Nick Norwitz MD PhD

A massive new paper just broke the internet: we are now gene-editing humans to lower cholesterol.

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/will…

Predictably, reactions are split. Some people think this is the future of medicine. Others think it’s reckless insanity.

But almost everyone is missing the bigger story.

This wasn’t simply a cholesterol trial. It was a technological breakthrough in targeted gene-editing delivery.

Researchers successfully packaged a gene-editing system into lipid nanoparticles engineered to target a specific organ — in this case, the liver.

And yes, the LDL-lowering results were impressive.

But the truly important question is: What happens when we can reliably deliver gene edits to other tissues?

Muscle. Fat. Immune cells. Maybe one day even the brain. Could this eventually become a pathway toward preventing diseases like Alzheimer’s?

There are still major technical hurdles, and in today’s deep dive we unpack all of it:

•⁠ ⁠What the trial actually showed
•⁠ ⁠What the media is getting wrong
•⁠ ⁠Why targeted delivery may be the real breakthrough
•⁠ ⁠What comes next
•⁠ ⁠And a preview of an upcoming experiment where I lowered my own LDL and ApoB even more than in this gene editing trial — without statins, PCSK9 inhibitors, gene therapy, or Oreos

Just something else very popular that most people have heard about… but very few actually understand mechanistically.

Check the link above for the full breakdown.

#CRISPR #ApoB #cholesterol #educational #staycurious #metabolichealth #NEJM

11 hours ago | [YT] | 191

Nick Norwitz MD PhD

As an MD-PhD neuroscientist—and someone who carries two copies of the highest-risk genetic variant for Alzheimer’s (ApoE4/4)—I’m highly motivated to find every way possible to protect my brain from Alzheimer’s

Today’s letter is devoted to that topic. It’s a high-yield, heavily referenced summary of the most promising available molecules you can take today to protect your brain for tomorrow. Here’s a teaser…

Lithium orotate (microdose).

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/my-p…

Higher trace lithium exposure correlates with lower Alzheimer’s rates geographically, and Alzheimer’s brains tend to show lower lithium levels. In animal models, low-dose lithium improves memory, reduces neuroinflammation, and mitigates amyloid and tau pathology. I personally take 5 mg/day of lithium orotate.
NAD⁺.

Alzheimer’s I a disease of impaired brain energy metabolism. NAD⁺—a central molecule in mitochondrial function—declines with age and is unusually low in Alzheimer’s. Exercise (especially improving muscle mass and VO₂ max) robustly supports NAD⁺ production. NAD⁺ precursors like NR or NMN can also meaningfully raise levels in humans. (Dosing details in the full letter).
LPC-DHA.

The omega-3 DHA is structurally and functionally essential to the brain. But form matters. DHA bound to lysophosphatidylcholine has preferential access to the brain and appears more effective at raising brain DHA than conventional fish oil.

This is just a nibble. For an Alzheimer’s Prevention deep-dive you don’t want to miss, check the link above.

#AlzheimersPrevention #BrainHealth #CognitiveLongevity #Neuroscience #APOE4 #MetabolicHealth #NAD #Omega3 #Lithium #PreventiveMedicine

1 day ago | [YT] | 619

Nick Norwitz MD PhD

The FDA recently approved a peptide for a rare mitochondrial disease.

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/the-…

But that’s not the interesting part.
What is interesting… this same peptide may have implications for some of the most common and burdensome chronic diseases on the planet. (Link at the end)
The compound is called SS-31.

At a high level, here’s how it works: Inside your mitochondria is a critical lipid called “cardiolipin,” located in the inner mitochondrial membrane. It helps form those elegant folds that optimize energy production.

SS-31 uniquely localizes to the inner mitochondrial membrane and binds to cardiolipin. In doing so, it helps recruit and stabilize the proteins and enzymes that drive energy production.

In effect, SS-31 can help restore mitochondrial efficiency when it’s impaired and/or under conditions of extreme metabolic stress.

Late last year, the FDA approved SS-31 for Barth syndrome—a one-in-a-million genetic disorder of cardiolipin metabolism.
In a randomized, double-blind, placebo-controlled trial (with a 168-week extension), SS-31 significantly improved functional capacity across the board.
That’s fascinating. But it’s only the beginning.

Because mitochondrial dysfunction isn’t unique to rare diseases—it’s a feature of almost every major chronic condition: heart disease, diabetes, Alzheimer’s, and so on.
In today’s deep dive, we break down:
Potential use cases
The future of mitochondrial medicine (mitochondrial transplants)
Peptide sourcing (‘not for human use’ vs compounding pharmacies)

Check the link above for the full breakdown.

#mitochondria #peptides #staycurious #metabolism #metabolichealth #medicaleducation

4 days ago | [YT] | 781

Nick Norwitz MD PhD

Last year, I read a paper last year and immediately thought, “this can’t be right.”

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/are-…

It was a human controlled study that found people who ate less protein burned dramatically more calories. The effect size was massive. Reducing dietary protein increased energy expenditure by ~600 calories per day… without any meaningful muscle loss.

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

I cut my protein intake roughly in half. I began losing weight—without losing strength or visible muscle. Then I increased calories, ultimately to +500 “extra” calories per day.

Over three weeks that created a 6,000+ Calorie surplus. I still lost 6.4 pounds.

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?’

Good news!

A brand-new paper may finally explain how this happens and answer those questions! There’s something going on in some of – the metabolically ‘gifted’ – and there may soon be a way to replicate it.

For the insights based on these new data, check the link above.

#Metabolism #Microbiome #HumanMetabolism #NutritionScience #MetabolicHealth #GutMicrobiome #BrownFat #BeigeFat #EnergyExpenditure #SystemsBiology #PrecisionNutrition #StayCurious

6 days ago | [YT] | 958

Nick Norwitz MD PhD

I wanted to give a big community shoutout and thank you, specifically in response to my personal disclosure at the end of Monday’s video.

In fact, and as a disclosure about the disclosure, there’s now a “Catch Me Up on This Video” AI tool in YouTube Studio. One of the things it highlighted was that my vulnerability regarding my career path and health journey led to a massive wave of support. It even suggested doing a community post going deeper into that personal transition.

So, for those of you who are interested, that’s what this post is about.

If you check out the video and go to the timestamp where I discuss it ( 12:54 in https://youtu.be/TmloFV0W6iQ ), you can hear the emotion in my voice.

For me, my journey into medicine started almost as soon as I was verbal. My parents are both MD-PhDs, and there have been many other doctors in my life. I had always aspired to be a caregiver.

I loved science, and I loved helping people — whether that meant raising money for polar bear conservation through my “Baking for Bears” club benefiting the World Wildlife Fund, or serving as a camp counselor for kids with muscular dystrophy.

Human connection is something I deeply value.

And I’m obviously a giant nerd.

So combining the science of the human body and helping people, through the profession of medicine, felt like the only thing I could ever imagine doing. It was my default path.

Then, as many of you know, during the transition between college and starting my PhD, and before medical school, I got very sick.

And I mean very sick.

I was in and out of intensive care and palliative care.

And the profession I had so much respect for — and still do — failed me.

I’m not pointing fingers at any individual clinician, but the system failed me. The tools available at the time were not sufficient to put my disease into remission.

And when the status quo fails, patients often end up discarded and desperate.

That’s where I was.

And that’s where many of you are or were. Or, perhaps worse, have a loved one who has been there or is there.

When this happens, people start trying things out of desperation, not expectation, including things considered fringe by the mainstream.

And let me be clear:

just because something is not “evidence-based” in the conventional sense does not mean it lacks biological validity.

Sometimes it simply hasn’t been studied adequately because there is no business model or institutional incentive to study it.

That was my case.

Through self-experimentation, I found something that saved my life: a ketogenic diet for inflammatory bowel disease.

There are still no large randomized controlled trials proving this works broadly.

But it absolutely, unequivocally worked for me.

So that became my framing entering medical school: someone who respected medicine deeply, but who also understood its limitations because I had lived them.

Then life threw me a number of curveballs during medical school.

And by the end, I realized I had many opportunities to do what I had ultimately wanted to do all along: help people improve their health through science.

When I started medical school, I thought the only way to do that was to become a practicing clinician.

But with the democratization of information, social media, and the networks I had built, I realized there are many ways to contribute to what I think of as “the new medicine” — a broader and evolving framework that involves patients far more directly in the conversation.

So, as I’ve now disclosed several times, I never applied to residency.

Not because I couldn’t have.

And I don’t mean to flex my resume, but in this context it probably does matter.

I was valedictorian at an Ivy League school. I earned a PhD from Oxford on a full merit scholarship. I attended Harvard Medical School. I even had a residency program director at Harvard-affiliated hospitals willing to write me a letter of recommendation.

The door was wide open. By this point, "become a clinician" was the path of least resistance.

But it's not the one I chose, knowing full well that would take me from being as much as an insider as one could be to being an outsider, as least in some sense.

The path I took risked everything I had worked for in order to try something unconventional. And no, this wasn’t just about becoming a YouTuber or social media influencer.

It was about trying to create real change.

To build platforms and programs that empower patients, educate people, and help individuals take ownership of their health journeys.

To encourage people to become leaders in their own health rather than placing blind faith in some supposedly omniscient authority figure.

And even with everything that has transpired over the past year since graduation — much of which I’m not yet ready to share — I am 100% confident this was the right decision for me.

Not only am I happier than I’ve ever been, but I genuinely believe that, given my skill set and interests, this path will allow me to have a far greater impact on both individual and public health than anything else I could have done.

Like I said, there are initiatives in the works far bigger than a YouTube channel or social media platforms.

But my public presence has already opened doors to some incredibly interesting professional connections, and I intend to leverage those relationships toward my broader mission: making metabolic health mainstream and inspiring people to stay curious and recognize the power they often don’t realize they have to improve their own health.

Not in opposition to medicine — but as part of the evolution of what medicine can become. And, I'm only going to be able to do this with your support. 

So, thank you... from the bottom of my perfectly healthy heart.

1 week ago | [YT] | 1,902

Nick Norwitz MD PhD

The Superhuman Future is Here

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/can-…

For most of human history, the idea of transforming the human body—becoming stronger, healthier, longer-lived—belonged to the realm of science fiction.

Captain America.
Wolverine.
Spider-Man.

But the gap between science fiction and real biology is closing—fast.
We’re entering an era where scientists can rewrite the operating system of the human body.

It started with drugs like Ozempic. For the first time, we can inject a molecule that fundamentally rewires hunger and metabolism.

But that’s only the beginning.

New therapies (just completing Phase II trials) are already showing something even more remarkable: fat loss with simultaneous muscle gain—no extra exercise required.

And that’s just pharmacology.

The next wave of biotechnology goes much further.

We can now edit DNA, correct disease-causing mutations, and potentially rewrite risk genes linked to conditions like Alzheimer’s.
Researchers are also exploring ways to reset the biological age of cells—making old tissue behave young again.

In other words, the tools that could reshape human biology are arriving.

Not through radioactive spiders or super-soldier serum.

But through gene editing, cellular reprogramming, and a new generation of bioengineering technologies.

The real question isn’t whether these capabilities will emerge.
It’s how wisely we’ll choose to use them.

The future may be closer than we think. Check the link above for the full breakdown.

#bioengineering #genetics #longevity #biotech #healthspan #precisionmedicine #genomeediting #crispr #futureofmedicine #agingresearch #innovation #healthtech #staycurious

1 week ago | [YT] | 489

Nick Norwitz MD PhD

The Heart Supplements I Recommend to Family 🧵 👇

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/the-…

Today's deep dive letter is a result of my obsessive fascination in heart health—a synthesis of tens of thousands of written words and hundreds of papers that I've gobbled up over time.

Let me give you a taste…

Take Nattokinase, an enzyme derived from Japanese fermented soybeans.
It's been shown to lower blood pressure in randomized controlled trials, and at higher doses may even reverse atherosclerosis. It reduces blood pressure, reduces blood clotting, and increases antioxidant defenses.

Dosing is key to efficacy.

Or take TUDCA.

This bile acid and hormone is also a supplement that can suppress inflammation within the artery wall and even potentially offset some of the negative effects of statins on GLP-1 and insulin sensitivity.

Or the seemingly mundane “omega-3 fats.”

These can improve heart rate variability and even offset statin-induced increases in blood sugar and mitochondria dysfunction, especially in females.
Today’s deep-dive (linked above), will cover 6 heart health supplements. No brand plugs or affiliate links. Just the data and hard science. 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)

1 week ago | [YT] | 785

Nick Norwitz MD PhD

Could peptides derived from the pineal gland and thymus extend actual human longevity?

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/can-…

I was skeptical… but data out of Russia certainly caught my attention. Most notably, a 2003 paper in Neuroendocrinology Letters found, in a double-blind trial, that people over 60 treated with thymalin and epithalamin saw up to a 4-fold reduction in mortality vs controls.

Later work identified the active components in these extracts, like the peptide epitalon: a simple peptide made of just 4 amino acids: alanine, glutamic acid, aspartic acid, glycine.

So how might these increase longevity?

One mechanism as to do with telomeres: the protective caps on our DNA.

They shorten as cells divide. Epitalon appears to activate telomerase, an enzyme that can rebuild them. But there’s a catch…

More telomerase should = higher cancer risk. After all, unlimited cell division is cancer’s favorite trick. But remarkably, that’s not what we see. In fact, some data suggest these peptides reduced cancer risk. Why? The hypothesis: these peptides don’t just affect telomeres.

They may also:
Enhance immune surveillance
Improve antioxidant defenses

So instead of chaos, you get regulated repair + protection.
This is just the tip of the iceberg. If you’re skeptical… good. You should be.

But you should also be Curious.

Check out the deep dive linked above, where I discuss the mechanisms, longevity protocols based on the human data, and how I source peptides.

1 week ago | [YT] | 709

Nick Norwitz MD PhD

New Paper: Seven Years of 700 Cholesterol Without Coronary Atherosclerosis: A Lean Mass Hyper-Responder Case Report
Link: doi.org/10.3390/diseases14050168

For the past 7 years, I’ve been running what is essentially a natural experiment in cholesterol and heart health.

During that time, I’ve largely lived with:

Total cholesterol around 700 mg/dl
LDL cholesterol between 500–600 mg/dL

I recently underwent advanced coronary CT angiography imaging — not just looking for calcified plaque, but all plaque (soft + calcified) — with expert interpretation and AI-guided analysis capable of quantifying plaque down to the cubic millimeter.

Now, to address the obvious question:

Am I too young for plaque?

In brief: No.

The clearest comparison is individuals with homozygous familial hypercholesterolemia, who often have similarly extreme LDL/ApoB levels and can develop advanced plaque as toddlers, and even heart attacks as early as age 8.

Also, nutrition influencers in their 30s have publicly shared quantified plaque scores from these same imaging technologies. In one recent case, a plant-based influencer in his thirties was found to have 61.3 mm³ of plaque despite having far lower lifetime LDL exposure.

My case also isn’t a one-off.

There are many individuals like me. The difference is that I’m an unusually well-characterized subject, with extensive metabolic data and health markers tracked over time. You can learn more at the newsletter or open-access paper.

The science of heart health is not settled. And cholesterol is not a simple story.

How to help promote this paper:


👉Create an original post on social media (Facebook and/or X, formerly Twitter)
👉Include the copied link, doi.org/10.3390/diseases14050168

How this helps: Academic papers are increasingly evaluated using attention metrics. Original posts from unique users are one way to increase these metrics and help ultimately increase its reach.

Note: it will take about 4–5 weeks to appear on PubMed, but then you can find it there as well.

#cholesterol #apob #LMHR #staycurious #CCTA

2 weeks ago | [YT] | 1,646

Nick Norwitz MD PhD

MOTS-c: The Mitochondrial Hormone That Mimics Exercise

Deep dive here: open.substack.com/pub/staycuriousmetabolism/p/mots…

MOTS-c is not just any peptide. It’s a mitochondrial hormone that can enhance insulin sensitivity, decrease body fat, and improve physical performance.
Here’s what you need to know. And why I’m testing it myself…
We used to think the mitochondrial genome only had 13 genes—but there’s more nuance. There are short sequences coding for mitochondrial hormones, including MOTS-c.

In humans, MOTS-c increases ~11.9-fold in skeletal muscle with exercise, along with increases in the blood. It helps increase glucose uptake in muscle, in part by activating AMPK—but it also does something more interesting: MOTS-c can move into the nucleus and change the expression of the nuclear genome—decreasing inflammation and enhancing pathways related to healthspan and metabolic flexibility.

The preclinical data are also impressive: fat loss with muscle preservation and improved physical performance.
In one treadmill test, only 16.6% of control animals could reach top speed. By comparison, 100% in the MOTS-c group reached top speed.
And there may be even greater potential here: for extending healthspan and preventing chronic metabolic disease.
It’s genuinely exciting! So much so that after I went down the rabbit hole on this, I decided to test it myself.

For the full deep dive (science + dosing), see the link above.

2 weeks ago | [YT] | 738