SS-31

SS-31 (also known as Elamipretide, MTP-131, Bendavia) is a anti-aging research peptide. A cell-permeable tetrapeptide that selectively concentrates in the inner mitochondrial membrane by binding cardiolipin. Protects mitochondrial cristae structure and reduces oxidative stress without scavenging ROS directly.

SS-31 (D-Arg-Dmt-Lys-Phe-NH₂) is a synthetic aromatic-cationic tetrapeptide from the Szeto-Schiller series designed to target the inner mitochondrial membrane. It concentrates 1000-fold in mitochondria via electrostatic and hydrophobic interactions with cardiolipin — a phospholipid unique to the inner mitochondrial membrane essential for electron transport chain efficiency. By stabilizing cardiolipin, SS-31 preserves cristae structure, reduces cytochrome c release, and dramatically reduces mitochondrial ROS without directly scavenging free radicals. It has demonstrated efficacy in models of heart failure, ischemia-reperfusion, renal disease, and age-related muscle decline.

1 Mechanism of action

Binds cardiolipin on the inner mitochondrial membrane. Stabilizes cristae structure and preserves Complex I/III/IV electron transport efficiency. Reduces mitochondrial ROS via cardiolipin protection rather than direct scavenging. Prevents cytochrome c release and apoptosis.

Primary targets: Cardiolipin (direct binding) · Inner mitochondrial membrane

2 Reported effects

Effects below are those reported in the published literature cited on this page. They are not claims of clinical benefit and not medical advice.

2.1 Reported benefits

• Mitochondria-specific cardiolipin stabilization
• Reduced mitochondrial ROS at source (not scavenging)
• Improved cardiac function and exercise capacity in Phase 2

2.2 Side effects

• Injection site pain and erythema
• Transient blood pressure decrease
• Nausea reported in some trial participants

3 Chemical and physical properties

3.1 Amino acid sequence

4 Research dosages

0.25–3.0 mg/kg SC in clinical trials; 2–4 mg/kg in preclinical mitochondrial models.

5 Research studies (8)

1. SS-31 Recharges Mitochondria in Aged Mouse Skeletal Muscle
   Aging Cell (2018) · Preclinical · N=64 (mice)
   SS-31 treatment reversed age-related declines in mitochondrial membrane potential, ATP production, and muscle fatigue resistance in old mice.
   Key finding: SS-31 restored mitochondrial ATP production in aged muscle to young-adult levels — cardiolipin stabilization as anti-aging strategy.
2. Elamipretide (SS-31) in Heart Failure with Reduced Ejection Fraction
   JACC: Heart Failure (2020) · RCT · N=72
   Phase 2 RCT. Elamipretide improved left ventricular end-systolic volume and 6-minute walk distance vs placebo over 4 weeks in HFrEF patients.
   Key finding: Improved LV end-systolic volume (−7.3 mL) and 6-min walk distance (+44 m) vs placebo in HFrEF — Phase 2 efficacy signal.
3. Mitochondrial-targeted SS-31 peptide attenuates radiation-induced cardiomyocyte senescence
   Journal of radiation research (2026) · Preclinical
   Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.
4. Mitochondrial-Targeted SS-31 Attenuates the Doxorubicin-Induced Cardiomyoblast H9C2 Cell Senescence
   Biology (2026) · Preclinical
   These data suggest that SS-31 is a promising drug to treat DOX-induced cardiomyocyte senescence.
5. Elamipretide (SS-31) and Nicotinamide Mononucleotide (NMN) Combination Therapy Targets TREM2 to Mitigate Post-ischemic Brain Injury in Mice
   Neurochemical research (2026) · Preclinical
   All animal experiments were performed in accordance with institutional and national guidelines for the care and use of laboratory animals and adhered to the ARRIVE guidelines.
6. Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model
   Circulation. Heart failure (2026) · RCT
   Our data highlight cardiolipin stabilization as a key modulator of mitochondrial and contractile function in HFpEF, identifying Elamipretide as a promising therapeutic approach for skeletal muscle dysfunction.
7. Therapeutic Peptide SS-31 Modulates Membrane Binding and Aggregation of α-Synuclein and Restores Impaired Mitochondrial Function
   Chemical biology & drug design (2026) · Preclinical
   Chemical Biology & Drug Design published by John Wiley & Sons Ltd.
8. Elamipretide (SS-31) promotes recovery by preserving mitochondrial bioenergetics and neural remodeling after spinal cord injury
   Neurochemistry international (2026) · Preclinical
   Collectively, these findings suggest that SS-31 promotes recovery after SCI, potentially by mitigating early apoptotic injury and supporting mitochondrial homeostasis and neural remodeling.

6 Safety and risk profile

6.1 Regulatory status

SS-31 is currently classified as Phase 3 clinical trials. It has no approved human indication in the United States; availability elsewhere does not imply demonstrated safety or efficacy.

Safety score: 55/100 — moderate concern. Derived from clinical data volume, known risks and regulatory status.

6.2 Contraindications

Conditions and populations in which use is contraindicated:

• Hypotension (SS-31 can mildly reduce BP)
• Pregnancy (limited safety data)
• Known hypersensitivity to aromatic-cationic peptides

6.3 Drug interactions

6.4 Long-term risks

• Cardiolipin remodeling effects with chronic use unknown
• Potential for mitochondrial compensatory adaptations
• Limited human safety data beyond 12 months

6.5 Research best practices

• Store at −20 °C; amber vials for light protection
• Reconstitute with sterile saline; use immediately
• Monitor blood pressure and heart rate post-administration in cardiac protocols

7 Frequently asked questions

How does SS-31 differ from other antioxidants?

Unlike conventional antioxidants (vitamin C, NAC) that float freely through cells and can paradoxically worsen oxidative stress, SS-31 concentrates 1000-fold specifically inside mitochondria and stabilizes cardiolipin — preventing ROS production at its source rather than scavenging ROS after they form.

What clinical trials has SS-31 been in?

SS-31 (Elamipretide) has completed Phase 2 trials for heart failure, Barth syndrome, and mitochondrial myopathy. It showed promising signals in cardiac function and exercise capacity but the Phase 3 Barth syndrome trial missed its primary endpoint in 2023.

8 References

1. Mitochondrial-targeted SS-31 peptide attenuates radiation-induced cardiomyocyte senescence PubMed (2026). Xie L, et al.. View source
2. Mitochondrial-Targeted SS-31 Attenuates the Doxorubicin-Induced Cardiomyoblast H9C2 Cell Senescence PubMed (2026). Fan J, et al.. View source
3. Elamipretide (SS-31) and Nicotinamide Mononucleotide (NMN) Combination Therapy Targets TREM2 to Mitigate Post-ischemic Brain Injury in Mice PubMed (2026). Yang Q, et al.. View source
4. Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model PubMed (2026). Vahle B, et al.. View source

9 See also

• Peptide encyclopedia index
• Peptide reconstitution calculator
• Glossary of peptide research terms