Why Your Metformin Might Be Stealing Your Gains (And What To Take Instead)

The popular “anti-aging” drug blocks the exact adaptations that make exercise work

Metformin is a diabetes drug that’s becoming popular for longevity. Metformin activates AMPK, a cellular energy sensor that triggers many of the same longevity pathways as caloric restriction. It also lowers blood glucose and improves insulin sensitivity. This is critical for longevity since high glucose accelerates aging through inflammation, oxidative stress, and glycation damage.

In animal studies, metformin extends lifespan. The FDA is even testing it in the TAME trial to see if it can slow aging in humans. Millions take it for blood sugar control, and increasingly, healthy people are asking their doctors for it as a preventive anti-aging strategy.

Here’s what nobody tells you: metformin inhibits your mitochondria.

And when you combine it with exercise, it blocks the metabolic and mitochondrial adaptations that exercise provides. We’re talking about blunted gains in VO2 max, reduced muscle growth, and blocked insulin sensitivity improvements from training. The very adaptations that make you healthier, stronger, and more metabolically flexible.

If you’re taking metformin while training hard, you’re leaving major gains on the table.

The Mitochondrial Problem

Metformin lowers blood sugar by inhibiting complex I in your mitochondrial respiratory chain. Think of complex I as the first major checkpoint in your cellular energy production line. When metformin blocks it, your cells can’t produce ATP as efficiently.

This energy crisis forces your cells to activate AMPK, which improves insulin sensitivity by making your cells desperate for fuel. It’s like cutting off someone’s electricity to make them more efficient with energy. Sure, it works, but at what cost?

The mechanism sounds clever in a lab. But in real life, when you’re trying to build muscle, increase endurance, or just function at your best, deliberately damaging your mitochondria creates serious problems.

The Exercise Interference Studies

Multiple randomized controlled trials have shown metformin sabotages exercise adaptations.

The 2019 Konopka study tested 53 older adults during 12 weeks of aerobic training. Half received metformin; half got a placebo. The placebo group increased their VO2 max significantly. The metformin group showed almost no improvement, with metformin reducing their gains by roughly 50%.

The metformin group also failed to improve insulin sensitivity from exercise, while the placebo group saw major improvements. The reason: metformin completely blocked the improvements in how well their mitochondria produced energy.

A 2019 resistance training study found similar results. Older adults taking metformin during 14 weeks of progressive resistance training gained significantly less lean mass and muscle compared to placebo.

A 2025 study published in October tested metformin with both low-intensity and high-intensity exercise training. The results were identical across intensities: metformin blocked the VO2 max improvements and prevented the exercise-induced improvements in blood vessel function and inflammation markers.

When you exercise on metformin, you still burn calories and move your body, but you miss out on the deeper adaptations that make exercise so powerful.

Why This Matters for Longevity

You might think “Well, I don’t care about VO2 max or muscle, I just want to live longer.”

But actually, this does matter for you. Here’s why: VO2 max is one of the strongest predictors of longevity we have. Research shows that every 1 mL/kg/min increase in VO2 max reduces all-cause mortality risk by roughly 9-15%. The difference between the lowest and highest fitness groups can mean a 5-fold difference in mortality risk.

When metformin blocks the VO2 max improvements from exercise, you’re missing out on one of the most powerful longevity interventions available.

Exercise also improves insulin sensitivity better than metformin does on its own. Studies show exercise alone can improve insulin sensitivity by 25% or more. But when you take metformin while exercising, you block those additional improvements. You get metformin’s insulin sensitivity benefit, but you don’t get the extra increase that exercise would normally provide.

Metformin’s complex I inhibition also blocks the increase in mitochondrial density that normally happens with endurance training. Your mitochondria are the power plants of your cells. More mitochondria means more energy, better aging, and improved metabolic health. Exercise builds them. Metformin blocks that process.

So even if metformin has some direct longevity benefits, it’s preventing you from getting the much larger benefits that come from exercise adaptations. That’s a bad tradeoff for anyone who trains consistently.

What About Berberine?

Before you swap metformin for berberine, know this: berberine works through nearly the same mechanism.

Berberine inhibits mitochondrial complex I just like metformin does. Multiple studies confirm this. Berberine reduces oxygen consumption and ATP production in liver and muscle tissue. It activates AMPK by creating the same energy stress that metformin does.

One study on neurons found that berberine causes rapid mitochondrial toxicity, including mitochondrial swelling, increased oxidative stress, decreased ATP, and cell death.

Research shows berberine helps with blood sugar and weight loss, but those benefits come with the same tradeoff: impaired mitochondrial function. If you’re concerned about metformin blocking exercise adaptations, berberine will do the same thing.

I don’t recommend berberine, but your mileage may vary. Some people tolerate it fine and see benefits. Just know that it also can inhibit mitochondria, and it can cause heart rate and blood pressure issues on top of that if you’re sensitive.

So maybe you’re rethinking the metformin now.

The paid section reveals the better alternatives that improve glucose control and support longevity without blocking your exercise adaptations. I also share the complete protocol for combining multiple interventions for maximum effect.

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