transplantation

• The two main classes of peptide suppliers

  • How I’m sourcing my peptides

This isn’t about prescriptions—it’s about information. I know a lot of you are interested in this topic, so we may as well practice “informed compounding.”

Now, come find out why Stay Curious Metabolism is a Top 3 Bestselling Science Newsletter Globally, and why members call it a staple in their health routines.

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It was a human controlled study published in Nature Metabolism that found people who ate less protein burned dramatically more calories—without any meaningful muscle loss.

So, I return to, “this has to be wrong. I just has to be wrong!”

But, I was curious. So, I decided to test it on myself.

And it wasn’t wrong. I was.

But let’s back up and give some more context before I tell you about my experiment and then… why it worked and how this system can be hacked!

The Study in a Nutshell

In the study, young men eating a higher-protein diet, were dropped down to a low-protein diet—just 9% of their calories from protein—before returning to the higher-protein diet. The low-protein diet phase lasted five weeks.

And what did the researchers find? Well… I already gave that away.

Eating less protein caused people to burn dramatically more calories. Not a little more. A lot more. About 20% more Calories, or about +600 extra Calories burned per day.

• No extra exercise.

• No lifestyle change.

• Just diet composition.

In fact, the effect was even independent of the source of the present calories.

High-carb, low-protein or even high-fat + high-carb + low-protein worked to increase Caloric burn massively! And, after five weeks, researchers found no meaningful muscle loss.

My Self-Experiment: +6000 Calories. – 6.4 lbs.

I couldn’t help but to test it on myself.

After speaking with the first and senior authors of the study to get some more insights, I gradually lowered my own protein intake from my usual 18% of calories down to 9%. I began losing weight.

So, I started overall intake to compensate.

I kept increasing…

By the end of the experiment, I was eating about 500 “extra” calories per day. On paper, over three weeks, I had accumulated a 6,000+ Calorie “surplus” from moderate-consistent “overeating.”

And yet… I still lost 6.4 pounds.

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I didn’t run a DXA scan, but my gym performance didn’t drop. If anything, my strength-to-weight ratio slightly improved.

Now to be clear: I am not advocating low-protein diets without caveats.

But I am extremely interested in metabolic phenomena that challenge our assumptions. Because if this effect is real, there are two much more interesting questions hiding underneath:

• Why would the body burn more energy when protein intake drops?

• Can we hack this system to ‘have our steak and eat it too?’

In this StayCurious Metabolism special for premium subscribers, we’ll answer those questions and break into new 2026 research that makes it all click! We’ll cover:

• An analogy to help you understand how this might work at a conceptual level.

• New human data showing how some people appear metabolically “blessed” while others less so.

• How studying those differences allowed researchers to reprogram metabolism in animal models.

• How scientists identified the key players and ultimately engineered a fat-burning cocktail.

• Finally, we’ll close with practical takeaways and a look at what’s coming next.

If you’re not already a Premium subscriber, now’s the perfect time to find out what everyone’s been talking about. I promise—it’s nuance worth your nickel!

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Think Spider-Man bitten by a radioactive spider, or Captain America infused with the super-soldier serum.

Of course, these stories are fantasy.

But they capture something deeper in the human imagination than simple childhood wonder. They tap into a timeless desire: the urge to engineer ourselves into something greater. Stronger. Smarter. Healthier. Maybe even morally better.

Some people wrinkle their noses at that idea. They say it’s “playing God.”

But personally, I welcome the possibility.

Because today I want to talk about something that still sounds like science fiction—but is rapidly becoming science fact: the future of human bioengineering.

Believe it or not, we may be only years away from technologies that could dramatically reshape the human body and mind. The possibility of engineering stronger muscles, sharper cognition, longer healthspan and lifespan.

We are rapidly approaching that fantasy we’ve all imagined at some point.

Let’s start with where we are right now.

“Miracle” Weight Loss Drugs, and Their Limitations

*For more details, see THIS dedicated letter.

A good case study is what many people call the “miracle drugs” of our time: GLP-1 receptor agonists. Medications like Ozempic and Wegovy.

Now, I know these drugs are controversial.

But whatever your opinion of them, one thing isn’t in dispute: their biological effects are profound.

We can inject a compound that fundamentally alters hunger signaling and metabolism, leading to dramatic weight loss.

In recent trials with a next-generation drug, retatrutide—a so-called “GLP-3”—participants lost roughly a quarter of their body weight in just 48 weeks.

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*Nuance note: And for the XX chromosomes watching… the effect was even larger in women. Finally, the fairer sex gets a slightly bigger bite of the apple.

Now, like it or not, these drugs represent a major technological advance in treating one of the most common and debilitating diseases of modern society: obesity.

And yes, it’s true: In many ways we created this problem ourselves—by engineering an environment optimized for comfort, convenience, and junk food.

But the fact that we can now begin to bioengineer our way out of that problem—at least partially—is remarkable.

Now to be clear: I am not saying people should be taking these drugs willy-nilly, using them as an excuse to avoid lifestyle modifications, or using them for what’s come to be known as “looks-maxing.”

I’m simply saying the metabolic biology here is extraordinary.

But these drugs still have major limitations.

One of the most important is that the weight loss they cause isn’t purely fat loss. A meaningful portion comes from lean muscle mass—roughly 25 to 39% of total weight lost.

That’s obviously not ideal.

My own hypothesis is that much of this may be behavioral. And resistance training and adequate protein intake likely mitigate a good portion of the lean mass loss. But not all of it.

So, the obvious next step in human bioengineering would be a therapy that does something better: selectively reduce body fat while preserving—or even increasing—muscle mass.

That sounds like science fiction.

Except data suggest it’s already here.

The Future of Fat Loss (And Muscle Gain)

*For more details, see THIS dedicated letter.

A paper recently published in Nature Medicine suggests we may truly be on the cusp of developing the ideal body recomposition drug.

The inspiration for this treatment comes directly from nature—specifically a rare mutation in the myostatin gene found in so-called double-muscled cattle, bully whippets, and a handful of humans who, through genetics, develop extraordinary musculature and remarkably low body fat.

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I say this lovingly: they’re genetic freaks.

Think something close to Captain America physiology—bigger muscles, less fat, and striking physical performance.

Interestingly, the animal literature suggests these mutations may even confer advantages for healthspan and possibly longevity.

That’s not entirely surprising when you consider that muscle itself is an endocrine organ. It secretes signaling molecules—myokines—that can protect other organs, including the brain.

So, what we might be looking at here is a genuine metabolic goldmine.

Bimagrumab Phase II Trial Complete

The new trial tested a fully human monoclonal antibody called bimagrumab.

The goal is to partially mimic the biological pathways seen in these genetically gifted individuals by targeting the signaling systems that normally limit muscle growth.

And the results were striking.

Participants with obesity didn’t just lose weight. Every gram of weight loss came from fat.

In other words: 100% fat loss.

Even more remarkable, participants simultaneously gained some muscle mass and experienced improvements in strength—all without any recorded increase in physical activity.

So here we have a therapy that can simultaneously reduce fat, increase muscle, and improve strength without requiring additional effort.

That begins to edge into territory that once belonged purely to comic books.

An intervention that moves the human body toward the superhero aesthetic: leaner, stronger, and more metabolically resilient.

And this isn’t hypothetical science fiction. This innovation has already completed phase II human trials.

It’s here.

Now, to be fair, the treatment isn’t completely without drawbacks.

Some participants reported mild side effects like gastrointestinal upset, headaches, and acne.

But the larger point remains: We are beginning to glimpse a future where the human body can be directly engineered toward greater strength, lower fat mass, and improved metabolic health.

And that future may be arriving much sooner than most people realize.

That’s Today. What About Tomorrow?

So here we have a therapy that can simultaneously reduce fat, increase muscle, and improve strength without requiring additional effort.

That begins to edge into territory that once belonged purely to comic books.

An intervention that moves the human body toward the superhero aesthetic: leaner, stronger, and more metabolically resilient.

And this isn’t hypothetical science fiction. This innovation has already completed phase II human trials.

It’s here!

But this is just the beginning.

Because everything we’ve talked about so far—GLP-1s, muscle-building antibodies—still works within your existing biology.

What if we didn’t have to work within those constraints at all?

What if we could rewrite the biology itself?

Because we already can, and with rapidly increasing precision.

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

• Gene Editing, and what that means for diseases from sickle cell to Alzheimer’s.

• Cellular Reprogramming and rejuvenation

• Molecular Messengers & Mitochondrial Transfusions

If you’re not already a StayCurious Metabolism Premium subscriber, now’s the time. This one’s a ride—a glimpse into the future!

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I should be having heart attacks like rabbits have babies.

For most of the last seven years, my total cholesterol has hovered around 700 mg/dL. I also have a history of inflammatory disease (ulcerative colitis), my Lp(a) is 194 nmol/L, and my father had a cardiovascular event in his 40s.

In other words, things should not be looking great for me.

And yet, what I’ve found is the opposite: my heart is perfectly clean.

Not only am I asymptomatic, but on advanced cardiac imaging, my plaque burden is zero.

And when I say zero, I mean zero—after expert review of my coronary CT angiography for both calcified and non-calcified plaque, plus an additional AI-guided quantification designed to detect plaque down to the lowest cubic millimeter, I have 0 mm³ of plaque in my coronary arteries.

Now, yes, you could say I’m young—I turned 30 on November 3, 2025. But keep in mind: the patients with homozygous familial hypercholesterolemia, the genetic disorder whose study helped catapult LDL cholesterol into its role as cardiology’s chief villain, often had LDL and total cholesterol levels similar to my own, and were developing severe disease and having heart attacks by as young as age 10.

So, it is genuinely remarkable that I have no plaque. The reasons why are manifold. My overall good metabolic health. The physiological reason my LDL is high in the first place. And so on.

And while I certainly won’t chalk up my pristine coronary arteries to supplements, nor use my story as a lever to sell you products, my medical history has inspired a deep curiosity about everything I can do to protect my heart while supporting my overall health at the same time.

That is the purpose of this letter: to review, with rigor and precision, supplements that may support heart health through different mechanisms—and to clarify who might benefit most from what.

For example, compound #1 may offer particular advantages to someone with high blood pressure; compound #3 may make more sense for someone on statins; compound #5 for people with high Lp(a); and compound #6 may have unique relevance for people with a second X chromosome.

Author’s aside: What This Letter Is and Is Not

Before we begin, I want to clarify what this letter is, and what it is not. This is not AI slop. This is not me leveraging credentials or personal story to sell you anything other than information.

This is a synthesis of dozens of studies I’ve read, printed, marked up, and deeply processed; work I’ve discussed with colleagues in journal clubs and interviews, with evidence throughout via hyperlinks to prior deep dives (just click on the section headings) totaling tens of thousands of words.

In the end, you can decide whether this is trustworthy. But in a world of information overload, my goal is simple: to make what follows concise and high-quality. Go as deep as you’d like.

Now, let’s go on a journey of nuance, precision, rigor, and curiosity—all in the service of learning how to better protect your heart.

Nattokinase

One of the more intriguing compounds in the cardiovascular space comes from an unlikely source: nattō, a traditional Japanese fermented soybean food that has been consumed for over a thousand years.

Beyond its distinctive smell and texture, nattō has long been associated with longevity and cardiovascular health. In large observational studies, individuals with the highest intake of nattō have shown significantly lower rates of cardiovascular mortality—on the order of ~25% lower risk compared to those consuming the least.

*Higher nattō intake is associated with a 25% reduced risk of cardiovascular morality (hazard ratio 0.75). This effect appears specific to nattō and does not generalize to other soy-based products.

Now, observational data always raise the question of confounding.

Perhaps nattō eaters are simply healthier in other ways. That’s a fair concern.

But what makes this signal particularly interesting is that the benefit appears specific to nattō, not to soy intake more broadly. Other soy foods do not show the same association. Curious… That suggests there may be something unique about nattō itself.

Enter Nattokinase.

Nattokinase is an enzyme produced during the fermentation process by Bacillus subtilis. And it may be one of the key drivers of nattō’s cardiovascular effects.

In one large human study involving over 1,000 participants, individuals taking high-dose Nattokinase (10,800 fibrinolytic units daily) for one year showed something striking: regression of atherosclerosis.

Using ultrasound imaging of the carotid arteries, researchers observed:

• A ~22% reduction in carotid intima-media thickness (CCA-IMT)

• A ~36% reduction in coronary plaque surface area (CPS)

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Those are not trivial changes. They suggest not just slowing of disease progression, but potential reversal.

In addition, participants experienced:

• ~16% reduction in triglycerides

• ~18% reduction in LDL cholesterol

• ~16% increase in HDL cholesterol

Now, to be clear, this was not a randomized controlled trial, and participants were compared to their own baseline. So, we cannot definitively attribute causality.

But the magnitude of the effect, combined with the biological plausibility, makes this signal difficult to ignore.

Let’s double click on that term, “biological plausibility.” Effectively, I’m just saying a mechanism with extra syllables—because that’s how we scientists do.

Pneumonoultramicroscopicsilicovolcanoconiosis anyone?

Yes, that’s a real word you learn in medical school. And apologies to anyone with hippopotomonstrosesquippedaliophobia for the jump-scare. (That’s the medical term for fear of long words.)

Okay, back on track!

How might Nattokinase be working?

Broadly, its effects can be grouped into three categories.

1. Anti-thrombotic activity

Nattokinase has what’s called fibrinolytic activity—it helps break down fibrin, the structural “mesh” that stabilizes blood clots. It also enhances the body’s natural clot-dissolving system by increasing tissue plasminogen activator (tPA) and reducing its inhibitor, PAI-1. On top of that, it appears to reduce platelet aggregation. Taken together, this shifts the balance away from clot formation and toward clot breakdown.

2. Blood pressure regulation

Nattokinase appears to inhibit angiotensin-converting enzyme (ACE), a key regulator in the renin–angiotensin system. By reducing ACE activity, it may decrease vascular constriction and lower blood pressure.

This effect has been demonstrated in randomized controlled trials.

In one such study, participants taking 2,000 fibrinolytic units daily experienced modest but meaningful reductions in both systolic and diastolic blood pressure—comparable to what might be achieved through structured dietary interventions.

3. Reduction in oxidative stress

Oxidative stress plays a central role in vascular damage, inflammation, and atherosclerosis. Nattokinase may help by upregulating endogenous antioxidant systems, protecting blood vessels, and reducing lipid oxidation.

*Mechanisms by which Nattokinase can improve cardiovascular health: by reducing blood clotting, reducing blood pressure, and reducing oxidative stress.

Stepping back, what makes Nattokinase compelling is not just any one of these mechanisms, but the convergence of effects: It influences clotting; It influences blood pressure; It influences vascular health at the biochemical level.

And, at least in preliminary human data, these effects translate into meaningful clinical changes.

But here’s the catch…

The difference between something being “interesting” and actually working often comes down to how it’s used. So, this is where things get practical: dosing.

In the rest of this letter, we’ll cover how to actually apply these ideas, not just for Nattokinase, but for 5 additional supplements. We’ll walk through how to":

• Influence ApoB naturally

• Reduce inflammation inside your arteries

• Offset some of the metabolic harms of statins

• Reduce or eliminate risk associated with high Lp(a)

All of this is grounded in the scientific literature, with links to deep dives in the section headings and throughout so you can vet everything as thoroughly as you’d like—along with specific protocols, dosing strategies, and who stands to benefit most from each intervention.

If you haven’t yet joined the premium community, I invite you to do so now, and discover why members call it the best $8 they’ve ever spent on their health, “an oasis of nuance on the internet,” and “an intellectually stimulating environment unlike anything else.”

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