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Nick Norwitz MD PhD

@nicknorwitz

Jul 14

1/7) This is, without a doubt, the craziest “diabetes drug” ever invented.

It’s completed Phase II human clinical trials showing efficacy for reducing blood sugar and improving blood pressure. But the promise may extend far beyond that. In preclinical trials, it:

• Reduces fatty liver
• Increases energy expenditure
• Improves exercise endurance
• Cuts fat without sacrificing muscle

It’s called ATX-304. But how does it work?

2/7) The mechanism centers on one of the body’s master metabolic regulators: AMPK.

AMPK functions as a kind of cellular fuel gauge. When it’s “on,” it shifts the body away from energy storage and toward energy production—pulling fat out of fat cells and sugar out of the bloodstream and directing them toward muscles and energy output.

For that reason, AMPK has long been considered a highly desirable metabolic target.

There have been challenges (discussed in the full letter), but the key point is this:

ATX-304 appears to be a powerful AMPK activator. Now let’s look at some data.

3/7) In this study, researchers gave animals a high-fat, high-sugar diet to induce obesity.

One group (black triangles) was started on ATX-304. As you can see, ATX-304 almost completely prevented weight gain.

Then the researchers “flip-flopped” the groups at day 15—and later again. As you can see, treatment with ATX-304 either prevented weight gain or actively caused weight loss.

But what kind of weight was being lost?

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Nick Norwitz MD PhD

@nicknorwitz

Jul 9

1/5) Mitochondria are often called the “powerhouse of the cell,” as if they’re just little batteries.

But they’re so much more. They’re living, fluctuating, even dancing signaling networks that determine how your body generates energy — and even how you age.

For example, one striking feature of supercentenarians, including the woman who lived to 117, is remarkably robust and youthful mitochondria.

The amazing thing about mitochondria is that unlike a battery or car engine, they can recover, heal, and renew themselves.

And you can help them do this: through how you live, how you eat, how you sleep, and potentially through cutting-edge mitochondrial peptides.

In today’s deep dive (link at the end), we discuss: How to Reboot Your Mitochondria.

2/5) Let’s start with something free:

Morning sunlight. This isn’t influencer wellness woo-woo.

Morning light helps kick off your “mitochondrial dance.”

Mitochondria constantly undergo cycles of fusion & fission
• Fusion helps mitochondria become more efficient and powerful.
• Fission helps isolate damaged mitochondrial components so they can be recycled through a process called mitophagy.

And research suggests light helps orchestrate these cycles.

3/5) Now let’s get more cutting-edge. Take the peptide SS-31.

Inside mitochondria is a highly folded inner membrane where energy production occurs.

A molecule called cardiolipin helps stabilize this membrane and organize the energy-producing machinery.

SS-31 is a mitochondrial-targeting peptide that binds cardiolipin and helps stabilize mitochondrial structure and energy production.

Researchers are now exploring it in aging, metabolic disease, heart disease, and neurodegeneration.

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Nick Norwitz MD PhD

@nicknorwitz

Jul 1

Can One Peptide Reduce Visceral Fat and Promote Longevity? 🧵

1/5) Tesamorelin is a peptide shown in randomized controlled human trials to reduce visceral fat by ~20%.

But that may be one of its least interesting effects.

Stick around to the end for the big reveal…

2/5) Tesamorelin is a growth hormone-releasing hormone (GHRH) analog.

Rather than supplying growth hormone directly, it nudges your pituitary to release more of your own.

That can:

• Support lean muscle
• Reduce visceral fat
• Improve body composition

But there's more.

3/5) Growth hormone has a fascinating two-way relationship with deep sleep.

😴 Deep sleep increases growth hormone release.
🧠 Growth hormone also appears to promote deeper, more restorative sleep.

That may help explain why some people using tesamorelin report better sleep efficiency.

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Nick Norwitz MD PhD

@nicknorwitz

Jun 28

How to Hack a 7-Day Fast in 24 Hours

1/5) What happens when you fast for 7 days?

Not what I expected.

In a remarkable study published in Nature Metabolism, researchers put 12 healthy volunteers through a 7-day water-only fast and used advanced proteomics to track 2,923 circulating proteins simultaneously.

What they found was surprising—and suggests some people may stop fasting just before many of the benefits begin.

2/5) During the first two days, the body performed a fuel switch.

Proteins involved in fat transport and ketone production surged as participants transitioned away from glucose dependence. Basic. That’s fasting 101.

But the most interesting changes hadn't started yet… The real shift didn't begin until Day 3.

3/5) Day 3 marked a biological tipping point.

Researchers observed a massive wave of protein changes that dwarfed anything seen during the first two days.

Overall, 1,034 proteins changed significantly during the 7-day fast, with most of those changes emerging after the day 3 threshold.

This included proteins linked to cardiovascular health and proteins involved in the literal structure and function of the brain, offering new insights into how prolonged fasting may help prevent—or potentially even treat—certain neurological disorders.

This wasn't just an energy shift.

It looked more like a biological software update!

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Nick Norwitz MD PhD

@nicknorwitz

Jun 26

Do Statins Cause Alzheimer’s: The Uncomfortable Nuanced Truth

1/5) Can statins cause Alzheimer’s disease and dementia? The honest answer is more complex than people give it credit for.

There are data suggesting statins can impair cognition. There are also data showing neutral effects, and even potentially protective effects. That contradiction requires resolution, not echo chambers.

Take a 2012 study in patients with pre-existing cognitive decline:

• Removing statins for 6 weeks improved cognition
• Re-challenging with statins for 6 weeks worsened cognition

Sounds alarming. But that’s not the whole story.

2/5) Many studies and meta-analyses find: no cognitive harm, neutral effects, or even potential protection against dementia

So, what’s going on? The answer likely lies in the interaction between:

• The pleiotropic effects of statins and
• Individual host physiology

Context matters. (Shocker)

Most Americans are metabolically unhealthy.

They have endothelial dysfunction and chronic inflammation.

On THAT metabolic background, statins may improve: endothelial function, blood flow, and inflammation Potentially benefiting both heart AND brain.

3/5) But there’s a flip side. As one example, common statins like atorvastatin may inhibit Complex IV activity in mitochondria.

And impaired Complex IV activity is associated with energetic dysfunction in the brain and Alzheimer’s disease.

So, there’s a push-pull. Some benefits. Some potential costs.

Read 5 tweets

Nick Norwitz MD PhD

@nicknorwitz

Jun 23

The Longevity Molecule is Garlic Nobody Saw Coming 🧛‍♂️🧄

1/4) Look at these two graphs.

LEFT: This what happens to circulating levels of something called “eNAMPT” with age in humans. It drops.

eNAMPT is a form of the enzyme NAMPT packaged into tiny extracellular vesicles (e) that travel throughout the body.

Why does that matter?

NAMPT is critical for producing NAD+, a molecule essential for energy metabolism, DNA repair, and countless other biological processes.

RIGHT: This shows what happens when researchers treat animals with eNAMPT-containing vesicles.

Lifespan increases by roughly 10%.

But here's where the story takes a surprising turn... Garlic!?!

2/4) In a 2026 paper published in Cell Metabolism, researchers connected a compound found in aged garlic extract—called S1PC (1)—to this longevity pathway.

Specifically, S1PC stimulates fat cells to release eNAMPT (2). What happens next is pretty wild.

eNAMPT travels to the brain (3), increases NAD+ levels, and ultimately contributes to improvements in muscle function, strength, and frailty measures in aged animals (4).

What's more, in a randomized, double-blind, placebo-controlled trial in humans, supplementation with S1PC from aged garlic extract increased circulating eNAMPT levels.

The effect was particularly evident in adults over 40 who were not clinically underweight.

In other words, the mechanism appears to translate from mice to humans.

3/4) So, let's zoom out.

• eNAMPT declines with age in humans.
• eNAMPT treatment can improve NAD+, physical function, and lifespan in animals.
• S1PC from aged garlic stimulates eNAMPT production.
• S1PC increases circulating eNAMPT levels in humans.

I'm not claiming garlic is the secret to living to 120.

But this is one of the most unexpected longevity pathways I've seen in a long time—and there's much more to the story…

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Nick Norwitz MD PhD

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