{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "25738459",
      "year": "2015",
      "title": "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.",
      "doi": "10.1016/j.cmet.2015.02.009",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25738459/",
      "interpretation": "2015:12S-rRNA-region peptide candidate and controlled mouse glucose/clamp/diet experiments; genomic origin and supplied-peptide function enter the model separately."
    },
    {
      "pmid": "29983246",
      "year": "2018",
      "title": "The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.",
      "doi": "10.1016/j.cmet.2018.06.008",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29983246/",
      "interpretation": "2018:stress-induced nuclear localization and AMPK-dependent transcription in cells; cellular retrograde signaling is distinguished from human treatment."
    },
    {
      "pmid": "31066084",
      "year": "2019",
      "title": "Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects.",
      "doi": "10.1111/cen.14007",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31066084/",
      "interpretation": "2019:human intralipid/insulin and training responses expose context-dependent circulating-marker regulation rather than peptide administration."
    },
    {
      "pmid": "32182209",
      "year": "2020",
      "title": "Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition.",
      "doi": "10.18632/aging.102944",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32182209/",
      "interpretation": "2020:aging men show opposite plasma/muscle directions, challenging a simple systemic deficiency account."
    },
    {
      "pmid": "33473109",
      "year": "2021",
      "title": "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.",
      "doi": "10.1038/s41467-020-20790-0",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33473109/",
      "interpretation": "2021:late-life male-mouse grip/gait/walking benefit alongside human exercise-induced marker change; overall survival extension remains nonsignificant."
    },
    {
      "pmid": "33468709",
      "year": "2021",
      "title": "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.",
      "doi": "10.18632/aging.202529",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33468709/",
      "interpretation": "2021:WT/K14Q sequence contrasts and Japanese-ancestry genotype associations map sex/activity dependence rather than universal genotype causality."
    },
    {
      "pmid": "39559755",
      "year": "2024",
      "title": "MOTS-c modulates skeletal muscle function by directly binding and activating CK2.",
      "doi": "10.1016/j.isci.2024.111212",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39559755/",
      "interpretation": "2024:CK2 binding, inhibitor/ASO necessity and tissue-dependent responses strengthen targeted pharmacology; human genotype components retain overlap limitations."
    },
    {
      "pmid": "39457696",
      "year": "2024",
      "title": "The Relationship Between MOTS-c K14Q Polymorphism and Sarcopenia, Blood Lipids, and Mental Health in Older Korean Adults.",
      "doi": "10.3390/biomedicines12102384",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39457696/",
      "interpretation": "2024:older Korean male K14Q carriers show higher muscle/strength, requiring prospective population/context reconciliation."
    },
    {
      "pmid": "41520850",
      "year": "2026",
      "title": "MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.",
      "doi": "10.1016/j.freeradbiomed.2026.01.002",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41520850/",
      "interpretation": "2026:mouse PGC1alpha/AMPK-dependent mitochondrial effects and human no-gradient exercise measurement sharpen target and source questions."
    },
    {
      "pmid": "42324588",
      "year": "2026",
      "title": "Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells.",
      "doi": "10.1186/s41232-026-00431-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42324588/",
      "interpretation": "2026:AMPK activation can accompany worseMSCrepair, while obesity/bariatric data (PMID41551324) show that peptide levels need not normalize with metabolic improvement."
    }
  ],
  "gaps": [
    "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."
  ],
  "decisive_experiment": "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."
}