Common Longevity Medication… Performance Killer?

A medication used by millions (including off-label usage for “longevity” purposes) may alter the fundamental pathways responsible for exercise adaptation. This episode reviews new 2025 data showing reduced improvements in vascular insulin sensitivity, aerobic capacity, and glucose regulation when the medication is paired with structured training. We look at prior evidence of blunted mitochondrial respiration and diminished hypertrophy, along with 2020 transcriptomic findings that paint a more nuanced picture.

The goal: clarify when this medication interferes with exercise-driven improvements in muscle, mitochondria, and vascular function, and when it may support resilience during aging.

00:00 – Intro
00:48 – The Rise of a “Longevity” Medication
01:31 – New Clinical Data Challenges Expectations
03:34 – Earlier Trials Showed the Same Pattern
05:05 – Resolving the Apparent Contradiction
07:10 – Who Should, and Shouldn’t, Use This Medication

PMID: 30548390
PMID: 31557380
PMID: 33071237
PMID: 37928155

Chapters

• 0:00 The Exercise Adaptation Fingerprint
• 0:35 Metformin’s Rise Beyond Diabetes
• 1:31 Rutgers Trial: Blunted Training Response
• 2:44 Evidence Across Endurance And Strength
• 4:05 The Paradox: Protection Versus Progression
• 6:58 Practical Guidance And Key Takeaways

Transcript

SPEAKER_00: 0:00

Exercise has a predictable fingerprint, improve mitochondrial efficiency, increase insulin stimulated blood flow, expand aerobic capacity. The physiology is so reliable that it's a very accepted dogma. But in a new 2025 clinical trial, that fingerprint dissolved. People followed the same program, yet the expected improvements never appeared. It was as if the signal that tells muscle and blood vessels how to adapt had been muted altogether. The investigators trace that missing signal back to a medication trusted for decades, a medication prescribed 90 million times a year, one of the most commonly prescribed drugs in the world. I am William Wallace, and you are listening to Daily Value. It's safe, it's cheap, and it's been used continuously since the 1950s, but metformin didn't stay confined to diabetes care. Over the last decade or so, it became one of the most popular off-label longevity therapies. Influencers recommend it. Biohackers swear by it. Millions of people with perfectly normal blood glucose metabolism now take it daily because they've heard it might slow aging. In some corners of the internet, metformin is treated almost like a molecular seatbelt, something you take forever just in case. So when a new clinical trial from Rutgards landed this past October, it didn't just raise eyebrows, it reopened an old case. In this study, researchers enrolled adults at risk for metabolic syndrome and supervised them through a tightly controlled 16-week exercise program. High intensity intervals, lower intensity days, prescribed workloads, monitored adherence, precisely the kind of training expected to drive clear improvements in vascular function, insulin sensitivity, and fitness. And in the placebo group, it did. Arteries dilated more effectively, microvascular blood flow improved, and VO2 max climbed. Fasting blood glucose dropped, but in the metformin group, the expected adaptations barely appeared. The training stimulus was identical, the physiological response was not. This wasn't the first hint of metformin's interference to exercise adaptations. Years earlier, two small human studies showed the exact same pattern. Short-term metformin treatment and exercise did not synergize. Instead of enhancing the insulin-sensitizing effect of exercise, metformin appeared to attenuate it. Those findings were easy to dismiss, the samples were small, the designs were pretty limited, but the Rutgers data is a little bit different. It's larger, more comprehensive, and for the first time, it measured something that cuts to the heart of metabolic health, vascular insulin sensitivity, the ability of insulin to open blood vessels and deliver glucose to working muscle. Exercise normally strengthens that signal, no surprise there. In metformin users, the signal was muted, which presents a scientific contradiction. How can a drug used for 70 years to improve metabolic health weaken some of the very adaptations that exercise depends on? Why does this blunting appear not just in glucose control, but in overall fitness, in vascular responsiveness, in recovery, even in muscle hypertrophy, as we'll see in a minute? What does this all mean for the millions of people taking metformin, which you might call unnecessary in some respects, not for diabetes, but in the pursuit of longevity? To understand the Rutgers' findings, we have to look at earlier studies that hinted this might happen. In 2018, researchers had tested metformin during aerobic training in older adults. Endurance training normally increases mitochondrial respiration, oxidative enzyme activity, and VO2 max, but when metformin was added, mitochondrial improvements were blunted. VO2 max gains were smaller, insulin sensitivity improvements were reduced. It was a clear sign that metformin interfered with mitochondrial adaptation, the foundation of aerobic training. One year later, the master's trial examined resistance training. 14 weeks of progressive strength work should increase lean mass and strength in older adults, and it did, but only in the placebo group. With metformin, hypertrophy was significantly blunted, strength gains were smaller, muscle quality improved less. Follow-up muscle analyses explained why. The placebo group showed broad activation of genes involved in remodeling and growth. And in the metformin group, fewer genes changed and changes were smaller. The stimulus was identical, but the muscle's ability to adapt was reduced. When we line up the evidence, the pattern became pretty clear. Mitochondrial adaptation reduced, hypertrophic adaptation reduced, insulin-sensitizing adaptation also reduced. And now the Rutger study adds reduced insulin-stimulated blood flow and microvascular responsiveness. Across endurance, strength, metabolic, and vascular systems, metformin dampens the biological remodeling normally triggered by exercise. But here's a twist. Other research suggests metformin can protect muscle and aging, reduce fibrosis, lower inflammation, and improve cellular housekeeping, benefits that don't align with the idea that it simply blocks adaptation. That contradiction leads directly into what we now know about muscle aging and sets up the real explanation for all of this. The interference pattern across endurance, strength, and vascular studies seems straightforward until you look at a different category of research entirely. Because in aging muscle, metformin does something else. In 2023, researchers studying disuse atrophy in older adults found that metformin reduced muscle loss during bed rest, decreased fibrosis, and lowered markers of cellular senescence. The people taking metformin lost less muscle and recovered more effectively. A broader review the same year showed why this might happen. Metformin consistently improves autophagy, reduces inflammation, restores aspects of mitochondrial quality control, and modulates pathways linked to aging biology, not performance. And the 2020 transcriptomic follow-up to the master's trial, that's the one that showed reduced hypertrophy, showed something unexpected. While metformin did blunt muscle hypertrophy, it also shifted hundreds of aging-related genes toward a younger expression pattern, especially in pathways tied to metabolism and cellular maintenance. So now the picture kind of comes into focus. Metformin doesn't blunt everything. It blunts growth-driven adaptation, the type triggered by training, while supporting maintenance-driven adaptation, the type needed during aging, inflammation, or periods of muscle loss. That's why it can simultaneously interfere with the mitochondrial gains and protect muscle during disuse, why it can suppress hypertrophy, yet improve cellular housekeeping, why it can weaken fitness improvements, but strengthen resilience in older inflamed or immobilized muscle. The effect isn't random, it depends on what your muscle needs. And that distinction matters for how we use this drug. So what do you do with all of this? If you have type 2 diabetes or prediabetes, metformin remains an effective therapy. Exercise still works, just monitor your glucose response because some of the expected improvements in insulin sensitivity may be a little bit smaller. If you're older, inflamed, or facing surgery, injury, or periods of inactivity, metformin may actually help preserve muscle, reduce fibrosis, and support recovery. Its benefits here are maintenance oriented, not performance-oriented. If you're a healthy adult taking metformin for longevity, this is where caution matters. The strongest longevity interventions we have, muscle mass, strength, mitochondrial function, vascular fitness, are all built through exercise. And those are the same adaptations metformin consistently blunts. If you're training for performance, hypertrophy, or VO2 max, there's no evidence metformin helps and strong evidence it works against you. Metformin is powerful too, just in a different direction. It supports maintenance, not adaptation, protection, not progression. The key is alignment. If your goal is performance growth or maximal training response, metformin may not belong. If your goal is resilience during aging or recovery, it may. Knowing the difference is the real advantage here. Thank you for joining me today on Daily Value. As always, stay healthy.