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Nick Norwitz MD PhD

@nicknorwitz

Nov 25

🚨How Berberine Lowers Cholesterol: Blew My Mind! (link at the end)

1/6) I just learned how berberine lowers LDL-C/ApoB, and the *mechanism* blew my mind.

Unlike statins, it doesn’t inhibit cholesterol synthesis, or harm mitochondria, and doesn’t worsen insulin resistance.

In fact, it improves features of metabolic health, while also lowering LDL and ApoB in a totally unexpected way.

Let’s break it down...

⚠️ Warning: This is a heart-health nerd's only zone. Proceed at your own risk, especially with 4/6.
@ApoDudz @lipo_fan @realDaveFeldman @AdrianSotoMota @LDLSkeptic @AKoutnik @janellison @bschermd @tyler_smith @Hundredhealth @DrPaulMason @robbwolf @reallyoptimized

2/6) First, contrast with statins. Statins inhibit cholesterol synthesis, creating a relative “cholesterol starvation” state in liver cells.

The liver compensates by ramping up LDL receptor expression, which pulls LDL particles out of the bloodstream. Effective—but not without tradeoffs, which can include off-target effects in other organs:

👉Mitochondrial impairment
👉Reduced CoQ10 synthesis
👉Lower GLP-1 levels
👉Insulin resistance

I’m not saying statins don’t have a place—but their mechanism of action has real biological costs.

3/6) Berberine diverges completely. In a hypothesis-naive screen of natural compounds, it stood out by boosting LDL receptors through a weird route.

TL;DR: it stabilizes the receptor’s mRNA “instructions,” extending receptor production from ~60 minutes to >3 hours.

Read 6 tweets

Nick Norwitz MD PhD

@nicknorwitz

Nov 15

Microbiome Reset (Protocol)

1/6) If you’ve ever thought, “What if I just reset my microbiome?” Well, that’s what I want to help you do today.

But why even ask this question?

Let me back up—about 29 years—and share a bit of personal context.

As a newborn, I spiked a fever of 106°F. Out of caution, I was given powerful antibiotics.

Today, we better understand how critical early life is for microbiome development. Antibiotics like the ones I received can leave a lasting scar—even increasing risk for inflammatory bowel disease (IBD) later in life by ~500%.

Lo and behold, I did develop IBD—specifically, ulcerative colitis. It nearly killed me.

2/6) The truth is, our microbiomes are under constant assault—sabotaged daily by the booby traps of modern living.

From the moment you wake up and pour cereal into a bowl to the moment you collapse into bed, eyes glazed from “just one more” episode, our environments have drifted so far from nature’s blueprint that most of our microbiomes are evolutionarily unrecognizable.

So, what might a microbiome reset look like?

3/6) In today’s letter, we push the boundaries of science (and colon walls). We discuss:
👉A Step-by Step 4-Phase Guide
👉What to Avoid when you’re in microbiome in maintenance mode
👉Lifestyle inputs Beyond Food that shape your gut health.
staycuriousmetabolism.substack.com/p/how-im-rebui…

Read 6 tweets

Nick Norwitz MD PhD

@nicknorwitz

Nov 13

I just completed a month-long sardine diet.

1/5)The results were... surprising 😳
👉Body fat (7%)
👉Omega-3 levels, off the chart (literally, 25% higher than the visual scale goes and 2.7% above reference range)
👉Energy = Excellent (after some tweaks)
👉Cold Resistant. Maybe an impact of omega-3 on thermogenesis (via omega-3 derivatives, e.g. 12-HEPE)

2/5) The Rationale: Sardines are about as close to a superfood as one can get: packed with protein, omega-3, calcium, B12, CoQ10, creatine, etc.

They're like if a multivitamin had a baby with a protein supplement - but natural. So you can pretty much live off sardines

3/5) For the first several days I did only sardines. But then my energy dipped. So I adapted my 'sardine fast' into a sardine-based diet, supplementing with added fat - especially olive oil and MCTs.

This turned me into an energizer bunny and made the Sardine Diet sustainable for a full month.

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Nick Norwitz MD PhD

@nicknorwitz

Nov 6

New Therapy for Alzheimer’s Prevention: An ApoE2 “Bath”

1/5) My Alzheimer's risk is 10-15x higher than average because I'm in the ~2% of the population that carries two copies of the ApoE4 gene, the dominant genetic risk factor for Alzheimer's.

Some consider this a near guarantee of developing the disease if you live long enough.

But I'm optimistic.

A study just published in Molecular Therapy demonstrates a potential "antidote" that gives me, and many others, a reason for hope. It’s not a cure. Not a silver bullet… but a glimpse of what’s coming…

In today’s letter (🔗 at the end), I break down these data and tell you what I do today to protect my ‘future me’ brain.

(2/5) One core question has always been: Is ApoE4 actively "toxic," or is the problem a lack of functionality, functionality better provided by the most common “ApoE3” variant of the ApoE gene or protective ApoE2 variant.

If it's primarily a lack of functionality, the solution is simpler: add back what's missing.

That's exactly what this study tested. Researchers used a humanized mouse model carrying the ApoE4 gene to see if they could literally bathe the brain in extra ApoE2 to protect against Alzheimer’s pathology.

They developed a clever new gene therapy method to do to make this happen…

(3/5) How the technology works: Instead of trying to hit every neuron, they targeted a thin layer of cells called ependymal cells that line the brain's fluid-filled spaces (the ventricles, below).

Why? Because these cells naturally touch the cerebrospinal fluid (CSF), which bathes the entire brain.

They used a modified (generally safe) adeno-associated virus (AAV) to deliver the ApoE2 ‘antidote’ gene instructions only to these cells, turning them into little ApoE2 "factories" that pump the protective protein into the brain's natural plumbing system.

Thus, the ApoE4 brain is ‘bathed’ in ApoE2, without removing any ApoE4.

Read 5 tweets

Nick Norwitz MD PhD

@nicknorwitz

Nov 4

Stress Can Biologically Age Your Body and Brain. But How You Respond to Stress Matters More (🔗 in 7/7)

1/7) We often talk about stress metaphorically — "that job is aging me." But what if this is a literal biological truth?

A study published in Nature Aging provides a chilling mechanism, linking chronic psychosocial stress directly to accelerated biological aging.

The culprit? Stress is creating "zombie cells" (cellular senescence), especially in your most critical organ: your brain…

Are you surprised? And, how old do you think I am (biologically speaking)?

2/7) To test this, researchers used a robust model of chronic subordination stress in mice.

This isn't just "feeling stressed" — it's designed to simulate chronic social defeat. Think of it as the biological equivalent of a persistent bully at school or an aggressive, abusive boss with unchecked power.

Each day, the test mouse was exposed to a larger, aggressive mouse and physically subdued, creating a state of chronic, inescapable social stress.

3/7) The biological results were immediate and striking. The "bullied" mice showed a sharp increase in p16 expression, a key biomarker of cellular senescence.

Think of senescence as "cellular zombification."

These cells lose the ability to divide (which is part of healthy turnover) but refuse to die. Instead, they linger and secrete inflammatory signals that damage neighboring cells and drive chronic disease.

The stress was powerfully triggering this "zombie" state.

Read 7 tweets

Nick Norwitz MD PhD

@nicknorwitz

Nov 2

Creatine Mini-Masterclass
💪How is Really Work?
💪How Do You Maximize Benefits?
🔗 in 8/8

1/8) Creatine is one of the most extensively studied performance-enhancing supplements in the world of exercise science and nutrition.

For examples, a recent meta-analysis of RCTs examined the effects of full-body resistance training programs, with and without creatine supplementation.
The key findings:

💪Compared to resistance training alone, creatine supplementation significantly increased lean body mass by 2.5 lbs (1.14 kg).

💪Creatine also led to reductions in body fat percentage by 0.88% and total fat mass by 1.6 lbs (0.73 kg).

And yet, despite its popularity, few people truly understand how it works or what its full range of effects might be.

So... what is Creatine and How Does It Work?

2/8) Creatine is a naturally occurring compound made up of three amino acids: arginine, glycine, and methionine. Your body produces it in small amounts, and you also get some from food—especially meat and fish.

Creatine is primarily stored in muscle tissue, where it plays a critical role in cellular energy metabolism. Its main function? Helping to rapidly regenerate a molecule called ATP—the primary energy currency of your cells.

3/8) Phosphocreatine for Rapid Energy

When you engage in intense physical activity—sprinting, lifting weights, or even just climbing stairs—your muscles burn through ATP in a few seconds. Once ATP is used, it becomes ADP (adenosine diphosphate), and the cell needs a way to quickly replenish its ATP stores.
That’s where phosphocreatine comes in.

Phosphocreatine is simply creatine bonded to a phosphate group. This phosphate can be rapidly donated to ADP to regenerate ATP—restoring your energy supply nearly instantly. Even glycolysis is slow by comparison.

By supplementing with creatine, you increase your phosphocreatine stores, effectively boosting your energy buffering system. This leads to greater performance in high-intensity, short-duration efforts and quicker recovery between bursts of activity.

But that’s just the creatine biochemistry 101. I know you can handle more…

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More from @nicknorwitz

Nick Norwitz MD PhD

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Nick Norwitz MD PhD

Nick Norwitz MD PhD

Nick Norwitz MD PhD

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