MOTS-c

The foundational paper is Lee et al. 2015 in Cell Metabolism, from the Pinchas Cohen laboratory at USC. In mouse studies, exogenous MOTS-c administration prevented both age-dependent and high-fat-diet-induced insulin resistance, improved glucose tolerance, lowered circulating insulin levels, and enhanced skeletal-muscle glucose uptake — through the folate-AICAR-AMPK pathway characterized in the same paper. The Lee 2015 work is the basis for nearly every subsequent claim about MOTS-c's metabolic and longevity activity, and it opened the modern field of mitochondrial-derived peptide signaling as a class.

The clinical observational arm developed from there. Du et al. 2018 in Pediatric Diabetes measured circulating MOTS-c in 97 Chinese children and adolescents and found significantly lower levels in obese males with an inverse correlation to HOMA-IR, fasting insulin, and waist circumference — the first paediatric demonstration of the biomarker direction predicted by Lee 2015 and consistent with the loss-of-tonic-signaling hypothesis (lower endogenous MOTS-c tracks with the obesity-and-insulin-resistance phenotype). The exercise and aging axis was filled in by D'Souza et al. 2020 in Aging — 104 healthy men across three age strata showed plasma MOTS-c declining 21% from young to elderly cohorts, but skeletal-muscle MOTS-c expression moving in the opposite direction (roughly 1.5-fold higher in older men) and tracking slow-fibre composition. Reynolds et al. 2021 in Nature Communications then integrated human physiology with mouse pharmacology: acute exercise raised skeletal-muscle MOTS-c expression approximately 12-fold and circulating MOTS-c by ~50% in human volunteers, and exogenous MOTS-c roughly doubled treadmill running capacity in young, middle-aged, and old mice. MOTS-c levels rise with exercise; the peptide functions as part of an exercise-mimetic signaling network rather than as an isolated hormone.

The most recent extension is Peng et al. 2026 in Biomedicines — 72 acute myocardial infarction patients undergoing PCI, with postoperative peripheral serum MOTS-c significantly lower in the 34 patients who developed myocardial ischemia-reperfusion injury versus the 38 who did not (adjusted OR 0.986, 95% CI 0.976-0.996). This is the first human clinical-cohort biomarker data linking endogenous MOTS-c to a discrete acute cardiac outcome, and it converges with the preclinical cardioprotection signal that has been building in the broader mitochondrial-derived-peptide literature. The Mendias and Awan 2026 Sports Medicine review then places MOTS-c explicitly within the unapproved gray-market peptide channel that clinicians are now being asked to discuss with patients.

The honest framing: every controlled study in the corpus is preclinical or observational. No human RCT of exogenous MOTS-c dosing exists for any indication. The biohacker case rests on rodent mechanism (Lee 2015, Reynolds 2021) plus observational human biomarker data (Du 2018, D'Souza 2020, Peng 2026) — not on clinical outcome data. The endogenous-decline-with-age plasma pattern and the exercise-induction finding are the most translationally interesting observations in the literature, but the leap from "endogenous MOTS-c tracks with X" to "exogenous MOTS-c improves X in humans" has not been tested. The mitochondrial peptides dossier walks the broader MDP class context alongside SS-31 and the emerging humanin and SHLP literature.