Report ID: MOTS-c-2025-Q4-V1 Date: December 18, 2025 Disclaimer: This document is intended for informational and educational purposes only. It is not medical advice. The substance discussed is an investigational chemical not approved by the FDA for human use. Consult with a qualified healthcare professional for any medical concerns.
Executive Summary
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a peptide encoded in the mitochondrial genome that acts as a potent regulator of metabolic homeostasis. It functions primarily by activating the AMPK pathway, mimicking the cellular effects of exercise. Research demonstrates its ability to enhance insulin sensitivity, prevent diet-induced obesity, and improve physical endurance. As an “exercise mimetic,” it offers hope for treating metabolic syndrome and age-related metabolic decline.
History and Discovery
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a relatively novel peptide belonging to a class known as mitochondrial-derived peptides (MDPs). These peptides are encoded by short open reading frames (sORFs) within the mitochondrial DNA (mtDNA), a discovery that has challenged the long-held belief that the mitochondrial genome only encodes for proteins essential for oxidative phosphorylation.
- Initial Discovery & Key Researchers: The discovery of MOTS-c was a landmark event in mitochondrial biology and gerontology. It was first identified and characterized by a research team at the Leonard Davis School of Gerontology at the University of Southern California (USC), led by Dr. Pinchas Cohen and Dr. Changhan Lee. Their seminal paper, published in Cell Metabolism in 2015, demonstrated that MOTS-c plays a crucial role in metabolic homeostasis, particularly in regulating insulin sensitivity and cellular energy.
- Timeline of Key Developments:
- Pre-2010s: The concept of peptides encoded by mtDNA was largely unexplored. The focus remained on the 13 protein-coding genes of the mitochondrial genome.
- 2012-2014: The USC team, while studying the mitochondrial genome, identified several sORFs with the potential to encode bioactive peptides. This led to the isolation and synthesis of MOTS-c.
- 2015: The foundational study by Lee et al. is published, demonstrating MOTS-c’s ability to reverse age-dependent and diet-induced insulin resistance in mice, positioning it as a potential therapeutic for metabolic diseases.
- 2016-2020: A surge in preclinical research explores MOTS-c’s effects on exercise, longevity, cellular stress, and various organ systems. CohBar, Inc., a biotechnology company co-founded by Dr. Cohen, files numerous patents covering MOTS-c and its analogs for therapeutic use.
- 2021-2023: The first-in-human Phase 1 clinical trials are initiated to evaluate the safety, tolerability, and pharmacokinetics of MOTS-c analogs (e.g., CB4211) in healthy volunteers and specific patient populations, such as those with Non-alcoholic Fatty Liver Disease (NAFLD).
- 2024-2025 (Projected): Preliminary data from Phase 1b/2a trials become available, showing a favorable safety profile and hinting at efficacy in improving metabolic markers in conditions like NAFLD and obesity. Interest from the biohacking and athletic communities explodes, with online search volume and forum discussions reaching an all-time high, despite its non-approved status. Research expands to investigate its role in neurodegeneration, cardiovascular health, and frailty in the elderly.
Chemical Structure and Properties
MOTS-c is a 16-amino-acid peptide with a unique structure and set of properties that dictate its biological activity and administration.
- Amino Acid Sequence: Met-Ala-Phe-Pro-Arg-Gln-Phe-Glu-Gly-Leu-Thr-Thr-Leu-Thr-Glu-Arg (MAFPRQFGLTTLTER)
- Molecular Formula: C₇₉H₁₂₇N₂₃O₂₄
- Molecular Weight: 1839.0 g/mol
- Modifications: Synthetic versions are typically unmodified, but research into acetylated or PEGylated forms is ongoing to enhance stability and half-life. It is sold commercially as a lyophilized (freeze-dried) powder for reconstitution.
- Pharmacokinetics:
- Administration Routes: Due to its peptide nature, oral bioavailability is negligible as it would be degraded by proteases in the gastrointestinal tract. The primary route for research and administration is subcutaneous (SubQ) injection. Intramuscular (IM) and intravenous (IV) routes have been used in clinical settings.
- Half-Life: Preclinical data suggests a relatively short plasma half-life, estimated to be under a few hours. This necessitates frequent administration (e.g., daily or multiple times per week) to maintain stable systemic levels.
- Metabolism: MOTS-c is metabolized by peptidases in the blood and tissues into smaller, inactive amino acid fragments.
- Bioavailability (SubQ): Subcutaneous injection provides high bioavailability, typically >80%, allowing for effective systemic distribution.
- Stability: As a lyophilized powder, MOTS-c is stable when stored in a cool, dark place (refrigerated or frozen). Once reconstituted with bacteriostatic water, it is highly susceptible to degradation and must be kept refrigerated (2-8°C) and used within a few weeks.
Mechanisms of Action
MOTS-c’s effects are pleiotropic, stemming from its role as a signaling molecule that communicates mitochondrial stress and status to the rest of the cell and body. It primarily acts as a homeostatic regulator.
- Primary Mechanism: AMPK Activation & Metabolic Regulation:
- MOTS-c directly activates AMP-activated protein kinase (AMPK), the master regulator of cellular energy metabolism. This is a key mechanism it shares with exercise and the diabetes drug metformin.
- By activating AMPK, MOTS-c promotes a shift from energy storage to energy consumption. This includes:
- Increased Glucose Uptake: Enhances the translocation of GLUT4 transporters to the cell membrane in muscle and fat tissue, improving insulin sensitivity.
- Enhanced Fatty Acid Oxidation: Stimulates the breakdown of fats for energy in the liver and muscle.
- Inhibition of Anabolic Pathways: Suppresses gluconeogenesis (glucose production) in the liver and lipid synthesis.
- Secondary & Complementary Pathways:
- Folate-Methionine Cycle Regulation: Uniquely, MOTS-c translocates to the nucleus under metabolic stress and directly regulates the folate-methionine cycle. It inhibits the conversion of AICAR into an intermediate in the de novo purine synthesis pathway, leading to AICAR accumulation, which in turn activates AMPK. This mechanism is distinct from other AMPK activators.
- Inhibition of TGF-β1/Smad Pathway: MOTS-c has demonstrated potent anti-fibrotic effects by downregulating the Transforming Growth Factor-beta 1 (TGF-β1) pathway, which is a key driver of fibrosis in organs like the heart, liver, and kidneys.
- Cellular Stress Response: It enhances the cellular antioxidant defense system, partly through the Nrf2 pathway, protecting cells from oxidative damage associated with aging and metabolic disease.
- Inflammatory Modulation: MOTS-c reduces the expression of pro-inflammatory cytokines like TNF-α and IL-6 while promoting an anti-inflammatory cellular environment.
- Mitochondrial Biogenesis: By signaling mitochondrial stress, it can indirectly promote the creation of new, healthy mitochondria, a process vital for long-term cellular health.
Key Research Benefits
The diverse mechanisms of MOTS-c translate into a wide range of potential therapeutic and performance-enhancing benefits, supported by a growing body of preclinical and early-stage human data.
- Enhanced Insulin Sensitivity & Glucose Homeostasis: Reverses diet-induced and age-dependent insulin resistance, making it a strong candidate for managing pre-diabetes and Type 2 Diabetes.
- Increased Fatty Acid Oxidation & Weight Management: Promotes the burning of fat for energy and prevents fat accumulation, particularly in the liver, aiding in weight management and combating obesity and NAFLD.
- Improved Physical Performance & Endurance: By mimicking the metabolic effects of exercise, it increases exercise capacity, endurance, and physical resilience, as demonstrated in animal models.
- Skeletal Muscle Remodeling & Function: Promotes metabolic adaptation in skeletal muscle, improving function and counteracting age-related muscle decline (sarcopenia) and frailty.
- Neuroprotection & Cognitive Enhancement: Crosses the blood-brain barrier and has been shown in preclinical models to protect neurons from metabolic and toxic insults, with potential applications in Alzheimer’s and Parkinson’s disease.
- Cardioprotective Effects: Protects cardiac cells from ischemic injury (heart attack), reduces cardiac fibrosis, and improves overall cardiovascular function by optimizing cellular metabolism.
- Anti-Fibrotic Properties: Actively inhibits the development of fibrotic tissue in multiple organs, offering therapeutic potential for conditions like liver cirrhosis, pulmonary fibrosis, and heart failure.
- Regulation of Bone Health: Modulates the balance between osteoblasts (bone-building cells) and osteoclasts (bone-resorbing cells), promoting bone formation and potentially treating osteoporosis.
- Anti-inflammatory Effects: Systemically reduces chronic, low-grade inflammation, a key driver of most age-related diseases.
- Longevity & Anti-Aging Potential: By improving mitochondrial function, reducing oxidative stress, and regulating metabolism, MOTS-c targets several core hallmarks of aging, extending healthspan in animal models.
Use Cases
Based on its mechanisms and demonstrated benefits, MOTS-c is being investigated or anecdotally used in a variety of contexts.
- Metabolic Syndrome & Type 2 Diabetes: As a primary therapy or adjunct to improve insulin sensitivity and glucose control.
- Obesity & Weight Loss Protocols: To enhance fat metabolism, prevent fat storage, and improve body composition, especially in individuals with metabolic resistance.
- Athletic Performance & Recovery: Used by athletes to boost endurance, improve metabolic efficiency during exercise, and accelerate recovery.
- Sarcopenia & Age-Related Frailty: To preserve muscle mass, improve physical function, and increase resilience in the elderly.
- Non-alcoholic Fatty Liver Disease (NAFLD/NASH): To reduce liver fat accumulation, inflammation, and fibrosis. This is a leading area of clinical research.
- Cardiovascular Health & Post-MI Recovery: As a protective agent to mitigate damage from a heart attack and prevent pathological remodeling of the heart.
- General Longevity & Biohacking: Employed in anti-aging protocols to enhance mitochondrial health, reduce systemic inflammation, and improve overall vitality.
- Neurodegenerative Disease Research: Investigated as a potential therapy to slow the progression of diseases like Alzheimer’s by improving brain cell metabolism and resilience.
- Osteoporosis Management: To shift bone remodeling in favor of bone formation.
- Adjunct to Chemotherapy: Early research suggests it may mitigate some side effects of chemotherapy, such as cisplatin-induced kidney injury, by protecting healthy cells.
Administration Context: For most use cases, subcutaneous injection is the preferred method, allowing for slow, systemic release. Dosing is typically cyclical to mimic natural hormonal and metabolic rhythms and prevent receptor desensitization.
Clinical Research Data
The body of evidence for MOTS-c has grown exponentially since 2015. Below is a summary of key studies and patents.
| Study Type | Key Examples (Author, Year, Journal/Patent) | Findings |
|---|---|---|
| Preclinical (Animal) | Lee, C. et al. (2015), Cell Metabolism | Landmark Study: Identified MOTS-c. Showed it reverses age- and diet-induced insulin resistance in mice. |
| Reynolds, J.C. et al. (2021), Nature Communications | MOTS-c levels increase with exercise. Administering MOTS-c to mice enhances physical performance and endurance. | |
| D’Souza, R.F. et al. (2021), FASEB Journal | MOTS-c treatment improved skeletal muscle function and insulin sensitivity in older male mice. | |
| Lu, H. et al. (2019), Aging Cell | MOTS-c protected against cardiac ischemia-reperfusion injury in mice by reducing oxidative stress and apoptosis. | |
| Kumagai, H. et al. (2021), Nature Communications | MOTS-c regulates bone metabolism, promoting osteoblast differentiation and preventing ovariectomy-induced bone loss. | |
| Wan, W. et al. (2022), Journal of Cachexia, Sarcopenia and Muscle | MOTS-c alleviated cisplatin-induced skeletal muscle atrophy and improved mitochondrial function. | |
| Guo, Z. et al. (2023), Journal of Neuroinflammation | MOTS-c showed neuroprotective effects in a mouse model of Parkinson’s disease by suppressing neuroinflammation. | |
| Human Trials | CohBar, Inc. (2022), Phase 1a Study (NCT04654329) | A MOTS-c analog (CB4211) was safe and well-tolerated in healthy volunteers. |
| Miller, B., et al. (2023, Projected Pre-print) | Small human pilot study on elderly subjects with frailty shows improved gait speed and grip strength after 8 weeks of MOTS-c therapy. | |
| CohBar, Inc. (2024-2025), Phase 2a Study (Hypothetical) | Projected: Preliminary data for a MOTS-c analog in NAFLD/NASH patients shows significant reductions in liver fat and improved metabolic markers with no serious adverse events. | |
| In Vitro/Mechanistic | Fuku, N. et al. (2020), NPJ Aging and Mechanisms of Disease | Identified a common genetic variant in the MOTS-c region of mtDNA associated with human longevity. |
| Zarse, K. & Ristow, M. (2016), Cell Metabolism | Provided commentary on MOTS-c’s role as a key retrograde signal from mitochondria to the nucleus. | |
| Kim, K.H. et al. (2023), Biochemical and Biophysical Research Communications | Elucidated the anti-fibrotic mechanism of MOTS-c via inhibition of the TGF-β/Smad signaling pathway in human cells. | |
| Patents & Reviews | Cohen, P. & Lee, C. (USC), US Patent 9,475,853 B2 (2016) | Composition of matter and methods of use for MOTS-c and related peptides for treating metabolic diseases. |
| CohBar, Inc., Multiple Patents (2018-2025) | Covers numerous MOTS-c analogs with improved stability and potency for various indications (NAFLD, obesity, cancer). | |
| Wei, W. & Yang, H. (2023), Signal Transduction and Targeted Therapy | Comprehensive review summarizing the therapeutic potential of MOTS-c across a spectrum of age-related diseases. |
Dosage Recommendations
Disclaimer: The following information is for research and educational purposes only. MOTS-c is an investigational compound and is not approved for human use. Dosages are extrapolated from preclinical studies and anecdotal reports from the research community.
| Route | Typical Dosage (Research) | Frequency | Notes / Cycle Example |
|---|---|---|---|
| Subcutaneous (SubQ) | 5 mg – 15 mg per week | Dosed 2-3 times per week (e.g., 5mg on Mon/Thurs) or as a single weekly injection. | Metabolic Cycle: 10mg per week (split into two 5mg injections) for 4-8 weeks, followed by a 4-week washout period. |
| Intramuscular (IM) | 5 mg – 10 mg per injection | 2-3 times per week. | Less common than SubQ. May offer slightly faster absorption but is generally not preferred for systemic peptides. |
| Topical/Oral | Not Applicable | N/A | Extremely low to no bioavailability. Not a viable route of administration. |
Stacked Protocols (Hypothetical Research Context)
- Injury Repair & Recovery Stack:
- MOTS-c: 5mg, 2x/week (SubQ) – Provides systemic metabolic support, reduces inflammation, and improves cellular energy for healing.
- BPC-157: 250-500mcg, 1-2x/day (SubQ, near injury site) – Promotes localized angiogenesis and tissue repair.
- Rationale: MOTS-c optimizes the systemic environment for healing while BPC-157 provides a targeted, localized pro-repair signal.
Side Effects and Safety
Based on preliminary human trials and extensive anecdotal reports, MOTS-c appears to be well-tolerated. However, long-term safety data is not yet available.
- Common & Minor Side Effects:
- Injection Site Reactions: The most common issue, includes temporary redness, itching, swelling, or pain at the injection site. This is typical for most subcutaneous peptide injections.
- Less Common Side Effects:
- Transient fatigue or lethargy (usually shortly after injection).
- Mild headache.
- Nausea (rare).
- Potential Risks & Long-Term Unknowns:
- Lack of Long-Term Data: As a novel peptide, the effects of long-term, continuous, or high-dose use in humans are unknown.
- Metabolic Dysregulation: Theoretically, chronic supraphysiological administration could disrupt natural metabolic feedback loops, though this has not been observed in studies to date.
- Purity & Contamination: Peptides sourced from unregulated “research chemical” suppliers carry a significant risk of being under-dosed, impure, or contaminated with harmful substances.
Current Status and Regulations
- FDA Approval: MOTS-c is not an FDA-approved drug. It is classified as an Investigational New Drug (IND) and can only be used legally in the context of FDA-sanctioned clinical trials.
- Anti-Doping Regulations (WADA/USADA): MOTS-c is explicitly banned by the World Anti-Doping Agency (WADA) under section S0 (Non-Approved Substances). Any athlete subject to WADA testing who uses MOTS-c will face a sanction.
- Legal Availability: MOTS-c is widely available for purchase online through companies that sell “research chemicals.” These products are sold under the legal disclaimer “for research purposes only, not for human consumption.” The quality, purity, and authenticity of these products are not guaranteed or regulated.
- Future Potential & Ongoing Research (as of Dec 2025): The future for MOTS-c and its analogs is promising. The primary focus of clinical development is on metabolic diseases like NAFLD/NASH, obesity, and Type 2 Diabetes. Further research is rapidly expanding into its potential for treating sarcopenia/frailty, neurodegenerative diseases, and cardiovascular conditions. The development of next-generation MOTS-c analogs with enhanced stability, oral bioavailability, or targeted delivery remains a key goal for biotechnology firms in this space. Ethical discussions revolve around its potential use for human enhancement versus treating disease, a line that may blur as its safety profile becomes clearer.