Metformin
The diabetes drug everyone's taking for aging
Biguanide / Geroprotector
Evidence Level: Moderate Evidence
Some human data, strong animal studies, plausible mechanism
Regulatory Status: FDA-approved for type 2 diabetes. Off-label use for longevity is common but not FDA-approved.
Metformin is the ninth most prescribed drug in the world, used by over 120 million people for type 2 diabetes. But in longevity circles, it's become something of a holy grail: a cheap, well-studied medication that might slow biological aging itself. The excitement started when researchers noticed that diabetics on metformin seemed to live longer than non-diabetics—despite having a chronic disease. This paradox sparked intense interest in metformin as an anti-aging intervention. The landmark TAME trial (Targeting Aging with Metformin) is designed to test this directly, though it remains only partially funded as of 2024. Here's the honest truth: the evidence is promising but not definitive. Metformin activates cellular pathways associated with longevity, and observational data is intriguing. But we don't yet have proof it extends healthy lifespan in people without diabetes.
How It Works
AMPK Activation
Metformin partially inhibits complex I of the mitochondrial electron transport chain, which increases the AMP/ATP ratio. This activates AMPK (AMP-activated protein kinase), your cells' master energy sensor. When AMPK is activated, cells shift from growth mode to maintenance mode—cleaning up damaged components and improving efficiency. According to research published in Nature, metformin achieves this through binding to PEN2, a subunit of γ-secretase, which leads to v-ATPase inhibition and AMPK activation.
mTOR Inhibition
By activating AMPK, metformin indirectly inhibits mTOR (mechanistic target of rapamycin), a key growth pathway. Reduced mTOR signaling is one of the most consistent findings across species that live longer—from yeast to mice. Research in Molecules confirms that metformin inhibits mTORC1 through both AMPK-dependent and independent mechanisms.
Enhanced Autophagy
With mTOR suppressed and AMPK activated, cells ramp up autophagy—the process of clearing out damaged proteins and organelles. Think of it as cellular spring cleaning. This may help prevent the accumulation of cellular garbage that contributes to aging.
Reduced Inflammation
Metformin appears to reduce chronic low-grade inflammation (sometimes called "inflammaging") through multiple pathways, including NF-κB inhibition. A 2024 study in Signal Transduction and Targeted Therapy showed metformin decelerates biological aging clocks in male monkeys.
Improved Insulin Sensitivity
By reducing blood glucose and improving insulin sensitivity, metformin may reduce the metabolic stress that accelerates aging. High insulin levels are associated with faster aging in multiple studies.
Potential Benefits
- Extremely well-studied safety profile over 60+ years of use
- Very affordable—often $4-10/month for generic versions
- Activates AMPK and inhibits mTOR, two key longevity pathways
- May reduce risk of several age-related diseases based on observational data
- The TRAVERSE trial (2023) found no increased cardiovascular risk in men with pre-existing risk factors
- Potential reduction in cancer incidence based on epidemiological studies
- Improved insulin sensitivity and metabolic health
Risks & Considerations
- GI side effects are common (30-50%): nausea, diarrhea, stomach upset—usually improve over time
- Can cause vitamin B12 deficiency with long-term use (affects up to 1 in 10 users)—requires monitoring
- Rare but serious risk of lactic acidosis (about 9 per 100,000 person-years), especially with kidney problems
- May blunt some exercise adaptations and muscle protein synthesis in some studies
- Not appropriate for people with significant kidney or liver disease
- Longevity benefits are not proven in non-diabetics—observational data has limitations
- The TAME trial that would provide definitive evidence remains underfunded
Dosing Information
For diabetes, typical dosing is 500-2000mg daily, split into two doses with meals. For longevity purposes (off-label), some clinicians prescribe lower doses of 500-1000mg daily, often extended-release to reduce GI side effects. The planned TAME trial uses 1500mg daily. There's no established "longevity dose"—this remains an area of active research.
- •Start low (250-500mg) and increase gradually to minimize GI side effects
- •Extended-release (ER) formulations are better tolerated than immediate-release
- •Take with food to reduce stomach upset
- •Monitor B12 levels annually if using long-term
- •Kidney function should be checked before starting and periodically thereafter
- •Some longevity practitioners cycle metformin (e.g., 5 days on, 2 days off) to preserve exercise benefits
Practical Tips
- 1Get a prescription from a longevity-focused physician—this requires a doctor's involvement
- 2Start with extended-release metformin to minimize digestive issues
- 3Supplement with B12 and consider periodic blood tests for B12 levels
- 4If you exercise intensely, discuss timing with your doctor—some skip metformin on training days
- 5Stay hydrated and avoid excessive alcohol (increases lactic acidosis risk)
- 6Be patient—GI side effects typically improve after 2-4 weeks
- 7Consider berberine as a partial alternative if you can't access metformin (similar mechanisms, but less studied)
Key Research
TAME Trial Design
American Federation for Aging Research, 2024
The landmark TAME trial plans to enroll 3,000 subjects ages 65-79 across 14 US centers, measuring time to cardiovascular events, cancer, dementia, and mortality over 6 years of 1500mg/day metformin. FDA has approved the trial design, establishing precedent for targeting aging as an indication.
View StudyMetformin decelerates aging clock in male monkeys
Signal Transduction and Targeted Therapy (Nature), 2024
Metformin slowed epigenetic aging markers in male monkeys, providing some of the first primate evidence for anti-aging effects.
View StudyBenefits of Metformin in Attenuating the Hallmarks of Aging
Cell Metabolism, 2020
Comprehensive review showing metformin improves nutrient-sensing, enhances autophagy, protects against macromolecular damage, delays stem-cell aging, and modulates mitochondrial function—addressing multiple hallmarks of aging.
View StudyLow-dose metformin targets the lysosomal AMPK pathway through PEN2
Nature, 2022
Identified PEN2 as the direct molecular target of metformin at clinically relevant doses, explaining how metformin activates AMPK without depleting cellular ATP.
View StudyCritical Review of Metformin as Anti-Aging Drug
Frontiers in Endocrinology, 2021
Noted that while observational data is promising, the longevity benefits in mice were small (5% at best) and dose-dependent—higher doses actually shortened lifespan. Cautions against over-extrapolating from current evidence.
View StudyRelated Goals
Related Treatments
Disclaimer: This information is for educational purposes only and is not medical advice. Always consult with a qualified healthcare provider before starting any treatment. Evidence levels and regulatory status can change—this content was last updated December 2024.