I'm looking forward to joining David and John Gildea tomorrow to record a new episode of the Mara Labs podcast! Stay tuned.
Translating the Science of Health & Longevity USD Bio Professor, Drug Developer 📖 Longer content on LinkedIn: linkedin.com/in/jon-brudvig-phd-9b1830134 📰Sign up for my monthly Substack newsletter, Translation: jonbrudvig.substack.com
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I'm looking forward to joining David and John Gildea tomorrow to record a new episode of the Mara Labs podcast! Stay tuned.
David Roberts and Mara Labs just posted a nice, concise article on the #microplastics health problem and #sulforaphane as a potential tool for liberating the particles from cells. 🧪 Definitely worth a read if you are looking for a quick intro. mara-labs.com/blogs/journa... #Longevity
Key sources 2: 🧪 📰 Lithium stabilizes cognitive impairment in AD: pubmed.ncbi.nlm.nih.gov/22746245/ 📰 Mechanistic insights in mice and observational data in humans: www.nature.com/articles/s41...
Key sources 1: 🧪 📰 AD incidence with and without APOE4: www.nature.com/articles/s41... 📰 Lithium in drinking water and AD prevalence: jamanetwork.com/journals/jam... pmc.ncbi.nlm.nih.gov/articles/PMC...
Discussed in detail in my latest Substack post. 🧪 jonbrudvig.substack.com/p/lithium-pr...
Observational and interventional studies tell us that microdoses in the range of 0.02–0.3 mg/day are protective. That’s thousands of times lower than psychiatric doses, with a nearly zero risk of toxicity or side effects, and very inexpensive. This is easily achieved with lithium supplements. 🧪
So, why aren't we using it? Experts are hesitating to recommend lithium until optimal doses are confirmed in large, definitive trials. But in high-stakes scenarios like this, waiting for confirmatory evidence could mean missing the window for prevention. Acting now is wise. 🧪
🧠 Mechanisms: blocks tau phosphorylation, shifts amyloid processing, clears plaques. 🧪
💊 Supplementing with 0.3 mg/day slows cognitive decline in Alzheimer's patients. 🧪
🫗 Natural lithium in drinking water → 20%+ reduction in Alzheimer’s rates. 🧪
This is supported by robust observational data from many thousands of individuals, small interventional studies in Alzheimer’s patients, and a relatively robust understanding of mechanism. 🧪
If you live to 95, your risk of developing dementia is 42%. For APOE4 carriers, it’s as high as 59%. A trace mineral, lithium, can lower that risk at extremely low doses. So potently, that it could even counteract the impact of the worst genetic and environmental risk factors. 🧪
Lithium prevents Alzheimer’s. Here’s how to use it. 🧪 jonbrudvig.substack.com/p/lithium-pr... #Alzheimer's #Longevity #Prevention
Huge disappointment is an understatement. We have massive incentives to prioritize the health of ourselves and the planet over economic growth, but again and again we fail to do so. Devastating.
Even as evidence builds, many experts hesitate to recommend lithium for Alzheimer’s prevention. That’s a mistake. 🧪 My latest post breaks down the science and gives practical recommendations for implementation. jonbrudvig.substack.com/p/lithium-pr... #Alzheimer's #Longevity #BrainHealth
Key Sources 3: 🧪 📰 Metformin blunts exercise adaptations: pmc.ncbi.nlm.nih.gov/articles/PMC... 📰 The case against metformin in healthy individuals: drglorioso.substack.com/p/should-you...
Key Sources 2: 🧪 📰 Low dose metformin improves healthspan and lifespan in mice: pmc.ncbi.nlm.nih.gov/articles/PMC... 📰 Metformin decreases PD risk only when used at low doses: pmc.ncbi.nlm.nih.gov/articles/PMC... 📰 Metformin blunts exercise adaptations: pubmed.ncbi.nlm.nih.gov/31557380/
Key Sources: 🧪 📰 Metformin MOA: www.nature.com/articles/s41... 📰 Metformin promotes metabolic health, prevents diabetes, and promotes modest, durable weight loss: pubmed.ncbi.nlm.nih.gov/11832527/ 📰 Metformin reduces systemic inflammation: pubmed.ncbi.nlm.nih.gov/33412927/
We don’t yet have RCTs that can confirm the benefits in healthy individuals, and we likely won’t for quite some time. But with current evidence pointing towards benefits across many aging organs, one must also consider the risks of waiting for that evidence to exist.
While Peter Attia calls 500 mg a “homeopathic” dose, I disagree. In a healthy individual shooting for gut AMPK activation, a boost in incretin hormones, and mild glycemic benefits, 500 mg ER is plenty. Low doses will also minimize risks from drug effects outside of the gut. 🧪
Risks can be mitigated by using a low dose (e.g., 500 mg ER 1x or 2x daily) paired with B12 supplementation, taking periodic breaks, and combining with resistance training to prevent muscle loss. Work with a good longevity doc and stop the drug if you feel worse or see deterioration in biomarkers. 🧪
Is it wise to use this drug off-label for longevity purposes? 🧪 My read of the current evidence is a qualified “yes.” In a healthy person that leans towards overnutrition moreso than undernutrition, metformin likely offers systemic benefits and protects against metabolic and inflammatory diseases.
What are the key risks? 🧪 🚫 Vitamin B12 deficiency 🧠 Increased risk of Parkinson’s disease in some (not all) observational studies, presumably from brain penetration of higher doses 💪 Potential for blunted adaptive responses from exercise
Why might metformin be good for longevity? 🧪 ☑️ Supports metabolic health, prevents diabetes, and promotes modest, durable weight loss ☑️ Decreased inflammation in tissues throughout the body, strongly linked to positive health outcomes ☑️ Extends lifespan (modestly) in animal models at low doses
These hormones then exert a range of beneficial effects on target tissues, improving metabolism, increasing satiety, and decreasing inflammation in tissues throughout the body. This is quite similar to #GLP-1 injectables, but occurs in a more coordinated, integrated way. 🧪
What’s the rationale for and against metformin for #longevity? First, how does it work? As we’ve discussed in recent posts, metformin acts in the gut by binding a lysosomal protein called PEN2 and activating a response that increases production of incretin hormones like GLP-1, GIP, and PYY. 🧪
Thank you! I’ll check it out.
Just realized part of the issue here. Look at the years on the y-axis. The gaps between ticks change from three years before ~2020 to 11 and then 15 years after 2020, which exaggerates the impression of acceleration.
And still, there are other examples where the predictions proved to be accurate or even understated. For example, the global rise in CO2 levels and temperatures.
Here is the original source for that projection. I haven't watched it yet, so can't speak to it: www.oecd.org/en/events/20...
Yes, criticised mostly by people with close ties to the plastics industry. There are known limitations with the methodology (some inevitable noise from contaminating lipids), but that does not call the conclusions (trends over time, dementia vs. healthy) into question. It is an excellent paper.
Bonus source for increasing concentrations in human tissues: 🧪 www.nature.com/articles/s41...
In doing so, we can help build support for global treaties aimed at minimizing plastic pollution, and for finding creative solutions that address the health consequences. Please read The Lancet Countdown on Health and Plastics. DM for a copy.🧪 www.thelancet.com/journals/lan...
What can we, as scientists, healthcare professionals, and humans do about this? We can care enough to spread the word. To educate the public on this very real health concern. To help people understand that this is not a fringe concern, pseudoscience, or internet hype.🧪
And this is about to get much, much worse, as plastic production triples from current levels by 2060. 🧪
As plastic production and pollution has increased, levels of microplastics in our brains and bodies have increased in parallel. 🧪 (This figure from another recent paper, in sources at the end)
This new report on the health implications from plastics pollution doesn’t mince words. Evidence is piling up that “plastics are a grave, growing, and under-recognised danger to human and planetary health.”🧪
This week in the Lancet: “Plastics cause disease and death from infancy to old age and are responsible for health-related economic losses exceeding $1.5 trillion annually.” 🧪 A quick break down and call to action in this thread. #Microplastics #Longevity
It was fun to see Felix Harder break down my #microplastics experiments on YouTube 🧪: www.youtube.com/watch?v=JZaJ... I'm working on a follow up post now, with a science update and protocol insights. Stay tuned! Original post on Substack: jonbrudvig.substack.com/p/first-evid...
I take that as a major compliment!
In other words, metformin isn't just a glucose-lowering drug—it's a top-down rewiring agent for gut nutrient sensing and hormone modulation, which likely underlies the benefits observed across so many organ systems. 🧪
🧩 Together, these studies reinforce a clear effect on the gut–brain axis: metformin activates AMPK in enteroendocrine cells, restoring their ability to sense nutrient status and secrete hormones that shift metabolism in a positive direction. 🧪
🧬 Study #2 (Diabetes, July 2025): In high-fat-fed rats, met restored lipid sensing in the upper intestine, triggering release of the gut hormone GIP. • A chronic high-fat diet blocks GIP secretion in response to feeding. Metformin relieves this blockage, restoring nutrient sensing and satiety. 🧪
🔬 Study #1 (Lancet eBioMedicine, July 2025): Longitudinal plasma proteomics in ~100 humans before and after met revealed 23 consistently altered proteins. Top hits are signatures of the enteroendocrine cells that produce GLP-1 and GIP, reinforcing that these are the key cellular targets. 🧪
We’ve known for a while now that metformin doesn’t act primarily in the liver or mitochondria as was once believed. Instead, it concentrates in the gut, where it activates a cellular stress response. Now, two new studies show exactly how this local response ripples outward to benefit metabolism. 🧪
Metformin doesn’t just lower glucose; it teaches your gut how to sense nutrients again. Two new papers show exactly how this works, and why it matters. 💊🧪💊 Broken down in this thread. #Longevity #Aging #Healthspan
It means that they didn't let all of the mice age out long enough to die of "natural" causes. That would have been even better, but would have also delayed the publication. Hopefully someone will replicate with a full lifespan study.
Life is Shorter Than You Think. Don’t Miss Your Bonus Chapter. My new full-length post is a simple inquiry into the true impact of lifestyle interventions, with simple, striking visuals that reframe the entire question. jonbrudvig.substack.com/p/life-is-sh... #Longevity #Healthspan #Aging 🧪
Most clinical studies have tested 10, 20, or 25 mg. For depression at least, the effects are dose dependent, with the strongest benefit at 25mg. Not medical advice, of course
Psilocybin extends lifespan in mice. But this is bigger than just a new geroprotective drug; it suggests an entirely new drug target—and it probably isn't the one you think. 🧪🧠🧪 substack.com/profile/1091... #longevity #psychedelics #psilocybin
In case you missed it, my last Substack post summarizes the #microplastics problem for human health and shares some encouraging initial experiments into a clearance protocol. This one has generated a LOT of great discussion. Next steps are in the works! 🧪 jonbrudvig.substack.com/p/first-evid...
The newest paper is open access. You should be able to read it here: www.nature.com/articles/s41...
That may be true for cancer, but more broadly, an estimated 80% of chronic disease is preventable. pubmed.ncbi.nlm.nih.gov/28523941/
Sources 🧪: New 2025 Organ Age Study from Wyss-Coray Group: www.nature.com/articles/s41... 2023 Organ Age Study from Wyss-Coray Group: www.nature.com/articles/s41... Time Magazine Piece on Organ Aging Clocks and Brain Aging: time.com/7301118/brai... Another Clock: www.nature.com/articles/s41...
This organ aging test will add a real, data-driven layer of personalization to longevity care and even mainstream medicine. It’s exactly the kind of tool we need to move next-generation preventative care from theory to practice. 🧪
Or maybe you’re three months into your new exercise program and want to assess the impact. If the test shows that you’ve decreased your brain age by three years, along with significant benefits across several other organ systems, that might be the inspiration you need to stay on track. 🧪
If your brain is aging faster than the rest of your body, it may be time to cut alcohol and commit to regular exercise. If your brain is aging slowly but your gut is aging quickly, cleaning up your diet might be the most important place to start (Yes, you should still exercise). 🧪
How will it be used? As a diagnostic tool to identify disease risk years before symptoms appear and as a feedback tool to track intervention impact in real time. Want to know where to focus your health efforts? Take the test. 🧪
The rate of aging for each organ can be measured with a simple blood test. 🩸🧪🩸 Vero is bringing this test to the masses—first to select longevity and concierge clinics by the end of the year, and eventually direct-to-consumer. You can sign up for early access at verobioscience.com.
New research from the Wyss-Coray group confirms this idea, showing that organs do indeed age at different rates in a cohort of 40,000+ people. Perhaps more importantly, accelerated organ aging is linked to increased disease risk and earlier mortality. 🧪
First, the scientific premise. Your organs don't all age at the same rate. This might seem intuitive—you’ve seen some people develop Alzheimer’s (brain disease) in old age, while others develop atrial fibrillation (heart disease) or kidney disease. 🧪
What if a quick blood test could tell you how fast each of your organs are aging? 🧪🩸🧪 That’s the promise of Vero Bioscience, a new startup commercializing the organ-specific aging test developed by the Wyss-Coray group at Stanford. Broken down in this thread. #Longevity #Aging
Given our ever-growing reliance on single-use plastics, this problem is poised to accelerate. We need the #microplastics equivalent of the Clean Air Act or the Paris Climate Accord. There are realistic, economically feasible solutions to this very real problem. www.nature.com/articles/s41...
These nanoscale particles aren’t just abundant; they’re bioavailable, entering marine life, contaminating our food supply, and accumulating in human tissues. Early evidence links them to immune dysfunction, cardiovascular disease, dementia, and other health risks we’re only beginning to understand.🧪
This changes the scale of the #microplastics crisis. We’ve known about the 3 million tonnes (MT) of floating plastic in our oceans for years. But that’s just the surface. In the North Atlantic alone, 27 MT (9x!) of nanoplastics are suspended in the water column. 🧪 www.nature.com/articles/d41...
In other words, #inflammaging is environmental, and that makes it modifiable. #Longevity interventions targeting this hallmark of aging could make a large impact in industrialized nations. 🧪 📰 Full (paywalled) study: www.nature.com/articles/s43...
This is a clear demonstration that inflammaging is not a universal biological process; It is the result of environmental mismatch. Our immune systems evolved in one world but are now reacting to another—one with sedentary lifestyles, ultra-processed foods, chronic stress, and low pathogen exposure.🧪
Despite frequent infections, the Tsimane and Orang Asli showed no increase in cytokine-driven inflammation with age. And despite persistently elevated infection-driven inflammation, they exhibit virtually no chronic disease, a pattern also observed in other Indigenous societies around the world. 🧪
The inflammaging signature in Italy and Singapore (blue and red lines below) was dramatically reduced or entirely absent in the Indigenous groups (green and purple lines). In these populations, inflammatory markers showed little to no increase with age and no association with age-related disease. 🧪
In the new study, researchers examined immune aging signatures across four distinct populations: two from industrialized nations (Italy and Singapore), and two Indigenous, non-industrialized societies, the Tsimane of the Bolivian Amazon and the Orang Asli of Malaysia. 🧪
For decades, chronic low-grade inflammation has been recognized as a hallmark of aging. It's linked to nearly every major age-related disease: cancer, cardiovascular disease, Alzheimer’s. The assumption has been that it is an inevitable consequence of cellular aging. That assumption was wrong. 🧪
#Inflammaging isn’t a biological inevitability. It’s a byproduct of industrialized lifestyles, as confirmed in a new study this week in Nature Aging. Broken down in this thread. 🧪
100% plastic-free coffee solutions 🧪: ☕ A fully plastic-free drip brewer (finally!): simplygoodcoffee.com/products/the... ☕ The classic manual pour over: www.hario-usa.com/products/vd-... … and, the combo I use every day: ☕ A Chemex 10 cup pour over… chemexcoffeemaker.com/products/ten...
☕ 3. When you brew drip coffee, you are heating water to near boiling temperatures in plastic and then flowing hot, acidic coffee through a plastic spout. This is a great protocol for extracting microplastics! Switch to an all-glass or metal brewing system. Several good options below. 🧪
🪥 2. You know how those electric toothbrush bristles wear down over time? That’s because they are wearing down and releasing microplastics inside of your mouth. Rinse and spit thoroughly after brushing. Twice. Or, better yet, switch to a plastic-free toothbrush head. Yes, they exist. 🧪
👚 1. Your dryer lint trap is essentially a microplastic collection device. When you clean the lint screen, you are handling perhaps the most concentrated source of microplastics you will ever encounter. Keep an N95 in the laundry room and wear it when you handle the lint. 🧪
#Microplastics are building up in your body. You can reduce your exposure, starting with three major sources you probably haven’t even thought about. 🧪🔬🪥
Turning #microplastics into Tylenol? 🧪 This isn't going to solve the plastic mess we've created, but it does illustrate how bacteria can be engineered to break down plastic, sometimes with useful bioproducts. Microbes may be the solution to the environmental problem. www.nature.com/articles/d41...
Doctor Steven Murphy gives an excellent perspective and case examples ( #rapamycin ) in a recent post. Worth a read for anyone curious about how longevity docs actually make decisions when faced with incomplete evidence. 🧪🩺💊 substack.com/home/post/…
When you triangulate across mechanistic understanding, preclinical data, and clinical outcomes in related populations, the case for cautious off-label use becomes quite strong. 💪💉🧪
We also have animal studies showing lifespan extension, insights into cellular-level benefits, and observational evidence in humans suggesting broader systemic and organ-level benefits. 🐁🧪🔬 Is this definitive proof of longevity effects in healthy individuals? No. But it’s far from "no evidence."
Consider SGLT2 inhibitors. These drugs already have robust Phase 3 data in type 2 diabetes, heart failure, and chronic kidney disease, showing not just glucose-lowering effects, but real-world reductions in mortality and cardiovascular events. 💊🧪
I've noticed a lot of recent pushback on the notion of #longevity medicine 🧪 in the popular press. Respected clinicians, scientists, and thought leaders (including one of my favorites, Eric Topol) repeat the claim that “there is no evidence for these treatments.” This is objectively false.
Absolutely. NRF2 activators show a lot of promise for longevity. Sulforaphane is one of the best life extending compounds in C. elegans (worms), and Protandim (an herbal NRF2 activating mixture) extends lifespan in mice. Both also appear beneficial in humans.
See the last two posts of the thread: bsky.app/profile/jonb... and bsky.app/profile/jonb...
Key Sources Continued: 📰 Trevogrumab/Garetosmab clinical results: www.nature.com/articles/s41... diabetesjournals.org/diabetes/art... newsroom.regeneron.com/news-release... 📰 Bimagrumab clinical results: pubmed.ncbi.nlm.nih.gov/33439265/ www.statnews.com/2025/06/23/b...
Key sources: 📰 Myostatin knockout mice are jacked. 💪 A new drug target? pubmed.ncbi.nlm.nih.gov/9139826/ 📰 Domagrozumab fails in phase 2 for DMD: pubmed.ncbi.nlm.nih.gov/32522498/ 📰 Activin A more prominently regulates muscle mass in primates than does GDF8: pubmed.ncbi.nlm.nih.gov/28452368/
Finally, the kinds of changes drug developers were hoping to see in humans! Now that we understand the biology, effective drugs are on the horizon. A classic example of how effective medicines stem from a thorough understanding of basic biology. 🧪
When these drugs are paired with a GLP-1 for weight loss, patients lose more body fat and less muscle, with impressive effect sizes. The drugs even work well on their own, leading to about a 20% reduction in fat mass and single digit gains in % muscle mass over 6-12 months. 🧪
These findings gave a big boost in confidence for therapies that block the ActRIIb receptor (e.g., bimagrumab; Eli Lilly and Company) or that simultaneously inhibit both proteins (e.g., Trevogrumab/Garetosmab; Regeneron). These are far more likely to succeed, since they also inhibit Activin A. 💊🧪💊
In primates, myostatin-only blockade barely moves the needle, but dual blockade of myostatin + Activin A boosts lean mass by ~14 % in 11 weeks. Blocking the receptor itself does something similar. 💪🧪💪
Around the same time, we learned that Activin A, a second protein that signals through the same ActRIIb receptor, plays a redundant, perhaps greater role in regulating muscle size in primates including humans (who have only a fraction of the myostatin that a mouse does). 🧪
These findings led to widespread interest in myostatin as a drug target for conditions where muscle growth or maintenance is desirable. But in human trials of myostatin inhibition, results were modest, with most studies showing little or no muscle growth. 💪🧪💪
Myostatin was first identified as a regulator of muscle mass in mice. In rodents, blocking myostatin (AKA GDF8) increases muscle mass by ~20-30% in just a few weeks. Something similar happens in mice, dogs, or cattle lacking the gene. It’s a dramatic result—you’ve probably seen the pictures. 🧪
Myostatin inhibitors have received a lot of attention in the muscle space. They work great in mice, but there's another strategy with far greater potential in humans. I break down the #Science in this thread. 🧪💊🧪 #myostatin #muscle #healthspan #longevity
Key Refs: 🧪💉💊 📰 Antidepressants act via TRKB: pubmed.ncbi.nlm.nih.gov/33606976/ 📰 Psychedelics act via TrkB: www.nature.com/articles/s41... 📰 BDNF receptor TrkB as the mediator of the antidepressant drug action: www.frontiersin.org/journals/mol...
The depression benefits are very real. Check out the fresh phase III data from Compass Pathways, showing statistically significant improvements in treatment resistant depression patients following a single dose of psilocybin. 🧪 ir.compasspathways.com/News--Events...
This emerging model opens new doors for developing faster, more targeted antidepressants and better treatments that capitalize on the enhanced neuroplasticity with cognitive tools like talk therapy, therapeutic writing, etc. 💊🧪💊
2. 🧪 In animal models, psychedelics fail to produce antidepressant effects when TrkB signaling is blocked. 3. 🧠 Blocking 5-HT2A eliminates the hallucinogenic effects, but not the antidepressant response, decoupling the trip from the therapeutic mechanism.
What's the evidence? 1. Psychedelics bind TrkB with nanomolar affinity. SSRIs bind TrkB ~1,000× more weakly, perhaps explaining the lag in their efficacy (it takes time to build up to concentrations that bind TrkB). 🧪
