Angiotensin (1-7) vs MOTS-c

Binds Mas receptor (MasR), activating nitric oxide synthase and reducing oxidative stress. Opposes TGF-β and angiotensin II signaling to reduce fibrosis. Enhances insulin sensitivity and provides cardiovascular protection.

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone generated primarily through cleavage of angiotensin II by ACE2, functioning as a counter-regulatory arm of the renin-angiotensin system (RAS) by binding the Mas receptor to promote vasodilation, anti-fibrotic, anti-inflammatory, and cardioprotective effects that oppose the vasoconstrictive actions of angiotensin II. Ang-(1-7) acts through the ACE2/Mas receptor axis to reduce oxidative stress, attenuate NF-kB-mediated inflammation, and suppress TGF-beta fibrosis signaling; the ACE2/Ang-(1-7)/Mas axis has emerged as a key regulatory pathway in cardiovascular and metabolic disease, and gained renewed research attention given ACE2's role as the SARS-CoV-2 entry receptor. A Phase 1-2 randomized clinical trial of Ang-(1-7) infusion in COVID-19 ICU patients reported preliminary safety, tolerability, and dose-response data, providing the primary indexed human pharmacokinetic evidence; broader cardiovascular protective applications are supported by preclinical data but have not been established by completed Phase 3 trials. Ang-(1-7) has no FDA approval and no approved therapeutic indication in any jurisdiction; it is an endogenous peptide under active clinical investigation as a candidate for cardiovascular, metabolic, and inflammatory conditions, with emerging human safety data but an incomplete evidence base for any specific approved clinical use.

Mitochondria-derived peptide that translocates to nucleus under stress; activates AMPK pathway, regulates AICAR and folate-methionine cycle

MOTS-c (mitochondrial ORF of the 12S rRNA type-c) is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded within the 12S ribosomal RNA gene of the mitochondrial genome, secreted from mitochondria into the cytoplasm and circulation in response to metabolic stress and exercise, where it functions as a hormonal signal regulating nuclear gene expression to promote metabolic homeostasis and insulin sensitivity. MOTS-c translocates from mitochondria to the nucleus under metabolic stress conditions, where it activates AMPK-dependent pathways that increase glucose uptake in skeletal muscle and adipose tissue, reduce lipid accumulation, and modulate one-carbon metabolism through the AICAR-AMPK-folate cycle — effects that parallel some metabolic actions of physical exercise and metformin. Foundational research published in Cell Metabolism characterized MOTS-c as a mitochondrially encoded metabolic hormone that promotes metabolic homeostasis, reduces obesity, and improves insulin resistance in preclinical models, and subsequent work has analyzed its broad metabolic regulatory role and clinical potential as an insulin-sensitizing agent. MOTS-c is a research compound with no regulatory approval in any jurisdiction; while circulating MOTS-c levels in humans have been characterized and decline with age, no clinical trials have established safety or efficacy for exogenous MOTS-c administration. MOTS-c dosage protocol: No human clinical trial has established a reference dosing protocol for exogenous MOTS-c administration. Animal research protocols examining MOTS-c metabolic effects have used subcutaneous injection as the primary delivery route, with doses determined by body weight in rodent models. Human circulating MOTS-c levels have been measured in exercise and aging studies — endogenous levels decline with age and rise transiently with aerobic exercise — but these observations do not establish a target dose for supplemental administration. Research interest focuses on MOTS-c as a potential exercise mimetic and insulin sensitizer, with investigation of dosing frequency and timing relative to metabolic challenge or fasted states. MOTS-c is a research compound; there are no approved human dosing guidelines for any indication.