Metformin
Antidiabetic biguanide; activates AMPK (ZHO2001) and inhibits mTORC1. How much of its action actually runs through AMPK is disputed: metformin still suppresses hepatic gluconeogenesis in AMPK-null and LKB1-null mouse liver (FOR2010) and still inhibits mTORC1 in AMPK-null cells, via the Rag GTPases (KAL2010). Frequently discussed as a geroprotector alongside rapamycin.
A diabetes drug that quietens mTORC1 indirectly.
Complex I inhibition→AMPK, AMPK-independent Rag inhibition, lysosomal PEN2–ATP6AP1 sensing and gut-microbiome effects have all been proposed; clinical doses may not reach the concentrations used in vitro.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| M | Molecular — cells, biochemistry, structure | 2 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2014 | H | Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls BAN2014 Diabetic patients started on metformin had longer median survival than matched non-diabetic controls without the drug. Retrospective and observational: consistent with a survival benefit, but confounding by indication and healthy-adherer effects cannot be excluded. |
| 2017 | M | Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex HOW2017 Pinned down HOW the diabetes drug metformin - a major longevity candidate - actually reaches mTOR. In the liver, metformin lowers cellular energy, and at low doses this shuts down mTORC1 specifically through AMPK and the TSC complex. Direct mechanistic bridge between a widely-used drug, energy sensing, and the mTOR pathway. |
| 2001 | M | Role of AMP-activated protein kinase in mechanism of metformin action ZHO2001 Metformin activates AMPK, suppressing hepatic gluconeogenesis and lipogenesis. |