MOTS-c

Encoded by a short stretch of mitochondrial DNA (the 12S rRNA gene) and discovered in 2015. It is a natural peptide with no non-natural modifications.

In the discovery work it mainly targeted skeletal muscle, inhibiting the folate cycle and linked purine synthesis, which activated AMPK, a cellular energy-sensing switch. Under metabolic stress it moves into the cell nucleus and affects stress-response genes; effects on NRF2 and Akt signaling are also reported. How it enters cells is not known.

Mouse studies report that MOTS-c prevented diet-induced obesity and insulin resistance and improved running and grip performance in young and old mice. In people it has only been measured: blood and muscle levels rise after exercise, and studies of levels in obesity give mixed results with unstandardized assays. A modified analog, CB4211, had a small phase 1 program in which liver enzymes and glucose fell modestly over four weeks, but liver fat fell about equally on placebo. Human pharmacokinetics, half-life and long-term safety are unknown.

There are no human safety data for MOTS-c itself. With the CB4211 analog, injection-site reactions occurred in 79% of participants versus 33% on placebo, and the study was paused once because the analog persisted at the administration site; no serious events were reported. FDA lists immunogenicity risk and missing human exposure data.

Not FDA-approved. FDA removed it from Category 2 in April 2026, and in July 2026 its Pharmacy Compounding Advisory Committee voted 7–5–2 to recommend adding it to the 503A bulks list; the vote is advisory, FDA had issued no final rule as of October 2026, and it concerns pharmacy compounding for patients, not research-grade material. WADA prohibits it at all times under S4 (AMPK activators).