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

"The Science Isn't Settled" - Please read this thread to the end if you've been following the KETO-CTA "drama" ... there's a BIG surprise... 🧵💣

1/6) One thing that's become obvious to me in the past month is that social media is shaped by Selective Attention.

This thought occurred to me this morning as I was composing a reply to the first comment on this morning's #StayCurious Metabolism Newsletter about CAC Scores.

I'll copy that in (2/7) below for easier reading (pictured on the bottom left).

For what it's worth my colleagues and I cc @realDaveFeldman @AdrianSotoMota @khurramn1 et al. are not dogmatic with respect to #statins, keto, etc. nor do we ever discourage anyone #LMHR or otherwise, from thinking critically and responsibly about their own INDIVIDUAL health journey.

You'll note quite clearly that I said in the reply (and/or I've said before) that were I to be over 40 y/o (see letter for why I said 40) with a positive CAC I'd take lipid lowering medications even in the light of the KETO-CTA data where ApoB did not predict progression (rationale, below). That's not news. Now, I wouldn't do it blindly. I have my thoughtful concerns. But I would do it.

One point @PeterAttiaMD has made with which I more-or-less agree (although we certainly don't see eye-to-eye on this topic), is that the buffet of pharmaceutical options for lipid management has grown, providing more choices for patients to fit their preferences and concerns. 2/6) Here's the copy & pasted reply to the first comment. I'd highlight that this is not an outlier reply, but routine. While we are very careful not to give medical advice via social media, we do spend a tremendous amount of time trying to support people (esp #LMHR) 'caught between a rock and a hard place.'

Often, this is in private DMs, or even phone calls. The irony is I've probably spent more time indirectly helping #LMHR individuals lowering LDL/ApoB than almost all of our detractors and - I'll just call a duck a duck - trolls. This is not because I ever push the "you should" do X. But - I think - because I walk people thought the thought processes that would go through my own head.

The Copy & Pasted Reply from this AM (open to critique):

If I were in your shoes, here a few questions I'd ask myself:

1) Did keto change my LDL/ApoB? For most, this is not the case. But, in your case, certainly seems your LDL is higher on keto than vegan.

2) If 'yes' keto did increase your LDL/ApoB what is the relative contribution of fiber vs SAT/UNSAT ratio vs lipid energy model/ #LMHR physiology? You can play with these variables within a ketogenic diet, e.g. swapping butter as a cooking fat for sesame oil or avocado oil, or adding soluble fiber in the form of low-carb whole foods.

3) Do I know if your/my CAC increased on keto, or was 128 at baseline when I started keto?

4) Even if it did, e.g. if you're LMHR, do the data suggest LDL/ApoB lowering would improve risk? I'd say the data aren't clear. In our analyses (KETO-CTA), while NCPV metric specifically increased more in those with positive baseline CAC-- and with a high degree of inter-metric variability (e.g. median TPS score change was 0 -- in both those with positive and negative CAC, ApoB did not predict plaque progression. We will definitely have more to say on this over the summer and I'm sorry academic moves at the pace of a narcoleptic turtle.

5) That said, I'd also ask myself about the additional possible benefits of a given medication, e.g. anti-inflammatory effects of statins, potential effect on MPO (see other letter), etc.

6) On balance, if it were me in your shoes, I would apply the precautionary principle where possible (emphasis on "where possible," as idk if you're using a ketogenic diet therpauetically). That means, if I were >40 and had a positive CAC and was able to add carbs (e.g. going from <20g/d to 150g/d of 'healthy carbs') and/or carb cycle (see prior letter) and/or start pharmacotherapy with careful monitoring of biomarkers of personal interest (e.g. desmosterol levels were I to take a statin) that's what I would do.

The Power of CAC = 0: When Does LDL Matter?
(🔗to full letter at the end)
1/7) One landmark study published in the journal Circulation in 2023 followed 23,132 middle-aged people (median age 57) from the Western Denmark Heart Registry for a median follow-up of 4.3 years.

Over this time, 552 had cardiovascular events. And the researchers sought to answer the question: What predicted who would have a cardiovascular event?
But there’s more…

They broke those 23,132 participants into those who had a positive Coronary Artery Calcium (CAC) scan and those who had a CAC of 0.

🫀Among those with CAC > 0, LDL-C did predict who would have a cardiovascular event.
🫀Among those with CAC = 0, there was no association between LDL-C and cardiovascular disease events. 2/7) Here are data from Figure 1.

If CAC > 0: As LDL-C rises, the adjusted Hazard Ratio (aHR) increases. aHR is a ratio of how likely an event is to occur in one group compared to another over time.

Here, we are comparing people across LDL-C spectrum. Among those with CAC > 0, higher LDL-C has an aHR > 1 meaning higher risk of heart events and cardiovascular disease in those with higher versus those with lower LDL-C.
* “adjusted” for age, sex, smoking status and diabetes.

If CAC = 0: What you can clearly see is a flat red line at 1. This suggests higher LDL-C does not associate with higher risk of heart events and cardiovascular disease in those with CAC = 0. It provides some warranty.

What’s more, even when they took those with very high LDL-C > 193 mg/dl vs LDL-C <116 mg/dl, when CAC = 0 there was no observed benefit of having lower cholesterol (aHR = 0.95).

Ref, PMID: 36621817

1/4) Today’s Video (just released) is a Microbiome Masterclass! (link at the end)
I’ll review

1️. Why your microbiome is CRUCIAL to your health

2️. How to tell if your microbiome is OUT OF BALANCE, scientifically this is called “microbiome dysbiosis,” although the answer might not be what you expect.

3️. What all those gut health BUZZWORDS actually mean—like prebiotics, probiotics, postbiotics, fermented foods, and more

4️. How to TAKE CARE OF your microbiome—including surprising ways your mind can directly influence your gut.

5️. Where THE FUTURE of microbiome science is headed…


2/4) As a teaser, in this thread, let me give you a peek from part 4, subsection 6 (How to TAKE CARE OF your microbiome: Your Mental Health Changes Your Gut Health)

While we all intuitively know our gut feeling can impact our mood, our guts and brains have a bidirectional relationship.

What I’m really trying to say is that your mind and brain can talk to your gut and influence gut and microbiome health. Let me give you 2 examples:

A recent study showed that the brain can alter levels of a molecule, indole-3-acetate (IAA), that can effectively poison stem cells in the lining of the intestines, contributing to poor gut health and gastrointestinal symptoms.

👉 Specifically, psychological stress, via activation of the fight-or-flight branch of the nervous system, causes changes in microbiome function…
👉 This increases levels of the indole-3-acetate molecule in the gut
👉 IAA harms the energy producing mitochondria in intestinal stem cells, leading to stem cell failure and contributing to poor gut health.

Is eating keto all the time really optimal? Or should you Carb Cycle? 🥯🔄🥯

1/4) Let’s discuss “Cyclic Metabolic Switching” (CMS) Theory

The CMS posits that extended fasting (or carbohydrate restriction) sufficient to trigger the metabolic state of ketosis leads to the activation of adaptive cellular stress response pathways.

During this time, cell growth pathways—including those stimulated by the hormone insulin, and a key metabolic regulator called mTOR—are inhibited. Then, during refeeding, pathways that promote cell growth (like those downstream of insulin and mTOR) are activated

🔄This creates cycles of activation between stress response pathways and growth and development pathways. 2/4) Analogy: It’s the metabolic equivalent of a good weightlifting program: you stress your muscles to trigger adaptation. Then, you need to rest and recover—and it’s during that rest (when you eat and sleep that growth occurs.

But if you spend too much time in either phase—too much exercise with too little recovery, or too much eating and sleeping with not enough stress—your health will suffer.

🌊In general, and as a high-level truth, biology and physiology operate in ebbs and flows

1/11) Since our KETO-CTA paper was published on April 7, 2025 there has been an undeniable and conspicuous spiral of events, leading to a strong diverse set of opinions on the data.

It’s also been noted that since around April 18th, my co-authors and I have been quiet regarding criticisms rendered. I’ll speak for myself when I say this wasn’t personal my preferred approach.

However, it was the strong preference of JACC Advances that we work through the preferred academic channels – namely, by responding to Letters to the Editors passed to us from the journal. Now that we’ve done so (links at the end), I’m pleased to break my silence and speak more freely.


2/11) First and foremost, I encourage everyone to listen to this recent hour-long conversation between Dave Feldman and Chris MacAskill about the controversy.

Truthfully, I think it was among the most honest, humble, and sincere conversations my ears have ever had the pleasure of capturing.

Please start there if you’ve been following the controversy and want a grounding perspective.
youtu.be/cM0KaSp5IIE?si…

How to Start a Mediterranean Ketogenic Diet: A Step-by-Step Guide (Link to more🔗 in 5/5)

1/6) I started a ketogenic diet on June 1, 2019, and it saved me from debilitating inflammatory bowel disease.

But here’s a hard fact: despite its many benefits—including for obesity, diabetes, mental health, autoimmune and inflammatory conditions—ketogenic diets are still grossly misunderstood. Many people assume keto is all about bacon, butter, and steak, low in fiber, and at odds with what most have been taught, and internalized over their life courses, is “healthy.”

🚨That’s a huge misconception!🚨

Ketosis isn’t about specific foods—it’s about a metabolic state, where you’re producing ketone bodies. You can be keto while eating anything from a fully #vegan diet to a fully #carnivore one.

There is not one ketogenic diet. There are infinite.

And a Mediterranean ketogenic diet is an excellent entry point for many people because it balances the perceived health benefits of Mediterranean eating with the metabolic advantages of keto

Simply put, Medi-Keto is a low-friction dietary entry point to low-carb diets for many people.

Today’s Newsletter breaks down the how-to of Medi-Keto, including:

👉 4 ‘musts’ for preparing to start on your ketogenic lifestyle.
👉 My 9 favorite Medi-Keto foods and help flesh out your shopping list.
👉Common Q&A

In this thread, I’ll tease you with a few highlights…


2/6) Fatty Fish

Fatty Fish are a great source of protein, healthy fats, and micronutrients to support muscle growth, brain health, healthspan and even longevity.

Remember the acronym “SMASH” for Salmon, Mackerel, Anchovies, Sardines and Herring.

For salmon, I’d give Wild Alaskan Sockeye the edge of health and for Sardines, I suggest getting whole sardines (skin and bone) packed in BPA-free tins with water or brine, rather than with oil. (My personal go-to is Wild Planet)

🚨How Chronic Stress Causes Depression🧠
(Link to Letter 🔗 at the end)

1/8) A new paper about the neuroscience of depression is the most fascinating mental health papers I’ve read in 2025!

It reveals a possible central biological mechanism by which chronic stress can contribute to depression and opens doors to innovative solutions for improving mental health. (link at the end)

Let’s get into it…
#depression #mentalhealthmatters #autophagy
cc/of interest @janellison @ChrisPalmerMD @NTFabiano @KetoCounselor @TuitNutrition @hubermanlab @AllyTransforms @bschermd @Metabolic_Mind 2/8) Background to Know: Lateral Habenula 🌶️ & Autophagy♻️

The habenula is a region in the middle of the brain important in processing
aversive and unpleasant stimuli and in the stress response.

🌶️Because I love memory tricks, the way I remember this is: habenula sounds like habanero, the spicy pepper that can be 100x hotter than a jalapeño — and is therefore an aversive and unpleasant stimulus for most people. So now you won’t forget it! Specifically, the lateral habenula is important in processing responses to unpleasant stimuli and stress.

♻️Think of autophagy as your brain’s janitor crew. It’s a built-in cleanup and recycling system within cells. When proteins get old or broken, a membrane wraps around them like a trash bag, isolating the waste from the rest of the cell. That bag — called an autophagosome — then fuses with the cell’s digestive center and breaks the waste down into reusable parts.

But here’s the catch: under chronic stress, it’s like the janitors go on strike. The trash piles up, the system clogs, and neurons start to malfunction. That’s where things start to go wrong — and potentially spiral toward depression.

And that’s what they show in this paper — at a high level — autophagy within the lateral habenula is impaired, contributing to depression.

🚨 New Genetic Discovery: Why Some People Naturally Eat Less Sugar & Stay Lean 🍫➡️🚫 (link at the end)

Scientists may have just uncovered a hidden biological quirk that makes some people naturally eat less sugar, crave less sugar, and stay lean.

1/5) A paper just published in Gastroenterology found that people with mutations in a gene coding for a carbohydrate-digesting protein called “sucrase-isomaltase” had:
✅Lower intake of added sugar
✅Lower BMI
✅Improved metabolic health

But here’s the kicker: there may be a way to hack this system, even if you weren’t born with these lucky genetics 👀…

#SugarCravings #Metabolism #NutritionScience #GLP1 #FunctionalFood #Genetics #HealthHack 2/5) Researchers found that people with a Sucrase-isomaltase mutation that reduces this protein’s function not only consumed less sugar but also experienced better metabolic health overall.

🍭 Voluntarily ate less sugar
🥤 Drank less sugary fluids
🔁 AND released more GLP-1 in response to sugar

'Lettuce' Be Honest: Fiber Isn’t Always the Answer🥬🤥(Refs linked in letter at the end) 🧵

1/6) We’ve been told for years that fiber is a must-have for gut health—that without it, your microbiome will crumble faster than a stale bran muffin.

But what if I told you… you don’t actually "need" fiber?

But before you throw your kale smoothie at the screen, let’s break down the science—because the truth about fiber is way more complex than a simple 'good' or 'bad.'

#fiber #microbiome #guthealth #educational #SCFA #ketodiet #carnivore #plantbased #metabolism #metabolichealth 2/6) Fiber & Inflammation🔥🥬

Some people argue that fiber-rich foods are anti-inflammatory. But that’s not entirely true.

For example, a landmark randomized controlled trial published in Cell found that some people were inflammatory responders to dietary fiber. Reading from the paper, “Taken together, these data suggest divergent immune system responses to the high-fiber intervention, with high-inflammation participants exhibiting broad increases in steady-state immune activation.”

To be clear, this was NOT the majority of participants.

And it's also worth noting that those with lower microbiome diversity tended to be the inflammatory responders, raising the 🤔hypothesis🤔 that there might be protocols by which one could train-up a microbiome such that it responds with a healthier anti-inflammatory response to fiber...

It’s possible.

But the fact remains that some people have a pro-inflammatory response to fiber that could have negative health consequences and contribute to or exacerbate chronic disease.