Selected publication milestones, not an exhaustive history or discovery priority claim.
2015 — 2015:12S-rRNA-region peptide candidate and controlled mouse glucose/clamp/diet experiments; genomic origin and supplied-peptide function enter the model separately. Original PMID25738459.
2018 — 2018:stress-induced nuclear localization and AMPK-dependent transcription in cells; cellular retrograde signaling is distinguished from human treatment. Original PMID29983246.
2019 — 2019:human intralipid/insulin and training responses expose context-dependent circulating-marker regulation rather than peptide administration. Original PMID31066084.
2020 — 2020:aging men show opposite plasma/muscle directions, challenging a simple systemic deficiency account. Original PMID32182209.
2021 — 2021:late-life male-mouse grip/gait/walking benefit alongside human exercise-induced marker change; overall survival extension remains nonsignificant. Original PMID33473109.
2021 — 2021:WT/K14Q sequence contrasts and Japanese-ancestry genotype associations map sex/activity dependence rather than universal genotype causality. Original PMID33468709.
2024 — 2024:CK2 binding, inhibitor/ASO necessity and tissue-dependent responses strengthen targeted pharmacology; human genotype components retain overlap limitations. Original PMID39559755.
2024 — 2024:older Korean male K14Q carriers show higher muscle/strength, requiring prospective population/context reconciliation. Original PMID39457696.
2026 — 2026:mouse PGC1alpha/AMPK-dependent mitochondrial effects and human no-gradient exercise measurement sharpen target and source questions. Original PMID41520850.
2026 — 2026:AMPK activation can accompany worseMSCrepair, while obesity/bariatric data (PMID41551324) show that peptide levels need not normalize with metabolic improvement. Original PMID42324588.
Native transcript export, cellular translation machinery and quantitative peptide identity need direct orthogonal tests.
No examined primary native-MOTS-c human administration study establishes metabolic function plus durable healthspan.
Physiological concentrations and synthetic pharmacologic dosing need a validated exposure bridge.
Late-life functional benefit and overall lifespan are different; natural-aging replication across backgrounds/species and sexes is incomplete.
K14Q cohort findings depend on sex, age and activity and can point in opposite directions across populations;12S-rRNA and mitochondrial linkage alternatives require selective tests.
Circulating peptide can rise with metabolic stress and remain elevated after improvement; tissue sources and renal handling are unresolved.
AMPK/mitochondrial marker activation can coexist with worse repair; functional and adverse outcomes must be prespecified.
Shared cohorts, peptide reagents and assay platforms require independent error-mode assessment rather than paper-count convergence.
First validate native human peptide identity, quantitative exposure and translation/export separately from synthetic material. Then preregister placebo-controlled native-MOTS-c dosing in a baseline-defined human metabolic/age cohort, with pharmacokinetics, tissue-specific engagement and prespecified glucose/physical-function endpoints plus durable clinical healthspan follow-up. Prospectively stratify sex/age/genotype and independently replicate; separately use a peptide-selective production perturbation preserving12S-rRNA function to test endogenous necessity with sequence-specific rescue.