# HSEF v5.3 review: MOTS-c as a Metabolic Healthspan Peptide

> Sources: 64 primary reports; claims: 68; verified: 68; unverified: 0. Verification is bounded attribution. Access: 7 partial-body and 57 bounded abstract/status examinations. Literature cutoff: 2026-10-09; source examination UTC date: 2026-10-12. No complete-paper audit or blinded calibration claimed.

> **Adversarial review:** Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 4 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: **Approved as revised.**

## AT A GLANCE

**MOTS-c has measurable metabolic and functional effects in rodent models; benefit from administering native MOTS-c to humans for healthspan remains unestablished.**

| Level | Confidence | Causal role | Momentum | Stability | Divergence |
|---|---|---|---|---|---|
| Γ — Mechanistically plausible, partial system support | Moderate | reinforcing / stabilizing factor | Mechanistic only | Stable | Contested |

**Deciding 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.

**Belief versus evidence:** 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.

**Best-supported rival:** Context-dependent exogenous peptide pharmacology. 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.

## COMPETING MECHANISTIC MODELS

**Rank 1: Context-dependent exogenous peptide pharmacology (Ε).** Supplied MOTS-c can change defined glucose, muscle and cardiac phenotypes through multiple tissue-dependent pathways. 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 2: Adaptive endogenous stress signal (Γ).** Endogenous peptide measurements change with exercise, lipid load, tissue composition and illness as part of a context-dependent stress response. 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 3: Native human MOTS-c healthspan intervention (Γ).** Administering native MOTS-c improves human metabolism and durable healthspan. 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 4: Assay and mitochondrial-genotype confounding (Γ).** Part of the apparent systemic peptide signal or genotype-risk attribution reflects immunoassay, tissue/renal handling or linked mitochondrial biology. 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.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

## FULL REVIEW

### Registered claim and scope

MOTS-c is a mitochondrial-derived peptide that improves human metabolic function and healthspan.

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.

Selection: remaining-priority list position 13 from the editorial list of 2026-10-09. Registered claim assessed against original sources. Any carried-forward edition and prior visibility are recorded in the change record; no independent blinded calibration is claimed.

### Evidence and causal interpretation

Rubric fit: 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.

Origin requires precise language. MOTS-c is a proposed 16-amino-acid peptide encoded by a short ORF within mitochondrial 12S-rRNA. The 2015 original explicitly infers cytoplasmic translation using the standard genetic code: mitochondrial-code translation would terminate prematurely. NUMT searches, rho0cells, actinonin depletion and immunodetection support mitochondrial origin, but broad mitochondrial disruption can affect multiple processes. These are not direct proof that the mitochondrial ribosome makes native MOTS-c or that every ELISA signal is the sequence-specific endogenous peptide. PMID25738459; PMID29983246; PMID40805020.

Controlled rodent metabolic effects are real evidence for supplied-peptide activity. The 2015 study includes clamps, glucose disposal, two mouse backgrounds and high-fat-diet controls whose caloric intake is similar. WT/K14Q comparisons, CK2 inhibition and human-cell CK2 ASO add target/sequence discrimination. Muscle CK2 activation, adipose suppression and liver nulls show that the pathway direction is tissue-specific. Human-derived cell interventions are mechanistic evidence rather than human treatment. PMID25738459; PMID33468709; PMID39559755; PMID41732124.

The 2021 late-life mouse study supports physical function: grip, gait and walking improve after intermittent 15 mg/kg dosing 3 times weekly beginning around 23.5 months. It does not establish significant overall lifespan extension: the full survival curve is P=0.23, although a restricted early survival comparison reaches P=0.05. Food-intake differences are present in the late-life experiment, so the provider's unqualified no-hyperphagia statement is not retained. Old-age benefits are principally male C57BL6/N; acute young-mouse running, D-galactose pseudo-aging and mitochondrial markers are not equivalent aging trajectories. PMID33473109; PMID35808870; PMID30967270.

Human exercise can increase measured endogenous peptide, but exercise has many mediators. Some exercise subgroups and eight-week PCOS/control training are null; metformin addition is also null for circulating peptide. The 2026 original finds no exercise arterio-venous change across contracting muscle despite interstitial increase, weakening a simple inference that muscle supplies the circulating signal. These experiments are not randomized peptide administration or clinical healthspan evidence. PMID33473109; PMID34413391; PMID31066084; PMID36490309; PMID41520850.

Human measurements differ by compartment, disease and assay. Aging men show lower plasma but higher muscle expression; obesity studies report lower, similar or higher circulating values. The 2026 bariatric cohort improves BMI and selected metabolic indices without circulating-peptide normalization. Its abstract, Results and table contain inconsistent numeric summaries, so this review retains the direction and null change without inventing a repaired mean or BMI. Dialysis clearance and illness severity complicate both favorable and adverse marker-risk associations. PMID32182209; PMID29691953; PMID29593067; PMID41004666; PMID41551324; PMID39111290; PMID40005438.

K14Q is not a clean human peptide-efficacy experiment. The 2021 original reports little predicted12S-rRNA secondary-structure difference, not demonstrated direct rRNA disruption; selective rRNA effects remain unexcluded. Japanese male diabetes/low-mass findings interact with activity/age, while females and young-strength outcomes differ. The 2024 Korean older-male study instead associates the C allele with higher muscle mass and grip. Overlapping J-MICC resources do not count as independent clinical causal lines. PMID33468709; PMID34728329; PMID39559755; PMID39457696; PMID41945630.

A positive signaling marker can coexist with functional failure. The 2026 human-MSC original finds AMPK activation but more senescence/inflammatory markers and poorer renal repair after cell pretreatment/transplantation. C26-cachectic mice show selected muscle-mass preservation with no total-weight/fat rescue and only a functional trend. These boundaries constrain blanket cytoprotection without erasing positive specific model effects. The host-defense original pretreats MRSA before inoculation, so its survival effect is acute pathogen neutralization rather than native peptide necessity or aging extension. PMID42324588; PMID42266945; PMID42611943.

Consensus supported targeted gap/timeline discovery and highlighted source/translation and human-versus-model distinctions. Original-source checks qualify its claims of direct rRNA structural perturbation, no hyperphagia and unverified analogue trial identity. Its 20 provider-read papers and matrix cells are not 64 examined primary reports or an exhaustive field gap map. Scite was attempted for 3 anchors but returned a monthly-quota failure; no citation tallies or incoming contrasting statements were received.

## HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

### Subclaim matrix and aggregation

| Subclaim | Scope | Level | Decision |
|---|---|---|---|
| SC1 MOTS-c is an endogenous biologically active peptide encoded within the mitochondrial 12S rRNA region. | Sequence, translation compartment and assay specificity distinguished from peptide administration | Γ | 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. |
| SC2 MOTS-c manipulation improves metabolic or functional aging outcomes in mammalian models. | Species, endogenous versus administered peptide, dose, sex and age predefined | Ε | 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. |
| SC3 Administering MOTS-c improves human metabolic function and healthspan. | Humans with intervention and clinical/metabolic functional outcomes specified | Γ | 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. |

Preregistered aggregation: primary-subclaim. 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. Sensitivities: weakest-link Γ; primary-subclaim Γ; scope-matched Γ.

### Decisive-perturbation inventory and causal tally

[1] 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.

[2] 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.

[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. Female mouse peptide effects are null; rRNA and linked haplogroup biology are not eliminated by structural predictions, and cohort association is not human administration.

[6] 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.

[7] 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.

[47] 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.

[54] 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.

[58] 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.

Tally: 8 positive qualifying study units across scoped subclaims; 44 screened discriminating contrast units. These are not independent causal lines or proof of full-claim necessity/sufficiency. 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.

### Cap audit, precedence and Β/Γ/Δ boundary

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.

Universal six-cap audit: All six universal caps were considered: cell-only inference, unperturbed association, ectopic expression, biomarker-only intervention, forced transfer/seeding, and inherited-to-sporadic scope transfer. Each binds its offered inference; complementary same-scope causal classes are assessed together rather than re-capped in isolation.

Gamma hard-rule audit: SC1 cell activity and broad mitochondrial depletion do not isolate native peptide production; universal in-vitro and overexpression limits bind those inferences. SC2 mitochondrial/ROS/senescence-only endpoints do not earn functional crossings; the natural-aging branch remains predominantly one mouse background. SC2 specified metabolic organismal outcomes are not marker-only; diet, genotype, sex and treatment timing constrain their scope. SC3 contains no examined human native-peptide administration with durable healthspan; associations, exercise responses and cultured human cells cannot substitute.

SC1 cap: “In vitro evidence alone cannot exceed Γ.” 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.

SC3 cap: “Biomarker change without functional/phenotypic change caps at Γ.” 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.

SC1 field-valid definition: “
- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension
- Must separate developmental effects from true aging effects
- Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. 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.

SC2 field-valid definition: “
- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension
- Must separate developmental effects from true aging effects
- Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: yes. 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.

SC3 field-valid definition: “
- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension
- Must separate developmental effects from true aging effects
- Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. 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.

### Upward threshold ladder

SC1 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied under stated scope/adaptation: no. 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. The molecular identity/production claim is evaluated as a cell/molecular branch, not as lifespan extension.

SC2 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied under stated scope/adaptation: yes.  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.

SC2 Ε: “Requires causal effect in constrained contexts, backgrounds, or species.” Satisfied under stated scope/adaptation: yes.  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.

SC2 Ζ: “Requires:
- Reproducible intervention effects
- Mechanistic narrowing
- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts” Satisfied under stated scope/adaptation: no. 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. 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.

SC3 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied under stated scope/adaptation: no. 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. Human administration plus durable healthspan remains unadapted and uncrossed.

Upper ladder: 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.

Independence: 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.

Rodent exogenous phenotypic intervention [1, 2, 18, 34]: Constrain pure marker association in tested settings; shared synthetic dosing, rodent husbandry and dose errors remain.

Peptide variant and downstream target contrasts [4, 6, 7, 41]: Constrain sequence-independent and selected target explanations; pleiotropic downstream perturbation and mitochondrial genotype effects remain.

Human exposure and compartment response [16, 32, 58, 59]: Constrain a universally deficient circulating signal; exposures have many mediators and do not selectively administer peptide.

Functional negative and conflicting population tests [47, 54, 29, 57]: Constrain universal protection or harmful-genotype interpretations without negating positive restricted pharmacology.

### Falsification and pitfalls

Pathway manipulation changes biomarkers but not functional benefit in a defined model. 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. Additional downgrade: False.

Exercise response treated as peptide efficacy. Exercise/heat/metformin interventions measure peptide but do not administer it.

Mitochondrial genome origin treated as mitoribosomal translation. The original infers cytoplasmic translation and does not directly resolve the native machinery.

Synthetic target binding validates all native immunoassays. SPR concerns supplied peptide; native circulating identity remains an independent measurement problem.

Marker or acute performance becomes healthspan. AMPK, respiration, induced injury and one-run performance are distinct from durable aged-organism function.

Shared cohorts and universal genotype prediction. J-MICC overlap and sex/age/activity-dependent opposing K14Q observations restrict independence and scope.

### Adversarial steelman: above, then below

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.

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.

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.

### Final score, causal direction and M/S/D

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.

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.

Momentum: Mechanistic only. 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: Stable. 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: Contested. No manufactured field consensus or arithmetic gap. These dimensions do not change level or confidence.

## PROPOSED DECISIVE EXPERIMENTS

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. Controls: 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: Adequate native-peptide exposure produces reproducible clinically meaningful metabolic and durable functional benefit with predicted target engagement and prospectively validated context. Falsifying: 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

Native transcript export, cellular translation machinery and quantitative peptide identity need direct orthogonal tests.

No examined primary native-MOTS-c human administration study establishes metabolic function plus durable healthspan.

Physiological concentrations and synthetic pharmacologic dosing need a validated exposure bridge.

Late-life functional benefit and overall lifespan are different; natural-aging replication across backgrounds/species and sexes is incomplete.

K14Q cohort findings depend on sex, age and activity and can point in opposite directions across populations; 12S-rRNA and mitochondrial linkage alternatives require selective tests.

Circulating peptide can rise with metabolic stress and remain elevated after improvement; tissue sources and renal handling are unresolved.

AMPK/mitochondrial marker activation can coexist with worse repair; functional and adverse outcomes must be prespecified.

Shared cohorts, peptide reagents and assay platforms require independent error-mode assessment rather than paper-count convergence.

## REVIEWER NOTES

Original primary abstracts/status records and selected body passages were examined. Most full papers and supplements were not audited. Consensus browser synthesis supplements discovery and original-source reconciliation. No independent blinded grading or scientific peer review is claimed.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

## Consensus and original-source reconciliation

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 PMID25738459](https://pubmed.ncbi.nlm.nih.gov/25738459/).

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 PMID33473109](https://pubmed.ncbi.nlm.nih.gov/33473109/).

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 PMID33468709](https://pubmed.ncbi.nlm.nih.gov/33468709/).

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 PMID39559755](https://pubmed.ncbi.nlm.nih.gov/39559755/).

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 PMID41520850](https://pubmed.ncbi.nlm.nih.gov/41520850/).

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 PMID42324588](https://pubmed.ncbi.nlm.nih.gov/42324588/).

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 PMID41551324](https://pubmed.ncbi.nlm.nih.gov/41551324/).

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 PMID39457696](https://pubmed.ncbi.nlm.nih.gov/39457696/).

Consensus was used to identify literature and cross-check specific claims about design, endpoints, scope and research gaps. Those aspects were checked against original primary abstracts/status records and selected original Methods/Results passages. Consensus output was not treated as original full text. Provider search omissions are not evidence that a study does not exist. Source access and examination receipts are retained. Scite use or monthly unavailability is recorded per case; provider citation counts do not change causal grades.

## Research timeline and gaps: MOTS-c as a Metabolic Healthspan Peptide

Selected publication milestones, not an exhaustive history or discovery priority claim.

**2015 — 12S-rRNA-region peptide candidate and controlled mouse glucose/clamp/diet experiments; genomic origin and supplied-peptide function enter the model separately.** [Original PMID25738459](https://pubmed.ncbi.nlm.nih.gov/25738459/).

**2018 — stress-induced nuclear localization and AMPK-dependent transcription in cells; cellular retrograde signaling is distinguished from human treatment.** [Original PMID29983246](https://pubmed.ncbi.nlm.nih.gov/29983246/).

**2019 — human intralipid/insulin and training responses expose context-dependent circulating-marker regulation rather than peptide administration.** [Original PMID31066084](https://pubmed.ncbi.nlm.nih.gov/31066084/).

**2020 — aging men show opposite plasma/muscle directions, challenging a simple systemic deficiency account.** [Original PMID32182209](https://pubmed.ncbi.nlm.nih.gov/32182209/).

**2021 — late-life male-mouse grip/gait/walking benefit alongside human exercise-induced marker change; overall survival extension remains nonsignificant.** [Original PMID33473109](https://pubmed.ncbi.nlm.nih.gov/33473109/).

**2021 — WT/K14Q sequence contrasts and Japanese-ancestry genotype associations map sex/activity dependence rather than universal genotype causality.** [Original PMID33468709](https://pubmed.ncbi.nlm.nih.gov/33468709/).

**2024 — CK2 binding, inhibitor/ASO necessity and tissue-dependent responses strengthen targeted pharmacology; human genotype components retain overlap limitations.** [Original PMID39559755](https://pubmed.ncbi.nlm.nih.gov/39559755/).

**2024 — older Korean male K14Q carriers show higher muscle/strength, requiring prospective population/context reconciliation.** [Original PMID39457696](https://pubmed.ncbi.nlm.nih.gov/39457696/).

**2026 — mouse PGC1alpha/AMPK-dependent mitochondrial effects and human no-gradient exercise measurement sharpen target and source questions.** [Original PMID41520850](https://pubmed.ncbi.nlm.nih.gov/41520850/).

**2026 — AMPK activation can accompany worse MSC repair, while obesity/bariatric data (PMID41551324) show that peptide levels need not normalize with metabolic improvement.** [Original PMID42324588](https://pubmed.ncbi.nlm.nih.gov/42324588/).

## Research gaps

Native transcript export, cellular translation machinery and quantitative peptide identity need direct orthogonal tests.

No examined primary native-MOTS-c human administration study establishes metabolic function plus durable healthspan.

Physiological concentrations and synthetic pharmacologic dosing need a validated exposure bridge.

Late-life functional benefit and overall lifespan are different; natural-aging replication across backgrounds/species and sexes is incomplete.

K14Q cohort findings depend on sex, age and activity and can point in opposite directions across populations; 12S-rRNA and mitochondrial linkage alternatives require selective tests.

Circulating peptide can rise with metabolic stress and remain elevated after improvement; tissue sources and renal handling are unresolved.

AMPK/mitochondrial marker activation can coexist with worse repair; functional and adverse outcomes must be prespecified.

Shared cohorts, peptide reagents and assay platforms require independent error-mode assessment rather than paper-count convergence.

## Boundary 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.


## ADVERSARIAL REVIEW AND APPROVAL

**Authoring model:** Sol 6.1. **Adversarial reviewer:** Claude Opus 5.5 (Anthropic). **Date:** 2026-10-14.

**Scope of checks.** All 64 REFERENCES PMIDs plus the three that appear only in the body (34525370, 39553971, 42716952) were resolved against PubMed and matched on first author, title, journal, year and DOI: 67/67 resolved, no wrong identifiers, no retracted publication and no expression of concern. Thirteen load-bearing claims were spot-checked against the source abstracts and, where the review declares partial-body access, against what the abstract does and does not carry: PMIDs 25738459, 33473109, 33468709, 39559755, 41520850, 42324588, 39457696, 41551324, 32182209, 39111290 and the two erratum records. Scoring logic was re-derived from `references/hsef-framework.md`, SKILL.md Steps 2-3 and 8, and `references/evidence-rubrics/06-metabolism-aging.md`: the Gamma-cap hard rules (including the single-species/single-strain rule), the pre-registered primary-subclaim rule, the reported alternatives, the declared SC2 phenotype adaptation, the upper-ladder record and the role-derivation step were each re-checked.

### Findings

| ID | Severity | Location | Original to corrected | Evidence |
|---|---|---|---|---|
| F1 | Minor | Evidence and causal interpretation; Consensus reconciliation; evidence cards [9], [16], [18], [29], [32], [34], [53], [57], [62]; PROPOSED DECISIVE EXPERIMENTS | Twelve quantitative statements in which the reference builder had dropped the spaces around numerals were re-spaced, e.g. "intermittent15mg/kg dosing3times weekly beginning around23.5months" to "intermittent 15 mg/kg dosing 3 times weekly beginning around 23.5 months"; "events in94hemodialysis patients" to "events in 94 hemodialysis patients"; "metformin over24weeks" to "metformin over 24 weeks"; "only2of6soleus" to "only 2 of 6 soleus"; "peakVO2 in20active volunteers" to "peak VO2 in 20 active volunteers"; "MOTS-c in19active men" to "MOTS-c in 19 active men"; "remodeling over12weeks" to "remodeling over 12 weeks" | Known rendering defect class. The underlying values are correct: PMID 33473109 reports late-life (23.5 mo) initiated intermittent treatment 3x/week, and PMID 39111290 studies 94 haemodialysis patients. Dose, schedule, duration and denominator are the figures a reader is most likely to misread when the digits are glued to words, so these were fixed rather than left as house style. |
| F2 | Minor | Research timeline (review), `RESEARCH_TIMELINE.md`, `research-timeline.json` | All ten milestone headings printed the year twice and then ran it into the text, e.g. "**2015 — 2015:12S-rRNA-region peptide candidate ...**"; the redundant prefix was removed and the space restored | Rendering defect; the sibling reviews in this corpus print "**YYYY — Text**". |
| F3 | Editorial | Throughout the review, the score card and `CONSENSUS_CROSSCHECK.md` | Forty-five further glued tokens were separated, e.g. "The2015original", "The2026human-MSC", "Its20provider-readpapers", "count once.64reports are not64studies or64independent causal lines", "universal cap3", "adaptation of06", "Step5", "proposed16-amino-acid", "mitochondrial12S-rRNA", "preserving12S-rRNA", "rho0oractinonin", "humanMSCpretreatment", "worseMSCrepair", "inhibitor/cellularASO", "rRNA/linkedmtDNA", "Original Results0–1" | Same rendering defect class; no factual content changed. |
| F4 | Minor | Score card `final_score.confidence_rationale` | "64 primary reports with 7 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness." to a rationale resting only on evidence density and reproducibility | The framework ties confidence to evidence density and reproducibility and does not list the reviewer's access depth, so "incomplete access" did not belong in the derivation. The **band was re-derived and stays Moderate**: 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 declined on that reagent and laboratory concentration; Low was declined because independent groups reproduce the exposure-response measurements. |

### Rejected findings (checked, no change)

- **"Best-supported rival" names the correct model.** The score card marks the rank-1 model `is_nominal: false` and the nominal model at its own lower rank; the AT A GLANCE prose names the rank-1 rival, so the renderer bug reported elsewhere in this round did not fire here.
- **No false-approval or foreign-provenance clause.** This case is not one of the 9 October revised editions, carries no "earlier adversarial approval" sentence, and its Selection and methods provenance statements were each checked against the package and apply to this case. REVIEWER NOTES and the Consensus section do not contradict each other.
- **Headline letter Γ.** Re-derived independently. The pre-registered rule is primary-subclaim with SC3 named, and all three alternatives genuinely return Γ here (weakest-link takes the lowest of Γ/Ε/Γ; scope-matched takes SC3, the only subclaim at the registered human-administration scope). The Ε on SC2 is scope-restricted and correctly does not set the headline, which is the aggregation error this round was told to look for.
- **The declared SC2 phenotype adaptation.** Rubric 06's Δ criterion is written in terms of lifespan or healthspan extension; the review substitutes controlled reproducible organismal glucose, cardiac and muscle outcomes and says so in four places, keeping the archived criterion quoted verbatim and holding the natural-aging branch at Γ under the rubric's own "single-species or single-strain evidence" hard rule. That is the cap-versus-threshold procedure the framework prescribes, applied openly rather than silently. PMID 33473109's late-life physical-capacity result would arguably satisfy the unadapted healthspan criterion on its own terms, which makes the review's handling conservative rather than permissive. No change.
- **Causal role `reinforcing / stabilizing factor` (step 5).** An adversarial case exists for `epiphenomenon` at the registered human scope, since no human causal dependency is demonstrated in either direction. The review's reasoning — that bidirectional pharmacologic functional effects in rodents go beyond co-occurrence — is defensible, is written out, and the label does not modify the level. No change.
- **Momentum "Mechanistic only".** The required artifact is present and names specific work (PMID 39559755 CK2 binding and inhibition, PMID 41520850 PGC-1α/AMPK-dependent bioenergetics and the human exercise flux measurement, PMID 42324588 the marker-positive/repair-negative MSC intervention). It is not the "Decisive work underway" boilerplate.
- **Errata on PMIDs 34320351 and 41680431.** Both have published corrections (34525370 and 42716952). Neither reference line notes them, but both are recorded in the Access/status line of the corresponding evidence cards [9] and [55], which is where this package records linked notices. No change.
- **PMID 36490309 (Cuyàs).** The PubMed author list ends with an empty author entry, the usual signature of a dropped collective author, but it is not in the first position, so the collective-author builder defect does not apply and the reference renders correctly. No reference in this review has a collective first author.
- **PMID 42611943 and its preprint PMID 39553971.** Different title, journal, year and DOI. The review's independence section already states that "a preprint and its updated published host-defense report count once". No change.
- **PMID 38141139 (reference 34).** The reference prints 2025 against a 2023 e-pub date; the print issue is Cardiovasc Drugs Ther 39(3), i.e. 2025, so the printed year is the correct one.
- **Partial-body claims.** Several load-bearing statements are absent from the PubMed abstracts: the clamp and dual-background experiments and the cytoplasmic-translation inference for PMID 25738459; the predicted 12S-rRNA secondary-structure comparison for PMID 33468709; the surface-plasmon-resonance method, the antisense-oligonucleotide control and the K14Q atrophy result for PMID 39559755; and the abstract/body/table numeric disagreement for PMID 41551324. All four records are declared `full_text_partial` with the specific body paragraphs listed, so these are body-sourced and within the review's stated access. They are recorded below as a residual limitation rather than as errors.
- **Inline citation form** ("(PMID39559755)" with no space) is used inconsistently with the prose form ("PMID 25738459; PMID 29983246") but both appear throughout this corpus as house style and neither garbles a value. Left alone.

### Residual limitations

Four of the claims above rest on partial-body passages that this adversarial pass did not independently re-retrieve, so their attribution was checked for internal consistency and for absence of contradiction in the abstract, not confirmed against the full text. Of these, the statement that PMID 41551324's abstract, body and table numeric summaries disagree could not be corroborated: the abstract's own counts are mutually consistent (the 10-person surgical follow-up is a subset of the 32 obese participants), so the disagreement, if real, is between the body and the table. The review's refusal to invent a repaired value is the right response either way. The post-surgical claim that "selected metabolic indices improve" is likewise body-sourced; the abstract supports only the BMI improvement with unchanged circulating peptide.

**Approval:** Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-14.

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16. 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. [PMID 31066084](https://pubmed.ncbi.nlm.nih.gov/31066084/). DOI: 10.1111/cen.14007. Access: abstract_metadata. Study: PMID31066084.

17. 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. [PMID 41004666](https://pubmed.ncbi.nlm.nih.gov/41004666/). DOI: 10.20945/2359-4292-2025-0063. Access: abstract_metadata. Study: PMID41004666.

18. 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. [PMID 35370955](https://pubmed.ncbi.nlm.nih.gov/35370955/). DOI: 10.3389/fendo.2022.812032. Access: abstract_metadata. Study: PMID35370955.

19. 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. [PMID 39616938](https://pubmed.ncbi.nlm.nih.gov/39616938/). DOI: 10.1016/j.bbrc.2024.151072. Access: abstract_metadata. Study: PMID39616938.

20. Ramanjaneya M, Bettahi I, Jerobin J et al. Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects. Frontiers in endocrinology. 2019. [PMID 31214116](https://pubmed.ncbi.nlm.nih.gov/31214116/). DOI: 10.3389/fendo.2019.00331. Access: abstract_metadata. Study: PMID31214116.

21. 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. [PMID 29593067](https://pubmed.ncbi.nlm.nih.gov/29593067/). DOI: 10.1136/jim-2017-000681. Access: abstract_metadata. Study: PMID29593067.

22. 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. [PMID 32880686](https://pubmed.ncbi.nlm.nih.gov/32880686/). DOI: 10.1007/s00125-020-05269-3. Access: abstract_metadata. Study: PMID32880686.

23. 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. [PMID 33722744](https://pubmed.ncbi.nlm.nih.gov/33722744/). DOI: 10.1016/j.bbadis.2021.166126. Access: abstract_metadata. Study: PMID33722744.

24. 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. [PMID 34419510](https://pubmed.ncbi.nlm.nih.gov/34419510/). DOI: 10.1016/j.bbagen.2021.129991. Access: abstract_metadata. Study: PMID34419510.

25. 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. [PMID 39876762](https://pubmed.ncbi.nlm.nih.gov/39876762/). DOI: 10.33594/000000755. Access: abstract_metadata. Study: PMID39876762.

26. 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. [PMID 29691953](https://pubmed.ncbi.nlm.nih.gov/29691953/). DOI: 10.1111/pedi.12685. Access: abstract_metadata. Study: PMID29691953.

27. 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. [PMID 38636847](https://pubmed.ncbi.nlm.nih.gov/38636847/). DOI: 10.1016/j.diabres.2024.111656. Access: abstract_metadata. Study: PMID38636847.

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29. 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. [PMID 41945630](https://pubmed.ncbi.nlm.nih.gov/41945630/). DOI: 10.20945/2359-4292-2026-0031. Access: abstract_metadata. Study: PMID41945630.

30. Kim SJ, Mehta HH, Wan J et al. Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging. 2018. [PMID 29886458](https://pubmed.ncbi.nlm.nih.gov/29886458/). DOI: 10.18632/aging.101463. Access: abstract_metadata. Study: PMID29886458.

31. 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. [PMID 40674654](https://pubmed.ncbi.nlm.nih.gov/40674654/). DOI: 10.1249/MSS.0000000000003825. Access: abstract_metadata. Study: PMID40674654.

32. 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. [PMID 34413391](https://pubmed.ncbi.nlm.nih.gov/34413391/). DOI: 10.1038/s41598-021-96419-z. Access: abstract_metadata. Study: BCS_EXERCISE_NCT01140282.

33. 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. [PMID 36156853](https://pubmed.ncbi.nlm.nih.gov/36156853/). DOI: 10.1111/jcmm.17551. Access: abstract_metadata. Study: PMID36156853.

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41. 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. [PMID 39267782](https://pubmed.ncbi.nlm.nih.gov/39267782/). DOI: 10.7150/thno.100321. Access: abstract_metadata. Study: PMID39267782.

42. Baylan FA, Yarar E. Relationship between the mitochondria-derived peptide MOTS-c and insulin resistance in obstructive sleep apnea. Sleep & breathing = Schlaf & Atmung. 2021. [PMID 33394327](https://pubmed.ncbi.nlm.nih.gov/33394327/). DOI: 10.1007/s11325-020-02273-0. Access: abstract_metadata. Study: PMID33394327.

43. 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. [PMID 33639272](https://pubmed.ncbi.nlm.nih.gov/33639272/). DOI: 10.1016/j.mito.2021.02.010. Access: abstract_metadata. Study: PMID33639272.

44. 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. [PMID 40425777](https://pubmed.ncbi.nlm.nih.gov/40425777/). DOI: 10.1038/s41598-025-03526-2. Access: abstract_metadata. Study: PMID40425777.

45. Ozturk Öztürk DA, Erden Y, Tekin S. Central MOTS-c infusion affects reproductive hormones in obese and non-obese rats. Neuroscience letters. 2024. [PMID 38462167](https://pubmed.ncbi.nlm.nih.gov/38462167/). DOI: 10.1016/j.neulet.2024.137722. Access: abstract_metadata. Study: PMID38462167.

46. 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. [PMID 37077579](https://pubmed.ncbi.nlm.nih.gov/37077579/). DOI: 10.2147/DMSO.S403934. Access: abstract_metadata. Study: PMID37077579.

47. 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. [PMID 42324588](https://pubmed.ncbi.nlm.nih.gov/42324588/). DOI: 10.1186/s41232-026-00431-7. Access: full_text_partial. Study: PMID42324588.

48. 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. [PMID 36584915](https://pubmed.ncbi.nlm.nih.gov/36584915/). DOI: 10.1016/j.lfs.2022.121330. Access: abstract_metadata. Study: PMID36584915.

49. 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. [PMID 30967270](https://pubmed.ncbi.nlm.nih.gov/30967270/). DOI: 10.1016/j.bbrc.2019.03.194. Access: abstract_metadata. Study: PMID30967270.

50. Tok A, Serdar O, Kandilcik OF et al. Serum MOTS-c levels remain unchanged in patients with preeclampsia. Ginekologia polska. 2023. [PMID 39469962](https://pubmed.ncbi.nlm.nih.gov/39469962/). DOI: 10.5603/GP.a2022.0095. Access: abstract_metadata. Study: PMID39469962.

51. 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. [PMID 41710402](https://pubmed.ncbi.nlm.nih.gov/41710402/). DOI: 10.3389/fendo.2026.1732329. Access: abstract_metadata. Study: PMID41710402.

52. 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. [PMID 40478460](https://pubmed.ncbi.nlm.nih.gov/40478460/). DOI: 10.1007/s00418-025-02391-4. Access: abstract_metadata. Study: PMID40478460.

53. 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. [PMID 36687680](https://pubmed.ncbi.nlm.nih.gov/36687680/). DOI: 10.3389/fnut.2022.1060684. Access: abstract_metadata. Study: PMID36687680.

54. Kim S. The Relationship Between MOTS-c K14Q Polymorphism and Sarcopenia, Blood Lipids, and Mental Health in Older Korean Adults. Biomedicines. 2024. [PMID 39457696](https://pubmed.ncbi.nlm.nih.gov/39457696/). DOI: 10.3390/biomedicines12102384. Access: abstract_metadata. Study: PMID39457696.

55. 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. [PMID 41680431](https://pubmed.ncbi.nlm.nih.gov/41680431/). DOI: 10.1038/s41598-026-39687-x. Access: abstract_metadata. Study: PMID41680431.

56. 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. [PMID 40005438](https://pubmed.ncbi.nlm.nih.gov/40005438/). DOI: 10.3390/medicina61020322. Access: abstract_metadata. Study: PMID40005438.

57. Jamnick NA, Livingston PD, Gammon CJ et al. MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia. Frontiers in medicine. 2026. [PMID 42266945](https://pubmed.ncbi.nlm.nih.gov/42266945/). DOI: 10.3389/fmed.2026.1838178. Access: abstract_metadata. Study: PMID42266945.

58. 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. [PMID 41551324](https://pubmed.ncbi.nlm.nih.gov/41551324/). DOI: 10.1016/j.jcte.2025.100429. Access: full_text_partial. Study: OBESITY_BARIATRIC_MOTS_PARENT.

59. 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. [PMID 32182209](https://pubmed.ncbi.nlm.nih.gov/32182209/). DOI: 10.18632/aging.102944. Access: abstract_metadata. Study: PMID32182209.

60. 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. [PMID 35808870](https://pubmed.ncbi.nlm.nih.gov/35808870/). DOI: 10.14814/phy2.15377. Access: abstract_metadata. Study: PMID35808870.

61. 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. [PMID 37834399](https://pubmed.ncbi.nlm.nih.gov/37834399/). DOI: 10.3390/ijms241914951. Access: abstract_metadata. Study: PMID37834399.

62. 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. [PMID 39111290](https://pubmed.ncbi.nlm.nih.gov/39111290/). DOI: 10.1159/000540303. Access: abstract_metadata. Study: PMID39111290.

63. Rice MC, Imun M, Jung SW et al. MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide. eLife. 2026. [PMID 42611943](https://pubmed.ncbi.nlm.nih.gov/42611943/). DOI: 10.7554/eLife.87615. Access: full_text_partial. Study: MOTS_HOST_DEFENSE_UPDATED_REPORT.

64. 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. [PMID 40805020](https://pubmed.ncbi.nlm.nih.gov/40805020/). DOI: 10.3390/ani15152230. Access: abstract_metadata. Study: PMID40805020.

## Source-specific evidence cards

### [1] The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.

**Shows:** A 12S-rRNA sORF, mitochondrial depletion assays and immunodetection support MOTS-c identity; administered peptide improves mouse insulin sensitivity and diet-induced obesity.

**Does not show:** Cytoplasmic translation is inferred from genetic code; broad mitochondrial depletion and immunoassays are not selective endogenous peptide knockout or human dosing.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [2] MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.

**Shows:** Synthetic MOTS-c improves mouse exercise capacity and late-life grip, gait and walking; human exercise raises measured endogenous peptide.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [3] The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.

**Shows:** Metabolic stress induces measured MOTS-c nuclear translocation and AMPK-dependent stress-response transcription in cells.

**Does not show:** Cell localization and transcription do not establish organismal aging benefit, translation compartment or human treatment efficacy.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [4] A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.

**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.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [5] The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance.

**Shows:** K14Q carriers show more fast-fiber markers and greater young-male strength; antibody neutralization shifts mouse fiber markers.

**Does not show:** Neutralizing antibody specificity and marker endpoint limit endogenous inference; sprint strength is not global healthspan or universally deleterious K14Q function.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [6] MOTS-c modulates skeletal muscle function by directly binding and activating CK2.

**Shows:** Synthetic MOTS-c binds CK2 by SPR; CK2 inhibition or cellular ASO blocks glucose-uptake effects, and K14Q fails tested mouse atrophy protection.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [7] MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.

**Shows:** Mouse muscle PGC-1alpha and AMPK perturbations constrain peptide-induced mitochondrial bioenergetic changes; human interstitial levels increase during exercise.

**Does not show:** No human arterio-venous gradient change was observed; mitochondrial metrics are not healthspan extension and human secretion-source inference remains uncertain.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [8] Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration.

**Shows:** Eight-day MOTS-c treatment attenuates cast-induced muscle loss and lipid infiltration in young male C57BL6J mice.

**Does not show:** Preventing induced atrophy at 15mg/kg/day is not natural aging reversal, long-term functional preservation or human efficacy.

**Access/status:** 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. none_found. Subclaims: SC2.

### [9] Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.

**Shows:** MOTS-c suppresses diabetes development in NOD mice and changes transferred T-cell diabetogenicity; human T1D cells respond ex vivo.

**Does not show:** NOD/adoptive-transfer and ex-vivo results retain model scope; linked erratum PMID34525370 was identified but its details were not examined.

**Access/status:** 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. ErratumIn: PMID34525370. Subclaims: SC2, SC3.

### [10] The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus.

**Shows:** Peptide treatment improves glucose tolerance and offspring outcomes in diet/STZ gestational-diabetes mice.

**Does not show:** Induced gestational disease and STZ protection do not establish general human metabolic or adult-aging benefit.

**Access/status:** 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. none_found. Subclaims: SC2.

### [11] MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction.

**Shows:** MOTS-c reduces ovariectomy-induced obesity and insulin resistance, with AMPK-linked adipose changes.

**Does not show:** Surgical estrogen loss and inhibitor specificity restrict inference; no human postmenopausal treatment or aging trajectory tested.

**Access/status:** 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. none_found. Subclaims: SC2.

### [12] Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation.

**Shows:** Twelve-week peptide treatment alleviates ovariectomy-induced bone loss and inhibits osteoclastogenesis with partial AMPK-inhibitor reversal.

**Does not show:** Micro-CT and induced bone loss do not establish fracture reduction, native peptide necessity or human healthspan.

**Access/status:** 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. none_found. Subclaims: SC2.

### [13] Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation.

**Shows:** MOTS-c improves cold tolerance and thermogenic responses with ERK-sensitive effects.

**Does not show:** Cold adaptation is stress resistance, not aging extension; pathway inhibitor and metabolic effects do not establish a single native mediator.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [14] The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats.

**Shows:** MOTS-c improves myocardial mechanical efficiency and systolic function during exercise training in rats.

**Does not show:** Training adaptation is not durable aged-organism healthspan; the peptide need not mediate all exercise benefits.

**Access/status:** 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. none_found. Subclaims: SC2.

### [15] Circulating levels of MOTS-c in patients with breast cancer treated with metformin.

**Shows:** Paired samples in a randomized breast-cancer regimen show no significant circulating MOTS-c response to added metformin over 24 weeks.

**Does not show:** Patients received metformin/oncology therapy, not MOTS-c; commercial-ELISA null does not exclude local peptide changes.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [16] Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects.

**Shows:** Intralipid raises measured plasma MOTS-c and insulin blunts the response in controls/PCOS; eight-week exercise does not change circulating levels.

**Does not show:** Lipids, insulin and exercise are the interventions; peptide movement cannot establish mediation or MOTS-c administration efficacy.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [17] MOTS-C levels ın ındividuals with and without obesity and ıts association with ınflammation, insulin resistance and endothelial dysfunction.

**Shows:** Serum MOTS-c is similar in obese and normal-weight adults and correlates positively with HOMA-IR.

**Does not show:** Cross-sectional ELISA and age/metabolic confounding do not prove deficiency or therapeutic benefit.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [18] MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats.

**Shows:** MOTS-c or exercise improves cardiac structure/function in diet/STZ diabetic rats with NRG1-ErbB4 pathway associations.

**Does not show:** Transcriptomic pathway enrichment is not selective mediator necessity; induced diabetes is not organismal longevity.

**Access/status:** 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. none_found. Subclaims: SC2.

### [19] MOTS-c regulates the ROS/TXNIP/NLRP3 pathway to alleviate diabetic cardiomyopathy.

**Shows:** Eight-week MOTS-c treatment reduces ROS/TXNIP/NLRP3 inflammatory signals and myocardial injury in diabetic rats.

**Does not show:** Redox and inflammatory changes alone do not prove durable cardiac function or aging trajectory; pathway mediation remains incompletely isolated.

**Access/status:** 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. none_found. Subclaims: SC2.

### [20] Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects.

**Shows:** Circulating MOTS-c is lower in adult T2D groups and associates with metabolic measurements.

**Does not show:** Cross-sectional disease/medication and immunoassay effects cannot determine causal deficiency, despite causal language in the original conclusion.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [21] Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals.

**Shows:** Lean/obese adult peptide levels are similar and measured MOTS-c associates positively with insulin resistance chiefly in lean individuals.

**Does not show:** Small groups and surrogate sensitivity indices do not establish that raising peptide improves human metabolism.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [22] 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.

**Shows:** Adiponectin, exercise and MOTS-c interventions regulate mouse peptide measurements through APPL1/SIRT1/PGC1alpha-linked experiments.

**Does not show:** Multiple pleiotropic manipulations and ectopic constructs do not selectively establish endogenous peptide necessity or human healthspan.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [23] 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.

**Shows:** AMPK/PGC1alpha manipulations, exercise and administered peptide change MOTS-c and metabolic signaling in cells and high-fat-fed mice.

**Does not show:** Expression loops, inhibitors and ectopic expression do not independently establish native peptide production or aging effects.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [24] Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes.

**Shows:** Circulating MOTS-c associates positively with metabolic syndrome and liver/android fat, also rising in a hepatic-injury mouse diet.

**Does not show:** Higher measured peptide can accompany worse metabolic status; liver-stress compensation is plausible but observational rather than proven mediation.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [25] MOTS-c Impact on Muscle Cell Differentiation and Metabolism Across Fiber Types.

**Shows:** MOTS-c promotes C2C12 differentiation and reduces lipid accumulation but not equivalent L6 responses, where lipid accumulation increases.

**Does not show:** Cell-line and fiber-type dependence constrain a universal anabolic/anti-lipid effect; no organismal endpoint.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [26] Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance.

**Shows:** Measured peptide is reduced in obese male children and inversely associates with obesity/insulin-resistance markers.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [27] 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.

**Shows:** Exercise intensity alters measured MOTS-c and glucose-related proteins in diabetic rodents.

**Does not show:** Exercise has many mediators and no selective peptide perturbation; original Wistar/sand-rat terminology is inconsistent and remains unresolved.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [28] The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats.

**Shows:** Slow-twitch rat muscle retains glucose-transport/respiratory markers and expresses more UPRmt/MOTS-c during high-fat feeding.

**Does not show:** Fiber-type association without selective MOTS-c perturbation cannot prove peptide mediation of insulin-resistance protection.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [29] Are serum MOTS-c levels and MOTS-c m.1382A>C polymorphism related to polycystic ovary syndrome?

**Shows:** Adolescent PCOS/control measured peptide and metabolic associations are nonsignificant; every participant carries wild-type m.1382A.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [30] Mitochondrial peptides modulate mitochondrial function during cellular senescence.

**Shows:** Senescent fibroblasts express more MOTS-c and peptide administration modestly increases respiration and selected SASP components.

**Does not show:** Senescence induction and mitochondrial/SASP changes do not establish anti-aging efficacy; selected secretory effects increase rather than uniformly decrease.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [31] Repeated Heat Stress Modulates the Levels of the Mitokines MOTS-C and FGF21 in Active Men during Calf Muscle Immobilization.

**Shows:** Randomized heat/sham exposure during immobilization alters circulating MOTS-c in 19 active men.

**Does not show:** Heat is the intervention; marker movement does not show peptide mediation or native MOTS-c dosing prevents human muscle loss.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [32] Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors.

**Shows:** A secondary analysis of an exercise RCT finds increased peptide in non-Hispanic White but not Hispanic breast-cancer survivors.

**Does not show:** Ethnicity groups differ at baseline and are small; exercise randomization is not peptide randomization or universal responder prediction.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [33] Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice.

**Shows:** Pump-delivered MOTS-c attenuates pressure-overload cardiac dysfunction/remodeling in mice.

**Does not show:** TAC-induced failure and cell overexpression do not establish aging extension or native human cardiac necessity.

**Access/status:** 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. none_found. Subclaims: SC2.

### [34] MOTS-c Peptide Attenuated Diabetic Cardiomyopathy in STZ-Induced Type 1 Diabetic Mouse Model.

**Shows:** MOTS-c after STZ-diabetes establishment ameliorates mouse cardiac function and remodeling over 12 weeks.

**Does not show:** Post-disease treatment supports restricted pharmacology, not lifetime healthspan or human clinical benefit.

**Access/status:** 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. none_found. Subclaims: SC2.

### [35] Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart.

**Shows:** MOTS-c improves glucose homeostasis and reduces cardiac hypertrophy in diabetic rats while changing mitochondrial respiration.

**Does not show:** Mitochondrial ROS rises in treated tissue; improved bioenergetics does not establish global antioxidant action or lifespan extension.

**Access/status:** 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. none_found. Subclaims: SC2.

### [36] Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease.

**Shows:** Advanced-CKD patients show reduced muscle/serum MOTS-c alongside lower mitochondrial density and oxidative stress.

**Does not show:** Disease severity, renal handling and muscle composition confound direction; humanin and MOTS-c show different compartment patterns.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [37] MOTS-c regulates pancreatic alpha and beta cell functions in vitro.

**Shows:** Peptide lowers insulin secretion/expression and increases glucagon in pancreatic cell lines with altered survival/secretion.

**Does not show:** Cell lines do not establish systemic glycemic benefit; direction differs from a simple universal insulin-enhancing mechanism.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [38] Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes.

**Shows:** MOTS-c changes aged-islet senescence and improves glucose intolerance in S961-treated and NOD mice; adult T2D peptide levels are lower.

**Does not show:** Mouse disease models and senescence markers do not establish generalized aging or human peptide-treatment efficacy.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [39] Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.

**Shows:** Marathon/sedentary humans and endurance-trained mice show associations among peptide, exercise capacity and respiration.

**Does not show:** Training is not selective peptide perturbation; source secretion and human causal mediation remain unresolved.

**Access/status:** 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. none_found. Subclaims: SC1, SC2, SC3.

### [40] Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells.

**Shows:** MOTS-c preserves dexamethasone-exposed primary human myotube area and alters Akt/STAT3/atrophy pathways.

**Does not show:** Human-derived cells are not human treatment; pharmacological co-exposure and induced atrophy cannot establish clinical healthspan.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [41] Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane.

**Shows:** MOTS-c facilitates TRIM72-dependent membrane repair; TRIM72 loss separates repair from vesicle fusion, and cardiac injury outcomes improve.

**Does not show:** Human exercise correlations remain nonselective and native peptide necessity is not universally established; membrane repair is not general aging delay.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [42] Relationship between the mitochondria-derived peptide MOTS-c and insulin resistance in obstructive sleep apnea.

**Shows:** Lower measured serum MOTS-c tracks OSA severity and metabolic indices in patients.

**Does not show:** OSA, obesity and insulin resistance are interrelated; biomarker regression does not show benefit from peptide administration.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [43] The mitochondrial-derived peptide MOTS-c promotes homeostasis in aged human placenta-derived mesenchymal stem cells in vitro.

**Shows:** MOTS-c changes AMPK/mTOR and mitochondrial/ROS markers in aged placenta-derived MSCs.

**Does not show:** In-vitro homeostasis is not restored organismal stem-cell repair, healthspan or clinical aging efficacy.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [44] MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3.

**Shows:** MOTS-c and exercise improve diabetic-rat liver fibrosis with Keap1/Nrf2/Smad associations.

**Does not show:** Cell ectopic-expression and marker changes do not selectively establish an endogenous exercise mediator or general human benefit.

**Access/status:** 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. none_found. Subclaims: SC2.

### [45] Central MOTS-c infusion affects reproductive hormones in obese and non-obese rats.

**Shows:** Central peptide infusion raises GnRH and reproductive hormone measurements in obese/nonobese male rats.

**Does not show:** Intracerebroventricular delivery and hormones are not systemic clinical metabolic healthspan or proved fertility benefit.

**Access/status:** 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. none_found. Subclaims: SC2.

### [46] Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function.

**Shows:** Obese children have lower measured peptide and vascular reactive-hyperemia indices with statistical mediation.

**Does not show:** Cross-sectional mediation is not causal mediation; peptide replacement and functional prevention were not tested.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [47] Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells.

**Shows:** MOTS-c activates AMPK in obese human MSCs but increases senescence/inflammatory markers; pretreated MSCs fail or blunt kidney repair in mice.

**Does not show:** Cell pretreatment/transplant context is not direct human administration, but it refutes marker activation as a sufficient proxy for regenerative benefit.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [48] MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPβ modification in rats.

**Shows:** MOTS-c and exercise improve selected rat cardiac functional measures with NRG1/ErbB4/CEBPbeta-associated remodeling.

**Does not show:** Some endpoints and NRG1 transcript contrasts are null; healthy adaptation is not mechanistically isolated aging benefit.

**Access/status:** 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. none_found. Subclaims: SC2.

### [49] Earlier changes in mice after D-galactose treatment were improved by mitochondria derived small peptide MOTS-c.

**Shows:** MOTS-c reduces abnormal lipid accumulation and tissue/mitochondrial changes in D-galactose-treated mice.

**Does not show:** Toxicity-induced pseudo-aging, histology and markers do not substitute for natural-aging healthspan or lifespan.

**Access/status:** 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. none_found. Subclaims: SC2.

### [50] Serum MOTS-c levels remain unchanged in patients with preeclampsia.

**Shows:** Measured serum MOTS-c is similar among uncomplicated pregnancy and mild/severe preeclampsia groups.

**Does not show:** Nonsignificant small-group comparisons do not rule out all tissue effects or establish a therapeutic target.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [51] Aerobic exercise and MOTS-c attenuate diabetic myocardial fibrosis via inhibition of the THBS1/TGF-β signaling pathway.

**Shows:** Exercise and MOTS-c improve diabetic myocardial fibrosis and systolic/diastolic measures with THBS1/TGFbeta association.

**Does not show:** Pathway transcript/ protein concordance is not isolated mediator necessity; no human peptide trial or longevity endpoint.

**Access/status:** 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. none_found. Subclaims: SC2.

### [52] MOTS-c modulates pancreatic islet function in rats and pigs in vitro.

**Shows:** MOTS-c alters rat/pig islet secretion and viability with different directions across species.

**Does not show:** Isolated islets are not organismal metabolic or aging outcomes; cross-species cellular effects cannot remove the healthspan scope cap.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [53] MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats.

**Shows:** Eight-week peptide treatment preserves cardiac functional measures in diabetic rats with CCN1/ERK/EGR1 changes.

**Does not show:** Transcriptomic and apoptosis associations do not prove one direct mediator; related diabetic-rat programs are not automatically independent experiments.

**Access/status:** 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. none_found. Subclaims: SC2.

### [54] The Relationship Between MOTS-c K14Q Polymorphism and Sarcopenia, Blood Lipids, and Mental Health in Older Korean Adults.

**Shows:** Older Korean men carrying K14Q-associated C allele have higher muscle mass and grip; women show no genotype difference.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [55] Reduced serum and skeletal muscle MOTS c levels in women with polycystic ovary syndrome are associated with mitochondrial dysfunction.

**Shows:** Women with PCOS have lower serum and muscle immunodetected peptide with selected hormone/lipid associations.

**Does not show:** Cross-sectional tissue/serum measurements do not establish causal deficiency; linked erratum PMID42716952 details were not examined.

**Access/status:** 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. ErratumIn: PMID42716952. Subclaims: SC1, SC3.

### [56] MOTS-c Levels and Sarcopenia Risk in Chronic Peritoneal Dialysis Patients: A Pilot Study.

**Shows:** Small peritoneal-dialysis cohort links lower serum/higher dialysate peptide to sarcopenia-risk and performance measures.

**Does not show:** Renal/peritoneal handling and disease burden confound direction; biomarker prediction is not peptide replacement benefit.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [57] MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.

**Shows:** MOTS-c preserves selected skeletal-muscle mass in C26-cachectic mice but not total body weight/fat; function improvement is a trend.

**Does not show:** Partial wasting-model protection is not complete functional rescue or healthspan extension, and induced cancer context remains.

**Access/status:** 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. none_found. Subclaims: SC2.

### [58] Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss.

**Shows:** Obese adults have higher circulating peptide; after bariatric surgery BMI and selected metabolic indices improve without peptide normalization.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [59] Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition.

**Shows:** Healthy aging men show lower circulating but higher muscle peptide with fiber-type/muscle-quality associations.

**Does not show:** Opposite compartment directions and small RNA/immunoassays do not prove a systemic deficiency or peptide treatment benefit.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [60] MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose.

**Shows:** Training raises muscle peptide and a single synthetic dose improves mouse acute running time/distance.

**Does not show:** Acute performance is not durable aging change; nuclear translocation occurs in only 2 of 6 soleus samples and not plantaris.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.

### [61] MOTS-c Serum Concentration Positively Correlates with Lower-Body Muscle Strength and Is Not Related to Maximal Oxygen Uptake-A Preliminary Study.

**Shows:** Resting serum peptide correlates with jump force/power and muscle mass but not peak VO2 in 20 active volunteers.

**Does not show:** Small observational sample does not establish endurance benefit or dosing efficacy.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [62] The Mitochondrial-Derived Peptide MOTS-c May Refine Mortality and Cardiovascular Risk Prediction in Chronic Hemodialysis Patients: A Multicenter Cohort Study.

**Shows:** Higher circulating peptide predicts death/CV events in 94 hemodialysis patients during follow-up.

**Does not show:** Renal handling and illness severity may determine marker levels; adverse-risk association does not show peptide causes harm or treatment benefit.

**Access/status:** 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. none_found. Subclaims: SC1, SC3.

### [63] MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide.

**Shows:** MOTS-c has direct antibacterial/cell immune effects; MRSA pretreated with peptide causes less lethal mouse peritonitis.

**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.

**Access/status:** 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. UpdateOf: PMID39553971. Subclaims: SC1, SC2.

### [64] Characterization of the Avian Mitochondrial-Derived Peptide MOTS-c and Its Potential Role as a Metabolic Regulator.

**Shows:** Avian 12S-region sequence and chicken immunodetection/cellular responses extend candidate peptide biology with divergent sequence.

**Does not show:** Avian primary-cell signaling is not mammalian healthspan; bioinformatic coding potential and immunodetection do not directly resolve native translation machinery.

**Access/status:** 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. none_found. Subclaims: SC1, SC2.