SS-31

SS-31 (now known as elamipretide) is a synthetic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH2 that selectively concentrates in the inner mitochondrial membrane. Developed by Dr. Hazel Szeto at Cornell University (the "SS" stands for Szeto-Schiller), it was designed to target cardiolipin, a phospholipid unique to the inner mitochondrial membrane that plays a critical role in electron transport chain function and mitochondrial bioenergetics.

The mechanism of SS-31 is unique among peptides. Rather than acting on a cell surface receptor, it penetrates cells and accumulates in mitochondria driven by the mitochondrial membrane potential. Once there, it interacts with cardiolipin, stabilizing its structure and optimizing electron transport chain function. This results in improved ATP production, reduced reactive oxygen species (ROS) generation, and protection against mitochondrial dysfunction — effects that address fundamental aspects of cellular aging and disease.

SS-31 has been evaluated in clinical trials for multiple conditions characterized by mitochondrial dysfunction. These include Barth syndrome (a genetic mitochondrial cardiomyopathy caused by cardiolipin deficiency), heart failure, primary mitochondrial myopathy, age-related macular degeneration, and renal ischemia-reperfusion injury. In the TAZPOWER trial for Barth syndrome, elamipretide showed improvements in functional measures though the primary endpoint results were mixed.

The aging research community has shown particular interest in SS-31 because mitochondrial dysfunction is considered one of the hallmarks of aging. Animal studies have demonstrated that SS-31 can reverse age-related mitochondrial dysfunction, improve exercise capacity in aged animals, and protect against age-related organ decline. These findings suggest that targeting mitochondrial cardiolipin may be a viable strategy for addressing multiple aspects of biological aging simultaneously.