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. 🧪
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. 🧪
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
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
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.
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. 🧪
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. 🧪
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.
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/
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 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...