Mitochondrial Peptides, con't
SLU-PP-332
I'll talk about SLU-PP-332 (often referred to as "Sloop") next because it is similar to MOTS-c and works on similar pathways. Technically, SLU-PP-332 isn't a peptide, it's a synthetic organic compound often being classed as a 'small molecule,' but it gets grouped in with peptides due to its similar actions. Apparently the compound was developed at St. Luis University, hence the 'SLU'; the 'PP' standing for peptide project and the number just being a cataloguing reference. I couldn't confirm any of this, though, so take it with a grain of salt.
Unlike MOTS-c, which needs to be injected, most people are taking SLU-PP-332 as an oral pill. This is controversial, however, since due to the chemical properties of the SLU-PP-332 molecule it should have extremely low bioavailability when taken orally. None the less, there are so many people out there reporting the effects of taking SLU-PP-332 in pill form that there's simply no way this could be some kind of mass placebo effect. And taking SLU-PP-332 in injectable form is no easy task: because its not water soluble, the powder needs to be mixed with fat or alcohol before injecting (a number of people actually mix it carefully with a little DMSO first, then add the bacteriostatic water to make a stable injectable solution, but this is pretty advanced and it's not clear how much of an advantage this would be since people are getting effects taking pills).
SLU-PP-332 is estrogen related receptor (ERR) agonist, activating ERRα (alpha), ERRγ (gamma) and to a lesser extent ERRβ (beta), but ERRα is the true star of the show. If you reference the flow chart in the MOTS-c post, you'll see that ERR is activated downstream from AMPK, which MOTS-c activates. Although SLU doesn't directly stimulate AMPK, it stimulates it indirectly as a downstream effect.
As such, many of the benefits of SLU-PP-332 are similar to what is claimed for MOTS-c: increased muscular endurance, increased fat burning, more energy, etc. There are differences found in the studies, however. Like MOTS-c, much of the research on SLU-PP-332 is animal-based, but there are some human studies. This is likely due to the fact that it is a synthetic molecule, and therefore patentable and a potential money-maker, unlike MOTS-c which is a molecule produced in the human body and therefore unpatentable.
Just a note, which I probably should have mentioned in the MOTS-c post, estrogen related receptors (ERRs) don't actually have any estrogenic properties. They're structurally similar to estrogen receptors, which is where they get their name, but they don't bind estrogenic compounds or other steroid hormones.
SLU-PP-332 activates the ERR nuclear receptors making the body think that it's low in energy which then activates AMPK, ramping up ATP production by burning fat and increasing glucose uptake. Because it regulates mitochondrial function, ERRα is highly expressed in energy demanding tissues like skeletal muscles, the heart, the brain, the liver, white and brown adipose tissue.
Once activated, ERRs target specific genes that regulate energy production, increasing acute aerobic exercise endurance. One study gave it to mice and it allowed them to run ~70% longer and ~45% further compared to placebo (see A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity below). The crazy thing is that, in animal models, it was found to activate these genes even while in a sedentary state making it a direct exercise mimetic. One study found it can enhance beta oxidation and lypolysis (fat breakdown and burning), when in a parasympathetic state (rest and digest); which is notable as it's usually seen only when in a sympathic activity state, like exercise. That said, all its effects are compounded when taken pre-workout, combining it with exercise. It's like hooking up to an amplifier to exercise, boosting all its benefits and increasing adaptation. (Just to speculate here; there may be potential uses for SLU use in individuals who struggle to, or are unable to, exercise. Maybe it could even get them to the point where they could exercise).
In the same way MOTS-c works, SLU-PP-332 increases mitochondrial biogenesis through PGC-1α (the master architect of mitochondrial creation), improves ATP production efficiency making the mitochondria work with better fuel flexibility (the ability to switch between fat and glucose), improves beta oxidation (breaking down fat to be burned), revs up enzymes that help burn stored fat, increases resilience against oxidative stress, and supports mitophagy (the destruction and recycling of broken mitochondria; the clean up phase). Apparently many professional athletes have been using this small molecule for years as it's very good at building efficient muscle which can switch between glucose and fat metabolism. In bodybuilders it can switch them over from being in a mostly glycolytic metabolic state (burning mostly glucose for energy) to being able to use fat metabolism. It also helps to improve VO2 max (see this interview with professional coach Anthony Castore for more on its use in athletes).
Other Benefits
Before you think SLU-PP-332 is only about athletics and workouts, there's much more to this molecule. One area where SLU-PP-332 differs from MOTS-c is that it was found to upregulate the genes PER1 and PER2, which are exercise-induced circadian regulation genes. This needs to be confirmed, but anecdotally many people have reported better sleep while using SLU-PP-332 (with a small subset of what may be hyper-responders, who report having such profound increases in energy that they don't sleep well; it's unclear whether or not this could be mitigated by adjusting the dose or timing of the dose).
It can also improve liver and kidney function and, long term, will improve levels of liver enzymes AST and ALT (it can cause a small temporary rise in liver enzymes when first taking it, but this is apparently transient and usually drops within a month). Anecdotally, clinicians have also seen a whole point drop in A1C levels within 10 weeks. In mouse studies, SLU-PP-332 significantly reduced age-related kidney impairments, including lowering albuminuria (a key indicator of kidney damage) and preserving podocyte numbers, which are specialized cells critical for kidney filtration. It also decreased glomerulosclerosis (kidney blood vessel scarring) and reduced fibrosis in kidney tissues.
Many people report neurological benefits as well, reporting less brain fatigue, sustainable mental clarity and improved memory recall. Only about 5% of SLU-PP-332 crosses the blood brain barrier, which isn't much. However, if system-wide mitochondrial effectiveness is improved, there may be knock-on effects specific to the brain; having more energy in the tank leads to more energy available for the brain.
SLU-PP-332 also increases grip strength (in animal models), which is one of the hallmarks of longevity.
There is also an interesting study that looked at its use, and the use of a related compound SLU-PP-915, as an intervention for heart failure. They found "significantly improved ejection fraction and ameliorated fibrosis against pressure overload-induced heart failure without affecting cardiac hypertrophy," and that the molecules "maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo."
Side Effects
The most commonly reported, and often only noticed, side effect is an increase in basal body temperature and increased sweating, likely due to the increase in metabolic rate. Some people report sweating buckets during workouts. The previously noted transient increase in liver enzymes is also a possible side effect.
Studies
A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity https://www.biorxiv.org/content/10.1101/2022.10.05.510974v1.full
Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study Frontiers | Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study
SLU-PP-332 and Related ERRα Agonists: A Focused Minireview of Metabolic Regulation, and Therapeutic Potential https://ujpronline.com/index.php/journal/article/download/1355/1899 [pdf download link]
A Synthetic ERR Agonist Alleviates Metabolic Syndrome A Synthetic ERR Agonist Alleviates Metabolic Syndrome - PMC
Transcriptional Regulation of Dehydroepiandrosterone Sulfotransferase (SULT2A1) by Estrogen-Related Receptor α.
Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney.
Novel ERR pan-agonists ameliorate heart failure through boosting cardiac fatty acid metabolism and mitochondrial function.
SLU-PP-332
I'll talk about SLU-PP-332 (often referred to as "Sloop") next because it is similar to MOTS-c and works on similar pathways. Technically, SLU-PP-332 isn't a peptide, it's a synthetic organic compound often being classed as a 'small molecule,' but it gets grouped in with peptides due to its similar actions. Apparently the compound was developed at St. Luis University, hence the 'SLU'; the 'PP' standing for peptide project and the number just being a cataloguing reference. I couldn't confirm any of this, though, so take it with a grain of salt.
Unlike MOTS-c, which needs to be injected, most people are taking SLU-PP-332 as an oral pill. This is controversial, however, since due to the chemical properties of the SLU-PP-332 molecule it should have extremely low bioavailability when taken orally. None the less, there are so many people out there reporting the effects of taking SLU-PP-332 in pill form that there's simply no way this could be some kind of mass placebo effect. And taking SLU-PP-332 in injectable form is no easy task: because its not water soluble, the powder needs to be mixed with fat or alcohol before injecting (a number of people actually mix it carefully with a little DMSO first, then add the bacteriostatic water to make a stable injectable solution, but this is pretty advanced and it's not clear how much of an advantage this would be since people are getting effects taking pills).
SLU-PP-332 is estrogen related receptor (ERR) agonist, activating ERRα (alpha), ERRγ (gamma) and to a lesser extent ERRβ (beta), but ERRα is the true star of the show. If you reference the flow chart in the MOTS-c post, you'll see that ERR is activated downstream from AMPK, which MOTS-c activates. Although SLU doesn't directly stimulate AMPK, it stimulates it indirectly as a downstream effect.
As such, many of the benefits of SLU-PP-332 are similar to what is claimed for MOTS-c: increased muscular endurance, increased fat burning, more energy, etc. There are differences found in the studies, however. Like MOTS-c, much of the research on SLU-PP-332 is animal-based, but there are some human studies. This is likely due to the fact that it is a synthetic molecule, and therefore patentable and a potential money-maker, unlike MOTS-c which is a molecule produced in the human body and therefore unpatentable.
Just a note, which I probably should have mentioned in the MOTS-c post, estrogen related receptors (ERRs) don't actually have any estrogenic properties. They're structurally similar to estrogen receptors, which is where they get their name, but they don't bind estrogenic compounds or other steroid hormones.
SLU-PP-332 activates the ERR nuclear receptors making the body think that it's low in energy which then activates AMPK, ramping up ATP production by burning fat and increasing glucose uptake. Because it regulates mitochondrial function, ERRα is highly expressed in energy demanding tissues like skeletal muscles, the heart, the brain, the liver, white and brown adipose tissue.
Once activated, ERRs target specific genes that regulate energy production, increasing acute aerobic exercise endurance. One study gave it to mice and it allowed them to run ~70% longer and ~45% further compared to placebo (see A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity below). The crazy thing is that, in animal models, it was found to activate these genes even while in a sedentary state making it a direct exercise mimetic. One study found it can enhance beta oxidation and lypolysis (fat breakdown and burning), when in a parasympathetic state (rest and digest); which is notable as it's usually seen only when in a sympathic activity state, like exercise. That said, all its effects are compounded when taken pre-workout, combining it with exercise. It's like hooking up to an amplifier to exercise, boosting all its benefits and increasing adaptation. (Just to speculate here; there may be potential uses for SLU use in individuals who struggle to, or are unable to, exercise. Maybe it could even get them to the point where they could exercise).
In the same way MOTS-c works, SLU-PP-332 increases mitochondrial biogenesis through PGC-1α (the master architect of mitochondrial creation), improves ATP production efficiency making the mitochondria work with better fuel flexibility (the ability to switch between fat and glucose), improves beta oxidation (breaking down fat to be burned), revs up enzymes that help burn stored fat, increases resilience against oxidative stress, and supports mitophagy (the destruction and recycling of broken mitochondria; the clean up phase). Apparently many professional athletes have been using this small molecule for years as it's very good at building efficient muscle which can switch between glucose and fat metabolism. In bodybuilders it can switch them over from being in a mostly glycolytic metabolic state (burning mostly glucose for energy) to being able to use fat metabolism. It also helps to improve VO2 max (see this interview with professional coach Anthony Castore for more on its use in athletes).
Other Benefits
Before you think SLU-PP-332 is only about athletics and workouts, there's much more to this molecule. One area where SLU-PP-332 differs from MOTS-c is that it was found to upregulate the genes PER1 and PER2, which are exercise-induced circadian regulation genes. This needs to be confirmed, but anecdotally many people have reported better sleep while using SLU-PP-332 (with a small subset of what may be hyper-responders, who report having such profound increases in energy that they don't sleep well; it's unclear whether or not this could be mitigated by adjusting the dose or timing of the dose).
It can also improve liver and kidney function and, long term, will improve levels of liver enzymes AST and ALT (it can cause a small temporary rise in liver enzymes when first taking it, but this is apparently transient and usually drops within a month). Anecdotally, clinicians have also seen a whole point drop in A1C levels within 10 weeks. In mouse studies, SLU-PP-332 significantly reduced age-related kidney impairments, including lowering albuminuria (a key indicator of kidney damage) and preserving podocyte numbers, which are specialized cells critical for kidney filtration. It also decreased glomerulosclerosis (kidney blood vessel scarring) and reduced fibrosis in kidney tissues.
Many people report neurological benefits as well, reporting less brain fatigue, sustainable mental clarity and improved memory recall. Only about 5% of SLU-PP-332 crosses the blood brain barrier, which isn't much. However, if system-wide mitochondrial effectiveness is improved, there may be knock-on effects specific to the brain; having more energy in the tank leads to more energy available for the brain.
SLU-PP-332 also increases grip strength (in animal models), which is one of the hallmarks of longevity.
There is also an interesting study that looked at its use, and the use of a related compound SLU-PP-915, as an intervention for heart failure. They found "significantly improved ejection fraction and ameliorated fibrosis against pressure overload-induced heart failure without affecting cardiac hypertrophy," and that the molecules "maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo."
Side Effects
The most commonly reported, and often only noticed, side effect is an increase in basal body temperature and increased sweating, likely due to the increase in metabolic rate. Some people report sweating buckets during workouts. The previously noted transient increase in liver enzymes is also a possible side effect.
Studies
A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity https://www.biorxiv.org/content/10.1101/2022.10.05.510974v1.full
Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study Frontiers | Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study
SLU-PP-332 and Related ERRα Agonists: A Focused Minireview of Metabolic Regulation, and Therapeutic Potential https://ujpronline.com/index.php/journal/article/download/1355/1899 [pdf download link]
A Synthetic ERR Agonist Alleviates Metabolic Syndrome A Synthetic ERR Agonist Alleviates Metabolic Syndrome - PMC
Transcriptional Regulation of Dehydroepiandrosterone Sulfotransferase (SULT2A1) by Estrogen-Related Receptor α.
Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney.
Novel ERR pan-agonists ameliorate heart failure through boosting cardiac fatty acid metabolism and mitochondrial function.
