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60+ Years of Clinical Use

# Metformin: The Gold Standard for Metabolic Longevity

The world's most studied anti-aging drug. AMPK activator, mTOR inhibitor, and the centerpiece of the landmark TAME trial.

60+
Years Clinical Use
$4-20
Monthly Cost
150M+
Users Worldwide

## What Is Metformin?

Metformin is a medication that has been prescribed for type 2 diabetes since the 1950s in Europe and 1995 in the United States. Derived from the French lilac plant (Galega officinalis), it has become the most prescribed diabetes drug in the world—with over 150 million users globally.

But metformin's story doesn't end with blood sugar control. Decades of observational data revealed something remarkable: diabetic patients taking metformin appeared to live longer than non-diabetics who weren't taking it. This discovery sparked intense scientific interest in metformin as a potential anti-aging compound.

## How Does It Work?

Metformin's longevity benefits stem from its effects on fundamental cellular pathways that regulate aging:

#### AMPK Activation

Metformin activates AMP-activated protein kinase (AMPK), often called the body's "metabolic master switch." AMPK activation triggers cellular cleanup processes, improves insulin sensitivity, and mimics some effects of caloric restriction—one of the most robust longevity interventions known.

#### mTOR Inhibition

By activating AMPK, metformin indirectly inhibits mTOR (mechanistic target of rapamycin). Overactive mTOR is linked to accelerated aging, cancer growth, and metabolic dysfunction. Reducing mTOR signaling is associated with lifespan extension across multiple species.

#### Reduced Insulin & IGF-1

Metformin lowers circulating insulin and insulin-like growth factor 1 (IGF-1). Elevated insulin and IGF-1 are associated with accelerated aging and increased cancer risk. Lower levels correlate with longevity in centenarian studies.

## The TAME Trial: Testing Metformin for Aging

#### TAME (Targeting Aging with Metformin)

The landmark TAME trial is the first FDA-approved study to test a drug specifically for aging rather than a single disease. Led by Dr. Nir Barzilai at Albert Einstein College of Medicine, this trial will follow 3,000 adults aged 65-79 over 6 years.

Primary endpoint: Time to onset of age-related diseases (heart disease, cancer, dementia, death)

Status: Currently enrolling, with results expected to reshape how we approach aging medicine.

## Key Research Findings

#### UK Prospective Diabetes Study (UKPDS)

This 20-year follow-up study found that metformin reduced cardiovascular events by 33% and all-cause mortality by 27% compared to diet alone in overweight diabetic patients.

#### Bannister et al. (2014)

Analysis of 180,000 patients showed diabetics on metformin had 15% lower mortality than matched non-diabetic controls—suggesting metformin may do more than offset diabetes risk.

#### Cancer Risk Reduction

Multiple meta-analyses show metformin users have 30-40% reduced risk of various cancers including colorectal, breast, prostate, and pancreatic cancer.

## Longevity Benefits

- Improved Insulin Sensitivity: Restores metabolic flexibility and glucose control
- Reduced Cancer Risk: 30-40% reduction across multiple cancer types
- Cardiovascular Protection: Reduces heart attack and stroke risk
- Anti-Inflammatory Effects: Lowers CRP and inflammatory markers
- Neuroprotection: Associated with reduced dementia and Alzheimer's risk
- Cellular Cleanup: Promotes autophagy—the body's recycling system

## Dosing Protocol

### Extended Release (ER) Preferred

Extended-release metformin is preferred over immediate-release due to better GI tolerability and more stable blood levels.

- Starting dose: 500 mg once daily with dinner
- Titration: Increase by 500 mg every 1-2 weeks as tolerated
- Longevity dose: 500-1000 mg/day (lower than diabetes dosing)
- Maximum dose: 2000-2550 mg/day (diabetes treatment)
- Timing: Take with food, preferably evening meal

Note: Many longevity physicians recommend 500-1000mg daily for non-diabetics—lower than diabetes treatment doses but sufficient for metabolic benefits.

## Side Effects & Considerations

#### Common Side Effects

GI side effects are common initially but typically improve over 2-4 weeks:

- Nausea and stomach upset
- Diarrhea (most common)
- Metallic taste
- Reduced appetite

### Important: B12 Monitoring

Long-term metformin use can reduce vitamin B12 absorption by 30-40%. Regular B12 testing is essential, and supplementation (500-1000 mcg daily) is often recommended for long-term users.

### Who Should Avoid Metformin

- Severe kidney disease (eGFR below 30)
- Liver disease or heavy alcohol use
- History of lactic acidosis
- Before contrast dye procedures (temporary hold)

## Exercise Timing Consideration

### The Exercise-Metformin Question

Some research suggests metformin may blunt some exercise adaptations, particularly muscle protein synthesis and mitochondrial biogenesis. For those prioritizing exercise benefits:

- Consider taking metformin in the evening, away from workouts
- Some practitioners skip metformin on heavy training days
- The clinical significance of this interaction remains debated

Most longevity experts believe the metabolic benefits outweigh any minor attenuation of exercise gains, especially for those over 50.

## Cost & Availability

Metformin is remarkably affordable—one of the cheapest prescription medications available:

$4-10
Generic (30-day)
$10-20
Extended Release
$0
Many Insurance Plans

Many pharmacies offer metformin on their $4 generic lists. GoodRx coupons can further reduce costs. For a longevity intervention, the cost-to-benefit ratio is exceptional.

## The Bottom Line

Metformin represents one of the most compelling longevity interventions available today. With 60+ years of safety data, billions of patient-years of use, and a remarkably low cost, it offers a unique combination of proven safety and promising anti-aging mechanisms.

The TAME trial will provide definitive evidence, but many longevity physicians already prescribe metformin off-label for healthy aging. Key benefits include:

- Activates the same pathways as caloric restriction
- Reduces cancer risk significantly
- Protects cardiovascular health
- Extremely affordable and widely available
- Decades of safety data

If you're interested in metformin for longevity, discuss with a physician familiar with its off-label use. Remember to monitor B12 levels and start with a low dose to minimize GI side effects.

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