{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "MOTS-c as a Metabolic Healthspan Peptide", "entry_form": "claim", "gradeable_restatement": "MOTS-c is a mitochondrial-derived peptide that improves human metabolic function and healthspan.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, developmental window, exposure, baseline disease and measurement fixed before outcomes", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "MOTS-c as a Metabolic Healthspan Peptide", "central_claim": "MOTS-c is a mitochondrial-derived peptide that improves human metabolic function and healthspan.", "proposed_mechanism": "MOTS-c is a mitochondrial-derived peptide that improves human metabolic function and healthspan.", "claimed_scope": "Humans receiving native MOTS-c for metabolic function and durable healthspan; peptide identity, mammalian model pharmacology and human marker associations are adjudicated separately", "claimed_level": [ "initiation", "maintenance", "progression" ], "is_conjunctive": true, "conjunctive_note": "SC3 is the causal claim at the registered human/disease or endogenous scope; narrower physiology, model interventions and associations are reported separately. Primary-subclaim aggregation is fixed before new grading." }, "rubric_routing": { "primary_rubric": "06-metabolism-aging.md", "secondary_rubrics": [], "index_notes_applied": [ "SC3 is the causal claim at the registered human/disease or endogenous scope; narrower physiology, model interventions and associations are reported separately. Primary-subclaim aggregation is fixed before new grading." ], "rubric_fit_note": "06 separates biomarker change, acute metabolism, functional healthspan and lifespan. SC1 is a molecular-existence/production branch whose cell-only or nonspecific-depletion inference remains Γ; it is not scored as an aging trajectory. For SC2, the registered metabolic-function branch is evaluated against controlled, reproducible organismal glucose/cardiac/muscle phenotypes rather than requiring every metabolic benefit to extend lifespan: this is an explicit phenotype adaptation of 06, not a silent threshold substitution. The aging-specific branch retains 06's single-species/strain and healthspan-versus-lifespan restrictions. SC3's human treatment plus healthspan conjunction uses the unadapted human scope and does not cross Δ. Coordinator retains this explicitly limited metabolic-function adaptation; it does not raise the natural-aging or human-healthspan branches." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "MOTS-c is an endogenous biologically active peptide encoded within the mitochondrial 12S rRNA region.", "subclaim_type": "existence", "scope": "Sequence, translation compartment and assay specificity distinguished from peptide administration", "claimed_scope": "Sequence, translation compartment and assay specificity distinguished from peptide administration", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Orthogonal identity/production assays and genotype contrasts", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The 12S-rRNA-region sequence, rho0/actinonin depletion and immunodetection support mitochondrial genomic origin and a bioactive peptide. Synthetic sequence-specific activity and stress localization are reproducible in selected systems. Native production, transcript export, translation machinery and quantitative assay specificity are not selectively resolved by broad mitochondrial depletion or by activity of administered peptide. Γ records partial endogenous molecular support, not denial that the reported sequence or synthetic peptide exists." }, { "id": "SC2", "statement": "MOTS-c manipulation improves metabolic or functional aging outcomes in mammalian models.", "subclaim_type": "mechanism", "scope": "Species, endogenous versus administered peptide, dose, sex and age predefined", "claimed_scope": "Species, endogenous versus administered peptide, dose, sex and age predefined", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Physiological perturbation or controlled peptide intervention with functional endpoints", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Controlled peptide administration changes glucose handling, induced cardiac dysfunction, muscle atrophy and late-life physical capacity in defined rodent settings. Metabolic outcomes span CD1 and C57BL6 backgrounds and rat models, with mapped sex, variant, tissue and cell-context boundaries. Ε applies to context-specific mammalian metabolic/functional pharmacology under the explicitly declared phenotype adaptation. The aging-specific branch is narrower: late-life physical-function evidence remains principally male C57BL6/N, and overall lifespan is not significantly extended. This does not establish generalized mammalian aging delay or endogenous peptide necessity." }, { "id": "SC3", "statement": "Administering MOTS-c improves human metabolic function and healthspan.", "subclaim_type": "generalization", "scope": "Humans with intervention and clinical/metabolic functional outcomes specified", "claimed_scope": "Humans with intervention and clinical/metabolic functional outcomes specified", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Controlled human treatment and durable healthspan outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The registered human administration-and-healthspan claim has mechanistic and preclinical support, but no examined original report administers native MOTS-c to humans and demonstrates durable clinical metabolic function plus healthspan. Human exercise, heat, metformin, lipid/insulin infusion and bariatric surgery manipulate other exposures; peptide associations or marker changes cannot supply peptide treatment causality. Genotype evidence is sex/activity/age dependent and not a clean intervention instrument. Overall Γ follows this registered SC3 gate." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "SC3 is the causal claim at the registered human/disease or endogenous scope; narrower physiology, model interventions and associations are reported separately. Primary-subclaim aggregation is fixed before new grading.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Overall Γ follows preregistered primary human-administered SC3. Partial native molecular SC1 is Γ and explicitly scoped rodent metabolic/functional pharmacology SC2 is Ε under a declared phenotype adaptation. Controlled model benefit is retained; neither endogenous exercise-marker induction, K14Q population association nor an analogue program supplies native human healthspan causality.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered full-scope gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Context-dependent exogenous peptide pharmacology", "core_claim": "Supplied MOTS-c can change defined glucose, muscle and cardiac phenotypes through multiple tissue-dependent pathways.", "explains_what_nominal_does_not": "Supplied MOTS-c can change defined glucose, muscle and cardiac phenotypes through multiple tissue-dependent pathways.", "strongest_supporting_evidence": [ "Controlled rodent glucose/atrophy/cardio-function experiments, WT/K14Q contrasts and CK2-dependent uptake support restricted causal effects." ], "strongest_contradictory_evidence": [ "Native physiological dose and necessity are incompletely isolated; female and cell-repair boundaries prevent a universal protective interpretation." ], "hsef_level_for_this_model": "Ε", "rationale": "Controlled rodent glucose/atrophy/cardio-function experiments, WT/K14Q contrasts and CK2-dependent uptake support restricted causal effects. Native physiological dose and necessity are incompletely isolated; female and cell-repair boundaries prevent a universal protective interpretation." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Adaptive endogenous stress signal", "core_claim": "Endogenous peptide measurements change with exercise, lipid load, tissue composition and illness as part of a context-dependent stress response.", "explains_what_nominal_does_not": "Endogenous peptide measurements change with exercise, lipid load, tissue composition and illness as part of a context-dependent stress response.", "strongest_supporting_evidence": [ "Human exercise and lipid/insulin experiments, compartment differences with age and obesity/higher-risk cohorts favor regulated responses rather than a universal deficiency." ], "strongest_contradictory_evidence": [ "Human source/export/translation and mediator necessity remain incomplete; marker responses cannot explain all synthetic pharmacology." ], "hsef_level_for_this_model": "Γ", "rationale": "Human exercise and lipid/insulin experiments, compartment differences with age and obesity/higher-risk cohorts favor regulated responses rather than a universal deficiency. Human source/export/translation and mediator necessity remain incomplete; marker responses cannot explain all synthetic pharmacology." }, { "rank_in_tournament": 3, "model_id": "M1", "is_nominal": true, "name": "Native human MOTS-c healthspan intervention", "core_claim": "Administering native MOTS-c improves human metabolism and durable healthspan.", "explains_what_nominal_does_not": "Administering native MOTS-c improves human metabolism and durable healthspan.", "strongest_supporting_evidence": [ "Mouse late-life physical benefits, metabolic experiments and cellular target evidence provide its strongest translational rationale." ], "strongest_contradictory_evidence": [ "No examined original human native-peptide efficacy/healthspan trial and heterogeneous marker/genotype results prevent the registered causal crossing." ], "hsef_level_for_this_model": "Γ", "rationale": "Mouse late-life physical benefits, metabolic experiments and cellular target evidence provide its strongest translational rationale. No examined original human native-peptide efficacy/healthspan trial and heterogeneous marker/genotype results prevent the registered causal crossing." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Assay and mitochondrial-genotype confounding", "core_claim": "Part of the apparent systemic peptide signal or genotype-risk attribution reflects immunoassay, tissue/renal handling or linked mitochondrial biology.", "explains_what_nominal_does_not": "Part of the apparent systemic peptide signal or genotype-risk attribution reflects immunoassay, tissue/renal handling or linked mitochondrial biology.", "strongest_supporting_evidence": [ "Large between-study concentration differences, acknowledged nonspecific bands, compartment discordance and opposing K14Q associations make this a testable alternative." ], "strongest_contradictory_evidence": [ "This is not proof that all endogenous signal is artefact; antibody-independent SPR and sequence-specific animal effects retain synthetic peptide biology." ], "hsef_level_for_this_model": "Γ", "rationale": "Large between-study concentration differences, acknowledged nonspecific bands, compartment discordance and opposing K14Q associations make this a testable alternative. This is not proof that all endogenous signal is artefact; antibody-independent SPR and sequence-specific animal effects retain synthetic peptide biology." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. The WT/K14Q and CK2-inhibitor/ASO contrasts (PMID39559755), glucose-clamp/diet controls (PMID25738459), female nulls (PMID33468709), and the AMPK-positive but repair-negative human-MSC/mouse transplant experiment (PMID42324588) favor context-specific pharmacology over a universal protective signal. Human trans-organ exercise measurements (PMID41520850) constrain a simple muscle-derived endocrine account.", "study_separating_rank1_from_rank2": "The WT/K14Q and CK2-inhibitor/ASO contrasts (PMID39559755), glucose-clamp/diet controls (PMID25738459), female nulls (PMID33468709), and the AMPK-positive but repair-negative human-MSC/mouse transplant experiment (PMID42324588) favor context-specific pharmacology over a universal protective signal. Human trans-organ exercise measurements (PMID41520850) constrain a simple muscle-derived endocrine account.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "25738459", "title": "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.", "citation": "Lee C, Zeng J, Drew BG et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell metabolism. 2015.", "doi": "10.1016/j.cmet.2015.02.009", "pmcid": "PMC4350682", "url": "https://pubmed.ncbi.nlm.nih.gov/25738459/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25738459/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25738459", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A 12S-rRNA sORF, mitochondrial depletion assays and immunodetection support MOTS-c identity; administered peptide improves mouse insulin sensitivity and diet-induced obesity.", "what_it_does_not_show": "Cytoplasmic translation is inferred from genetic code; broad mitochondrial depletion and immunoassays are not selective endogenous peptide knockout or human dosing.", "confounders_present": [ "Cytoplasmic translation is inferred from genetic code; broad mitochondrial depletion and immunoassays are not selective endogenous peptide knockout or human dosing." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 2, "pmid": "33473109", "title": "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.", "citation": "Reynolds JC, Lai RW, Woodhead JST et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature communications. 2021.", "doi": "10.1038/s41467-020-20790-0", "pmcid": "PMC7817689", "url": "https://pubmed.ncbi.nlm.nih.gov/33473109/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33473109/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33473109", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Synthetic MOTS-c improves mouse exercise capacity and late-life grip, gait and walking; human exercise raises measured endogenous peptide.", "what_it_does_not_show": "Overall lifespan curve is not significant (P=0.23); human experiment is exercise, not peptide administration, and old-age functional benefit is male C57BL6/N specific.", "confounders_present": [ "Overall lifespan curve is not significant (P=0.23); human experiment is exercise, not peptide administration, and old-age functional benefit is male C57BL6/N specific." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Related mitochondrial-peptide discovery laboratory, assays and synthetic administration program to PMID25738459." ] }, { "n": 3, "pmid": "29983246", "title": "The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.", "citation": "Kim KH, Son JM, Benayoun BA et al. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell metabolism. 2018.", "doi": "10.1016/j.cmet.2018.06.008", "pmcid": "PMC6185997", "url": "https://pubmed.ncbi.nlm.nih.gov/29983246/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29983246/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29983246", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Metabolic stress induces measured MOTS-c nuclear translocation and AMPK-dependent stress-response transcription in cells.", "what_it_does_not_show": "Cell localization and transcription do not establish organismal aging benefit, translation compartment or human treatment efficacy.", "confounders_present": [ "Cell localization and transcription do not establish organismal aging benefit, translation compartment or human treatment efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 4, "pmid": "33468709", "title": "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.", "citation": "Zempo H, Kim SJ, Fuku N et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging. 2021.", "doi": "10.18632/aging.202529", "pmcid": "PMC7880332", "url": "https://pubmed.ncbi.nlm.nih.gov/33468709/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33468709/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MOTS_K14Q_JMICC_MEC_TMM", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph6, 1:RESULTS:paragraph11, 1:RESULTS:paragraph14. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Wild-type and K14Q peptides differ in insulin sensitization; three Japanese-ancestry cohorts link m.1382A>C with T2D in males and activity-dependent subgroups.", "what_it_does_not_show": "Female mouse peptide effects are null; rRNA and linked haplogroup biology are not eliminated by structural predictions, and cohort association is not human administration.", "confounders_present": [ "Female mouse peptide effects are null; rRNA and linked haplogroup biology are not eliminated by structural predictions, and cohort association is not human administration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Japanese J-MICC genotype/physical-activity resource overlaps the research program in PMID39559755." ] }, { "n": 5, "pmid": "34728329", "title": "The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance.", "citation": "Kumagai H, Natsume T, Kim SJ et al. The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance. Biochimica et biophysica acta. General subjects. 2022.", "doi": "10.1016/j.bbagen.2021.130048", "pmcid": "PMC8741734", "url": "https://pubmed.ncbi.nlm.nih.gov/34728329/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34728329/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34728329", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "K14Q carriers show more fast-fiber markers and greater young-male strength; antibody neutralization shifts mouse fiber markers.", "what_it_does_not_show": "Neutralizing antibody specificity and marker endpoint limit endogenous inference; sprint strength is not global healthspan or universally deleterious K14Q function.", "confounders_present": [ "Neutralizing antibody specificity and marker endpoint limit endogenous inference; sprint strength is not global healthspan or universally deleterious K14Q function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 6, "pmid": "39559755", "title": "MOTS-c modulates skeletal muscle function by directly binding and activating CK2.", "citation": "Kumagai H, Kim SJ, Miller B et al. MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience. 2024.", "doi": "10.1016/j.isci.2024.111212", "pmcid": "PMC11570452", "url": "https://pubmed.ncbi.nlm.nih.gov/39559755/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39559755/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MOTS_K14Q_CK2_WITH_JMICC_COMPONENT", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph15, 1:Results:paragraph33, 1:Results:paragraph42, 1:Results:paragraph54. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Synthetic MOTS-c binds CK2 by SPR; CK2 inhibition or cellular ASO blocks glucose-uptake effects, and K14Q fails tested mouse atrophy protection.", "what_it_does_not_show": "CK2 responses differ between muscle and fat; an acknowledged nonspecific immunoblot band and overlapping human cohorts limit native identity and independent clinical inference.", "confounders_present": [ "CK2 responses differ between muscle and fat; an acknowledged nonspecific immunoblot band and overlapping human cohorts limit native identity and independent clinical inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Japanese genotype/physical-activity cohorts may overlap PMID33468709; synthetic peptide/antibody resources shared with other program reports." ] }, { "n": 7, "pmid": "41520850", "title": "MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.", "citation": "Gudiksen A, Hansen CC, van der Stede T et al. MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner. Free radical biology & medicine. 2026.", "doi": "10.1016/j.freeradbiomed.2026.01.002", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41520850/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41520850/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41520850", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Mouse muscle PGC-1alpha and AMPK perturbations constrain peptide-induced mitochondrial bioenergetic changes; human interstitial levels increase during exercise.", "what_it_does_not_show": "No human arterio-venous gradient change was observed; mitochondrial metrics are not healthspan extension and human secretion-source inference remains uncertain.", "confounders_present": [ "No human arterio-venous gradient change was observed; mitochondrial metrics are not healthspan extension and human secretion-source inference remains uncertain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 8, "pmid": "38170165", "title": "Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration.", "citation": "Kumagai H, Kim SJ, Miller B et al. Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration. American journal of physiology. Endocrinology and metabolism. 2024.", "doi": "10.1152/ajpendo.00285.2023", "pmcid": "PMC11196098", "url": "https://pubmed.ncbi.nlm.nih.gov/38170165/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38170165/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38170165", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Eight-day MOTS-c treatment attenuates cast-induced muscle loss and lipid infiltration in young male C57BL6J mice.", "what_it_does_not_show": "Preventing induced atrophy at 15mg/kg/day is not natural aging reversal, long-term functional preservation or human efficacy.", "confounders_present": [ "Preventing induced atrophy at 15mg/kg/day is not natural aging reversal, long-term functional preservation or human efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 9, "pmid": "34320351", "title": "Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.", "citation": "Kong BS, Min SH, Lee C et al. Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes. Cell reports. 2021.", "doi": "10.1016/j.celrep.2021.109447", "pmcid": "PMC10083145", "url": "https://pubmed.ncbi.nlm.nih.gov/34320351/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34320351/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID34525370" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34320351", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c suppresses diabetes development in NOD mice and changes transferred T-cell diabetogenicity; human T1D cells respond ex vivo.", "what_it_does_not_show": "NOD/adoptive-transfer and ex-vivo results retain model scope; linked erratum PMID34525370 was identified but its details were not examined.", "confounders_present": [ "NOD/adoptive-transfer and ex-vivo results retain model scope; linked erratum PMID34525370 was identified but its details were not examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 10, "pmid": "34798268", "title": "The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus.", "citation": "Yin Y, Pan Y, He J et al. The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus. Pharmacological research. 2022.", "doi": "10.1016/j.phrs.2021.105987", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34798268/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34798268/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34798268", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Peptide treatment improves glucose tolerance and offspring outcomes in diet/STZ gestational-diabetes mice.", "what_it_does_not_show": "Induced gestational disease and STZ protection do not establish general human metabolic or adult-aging benefit.", "confounders_present": [ "Induced gestational disease and STZ protection do not establish general human metabolic or adult-aging benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 11, "pmid": "30725119", "title": "MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction.", "citation": "Lu H, Wei M, Zhai Y et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. Journal of molecular medicine (Berlin, Germany). 2019.", "doi": "10.1007/s00109-018-01738-w", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30725119/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30725119/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30725119", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c reduces ovariectomy-induced obesity and insulin resistance, with AMPK-linked adipose changes.", "what_it_does_not_show": "Surgical estrogen loss and inhibitor specificity restrict inference; no human postmenopausal treatment or aging trajectory tested.", "confounders_present": [ "Surgical estrogen loss and inhibitor specificity restrict inference; no human postmenopausal treatment or aging trajectory tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 12, "pmid": "27237975", "title": "Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation.", "citation": "Ming W, Lu G, Xin S et al. Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. Biochemical and biophysical research communications. 2016.", "doi": "10.1016/j.bbrc.2016.05.135", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27237975/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27237975/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27237975", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Twelve-week peptide treatment alleviates ovariectomy-induced bone loss and inhibits osteoclastogenesis with partial AMPK-inhibitor reversal.", "what_it_does_not_show": "Micro-CT and induced bone loss do not establish fracture reduction, native peptide necessity or human healthspan.", "confounders_present": [ "Micro-CT and induced bone loss do not establish fracture reduction, native peptide necessity or human healthspan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 13, "pmid": "31109005", "title": "Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation.", "citation": "Lu H, Tang S, Xue C et al. Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation. International journal of molecular sciences. 2019.", "doi": "10.3390/ijms20102456", "pmcid": "PMC6567243", "url": "https://pubmed.ncbi.nlm.nih.gov/31109005/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31109005/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31109005", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c improves cold tolerance and thermogenic responses with ERK-sensitive effects.", "what_it_does_not_show": "Cold adaptation is stress resistance, not aging extension; pathway inhibitor and metabolic effects do not establish a single native mediator.", "confounders_present": [ "Cold adaptation is stress resistance, not aging extension; pathway inhibitor and metabolic effects do not establish a single native mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 14, "pmid": "34635713", "title": "The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats.", "citation": "Yuan J, Wang M, Pan Y et al. The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats. Scientific reports. 2021.", "doi": "10.1038/s41598-021-99568-3", "pmcid": "PMC8505603", "url": "https://pubmed.ncbi.nlm.nih.gov/34635713/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34635713/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34635713", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c improves myocardial mechanical efficiency and systolic function during exercise training in rats.", "what_it_does_not_show": "Training adaptation is not durable aged-organism healthspan; the peptide need not mediate all exercise benefits.", "confounders_present": [ "Training adaptation is not durable aged-organism healthspan; the peptide need not mediate all exercise benefits." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 15, "pmid": "36490309", "title": "Circulating levels of MOTS-c in patients with breast cancer treated with metformin.", "citation": "Cuyàs E, Verdura S, Martin-Castillo B et al. Circulating levels of MOTS-c in patients with breast cancer treated with metformin. Aging. 2022.", "doi": "10.18632/aging.204423", "pmcid": "PMC10008497", "url": "https://pubmed.ncbi.nlm.nih.gov/36490309/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36490309/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "METFORMIN_BREAST_CANCER_MOTS_SECONDARY", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Paired samples in a randomized breast-cancer regimen show no significant circulating MOTS-c response to added metformin over 24 weeks.", "what_it_does_not_show": "Patients received metformin/oncology therapy, not MOTS-c; commercial-ELISA null does not exclude local peptide changes.", "confounders_present": [ "Patients received metformin/oncology therapy, not MOTS-c; commercial-ELISA null does not exclude local peptide changes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 16, "pmid": "31066084", "title": "Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects.", "citation": "Ramanjaneya M, Jerobin J, Bettahi I et al. Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects. Clinical endocrinology. 2019.", "doi": "10.1111/cen.14007", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31066084/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31066084/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31066084", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Intralipid raises measured plasma MOTS-c and insulin blunts the response in controls/PCOS; eight-week exercise does not change circulating levels.", "what_it_does_not_show": "Lipids, insulin and exercise are the interventions; peptide movement cannot establish mediation or MOTS-c administration efficacy.", "confounders_present": [ "Lipids, insulin and exercise are the interventions; peptide movement cannot establish mediation or MOTS-c administration efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 17, "pmid": "41004666", "title": "MOTS-C levels ın ındividuals with and without obesity and ıts association with ınflammation, insulin resistance and endothelial dysfunction.", "citation": "Ozkaya DY, Haymana C, Demirci I et al. MOTS-C levels ın ındividuals with and without obesity and ıts association with ınflammation, insulin resistance and endothelial dysfunction. Archives of endocrinology and metabolism. 2025.", "doi": "10.20945/2359-4292-2025-0063", "pmcid": "PMC12468430", "url": "https://pubmed.ncbi.nlm.nih.gov/41004666/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41004666/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41004666", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Serum MOTS-c is similar in obese and normal-weight adults and correlates positively with HOMA-IR.", "what_it_does_not_show": "Cross-sectional ELISA and age/metabolic confounding do not prove deficiency or therapeutic benefit.", "confounders_present": [ "Cross-sectional ELISA and age/metabolic confounding do not prove deficiency or therapeutic benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 18, "pmid": "35370955", "title": "MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats.", "citation": "Li S, Wang M, Ma J et al. MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats. Frontiers in endocrinology. 2022.", "doi": "10.3389/fendo.2022.812032", "pmcid": "PMC8969227", "url": "https://pubmed.ncbi.nlm.nih.gov/35370955/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35370955/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35370955", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c or exercise improves cardiac structure/function in diet/STZ diabetic rats with NRG1-ErbB4 pathway associations.", "what_it_does_not_show": "Transcriptomic pathway enrichment is not selective mediator necessity; induced diabetes is not organismal longevity.", "confounders_present": [ "Transcriptomic pathway enrichment is not selective mediator necessity; induced diabetes is not organismal longevity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Related diabetic-rat/exercise cardiac laboratory/model program; exact sample reuse was not independently established." ] }, { "n": 19, "pmid": "39616938", "title": "MOTS-c regulates the ROS/TXNIP/NLRP3 pathway to alleviate diabetic cardiomyopathy.", "citation": "Fu Y, Tang M, Duan Y et al. MOTS-c regulates the ROS/TXNIP/NLRP3 pathway to alleviate diabetic cardiomyopathy. Biochemical and biophysical research communications. 2024.", "doi": "10.1016/j.bbrc.2024.151072", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39616938/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39616938/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39616938", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Eight-week MOTS-c treatment reduces ROS/TXNIP/NLRP3 inflammatory signals and myocardial injury in diabetic rats.", "what_it_does_not_show": "Redox and inflammatory changes alone do not prove durable cardiac function or aging trajectory; pathway mediation remains incompletely isolated.", "confounders_present": [ "Redox and inflammatory changes alone do not prove durable cardiac function or aging trajectory; pathway mediation remains incompletely isolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 20, "pmid": "31214116", "title": "Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects.", "citation": "Ramanjaneya M, Bettahi I, Jerobin J et al. Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects. Frontiers in endocrinology. 2019.", "doi": "10.3389/fendo.2019.00331", "pmcid": "PMC6554664", "url": "https://pubmed.ncbi.nlm.nih.gov/31214116/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31214116/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31214116", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Circulating MOTS-c is lower in adult T2D groups and associates with metabolic measurements.", "what_it_does_not_show": "Cross-sectional disease/medication and immunoassay effects cannot determine causal deficiency, despite causal language in the original conclusion.", "confounders_present": [ "Cross-sectional disease/medication and immunoassay effects cannot determine causal deficiency, despite causal language in the original conclusion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 21, "pmid": "29593067", "title": "Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals.", "citation": "Cataldo LR, Fernández-Verdejo R, Santos JL et al. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2018.", "doi": "10.1136/jim-2017-000681", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29593067/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29593067/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29593067", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Lean/obese adult peptide levels are similar and measured MOTS-c associates positively with insulin resistance chiefly in lean individuals.", "what_it_does_not_show": "Small groups and surrogate sensitivity indices do not establish that raising peptide improves human metabolism.", "confounders_present": [ "Small groups and surrogate sensitivity indices do not establish that raising peptide improves human metabolism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 22, "pmid": "32880686", "title": "Adiponectin treatment improves insulin resistance in mice by regulating the expression of the mitochondrial-derived peptide MOTS-c and its response to exercise via APPL1-SIRT1-PGC-1α.", "citation": "Guo Q, Chang B, Yu QL et al. Adiponectin treatment improves insulin resistance in mice by regulating the expression of the mitochondrial-derived peptide MOTS-c and its response to exercise via APPL1-SIRT1-PGC-1α. Diabetologia. 2020.", "doi": "10.1007/s00125-020-05269-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32880686/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32880686/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32880686", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Adiponectin, exercise and MOTS-c interventions regulate mouse peptide measurements through APPL1/SIRT1/PGC1alpha-linked experiments.", "what_it_does_not_show": "Multiple pleiotropic manipulations and ectopic constructs do not selectively establish endogenous peptide necessity or human healthspan.", "confounders_present": [ "Multiple pleiotropic manipulations and ectopic constructs do not selectively establish endogenous peptide necessity or human healthspan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 23, "pmid": "33722744", "title": "MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway.", "citation": "Yang B, Yu Q, Chang B et al. MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway. Biochimica et biophysica acta. Molecular basis of disease. 2021.", "doi": "10.1016/j.bbadis.2021.166126", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33722744/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33722744/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33722744", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "AMPK/PGC1alpha manipulations, exercise and administered peptide change MOTS-c and metabolic signaling in cells and high-fat-fed mice.", "what_it_does_not_show": "Expression loops, inhibitors and ectopic expression do not independently establish native peptide production or aging effects.", "confounders_present": [ "Expression loops, inhibitors and ectopic expression do not independently establish native peptide production or aging effects." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 24, "pmid": "34419510", "title": "Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes.", "citation": "Sequeira IR, Woodhead JST, Chan A et al. Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes. Biochimica et biophysica acta. General subjects. 2021.", "doi": "10.1016/j.bbagen.2021.129991", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34419510/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34419510/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34419510", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Circulating MOTS-c associates positively with metabolic syndrome and liver/android fat, also rising in a hepatic-injury mouse diet.", "what_it_does_not_show": "Higher measured peptide can accompany worse metabolic status; liver-stress compensation is plausible but observational rather than proven mediation.", "confounders_present": [ "Higher measured peptide can accompany worse metabolic status; liver-stress compensation is plausible but observational rather than proven mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Related metabolic peptide assay and physiology program; distinct cohort does not by itself establish an independent mechanism line." ] }, { "n": 25, "pmid": "39876762", "title": "MOTS-c Impact on Muscle Cell Differentiation and Metabolism Across Fiber Types.", "citation": "Leciejewska N, Pruszyńska-Oszmałek E, Kołodziejski P et al. MOTS-c Impact on Muscle Cell Differentiation and Metabolism Across Fiber Types. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2025.", "doi": "10.33594/000000755", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39876762/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39876762/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39876762", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "MOTS-c promotes C2C12 differentiation and reduces lipid accumulation but not equivalent L6 responses, where lipid accumulation increases.", "what_it_does_not_show": "Cell-line and fiber-type dependence constrain a universal anabolic/anti-lipid effect; no organismal endpoint.", "confounders_present": [ "Cell-line and fiber-type dependence constrain a universal anabolic/anti-lipid effect; no organismal endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 26, "pmid": "29691953", "title": "Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance.", "citation": "Du C, Zhang C, Wu W et al. Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. Pediatric diabetes. 2018.", "doi": "10.1111/pedi.12685", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29691953/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29691953/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29691953", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Measured peptide is reduced in obese male children and inversely associates with obesity/insulin-resistance markers.", "what_it_does_not_show": "Female comparison is null; pediatric cross-sectional findings do not generalize to adults or demonstrate treatment effects, and assay units vary greatly across reports.", "confounders_present": [ "Female comparison is null; pediatric cross-sectional findings do not generalize to adults or demonstrate treatment effects, and assay units vary greatly across reports." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 27, "pmid": "38636847", "title": "An 8-Week study on the effects of high and Moderate-Intensity interval exercises on mitochondrial MOTS-C changes and their relation to metabolic markers in male diabetic sand rats.", "citation": "Parseh S, Shakerian S, Reza Tabandeh M et al. An 8-Week study on the effects of high and Moderate-Intensity interval exercises on mitochondrial MOTS-C changes and their relation to metabolic markers in male diabetic sand rats. Diabetes research and clinical practice. 2024.", "doi": "10.1016/j.diabres.2024.111656", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38636847/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38636847/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38636847", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Exercise intensity alters measured MOTS-c and glucose-related proteins in diabetic rodents.", "what_it_does_not_show": "Exercise has many mediators and no selective peptide perturbation; original Wistar/sand-rat terminology is inconsistent and remains unresolved.", "confounders_present": [ "Exercise has many mediators and no selective peptide perturbation; original Wistar/sand-rat terminology is inconsistent and remains unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 28, "pmid": "37008907", "title": "The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats.", "citation": "Li C, Li N, Zhang Z et al. The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats. Frontiers in endocrinology. 2023.", "doi": "10.3389/fendo.2023.1127524", "pmcid": "PMC10061072", "url": "https://pubmed.ncbi.nlm.nih.gov/37008907/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37008907/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37008907", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Slow-twitch rat muscle retains glucose-transport/respiratory markers and expresses more UPRmt/MOTS-c during high-fat feeding.", "what_it_does_not_show": "Fiber-type association without selective MOTS-c perturbation cannot prove peptide mediation of insulin-resistance protection.", "confounders_present": [ "Fiber-type association without selective MOTS-c perturbation cannot prove peptide mediation of insulin-resistance protection." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 29, "pmid": "41945630", "title": "Are serum MOTS-c levels and MOTS-c m.1382A>C polymorphism related to polycystic ovary syndrome?", "citation": "Filibeli BE, Dedemoglu F, Garipçin P et al. Are serum MOTS-c levels and MOTS-c m.1382A>C polymorphism related to polycystic ovary syndrome? Archives of endocrinology and metabolism. 2026.", "doi": "10.20945/2359-4292-2026-0031", "pmcid": "PMC13055642", "url": "https://pubmed.ncbi.nlm.nih.gov/41945630/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41945630/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41945630", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Adolescent PCOS/control measured peptide and metabolic associations are nonsignificant; every participant carries wild-type m.1382A.", "what_it_does_not_show": "An all-wild-type cohort cannot test the effect of K14Q genotype; a null group comparison is not proof of no peptide biology.", "confounders_present": [ "An all-wild-type cohort cannot test the effect of K14Q genotype; a null group comparison is not proof of no peptide biology." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 30, "pmid": "29886458", "title": "Mitochondrial peptides modulate mitochondrial function during cellular senescence.", "citation": "Kim SJ, Mehta HH, Wan J et al. Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging. 2018.", "doi": "10.18632/aging.101463", "pmcid": "PMC6046248", "url": "https://pubmed.ncbi.nlm.nih.gov/29886458/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29886458/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29886458", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Senescent fibroblasts express more MOTS-c and peptide administration modestly increases respiration and selected SASP components.", "what_it_does_not_show": "Senescence induction and mitochondrial/SASP changes do not establish anti-aging efficacy; selected secretory effects increase rather than uniformly decrease.", "confounders_present": [ "Senescence induction and mitochondrial/SASP changes do not establish anti-aging efficacy; selected secretory effects increase rather than uniformly decrease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 31, "pmid": "40674654", "title": "Repeated Heat Stress Modulates the Levels of the Mitokines MOTS-C and FGF21 in Active Men during Calf Muscle Immobilization.", "citation": "Elhusseiny R, Ihsan M, Labidi M et al. Repeated Heat Stress Modulates the Levels of the Mitokines MOTS-C and FGF21 in Active Men during Calf Muscle Immobilization. Medicine and science in sports and exercise. 2025.", "doi": "10.1249/MSS.0000000000003825", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40674654/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40674654/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40674654", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized heat/sham exposure during immobilization alters circulating MOTS-c in 19 active men.", "what_it_does_not_show": "Heat is the intervention; marker movement does not show peptide mediation or native MOTS-c dosing prevents human muscle loss.", "confounders_present": [ "Heat is the intervention; marker movement does not show peptide mediation or native MOTS-c dosing prevents human muscle loss." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 32, "pmid": "34413391", "title": "Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors.", "citation": "Dieli-Conwright CM, Sami N, Norris MK et al. Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors. Scientific reports. 2021.", "doi": "10.1038/s41598-021-96419-z", "pmcid": "PMC8376922", "url": "https://pubmed.ncbi.nlm.nih.gov/34413391/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34413391/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "BCS_EXERCISE_NCT01140282", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "A secondary analysis of an exercise RCT finds increased peptide in non-Hispanic White but not Hispanic breast-cancer survivors.", "what_it_does_not_show": "Ethnicity groups differ at baseline and are small; exercise randomization is not peptide randomization or universal responder prediction.", "confounders_present": [ "Ethnicity groups differ at baseline and are small; exercise randomization is not peptide randomization or universal responder prediction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 33, "pmid": "36156853", "title": "Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice.", "citation": "Zhong P, Peng J, Hu Y et al. Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice. Journal of cellular and molecular medicine. 2022.", "doi": "10.1111/jcmm.17551", "pmcid": "PMC9639045", "url": "https://pubmed.ncbi.nlm.nih.gov/36156853/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36156853/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36156853", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Pump-delivered MOTS-c attenuates pressure-overload cardiac dysfunction/remodeling in mice.", "what_it_does_not_show": "TAC-induced failure and cell overexpression do not establish aging extension or native human cardiac necessity.", "confounders_present": [ "TAC-induced failure and cell overexpression do not establish aging extension or native human cardiac necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 34, "pmid": "38141139", "title": "MOTS-c Peptide Attenuated Diabetic Cardiomyopathy in STZ-Induced Type 1 Diabetic Mouse Model.", "citation": "Wu N, Shen C, Wang J et al. MOTS-c Peptide Attenuated Diabetic Cardiomyopathy in STZ-Induced Type 1 Diabetic Mouse Model. Cardiovascular drugs and therapy. 2025.", "doi": "10.1007/s10557-023-07540-2", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38141139/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38141139/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38141139", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c after STZ-diabetes establishment ameliorates mouse cardiac function and remodeling over 12 weeks.", "what_it_does_not_show": "Post-disease treatment supports restricted pharmacology, not lifetime healthspan or human clinical benefit.", "confounders_present": [ "Post-disease treatment supports restricted pharmacology, not lifetime healthspan or human clinical benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 35, "pmid": "40661667", "title": "Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart.", "citation": "Pham T, Taberner A, Hickey A et al. Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart. Frontiers in physiology. 2025.", "doi": "10.3389/fphys.2025.1602271", "pmcid": "PMC12257629", "url": "https://pubmed.ncbi.nlm.nih.gov/40661667/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40661667/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40661667", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c improves glucose homeostasis and reduces cardiac hypertrophy in diabetic rats while changing mitochondrial respiration.", "what_it_does_not_show": "Mitochondrial ROS rises in treated tissue; improved bioenergetics does not establish global antioxidant action or lifespan extension.", "confounders_present": [ "Mitochondrial ROS rises in treated tissue; improved bioenergetics does not establish global antioxidant action or lifespan extension." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 36, "pmid": "31432706", "title": "Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease.", "citation": "Liu C, Gidlund EK, Witasp A et al. Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease. American journal of physiology. Renal physiology. 2019.", "doi": "10.1152/ajprenal.00202.2019", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31432706/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31432706/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31432706", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Advanced-CKD patients show reduced muscle/serum MOTS-c alongside lower mitochondrial density and oxidative stress.", "what_it_does_not_show": "Disease severity, renal handling and muscle composition confound direction; humanin and MOTS-c show different compartment patterns.", "confounders_present": [ "Disease severity, renal handling and muscle composition confound direction; humanin and MOTS-c show different compartment patterns." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 37, "pmid": "38430258", "title": "MOTS-c regulates pancreatic alpha and beta cell functions in vitro.", "citation": "Bień J, Pruszyńska-Oszmałek E, Kołodziejski P et al. MOTS-c regulates pancreatic alpha and beta cell functions in vitro. Histochemistry and cell biology. 2024.", "doi": "10.1007/s00418-024-02274-0", "pmcid": "PMC11162381", "url": "https://pubmed.ncbi.nlm.nih.gov/38430258/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38430258/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38430258", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Peptide lowers insulin secretion/expression and increases glucagon in pancreatic cell lines with altered survival/secretion.", "what_it_does_not_show": "Cell lines do not establish systemic glycemic benefit; direction differs from a simple universal insulin-enhancing mechanism.", "confounders_present": [ "Cell lines do not establish systemic glycemic benefit; direction differs from a simple universal insulin-enhancing mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 38, "pmid": "40855115", "title": "Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes.", "citation": "Kong BS, Lee H, L'Yi S et al. Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes. Experimental & molecular medicine. 2025.", "doi": "10.1038/s12276-025-01521-1", "pmcid": "PMC12411631", "url": "https://pubmed.ncbi.nlm.nih.gov/40855115/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40855115/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40855115", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c changes aged-islet senescence and improves glucose intolerance in S961-treated and NOD mice; adult T2D peptide levels are lower.", "what_it_does_not_show": "Mouse disease models and senescence markers do not establish generalized aging or human peptide-treatment efficacy.", "confounders_present": [ "Mouse disease models and senescence markers do not establish generalized aging or human peptide-treatment efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 39, "pmid": "39706498", "title": "Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.", "citation": "Feng Y, Rao Z, Tian X et al. Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion. Free radical biology & medicine. 2025.", "doi": "10.1016/j.freeradbiomed.2024.12.038", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39706498/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39706498/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39706498", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Marathon/sedentary humans and endurance-trained mice show associations among peptide, exercise capacity and respiration.", "what_it_does_not_show": "Training is not selective peptide perturbation; source secretion and human causal mediation remain unresolved.", "confounders_present": [ "Training is not selective peptide perturbation; source secretion and human causal mediation remain unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 40, "pmid": "41732124", "title": "Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells.", "citation": "Elhusseiny R, Ihsan M, Bellefroid T et al. Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells. Physiological reports. 2026.", "doi": "10.14814/phy2.70791", "pmcid": "PMC12930096", "url": "https://pubmed.ncbi.nlm.nih.gov/41732124/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41732124/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41732124", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c preserves dexamethasone-exposed primary human myotube area and alters Akt/STAT3/atrophy pathways.", "what_it_does_not_show": "Human-derived cells are not human treatment; pharmacological co-exposure and induced atrophy cannot establish clinical healthspan.", "confounders_present": [ "Human-derived cells are not human treatment; pharmacological co-exposure and induced atrophy cannot establish clinical healthspan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 41, "pmid": "39267782", "title": "Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane.", "citation": "Jia H, Zhou LC, Chen YF et al. Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane. Theranostics. 2024.", "doi": "10.7150/thno.100321", "pmcid": "PMC11388074", "url": "https://pubmed.ncbi.nlm.nih.gov/39267782/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39267782/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39267782", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "MOTS-c facilitates TRIM72-dependent membrane repair; TRIM72 loss separates repair from vesicle fusion, and cardiac injury outcomes improve.", "what_it_does_not_show": "Human exercise correlations remain nonselective and native peptide necessity is not universally established; membrane repair is not general aging delay.", "confounders_present": [ "Human exercise correlations remain nonselective and native peptide necessity is not universally established; membrane repair is not general aging delay." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 42, "pmid": "33394327", "title": "Relationship between the mitochondria-derived peptide MOTS-c and insulin resistance in obstructive sleep apnea.", "citation": "Baylan FA, Yarar E. Relationship between the mitochondria-derived peptide MOTS-c and insulin resistance in obstructive sleep apnea. Sleep & breathing = Schlaf & Atmung. 2021.", "doi": "10.1007/s11325-020-02273-0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33394327/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33394327/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33394327", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Lower measured serum MOTS-c tracks OSA severity and metabolic indices in patients.", "what_it_does_not_show": "OSA, obesity and insulin resistance are interrelated; biomarker regression does not show benefit from peptide administration.", "confounders_present": [ "OSA, obesity and insulin resistance are interrelated; biomarker regression does not show benefit from peptide administration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 43, "pmid": "33639272", "title": "The mitochondrial-derived peptide MOTS-c promotes homeostasis in aged human placenta-derived mesenchymal stem cells in vitro.", "citation": "Yu WD, Kim YJ, Cho MJ et al. The mitochondrial-derived peptide MOTS-c promotes homeostasis in aged human placenta-derived mesenchymal stem cells in vitro. Mitochondrion. 2021.", "doi": "10.1016/j.mito.2021.02.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33639272/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33639272/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33639272", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c changes AMPK/mTOR and mitochondrial/ROS markers in aged placenta-derived MSCs.", "what_it_does_not_show": "In-vitro homeostasis is not restored organismal stem-cell repair, healthspan or clinical aging efficacy.", "confounders_present": [ "In-vitro homeostasis is not restored organismal stem-cell repair, healthspan or clinical aging efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 44, "pmid": "40425777", "title": "MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3.", "citation": "Chen F, Li Z, Wang T et al. MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3. Scientific reports. 2025.", "doi": "10.1038/s41598-025-03526-2", "pmcid": "PMC12116857", "url": "https://pubmed.ncbi.nlm.nih.gov/40425777/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40425777/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40425777", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c and exercise improve diabetic-rat liver fibrosis with Keap1/Nrf2/Smad associations.", "what_it_does_not_show": "Cell ectopic-expression and marker changes do not selectively establish an endogenous exercise mediator or general human benefit.", "confounders_present": [ "Cell ectopic-expression and marker changes do not selectively establish an endogenous exercise mediator or general human benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 45, "pmid": "38462167", "title": "Central MOTS-c infusion affects reproductive hormones in obese and non-obese rats.", "citation": "Ozturk Öztürk DA, Erden Y, Tekin S. Central MOTS-c infusion affects reproductive hormones in obese and non-obese rats. Neuroscience letters. 2024.", "doi": "10.1016/j.neulet.2024.137722", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38462167/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38462167/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38462167", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Central peptide infusion raises GnRH and reproductive hormone measurements in obese/nonobese male rats.", "what_it_does_not_show": "Intracerebroventricular delivery and hormones are not systemic clinical metabolic healthspan or proved fertility benefit.", "confounders_present": [ "Intracerebroventricular delivery and hormones are not systemic clinical metabolic healthspan or proved fertility benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 46, "pmid": "37077579", "title": "Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function.", "citation": "Luo YH, Xie L, Li JY et al. Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function. Diabetes, metabolic syndrome and obesity : targets and therapy. 2023.", "doi": "10.2147/DMSO.S403934", "pmcid": "PMC10106799", "url": "https://pubmed.ncbi.nlm.nih.gov/37077579/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37077579/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37077579", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Obese children have lower measured peptide and vascular reactive-hyperemia indices with statistical mediation.", "what_it_does_not_show": "Cross-sectional mediation is not causal mediation; peptide replacement and functional prevention were not tested.", "confounders_present": [ "Cross-sectional mediation is not causal mediation; peptide replacement and functional prevention were not tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 47, "pmid": "42324588", "title": "Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells.", "citation": "Xing L, Lu B, Zhu X et al. Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells. Inflammation and regeneration. 2026.", "doi": "10.1186/s41232-026-00431-7", "pmcid": "PMC13536784", "url": "https://pubmed.ncbi.nlm.nih.gov/42324588/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42324588/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42324588", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results:paragraph3, 2:Results:paragraph5, 2:Results:paragraph7, 2:Results:paragraph11. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "MOTS-c activates AMPK in obese human MSCs but increases senescence/inflammatory markers; pretreated MSCs fail or blunt kidney repair in mice.", "what_it_does_not_show": "Cell pretreatment/transplant context is not direct human administration, but it refutes marker activation as a sufficient proxy for regenerative benefit.", "confounders_present": [ "Cell pretreatment/transplant context is not direct human administration, but it refutes marker activation as a sufficient proxy for regenerative benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 48, "pmid": "36584915", "title": "MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPβ modification in rats.", "citation": "Yuan J, Xu B, Ma J et al. MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPβ modification in rats. Life sciences. 2023.", "doi": "10.1016/j.lfs.2022.121330", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36584915/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36584915/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36584915", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c and exercise improve selected rat cardiac functional measures with NRG1/ErbB4/CEBPbeta-associated remodeling.", "what_it_does_not_show": "Some endpoints and NRG1 transcript contrasts are null; healthy adaptation is not mechanistically isolated aging benefit.", "confounders_present": [ "Some endpoints and NRG1 transcript contrasts are null; healthy adaptation is not mechanistically isolated aging benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 49, "pmid": "30967270", "title": "Earlier changes in mice after D-galactose treatment were improved by mitochondria derived small peptide MOTS-c.", "citation": "Li Q, Lu H, Hu G et al. Earlier changes in mice after D-galactose treatment were improved by mitochondria derived small peptide MOTS-c. Biochemical and biophysical research communications. 2019.", "doi": "10.1016/j.bbrc.2019.03.194", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30967270/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30967270/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30967270", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c reduces abnormal lipid accumulation and tissue/mitochondrial changes in D-galactose-treated mice.", "what_it_does_not_show": "Toxicity-induced pseudo-aging, histology and markers do not substitute for natural-aging healthspan or lifespan.", "confounders_present": [ "Toxicity-induced pseudo-aging, histology and markers do not substitute for natural-aging healthspan or lifespan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 50, "pmid": "39469962", "title": "Serum MOTS-c levels remain unchanged in patients with preeclampsia.", "citation": "Tok A, Serdar O, Kandilcik OF et al. Serum MOTS-c levels remain unchanged in patients with preeclampsia. Ginekologia polska. 2023.", "doi": "10.5603/GP.a2022.0095", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39469962/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39469962/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39469962", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Measured serum MOTS-c is similar among uncomplicated pregnancy and mild/severe preeclampsia groups.", "what_it_does_not_show": "Nonsignificant small-group comparisons do not rule out all tissue effects or establish a therapeutic target.", "confounders_present": [ "Nonsignificant small-group comparisons do not rule out all tissue effects or establish a therapeutic target." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 51, "pmid": "41710402", "title": "Aerobic exercise and MOTS-c attenuate diabetic myocardial fibrosis via inhibition of the THBS1/TGF-β signaling pathway.", "citation": "Li Z, Wang T, Fu Y et al. Aerobic exercise and MOTS-c attenuate diabetic myocardial fibrosis via inhibition of the THBS1/TGF-β signaling pathway. Frontiers in endocrinology. 2026.", "doi": "10.3389/fendo.2026.1732329", "pmcid": "PMC12909204", "url": "https://pubmed.ncbi.nlm.nih.gov/41710402/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41710402/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41710402", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Exercise and MOTS-c improve diabetic myocardial fibrosis and systolic/diastolic measures with THBS1/TGFbeta association.", "what_it_does_not_show": "Pathway transcript/ protein concordance is not isolated mediator necessity; no human peptide trial or longevity endpoint.", "confounders_present": [ "Pathway transcript/ protein concordance is not isolated mediator necessity; no human peptide trial or longevity endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Related diabetic-rat cardiac/exercise research program; not automatically an independent causal line." ] }, { "n": 52, "pmid": "40478460", "title": "MOTS-c modulates pancreatic islet function in rats and pigs in vitro.", "citation": "Bień J, Pruszynska-Oszmalek E, Kolodziejski P et al. MOTS-c modulates pancreatic islet function in rats and pigs in vitro. Histochemistry and cell biology. 2025.", "doi": "10.1007/s00418-025-02391-4", "pmcid": "PMC12144051", "url": "https://pubmed.ncbi.nlm.nih.gov/40478460/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40478460/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40478460", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "ex vivo", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "MOTS-c alters rat/pig islet secretion and viability with different directions across species.", "what_it_does_not_show": "Isolated islets are not organismal metabolic or aging outcomes; cross-species cellular effects cannot remove the healthspan scope cap.", "confounders_present": [ "Isolated islets are not organismal metabolic or aging outcomes; cross-species cellular effects cannot remove the healthspan scope cap." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 53, "pmid": "36687680", "title": "MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats.", "citation": "Wang M, Wang G, Pang X et al. MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats. Frontiers in nutrition. 2022.", "doi": "10.3389/fnut.2022.1060684", "pmcid": "PMC9846618", "url": "https://pubmed.ncbi.nlm.nih.gov/36687680/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36687680/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36687680", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Eight-week peptide treatment preserves cardiac functional measures in diabetic rats with CCN1/ERK/EGR1 changes.", "what_it_does_not_show": "Transcriptomic and apoptosis associations do not prove one direct mediator; related diabetic-rat programs are not automatically independent experiments.", "confounders_present": [ "Transcriptomic and apoptosis associations do not prove one direct mediator; related diabetic-rat programs are not automatically independent experiments." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Related diabetic-rat cardiac laboratory/model program; independence not inferred from a different pathway report." ] }, { "n": 54, "pmid": "39457696", "title": "The Relationship Between MOTS-c K14Q Polymorphism and Sarcopenia, Blood Lipids, and Mental Health in Older Korean Adults.", "citation": "Kim S. The Relationship Between MOTS-c K14Q Polymorphism and Sarcopenia, Blood Lipids, and Mental Health in Older Korean Adults. Biomedicines. 2024.", "doi": "10.3390/biomedicines12102384", "pmcid": "PMC11504729", "url": "https://pubmed.ncbi.nlm.nih.gov/39457696/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39457696/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39457696", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Older Korean men carrying K14Q-associated C allele have higher muscle mass and grip; women show no genotype difference.", "what_it_does_not_show": "Cross-sectional population/context differs from Japanese low-mass-risk findings; direction is not universally adverse, and genotype is not administered peptide.", "confounders_present": [ "Cross-sectional population/context differs from Japanese low-mass-risk findings; direction is not universally adverse, and genotype is not administered peptide." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 55, "pmid": "41680431", "title": "Reduced serum and skeletal muscle MOTS c levels in women with polycystic ovary syndrome are associated with mitochondrial dysfunction.", "citation": "Kutuk IS, Akin S, Demirel H et al. Reduced serum and skeletal muscle MOTS c levels in women with polycystic ovary syndrome are associated with mitochondrial dysfunction. Scientific reports. 2026.", "doi": "10.1038/s41598-026-39687-x", "pmcid": "PMC12976357", "url": "https://pubmed.ncbi.nlm.nih.gov/41680431/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41680431/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID42716952" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41680431", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Women with PCOS have lower serum and muscle immunodetected peptide with selected hormone/lipid associations.", "what_it_does_not_show": "Cross-sectional tissue/serum measurements do not establish causal deficiency; linked erratum PMID42716952 details were not examined.", "confounders_present": [ "Cross-sectional tissue/serum measurements do not establish causal deficiency; linked erratum PMID42716952 details were not examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 56, "pmid": "40005438", "title": "MOTS-c Levels and Sarcopenia Risk in Chronic Peritoneal Dialysis Patients: A Pilot Study.", "citation": "Zicarelli M, Greco M, Roumeliotis S et al. MOTS-c Levels and Sarcopenia Risk in Chronic Peritoneal Dialysis Patients: A Pilot Study. Medicina (Kaunas, Lithuania). 2025.", "doi": "10.3390/medicina61020322", "pmcid": "PMC11857303", "url": "https://pubmed.ncbi.nlm.nih.gov/40005438/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40005438/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40005438", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Small peritoneal-dialysis cohort links lower serum/higher dialysate peptide to sarcopenia-risk and performance measures.", "what_it_does_not_show": "Renal/peritoneal handling and disease burden confound direction; biomarker prediction is not peptide replacement benefit.", "confounders_present": [ "Renal/peritoneal handling and disease burden confound direction; biomarker prediction is not peptide replacement benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 57, "pmid": "42266945", "title": "MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.", "citation": "Jamnick NA, Livingston PD, Gammon CJ et al. MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia. Frontiers in medicine. 2026.", "doi": "10.3389/fmed.2026.1838178", "pmcid": "PMC13243040", "url": "https://pubmed.ncbi.nlm.nih.gov/42266945/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42266945/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42266945", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "MOTS-c preserves selected skeletal-muscle mass in C26-cachectic mice but not total body weight/fat; function improvement is a trend.", "what_it_does_not_show": "Partial wasting-model protection is not complete functional rescue or healthspan extension, and induced cancer context remains.", "confounders_present": [ "Partial wasting-model protection is not complete functional rescue or healthspan extension, and induced cancer context remains." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 58, "pmid": "41551324", "title": "Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss.", "citation": "Yoon SH, Yuan F, Zhu X et al. Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss. Journal of clinical & translational endocrinology. 2026.", "doi": "10.1016/j.jcte.2025.100429", "pmcid": "PMC12807633", "url": "https://pubmed.ncbi.nlm.nih.gov/41551324/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41551324/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "OBESITY_BARIATRIC_MOTS_PARENT", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results:paragraph5, 2:Results:paragraph19, 2:Results:paragraph22. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Obese adults have higher circulating peptide; after bariatric surgery BMI and selected metabolic indices improve without peptide normalization.", "what_it_does_not_show": "Ten-person observational follow-up and ELISA limit mediation; original body/abstract/table numbers disagree, so no single repaired numeric value is invented.", "confounders_present": [ "Ten-person observational follow-up and ELISA limit mediation; original body/abstract/table numbers disagree, so no single repaired numeric value is invented." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 59, "pmid": "32182209", "title": "Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition.", "citation": "D'Souza RF, Woodhead JST, Hedges CP et al. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging. 2020.", "doi": "10.18632/aging.102944", "pmcid": "PMC7138593", "url": "https://pubmed.ncbi.nlm.nih.gov/32182209/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32182209/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32182209", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Healthy aging men show lower circulating but higher muscle peptide with fiber-type/muscle-quality associations.", "what_it_does_not_show": "Opposite compartment directions and small RNA/immunoassays do not prove a systemic deficiency or peptide treatment benefit.", "confounders_present": [ "Opposite compartment directions and small RNA/immunoassays do not prove a systemic deficiency or peptide treatment benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 60, "pmid": "35808870", "title": "MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose.", "citation": "Hyatt JK. MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose. Physiological reports. 2022.", "doi": "10.14814/phy2.15377", "pmcid": "PMC9270643", "url": "https://pubmed.ncbi.nlm.nih.gov/35808870/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35808870/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35808870", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Training raises muscle peptide and a single synthetic dose improves mouse acute running time/distance.", "what_it_does_not_show": "Acute performance is not durable aging change; nuclear translocation occurs in only 2 of 6 soleus samples and not plantaris.", "confounders_present": [ "Acute performance is not durable aging change; nuclear translocation occurs in only 2 of 6 soleus samples and not plantaris." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 61, "pmid": "37834399", "title": "MOTS-c Serum Concentration Positively Correlates with Lower-Body Muscle Strength and Is Not Related to Maximal Oxygen Uptake-A Preliminary Study.", "citation": "Domin R, Pytka M, Żołyński M et al. MOTS-c Serum Concentration Positively Correlates with Lower-Body Muscle Strength and Is Not Related to Maximal Oxygen Uptake-A Preliminary Study. International journal of molecular sciences. 2023.", "doi": "10.3390/ijms241914951", "pmcid": "PMC10573682", "url": "https://pubmed.ncbi.nlm.nih.gov/37834399/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37834399/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37834399", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Resting serum peptide correlates with jump force/power and muscle mass but not peak VO2 in 20 active volunteers.", "what_it_does_not_show": "Small observational sample does not establish endurance benefit or dosing efficacy.", "confounders_present": [ "Small observational sample does not establish endurance benefit or dosing efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 62, "pmid": "39111290", "title": "The Mitochondrial-Derived Peptide MOTS-c May Refine Mortality and Cardiovascular Risk Prediction in Chronic Hemodialysis Patients: A Multicenter Cohort Study.", "citation": "Bolignano D, Greco M, Presta P et al. The Mitochondrial-Derived Peptide MOTS-c May Refine Mortality and Cardiovascular Risk Prediction in Chronic Hemodialysis Patients: A Multicenter Cohort Study. Blood purification. 2024.", "doi": "10.1159/000540303", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39111290/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39111290/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39111290", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Higher circulating peptide predicts death/CV events in 94 hemodialysis patients during follow-up.", "what_it_does_not_show": "Renal handling and illness severity may determine marker levels; adverse-risk association does not show peptide causes harm or treatment benefit.", "confounders_present": [ "Renal handling and illness severity may determine marker levels; adverse-risk association does not show peptide causes harm or treatment benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 63, "pmid": "42611943", "title": "MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide.", "citation": "Rice MC, Imun M, Jung SW et al. MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide. eLife. 2026.", "doi": "10.7554/eLife.87615", "pmcid": "PMC13485304", "url": "https://pubmed.ncbi.nlm.nih.gov/42611943/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42611943/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39553971" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MOTS_HOST_DEFENSE_UPDATED_REPORT", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph9. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOTS-c has direct antibacterial/cell immune effects; MRSA pretreated with peptide causes less lethal mouse peritonitis.", "what_it_does_not_show": "Bacteria were exposed before inoculation, so this is not endogenous peptide necessity or aging treatment; updated preprint is not a separate primary study.", "confounders_present": [ "Bacteria were exposed before inoculation, so this is not endogenous peptide necessity or aging treatment; updated preprint is not a separate primary study." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 64, "pmid": "40805020", "title": "Characterization of the Avian Mitochondrial-Derived Peptide MOTS-c and Its Potential Role as a Metabolic Regulator.", "citation": "Shu X, Liu J, Xu B et al. Characterization of the Avian Mitochondrial-Derived Peptide MOTS-c and Its Potential Role as a Metabolic Regulator. Animals : an open access journal from MDPI. 2025.", "doi": "10.3390/ani15152230", "pmcid": "PMC12345487", "url": "https://pubmed.ncbi.nlm.nih.gov/40805020/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40805020/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40805020", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Avian 12S-region sequence and chicken immunodetection/cellular responses extend candidate peptide biology with divergent sequence.", "what_it_does_not_show": "Avian primary-cell signaling is not mammalian healthspan; bioinformatic coding potential and immunodetection do not directly resolve native translation machinery.", "confounders_present": [ "Avian primary-cell signaling is not mammalian healthspan; bioinformatic coding potential and immunodetection do not directly resolve native translation machinery." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 68, "verified": 68, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "In vitro evidence alone cannot exceed Γ.", "specific_trigger": "The 12S-rRNA-region sequence, rho0/actinonin depletion and immunodetection support mitochondrial genomic origin and a bioactive peptide. Synthetic sequence-specific activity and stress localization are reproducible in selected systems. Native production, transcript export, translation machinery and quantitative assay specificity are not selectively resolved by broad mitochondrial depletion or by activity of administered peptide. Γ records partial endogenous molecular support, not denial that the reported sequence or synthetic peptide exists.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Biomarker change without functional/phenotypic change caps at Γ.", "specific_trigger": "The registered human administration-and-healthspan claim has mechanistic and preclinical support, but no examined original report administers native MOTS-c to humans and demonstrates durable clinical metabolic function plus healthspan. Human exercise, heat, metformin, lipid/insulin infusion and bariatric surgery manipulate other exposures; peptide associations or marker changes cannot supply peptide treatment causality. Genotype evidence is sex/activity/age dependent and not a clean intervention instrument. Overall Γ follows this registered SC3 gate.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "MOTS-c is a mitochondrial-derived peptide that improves human metabolic function and healthspan.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Administered peptide crosses only within the specified metabolic/functional model setting. Exogenous administration is not ectopic-gene overexpression, so genuine organismal phenotypic results are not dismissed under universal cap 3; cell overexpression is capped for endogenous necessity. The explicit SC2 metabolic-phenotype adaptation preserves those narrow results, while 06's single-species/strain, biomarker and age-versus-development rules remain binding on generalized aging. Human associations and other-exposure interventions cannot be combined into a native peptide human dosing result. A genotype-dependent peptide sequence contrast does not automatically exclude effects on mitochondrial rRNA or linked haplogroup biology.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "In vitro evidence alone cannot exceed Γ." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "The 12S-rRNA-region sequence, rho0/actinonin depletion and immunodetection support mitochondrial genomic origin and a bioactive peptide. Synthetic sequence-specific activity and stress localization are reproducible in selected systems. Native production, transcript export, translation machinery and quantitative assay specificity are not selectively resolved by broad mitochondrial depletion or by activity of administered peptide. Γ records partial endogenous molecular support, not denial that the reported sequence or synthetic peptide exists.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID25738459, PMID33473109, PMID33468709, PMID39559755, PMID35370955, PMID36156853, PMID38141139, PMID40855115", "gamma_hard_rules_triggered": [ "Aging branch: Single-species or single-strain evidence; biomarker-only mitochondrial/ROS/senescence studies remain Γ for healthspan.", "Metabolic-function branch: controlled organismal phenotypes across mouse backgrounds and rat contexts, with explicit rubric-fit adaptation; no universal aging inference." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Controlled peptide administration changes glucose handling, induced cardiac dysfunction, muscle atrophy and late-life physical capacity in defined rodent settings. Metabolic outcomes span CD1 and C57BL6 backgrounds and rat models, with mapped sex, variant, tissue and cell-context boundaries. Ε applies to context-specific mammalian metabolic/functional pharmacology under the explicitly declared phenotype adaptation. The aging-specific branch is narrower: late-life physical-function evidence remains principally male C57BL6/N, and overall lifespan is not significantly extended. This does not establish generalized mammalian aging delay or endogenous peptide necessity.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Biomarker-only improvement without organismal benefit", "Human native-peptide functional healthspan administration was not identified in the examined originals." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "The registered human administration-and-healthspan claim has mechanistic and preclinical support, but no examined original report administers native MOTS-c to humans and demonstrates durable clinical metabolic function plus healthspan. Human exercise, heat, metformin, lipid/insulin infusion and bariatric surgery manipulate other exposures; peptide associations or marker changes cannot supply peptide treatment causality. Genotype evidence is sex/activity/age dependent and not a clean intervention instrument. Overall Γ follows this registered SC3 gate.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Demonstrate endogenous sequence identity by orthogonal quantitative proteomics, track a native transcript and translation/export compartment, and selectively alter peptide production while preserving 12S-rRNA function, with peptide-specific rescue.", "rubric_fit_adaptation": "The molecular identity/production claim is evaluated as a cell/molecular branch, not as lifespan extension." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "yes", "supporting_evidence": [ "[1] A 12S-rRNA sORF, mitochondrial depletion assays and immunodetection support MOTS-c identity; administered peptide improves mouse insulin sensitivity and diet-induced obesity.", "[2] Synthetic MOTS-c improves mouse exercise capacity and late-life grip, gait and walking; human exercise raises measured endogenous peptide.", "[4] Wild-type and K14Q peptides differ in insulin sensitization; three Japanese-ancestry cohorts link m.1382A>C with T2D in males and activity-dependent subgroups.", "[6] Synthetic MOTS-c binds CK2 by SPR; CK2 inhibition or cellular ASO blocks glucose-uptake effects, and K14Q fails tested mouse atrophy protection.", "[18] MOTS-c or exercise improves cardiac structure/function in diet/STZ diabetic rats with NRG1-ErbB4 pathway associations.", "[33] Pump-delivered MOTS-c attenuates pressure-overload cardiac dysfunction/remodeling in mice.", "[34] MOTS-c after STZ-diabetes establishment ameliorates mouse cardiac function and remodeling over 12 weeks.", "[38] MOTS-c changes aged-islet senescence and improves glucose intolerance in S961-treated and NOD mice; adult T2D peptide levels are lower." ], "what_would_cross_it": "", "rubric_fit_adaptation": "Applied metabolic-function criterion: controlled reproducible organismal glucose/cardiac/muscle outcomes in prespecified rodent contexts. The exact archived lifespan/healthspan criterion is quoted unchanged below and is not satisfied for generalized mammalian aging. Narrow metabolic Ε is a declared rubric-fit adaptation; natural-aging evidence retains Γ under the single-background rule." }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[1] A 12S-rRNA sORF, mitochondrial depletion assays and immunodetection support MOTS-c identity; administered peptide improves mouse insulin sensitivity and diet-induced obesity.", "[2] Synthetic MOTS-c improves mouse exercise capacity and late-life grip, gait and walking; human exercise raises measured endogenous peptide.", "[4] Wild-type and K14Q peptides differ in insulin sensitization; three Japanese-ancestry cohorts link m.1382A>C with T2D in males and activity-dependent subgroups.", "[6] Synthetic MOTS-c binds CK2 by SPR; CK2 inhibition or cellular ASO blocks glucose-uptake effects, and K14Q fails tested mouse atrophy protection.", "[18] MOTS-c or exercise improves cardiac structure/function in diet/STZ diabetic rats with NRG1-ErbB4 pathway associations.", "[33] Pump-delivered MOTS-c attenuates pressure-overload cardiac dysfunction/remodeling in mice.", "[34] MOTS-c after STZ-diabetes establishment ameliorates mouse cardiac function and remodeling over 12 weeks.", "[38] MOTS-c changes aged-islet senescence and improves glucose intolerance in S961-treated and NOD mice; adult T2D peptide levels are lower." ], "what_would_cross_it": "", "rubric_fit_adaptation": "Applied metabolic-function criterion: controlled reproducible organismal glucose/cardiac/muscle outcomes in prespecified rodent contexts. The exact archived lifespan/healthspan criterion is quoted unchanged below and is not satisfied for generalized mammalian aging. Narrow metabolic Ε is a declared rubric-fit adaptation; natural-aging evidence retains Γ under the single-background rule." }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "no", "supporting_evidence": [ "[1] A 12S-rRNA sORF, mitochondrial depletion assays and immunodetection support MOTS-c identity; administered peptide improves mouse insulin sensitivity and diet-induced obesity.", "[2] Synthetic MOTS-c improves mouse exercise capacity and late-life grip, gait and walking; human exercise raises measured endogenous peptide.", "[4] Wild-type and K14Q peptides differ in insulin sensitization; three Japanese-ancestry cohorts link m.1382A>C with T2D in males and activity-dependent subgroups.", "[6] Synthetic MOTS-c binds CK2 by SPR; CK2 inhibition or cellular ASO blocks glucose-uptake effects, and K14Q fails tested mouse atrophy protection.", "[18] MOTS-c or exercise improves cardiac structure/function in diet/STZ diabetic rats with NRG1-ErbB4 pathway associations.", "[33] Pump-delivered MOTS-c attenuates pressure-overload cardiac dysfunction/remodeling in mice.", "[34] MOTS-c after STZ-diabetes establishment ameliorates mouse cardiac function and remodeling over 12 weeks.", "[38] MOTS-c changes aged-islet senescence and improves glucose intolerance in S961-treated and NOD mice; adult T2D peptide levels are lower." ], "what_would_cross_it": "Independently replicate late-life durable functional healthspan in multiple prespecified backgrounds/species and both sexes, separate food intake/developmental effects, and selectively test endogenous peptide necessity and rescue rather than only synthetic dosing or mitochondrial markers.", "rubric_fit_adaptation": "Applied metabolic-function criterion: controlled reproducible organismal glucose/cardiac/muscle outcomes in prespecified rodent contexts. The exact archived lifespan/healthspan criterion is quoted unchanged below and is not satisfied for generalized mammalian aging. Narrow metabolic Ε is a declared rubric-fit adaptation; natural-aging evidence retains Γ under the single-background rule." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Run registered controlled native-MOTS-c administration in a baseline-defined human population, with validated exposure and target engagement, metabolic functional endpoints and durable healthspan follow-up; preserve nulls and prospectively replicate the predicted dose/sex/age/genotype boundary.", "rubric_fit_adaptation": "Human administration plus durable healthspan remains unadapted and uncrossed." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "WT and K14Q peptide effects are absent in the tested female high-fat-fed mice (PMID33468709).", "K14Q fails tested muscle atrophy/glucose-uptake effects and CK2 inhibition/ASO blocks selected responses (PMID39559755).", "Muscle and adipose CK2 responses have opposite directions and liver response is not detected (PMID39559755).", "Overall lifespan curve is nonsignificant despite old-mouse functional gains; Y-maze learning/memory is unaffected (PMID33473109).", "MOTS-c activates AMPK yet worsens selected human-MSC senescence/repair outcomes (PMID42324588).", "Metformin and selected exercise paradigms do not alter measured circulating peptide; bariatric metabolic improvement need not normalize it (PMID36490309, PMID31066084, PMID41551324).", "Older Korean K14Q carriers show higher muscle/strength, opposing an unqualified universal adverse-genotype prediction (PMID39457696)." ], "note": "Species, background, sex, age, baseline metabolic status, tissue, dose/route and functional endpoint are measurable before results. Published post-hoc activity/age strata need prospective replication, not responder-defined rescue of the broad claim. Rodent insulin handling, acute running performance, cast atrophy and mouse late-life walking are separate endpoints; none establishes human healthspan." }, "falsification_patterns_met": [ { "pattern": "Pathway manipulation changes biomarkers but not functional benefit in a defined model", "evidence": "MOTS-c-pretreated human MSCs activate AMPK yet fail or blunt repair in recipient mouse kidneys (PMID42324588). This maps a boundary of the broad protection claim; it does not independently negate positive metabolic contexts.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Exercise response treated as peptide efficacy", "where": "Exercise/heat/metformin interventions measure peptide but do not administer it." }, { "pitfall": "Mitochondrial genome origin treated as mitoribosomal translation", "where": "The original infers cytoplasmic translation and does not directly resolve the native machinery." }, { "pitfall": "Synthetic target binding validates all native immunoassays", "where": "SPR concerns supplied peptide; native circulating identity remains an independent measurement problem." }, { "pitfall": "Marker or acute performance becomes healthspan", "where": "AMPK, respiration, induced injury and one-run performance are distinct from durable aged-organism function." }, { "pitfall": "Shared cohorts and universal genotype prediction", "where": "J-MICC overlap and sex/age/activity-dependent opposing K14Q observations restrict independence and scope." } ], "causal_tally_audit": { "tally_claimed_by_document": 8, "tally_after_audit": 8, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 44, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Reports sharing participants, models or instruments are not independent causal lines.", "Pivotal nulls do not earn positive threshold crossings." ] }, "steelman": { "case_one_rung_higher": "One rung above, Δ: animal functional benefits and human K14Q associations could be interpreted as evidence for a clinically relevant conserved pathway. The blocker is the actual SC3 scope: no selective human native-MOTS-c administration or validated exposure instrument with durable healthspan is in this examined set. Physical exercise and an analogue trial cannot be substituted for that result.", "case_one_rung_lower": "One rung below, Β: human evidence is mostly correlational and immunoassay-dependent. However, controlled sequence/target perturbations and model functional benefits supply mechanistic content beyond association; Γ retains that translational plausibility without granting human efficacy.", "which_rejected": "Retain Γ for the registered human treatment conjunction and report narrow SC2 Ε with its explicit adaptation. Reject both unverified human healthspan benefit and a dismissal of all peptide pharmacology as correlation.", "blocking_cap_threshold_or_missing_experiment": "Missing 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 preserving 12S-rRNA function to test endogenous necessity with sequence-specific rescue." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Moderate reflects evidence density and reproducibility, not the reviewer's access depth and not any belief about correctness: the rodent pharmacology replicates across backgrounds and two species, but much of the programme shares peptide reagents, antibodies and paradigms across closely connected laboratories, native-peptide immunoassay specificity is unresolved, and no human administration study exists. High was considered and declined on that reagent and laboratory concentration; Low was declined because independent groups reproduce the exposure-response measurements.", "rests_on_non_peer_reviewed_work": false, "rationale": "Overall Γ follows preregistered primary human-administered SC3. Partial native molecular SC1 is Γ and explicitly scoped rodent metabolic/functional pharmacology SC2 is Ε under a declared phenotype adaptation. Controlled model benefit is retained; neither endogenous exercise-marker induction, K14Q population association nor an analogue program supplies native human healthspan causality." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Exercise, metabolic load and illness can regulate endogenous measurements, but bidirectional pharmacologic functional effects are also demonstrated in models, so a purely downstream or coincidental account does not cover the whole inventory. Removing native MOTS-c has not been shown to prevent/initiate or rate-limit human aging, and universal requirement is not established. Step 5 is a provisional context-specific modifier of upstream metabolic stress and tissue function, not a demonstrated human primary aging driver; endogenous physiological role and supplied-peptide pharmacology remain distinct.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "CK2-binding/inhibition and human-cell ASO (PMID39559755), PGC1alpha/AMPK-dependent mouse bioenergetics and human exercise flux (PMID41520850), and marker-positive/repair-negative MSC intervention (PMID42324588) address mechanisms and boundaries. No verified native human healthspan trial result was identified in examined originals; the provider's analogue registry identifier was not accepted as verified.", "justification": "CK2-binding/inhibition and human-cell ASO (PMID39559755), PGC1alpha/AMPK-dependent mouse bioenergetics and human exercise flux (PMID41520850), and marker-positive/repair-negative MSC intervention (PMID42324588) address mechanisms and boundaries. No verified native human healthspan trial result was identified in examined originals; the provider's analogue registry identifier was not accepted as verified." }, "stability": { "value": "Stable", "trigger": "No verified named pending native-MOTS-c human functional/healthspan result was identified in this bounded search. A confirmed registered administered-native-peptide trial could raise the grade, but the specific provider registry identifier remains unverified and is omitted.", "justification": "No verified named pending native-MOTS-c human functional/healthspan result was identified in this bounded search. A confirmed registered administered-native-peptide trial could raise the grade, but the specific provider registry identifier remains unverified and is omitted." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "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 preserving 12S-rRNA function to test endogenous necessity with sequence-specific rescue.", "readout": "Validated native/synthetic peptide exposure, human metabolic functional measurements and durable physical/clinical healthspan rather than only AMPK, ROS or aging clocks", "critical_control": "Orthogonal LC-MS/MS identity and spike recovery, antibody cross-reactivity, native 12S-rRNA preservation, renal clearance, baseline diet/activity, sex/age/genotype, caloric intake, blinded dosing and predeclared endpoints", "supporting_result": "Adequate native-peptide exposure produces reproducible clinically meaningful metabolic and durable functional benefit with predicted target engagement and prospectively validated context", "falsifying_result": "Exposure/engagement changes only biomarkers, fails prespecified functional outcomes, or harms baseline-defined subgroups; native-selective production loss leaves the proposed physiological dependency intact" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Native transcript export, cellular translation machinery and quantitative peptide identity need direct orthogonal tests.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "No examined primary native-MOTS-c human administration study establishes metabolic function plus durable healthspan.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Physiological concentrations and synthetic pharmacologic dosing need a validated exposure bridge.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Late-life functional benefit and overall lifespan are different; natural-aging replication across backgrounds/species and sexes is incomplete.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "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.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Circulating peptide can rise with metabolic stress and remain elevated after improvement; tissue sources and renal handling are unresolved.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "AMPK/mitochondrial marker activation can coexist with worse repair; functional and adverse outcomes must be prespecified.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Shared cohorts, peptide reagents and assay platforms require independent error-mode assessment rather than paper-count convergence.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-12", "reviewer": "Codex", "evidence_base_note": "64 primary reports; literature cutoff 2026-10-09; source examination UTC date 2026-10-12; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite is queried per case where connected; received tallies/outgoing reference contexts are not audited incoming contrasting statements. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": true, "why_not_sufficient": "Human genotype/ancestry contrasts, controlled rodent pharmacology, selective downstream-target tests and exposure-responsive human biomarkers were considered. They exclude different alternatives in restricted settings but are not a same-scope causal set demonstrating human native-MOTS-c administration and durable healthspan. The upper ladder remains reachable through a validated selective genetic instrument or registered human exposure intervention, not only one particular trial design." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Human genotype/ancestry contrasts, controlled rodent pharmacology, selective downstream-target tests and exposure-responsive human biomarkers were considered. They exclude different alternatives in restricted settings but are not a same-scope causal set demonstrating human native-MOTS-c administration and durable healthspan. The upper ladder remains reachable through a validated selective genetic instrument or registered human exposure intervention, not only one particular trial design." }, { "kind": "dose_response_across_populations", "available": true, "why_not_sufficient": "Human genotype/ancestry contrasts, controlled rodent pharmacology, selective downstream-target tests and exposure-responsive human biomarkers were considered. They exclude different alternatives in restricted settings but are not a same-scope causal set demonstrating human native-MOTS-c administration and durable healthspan. The upper ladder remains reachable through a validated selective genetic instrument or registered human exposure intervention, not only one particular trial design." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Human genotype/ancestry contrasts, controlled rodent pharmacology, selective downstream-target tests and exposure-responsive human biomarkers were considered. They exclude different alternatives in restricted settings but are not a same-scope causal set demonstrating human native-MOTS-c administration and durable healthspan. The upper ladder remains reachable through a validated selective genetic instrument or registered human exposure intervention, not only one particular trial design." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Human genotype/ancestry contrasts, controlled rodent pharmacology, selective downstream-target tests and exposure-responsive human biomarkers were considered. They exclude different alternatives in restricted settings but are not a same-scope causal set demonstrating human native-MOTS-c administration and durable healthspan. The upper ladder remains reachable through a validated selective genetic instrument or registered human exposure intervention, not only one particular trial design." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 64, "claims_total": 68, "claims_verified": 68, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 64, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "A 12S-rRNA sORF, mitochondrial depletion assays and immunodetection support MOTS-c identity; administered peptide improves mouse insulin sensitivity and diet-induced obesity. Cytoplasmic translation is inferred from genetic code; broad mitochondrial depletion and immunoassays are not selective endogenous peptide knockout or human dosing.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C2", "text": "Synthetic MOTS-c improves mouse exercise capacity and late-life grip, gait and walking; human exercise raises measured endogenous peptide. Overall lifespan curve is not significant (P=0.23); human experiment is exercise, not peptide administration, and old-age functional benefit is male C57BL6/N specific.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C3", "text": "Metabolic stress induces measured MOTS-c nuclear translocation and AMPK-dependent stress-response transcription in cells. Cell localization and transcription do not establish organismal aging benefit, translation compartment or human treatment efficacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C4", "text": "Wild-type and K14Q peptides differ in insulin sensitization; three Japanese-ancestry cohorts link m.1382A>C with T2D in males and activity-dependent subgroups. Female mouse peptide effects are null; rRNA and linked haplogroup biology are not eliminated by structural predictions, and cohort association is not human administration.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph6, 1:RESULTS:paragraph11, 1:RESULTS:paragraph14. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C5", "text": "K14Q carriers show more fast-fiber markers and greater young-male strength; antibody neutralization shifts mouse fiber markers. Neutralizing antibody specificity and marker endpoint limit endogenous inference; sprint strength is not global healthspan or universally deleterious K14Q function.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C6", "text": "Synthetic MOTS-c binds CK2 by SPR; CK2 inhibition or cellular ASO blocks glucose-uptake effects, and K14Q fails tested mouse atrophy protection. CK2 responses differ between muscle and fat; an acknowledged nonspecific immunoblot band and overlapping human cohorts limit native identity and independent clinical inference.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph15, 1:Results:paragraph33, 1:Results:paragraph42, 1:Results:paragraph54. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C7", "text": "Mouse muscle PGC-1alpha and AMPK perturbations constrain peptide-induced mitochondrial bioenergetic changes; human interstitial levels increase during exercise. No human arterio-venous gradient change was observed; mitochondrial metrics are not healthspan extension and human secretion-source inference remains uncertain.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C8", "text": "Eight-day MOTS-c treatment attenuates cast-induced muscle loss and lipid infiltration in young male C57BL6J mice. Preventing induced atrophy at 15mg/kg/day is not natural aging reversal, long-term functional preservation or human efficacy.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C9", "text": "MOTS-c suppresses diabetes development in NOD mice and changes transferred T-cell diabetogenicity; human T1D cells respond ex vivo. NOD/adoptive-transfer and ex-vivo results retain model scope; linked erratum PMID34525370 was identified but its details were not examined.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C10", "text": "Peptide treatment improves glucose tolerance and offspring outcomes in diet/STZ gestational-diabetes mice. Induced gestational disease and STZ protection do not establish general human metabolic or adult-aging benefit.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C11", "text": "MOTS-c reduces ovariectomy-induced obesity and insulin resistance, with AMPK-linked adipose changes. Surgical estrogen loss and inhibitor specificity restrict inference; no human postmenopausal treatment or aging trajectory tested.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C12", "text": "Twelve-week peptide treatment alleviates ovariectomy-induced bone loss and inhibits osteoclastogenesis with partial AMPK-inhibitor reversal. Micro-CT and induced bone loss do not establish fracture reduction, native peptide necessity or human healthspan.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C13", "text": "MOTS-c improves cold tolerance and thermogenic responses with ERK-sensitive effects. Cold adaptation is stress resistance, not aging extension; pathway inhibitor and metabolic effects do not establish a single native mediator.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C14", "text": "MOTS-c improves myocardial mechanical efficiency and systolic function during exercise training in rats. Training adaptation is not durable aged-organism healthspan; the peptide need not mediate all exercise benefits.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C15", "text": "Paired samples in a randomized breast-cancer regimen show no significant circulating MOTS-c response to added metformin over 24 weeks. Patients received metformin/oncology therapy, not MOTS-c; commercial-ELISA null does not exclude local peptide changes.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C16", "text": "Intralipid raises measured plasma MOTS-c and insulin blunts the response in controls/PCOS; eight-week exercise does not change circulating levels. Lipids, insulin and exercise are the interventions; peptide movement cannot establish mediation or MOTS-c administration efficacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C17", "text": "Serum MOTS-c is similar in obese and normal-weight adults and correlates positively with HOMA-IR. Cross-sectional ELISA and age/metabolic confounding do not prove deficiency or therapeutic benefit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C18", "text": "MOTS-c or exercise improves cardiac structure/function in diet/STZ diabetic rats with NRG1-ErbB4 pathway associations. Transcriptomic pathway enrichment is not selective mediator necessity; induced diabetes is not organismal longevity.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C19", "text": "Eight-week MOTS-c treatment reduces ROS/TXNIP/NLRP3 inflammatory signals and myocardial injury in diabetic rats. Redox and inflammatory changes alone do not prove durable cardiac function or aging trajectory; pathway mediation remains incompletely isolated.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C20", "text": "Circulating MOTS-c is lower in adult T2D groups and associates with metabolic measurements. Cross-sectional disease/medication and immunoassay effects cannot determine causal deficiency, despite causal language in the original conclusion.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C21", "text": "Lean/obese adult peptide levels are similar and measured MOTS-c associates positively with insulin resistance chiefly in lean individuals. Small groups and surrogate sensitivity indices do not establish that raising peptide improves human metabolism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C22", "text": "Adiponectin, exercise and MOTS-c interventions regulate mouse peptide measurements through APPL1/SIRT1/PGC1alpha-linked experiments. Multiple pleiotropic manipulations and ectopic constructs do not selectively establish endogenous peptide necessity or human healthspan.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C23", "text": "AMPK/PGC1alpha manipulations, exercise and administered peptide change MOTS-c and metabolic signaling in cells and high-fat-fed mice. Expression loops, inhibitors and ectopic expression do not independently establish native peptide production or aging effects.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C24", "text": "Circulating MOTS-c associates positively with metabolic syndrome and liver/android fat, also rising in a hepatic-injury mouse diet. Higher measured peptide can accompany worse metabolic status; liver-stress compensation is plausible but observational rather than proven mediation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C25", "text": "MOTS-c promotes C2C12 differentiation and reduces lipid accumulation but not equivalent L6 responses, where lipid accumulation increases. Cell-line and fiber-type dependence constrain a universal anabolic/anti-lipid effect; no organismal endpoint.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C26", "text": "Measured peptide is reduced in obese male children and inversely associates with obesity/insulin-resistance markers. Female comparison is null; pediatric cross-sectional findings do not generalize to adults or demonstrate treatment effects, and assay units vary greatly across reports.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C27", "text": "Exercise intensity alters measured MOTS-c and glucose-related proteins in diabetic rodents. Exercise has many mediators and no selective peptide perturbation; original Wistar/sand-rat terminology is inconsistent and remains unresolved.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C28", "text": "Slow-twitch rat muscle retains glucose-transport/respiratory markers and expresses more UPRmt/MOTS-c during high-fat feeding. Fiber-type association without selective MOTS-c perturbation cannot prove peptide mediation of insulin-resistance protection.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C29", "text": "Adolescent PCOS/control measured peptide and metabolic associations are nonsignificant; every participant carries wild-type m.1382A. An all-wild-type cohort cannot test the effect of K14Q genotype; a null group comparison is not proof of no peptide biology.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C30", "text": "Senescent fibroblasts express more MOTS-c and peptide administration modestly increases respiration and selected SASP components. Senescence induction and mitochondrial/SASP changes do not establish anti-aging efficacy; selected secretory effects increase rather than uniformly decrease.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C31", "text": "Randomized heat/sham exposure during immobilization alters circulating MOTS-c in 19 active men. Heat is the intervention; marker movement does not show peptide mediation or native MOTS-c dosing prevents human muscle loss.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C32", "text": "A secondary analysis of an exercise RCT finds increased peptide in non-Hispanic White but not Hispanic breast-cancer survivors. Ethnicity groups differ at baseline and are small; exercise randomization is not peptide randomization or universal responder prediction.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C33", "text": "Pump-delivered MOTS-c attenuates pressure-overload cardiac dysfunction/remodeling in mice. TAC-induced failure and cell overexpression do not establish aging extension or native human cardiac necessity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C34", "text": "MOTS-c after STZ-diabetes establishment ameliorates mouse cardiac function and remodeling over 12 weeks. Post-disease treatment supports restricted pharmacology, not lifetime healthspan or human clinical benefit.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C35", "text": "MOTS-c improves glucose homeostasis and reduces cardiac hypertrophy in diabetic rats while changing mitochondrial respiration. Mitochondrial ROS rises in treated tissue; improved bioenergetics does not establish global antioxidant action or lifespan extension.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C36", "text": "Advanced-CKD patients show reduced muscle/serum MOTS-c alongside lower mitochondrial density and oxidative stress. Disease severity, renal handling and muscle composition confound direction; humanin and MOTS-c show different compartment patterns.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C37", "text": "Peptide lowers insulin secretion/expression and increases glucagon in pancreatic cell lines with altered survival/secretion. Cell lines do not establish systemic glycemic benefit; direction differs from a simple universal insulin-enhancing mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C38", "text": "MOTS-c changes aged-islet senescence and improves glucose intolerance in S961-treated and NOD mice; adult T2D peptide levels are lower. Mouse disease models and senescence markers do not establish generalized aging or human peptide-treatment efficacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C39", "text": "Marathon/sedentary humans and endurance-trained mice show associations among peptide, exercise capacity and respiration. Training is not selective peptide perturbation; source secretion and human causal mediation remain unresolved.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C40", "text": "MOTS-c preserves dexamethasone-exposed primary human myotube area and alters Akt/STAT3/atrophy pathways. Human-derived cells are not human treatment; pharmacological co-exposure and induced atrophy cannot establish clinical healthspan.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C41", "text": "MOTS-c facilitates TRIM72-dependent membrane repair; TRIM72 loss separates repair from vesicle fusion, and cardiac injury outcomes improve. Human exercise correlations remain nonselective and native peptide necessity is not universally established; membrane repair is not general aging delay.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C42", "text": "Lower measured serum MOTS-c tracks OSA severity and metabolic indices in patients. OSA, obesity and insulin resistance are interrelated; biomarker regression does not show benefit from peptide administration.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C43", "text": "MOTS-c changes AMPK/mTOR and mitochondrial/ROS markers in aged placenta-derived MSCs. In-vitro homeostasis is not restored organismal stem-cell repair, healthspan or clinical aging efficacy.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C44", "text": "MOTS-c and exercise improve diabetic-rat liver fibrosis with Keap1/Nrf2/Smad associations. Cell ectopic-expression and marker changes do not selectively establish an endogenous exercise mediator or general human benefit.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C45", "text": "Central peptide infusion raises GnRH and reproductive hormone measurements in obese/nonobese male rats. Intracerebroventricular delivery and hormones are not systemic clinical metabolic healthspan or proved fertility benefit.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C46", "text": "Obese children have lower measured peptide and vascular reactive-hyperemia indices with statistical mediation. Cross-sectional mediation is not causal mediation; peptide replacement and functional prevention were not tested.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C47", "text": "MOTS-c activates AMPK in obese human MSCs but increases senescence/inflammatory markers; pretreated MSCs fail or blunt kidney repair in mice. Cell pretreatment/transplant context is not direct human administration, but it refutes marker activation as a sufficient proxy for regenerative benefit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results:paragraph3, 2:Results:paragraph5, 2:Results:paragraph7, 2:Results:paragraph11. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C48", "text": "MOTS-c and exercise improve selected rat cardiac functional measures with NRG1/ErbB4/CEBPbeta-associated remodeling. Some endpoints and NRG1 transcript contrasts are null; healthy adaptation is not mechanistically isolated aging benefit.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C49", "text": "MOTS-c reduces abnormal lipid accumulation and tissue/mitochondrial changes in D-galactose-treated mice. Toxicity-induced pseudo-aging, histology and markers do not substitute for natural-aging healthspan or lifespan.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C50", "text": "Measured serum MOTS-c is similar among uncomplicated pregnancy and mild/severe preeclampsia groups. Nonsignificant small-group comparisons do not rule out all tissue effects or establish a therapeutic target.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C51", "text": "Exercise and MOTS-c improve diabetic myocardial fibrosis and systolic/diastolic measures with THBS1/TGFbeta association. Pathway transcript/ protein concordance is not isolated mediator necessity; no human peptide trial or longevity endpoint.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C52", "text": "MOTS-c alters rat/pig islet secretion and viability with different directions across species. Isolated islets are not organismal metabolic or aging outcomes; cross-species cellular effects cannot remove the healthspan scope cap.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C53", "text": "Eight-week peptide treatment preserves cardiac functional measures in diabetic rats with CCN1/ERK/EGR1 changes. Transcriptomic and apoptosis associations do not prove one direct mediator; related diabetic-rat programs are not automatically independent experiments.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C54", "text": "Older Korean men carrying K14Q-associated C allele have higher muscle mass and grip; women show no genotype difference. Cross-sectional population/context differs from Japanese low-mass-risk findings; direction is not universally adverse, and genotype is not administered peptide.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C55", "text": "Women with PCOS have lower serum and muscle immunodetected peptide with selected hormone/lipid associations. Cross-sectional tissue/serum measurements do not establish causal deficiency; linked erratum PMID42716952 details were not examined.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C56", "text": "Small peritoneal-dialysis cohort links lower serum/higher dialysate peptide to sarcopenia-risk and performance measures. Renal/peritoneal handling and disease burden confound direction; biomarker prediction is not peptide replacement benefit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C57", "text": "MOTS-c preserves selected skeletal-muscle mass in C26-cachectic mice but not total body weight/fat; function improvement is a trend. Partial wasting-model protection is not complete functional rescue or healthspan extension, and induced cancer context remains.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C58", "text": "Obese adults have higher circulating peptide; after bariatric surgery BMI and selected metabolic indices improve without peptide normalization. Ten-person observational follow-up and ELISA limit mediation; original body/abstract/table numbers disagree, so no single repaired numeric value is invented.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results:paragraph5, 2:Results:paragraph19, 2:Results:paragraph22. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C59", "text": "Healthy aging men show lower circulating but higher muscle peptide with fiber-type/muscle-quality associations. Opposite compartment directions and small RNA/immunoassays do not prove a systemic deficiency or peptide treatment benefit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C60", "text": "Training raises muscle peptide and a single synthetic dose improves mouse acute running time/distance. Acute performance is not durable aging change; nuclear translocation occurs in only 2 of 6 soleus samples and not plantaris.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C61", "text": "Resting serum peptide correlates with jump force/power and muscle mass but not peak VO2 in 20 active volunteers. Small observational sample does not establish endurance benefit or dosing efficacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C62", "text": "Higher circulating peptide predicts death/CV events in 94 hemodialysis patients during follow-up. Renal handling and illness severity may determine marker levels; adverse-risk association does not show peptide causes harm or treatment benefit.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C63", "text": "MOTS-c has direct antibacterial/cell immune effects; MRSA pretreated with peptide causes less lethal mouse peritonitis. Bacteria were exposed before inoculation, so this is not endogenous peptide necessity or aging treatment; updated preprint is not a separate primary study.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph9. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C64", "text": "Avian 12S-region sequence and chicken immunodetection/cellular responses extend candidate peptide biology with divergent sequence. Avian primary-cell signaling is not mammalian healthspan; bioinformatic coding potential and immunodetection do not directly resolve native translation machinery.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC1", "text": "The 12S-rRNA-region sequence, rho0/actinonin depletion and immunodetection support mitochondrial genomic origin and a bioactive peptide. Synthetic sequence-specific activity and stress localization are reproducible in selected systems. Native production, transcript export, translation machinery and quantitative assay specificity are not selectively resolved by broad mitochondrial depletion or by activity of administered peptide. Γ records partial endogenous molecular support, not denial that the reported sequence or synthetic peptide exists.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 13, 15, 16, 17, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 36, 37, 38, 39, 41, 42, 46, 50, 52, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC2", "text": "Controlled peptide administration changes glucose handling, induced cardiac dysfunction, muscle atrophy and late-life physical capacity in defined rodent settings. Metabolic outcomes span CD1 and C57BL6 backgrounds and rat models, with mapped sex, variant, tissue and cell-context boundaries. Ε applies to context-specific mammalian metabolic/functional pharmacology under the explicitly declared phenotype adaptation. The aging-specific branch is narrower: late-life physical-function evidence remains principally male C57BL6/N, and overall lifespan is not significantly extended. This does not establish generalized mammalian aging delay or endogenous peptide necessity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 18, 19, 22, 23, 25, 27, 28, 30, 33, 34, 35, 37, 38, 39, 40, 41, 43, 44, 45, 47, 48, 49, 51, 52, 53, 57, 60, 63, 64 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC3", "text": "The registered human administration-and-healthspan claim has mechanistic and preclinical support, but no examined original report administers native MOTS-c to humans and demonstrates durable clinical metabolic function plus healthspan. Human exercise, heat, metformin, lipid/insulin infusion and bariatric surgery manipulate other exposures; peptide associations or marker changes cannot supply peptide treatment causality. Genotype evidence is sex/activity/age dependent and not a clean intervention instrument. Overall Γ follows this registered SC3 gate.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 4, 5, 6, 7, 9, 15, 16, 17, 20, 21, 24, 26, 29, 31, 32, 36, 38, 39, 40, 42, 43, 46, 47, 50, 54, 55, 56, 58, 59, 61, 62 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CH", "text": "MOTS-c has measurable metabolic and functional effects in rodent models; benefit from administering native MOTS-c to humans for healthspan remains unestablished.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 6, 7, 47, 58 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-12", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Lee C, Zeng J, Drew BG et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell metabolism. 2015.", "tier": "A", "kind": "primary", "pmid": "25738459", "doi": "10.1016/j.cmet.2015.02.009", "url": "https://pubmed.ncbi.nlm.nih.gov/25738459/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25738459", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 2, "citation": "Reynolds JC, Lai RW, Woodhead JST et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature communications. 2021.", "tier": "A", "kind": "primary", "pmid": "33473109", "doi": "10.1038/s41467-020-20790-0", "url": "https://pubmed.ncbi.nlm.nih.gov/33473109/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33473109", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 3, "citation": "Kim KH, Son JM, Benayoun BA et al. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell metabolism. 2018.", "tier": "A", "kind": "primary", "pmid": "29983246", "doi": "10.1016/j.cmet.2018.06.008", "url": "https://pubmed.ncbi.nlm.nih.gov/29983246/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29983246", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC2" ] }, { "n": 4, "citation": "Zempo H, Kim SJ, Fuku N et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging. 2021.", "tier": "A", "kind": "primary", "pmid": "33468709", "doi": "10.18632/aging.202529", "url": "https://pubmed.ncbi.nlm.nih.gov/33468709/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MOTS_K14Q_JMICC_MEC_TMM", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph6, 1:RESULTS:paragraph11, 1:RESULTS:paragraph14. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC2", "CSC3" ] }, { "n": 5, "citation": "Kumagai H, Natsume T, Kim SJ et al. The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance. Biochimica et biophysica acta. General subjects. 2022.", "tier": "A", "kind": "primary", "pmid": "34728329", "doi": "10.1016/j.bbagen.2021.130048", "url": "https://pubmed.ncbi.nlm.nih.gov/34728329/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34728329", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC2", "CSC3" ] }, { "n": 6, "citation": "Kumagai H, Kim SJ, Miller B et al. 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No complete-paper or supplement audit claimed.", "carries_claims": [ "C64", "CSC1", "CSC2" ] } ], "independence_basis": { "required": false, "lines": [ { "label": "Rodent exogenous phenotypic intervention", "sources": [ 1, 2, 18, 34 ], "excludes_error": "Constrain pure marker association in tested settings; shared synthetic dosing, rodent husbandry and dose errors remain." }, { "label": "Peptide variant and downstream target contrasts", "sources": [ 4, 6, 7, 41 ], "excludes_error": "Constrain sequence-independent and selected target explanations; pleiotropic downstream perturbation and mitochondrial genotype effects remain." }, { "label": "Human exposure and compartment response", "sources": [ 16, 32, 58, 59 ], "excludes_error": "Constrain a universally deficient circulating signal; exposures have many mediators and do not selectively administer peptide." }, { "label": "Functional negative and conflicting population tests", "sources": [ 47, 54, 29, 57 ], "excludes_error": "Constrain universal protection or harmful-genotype interpretations without negating positive restricted pharmacology." } ], "shared_failure_mode_checked": true, "note": "J-MICC-derived genotype analyses in PMID33468709 and PMID39559755 share population/genotype infrastructure and may overlap participants; they are not independent human causal lines. Related Lee/Cohen/Reynolds/Kim programs share peptide reagents, antibodies and paradigms despite different papers. Diabetic-rat exercise/cardiac pathway reports may share laboratory/model resources; exact animal reuse was not established by abstract access. A preprint and its updated published host-defense report count once. 64 reports are not 64 studies or 64 independent causal lines." }, "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed output and citation link mappings", "queries": [ "https://consensus.app/search/mots-c-mitochondrial-peptide-metabolism/8p8nFrY3Q5qnDyJaFh4rKA/" ], "query_record_note": "Exact visible question/response retained privately in raw browser receipt.", "primary_comparison_count": 8, "primary_comparisons": [ { "pmid": "25738459", "doi": "10.1016/j.cmet.2015.02.009", "source_type": "primary study report", "study_group": "PMID25738459", "access_depth": "full_text_partial", "consensus_aspect": "Mitochondrial genomic origin and translation compartment", "result_comparison": "Original Results 0–1 report 12S-region coding potential, NUMT searches and loss of immunodetected peptide/transcripts after rho0 or actinonin depletion. Cytoplasmic translation is an inference from the standard versus mitochondrial genetic code; native export/translation was not directly tracked. Provider genome-origin wording should not become proof of mitoribosomal production or complete native assay validation.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/25738459/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-0-16-3500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\body-presentation-receipts\\25738459-s1-p0-1-9-10-12.json" ] }, { "pmid": "33473109", "doi": "10.1038/s41467-020-20790-0", "source_type": "primary study report", "study_group": "PMID33473109", "access_depth": "full_text_partial", "consensus_aspect": "Late-life dosing, functional healthspan and survival", "result_comparison": "Original Results 6/8 verify male C57BL6/N functional gains and intermittent 15 mg/kg 3 times/week dosing beginning around 23.5 months. Overall survival is nonsignificant P=0.23. Food intake differs during late-life treatment, so the provider's no-hyperphagia description is not retained; a restricted early survival comparison is not whole-curve lifespan extension.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/33473109/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-0-16-3500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\body-presentation-receipts\\33473109-s1-p0-5-6-8.json" ] }, { "pmid": "33468709", "doi": "10.18632/aging.202529", "source_type": "primary study report", "study_group": "MOTS_K14Q_JMICC_MEC_TMM", "access_depth": "full_text_partial", "consensus_aspect": "K14Q genotype and 12S-rRNA structural alternative", "result_comparison": "Original Results 0 predicts little 12S-rRNA secondary-structure difference, not direct demonstrated structural perturbation as the provider states. Results 6 shows female mouse WT/K14Q nulls, and cohort effects are sex/activity dependent. rRNA/linked mtDNA effects remain possible rather than proven.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/33468709/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-0-16-3500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\body-presentation-receipts\\33468709-s1-p0-6-11-14.json" ] }, { "pmid": "39559755", "doi": "10.1016/j.isci.2024.111212", "source_type": "primary study report", "study_group": "MOTS_K14Q_CK2_WITH_JMICC_COMPONENT", "access_depth": "full_text_partial", "consensus_aspect": "Direct target and native assay specificity", "result_comparison": "Original Results 7/15/42 verify supplied-peptide SPR binding and CK2-dependent uptake through inhibitor/cellular ASO controls. Muscle/adipose kinase effects differ and an input immunoblot has an acknowledged nonspecific band. Synthetic target binding supports pharmacology but does not validate every native ELISA signal.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/39559755/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-0-16-3500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\body-presentation-receipts\\39559755-s1-p7-15-33-42-54.json" ] }, { "pmid": "41520850", "doi": "10.1016/j.freeradbiomed.2026.01.002", "source_type": "primary study report", "study_group": "PMID41520850", "access_depth": "abstract_metadata", "consensus_aspect": "Human exercise trans-organ flux", "result_comparison": "Complete original PubMed abstract verifies increased human interstitial peptide with no changed arterio-venous difference, plus mouse PGC1alpha/AMPK dependence of mitochondrial metrics. Provider muscle-source caution is supported, but absence of a gradient is not proof of zero muscle secretion. This source was examined at abstract depth, not full-text depth.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/41520850/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-0-16-3500.json" ], "body_receipts": [] }, { "pmid": "42324588", "doi": "10.1186/s41232-026-00431-7", "source_type": "primary study report", "study_group": "PMID42324588", "access_depth": "full_text_partial", "consensus_aspect": "Positive AMPK signal versus functional repair", "result_comparison": "Original Results 3/5/7/11 show AMPK activation with adverse senescence/inflammatory changes and impaired repair after human MSC pretreatment/transplantation in mice. This original negative-context test is missing from the provider synthesis and prevents signaling activation from being promoted to general regenerative benefit.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/42324588/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-32-48-4000.json", "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-40-48-4000.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\body-presentation-receipts\\42324588-s2-p3-5-7-11.json" ] }, { "pmid": "41551324", "doi": "10.1016/j.jcte.2025.100429", "source_type": "primary study report", "study_group": "OBESITY_BARIATRIC_MOTS_PARENT", "access_depth": "full_text_partial", "consensus_aspect": "Human systemic-marker direction and mediation", "result_comparison": "Original Results 5/19/22 show higher adult-obesity peptide measurements and no significant peptide change despite postsurgery metabolic/weight improvement. Abstract, body and table numeric summaries disagree, so the review retains direction/null status without an invented corrected value. Provider generalized deficiency framing is incomplete.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/41551324/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-48-64-4000.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\body-presentation-receipts\\41551324-s2-p5-19-22.json" ] }, { "pmid": "39457696", "doi": "10.3390/biomedicines12102384", "source_type": "primary study report", "study_group": "PMID39457696", "access_depth": "abstract_metadata", "consensus_aspect": "Opposite genotype-performance context", "result_comparison": "Complete original abstract reports higher muscle mass/grip among older Korean male C-allele carriers, with female nulls. This qualifies the provider's adverse-K14Q framing; observational population results are not proof of peptide dosing benefit or harm.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/39457696/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-48-56-4000.json", "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\examinations\\original-48-64-4000.json" ], "body_receipts": [] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\mots-c-mitochondrial\\consensus-browser-2026-10-12.json", "sha256": "f9ee3374a15bf9669903fca81efddc0af61ea48c08675b11bffaa50425179069" } ], "independent_blinded_audit": false, "cutoff": "2026-10-09", "completed_utc": "2026-10-12T19:55:27.108848+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }