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More from @nicknorwitz

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.

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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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Nick Norwitz MD PhD

@nicknorwitz

Nov 1

How to Hack the Black Hole of Sugar Cravings

(1/7) Why does one person politely decline dessert while another feels irresistibly pulled toward it, as if by a "gustatory black hole?" 🍰

It's NOT a failure of willpower. It's metabolic wiring.

A fascinating paper just published in Nature Microbiology uncovers a precise gut-to-brain pathway that modulates our biological preference for sugar.

2/7) Before we get to the rest of the thread, a quick reminder. This is DAY 1 of the Nuance November Promotion at 👉 StayCuriousMetabolism.com

Link to this letter: staycuriousmetabolism.substack.com/p/the-metaboli…

Now, ONWARD!

3/7) The story's main character is a gut receptor called FFAR4 (Free Fatty Acid Receptor 4).

Researchers found that FFAR4 levels are consistently reduced in human patients with diabetes and elevated fasting blood sugar.

Going deeper, they find that genetic differences in the FFAR4 gene are directly linked to increased sugar preferences in humans.

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Nick Norwitz MD PhD

@nicknorwitz

Oct 28

Measuring Insulin Resistance: Your Potato-to-Grape Ratio?! 🥔🍇 (link at the end)

1/5) Your potato-to-grape ratio might predict your insulin resistance.

A 2025 study from @Stanford Snyder Lab (@SnyderShot) published in @NatureMedicine is challenging one-size-fits-all nutrition, and the findings on personalized blood sugar spikes are fascinating.

2/5) Researchers studied 55 individuals, giving them seven standardized 50g carb test meals (white rice, bread, potatoes, pasta, beans, berries, and grapes).

They tracked everyone's individual glycemic response to each meal using CGMs.

One striking finding?

🚨Quoting the paper: "for each individual, different meals produced the highest glycemic response."

Someone might spike most from bread, another from grapes, someone else from potatoes.

But the patterns weren't random.

3/5) The researchers identified a metric they call the "potato-to-grape ratio" (PG-ratio).

They found that people who were more insulin-resistant consistently spiked more strongly from potatoes relative to grapes as compared to insulin-sensitive individuals.

It suggests this simple PG-ratio could one day serve as a real-world biomarker for muscle insulin resistance. It’s a powerful example of how your unique physiology matters more than a generic glycemic index chart.

The nuance goes deeper…

Read 5 tweets

Nick Norwitz MD PhD

@nicknorwitz

Oct 16

Why Lp(a) May Not Be as Dangerous as You Think—If This One Metric Is Low (🔗 in 8/8)

1/8) A new study offers real hope for those with high Lp(a), a genetic risk for heart disease. While you can’t change your genes, the risk of high Lp(a) appears to be conditional on a modifiable factor: your waist-to-hip ratio.

2/8) For context, Lp(a) is a cardiovascular boogeyman. Unlike LDL, its unique apolipoprotein(a) tail makes it "sticky," more likely to promote blood clotting, and more atherogenic on a per-particle basis.

Your Lp(a) level is largely genetically determined, a fact that has been frustratingly difficult to address as few effective, proven therapies currently exist that lower Lp(a) and lower cardiovascular risk.

3/8) This new analysis used data from the landmark MESA study to understand this risk. It followed 4,652 people for a median of 17.4 years, tracking 'new cardiovascular disease-related events'—a composite including heart attack, fatal/nonfatal CHD, specific angina, stroke, and other atherosclerotic deaths.

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More from @nicknorwitz

Nick Norwitz MD PhD

Nick Norwitz MD PhD

Nick Norwitz MD PhD

Nick Norwitz MD PhD

Nick Norwitz MD PhD

Nick Norwitz MD PhD

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