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Nick Norwitz

@nicknorwitz

Aug 7

GLP-1 vs Alzheimer’s: New Insights (Link in 5/5)

1/5) Look at the graph and brain images below. Let’s start with the graph, which represents the relationship between levels of the hormone GLP-1 circulating in the blood and levels of amyloid in the human brain. Clearly, there’s an inverse relationship: Lower GLP-1 levels associate with more amyloid; higher GLP-1 levels associate with less amyloid.

🧠The brain images reinforce the point: more yellow and red tones indicate more amyloid, whereas more green and blue tones suggest less amyloid. The brain on the left is the scan from the patient with the lowest GLP-1 levels of the twelve represented in the graph; the brain on the right is the scan from the patient with the highest GLP-1 level.

There’s unmistakably an antagonistic relationship between GLP-1 levels and amyloid. Let’s delve into new data to explain why this pattern exists — and what it might mean for your brain health.

2/5) The New Paper in Nature Aging Piqued my Curiosity

These data come from a new paper in Nature Aging, in which researchers set out to study the mechanism by which GLP-1 receptor agonist (GLP-1RA) medications might protect against Alzheimer’s disease.

There are already promising signals in the data, including results from a large cohort study and a Phase II randomized trial in adults with mild cognitive impairment. But the evidence is still early, and the mechanism murky. So, the researchers asked — in very technical terms — “What’s up doc?”

3/5) Unraveling the Mechanism - After observing an inverse association between GLP-1 and amyloid levels in both humans with Alzheimer’s disease and a mouse model of the disease, they conducted a set of carefully controlled mechanistic experiments that decoded the following pathway:

They uncovered the biological pathway:
1. GLP-1 binds to receptors in the brain.
2. This flips on a crucial metabolic switch called AMPK.
3. AMPK then shuts down a pro-inflammatory complex called NFκB, reducing inflammation in the brain.
4. With inflammation down, the brain’s immune cells — called microglia — become better at gobbling up amyloid and clearing debris.
5. Most importantly, AMPK suppresses an enzyme called BACE1 — the enzyme that starts the whole amyloid production process (pink, below). BACE1 is critical in making the amyloid oligomers that mark — and are thought to contribute to — the pathological cascade of Alzheimer’s disease. Specifically, BACE1 is the enzyme that initially chops the amyloid precursor protein (APP) into a form that then undergoes subsequent processing into neurotoxic Aβ40 and Aβ42 oligomers.

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Nick Norwitz

@nicknorwitz

Jul 31

A New Perspective on Sleep: Mitochondria Dance to the Rhythm of the Sun (🔗 in 6/6)
🚨Q&A with the first author of the new @Nature paper
🚨Book Giveaway (@hubermanlab) in 5/6

1/6) The sun—our oldest biological partner—does more than warm our skin or grow our food. Light is the literal foundation of the food chain, yes—but its relationship to metabolism goes far deeper.

Light doesn’t just hit your skin or enter your eyes. It interacts with the trillions of mitochondria scattered throughout your body. And when it does, it sets into motion a metabolic dance—a rhythm of fusion and fragmentation that underlies everything from energy production to sleep regulation.

Get the timing right? The dance flows.

Get it wrong? You’re stepping on your own metabolic toes.

Today, we’re exploring how light influences mitochondrial behavior—starting deep in the brain and extending into your eyes.

cc @R_Mohr @RafSarnataro

2/6) The Brain: Light and the Sleep Drive

A recent paper in @Nature reframes how we understand sleep pressure—the biological drive to sleep that builds the longer we’re awake—not through melatonin, but through mitochondrial choreography.

The researchers found that waking and sleeping drive opposite mitochondrial behaviors: an epic dance between fragmentation and fusion events that ebb and flow with day-night cycles.

This isn’t passive biology. It’s active regulation of sleep itself. When researchers manipulated these mitochondrial states in animals, they were able to alter sleep patterns.

This could be the root cause of why we sleep…

3/6) Why does this matter?

Fusion promotes the sharing of resources throughout mitochondrial networks and helps maintain metabolic efficiency.

Fission, on the other hand, allows cells to isolate and remove damaged mitochondria.

Both are essential—but they must happen at the right times and in the right balance.

This rhythmic dance of mitochondrial remodeling may be the very reason we evolved to sleep.

The authors note: “Power-hungry nervous systems appeared—and with them, apparently, the need for sleep... Sleep serves an ancient metabolic purpose.”

Yes, sleep restores your brain and consolidates memories—but at its core, it may exist to manage mitochondrial health.

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Nick Norwitz

@nicknorwitz

Jul 29

Two Waves of Aging: Molecular Shifts at 44 and 60
(🔗 at the end)

1/4) Aging is not a linear process. Intuitively, maybe you’ve sensed this. But researchers at @Stanford has now revealed—at an astonishing level of molecular detail—how aging unfolds.

Their key finding: aging shows at least two major molecular crests, around age 44 and age 60, when molecules across multiple biological systems shift dramatically.

These molecular “hotspots” may directly influence disease risk (and how we look) with age. I know what you might be feeling. But instead of fear, let’s channel that into curiosity—because these data are profound.

*Note: This paper was the #1 most viral study ever published in @NatureAging (this can be tracked with something called an Altmetric score, which for this paper is 5,453 ). In my opinion, the paper does deserve this honor!

2/4) The research was conducted by the world-renowned Snyder Lab at Stanford, pioneers in “longitudinal multiomics.” This approach combines various “omes”—like the genome, proteome, transcriptome, and microbiome—to form a detailed picture of how an organism functions at the deepest levels.

“Longitudinal” means this wasn’t a snapshot study. Each of the 108 participants (aged 25–75, about half female) was followed over an average of 1.7 years. Researchers collected 5,405 biological samples including blood, stool, nasal secretions, and skin swabs. These yielded 135,239 molecular features, which were analyzed through advanced machine learning.

Interestingly only 6.6% of the molecules exhibited linear aging patterns. The vast majority changed in nonlinear waves—with two major crests of change at ~44 and ~60-year marks.

3/4) Rather than sorting molecules by function, the researchers grouped them by how their activity changed over time. For example, Cluster 4 shows a distinct drop-off post-age 60.

Each color in their charts represents a different “ome,” and together, they paint a vivid picture: aging doesn’t happen evenly.

This data set is a gold mine—and raises crucial questions:
🤔What specific pathways shift at each crest?
🤔 What role does menopause (or not!) play?
🤔 Can targeted interventions optimize how we age?

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Nick Norwitz

@nicknorwitz

Jul 24

5 Facts to Know About Fructose vs Fruit

1. Fructose isn’t just “empty calories,” but a biochemically active molecule that can negatively impact your liver and mitochondria. But does that mean fruit is bad? No. (🔗 in 5/5)

2. The small intestine acts as a “fructose filter,” where moderate-dose fructose is bioconverted and “detoxed” before it reaches the portal vein heading to the liver. This system can handle a handful of blueberries but gets saturated and overwhelmed if you smash a large bowl of cereal and a tall glass of OJ.

3. Fruits are a large and heterogeneous group of foods that interact with a large and heterogeneous group of humans. Saying fruit is “healthy” or “unhealthy” is like judging all books in a library by one chapter of the first book you read—it oversimplifies something rich, varied, and context-dependent. (GIF just because it's hilarious)

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Nick Norwitz

@nicknorwitz

Jul 23

The Ketogenic Diet and the End of OCD Suffering
(🔗to full letter in 5/6)

1/6) Patient: “I used to tell myself in the depths of OCD, ‘The only way out is death,’ as a kind of mantra to put things into perspective. I’m happy to say I found another way. It would make me really happy if others knew about ketosis as a way to end their suffering.”

This dramatic quote, drawn from a new medical case series, describes one patient’s experience whereby they completely resolved their symptoms of debilitating obsessive-compulsive disorder (OCD) with a ketogenic diet. People with OCD can suffer terribly, sometimes to the point that death may appear a reasonable therapeutic, as was the case with this patient.

In today’s Newsletter, we discuss the case series at hand and why you should care, whether or not you or a loved one suffer with OCD. This is important for everyone to hear.

2/6) Patient A: Early Onset, Harvard Student

Patient 1 was a 22-year-old student at Harvard College, who first started exhibiting symptoms of OCD at 18 months. What began as consistent object alignment evolved into cleaning his friends’ toys, excessive handwashing, balanced twirling (if he spun twice clockwise, he’d need to spin twice counterclockwise to “balance things out”), balanced hugging and kissing, and exclusively symmetrical works of art. He was formally diagnosed with OCD at age 4.

The path that led this young boy to a ketogenic diet, like many others, was unexpected. Noting concerns about his weight, his parents supported him in removing grains from his diet, “unexpectedly noticing a dramatic reduction in his OCD symptoms.” Intensifying his dietary regimen towards a ketogenic diet at age 15 resulted in a “complete cessation of ritualistic behaviors” within two weeks.

Also, of note—and a key element in any ‘case experiment’—reintroduction of the independent variable (dietary carbohydrates sufficient to knock him out of ketosis) results in a change in the dependent variable (OCD symptoms). Indeed, excursions from the ketogenic diet consistently result in a return of symptoms for this patient (and for the others, as we will see). For instance, once while on vacation he indulged in a carbohydrate-rich meal. Shortly thereafter, he was found in his hotel room, late at night, organizing shampoo and conditioner bottles into neat rows.

Patient Perspective:
“The ketogenic diet was transformative for resolving my OCD, mood disorders, and focus issues. Without making the changes to my diet that I did, I would not have had the mental wherewithal to perform well enough in high school to get into Harvard, much less college.”

3/6) Patient B: Trauma-Triggered OCD

The second patient in this case series was a 35-year-old woman who developed symptoms of OCD at age 16 following a mass shooting near her school. The trauma triggered the development of overwhelming intrusive thoughts characterized by fear of loss. The obsessions were so severe she began to isolate herself from friends and family, ran away from home, and tried to harm her own head in a desperate attempt to alleviate the intrusive thoughts. She was formally diagnosed with OCD at age 20.

Again, the patient adopted a ketogenic diet serendipitously.

Again, the patient noted massive symptom improvements within two weeks.

Again, “[r]eintroducing high-carbohydrate foods triggers symptom recurrence, which she describes as feeling like ‘swimming in a lake as a thunderstorm approaches.’”
Patient Perspective:

“I used to tell myself in the depths of OCD, ‘The only way out is death,’ as a kind of mantra to put things into perspective. I’m happy to say I found another way. It would make me really happy if others knew about ketosis as a way to end their suffering.”

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Nick Norwitz

@nicknorwitz

Jul 22

The Sugar Diet, Protein Restriction, and Longevity: How It All Weirdly Connects (🔗 to full letter in 6/6)

Typically, my posts have twists and turns. I always aim to break expectations in some way, shape, or form.

But today I have a unique challenge: I’m going to try to thread together three seemingly unrelated topics — (1) the Sugar Diet, (2) protein restriction, and (3) longevity. We’ll work through each in turn, citing data from Nature Metabolism, Cell Metabolism and an N = 1 experiment.

2/6) The Sugar Diet: Absurd or Insightful? 🍭

To recap, if you missed my prior coverage on this topic, the Sugar Diet is a rising trend in the nutrition world that is exactly what it sounds like — a diet rich in sugar (candy, soda, fruit, fruit juices, honey, syrups) that supposedly helps you lose fat and boosts exercise performance.

When I first heard about the Sugar Diet, I had the reaction you might expect: assuming its practitioners were headed straight for diabetes and fatty liver disease and possibly had a pre-existing psychiatric disorder if they were willing to try something so absurd.

But biology has a way of humbling and mystifying — if you're open to the data.

The study that changed my perspective was published in Nature Metabolism (see links at the end). Briefly, it included three studies where young men followed a low-protein diet (9% of calories from protein), resulting in approximately a ⚡20% increase in energy expenditure⚡ — around 600 extra Calories burned per day — without any change in physical activity.
The effect appeared to be mediated by a hormone called FGF-21.

Based on these and other data, it appears that protein restriction — rather than sugar itself — increases FGF-21, which in turn ramps up energy expenditure and calorie burning. This helps explain how the Sugar Diet can work, operating in a subset of protein-restriction diets.

3/6) 4:1 Ketogenic Diet and Energy Expenditure 🥓⚡

After reading that paper, I was intensely curious about how generalizable these findings were. Specifically, I wondered whether the opposite extreme of a low-protein diet — a 4:1 ketogenic diet with 90% of calories from fat — would produce a similar increase in energy expenditure. There are reasons to suspect it might, or might not, as I outlined in the prior letter.

But now I have an answer: I tested the hypothesis on myself.

Following a protocol similar to the Nature Metabolism study, I established my weight-maintenance intake at 2,933 Calories per day with 18% of calories from protein for two weeks. I then reduced my protein intake to 9% of calories, replacing the difference with fat.

My weight started to drop. And just as in the study, I adjusted my calorie intake upward to compensate for the weight loss — adding several hundred calories per day — yet still lost weight. Over the next three weeks, I consumed roughly 300 more Calories per day on average on the 9% protein diet compared to the 18% protein diet, yet I lost 6.4 lbs.

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