Metformin and Longevity, What the Evidence Shows

The mechanistic target of rapamycin (mTOR), and specifically the complex mTORC1, carries the opposing signal. Where AMPK reports scarcity, mTORC1 reports abundance. When amino acids, glucose, insulin and growth factors are plentiful, mTORC1 activates protein synthesis and cell growth and suppresses autophagy, the process by which a cell recycles and replaces its own damaged components. Chronic mTORC1 activation is one of the most reproducible drivers of ageing across species, and inhibiting it with rapamycin extends lifespan in mice more consistently than any other drug tested.

Metformin suppresses mTORC1 by at least two routes. The first runs through AMPK. Activated AMPK phosphorylates TSC2 and the mTORC1 subunit raptor, both of which restrain mTORC1, and this is the dominant route at the lower concentrations that correspond to therapeutic dosing (Howell et al., Cell Metabolism, 2017).

The second route is independent of AMPK. Metformin also inhibits mTORC1 through the Rag GTPases at the lysosomal surface, the machinery that reports to mTORC1 whether amino acids are available. That route operates in cells lacking AMPK entirely (Kalender et al., Cell Metabolism, 2010), and the lysosomal pathway is required for metformin’s lifespan effect in Caenorhabditis elegans (Chen et al., eLife, 2017).

Metformin therefore acts on the same pathway as rapamycin, but far more weakly and at a different point in it. The two drugs share a direction of travel and differ greatly in magnitude.

SIRT1, the third pathway usually named in this context, sits downstream. A rise in the ratio of NAD+ to NADH activates the sirtuins, and metformin’s effect here appears to be indirect and secondary to the AMPK signal rather than a separate action of the drug.

The randomised evidence for metformin in people without diabetes is thinner than the public discussion suggests.

In the Diabetes Prevention Program, metformin reduced progression from impaired glucose tolerance to type 2 diabetes by 31% over an average of 2.8 years, and the effect persisted through long-term follow-up in the Outcomes Study. Intensive lifestyle change in the same trial reduced progression by 58%, so the drug was the weaker of the two active arms from the outset.

Over roughly 21 years of combined follow-up in the same 3,234 participants, neither metformin nor intensive lifestyle change reduced major adverse cardiovascular events. For metformin against placebo the hazard ratio was 1.03 (95% CI 0.78 to 1.37) (Goldberg et al., Circulation, 2022). The importance of that result lies in the gap it exposes, since the drug prevented diabetes without producing fewer heart attacks and strokes in the same population.

In people who already have type 2 diabetes and are overweight, UKPDS 34 reported a reduction in diabetes-related endpoints and in all-cause mortality with metformin (The Lancet, 1998). That is a benefit in the treatment of diabetes rather than evidence of an effect on ageing.

The Metformin in Longevity Study was the first trial to look for an ageing signature rather than a clinical endpoint. It gave metformin to older adults without diabetes for six weeks and found changes in muscle and fat gene expression pointing towards mitochondrial and collagen pathways (Kulkarni et al., Aging Cell, 2018). The trial enrolled 14 participants, ran for six weeks and measured gene expression rather than health, so it generates a hypothesis rather than testing one.

This is the most consequential finding for a healthy adult considering metformin, and it is the least discussed.

In older adults randomised to twelve weeks of aerobic training with metformin or placebo, metformin blunted the improvement in whole-body insulin sensitivity and suppressed the expected gain in skeletal muscle mitochondrial respiration (Konopka et al., Aging Cell, 2019). A companion trial in resistance training found that metformin attenuated muscle hypertrophy in older adults (Walton et al., Aging Cell, 2019).

The mechanism follows directly from the drug’s action. Adaptation to training depends on a stimulus the muscle cell registers as energy stress, and on mTORC1 activation to build new contractile protein. Metformin damps both signals, so the adaptation they produce is damped with them. The pathway effect that makes metformin a longevity candidate is the same one that blunts the training response.

Exercise has considerably stronger evidence for extending healthy life than metformin has. A drug that interferes with it is held to a correspondingly high standard.

For people with type 2 diabetes or prediabetes, metformin is an established, evidence-based treatment, and the reasoning that follows does not apply to them.

For a healthy adult taking it purely to slow ageing, the current evidence does not support the practice. The observational survival advantage has been contradicted by a study designed to test it. The randomised cardiovascular data are null. The animal meta-analysis places metformin behind both dietary restriction and rapamycin. A replicated trade-off against exercise adaptation has also been demonstrated, and exercise is the single intervention with the best evidence for healthy ageing.

Practical considerations apply as well. Long-term metformin use is associated with vitamin B12 deficiency, which was observed in the Diabetes Prevention Program Outcomes Study (Aroda et al., Journal of Clinical Endocrinology and Metabolism, 2016). Metformin reduces the calcium-dependent absorption of the vitamin B12 and intrinsic factor complex in the terminal ileum, which is why deficiency develops over years rather than months, and why periodic measurement can be appropriate in long-term users. Gastrointestinal side effects are common in the first weeks of treatment.

For anyone seeking to influence the same pathways, the interventions with the strongest evidence are inexpensive and widely available, namely sustained aerobic and resistance training, adequate dietary protein, sufficient sleep, and reduction of visceral fat. These act on AMPK and mTOR as well, and they carry no trade-off against training.

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