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Nick Norwitz

@nicknorwitz

Aug 10

The Lithium for Alzheimer’s Paper Everyone is Talking About (🔗 in 8/8)

1/8) A major new paper published in @Nature from researchers at Harvard reinvigorated scientific interest in lithium for Alzheimer’s disease.

We will dive into the new data and end with practical takeaways that could change your daily routine to protect your brain.

And I promise to tell you what I’m doing personally, and what I’m and recommending for my family. But first, let’s lay the groundwork…

cc' @ChrisPalmerMD @janellison @louisanicola_ @Metabolic_Mind @hubermanlab

2/8) Lithium: The Simplest Metal with Mysterious Power

Common and trace metals play critical roles in biology — think about zinc or iron. They’re essential for cell signaling, enzyme activation, and altering biochemical pathways. But the simplest metal of all, and one of the smallest elements on the periodic table, is lithium.

Despite its simplicity, lithium is biologically potent and mysterious.

At very high doses, lithium is a mood stabilizer commonly prescribed for bipolar disorder.

Fascinating, isn’t it? One of the simplest elements in the universe is a frontline treatment for severe mental illness.

Over the years, signals have emerged in the literature suggesting that lithium may protect against Alzheimer’s disease. For example, population studies have found that regions with higher levels of trace lithium in drinking water tend to have lower rates of Alzheimer’s.

Quoting from JAMA Psychiatry: “Exposure to higher long-term lithium levels in drinking water may be associated with a lower incidence of dementia.”

Coincidence? I doubt it.

3/8) We also know that lithium inhibits a key protein involved in Alzheimer’s pathology — Glycogen Synthase Kinase 3β (GSK3β).

The name doesn’t exactly reveal its mischief: GSK3β (also called tau kinase 1) adds phosphate groups to a protein called tau in the brain, which drives the formation of one of the core hallmarks of Alzheimer’s disease— phospho-tau neurofibrillary tangles.

As a matter of fact GSK3β promotes the formation of both neuropathological hallmarks of Alzheimer’s disease: (1) the infamous amyloid plaques and (2) phospho-tau neurofibrillary tangles.

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Nick Norwitz

@nicknorwitz

Aug 9

Obesity Rewires Your Brain, Your Kidneys, and Your Blood Pressure (Full content🔗in 5/5; And 3/5 will freak you out 🫣)

1/5) For decades, we’ve been told to cut back on salt to control blood pressure.

The U.S. Dietary Guidelines still recommend limiting sodium intake to 2.3 grams per day.

But the science behind this advice is far from settled.

In fact, some long-term studies suggest the opposite: that lower sodium intake associates with higher blood pressure. (reference in letter, linked at the end).

And—curiously—people with obesity tend to be more salt-sensitive than lean individuals.

Why?

I promise, we’re going to unpack these questions today in the letter, and give you enough knowledge to terrify your cardiologist and woo your nephrologist.

#salt #bloodpressure #hearthealth #electrolytes @robbwolf @realDaveFeldman

2/5) Body Fat and Blood Pressure: A Complex Connection

Emerging research points to obesity as one culprit causing high blood pressure. Not just because of the extra weight, but because of what fat tissue does behind the scenes.

Let’s look at one such study—a remarkable tour de force published in @Cell_Metabolism ... In this study, researchers fed mice a high-sugar, high-fat, obesogenic diet. Blood pressure didn’t rise right away; it only increased after the mice had become obese. But something else happened first…

3/5) The high-sugar, high-fat diet caused obesity, which contributed to a thickening of vessels around the hypothalamus—something clearly visible below.

🧠The microscope images on the left are more zoomed-out and show how the high-sugar, high-fat diet increases the overall density of vessels around the hypothalamus at the base of the brain.

🧠The images on the right are more zoomed-in, showing blood vessels under a powerful electron microscope. What’s shown is a significant thickening—highlighted in the blue insets—of the basal membranes of the vessels.

If that didn’t totally make sense, the takeaway is simple: the high-sugar, high-fat diet caused obesity, an increase in leptin, and a significant remodeling of vessels around the brain’s hypothalamus. And—importantly—this vascular remodeling coincided with rising body fat and leptin levels and preceded the rise in blood pressure.

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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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