SS-31: Targeting Mitochondrial Dysfunction
SS-31: Targeting Mitochondrial Dysfunction
In 2004, a biochemist named Hazel Szeto was working on a seemingly unrelated problem: developing better ways to deliver drugs into cells. Her team at Weill Cornell Medical College had created a series of small peptides that could penetrate cellular membranes and accumulate in specific locations inside cells. When they examined where these peptides ended up, they made an unexpected discovery.
One peptide, which they designated SS-31, concentrated in mitochondria at levels hundreds of times higher than in the surrounding cell. More surprisingly, it seemed to improve mitochondrial function even in cells that weren't otherwise damaged. This serendipitous finding launched what has become one of the most promising lines of research in mitochondrial medicine.
SS-31, now also known as Elamipretide and branded as Bendavia in clinical development, has become a leading candidate for treating the mitochondrial dysfunction that underlies ageing and numerous diseases.
Why Mitochondria Matter
Mitochondria are the power plants of the cell, converting nutrients into ATP, the molecular currency of cellular energy. A single cell can contain thousands of mitochondria, and organs with high energy demands, like the heart, brain, and muscles, are particularly dependent on mitochondrial function.
As we age, mitochondrial function declines. The organelles become less efficient at producing ATP, they generate more damaging reactive oxygen species as byproducts, and their own DNA accumulates mutations. This mitochondrial decline is now recognised as one of the fundamental mechanisms of ageing, contributing to everything from decreased energy and muscle function to neurodegeneration and cardiovascular disease.
The problem is that mitochondria are difficult therapeutic targets. They're protected by two membranes, and most drugs can't reach them in meaningful concentrations. Even antioxidants, which might theoretically combat mitochondrial oxidative damage, largely fail to penetrate the mitochondrial inner membrane where they're needed most.
This is why SS-31's ability to concentrate in mitochondria was so significant. For the first time, researchers had a compound that could reach the site of dysfunction in therapeutically relevant amounts.
How SS-31 Works
SS-31 is a tetrapeptide, just four amino acids arranged in a specific sequence. Despite its simplicity, it has remarkable properties that make it uniquely suited for mitochondrial targeting.
The peptide carries a positive charge at physiological pH, which drives its accumulation in mitochondria. Mitochondria maintain a strong negative electrical potential across their inner membrane, part of the mechanism they use to produce ATP. Positively charged compounds are naturally drawn to this negative interior, and SS-31 concentrates there accordingly.
Once in the mitochondrial inner membrane, SS-31 interacts with cardiolipin, a lipid found exclusively in mitochondrial membranes. Cardiolipin is essential for the proper function of the electron transport chain, the molecular machinery that produces ATP. With age and disease, cardiolipin becomes oxidised and damaged, impairing electron transport and increasing the production of reactive oxygen species.
SS-31 appears to stabilise cardiolipin structure and protect it from oxidative damage. This doesn't just prevent further deterioration; research suggests it can actually restore function in mitochondria that have already been damaged. The peptide seems to optimise electron transport, reducing the leak of electrons that generates harmful superoxide radicals while improving ATP production.
The Research Programme
SS-31 has been studied extensively in preclinical models of various conditions involving mitochondrial dysfunction.
Heart failure has been a particular focus. In animal models of cardiac dysfunction, SS-31 improved mitochondrial function, reduced oxidative damage, and enhanced cardiac performance. A study published in the Journal of the American College of Cardiology demonstrated that SS-31 could reverse mitochondrial abnormalities in failing hearts and improve left ventricular function.
Kidney disease, particularly acute kidney injury, has shown responsiveness to SS-31 in preclinical studies. The kidneys are highly metabolically active and vulnerable to mitochondrial dysfunction. Research has shown that SS-31 can protect against ischemia-reperfusion injury, the type of damage that occurs when blood flow is interrupted and then restored.
Neurodegenerative diseases, which are characterised by mitochondrial dysfunction in neural tissue, have been studied in SS-31 research. In models of Parkinson's disease and Alzheimer's disease, the peptide showed neuroprotective effects and improved functional outcomes.
Ageing itself has been addressed in SS-31 research. Studies in aged animals have shown improvements in various measures of mitochondrial function and physical performance. A notable study in aged mice demonstrated that short-term SS-31 treatment could reverse age-related mitochondrial dysfunction and improve skeletal muscle performance.
Clinical Development
SS-31 has progressed into human clinical trials for multiple indications, providing valuable data on its effects in humans.
Heart failure has been the most advanced clinical application. Stealth BioTherapeutics, the company developing SS-31 under the name Elamipretide, conducted Phase II trials in patients with heart failure with reduced ejection fraction. The PROGRESS-HF trial showed improvements in left ventricular volumes and function, suggesting the mitochondrial effects observed in animals translate to humans.
Primary mitochondrial myopathy, a rare genetic condition causing muscle weakness due to inherited mitochondrial dysfunction, has been another clinical focus. The MMPOWER trials evaluated Elamipretide in this population and showed improvements in a six-minute walk test, a standard measure of functional capacity.
Barth syndrome, a rare genetic disorder affecting cardiolipin synthesis, represents a particularly relevant application given SS-31's mechanism involving cardiolipin. The TAZPOWER trial studied Elamipretide in Barth syndrome patients, with results showing improvements in some measures of cardiac and muscle function.
Dry age-related macular degeneration, where mitochondrial dysfunction in retinal cells contributes to vision loss, has been studied in the ReCLAIM trials. Results showed some evidence of improved visual function and reduced disease progression.
The clinical development programme has had both successes and setbacks. Regulatory approval has not yet been achieved for any indication, though development continues. The trials have confirmed that SS-31 can reach mitochondria in humans, that it improves markers of mitochondrial function, and that it's generally well-tolerated.
Implications for Ageing
The research on SS-31 has broader implications for understanding and potentially addressing ageing itself. If mitochondrial dysfunction is a fundamental mechanism of ageing, as substantial evidence suggests, then a compound that can restore mitochondrial function has potential anti-ageing applications beyond specific diseases.
The aged mouse studies are particularly intriguing. Research published in Cell Metabolism showed that eight weeks of SS-31 treatment in old mice improved skeletal muscle mitochondrial function to levels approaching those of young animals. The mice showed improved exercise capacity and reduced markers of oxidative stress. Remarkably, these benefits were maintained for some time after treatment ended, suggesting the peptide might catalyse lasting improvements rather than just temporary effects.
These findings have generated interest in SS-31 as a potential longevity intervention. If it can reverse mitochondrial ageing in mice, might it have similar effects in humans? This question remains open, and human longevity studies haven't been conducted. But the mechanistic rationale is compelling, and the animal data is encouraging.
What Users Report
Outside of formal clinical trials, SS-31 has been used by individuals seeking to address mitochondrial dysfunction or optimise mitochondrial function.
Energy levels are the most commonly reported improvement. Given mitochondria's role in energy production, this makes sense. Users often describe having more sustained energy throughout the day, without the peaks and crashes associated with stimulants.
Exercise capacity and recovery often improve. Users report being able to train harder and recover faster, consistent with improved mitochondrial function in muscle tissue. Endurance activities, which are particularly dependent on mitochondrial energy production, seem to benefit most.
Cognitive clarity is frequently mentioned. The brain is highly dependent on mitochondrial function, consuming a disproportionate amount of the body's ATP. Improved mitochondrial function could translate to better cognitive performance, and subjective reports align with this possibility.
These reports are consistent with what the research would predict but should be interpreted cautiously. Subjective reports are subject to placebo effects and expectation biases. Still, the consistency of reports with mechanistic predictions provides some support for SS-31's effects outside clinical trial populations.
Practical Considerations
SS-31 is typically administered by subcutaneous injection, though other routes including intravenous have been used in clinical trials. The peptide's stability and pharmacokinetics are generally favourable for practical use.
Dosing protocols vary, but clinical trials have typically used daily administration at doses that achieve meaningful mitochondrial concentrations. Individual protocols should be guided by specific goals and response.
Side effects in clinical trials have generally been mild. Injection site reactions are the most common. Some users report temporary fatigue during initial treatment, possibly reflecting cellular adaptations to improved mitochondrial function. Serious adverse effects have been rare.
Quality and sourcing matter significantly. The peptide market includes products of varying quality, and for a compound targeting such fundamental cellular machinery, purity and authenticity are important considerations.
The Mitochondrial Medicine Landscape
SS-31 exists within a broader landscape of mitochondrial medicine that's rapidly evolving. Other approaches to mitochondrial dysfunction include NAD+ precursors, which support the coenzymes mitochondria need; PQQ and other compounds that promote mitochondrial biogenesis; and various antioxidants specifically targeted to mitochondria.
SS-31 is distinguished by its unique mechanism and by the extent of its clinical development. No other mitochondria-targeted compound has undergone the same level of human clinical testing. This provides more confidence in its effects and safety in humans than is available for most compounds in this space.
The different approaches to mitochondrial support aren't necessarily competing. They address different aspects of mitochondrial health and could potentially be complementary. SS-31's effects on cardiolipin and electron transport are distinct from NAD+ support or mitochondrial biogenesis, suggesting combinations might provide broader benefits than any single approach.
A Note on Accessibility
One challenge with SS-31 is accessibility. As a compound in active pharmaceutical development, it's not available through conventional pharmaceutical channels except in clinical trials. This has led to a grey market of varying quality and reliability.
For those interested in SS-31, this creates a tension between the compound's well-documented potential and the challenges of obtaining it reliably. Working with practitioners experienced in peptide therapies and reputable sources for compounds is important for navigating this landscape.
The regulatory situation may evolve. If SS-31 achieves approval for any indication, legitimate pharmaceutical supply chains would emerge. But for now, access remains a practical challenge for those interested in its potential benefits.
Conclusion
SS-31 represents perhaps the most advanced approach to targeting mitochondrial dysfunction, the organelles' failing function that underlies so much of ageing and disease. Its ability to concentrate in mitochondria and stabilise cardiolipin addresses a fundamental limitation that has stymied other approaches to mitochondrial medicine.
The research base is substantial, spanning preclinical studies across multiple disease models and human clinical trials in several indications. While regulatory approval remains elusive, the data consistently supports SS-31's ability to improve mitochondrial function and translate that improvement into meaningful clinical benefits.
For those concerned about mitochondrial health, whether due to specific conditions, athletic performance goals, or interest in addressing fundamental mechanisms of ageing, SS-31 offers one of the most well-researched options available. It's not a complete solution to mitochondrial dysfunction, but it may be an important tool in the emerging field of mitochondrial medicine.
This article is for educational purposes and does not constitute medical advice. If you're interested in exploring whether SS-31 might be appropriate for your situation, we encourage you to book a consultation to discuss your individual circumstances with our clinical team.