Did SS-31 / elamipretide work in clinical trials?

No, on primary endpoints. PROGRESS-HF (heart failure, reduced ejection fraction) did not significantly change left ventricular end-systolic volume over 28 days at either tested dose. EMBRACE-STEMI did not significantly reduce infarct size in STEMI patients. Both trials reported acceptable tolerability. Clinical development in major indications was discontinued. The scientific rationale remains compelling, and Barth syndrome (a rare cardiolipin metabolism disorder) represents the most promising human data to date.

Why does SS-31 accumulate in mitochondria?

SS-31 concentrates at the inner mitochondrial membrane by binding cardiolipin — an anionic phospholipid found almost exclusively on the IMM. This uptake is driven by electrostatic and hydrophobic interactions rather than mitochondrial membrane potential, which is a key advantage: most other mitochondria-targeted antioxidants require an intact ΔΨm for uptake and concentrate less efficiently in damaged mitochondria with low membrane potential, where they are needed most.

Is SS-31 approved or legal? Is it on the WADA Prohibited List?

SS-31/elamipretide is not FDA-approved for any indication. It is not on the current WADA Prohibited List. Research-grade SS-31 is sold as a research compound only, is unregulated, and is not approved for human use. This is research-reference information only.

What dose is used in research and community settings?

In clinical trials: 4 mg/day or 40 mg/day subcutaneously (PROGRESS-HF). Community protocols are not standardized and typically fall in the 5–10 mg/day subcutaneous range, sometimes referencing the 4 mg/day trial dose. No validated human dose exists. This is anecdotal reference information, not dosing guidance.

What is SS-31's half-life?

Approximately 1–2 hours after intravenous or subcutaneous administration; systemic clearance is rapid. However, the cardiolipin-binding mechanism may produce durable structural changes at the IMM that persist after plasma clearance, which is the proposed rationale for once-daily dosing in trials.

What is the longevity rationale for SS-31?

Mitochondrial dysfunction — characterized by cardiolipin peroxidation, ETC supercomplex disassembly, increased mtROS, and reduced ATP synthesis — is implicated in cellular aging and age-related disease. SS-31's targeted cardiolipin protection addresses this mechanistically. Preclinical models of skeletal muscle aging and cardiac aging show improvements in mitochondrial energetics. However, this has not been demonstrated in human aging studies, and longevity benefit in humans is speculative.

Longevity

SS-31

Also known as: Elamipretide, MTP-131, Bendavia, Szeto-Schiller peptide 31, D-Arg-Dmt-Lys-Phe-NH2

An aromatic-cationic mitochondria-targeted tetrapeptide that selectively concentrates at the inner mitochondrial membrane by binding cardiolipin; it has reached Phase II...

Last updated July 11, 2026

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Overview

SS-31 (D-Arg-2',6'-dimethyltyrosine-Lys-Phe-NH2) is a synthetic tetrapeptide developed by Hazel Szeto and Peter Schiller — hence Szeto-Schiller peptide #31 — at Weill Cornell Medical College. It belongs to the aromatic-cationic peptide class and is notable for a unique pharmacological property: it selectively accumulates at the inner mitochondrial membrane (IMM) without requiring an intact mitochondrial membrane potential for uptake, unlike conventional mitochondria-targeted compounds such as MitoQ. The cardiolipin-binding mechanism that concentrates SS-31 at the IMM is the most thoroughly characterized aspect of its pharmacology and has been confirmed by multiple independent research groups. Cardiolipin is an anionic phospholipid found almost exclusively at the IMM and plays a central structural role in organizing the electron transport chain (ETC) supercomplexes and cristae architecture. By stabilizing cardiolipin and preventing its peroxidation, SS-31 is proposed to preserve ETC efficiency, reduce mitochondrial reactive oxygen species (mtROS), improve ATP synthesis, and protect against mitochondrial permeability transition pore (mPTP) opening. SS-31 reached Phase II clinical trials under the name elamipretide (or MTP-131/Bendavia), with development led by Stealth BioTherapeutics. Two key Phase II trials — PROGRESS-HF (heart failure with reduced ejection fraction) and EMBRACE-STEMI (ST-elevation myocardial infarction, ischemia-reperfusion injury) — were conducted in the 2010s. Both failed to achieve their primary endpoints, though SS-31 demonstrated acceptable tolerability. Larger Phase III programs were discontinued. SS-31 is not FDA-approved. It appears in research peptide markets primarily due to community interest in mitochondrial optimization and longevity. This entry is for research and educational reference only.

How it works

SS-31 concentrates at the IMM through electrostatic interaction with cardiolipin's anionic phosphate head groups, with hydrophobic stabilization from the dimethyltyrosine and phenylalanine residues. The peptide does not require mitochondrial membrane potential (ΔΨm) for uptake — a key mechanistic advantage over cationic lipophilic compounds like MitoQ. Biophysical studies show SS-31 reduces the electrostatic surface potential of cardiolipin-containing membranes by approximately 30 mV, blunting calcium-induced membrane stress. The primary downstream effect is prevention of cardiolipin peroxidation: without SS-31, cytochrome c acquires cardiolipin peroxidase activity under oxidative stress, oxidizing cardiolipin and triggering cytochrome c release (apoptosis initiation) and ETC supercomplex disassembly. SS-31 blocks this by sequestering cardiolipin in a protected conformation. Reported functional consequences in preclinical models include improved state 3 (ADP-stimulated) respiration, restored cristae architecture, reduced mtROS generation, improved ATP synthesis rates, and prevention of mPTP opening. In ischemia-reperfusion models, SS-31 administered before reperfusion reduces infarct size in rodents and pigs. These mechanisms are well supported in vitro and in preclinical models; human replication remains limited.

Researched effects

Preclinical Binds and stabilizes cardiolipin at the inner mitochondrial membrane, restoring ETC supercomplex organization in preclinical models
Preclinical Reduces mitochondrial ROS production and improves ATP synthesis in ischemia-reperfusion models
Preclinical Reduces infarct size in rodent and large-animal cardiac ischemia-reperfusion models
Clinical Showed numerical improvements in quality of life and exercise capacity in PROGRESS-HF Phase 2 (HFrEF), though primary endpoint was not met
Preclinical May improve mitochondrial function in skeletal muscle and heart in age-related or disease-related mitochondrial decline
Anecdotal Reported subjective improvements in energy and exercise tolerance by community users

Evidence levels: Clinical (human trials) · Preclinical (animal/lab) · Anecdotal (community-reported).

Dosing reference

For research reference only — not a recommendation.

Clinical / studied dosing

No approved clinical dosing exists. Phase II trial doses used: PROGRESS-HF — 4 mg/day or 40 mg/day subcutaneous injection once daily for 28 days (primary endpoint: change in left ventricular end-systolic volume — not significantly different from placebo for either dose). EMBRACE-STEMI — IV infusion at 0.05 mg/kg/hour for 1 hour administered before primary PCI (primary endpoint: CK-MB area under the curve as infarct size surrogate — no significant reduction vs. placebo). These doses are from discontinued clinical development programs, not current approved protocols.

Community-reported dosing (anecdotal)

Anecdotal and research-reference only; not medical advice. Community discussions of SS-31 are less prevalent than for peptides with larger user bases. Where discussed (primarily longevity-oriented peptide forums), common cited protocols involve subcutaneous injection of 5–10 mg per day, in cycles of varying length. Some users reference the 4 mg/day PROGRESS-HF dose as a lower bound. There is no validated community consensus and no human dose-response data to draw from. These figures are research-reference points only, not instructions.

Half-life: Approximately 1–2 hours terminal half-life after intravenous or subcutaneous administration; rapid systemic clearance. Exact human pharmacokinetic parameters are not fully published in peer-reviewed literature, but clearance is rapid. The clinical trial dosing intervals (once daily SC in PROGRESS-HF) suggest that biological effects may outlast plasma concentrations, consistent with the membrane-binding mechanism producing durable structural changes at the IMM that persist after peptide clearance.
Routes: subcutaneous, intravenous

Safety & side effects

SS-31/elamipretide has been consistently well tolerated across Phase I and Phase II clinical trials, with no serious drug-related adverse events attributed to it. The most common adverse event across trials was injection site reactions (pain, erythema, induration at the subcutaneous injection site), which were mild and transient. No significant organ toxicity, QTc prolongation, or laboratory abnormalities were identified in trial populations. However, Phase II trials were of short duration (28 days in PROGRESS-HF) in specific cardiovascular patient populations; long-term safety has not been systematically studied. SS-31 is not FDA-approved and is not available as a pharmaceutical. Research-grade SS-31 sold online is unregulated and carries product purity, sterility, and dosage accuracy risks. The compound is not on the WADA Prohibited List as of current published prohibited lists. It is research use only and not for human consumption in any therapeutic or performance context.

Research summary

The evidence for SS-31 sits in two distinct tiers. The mechanistic and preclinical evidence is strong and multi-source. Cardiolipin binding and the resulting stabilization of IMM structure are well-characterized by independent biophysical and biochemical studies. Multiple research groups have confirmed that SS-31 improves mitochondrial energetics in models of ischemia-reperfusion, heart failure, skeletal muscle aging, and genetic mitochondrial disease (notably Barth syndrome). The scientific rationale — targeting the root cause of mitochondrial dysfunction by protecting cardiolipin — is compelling and has attracted significant academic and clinical interest. The clinical translation, however, has been disappointing by primary endpoint metrics. PROGRESS-HF (Phase 2, 71 patients, HFrEF) did not significantly change left ventricular end-systolic volume over 28 days with either the 4 mg/day or 40 mg/day dose. EMBRACE-STEMI (Phase 2a, anterior STEMI patients undergoing primary PCI) did not significantly reduce infarct size by CK-MB AUC. Neither trial demonstrated the primary endpoint benefit that would advance development. Stealth BioTherapeutics, the primary sponsor, ceased development in major indications. A signal in the rare Barth syndrome population (cardiolipin metabolism disorder) remains the most intriguing human data point. For research-peptide community use motivated by longevity and mitochondrial optimization: the preclinical rationale is scientifically legitimate, but human benefit from subcutaneous SS-31 at community doses has not been demonstrated in controlled trials. Confident efficacy claims are not supported by the evidence.

FAQ

Did SS-31 / elamipretide work in clinical trials?: No, on primary endpoints. PROGRESS-HF (heart failure, reduced ejection fraction) did not significantly change left ventricular end-systolic volume over 28 days at either tested dose. EMBRACE-STEMI did not significantly reduce infarct size in STEMI patients. Both trials reported acceptable tolerability. Clinical development in major indications was discontinued. The scientific rationale remains compelling, and Barth syndrome (a rare cardiolipin metabolism disorder) represents the most promising human data to date.
Why does SS-31 accumulate in mitochondria?: SS-31 concentrates at the inner mitochondrial membrane by binding cardiolipin — an anionic phospholipid found almost exclusively on the IMM. This uptake is driven by electrostatic and hydrophobic interactions rather than mitochondrial membrane potential, which is a key advantage: most other mitochondria-targeted antioxidants require an intact ΔΨm for uptake and concentrate less efficiently in damaged mitochondria with low membrane potential, where they are needed most.
Is SS-31 approved or legal? Is it on the WADA Prohibited List?: SS-31/elamipretide is not FDA-approved for any indication. It is not on the current WADA Prohibited List. Research-grade SS-31 is sold as a research compound only, is unregulated, and is not approved for human use. This is research-reference information only.
What dose is used in research and community settings?: In clinical trials: 4 mg/day or 40 mg/day subcutaneously (PROGRESS-HF). Community protocols are not standardized and typically fall in the 5–10 mg/day subcutaneous range, sometimes referencing the 4 mg/day trial dose. No validated human dose exists. This is anecdotal reference information, not dosing guidance.
What is SS-31's half-life?: Approximately 1–2 hours after intravenous or subcutaneous administration; systemic clearance is rapid. However, the cardiolipin-binding mechanism may produce durable structural changes at the IMM that persist after plasma clearance, which is the proposed rationale for once-daily dosing in trials.
What is the longevity rationale for SS-31?: Mitochondrial dysfunction — characterized by cardiolipin peroxidation, ETC supercomplex disassembly, increased mtROS, and reduced ATP synthesis — is implicated in cellular aging and age-related disease. SS-31's targeted cardiolipin protection addresses this mechanistically. Preclinical models of skeletal muscle aging and cardiac aging show improvements in mitochondrial energetics. However, this has not been demonstrated in human aging studies, and longevity benefit in humans is speculative.

References

All content is for research and educational use only and is not medical advice. Products are sold for laboratory research only and are not for human consumption.