SS-31: The Mitochondria-Repairing Peptide
By Jay Campbell
January 27th, 2022
The mitochondria are being discovered to be more than just “the powerhouse of the cell”.
Emerging evidence shows their function is a critical sign of aging:
“Mitochondria have recently entered center stage as the major regulator of life and death in the cell…. oxidative damage to mitochondria can result in cytochrome c release into the cytosol and activation of the caspase cascade, leading to apoptosis (72, 73, 77).
Cell death induced by mitochondrial oxidative damage plays an important role in numerous clinical disorders, including ischemia-reperfusion injury, neurodegenerative disorders, diabetes, inflammatory disorders, drug-induced toxicity, and age-related degenerative diseases”
And although I’ve previously touted Metformin as a major hallmark product in the 2010s… that title for the 2020s may go to the therapeutic peptide SS-31.
SS-31 is a longevity bio-regulator you should keep your eyes on, and this article will tell you why.
What IS SS-31?
(NOTE: If you aren’t familiar with why mitochondrial health is important and all the things you can do to optimize it, read this article first before continuing)
SS-31 (a.k.a. Elampretide, Bendavia, MPT-141) is a synthetic tetrapeptide (i.e. 4 amino acids long) that was discovered by scientists Hazel H. Szeto and Peter W. Schiller in the early 2000s, hence why it is known as a Szeto-Schiller (SS) peptide.
And it was quite the happy accident — initially, Schiller and Szeto were working on new molecules that selectively targeted the μ opioid receptor in the brain and provided relief from severe pain.
The first surprise was that the peptide-based molecules were crossing the blood-brain barrier, but the second and arguably larger breakthrough was that the peptides very specifically targeted the mitochondria:
“Mitochondria fractionation studies ultimately revealed that >85% of SS-02 was found in the fraction containing inner mitochondrial membrane (IMM) [without being distributed in the mitochondrial matrix], making it the first compound to selectively target the IMM where the ETC resides. It was estimated that SS-02 concentrates >1,000-fold in the IMM when compared to extracellular concentrations.”
(BTW — I highly recommend reading that linked paper for all the intimate details on how SS-31 eventually came to be, but I’ll just skip to the important information)
SS-02 was the first iteration where the mitochondria-targeted antioxidant properties were observed, but Schiller and Szeto wanted to go further by keeping these new properties while decreasing SS-02’s affinity for the μ opioid receptor.
After a few amino acid substitutions, the final result was SS-31:
Just to put this in context, look at the picture below:
SS-20 was the intermediate between SS-02 and SS-31. SS-20 decreased affinity for the μ receptor by 450-fold, while SS-31 decreased affinity by 2,000-fold… virtually ZERO opioid activity despite extremely high doses in mouse studies!
But back to the mitochondria — why is SS-31 such a phenomenal discovery in the world of mitochondrial disease?
It’s because prior drugs and therapies failed to address the root of mitochondrial dysfunction:
“Elamipretide is a drug that reaches the inner mitochondrial membrane and targets part of the membrane critical to maintaining mitochondrial function. This is challenging because it is difficult to develop drugs that will pass through both the cell membrane and outer mitochondrial membranes.
Elamipretide is thought to normalize the structure of the inner mitochondrial membrane, which can lead to improvements in mitochondrial function. This can include improved energy production and a reduction in the formation of harmful free radicals.”
This attracted the interest of the pharmaceutical company Stealth BioTherapeutics (formerly Stealth Peptides), who happened to license the intellectual property from Szeto and Schiller’s universities in 2006 among several others.
SS-31’s Mechanism Of Action
The “secret sauce” behind SS-31’s function in the body revolves around lipid molecule located in the inner mitochondrial member (IMM) known as Cardiolipin:
“[Cardiolipin]is required for mitochondrial cristae formation and efficient oligomeric assembly of electron transport chain complexes…. it stabilizes the inner membrane proteins.
It enables optimal ATP production as it functions as a proton trap for ATP synthase and facilitates electron transfer by electrostatic interaction with cytochrome c. Cardiolipin enhances the peroxidase activity of cytochrome c, which results in higher levels of oxidized cardiolipin. Cardiolipin is also involved in the mitochondrial fission and fusion processes.
Therefore, Cardiolipin is vital in normal mitochondrial functioning and its deficiency disrupts the respiratory complexes, increases proton leak, enhances ROS [reactive oxygen species] production, impairs ATP synthesis, alters mitochondrial morphology, and subsequently compromises mitochondrial dynamics and stability.”
So where does SS-31 come in?
Simply put, it binds to Cardiolipin and prevents the undesirable effects (mitochondrial dysfunction via prevention of ROS accumulation and subsequent oxidative damage) while promoting the desirable effects (antioxidant properties, ATP production, etc.).
Genius biochemist Nick Andrews says the ATP-boosting capabilities of SS-31 are what primarily drive its health benefits.
He even had the following quote to share with me: “One injection of SS-31 is the ATP equivalent of six months of daily endurance and endurance training exercise.”
Top # Health Benefits Of SS-31
There are an overwhelming number of health benefits of SS-31 if you take a quick look at PubMed — approximately 135 studies published since 2005.
Which shouldn’t be surprising, given how intricately tied the mitochondria are to the human body functioning properly.
Let’s get right to it!
SS-31 Can Reverse Cognitive Dysfunction
One of the interesting applications of SS-31 could be in the treatment of chronic fatigue syndrome (CFS).
This is based on the hypothesis of Dr. Ron Davis that CFS cells don’t “behave” in the way that normal cells do:
“…an unknown factor in the blood is driving ME[Myalgic encephalomyelitis]/CFS and can cause healthy cells to behave like ME/CFS cells.
What proved to be revelatory in ME/CFS was the nanoneedle salt stress test. This simply involves adding some sodium chloride (table salt), which forces cells to use energy (sodium enters the cell and is a little toxic to them, so they must use energy to pump it out again).
When salt is added to a sample of healthy control cells, not much happens electrically. But when salt is added to an ME/CFS sample, electrical impedance shoots up… It does this for every patient tested (an initial sample of 20, then 26 more), and doesn’t do this for every control tested to date”
“So, something in (or missing from) the plasma seems to be affecting cells, making ME/CFS cells act abnormally. And finding the something responsible for that could provide a big clue to understanding ME/CFS.”
Although this does not mean a guarantee of treatment, his preliminary work shows that SS-31 is clearly doing something to normalize affected cells:
So while we don’t know how SS-31 will help already-energetic people, we have enough data to show it could help disaffected people.
For instance, one study in mice showed SS-31 was able to significantly improve memory impairment induced by lipopolysaccharide (LPS):
“Treatment with elamipretide significantly ameliorated LPS-induced learning and memory impairment during behavioral tests.
Notably, elamipretide not only provided protective effects against mitochondrial dysfunction and oxidative stress but also facilitated the regulation of brain-derived neurotrophic factor (BDNF) signaling, including the reversal of important synaptic-signaling proteins and increased synaptic structural complexity.”
A separate mouse study using isoflurane as the “poison” for inducing cognitive defects found the same result with SS-31 treatment, also noting how it was protective against mitochondrial damage.
This is important because as it turns out, mitochondrial oxidative damage (stress) can impair blood flow in the brain:
“Treatment with SS–31 [in aged mice] significantly improved neurovascular coupling responses by increasing NO-mediated cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination.
These findings are paralleled by the protective effects of SS–31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals.”
Other plausible mechanisms for SS-31 having this effect may include inhibition of neuronal cell death, enhancement of synaptic activity, and lowering of β -amyloid (Aβ) formation (a key contributor to cognitive decline in Alzheimer’s disease).
SS-31 May Improve Exercise Performance
Similar to what scientists have observed with the peptide MOTS-C, SS-31 has been shown to improve exercise endurance in both aged and young mice:
“SS-31 reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O) [NOTE: No changes in mitochondrial content were observed]… The gastrocnemius in the age+SS-31 mice was more fatigue resistant with significantly greater mass compared to aged controls. This contributed to a significant increase in treadmill endurance compared to both pretreatment and untreated control values.” (Source)
“Age related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle. These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial H2O2 emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment and eight days of SS-31 treatment led to increased whole animal endurance capacity.” (Source)
Fortunately, we have three human clinical trials which also demonstrate this same benefit.
In the first study examining mitochondrial energy capacity within muscle, SS-31 was able to improve it immediately before it fell back to baseline:
“A single ELAM [elamipretide] dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI.”
In the second study involving patients with primary mitochondrial myopathy (i.e. a genetic mutation where inefficient ATP production primarily affects skeletal muscle and leads to outcomes such as exercise intolerance and muscle fatigue), SS-31 treatment improved the patients’ ability to walk further after 5 days of treatment:
“Participants who received the highest dose of elamipretide walked a mean of 64.5 m farther at day 5 compared to a change of 20.4 m in the placebo group (p = 0.053). In addition, there was a dose-dependent increase in distance walked on the 6MWT with elamipretide treatment (p = 0.014). In a model that adjusted for additional covariates possibly affecting response, the adjusted change for the highest dose of elamipretide was 51.2 vs 3.0 m in the placebo group (p = 0.0297). No significant differences were observed in other efficacy and safety endpoints.”
“In part 1, 12 subjects were randomized to 40 mg per day of elamipretide or placebo for 12 weeks, followed by a 4-week washout and then 12 weeks on the opposite arm. Ten subjects continued on the open-label extension (part 2) of 40 mg per day of elamipretide, with eight subjects reaching 36 weeks. Primary endpoints were improvement on the 6-minute walk test (6MWT) and improvement on a BTHS Symptom Assessment (BTHS-SA) scale.”
“In part 1 neither primary endpoint was met. At 36 weeks in part 2, there were significant improvements in 6MWT (+95.9 m, p = 0.024) and BTHS-SA (-2.1 points, p = 0.031). There were also significant improvements in secondary endpoints including knee extensor strength, patient global impression of symptoms, and some cardiac parameters.”
Unfortunately, due to the failure to reach primary endpoints in the first part of the study, SS-31’s hopeful FDA approval for treating Barth syndrome is on hold for now.
SS-31 Shows Promise For The Treatment Of Type 2 Diabetes
For this particular health benefit, we only have a series of mechanisms demonstrating the ways in which SS-31 may be useful:
- Protection against podocyte death in vivo within rats (podocytes are specialized cells whose injury contributes to diabetic kidney disease)
- Maintained normal blood glucose levels in islet cell transplantation within diabetic mice (an experimental treatment for type 1 diabetes)
- Increases SIRT1 levels (an enzyme responsible for positively regulating insulin secretion) and decreased ROS concentrations while lowering levels of inflammatory markers NFκB-p65 and TNFα in Type 2 diabetes patients.
Hopefully something to use alongside Metformin? Only time will tell.
SS-31 Is Being Studied For Numerous Health Conditions
The following uses for SS-31 haven’t been as well-explored, but nevertheless demonstrate just how universal this peptide could be in fully optimizing human health:
- SS-31’s ability to treat mitochondrial dysfunction is being applied towards halting the progression of osteoarthritis
- Neuroprotective against the type of oxidative damage caused by Parkinson’s Disease (and perhaps fight against neuroinflammation too)
- Protective against spinal cord injury-induced lung injury in a separate study involving mice
- May be anti-inflammatory due to lowering the production of pro-inflammatory cytokines
- Has therapeutic potential to “ameliorate the adverse effects of burn injury in skeletal muscle”
- Shows promise in reversing mitochondrial dysfunction following traumatic brain injury (TBI)
- Could protect the liver from ischemia-reperfusion injury, according to one in vivo study
- Potential treatment of deterioration of the eyes, heart, and kidney
It’s almost like fixing the mitochondria has major positive downstream effects on other organs and tissues!
The BEST Dose Of SS-31 For Mitochondrial Restoration
The optimal dose SS-31 has more or less been figured out by Stealth BioTherapeutics, largely thanks to all the data they’ve accumulated from human research.
Only two SS-31 dosing protocols exist across the many trials conducted for various cardiovascular diseases:
- Protocol #1: 0.01 mg/kg/h – 0.25 mg/kg/h over 4 hours via intravenous infusion (Source)
- Protocol #2: 4 or 40 mg injected subcutaneously once a day (Source)
The latter protocol seems to be what ordinary people like you and I would opt for.
But even for the healthy biohacker, the subcutaneous dose used in human clinical trials may be overkill.
Here’s what one peptide biochemist had to say:
“…the therapeutic dose was 4mg/day (not 40mg). He stated that 40mg study was done at extremely high dosages but that high was not actually required to get very good results. I’ve been doing 4mg/day as directed for about 60 days with good results.”
My advice to you is the same as for any peptide or agent I recommend: Start at the lowest dose possible, see how you feel, and then GRADUALLY increase the dose over time until you get the desired outcome.
SS-31’s Side Effects And Safety Profile
Thanks to several human clinical trials (countless Phase 1 trials and five Phase 2 trials), we already know the expected side effects of SS-31.
According to RxList, it comes down to 3 infrequent and mild outcomes associated with most peptide injections:
- Mild redness/swelling at the site of injection
Regardless of the treated condition SS-31 was being studied for, or the formulation of SS-31 used (oral, intravenous, subcutaneous)… all of the above were true.
There were no deaths, the number of serious adverse events was virtually nill, and the frequency of side effects in the human subjects taking SS-31 was no different when compared to the people taking a placebo.
However… there are two caveats I want to make.
First, we do not have certainty on the long-term effects of daily SS-31 use beyond 4 weeks.
Second, the very few people who have used SS-31 for chronic fatigue and increasing energy levels haven’t experienced dramatic changes.
In one Reddit thread, two people injecting SS-31 subcutaneously at 20-50 mg daily did not notice any improvements of chronic fatigue syndrome.
And in the experience of one mitochondrial specialist, their patients experienced “no real benefit” with SS-31.
So take that for what it’s worth — SS-31 can either be amazing or a dud for fully optimized people.
How To Buy Pharma-Grade SS-31 Online
Here’s the bad news: I do not currently know of any reliable peptides vendor who will let you buy SS-31 online at the highest level of purity for an affordable price.
Every peptides seller I’ve seen offering SS-31 either:
- Offers SS-31 in 50mg vials for prices within the high hundreds (meaning an 8-12 week cycle will cost you several thousands of dollars), or
- Does not have the necessary quality checks in place to ensure you’re getting the best product possible.
Furthermore, it should be noted that Stealth BioTherapeutics is also developing a second-generation mitochondria-targeting therapeutic currently known as “SBT-272”.
Their Q3 2020 report released to the Securities and Exchange Commission (SEC) claims to have “showed a favorable safety profile in healthy human volunteers” as an oral formulation in a Phase 1 clinical trial, but that’s all we know for now.
(NOTE: Stealth BioTherapeutics’ current pipeline shows SS-31 in Phase 1/2 clinical trials for other eye and heart diseases, so don’t give up hope yet!)
And where else to get them other than Limitless Life Nootropics, the world’s #1 online peptides supplier for biohackers worldwide?
Use code JAY15 to get 15% off your order!
Additional Reading Resources For SS-31
SS-31 shows extraordinary promise as an anti-aging therapeutic peptide that re-optimizes mitochondrial function.
I frankly can’t think of another peptide with so much support from the pharmaceutical industry for multiple disease states.
Unlike other peptides whose use is heavily limited after being designated for a rare condition, SS-31 may be the exception.
But as always, there’s only so much information I can fit about this Golden Age agent in one article.
So here are two helpful resources if you want to dig even deeper into the background of SS-31 and where it’s headed:
The Alzheimer’s Drug Discovery Foundation has published an 18-page paper summarizing all the clinical evidence of SS-31’s effects on animals and humans
The official Stealth BioTherapeutics website is surprisingly transparent about the future applications of SS-31 and its progress towards hopeful FDA approval.
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