2/ The study in question is a mouse study, as you can really perform these fine mechanistic study in animal models
Data show that genetics variation among mice was a minor contributor and the variations in microbiome composition were more important for physical performance...
3/ To show the microbiome mediates the effects, they knocked out the microbiome with antibiotics in high-performer mice and the result was an impairment physical performance by 50%! (2a)
By contrast, microbiome transplant could enhance performance.
4/ Progressed to test hypothesis that motivation to exercise accounted for effect of microbiome on physical performance
Found that exercise ⬆️ dopamine levels (controls motivational state) AND exercise-induced ⬆️ in DA could be blunted w/ antibiotics to destroy microbiome
5/ Figure shows DA levels are NOT impacted in the basal state w/ antibiotic treatment but that antibiotics do prevent the rise in DA following exercise – consistent with the possibility that microbiome dysfunctioncould impact motivational states related to exercise @hubermanlab
6/ Zooming fwd so as not to get tedious, by blocking elements of pathways or activating elements, the team demonstrated there is an axis whereby certain bugs produce metabolites that activate neurons that signal to DA motivational centers in the brain to want to exercise
7/ Specifically, the most potent gut derived metabolites were fatty acid amines, such as N-oleoylethanolamide (OEA) (5e), which – for the super nerds out there – is a lipid that acts on the endocannabinoid pathway and is structured based on oleic acid, a monounsaturated fat
8/ The scientists were even able to show that gastric infusions of (OEA) recapitulated the effects of dopamine increase and improved exercise motivation/performance, and that more OEA correlated with more running (5g)
9/ These data spell out a story showing a strong link between the microbiome and exercise motivation
By better understanding these pathways, we could create dietary protocols or probiotics that could make us want to move our bodies more, improving personal and public health
10/ Plug again for 5 min video overview & Happy Saturday!
• • •
Missing some Tweet in this thread? You can try to
force a refresh
1/9) New study finds that high Lp(a) increases the risk of death from CVD by as much as 230%.
Since Lp(a) is thought to be genetically determined, some people think if you have high Lp(a), you’re screwed.
🚨But I don’t think so...
2/9) The researchers studied 1,027 patients with advanced coronary artery disease who were undergoing cardiac surgery.
The conventional view is that Lp(a) and related molecules promote atherosclerosis by physically sticking to the artery wall, infiltrating it, and essentially “seeding” plaque.
But there’s more to the story…
3/9) The researchers found that patients with higher Lp(a) also had higher levels of a molecule called “superoxide” (O2×).
And no, despite the name, it’s not Superman of the molecular world. It’s not a hero—it’s a villain.
O2× is a reactive oxygen species. It fuels oxidative stress and inflammation—core pathologies that can drive atherosclerosis.
1/6) A study published in Atherosclerosis found that 37% of individuals with “optimal” LDL (<70 mg/dL) still had measurable atherosclerosis.
That’s not a trivial number—but it does require nuance.
The first objection is familiar: a single LDL measurement may not reflect lifetime exposure.
Maybe these people lowered LDL later in life after years of higher levels?
But all participants were untreated—no lipid-lowering medications.
That makes it more likely that most had lifelong low LDL. Yet 37% still had atherosclerosis on CAC or carotid ultrasound.
🔗 Link to details at the end
PMID: 29751286
2/6) To be fair, this was modestly lower than the overall prevalence in the cohort (49%).
But a 12% relative difference, while not nothing, is a surprisingly small payoff compared to improving factors like blood sugar control or insulin sensitivity.
The punchline: across two diverse, untreated cohorts, having “optimal” LDL did not prevent atherosclerosis.
Not even close.
3/6) This is not to say LDL or ApoB don’t matter at all for anyone—it’s to say they’re only a small part of the puzzle. Yet LDL and ApoB dominate the cardio conversation, while risk factors related to global metabolic dysfunction—are consistently marginalized.
1/6) Today’s video on statins (linked below) dives into several key studies you need to understand, along with some provocative demonstrations that will definitely stick in your brain.
But in this short thread, let’s quickly review a few major takeaways...
2/6) Take Away 1: Across the board—whether you're looking at the 4S trial or more recent datasets involving cardiac imaging—a consistent pattern emerges:
People with good metabolic health and/or a zero-calcium score may see minimal benefit from statin therapy or LDL reduction.
Now, of course, there are nuances.
But broadly speaking, if your coronary artery calcium (CAC) score is zero, there's little to no reduction in cardiovascular events from lowering LDL.
3/6) And even if there is a tiny marginal benefit on subclinical progression at a population level (being generous)... does it outweigh the risks?
Statins are often treated as benign. They are not.
Side effects include—and go beyond—muscle pain:
↑ Insulin resistance
↓ GLP-1 levels (Shown, Atorvastatin vs Control)
↑ Risk of diabetes
Potential long-term muscle loss
Variable brain effects
This isn’t to say statins don’t have a place. It’s to say: the risk-benefit analysis must include actual risks.
Have High Lp(a)? You Need to See Today's Video covering a new 2025 study on Lp(a) and waist-to-hip ratio
1/5) Here's a quick breakdown...
The goal of this new study was to determine whether a measure of adiposity—waist-to-hip ratio—modifies the relationship between Lp(a) and cardiovascular disease risk.
2/5) To explore this, researchers analyzed data from 4,652 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), following them over a median of 17.4 years.
The study stratified individuals based on Lp(a) levels defined as >50 mg/dL and investigated how this risk interacted with waist-to-hip ratio as a marker of central adiposity and visceral fat
*Lp(a) (nmol/L) = Lp(a) (mg/dL) x 2.15
3/5) And—remarkably—in individuals with a ↓ waist-to-hip ratio, Lp(a) levels were not significantly associated with increased cardiovascular risk…
New Study: Person Study Finds Statin Use Associated Decline in Muscle Mass
1/6) A colleague of mine—a medical doctor—texted me recently: “I’m stopping my statin.”
The new paper referenced concludes: “Continuous statin use is associated with a decline in muscle function and mass over time (25% decline in grip strength and 73% decline in appendicular lean mass compared to never- users).”
Let’s discuss. (links in 5/6 and 6/6)
2/6) We’ll break this up by discussing the cross-sectional (single time point) and longitudinal (over time) results.
Cross-sectional analysis: In the fully adjusted model, adjusting for age, sex, education, smoking, BMI, activity score, diet quality score, high blood pressure, diabetes, and so on, statin use was associated with lower grip strength and lower appendicular lean mass.
3/6) Longitudinal Analysis: Statin Use Associated with Steeper Muscle Decline
Echoing the prior analysis, continuous statin use was significantly associated with accelerated declining grip strength and lean mass.
*Nuance note: For those with keen eyes, we discuss the y-intercept in the full letter
TL;DR: Statins use is linked to fasting muscular decline.
2/8) As a quick recap, I recently did a self-experiment that can be summarized in just two words: Sardine Diet. After a couple weeks on this extremely high omega-3 diet, I became conspicuously cold-resistant.
This was weird.
And I wanted to understand what might be happening. So, I dug into the literature.
3/8) Here's what could be happening...
Metabolically active brown fat can convert omega-3 fatty acids into a hormone called 12-HEPE.
12-HEPE stimulates thermogenesis in brown fat and ramps up glucose uptake into muscle as well.
This ultimately promotes heat production, cold adaptation, and energy expenditure.