How to read this guide
Keep the evidence tier, exposure type, population, endpoint, timeframe, comparator, source type, and limitation attached to every result. A biological signal is not automatically a clinical result.
01 / Definition
What is MOTS-c?
MOTS-c is a 16-amino-acid mitochondrial-derived peptide. It originates from a short open reading frame within mitochondrial 12S rRNA, also called MT-RNR1. That origin is a useful identity statement, not evidence that administering the peptide produces a clinical benefit.
Most human records discussed below measure endogenous MOTS-c in blood or tissue, or examine associations with exercise, age, body composition, or disease status. They do not administer native MOTS-c. Endogenous biomarker changes therefore cannot be used as proof that an administered peptide works, is safe, or causes the observed changes.
Mitochondrial origin
A short open reading frame within mitochondrial 12S rRNA / MT-RNR1.
Peptide identity
A 16-amino-acid peptide described in discovery and preclinical records.
Exposure boundary
Endogenous measurement is different from administered native MOTS-c exposure.
02 / Discovery and preclinical evidence
Discovery work begins in cells and models.
The 2015 Lee paper established the discovery and preclinical foundation for MOTS-c. Its cell and mouse experiments can support hypotheses about mitochondrial signaling and metabolic regulation. They are not human evidence, and they do not establish a dose, route, formulation, safety profile, or clinical outcome.
Later mouse and cell work, including the Reynolds paper, expanded questions about exercise, physical decline, and muscle homeostasis. Those mechanistic hypotheses remain separate from the small human biomarker components and from the recruiting native-MOTS-c trial.
Lee et al., Cell Metabolism 2015 discovery record
- Population / design
- Cell experiments and mouse models; not a human efficacy trial.
- Timeframe
- Discovery and preclinical work reported in 2015.
- Endpoint
- MOTS-c expression and experimental metabolic phenotypes in cells and mice.
- Comparator
- Experimental cell and mouse comparisons; no administered-human comparator.
Reported finding: The discovery paper described MOTS-c as a mitochondrial-encoded peptide and reported metabolic-signaling and glucose-handling findings in experimental models.
Limitation: Cell and mouse findings are preclinical. They do not establish human efficacy, safety, delivery, or clinical outcomes.
03 / Human biomarker and observational evidence
The human record is mostly endogenous measurement.
These cards keep population, design, timeframe, endpoint, comparator, finding, and limitation together. None is a completed native-MOTS-c administration efficacy trial. The Reynolds record includes a small human acute-exercise component, while its broader mouse and cell findings stay in the preclinical tier.
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
- Population / design
- Predominantly mouse and cell work, plus an acute-exercise human biomarker component of approximately 10 young men.
- Timeframe
- Acute exercise sampling in the small human component; broader work used experimental models.
- Endpoint
- Endogenous MOTS-c in skeletal muscle and circulation in humans; broader study endpoints included physical-decline and muscle-homeostasis measures in models.
- Comparator
- Exercise-related pre/post or group comparisons; no administered native MOTS-c comparator in humans.
Reported finding: The human component measured endogenous MOTS-c around acute exercise. The broader mouse and cell findings do not become human anti-aging or performance evidence.
Limitation: The human component was small and acute, with no native-MOTS-c administration, clinical outcome, or long-term human follow-up. Mouse and cell findings cannot be generalized to people.
Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans
- Population / design
- 30 subjects in endurance, resistance, and control groups, approximately 10 per group; acute exercise study.
- Timeframe
- Pre-exercise baseline, 30 minutes, and 3 hours after exercise.
- Endpoint
- Circulating mitochondrial-derived peptides, including MOTS-c.
- Comparator
- Endurance, resistance, and control group comparisons; no administered native MOTS-c comparator.
Reported finding: MOTS-c showed a trend toward increase after endurance exercise. The clearest statistically significant circulating result in the abstract was humanin, not a definitive MOTS-c effect.
Limitation: Acute sampling, small groups, endogenous measurement, and no clinical outcome or native-MOTS-c administration limit interpretation.
Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition
- Population / design
- Healthy men in young, middle-aged, and older groups, approximately 26 per group; cross-sectional age-group comparison.
- Timeframe
- Single cross-sectional comparison across age groups.
- Endpoint
- Plasma MOTS-c, skeletal-muscle MOTS-c expression, and associations with myofiber composition and muscle-quality measures.
- Comparator
- Observed age-group comparisons; no administered MOTS-c comparator.
Reported finding: Plasma MOTS-c decreased with age, while skeletal-muscle MOTS-c expression was approximately 1.5-fold higher in middle-aged and older men than in young men, with associations to slow-type markers and muscle-quality measures.
Limitation: This was cross-sectional, not longitudinal, and not a treatment study. Associations do not prove an anti-aging effect or causation.
Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors
- Population / design
- Secondary biomarker analysis of a randomized exercise trial with 25 Hispanic and 24 non-Hispanic White breast cancer survivors.
- Timeframe
- 16-week aerobic/resistance exercise versus usual care.
- Endpoint
- Fasting plasma MOTS-c and associations with body-composition, metabolic, and inflammatory measures.
- Comparator
- Exercise versus usual care and subgroup comparison by ethnicity; no administered native MOTS-c comparator.
Reported finding: Fasting plasma MOTS-c increased significantly in the non-Hispanic White group but not the Hispanic group, with associations to other body-composition, metabolic, and inflammatory measures.
Limitation: This small secondary analysis has subgroup and association limitations. It does not establish an administered-peptide effect or a clinical outcome.
Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes
- Population / design
- Human observational component with 45 people with type 2 diabetes and 19 healthy controls; most exposure and treatment work was in mice, islets, or cells.
- Timeframe
- Fasting serum comparison at a single observational assessment.
- Endpoint
- Serum MOTS-c concentration.
- Comparator
- People with type 2 diabetes versus healthy controls; no administered native MOTS-c comparator.
Reported finding: Fasting serum MOTS-c was lower in the diabetes group than in healthy controls.
Limitation: The human result is an association. Most exposure and treatment findings were preclinical and do not show that MOTS-c prevents or treats diabetes.
04 / Human evidence limits
What these human records cannot fill in.
As of August 22, 2026, no completed native-MOTS-c efficacy result was identified in the verified primary records checked. More precisely, no completed interventional efficacy evidence for administered native MOTS-c was identified. These human records measure endogenous levels or associations. They do not provide human safety, pharmacokinetic, delivery, durability, or clinical-outcome conclusions for administered native MOTS-c.
NCT07505745 is a recruiting native-MOTS-c Phase 2a study with no posted results. Its registration shows what investigators plan to measure, not what the study found.
05 / Registered studies
Registries show plans and status, not conclusions.
The records below are kept separate from peer-reviewed human findings. Status and enrollment reflect the retrieved records at the August 22, 2026 cutoff, and no unposted sponsor toplines are imported.
Native versus analog boundary
NCT07505745 concerns native MOTS-c. NCT03998514 concerns CB4211, a distinct peptide analog of MOTS-c. Their records must not be merged.
A registered study is not a result.
A Phase 2a, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Pharmacodynamics of MOTS-c (a Mitochondrial-Derived Peptide) in Adults With Prediabetes and Overweight/Obesity.
- Compound boundary
- Native MOTS-c, interventional Phase 2a study.
- Enrollment / location
- Estimated enrollment 120; Shenzhen, China.
- Timing
- Actual start February 2, 2026; estimated primary completion February 14, 2027; estimated completion May 17, 2028; last posted April 1, 2026.
- Planned endpoints
- Primary change from baseline in OGTT-derived Matsuda insulin-sensitivity index at 12 weeks; safety through 16 weeks; secondary HbA1c, fasting and 2-hour glucose, and immunogenicity.
Registry record: No results posted. This is a planned study question, not an efficacy or safety result.
Boundary: Until results are posted and evaluated, the registry cannot answer whether administered native MOTS-c improves a clinical outcome or is safe.
A Phase 1a/1b Study of Safety, Tolerability, and Pharmacokinetics of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease.
- Compound boundary
- CB4211 is a distinct peptide analog of MOTS-c, not native MOTS-c.
- Enrollment
- Actual enrollment 88.
- Planned context
- Safety, tolerability, pharmacokinetics, pharmacodynamics, MRI-PDFF, and antibody endpoints, all analog-only context.
Registry record: No registry results posted. Sponsor toplines are not imported into this guide.
Boundary: A completed analog study cannot establish native-MOTS-c efficacy, safety, pharmacokinetics, or delivery.
High On-treatment Platelet Reactivity, Increased B-amyloid and Downregulation of MOTS-c Predict Mortality in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus: a 2-year Follow up Study.
- Design / enrollment
- Observational follow-up; estimated enrollment 120.
- Timeframe
- Two-year follow-up.
- Planned question
- The planned biomarker and mortality question in patients with coronary artery disease and type 2 diabetes mellitus.
Registry record: No results posted. The registry title is not evidence that MOTS-c predicted mortality.
Boundary: Status is uncertain, and a planned observational question cannot establish a predictive result or causation.
Combined Exercise Program for Early Breast Cancer Survivors.
- Study boundary
- Parent exercise trial for PMID 34413391, not a native-MOTS-c administration trial.
- Enrollment
- Actual enrollment 106.
- Registry result
- No results posted; duration is omitted here because the retrieved record contains an inconsistency.
Registry record: The registry identifies an exercise program, not an administered MOTS-c study.
Boundary: It provides context for the later biomarker analysis but cannot establish a MOTS-c efficacy or safety result.
06 / Safety, pharmacology, and uncertainty
The safety record has a large unanswered space.
Verified native-MOTS-c human papers measure endogenous peptide and do not provide safety data for administered native MOTS-c. Human half-life, metabolism, distribution, bioavailability, exposure-response, delivery, immunogenicity, and durability remain unresolved. NCT07505745 lists immunogenicity, but its recruiting record has no posted results.
Human safety record
Verified native-MOTS-c human papers measure endogenous peptide and do not provide safety data for administered native MOTS-c.
Pharmacology still open
Human half-life, metabolism, distribution, bioavailability, exposure-response, delivery, immunogenicity, and durability remain unresolved.
Registered immunogenicity endpoint
NCT07505745 lists immunogenicity among its planned secondary endpoints, but the recruiting record has no posted results.
Biomarker is not exposure
An endogenous level or exercise-related change does not tell us what an administered exposure would do, how long it would last, or whether it would produce a clinical outcome.
No personal-use interpretation
This evidence gap cannot be filled with dosing, route, formulation, sourcing, or monitoring instructions, which are outside this guide.
07 / Regulatory and public-record status
Public records answer a narrow question.
As of August 22, 2026, no FDA-approved product containing native MOTS-c, no publicly identified FDA NDA/BLA record establishing native MOTS-c as an approved medicine, and no EMA centrally authorized marketing authorization for native MOTS-c were identified in the official records checked. This is a public-record finding, not a statement about confidential applications.
The 2026 briefing discusses MOTS-c free base and acetate, the lack of a USP/NF monograph, the fact that neither is a component of an FDA-approved drug, and a staff proposal not to add them to the Section 503A Bulks List. This is not approval, a ban, or permission for personal use.
MOTS-c is not listed among the six current Section 503A permitted bulk substances checked at the cutoff. A compounding-list status would still not equal approval.
The current page places “MOTs-C” in a withdrawn-nomination table, not the active Category 2 list. This does not establish approval, prohibition, efficacy, or permission for personal use.
This FDA page is regulatory compounding context. Its inclusion does not establish that native MOTS-c is approved, prohibited, effective, or permitted for personal use.
No MOTS-c product record was identified in the checked public database at the cutoff. Drugs@FDA has coverage caveats, and this is a public-record finding, not a statement about confidential applications.
No EMA centrally authorized marketing authorization for native MOTS-c was identified in the official EMA records checked. This wording does not address every national authorization.
08 / Known versus unresolved
Keep the record beside the open questions.
Known in this record
MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame within mitochondrial 12S rRNA / MT-RNR1.
A 2015 discovery paper provides a preclinical cell and mouse record, not administered-human efficacy evidence.
Human records include endogenous biomarker observations and associations in defined populations.
NCT07505745 is a registered native-MOTS-c Phase 2a study, and CB4211 remains a clearly separate analog.
At the cutoff, no completed interventional efficacy evidence for administered native MOTS-c was identified in the verified primary records checked.
Still unresolved
Administered-human efficacy and patient-important clinical outcomes
Human safety, half-life, metabolism, pharmacokinetics, and exposure-response
Delivery, formulation, bioavailability, immunogenicity, and long-term durability
Whether endogenous biomarker associations are causal or clinically meaningful
Results from NCT07505745 and the current status of every registered record
Current regulatory status beyond the public records checked at the cutoff
09 / Reader checklist
Questions to carry into the next record.
Identify the evidence tier: discovery/preclinical, human biomarker, observational, interventional, registry, or regulatory record.
Ask whether the exposure was endogenous or administered, and do not treat an endogenous level as a drug exposure.
Keep the population, design, endpoint, comparator, and timeframe attached to every finding.
Separate association from causation, especially for age, exercise, diabetes, and mortality-related biomarkers.
Distinguish native MOTS-c from CB4211 and other analog compounds.
Check whether a registry is recruiting, completed, or unknown, and whether results are posted.
Read the registry title as a planned question, not as a result.
Recheck current FDA, eCFR, Drugs@FDA, and EMA records whenever this guide is materially updated.
Keep a public-record finding separate from claims about confidential applications or personal use.
Keep the Axiolume review boundary visible: source coverage, evidence limits, disclosures, and general education.
10 / Source trail
Follow the primary and official records.
The source trail separates discovery and preclinical work, human biomarker and observational papers, the CB4211 analog boundary, ClinicalTrials.gov records, and regulatory or public-record sources. Dates identify publication or retrieval context at the August 22, 2026 cutoff. The optional partner resource is not part of this trail.
Discovery / preclinical
Direct links / datedHuman biomarker / observational
Direct links / datedvon Walden et al., Journal of Applied Physiology 2021, PMID 34351816
Publication: 2021; accessed August 22, 2026.
Dieli-Conwright et al., Scientific Reports 2021, PMID 34413391
Publication: 2021; accessed August 22, 2026.
Analog boundary
Direct links / datedClinicalTrials.gov
Direct links / datedNCT07505745, A Phase 2a, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Pharmacodynamics of MOTS-c (a Mitochondrial-Derived Peptide) in Adults With Prediabetes and Overweight/Obesity.
Registry record; retrieved August 22, 2026.
NCT03998514, A Phase 1a/1b Study of Safety, Tolerability, and Pharmacokinetics of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease.
Registry record; retrieved August 22, 2026.
NCT04027712, High On-treatment Platelet Reactivity, Increased B-amyloid and Downregulation of MOTS-c Predict Mortality in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus: a 2-year Follow up Study.
Registry record; retrieved August 22, 2026.
NCT01140282, Combined Exercise Program for Early Breast Cancer Survivors.
Registry record; retrieved August 22, 2026.
Regulatory / public record
Direct links / datedFDA certain bulk substances safety context
Official public record; checked August 22, 2026.
11 / Closing disclosure
Keep the boundary visible.
MOTS-c remains an investigational topic, and no completed interventional efficacy evidence for administered native MOTS-c was identified in the verified primary records checked at the August 22, 2026 cutoff. Axiolume reviewed this guide for source coverage, evidence boundaries, and disclosures. This is general health education, not medical advice, treatment guidance, a personal-use recommendation, medical or legal review, peer review, or regulatory approval. Sources, registry status, and regulatory records should be rechecked whenever the guide is materially updated.
Axiolume provides general health education. It does not provide medical advice, diagnosis, dosing, protocols, treatment recommendations, sourcing, or individualized guidance, and it does not encourage personal use of MOTS-c or CB4211.