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…

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.

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.

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.”

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.

The NEW Microbial Molecule Linking Diabetes and Heart Disease (🔗 in 7/7)

1/7) What if one molecule, made by the bacteria in your gut, could quietly sabotage your blood sugar and clog your arteries?

Meet “imidazole propionate” (ImP) a microbial molecule made by gut that is now metabolically linked to both diabetes and heart disease. 2/7) Let’s start with the most recent findings: a paper published in Nature just four days ago found that ImP was associated with atherosclerosis in two independent human cohorts (PESA and IGT) and was shown to cause atherosclerosis in an animal model.

Looking first at the human data: in both cohorts, higher ImP levels correlated with higher fasting glucose, increased markers of inflammation (such as hsCRP), more visceral fat, and lower HDL cholesterol—all signs of metabolic dysfunction.

What’s more, ImP levels directly correlated with the degree of atherosclerosis, as measured by vascular ultrasounds and coronary artery calcium (CAC) scores.

These are interesting associations. But—of course—we must ask: what came first, the chicken or the egg? In this case: the ImP or the metabolic dysfunction?

Omega-6/3 Ratio: What the Science Says about Mortality (🔗 in 5/6)

1/6) Perspective shapes everything. Sometimes, we can flip our viewpoint easily. But sometimes, the more informative lens takes effort to uncover. That’s what we’re going to do together in today’s newsletter — unpacking the story of Omega-3 and Omega-6 fats and why the ratio can be misleading.

As a brief primer: Omega-3 and Omega-6 fats are both essential nutrients — we need to consume them in our diets. However, the common belief is that, while both classes are essential, Omega-3s are “heart-healthy,” “brain-healthy,” and more is generally better for you.

Omega-6s, on the other hand, are considered easy to overconsume in modern diets, especially through processed foods and industrial seed oils. They can also be converted in the body into pro-inflammatory compounds.

What’s more, research consistently suggests that the balance between these fats matters. A lower Omega-6/3 ratio is associated with better health outcomes — including reduced cardiovascular risk and lower all-cause mortality.

So, it's understandable why many conclude: Eat more Omega-3s; Eat less Omega-6s; Improve your 6/3 ratio — and better health will follow. Sounds reasonable, right? Hold that thought.

And remember our theme: perspective. Because the full story of these fats is a more complex than the ratio alone might suggest. 2/6) In the study I want to review with you, researchers measured blood levels of Omega-6 and Omega-3 in 85,425 people and followed them for an average of 12.7 years. Over that period, 6,461 participants died of various causes. The researchers examined the association between fat levels and mortality — including the Omega-6/3 ratio.

They found that higher Omega-6/3 ratios were associated with a greater risk of death. Specifically, the highest quintile (median ratio of 14.8) exhibited a 26% increased risk of all-cause mortality relative to the lowest quintile (median ratio 5.9).

So once again, the conclusion seems clear: High Omega-6/3 ratio = bad. Lower ratio = good. Therefore, eat less Omega-6, more Omega-3, and you’ll optimize the ratio. Right? Well… not so fast…

How Stress Steals Your Willpower – And How to Steal It Back (🔗in 4/4)

1/4) A new study, published in Nature, explores how chronic stress rewires the brain. It shows that stress shuts down flexible, goal-directed thinking and pushes us into rigid, automatic habits. Let’s break down how it works.

🧠DMS. - The Hub of Willpower🧠

The dorsomedial striatum (DMS) is a brain region that plays a central role in action–outcome learning and goal-directed behavior. For simplicity, think of the DMS as the brain’s hub for agency and willpower.

In fact, when DMS activity is suppressed, people tend to lose a sense of control — and fall into inflexible, often unhelpful, habits.

✌️Two Pathways: Learning vs. Habit.

The DMS sits at a crossroads of two pathways. The “Learning” pathway leads to flexible, thoughtful behavior, whereas the “Habit” pathway… well, that one is obvious.

🧠“Learning Pathway” The basolateral amygdala (BLA) activates the DMS, supporting action–outcome learning and goal-directed decision-making.

🧠 “Habit Pathway” - The central amygdala (CeA) sends inhibitory signals to the DMS, promoting automatic, rigid habit formation. 2/4) To summarize:

BLA → DMS = learning and flexibility. Think BL = Brain Learning.

CeA → DMS = habits and rigidity. Think Ce = Craving Enforcer.

😩Chronic Stress Turns the Dial Toward Habits😩

The researchers found that chronic stress weakens the Learning Pathway (BLA → DMS) and strengthens the Habit Pathway (CeA → DMS).

In their study, mice exposed to mild, unpredictable stressors — like a tilted cage, damp bedding, or mild foot shocks — started falling back on ingrained habits. They’d press a lever for food even after they were satiated, just because that’s what they were used to doing. Sound familiar?

How Weighted Vests Trick Your Body into Losing Weight
(🔗 in 9/9)

1/9) Remarkable research is showing how mechanically loading your skeleton can toggle your brain to decrease hunger.

In today’s letter, I want to walk through three studies, including two human RCTs and a third study that blew me away! 2/9)👉Study #1 (RCT): Short-Term, Big Impact
In a proof-of-concept pilot trial, 72 participants with obesity were randomized to wear a weighted vest (11% body weight) or a non-weighted vest (1% body weight) eight hours per day for three weeks.

The study wearing the weighted vest resulted in statistically significant weight loss over just three weeks (1.61 kg). Furthermore, all of this weight loss was fat loss (-1.73 kg), with a +0.20 kg change in lean mass. Even for people with obesity, losing fat without losing (or maybe even gaining?) muscle over a short time period is impressive.

But this study was just three weeks. What happens if one were to wear a weighted vest for much longer?

The Molecule Behind Exercise’s Anti-Aging Effects

*Today's letter (link in 6/6) reviews a new paper in @CellCellPress published 2 days ago. And includes a shoutout to someone special.

💪1/6) Nothing matches the health benefits of exercise. It’s the closest thing we have to a universal prescription for healthy aging.

But have you ever wondered how movement actually slows aging?

Movement isn’t magic. Exercise initiates a complex cascade of biochemical events that lead to adaptations designed to improve whole-body health. By identifying what those adaptations are, we can tap into the systems nature has evolved to optimize our health.

That’s the question the researchers behind today’s study explored. They weren’t trying to replace exercise — but they were curious if they could “bottle up” part of its benefits.

Method: In this study, 13 relatively sedentary men were instructed to exercise by running 5 kilometers — first every other day, then every day — for 25 days. The researchers measured a broad suite of metabolites in their bodies before and after the exercise regimen...

#exercise #healthspan #longevity #staycurious 2/6) Exercise is Good for you (and water is wet). But there’s more…

Exercise decreased markers of inflammation, including hsCRP and TNF-alpha, and increased so-called geroprotective(anti-aging) antioxidant proteins and pathways like Nrf2, SOD1, and Glutathione. These proteins and pathways help defend your body from oxidative stress — basically, the wear and tear that contributes to aging.

So, exercise is good for aging. No duh, right?!

But then the researchers dug deeper...

They wanted to know which metabolites were linked to these anti-inflammatory and geroprotective effects of exercise.

One molecule stood out — betaine.

Untangling the Seed Oil Debate: ⚠️WARNING ⚠️Don’t Read If You Like Your Echo-Chamber
(🔗 at the end)

1/11) One of the most heated and fascinating debates in the nutrition space right now is that of “seed oils.”

It’s one of the keystone issues for the “Make America Healthy Again” #MAHA movement.

Robert F. Kennedy Jr., who calls the seed oils in which fast food chains now cook their French fries, “one of the most unhealthy ingredients we have in foods.”

This has led to a counterculture movement to replace industrialized plant-sourced fats, i.e., “seed oils,” with animal fats. There are cries to “Bring Back the Tallow Fries” to fast food chains like McDonald’s—the dietary version of “Make Fries Great Again.”

Up-front Acknowledgement

I spoke with several others composing this letter, including @drmarkhyman @paulsaladinomd @Physionic_PhD. Each provided references, input and/or feedback that was included in this letter in some form, and I look forward to ongoing conversations with each about this particularly controversial topic.

In fact, I’m releasing this letter now, rather than late July as originally planned, because I have a conversation planned with one of these men next week and thought community feedback would be ‘interesting’ fodder for our discussion.

The letter, should you choose to read it, may end up being a living document… 2/11) Restaurant chains are responding, literally “RFK’ing the fries,” meaning trading the seed oils for tallow for presumed health benefits.

But this isn’t really an issue or video about French fries. It’s about something much larger and more important.
It’s about how we dissect conflicting data in nutrition.

The reason there is such profound confusion on the topics of animal vs. plant fats and “seed oils” is because different sources of evidence make opposing arguments, and each side thinks their argument is best.

Rather than try to resolve the inconsistencies, we dismiss and bicker.

But in today’s letter, we try to dig into the details with data (nor dogma). This one is intense, but I hope you find it valuable.

Salmon Savvy: The Ultimate Guide to Choosing the Cleanest, Healthiest Fish

1/6) Salmon might wear the health halo, but not all salmon are created equal. Some are top-tier nutrition, and others are … well… toxic might not be an overstatement. Let’s talk fish fraud and how to avoid getting catfished at the seafood counter.

Let’s start with the elephant in the room—or manatee in the pool, as it were: farm-raised vs. wild salmon.

Is wild really better? YES.

The primary reason I always go wild over farm-raised is that farm-raised salmon tend to have much higher levels of chemicals like polychlorinated biphenyls (PCBs), pesticides, and dioxins, which largely derive from their feed and all of which have serious negative consequences on human health. 2/6) To take one of these as a representative example: dioxins, which are byproducts of various industrial processes such as burning waste, smelting metals, and bleaching. Some dioxins, like TCDD, are classified as Group I carcinogens (known to cause cancer in humans).

One study found that when eating farm-raised salmon, it would be easy to exceed the tolerable daily intake (TDI) of dioxins based on thresholds set by the World Health Organization. In some cases, as little as 4 servings of farm-raised salmon per month would push you past the dioxin TDI. By comparison, this analysis found that you could eat wild salmon every day (even twice per day!) and remain within safe levels of dioxin exposure.

What you’re seeing in the graph is the number of meals per month you’d need to eat of farm-raised salmon (white and light blue) or wild salmon (dark blue) to breach the safe intake limit. For farm-raised salmon, you can see only a handful of small servings will push you beyond the safe limit. But for wild salmon, they actually capped the analysis at “a practical consumption rate” of 60 meals/month.

🥛This Saturated Fat Can Burn Fat: A Milkshake Experiment?!🥛 (🔗at the end)

Saturated fat is one of the most misunderstood nutrients in nutrition. Part of this misunderstanding stems from a stereotype: Saturated fats are often lumped together as if they are homogenous entity.

But they are not.

1/7) In today’s StayCurious Metabolism Letter, I make the point by reviewing data showing how one specific saturated fat, stearic acid, positively influences mitochondrial fusion-fission dynamics and fat metabolism.

At the end I also provide you a boarder evolutionary framework in which to understand these data and related general principles of nutrition and offer some practical takeaways

Let’s dig in...

#saturatedfat #mitochondrialhealth #stearicacid #staycurious #metabolichealth 2/7) Stearic acid is an 18-carbon saturated fat found in certain tallow, cocoa butter, and shea butter.

👉The study in question set out to investigate the effects of stearic acid, an 18-carbon saturated fat (C18:0), on mitochondria. The researchers took a diverse group of individuals—including those who were healthy and those with type 2 diabetes—and placed them on a low-fat vegan diet for two days in order to reduce their saturated fat and stearic acid intake.

They then gave the participants a stearic acid milkshake (24g of C18:0) or a mock control shake looked at the participants’ mitochondria at 0, 3, and 6 hours later.

🚨When given stearic acid, but not the control, the percentage of “fused” mitochondria increases ~4-fold. This did not happen with the control drink.

🚨By contrast, stearic acid restriction in the form of the low stearic acid vegan diet caused mitochondria to fracture and fragment. (More on the long-term effects later.)

1/8) Vitamin C is everywhere 🍊🍋🥝🍓👀

But when it comes to heart health 🫀, Vitamin C is wildly underrated. We think we understand it. But we don’t. And what I found when I dove into the science shocked me. (🔗 with all references at the end)

First, a quick hat-tip to what had me running down this rabbit hole. I recently wrote a newsletter on Lp(a) that was my most popular to date. I encourage you to check that out if you’re interested in heart health.

But here’s what you need to know: Lp(a) is like LDL’s evil twin—the one that went to villain school and graduated top of its class in blood clotting. And Lp(a) is that’s thought to be genetically cemented.

However, some people have had anecdotal success lowering Lp(a) with high-dose vitamin C supplementation.

Weird, right? But it got my curious and started down another rabbit hole. I’ve broken today’s newsletter into 8 chapters:

1. Vitamin C & Lp(a) – Nature’s substitution
2. Vitamin C & Heart Disease – The human data
3. Vitamin C & oxLDL – Can it stop cholesterol from turning toxic?
4. Vitamin C & Nitric Oxide – Why your blood vessels care
5. Mechanistic Summary – Piecing together the puzzle
6. Vitamin C Dosing – How much do you really need?
7. Vitamin C & Lysine – Batman & Robin
8. Puzzling Together the Protocol 2/8) Vitamin C and Lp(a)

Lp(a) is a spherical particle that floats around in the blood. It looks like an LDL particle, except Lp(a) also has a protein tail called apolipoprotein(a). This tail endows Lp(a) with the ability to promote blood clots and is one way in which Lp(a) is thought to promote cardiovascular disease, atherosclerosis.

But in 1990, the double Nobel Laureate Linus Pauling and his colleague Dr. Rath came up with an interesting idea about Lp(a). They hypothesized that Lp(a) was a surrogate for vitamin C.

Most mammals can synthesize their own vitamin C. But about 40 - 60 million years ago, our primate lineage developed a mutation in the GLO gene that prevents us from synthesizing vitamin C. Since vitamin C helps to promote wound healing, this would have placed an environmental pressure to develop an alternative means to promote wound healing and halt bleeding. In effect, evolution called for a substitute: Lp(a), which can likewise promote wound healing.

Now, if it were true that Lp(a) is an evolutionary substitute and surrogate for vitamin C, we might expect a pattern whereby animals that can synthesize vitamin C lack Lp(a). This is indeed the case!

What’s more, species that have also lost the ability to synthesize vitamin C, including guinea pigs and the European hedgehog, also produce Lp(a).

☕How to Drink Coffee for Heart Health (Backed by Science)🫀🔗at the end (5/5)

1/5) What if I told you coffee was good for your heart?
Indeed, coffee isn’t just keeping you alive during Zoom meetings—it might actually be keeping you alive. In today’s letter, I’ll break down two human trials, one remarkable mouse study, the key molecule behind coffee’s heart benefits, how to dose and time your coffee for maximum impact, and what I enjoy even more than coffee these days.

First, let’s establish that there is a well-known association between coffee intake and reduced risk of cardiovascular disease—at least up to a point. But large-scale epidemiological studies provide limited insight on cause-effect relationships or mechanisms.

👉So, we turn to controlled trials and animal studies.
I want to review two human randomized controlled trials, and one fascinating animal study centered around a special chemical in coffee that is responsible for many of its health effects: chlorogenic acid.

If you follow me, you may recall chlorogenic acid from our discussions on how to stop sugar cravings or how the heart talks to the brain (these letters can be found at staycuriousmetabolism. com).

Briefly, it’s a well-studied polyphenolic compound enriched in coffee—especially lighter roasts, unroasted ‘green’ coffee, and Yerba Mate.

#coffee #hearthealth #cardiovascularhealth #LDL #ApoB #atherosclerosis #metabolichealth #metabolism #yerbamate #educational #coffeelover #staycurious 2/5) Human Randomized Controlled Trials

Let’s discuss two human randomized controlled trials. Both studies aimed to assess the effect of coffee and/or chlorogenic acid on vascular function. They measured vascular function using flow-mediated dilation (FMD), which evaluates the ability of the endothelium (the inner lining of blood vessels) to dilate in response to increased blood flow. It's a way to assess the health of blood vessels.

👉In one study, they gave participants one of two different coffees differing in chlorogenic acid content (89 mg or 310 mg), or a placebo control, and then measured FMD. As compared to the placebo, both coffees improved FMD, with the higher dose (310 mg) of chlorogenic acid appearing to have a larger effect.

To further prove it was the chlorogenic acid improving vascular function, they conducted another experiment in which they provided isolated chlorogenic acid rather than coffee. Again, the chlorogenic acid improved FMD.

👉These findings have been independently replicated. In another double-blinded randomized controlled trial, decaffeinated unroasted ‘green’ coffee containing chlorogenic acid at three different doses (302 mg, 604 mg, 906 mg) was compared to a placebo control for its effects on FMD. The chlorogenic acid significantly improved FMD versus placebo, although the higher doses did not provide additional benefit.

All in all, these studies suggest that chlorogenic acid in coffee improves vascular function.

1/4) A few months ago, in March 2025, a randomized controlled trial was published that claimed to debunk the Carbohydrate Insulin Model (CIM).

In this study, 120 lean young adults (mean BMI 21-22) were assigned to one of three meals that varied in glycemic index (GI). All diets were 60% of calories from carbs, but the glycemic indices were 33, 65, and 73 for the low-, medium-, and high-GI meals, which were composed primarily of pasta or bread.

🍝Baseline: The day before the test meal, subjects were given a standard meal, buffet style, and allowed to eat as much as they wanted.

🍝Intervention: The next morning, they were given the intervention meal—either spaghetti pasta, buckwheat noodles, or steamed bread

🍝Test Meal: 5 hours later, they were given another buffet-style meal and again allowed to eat freely.

The researchers wanted to measure how much energy intake *changed* between the two buffet meals based on which intervention meal the participants received.

The CIM predicts that those who got the lower-GI intervention would have a smaller increase in calorie intake compared to those who ate the higher-GI meals.

To be crystal clear; “The primary, prespecified outcome in the registry (Clinicaltrials.gov: NCT05804942) was a change in energy intake between the baseline and test meals, powered to detect a 63 kcal group difference.”

So, what did they find?

*CC @davidludwigmd @AdrianSotoMota co-authors on letter to the editor

*All links (original paper, LTE, and reply to LTE) can be found in the newsletter version of the thread linked in 4/4 2/4) Indeed, the higher-GI diets led to larger increases in calorie intake: The low-GI group only increased by 17 calories; The medium- and high-GI groups increased by over 140 calories—more than double the effect size expected.

🤔So, why the discrepancy in interpretations?

i. First, the original research team feature an altered version of the primary outcome in stating there was “[n]o effect of GI on intake at [the] next meal.” This is a shift away from “change” in energy intake and omits the prespecified baseline, providing a notably less precise effect estimate than the more powerful change score.

ii. Second, they highlight the absence of group difference in subjective hunger ratings.

But subjective hunger is poorly correlated with objective food intake. If you’ve ever opened the fridge “just to look” and ended up eating half a cheesecake, you already know this.

To do our due diligence, we conducted an analysis and found no relationship between hunger ratings and food intake using their publicly available data.

😰🔥 What causes anxiety?

1/5) Obviously, the answer is many things. But an underappreciated truth is that behavioral states and emotions — including anxiety — can be the consequence of a metabolic state.

New data show how inflammation can act directly on the brain to promote (or soothe) anxiety. (link at the end)

#anxiety #anxietyrelief #mentalhealth #inflammation 2/5) The story of this study begins with an inflammatory molecule called 🔥IL-17🔥

IL-17 levels are increased in inflammatory disorders like psoriasis, inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), rheumatoid arthritis, and ankylosing spondylitis.

👉It’s certainly relevant to humans. But to prove a causal connection between IL-17 and anxiety, researchers turned to animal models. Researchers treated mice with a chemical that increases IL-17 levels.

This made the mice more anxious on three different validated behavioral tests.

🍭The Sugar Diet Works—But Not for the Reason You Think❌ You win comments section.

On (extremely) popular demand, I decided to cover this viral trend #SugarDiet. What I discovered surprised me. You can find a link to a newsletter with more details at the end, but let’s review some of the data. 1/7) What is the Sugar Diet? If you haven’t been following. The sugar diet is defined by eating low-protein, low-fat and lots of carbs.

As an example, @MarkSmellyBell has been on the sugar diet for several weeks and eating ~0.5 grams of protein per pound of body weight (~100 grams at 209 lbs), keeping fat <30 grams and eating as much as 800 grams of sugary carbs per day. If we use the numbers 100g protein, 30g fat and 800g carbs that’s 3,870 Calories, with 83% from carbs.

He’s also including “sugar fasts” on top of his sugar diet, where for days at a time he’ll consume only these six foods: fruit, fruit juice, maple syrup, honey, sugar, and candy But he’s reporting rapid weight loss. And others are reporting similar. So, should you believe them, or are they just lying on behalf of Big Jellybean? Let’s discuss some important data, then you can decide for yourself. #sugardiet #metabolichealth #educational #staycurious #FGF21

cc @hubermanlab + @GardnerPhD re protein requirements. Andrew noted you have different perspectives on optimal protein intake on your recent May 12, 2025 HLP podcast. These Nat Metabolism data may provide an unexpected source of intellectual reconciliation @R_Mohr

@MikeMutzel @Physionic_PhD @drmarkhyman, I figure this is of general interest to you
@drgabriellelyon re protein restriction, invited comment 2/7) The Data

The study that captured my attention was recently published in Nature Metabolism. It investigated the effects of a low-protein, high-carb diet on energy expenditure. The subjects were healthy young men in their mid-20s, mean BMI ~25 kg/m2, who were placed on a diet that was **9% protein and 70% carbs** as percent of calories for five weeks, before reverting to a higher protein diet (18% protein) for the following five weeks.

🔥Remarkably, after about a week on the low-protein, high-carb diet the participants needed to increase their energy intake to maintain body weight.

By week five, they’d increased energy intake by **19% (574 Calories per day)** but had lost 1.0 kg. This 574 Calorie increase in energy intake while losing 1.0 kg occurred without a significant change in muscle mass and without an increase in physical activity.

They also replicated the low-protein, high-carb diet results on another set of young men. Again, energy intake needed to be increased by 20% to maintain weight, without any increase in physical activity.

🫀New Data! How Heart Diseases Causes Brain Damage🧠 – And How THESE Specific Foods Can Help (🔗 at the end)

1/7) If you have an unhealthy heart, you have an unhealthy brain as well. This is not just an association. Your organs talk to each other. And if you have heart atherosclerosis your heart transforms from a loving spouse into an abusive partner. New research shows HOW this works and how to potentially “intercept” the abusive messages to protect your brain (and your heart) and heal their relationship to support your health.

👉Overview👈
The new research in question was just published in Cell Metabolism and specifically reveals how immune cells in the heart called “foam cells,” in plaques in the heart, release little packages called “exosomes.” These travel to the brain where they cause oxidative stress, impair glucose metabolism, and otherwise cause metabolic dysfunction.

A Quick THANK YOU!
Before you continue through this thread (and hopefully the full letters), I wanted to share today is my graduation from Harvard Medical School. So, inevitably, I’m spending the morning with a Yerba Mate and a new paper to celebrate becoming "Nick Norwitz MD PhD." It’s certainly a time to reflect and be grateful.

And I’m incredibly grateful for all of you and your shared enthusiasm for metabolic health. I’m beyond thrilled to be able to ‘rebound’ what I learn off of all of you. So, a huge THANKS! This is just the beginning of our journey together! Now, today’s metabolic lesson… 2/7) Let’s define these 3 Key buzzwords quickly:
👉Foam cells: Type of immune cell (macrophage) that exist in plaques in coronary arteries and are core to the development of atherosclerotic cardiovascular disease. If macrophages are Bruce Banner, foam cells are little Hulks smashing and damaging all in their path.

👉Exosomes: Small, membrane-bound spherical packages that float around in the blood and carry biological cargo like proteins, lipids, and nucleic acids to other cells.

👉microRNA: In this case, the microRNA are the messages in the exosome packages microRNA are small RNA molecules. RNA is the readout from your genome. While some RNA, called mRNA, is used to make proteins, other RNA has regulatory jobs. microRNA are genetic regulators that change how DNA is read in cells throughout the body.

Can a ketogenic diet reduce your risk of colorectal cancer? 🤔💩 (link to more at end)

1/8) While we will never have long-term human randomized trials for dietary therapy for cancer prevention, animal studies can provide fascinating mechanistic insights.

This research was conducted in microbiome-humanized mice. What this means is that, to make this experiment more relevant to people, researchers created humanized microbiome mice. Specifically, they took stool samples from 5 healthy human beings, mixed them together, and gave that to mice that had no microbiomes of their own.

They then treated these humanized mice with compounds that cause intestinal inflammation and predisposed the mice to develop colon cancer.

After that, the mice were fed either a standard chow diet (with carbohydrates) or a low-carb, high-fat ketogenic diet, which increased circulating levels of ketone bodies.

🚨Impressively, the keto mice exhibited fewer tumors, smaller tumors, and an overall lower tumor burden.

#coloncancer #cancerresearch #ketodiet 2/8) Then, to prove a causal connection between the microbiome shift, via the ketogenic diet, and protection against colon cancer, the researchers did a “Fecal Microbiome Transplant” – they transferred microbiomes from keto-fed mice into other mice who hadn’t eaten a ketogenic diet.

Remarkably, the microbiome transplant transferred the anti-cancer protection to the receipt mice.

Lp(a) Explained: Genetics, Risk, and What You
Can Actually Do ❤️‍🔥🫀
🔗 all references and more info at the end

1/9) By now, you’ve probably heard the term Lp(a). But to get everyone up to speed, Lp(a) is a major causal risk factor for atherosclerosis. On a per particle basis, it’s thought to be ~6X as atherogenic as LDL particles.

Now, two more things to know about Lp(a):

i) Its levels are largely (~90%) genetically determined
ii) There aren’t many medications or lifestyle treatments to modify Lp(a)

So, what do you do if you’re genetically cursed, like me?

Well, if you read the full letter (🔗 at the end), I promise on my own heart that you'll understand of Lp(a): what it is, why it matters, and what you can do to reduce your risk... and why I'm not panicking, despite my 165 nmol/l.

#hearthealth #lpa #ApoB #LDL #inflammation #IL6 #niacin #cardiovascularhealth #ApoE4 #HRT #oxidation #seedoils #metabolichealth #medicaleducation #meded #atherosclerosis #siRNA # 2/9) The letter will progress in 7 chapters, the first three of which I'll review in this thread:
1. Defining Lp(a)
2. Guidelines on Measuring Lp(a) & Risk Thresholds
3. Medications in Development to Lower Lp(a) 🧪
4. How to Reduce Cardiovascular Risk if you have high Lp(a) 🫀
5. How Statins Increase Lp(a) and What is Means 💊
6. Oxidized Phospholipids: The Cargo of Lp(a)
7. Nuance Notes for the Nerds 🤓: Lp(a) as an acute phase reactant, Menopause, HRT, and ApoE4