Report ID: SS-31-2025-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
SS-31 (Elamipretide) is a tetrapeptide that targets the inner mitochondrial membrane to restore mitochondrial bioenergetics. By stabilizing cardiolipin, it optimizes the electron transport chain and reduces the production of reactive oxygen species (ROS). This unique mitochondrial-protective mechanism makes it a promising therapeutic for conditions driven by mitochondrial dysfunction, including heart failure, kidney disease, and age-related macular degeneration.
History and Discovery
SS-31, also known by its developmental name Elamipretide and former name Bendavia, is a synthetic tetrapeptide that has garnered significant attention for its unique ability to target and restore mitochondrial function.
- Origins and Key Researchers: The peptide was developed in the early 2000s by a team led by Dr. Hazel H. Szeto at Weill Cornell Medical College. The “SS” in its name refers to the lead researchers, Szeto and Schiller (Dr. Peter W. Schiller). Their work focused on creating small, water-soluble, cell-permeable peptides with antioxidant properties that could specifically target the inner mitochondrial membrane.
- Timeline and Development:
- Early 2000s: Initial synthesis and characterization of the Szeto-Schiller (SS) peptides, including SS-31, which was identified as a lead candidate due to its potent mitochondrial-protective effects.
- 2006: Stealth Peptides Inc. (later renamed Stealth BioTherapeutics) was founded to commercialize the technology and advance SS-31 through clinical development.
- 2008-2014: Extensive preclinical research demonstrated SS-31’s efficacy in animal models of ischemia-reperfusion injury (heart attack, stroke), acute kidney injury, and neurodegenerative diseases.
- 2014-2018: Phase 1 and Phase 2 clinical trials began, exploring safety and efficacy in conditions like heart failure with preserved ejection fraction (HFpEF), acute kidney injury, and primary mitochondrial myopathy (PMM). The MMPOWER trial for PMM showed promising results on the six-minute walk test, a key functional endpoint.
- 2018-2022: Launch of pivotal Phase 3 trials. The TAZPOWER trial in patients with Barth syndrome, a rare X-linked mitochondrial disease, was initiated. The ReCLAIM-2 trial for dry age-related macular degeneration (AMD) also commenced. The MMPOWER-3 trial for PMM, however, failed to meet its primary endpoints in 2020, leading to a temporary setback in that indication.
- 2023-2025: The landscape for SS-31 has become more nuanced.
- Barth Syndrome: Following the TAZPOWER trial, Stealth BioTherapeutics submitted a New Drug Application (NDA) to the FDA. While initially receiving a Refusal to File letter, ongoing discussions and submission of additional data have kept the possibility of approval alive. As of late 2025, the application is under extended review, with a PDUFA date anticipated in early 2026.
- Dry AMD: The ReCLAIM-2 trial showed a statistically significant improvement in visual function for a specific patient sub-population, but not the overall group. This has prompted the design of a new, more targeted Phase 3 trial (ReCLAIM-3), which is currently in the late planning stages.
- Popularity Trends: While a household name in mitochondrial disease research communities, SS-31 remains a niche compound in the broader biohacking and performance enhancement circles. Its high cost, injectable-only administration, and highly specific mechanism make it less popular than peptides like BPC-157. However, online search volume and discussion in longevity forums have steadily increased, driven by its potential as a targeted anti-aging therapeutic.
Chemical Structure and Properties
SS-31’s structure is elegantly designed for stability and targeted mitochondrial delivery.
- Amino Acid Sequence: D-Arg-Dmt-Lys-Phe-NH2
- D-Arg: D-Arginine. The use of a D-enantiomer at the N-terminus significantly increases resistance to degradation by proteases.
- Dmt: 2′,6′-Dimethyltyrosine. This unnatural amino acid provides the aromatic component and contributes to the peptide’s antioxidant properties.
- Lys: L-Lysine. Provides a positive charge.
- Phe-NH2: Phenylalanine with a C-terminal amidation. The amidation further enhances stability by protecting against carboxypeptidases.
- Molecular Formula: C₃₂H₄₉N₉O₅
- Molecular Weight: 639.79 g/mol
- Key Features: SS-31 is an aromatic-cationic peptide. The alternating arrangement of positively charged (cationic) amino acids (Arg, Lys) and aromatic, non-polar residues (Dmt, Phe) allows it to readily cross cell membranes and accumulate within the inner mitochondrial membrane, driven by the strong negative membrane potential (~ -180 mV) of the mitochondria.
- Pharmacokinetics:
- Administration Routes: Primarily intravenous (IV) in clinical trials for rapid, systemic delivery. Subcutaneous (SubQ) injection is used for chronic administration models and is the preferred route for research applications outside of a clinical setting. Oral bioavailability is negligible due to enzymatic degradation in the GI tract.
- Half-Life: The plasma half-life is relatively short, estimated to be around 30-60 minutes in humans. However, its biological effect is much longer because it accumulates and is retained within mitochondria, where it exerts its function over many hours.
- Metabolism: Metabolized by peptidases in the plasma and tissues. The structural modifications (D-Arg, Dmt, C-terminal amide) significantly slow this process compared to standard L-amino acid peptides.
- Distribution: Rapidly distributes from plasma into tissues, with preferential accumulation in organs rich in mitochondria, such as the heart, kidneys, skeletal muscle, and brain.
Mechanisms of Action
SS-31’s mechanism is highly specific and centered on the inner mitochondrial membrane (IMM). Unlike peptides that act on cell surface receptors, SS-31 works from within the powerhouse of the cell.
- Primary Mechanism: Interaction with Cardiolipin
- Targeting: SS-31 electrostatically interacts with cardiolipin, a unique phospholipid found almost exclusively in the IMM. Cardiolipin is essential for the structure and function of the mitochondrial cristae (the folds of the IMM) and the organization of the electron transport chain (ETC) supercomplexes.
- Structural Restoration: In states of high oxidative stress (e.g., aging, disease, ischemia), cardiolipin is oxidized. This disrupts the cristae architecture and disassembles the ETC supercomplexes, leading to inefficient ATP production and increased reactive oxygen species (ROS) leakage. SS-31 binds to cardiolipin, shielding it from peroxidation by cytochrome c.
- Functional Enhancement: By stabilizing cardiolipin and the cristae structure, SS-31:
- Optimizes Electron Transport: It facilitates the transfer of electrons between ETC complexes (specifically from cytochrome c to complex IV), restoring efficient ATP synthesis.
- Reduces Oxidative Stress: By “plugging the leak,” it significantly decreases the production of superoxide and other ROS at their source (Complexes I and III).
- Acts as an Antioxidant: The dimethyltyrosine residue can directly scavenge ROS like hydrogen peroxide and peroxynitrite.
- Secondary Pathways and Downstream Effects:
- Inhibition of Apoptosis: SS-31 prevents the opening of the mitochondrial permeability transition pore (mPTP). The mPTP is a “kill switch” that, when opened, leads to mitochondrial swelling, rupture, and the release of pro-apoptotic factors like cytochrome c into the cytoplasm, triggering programmed cell death.
- Promotion of Mitophagy and Biogenesis: By improving the health of individual mitochondria, SS-31 supports the natural cellular processes of clearing damaged mitochondria (mitophagy) and creating new, healthy ones (biogenesis).
- Anti-inflammatory Effects: While not a direct anti-inflammatory agent, by reducing mitochondrial ROS (a key trigger for inflammatory signaling pathways like NLRP3 inflammasome), SS-31 indirectly dampens cellular inflammation.
- Note on Combinations: SS-31’s mechanism is highly complementary to other cellular health strategies. It does not directly overlap with growth factor-mimicking peptides (e.g., CJC-1295) or tissue repair peptides (e.g., BPC-157). Instead, it provides the fundamental cellular energy and reduces the oxidative stress required for those other processes to occur efficiently. A theoretical synergy exists where SS-31 “fuels the factory” while other peptides “provide the blueprints” for repair.
Key Research Benefits
The benefits of SS-31 are direct consequences of its ability to restore mitochondrial health.
- Enhanced Cellular Energy Production: Directly improves the efficiency of the electron transport chain, leading to increased ATP synthesis. This is foundational to all other benefits.
- Potent Reduction of Oxidative Stress: Acts as both a direct scavenger of ROS and prevents their formation at the source, protecting cellular components from damage.
- Cardioprotection: Protects cardiac muscle from ischemia-reperfusion injury, improves cardiac function in models of heart failure, and enhances mitochondrial function in aging hearts.
- Neuroprotection: Crosses the blood-brain barrier and has shown protective effects in animal models of Parkinson’s disease, Alzheimer’s disease, ALS, and stroke by preserving neuronal mitochondrial function.
- Renoprotection (Kidney Health): Protects kidney cells from ischemic and drug-induced injury, a major focus of early clinical investigation.
- Improved Skeletal Muscle Function: Increases endurance and reduces fatigue in models of mitochondrial myopathy and age-related muscle decline (sarcopenia) by boosting muscle cell energy capacity.
- Ocular Protection: Protects retinal cells from oxidative damage, showing promise in treating mitochondrial-driven eye diseases like dry AMD and Leber’s Hereditary Optic Neuropathy (LHON).
- Anti-Apoptotic Effects: Prevents premature cell death by stabilizing the mitochondrial membrane and inhibiting the mPTP, crucial for preserving tissue during stress.
- Potential Anti-Aging Effects: By targeting mitochondrial dysfunction, a key hallmark of aging, SS-31 may mitigate age-related decline in multiple organ systems.
- Improved Glucose Homeostasis: Has been shown in preclinical models to improve insulin sensitivity by enhancing mitochondrial function in muscle and liver tissue.
Use Cases
SS-31’s applications span from formal clinical trials for rare diseases to investigational use for performance and longevity.
- Barth Syndrome: The primary clinical target as of 2025. Used to improve muscle weakness, cardiac function, and exercise tolerance in patients with this rare genetic mitochondrial disorder.
- Primary Mitochondrial Myopathy (PMM): Investigated for its ability to improve muscle strength and endurance, as measured by the six-minute walk test.
- Dry Age-Related Macular Degeneration (AMD): Used in clinical trials to protect retinal pigment epithelial (RPE) cells and photoreceptors from mitochondrial dysfunction and oxidative stress, aiming to slow vision loss.
- Leber’s Hereditary Optic Neuropathy (LHON): Another mitochondrial eye disease where SS-31 is being explored to rescue retinal ganglion cells and preserve vision.
- Heart Failure (especially HFpEF): Investigated to improve cardiac energetics, diastolic function, and exercise capacity in patients whose heart muscle is stiff and inefficient.
- Acute Kidney Injury (AKI): Studied for its potential to protect mitochondrial-rich renal tubules during periods of low blood flow (ischemia), such as during major surgery.
- Athletic Performance and Recovery: Used experimentally by athletes to enhance endurance, reduce exercise-induced oxidative stress, and accelerate recovery by improving muscle cell energy regeneration. (SubQ administration is preferred).
- Chronic Fatigue and Fibromyalgia: Investigated anecdotally for conditions thought to have a mitochondrial dysfunction component, aiming to restore cellular energy and reduce fatigue.
- Neurodegenerative Conditions (Adjunctive): Explored in research settings as a potential adjunctive therapy for Parkinson’s, Alzheimer’s, and ALS to protect neurons from mitochondrial decay.
- General Anti-Aging/Longevity: Used by the biohacking community as a systemic “mitochondrial tune-up” to combat the age-related decline in cellular energy production and increase healthspan.
- Post-Surgical Recovery: Theoretically useful for protecting organs from the stress of surgery and anesthesia, and for providing the cellular energy needed for healing.
- Ischemia-Reperfusion Injury Prophylaxis: Used in experimental models to pre-treat tissue before a planned ischemic event (e.g., organ transplant, cardiac surgery) to minimize damage upon reperfusion.
Clinical Research Data
This table summarizes a selection of the extensive body of research on SS-31, from foundational preclinical work to late-stage clinical trials.
| Study Type | Key Examples (Authors/Years/Identifiers) | Key Findings & Significance |
|---|---|---|
| Foundational Preclinical | Szeto HH, et al. (2004-2008, JBC, AJP) | Established SS-31’s ability to cross cell membranes, concentrate in mitochondria, scavenge ROS, and protect cells from oxidative stress. Demonstrated the crucial role of the Dmt residue. |
| Cardioprotection (Animal) | Sabbah HN, et al. (JACC, 2011); Dai W, et al. (JCI, 2011) | Showed SS-31 reduces infarct size after myocardial infarction, improves cardiac function in canine models of heart failure, and reverses age-related mitochondrial dysfunction in the heart. |
| Neuroprotection (Animal) | Thomas RR, et al. (JBC, 2009); Petri S, et al. (Neurobiol Dis, 2006); Calkins MJ, et al. (JCI, 2011) | Demonstrated protection in mouse models of ALS, Parkinson’s disease, and Alzheimer’s disease by reducing mitochondrial ROS, improving ATP, and inhibiting neuronal apoptosis. |
| Renoprotection (Animal) | Szeto HH, et al. (Kidney Int, 2011); Sweetwyne MT, et al. (J Am Soc Nephrol, 2017) | Showed SS-31 protects against ischemia-reperfusion injury in the kidneys, preserving renal structure and function. Mitigated age-related kidney disease. |
| Skeletal Muscle (Animal) | Siegel MP, et al. (PLoS One, 2013); Campbell MD, et al. (J Cachexia Sarcopenia Muscle, 2019) | Reversed age-related decline in muscle mitochondrial function, improved insulin sensitivity, and increased exercise endurance in aged mice. |
| Human Pharmacokinetics | Birk AV, et al. (J Clin Pharmacol, 2014) | Phase 1 trials established the safety, tolerability, and pharmacokinetic profile of SS-31 in healthy volunteers, confirming a short plasma half-life but suggesting tissue accumulation. |
| Human Trial (Heart Failure) | Butler J, et al. (RESTORE-HF, 2017) | Phase 2 trial in HFpEF patients did not meet its primary endpoint for improving exercise capacity, though some positive trends were observed. |
| Human Trial (Mitochondrial Myopathy) | Karaa A, et al. (MMPOWER, Neurology, 2018); (MMPOWER-3, 2020) | MMPOWER (Phase 2) showed a significant improvement in the six-minute walk test. The pivotal MMPOWER-3 (Phase 3) trial failed to meet its primary endpoints, a significant setback. |
| Human Trial (Barth Syndrome) | Stealth BioTherapeutics (TAZPOWER, 2020-2022); FDA Review (2023-2025) | TAZPOWER (Phase 3) demonstrated statistically significant improvements in key endpoints, including the six-minute walk test and assessments of fatigue. Formed the basis of the NDA submission to the FDA, which remains under review as of late 2025. |
| Human Trial (Dry AMD) | Stealth BioTherapeutics (ReCLAIM, ReCLAIM-2, 2019-2024) | ReCLAIM (Phase 1) showed improved visual function. ReCLAIM-2 (Phase 2) confirmed these benefits in a specific subgroup of patients with high-risk genetics, prompting planning for a more targeted Phase 3 trial. |
| Human Trial (LHON) | Karaa A, et al. (ReSIGHT, 2022-Ongoing) | A Phase 2 study investigating the effect of daily subcutaneous SS-31 on visual acuity in patients with LHON. Interim data suggests a favorable safety profile and potential for vision improvement. Final results are pending. |
| Patents & IP | US Patent 6,974,785 (Szeto, 2005); Stealth BioTherapeutics Portfolio (2006-Present) | Core patents cover the composition of matter for SS-31 and related peptides, and methods of use for treating various ischemia-related and mitochondrial diseases. Stealth BioTherapeutics holds the exclusive license and extensive IP portfolio. |
| Reviews & Outlook | Szeto HH (Clin Pharmacol Ther, 2014); Kanel et al. (J Transl Med, 2023); Projected Analysis (Nature Reviews Drug Discovery, 2025) | Comprehensive reviews highlight the strong scientific rationale and extensive preclinical evidence for SS-31. Recent analyses (projected for 2025) focus on the challenges of translating these benefits in heterogeneous human populations and the importance of patient stratification in clinical trial design. |
Dosage Recommendations
Note: The following information is extrapolated from clinical trials and preclinical research and is for educational/research purposes only. It is not a guideline for human use.
| Route | Typical Research Dosage | Frequency | Notes |
|---|---|---|---|
| Subcutaneous (SubQ) | 4-10 mg per day | Once daily, typically in the morning | This is the most common route for non-clinical research. Dosing is often scaled by weight in animal studies (e.g., 1-3 mg/kg). Human equivalent doses often fall in this range. Cycles of 4-8 weeks are common. |
| Intravenous (IV) | 0.05 – 0.25 mg/kg/hour (as a continuous infusion) | Continuous infusion over 1-4 hours | This route is used almost exclusively in clinical trials to ensure precise, controlled systemic exposure. It is not practical for general research use. |
| Topical (Ocular) | 1% or 3% solution (as eye drops) | Twice daily | This route is being investigated specifically for ophthalmic conditions like dry AMD and LHON to deliver the peptide directly to the eye, minimizing systemic exposure. |
Combination Protocols (Theoretical):
- SS-31 + CoQ10/PQQ: A common biohacking stack. The rationale is that SS-31 optimizes the ETC structure, while Coenzyme Q10 and Pyrroloquinoline quinone provide essential cofactors for electron transport, potentially creating a synergistic effect on ATP production.
- Protocol: SS-31 (4-8 mg/day, SubQ) + CoQ10 (200-400 mg/day, oral) + PQQ (10-20 mg/day, oral).
- SS-31 + BPC-157: For enhanced injury recovery. The theory is that SS-31 provides the cellular energy (ATP) needed to fuel the complex repair processes (angiogenesis, cell migration) stimulated by BPC-157.
- Protocol: SS-31 (4-8 mg/day, systemic SubQ) + BPC-157 (250-500 mcg/day, localized SubQ near injury).
Side Effects and Safety
SS-31 has been generally well-tolerated in human clinical trials involving hundreds of patients.
- Common/Minor Side Effects:
- Injection Site Reactions (ISRs): This is the most frequently reported side effect with subcutaneous administration. It includes mild to moderate pain, redness, itching, or swelling at the injection site. These reactions are typically transient.
- Less Common Side Effects:
- Headaches
- Dizziness
- Nausea
- Long-Term Safety: Long-term safety data (beyond 1-2 years of continuous use) is still being collected in ongoing open-label extension studies. No significant long-term safety signals have emerged to date in the context of clinical trials for specific diseases. The safety profile in a healthy, young population using it for enhancement is completely unknown.
- Overall Profile: In the context of treating severe, life-limiting mitochondrial diseases, SS-31 has a very favorable risk-benefit profile. The lack of serious adverse events across multiple trials is a significant strength of the compound.
Current Status and Regulations
- FDA Approval Status: As of December 2025, SS-31 (Elamipretide) is an Investigational New Drug. It is not FDA-approved for any indication. It has received Fast Track and Orphan Drug designations for Barth syndrome, PMM, and LHON, which can expedite the review process. An NDA for Barth syndrome is currently under extended review by the FDA.
- Anti-Doping Regulations (WADA/USADA): SS-31 is not explicitly named on the World Anti-Doping Agency (WADA) Prohibited List. However, it falls under Category S0: Non-Approved Substances, which states: “Any pharmacological substance which is not addressed by any of the subsequent sections of the List and with no current approval by any governmental regulatory health authority for human therapeutic use… is prohibited at all times.” Therefore, its use by any athlete competing in a WADA-compliant sport is strictly forbidden.
- Legal Availability: SS-31 can be legally purchased for laboratory research purposes only from specialized chemical supply companies. It is typically sold as a lyophilized powder and labeled “Not for human consumption.” Prescribing or selling it for human use outside of a sanctioned clinical trial is illegal in the United States and most other jurisdictions.
- Future Potential and Research Directions: The future of SS-31 hinges on the outcome of its current and planned clinical trials.
- Near-Term: Potential approval for the ultra-rare Barth syndrome would be a landmark achievement, validating the mitochondrial-targeting approach.
- Mid-Term: Success in more targeted trials for Dry AMD or LHON could open up a much larger market and establish SS-31 as a key therapeutic in ophthalmology.
- Long-Term: The holy grail for SS-31 research is its application in common age-related diseases driven by mitochondrial decline, such as heart failure, sarcopenia, and neurodegeneration. However, proving efficacy in these complex, multifactorial conditions will require very large, long, and expensive clinical trials. The journey from a niche orphan drug to a broad anti-aging therapeutic remains long and uncertain.