MOTS-c Vs. SS-31 | Which Mitochondria Peptide Is Right For You?

0:09 Hey everybody, this is Hunter Williams. I hope you're doing amazing wherever you are out in the world. Today's video is all about MOTC versus SS 31. So I actually wrote an email about this a few days ago and I thought it'd be a really good idea to do a whole video on this because I got a lot of good feedback on the email and this continues to be something that people get confused about and struggle with. And I want to assure you today that there's nothing to afraid of or nothing of fear or anything to confused There are different use cases for MOTC and SS31,

0:39 and I'm going to walk through both of those today and how to use them, what doses to us, but I just want to give you a good comparison of these. I think the easiest way to say this, I wrote this in my email, is that MotC is more of a software upgrade and that SS 31 is a hardware upgrade. So today I am going walkthrough exactly what that means and everything, so I really think you are going enjoy this one. whether you're a newbie and you are just starting to optimize mitochondrial health or you were a veteran user of peptides and used both of these, I'm going to give you a good framework on how to kind of use them throughout the year and what you should be mindful of and should keep in mind whenever

1:13 you cycling on and off of them. So that's what today's video is going be about. As always, check out the peptide cheat sheet down in the description below. I have the doses for Matzi and SS31 on there. that you can look at and look how to mix and reconstitute and all that good stuff. And then also don't forget to check out Fully Optimized Health, the best private community on the planet to talk about peptides. So that's it. Without further ado, I'm going to share my screen and today we're going learn about MATC versus SS31. All right. I am Hunter Williams. And today's video is all about Matzi versus SS 31. So let's jump into it.

1:46 Basically, as many of you are well aware, mitochondrial dysfunction is a hallmark of aging and numerous chronic diseases from neurodegeneration to metabolic and cardiovascular disorder. It's obviously a rampant problem in today society with all the chronic disease we have. In recent years, there's been a ton of different therapeutic peptides targeting the mitochondria that have gained attention for their potential to restore healthy mitochondrial function. So probably the two most prominent peptide that we know of today are SS31 and MOTC, and they each act through very different mechanisms to counteract mitochondrional dysfunction.

2:21 SS-31, it's also known as Elamepratide or Bendavia, or MTP-131, I like saying SS 31 better, is a synthetic tetrapeptide designed to penetrate mitochondria and protect them from damage. And that kind of goes to the hardware upgrade that I was speaking of. Then MOTC, which is short for, and this is the last time I'll say this, mitochondrial open reading frame of the 12S RNA type C, that's a mouthful, I like saying matzi a lot easier, is a 16 amino acid peptide encoded with the mitochondrial DNA acting as a natural signaling molecule

2:52 aka a mitokine that influences the metabolism and stress responses. So here's what we're going to look at today. We're gonna look their mechanisms of action, the structure and origin. Some of the evidence base we have around these, now obviously with peptides we don't have a ton quote unquote clinical literature, but we've got the therapeutic context, the safety profiles, The synergies of both of them when we use them together and or in isolation, and also just some usage considerations and best practices around that. So let's look at SS31 first. Again, if you don' have the hardware, it is tough to have The software, right?

3:22 So like I said, It's a synthetic tetrapeptide. I'm not going to go into the sequence name because it's A very long and drawn out word. but the SS actually comes to the set set toe Schiller family of cell permeable peptides. So that's what SS stands for, in case you were wondering, and you are a factoid enthusiast like myself, but it's design confers a unique amphipathic character. It contains two positively charged residues, one being the arginine, the other being lysing and two aromatic hydrophobic residus, One being dimethyl tyrosine and phenylalanine.

3:55 I always struggle to pronounce phenolalanin. But what this does is allows S31 to readily cross cell membranes and selectively accumulate in the inner mitochondrial membrane. Now that's going to be very important as we go through this, but it's drawn by the electrostatic attraction between its positive charges and the negatively charged phospholipid cardiolippin, which is also going be important, so remember that word, cardiolypin. that's abundant on the intermembrane. So notably, despite its charged nature, SS31 is highly cell permeable because the aromatic rings can shield the charges and the D amino acid confers resistance

4:28 to degradation. SS 31 is not derived from a natural sequence. It was actually designed by a guy named Dr. Hazel Seto, and that again is where the S comes from in SS-31. And it has a molecular weight of 639.8 daltons with a half-life of a few hours in vivo. Like I said, its primary molecular target is this thing called cardiolipin, which is an inner mitochondrial membrane lipid crucial for maintaining Christi structure and organizing the electron transport chain.

4:58 So remember that too. By binding to cardiolypin, SS31 stabilizes the mitochondria membrane and Christate, preventing the oxidation and peroxidation of cardioline that occurs during oxidative stress. That might sound a little confusing, but just remember those words. the inner mitochondrial membrane and oxidative stress. So this interaction has been shown to have multiple beneficial downstream effects. Let's look at those. There's this idea of the electron transport chain efficiency. SS31 modulates the interaction between cardiolipin and something called cytochrome C, which is a key electron-transport chain protein.

5:36 It shifts cytachromes C's role back to electron transfer and away from acting as a peroxidase that generates reactive oxygen species, which we know is bad for the body. So in essence, SS31 helps cytochrome C function normally for energy production while blunting the ROS producing peroxis activity that occurs when cytachromacy binds to oxidize cardiolipins. This leads to more efficient oxidative phosphorylation and ATP generation with less reactive oxygen species leakage.

6:06 So we're getting better energy without the ROS leakage now. What that means is it gives us this antioxidant effect. By reducing mitochondrial ROS production at its source, SS31 lowers overall oxidant stress in cells. Importantly, it also prevents the opening of the mitochondrial permeability transition pore, otherwise known as MPTP, under stress conditions. So the MPT is a channel that went open during extreme mitochondria stress, for instance ischemia or trauma. It causes the mitochondria to swell and release pro-apoptotic factors like cytochrome C leading to cell death.

6:42 So SS31's ability to inhibit MPTP opening protects mitochondrial from swelling and prevents this cytopchromacy release, thereby averting apoptosis in stressed cells. We're preventing the death of those stress cells that we may be going through, through trauma, stress, ischemia, any of these things. This mechanism has been observed in models of traumatic brain injury and stroke where SS31 preserved mitochondrial integrity. So a lot of people don't think of SS 31 as it relates to brain trauma, but it's something that I would absolutely use.

7:13 Now we also have this reduction of oxidative damage. So by guarding cardiolipid from oxidation and keeping electron transport chain electrons flowing properly, SS31 minimizes the formation of damaging reactive oxygen species. So it indirectly preserves mitochondrial DNA, lipids, and protein from oxidative damage. Over time, this helps to maintain mitochondria function and biogenesis capacity. When we sum all that together, ss31 acts directly on mitochondrion to actually change the structure and fortify them and optimize their function. So it does not require gene expression changes to exert its effects.

7:45 Rather, it works immediately at the mitochondrial membrane level to improve bioenergetics, reduce oxidative stress, and block cell death pathways. These actions make it a promising therapy for any condition where mitochondria are under stress as we are going to talk about in a minute. What I want you to think of is kind of like a house remodel. If we have the Mitochondria within our body, that we're optimizing. SS31 is coming in and changing structurally. I've always used the analogy of people decorating the inside of their house versus changing the actual structure. And it's really cool to have nice decorations, but if you have a leaky roof, if have poor foundation, none of the decorations are going to do anything nice.

8:21 So that's where SS 31 comes in, and it really helps kind of at the structural level of our mitochondria to help change things. Now, Let's contrast this with MOTC because it's a little bit different even though we're both optimizing mitochondrial health when we are using these. So like I said, it is a 16 amino acid peptide hormone that is naturally encoded by the mitochondria genome. It originates from a short open reading frame within the 12S ribosomal RNA gene of MTDNA. So I'm not going to say that sequence because it's 16 amino acids long, but structurally MOTC tends to form an alpha helix in solution,

8:54 a common motif that allows it to interact with various proteins. So because is encoded in mitochondria but can act elsewhere, it is classified as a mitochondrial derived peptide, otherwise known as an MDP. which is essentially a signaling molecule that mitochondria released to communicate with the rest of the cell and even distant tissues. So it is found not only inside cells but also circulating in our blood, indicating it functions like a hormone or a mitochondrion that can affect multiple organs in the body. It was actually discovered in 2015 as part of a search for novel peptides encoded by mtDNA, making it one of first examples of peptide coded by mitochondra

9:29 with regulatory roles. Other MDPs include human and small human like peptides, but MATC is unique in its specific sequence and functions from a peptide like human. Let's look at the mechanism of action. Like I said, they give SS31 as a structural change, whereas MATCI is a signaling change. It operates through a signaling and regulatory mechanism, which is, again, different from SS31's membrane targeted action. So let's look at some of these. The first one is going to be AMPK activation. Now, if you hear that word, you probably have heard it in the buzzwords of biohacking, right?

10:02 That's a good thing. This is kind of the metabolic pathway modulation. ModC's best characterized action is its ability to activate AMP-activated protein kinase, otherwise known as AMPk. which is the master regulator of cellular energy status. So it achieves this by interfering with the folate-mediated 1-carbon cycle and de novo purine synthesis pathway, which basically just means it leads to the accumulation of an intermediate called ICAR. ICar is also a known AMPK activator. You've probably actually seen that sold as a peptide at various research places.

10:33 Thus, MATSI essentially mimics an energy stress signal turning on this AMP in the body. So, active AMPK then triggers a host of downstream effects, which we want. It enhances glucose uptake and oxidation, stimulates fatty acid oxidation and generally shifts the cell into an energy producing and catabolic state while inhibiting energy storage pathways. So through this AMPk activation, MATSI also influences PGC-1-alpha, a co-activator that promotes mitochondrial biogenesis and antioxidant defense. suggesting that MATSI may help cells generate new mitochondria and improve their function via gene expression changes.

11:08 So, whereas SS31 doesn't work on gene-expression change, MATSII does, and it's a good thing in this case. Let's look at this mitochondrial stress signaling and hormetic effect. If you think of the hormetic effect that is basically a stress-induced change that actually benefits the body positively. So, interestingly, one immediate consequence of Matzi's action is a transient suppression of mitochondrial respiration. By inhibiting the folate cycle and purine synthesis, Matz can induce the flux of certain substrates needed for high mitochondria activity,

11:40 thereby mildly suppressing electron transport chain activity. So this might seem counterintuitive, right, because we want to increase that, but it mimics exercise or caloric restriction at a molecular level. So actually what we're doing when we take MOTC is we are signaling to the body that we were exercising without exercising. Now, does that mean you shouldn't exercise? No. But we signaling these hormetic stress responses to body to induce a cascade of reactions that are overall going to be beneficial to us. This creates a low energy signal that prompts the cell to adapt.

12:10 So in other words, it induces this hermetic response, which is a mild stress that triggers beneficial pathways like AMPK and PGC-1-alpha. This mechanism is analogous to how the diabetes drug metformin works. I think you should actually use met formin with MATC. And in fact, MATCs actions overlap considerably with met-formins in terms of AMP-K activation and metabolic effects. If you want a poor man's MAT-C, you could actually used met forming. BestMOTC improves mitochondrial function indirectly by nudging the cell signaling networks to boost insulin sensitivity,

12:40 enhance glucose utilization, and increase fat burning. I'll actually talk about this because there are times when I have used MOT-C and it definitely made me more insulin sensitive because I was using a very tiny amount of insulin to enhance my workouts and I actually went hypo a couple times that I never would have gone hypo without the insulin, but I definitely know if it's a good way to see if something is increasing insulin sensitivity, that, I went hypox in the presence of MOTC and using insulin.

13:11 So be very careful of using those together. But for me, it was a Good indicator that i was becoming more insulin sensitive because the same two units of insulin that was using post-workout actually made me go hy po even with carbs when it never had before. so I knew that Motsy was doing something. Don't try that at home. And I don't really want to ever get into talking about using insulin because that's an advanced protocol that you have to be very, very advanced and have a lot of expertise around kind of understanding your body and whatnot. So let's look at this nuclear gene regulation.

13:43 Beyond metabolic enzymes, MATSI has the remarkable ability to translocate to the nucleus in response to cellular stress. Now, what does that mean? It means once in the Nucleus, MatSI can bind to DNA or chromatin and influence the expression of nuclear genes, related to metabolism and stress resistance. For example, studies show that MOTC moving to the nucleus leads to activation of genes known as ATF1 and NRF2, which are involved in antioxidant responses and metabolic regulation. In T cells, adding Motsy increased mitochondrial oxidative phosphorylation and reduced glycolysis, but a mutant MotC that couldn't enter the new nucleus

14:16 lost its effect. So this suggests that the Mocys presence in the Nucleus is functionally important for reprogramming cell metabolism. So such minor nuclear communication is a novel concept. MODSI essentially allows mitochondria to signal the nucleus to help the cell cope with metabolic stress. This places MOIDSI at the intersection of mitochondrial function and gene expression control, which is also inducing and signaling to the body that when we become stressed metabolically to kind of reverse that stress, so Let's look at some of the systemic effects.

14:47 So through all of these mechanisms, matzi exerts system-wide metabolic benefits. It improves insulin sensitivity, which is good for us in the long run, and skeletal muscle and other tissues, meaning cells respond better to insulin. Like I was saying, I responded better the exogenous insulin I taking, so much so that it made me go hypo and take up glucose more effectively. so it also shifts the body towards using fats and carbohydrates more efficiently, again, goes back to the metabolic flexibility we're always striving to have. And it increases glucose utilization in fat tissue, promotes fatty acid oxidation, and also promotes the browning of white fat in the liver.

15:21 It reduces fatty accumulation and glucose output. And there's even evidence that MOTC can act in a brain to enhance cognitive function, possibly by improving neuronal energy metabolism. Again, that makes sense when you think of glucose, utilization by the brain and improving glucose. Utilization of the body will improve in brain, cognitive functioning is going to improve. So Matzi is induced by exercise and appears to mediate some exercise benefits, hence the hormetic or exercise mimetic effect, and an acute bout of exercise raises Matzzi's levels in human blood, human muscle and blood naturally and in mice, Matzie treatment increases running endurance

15:55 and muscle capacity, similar training. So, MODSI acts as a signaling peptide hormone that reprograms cellular metabolism and gene expression to enhance stress resistance and metabolic homeostasis. So conversely, to SS31, it doesn't primarily act by binding to mitochondrial membranes. Instead, It triggers adaptive pathways downstream that lead to improved mitochondria function over time. It effectively communicates the mitochondrion status to the rest of the cells and the body, coordinating a systemic response to metabolic stress or dysfunction.

16:26 So pretty fascinating. Now, let's just look at a comparison table between the two as we're examining these. So again, SS31 is a synthetic cell permeable peptide, whereas MOTC is an endogenous mitochondrial peptides. It's naturally in our body anyway. SS 31 is four amino acids long, where as MotC 16 amino acid long. SS31 localizes to inner mitochondrial membrane by binding negatively charged lipids, otherwise known as cardiolipin. And the MOTC is found in the cytoplasm and nucleus of cells, and it's also secreted into the bloodstream to act on distant tissues.

17:02 We look at the molecular targets, SS 31 is obviously cardiolypin, And it binds to cardiolepin and modulates cytochrome C function. whereas Matzi is more of an AMPK pathway and metabolic enzyme and also a nuclear gene regulator. When we have a summary of those two, SS31 basically works as a mitochondrial protector. It embeds in the inner membrane to preserve mitochondria structure and function. Immediately reduces ROS production, keeps the electron transport chain efficient and avert cell death.

17:36 by stabilizing the mitochondria does not require gene expression changes to take effect and MATSI acts more of a metabolic regulator. It functions as a signaling molecule that induces cellular stress responses and improves metabolic flexibility, helps the body adapt to and overcome mitochondrial stress by reprogramming our metabolism, and the effects develop via signaling cascades and gene expressions changes. So Both ultimately improve mitochondrial efficiency and reduce oxidative stress. However, the main difference is the SS-31 is going to work inside the mitochondria.

18:07 It's going take direct physical action on the membranes. Think of it as a mitochondrion shield. And MATSI works from the outside, think of that as mitochondrious signal or hormone. So again, to go back to the software versus hardware analogy. Now, Going one level deeper, let's look at some of the SS31 preclinical findings. I found these to be really cool when I was putting together research on this. So when we look a cardiovascular disease and cardiovascular models, SS 31 has been shown to protect the heart from ischemia, reperfusion, injury, and heart failure in animals.

18:38 In rodent models of myocardial infarction, otherwise known as heart attack, ss 31 reduced infarc size and preserved cardiac function by mitigating mitochondrial damage during reper fusion. A K-Dyme model of chronic heart failure, it also showed long-term therapy to improve left ventricular function and reduce fibrosis, and by preserving cardiolipin and the ETC function, SS31 supports energy production and cardiac muscle under stress, which translates into better pumping function. And less pathological remodeling of heart. Again, in my heart health stack, there's a reason that I included SS 31 in there, that's why.

19:12 When we look at muscle aging and weakness, age-related muscle loss and weaknesses have been linked to mitochondrial dysfunction, obviously, in muscle fibers. So SS31, it's actually shown efficacy in attenuating muscle atrophy and weakest in animal studies. For example, an aged mice SS 31 treatment improved mitochondria respiration and increased exercise tolerance. In a mouse model of muscle disuse atrophies, SS-31 helped maintain muscle fiber integrity and strength, and these benefits are attributed to improved ATP output and decreased oxidative damage in muscles mitochondrion. Pretty fascinating from that side of things.

19:43 Again, is it going to be a testosterone or hormone replacement? No, but alongside those things, it's going work pretty well to help optimize the prevention of muscle wasting. Now this is where I think it probably has a more pronounced effect in the neurodegenerative and neurological side of things. So mitochondrial damage is implicated in tons of diseases like Alzheimer's, Parkinson's et cetera, and acute brain injuries. And SS31 has neuroprotective effects and multiple preclinical models. In rodent studies of Alzheimer disease and cognitive impairment, SS 31 improved memory and synaptic health while reducing neuroinflammation at the same time.

20:17 In a mouse model of anesthetic induced cognitive impairment, SS31 preserved cognitive function by preventing mitochondrial membrane depolarization and excessive ROS production in the brain. So it also protects neurons and models of optic nerve injury and glaucoma, likely preventing retinal ganglion cell apoptosis. So, SS31 is actually one of the peptides I would say if you're trying to heal your vision is going to be very, very pronounced. Now, I can't guarantee that, but I've seen a lot of people that have taken SS 31 and had much improved eyesight, again, whether it's glaucoma,

20:48 optic nerve injury, or even age-related macular degeneration. So the diverse neuroprotective outcomes underscore its ability to keep neurons energized and alive under stress, although it's notable that no human trials have been done and probably never will. But we can hope for the best, right? We are the human trails. Put that as a quote on my tombstone. Let's look at metabolic syndrome and diabetes. So this is pretty cool because, you know, typically this was thought of to be more in relation to MOTC, but mitochondrial dysfunction contributes to insulin resistance and type 2 diabetes, and SS31 has shown anti-diabetic potential in pre-clinical studies.

21:22 Mice fed a high-fat, high sugar Western diet, had better outcomes when treated with SS 31. They gained less fat, improved insulin sensitivity, showed more normal blood sugar levels. So these benefits are thought to arise from SS31 improving mitochondrial function in metabolically active tissues like the muscle and the liver, thereby enhancing their ability to burn fats and respond to insulin. It also reduced organ damage and diabetic complications. For instance, it ameliorated kidney dysfunction, diabetic mites. Now, I will say this, if there was one peptide that you could take to massively improve kidney function, It would absolutely be SS 31. We'll talk about

21:55 this later, but 10 milligrams of SS-31 per day, which can get kind of pricey. is unlike anything else to heal CKD. So I will say, for those people out there struggling with that, if you can afford it, 10 milligrams a day of SS31 will do wonders for the kidneys. Now, when we look at some of the other conditions, its mitochondrial rescue abilities have been tested in, again, kidney transplant or acute kidney injury. It reduces tissue damage and preserves kidney function. Is also showing benefit in heart disease by reducing plaque and oxidative distress, and even in osteoarthritis models by protecting mitochondria leading

22:28 to reduce cartilage degeneration. So there's also this thing called Barth syndrome, which is a genetic disease of cardiolipin deficiency, a natural target. SS31 has been shown to restore mitochondrial structure and function in that. There is also a lot of pre-clinical evidence that shows SS 31 can restore myocondrial bioenergetics and reduce tissue damage in models of heart disease. muscle and brain aging, metabolic disorders, kidney injury, and more. And I like to think of it as a Swiss army knife peptide. If you're not on the SSRT1 train, you sleep in because SS 31 is amazing.

23:00 I've been using it for a few years now to great effect just for overall anti-aging longevity and feeling good. Now, let's go into MOTC pre-clinical findings. A little bit of similarities, a little differences. Let's look at obesity and insulin resistance. Typically, this is going to come up more with MATC. So in diet-induced obese mice, which were fed a high-fat diet, injections of MAT-C prevented obesity development and Insulin resistance, so treated mice did not gain as much weight despite similar food intake, and they maintained normal blood glucose and insuline levels compared to untreated mice.

23:31 Matzi also achieved this by increasing energy expenditure and treated mice showed higher resting metabolic rates, more heat production and a shift toward burning fats and carbohydrates rather than storing them. So at the cellular level, skeletal muscles from Matzzi treated, mice had improved insulin signaling, greater glucose uptake and impressively Matzie reversed age dependent metabolic decline. Middle-aged mice on Matzy had muscle insulin sensitivity restored to levels of young mice. Now this is something that humans obviously deal with as we age or hormones go down.

24:01 our insulin sensitivity goes down and using something like Motzi can help restore it and help replace some of that insulin-sensitivity that we lose. So, definitely shows that Motze can counteract diet and age-related metabolic disorders by re-tuning fuel metabolism. Now, what I will say, because I know some you were thinking this, cause I'm thinking it too, the little fat kid inside of me is thinking, well, can I take Motzie and eat whatever the heck I want? No, The answer is don't do that. I would strongly advise not to do that. You should be living insulin controlled. And I do in my life, for the most part, I'll have a cheat meal once or twice a week every now and then, but we can use MATC to help really set back the

24:37 negative effects. I think when we look at aging in general, it's really about optimizing this insulin cycle in the body, which I should probably do a whole video on about the insulin and aging and how closely those are interconnected. Let's look at exercise capacity because I think this is where definitely you'll see a more pronounced response from MATC than you would necessarily want. So again, it's earned this nickname as an exercise mimetic because it improves physical performance in animals. In a study spanning young to old mice, MAT-C treatment enhanced exercise, capacity across all age groups.

25:07 Old mice given MAT C could run significantly longer and farther than their untreated counterparts. And mechanistically, MATSI increased the expression of genes involved in muscle energy metabolism and elevated the muscle's oxidative capacity, mimicking the effects of endurance training. This is why MATSI is now banned by water. Additionally, MATC is naturally upregulated by exercise in both mice and humans. For example, young men showed a one-and-a-half-fold rise in plasma MAT-C after a brief cycling exercise. So this suggests MAT C is part of the body's normal adaptation to exercise, so in cell structure, Mat C also stimulated the AMPK PGC1 alpha pathway,

25:41 like we talked about, and muscle cells further supporting its role in promoting mitochondrial biogenesis. To sum that up, MITC can improve muscle mitochondria function and delay age-related physical decline. Now let's look at diabetes because this also has a use case for diabetes. So beyond diet-induced type 2 diabetes, Matzi has shown effects in autoimmune type 1 diabetes models. In mouse models where T cells attack pancreatic islets, matzi's treatment prevented or delayed the onset of diabetes So this unexpected result hints that

26:12 MOTC might modulate immune cell metabolism as well, which is pretty fascinating, making T cells less aggressive and possibly by shifting the metabolism from glycolysis to oxidative phosphorylation which can reduce inflammatory activity, Which again makes sense when we think of autoimmune disease as poor insulin signaling in the body, even though that might not manifest someone being obese a lot of times. autoimmune diseases are improved when you use things like megforma when You resensitize the body to insulin and kind of heal the inflammation that's coming from the impaired insulin cycle in the So while detailed mechanisms and type 1 diabetes require more research it underscores MOTC's Benefits that they

26:49 may extend to multiple forms of diabetes, which is pretty cool We also have cognitive function. So emerging research indicates MotC may have neuroprotective or cognitive benefits now I think you're gonna see you a little bit more I have a response to that immediately from SS31, but MOTC is expressed in the brain and the study of mice showed that it can act centrally to improve memory. In one experiment, mice that received Motsy performed better in memory task, correlating with changes in brain metabolism and positively reduced neuroinflammation. So given its ability to activate AMPK and antioxidant pathways, it is plausible MotC helps neurons cope with stress, much like it does for muscle cells.

27:24 However, this is less developed than SS 31's neuro studies and more research is needed. which will probably be never done again. At least we have more, I think we had more pound for pound research on SS31 to MODSI. One thing that came up that was pretty cool again to the muscle wasting idea of things was bone metabolism. So there's an intriguing line of research that connects MODSI to bone health. Bones undergo continuous remodeling and energy metabolism plays a role in this remodel process. So a study found that MOTC promotes osteoblast proliferation and mineralization while inhibiting osteoclast, which is bone resorbing cell formation.

27:57 So this results in increased bone density and strength in animal models. It basically acts as an anti-osteoporosis agent in these preclinical tests, improving bone mass. Bone mass is pretty cool for aging women. This is something that's obviously one of the number one indicators and leaders of their early demise. But the mechanism likely involves AMPK in bone cells and crosstalk with hormonal regulators of bone. So this shows that Matzi's profile beyond classic metabolic tissues and suggest that maybe a systemic regulator of aging associated conditions like osteoporosis

28:28 is pretty cool. And then lastly, cardiovascular function. While SS31 obviously has much more data and I would say strength around helping with heart tissue, MATSI also shows some cardioprotective signals in preclinical studies. 2021 study reported that MATSIs improved cardiac mechanical function in mice treated animals had better systolic and diastolic performance of the heart. And so the improvement in cardiac function could be secondary to MOTC's metabolic effects. Additionally, by activating AMPK, MotC might directly benefit cardiac muscle energetics and reduce lipid accumulation in the heart.

29:00 However, this has not been tested a lot, so we don't have as much data for that as we do for SS31. To sum up, Matzi's preclinical evidence highlights its role as a comprehensive metabolic booster and age-related decline mitigator. It robustly improves glucose and lipid metabolism, prevents weight gain, and enhances physical performance in animals. Also shows protective effects in bones and possibly the brain. And these systemic benefits underscore its ability as hormone-like peptide orchestrating complex physiological improvements. Again, think of Matzzi as being this metabolic disease.

29:32 battler or warrior to prevent you from that. Now, we do have a little bit of human trials from both of these. So in SS 31, when we look at heart failure, there was a, it was called the progress HF trial phase two evaluated SS31 in patients with stable heart, failure with reduced injection fraction. While the primary endpoint improvement and left ventricular end systolic volume was not met. There was signs of benefit there. These patients showed improved mitochondrial function of muscle and reported better quality of life scores, although the echocardiograph parameters did

30:06 not significantly change versus placebo, they did have better of quality life. When we look at acute myocardial infarction in a Phase 2A study, SS31 was given IV during angioplasty for acute ST elevation. And this treatment did not significantly reduce in FARC size compared to placebo when measured by imaging. However, the SS31 treated group had a lower incidence of heart failure in the immediate 24 hours post MI. So this sense that while SS 31 didn't outright salvage more heart muscle acutely, it may have stabilized mitochondria enough to prevent some early heart-failure events, which is pretty cool. Like I talked about Barth syndrome, There was this thing called the TAS power trial was a random, it was randomized placebo controlled crossover phase

30:43 two and bar syndrome patients followed by an open label extension. And the results were the SS 31 significantly improved skeletal muscle strength and reduced fatigue and, and Barth patients, which was pretty cool. We also have mitochondrial myopathy. So mitochondria myopathies are genetic disorders causing muscle weakness due to electron transport chain defects. And the MMPOWER trials, phase two and a larger phase three, called M-POWR phase 3, tested SS31 adults with some of these mitochondrio myopedies and did

31:13 not meet the end points. However, a closer look revealed that patients with mitochondrion DNA mutations showed a trend towards reduced fatigue and some functional improvement. It definitely helped there. With macular degeneration, again, to go back to the eyes, the reclaimed 1 in 2 trials tested topical or injected SS31 in patients with dry AMD. And it showed that SS 31 slowed the de-generation of photoreceptors ellipsoid zone, otherwise known as EZ, on optical coherence imaging. It shows that the SS-31 might preserve mitochondrial function in retinal cells and slow disease progression, even if it didn't reverse damage that was

31:48 already there, which is pretty cool. And then as far as other studies go, they have looked at SS31 in Friedrich's ataxia, which is a mitochondrial disease affecting nerves in the heart. And its broad mechanism has prompted interest in testing for neurodegenerative diseases like ALS, Alzheimer's, Parkinson's etc. So pretty cool when we look at actual human trials. There's not a ton on MOTC in terms of clinical literature. There was one instance where obese and diabetic individuals tend to have lower circulating MOTC levels and healthy controls.

32:19 And one study found that obese male children had significantly reduced Motsy in their bloodstream, which suggests a deficiency might contribute to early insulin resistance, hence supplementing with it could prevent insulin resistant. There is this one peptide called CoBars CB4211, Which is a direct MotC peptides. that is an analog of MOTC intended for better stability and potency. And in phase 1A trials in healthy adults, it was reported to be safe and well-tolerated over short-term dosing.

32:49 The main effect observed was some nausea at higher doses, but no serious adverse events. But CB4211 led to reductions in liver fat, improvements in the liver enzyme. So it's kind of an analogue of motC, like I said, pretty cool that it helped there. Again, because of MotC being an endogenous peptide hormone in a body, you're not going to see anyone patent it. As of 2025, there are formal clinical trials of Native Matzi are still limited. Researchers are likely considering small trials on age-related muscle decline, but there is mention that clinical trial to test Matzzi is ongoing but limited

33:24 And MAT-C holds promises of therapy for metabolic syndrome, type 2 diabetes, and a possible longevity booster, but we do not have a lot of clinical data. We do have this MATC analog CB4211, But nothing huge there. Now, when we look at safety, both of these are very, very safe and well tolerated. SS31 is shown a favorable safety profile. The most common reported side effect is injection site reactions when done with a subcutaneous administration. But systemic side effects are relatively uncommon and also mild.

33:54 There's no serious safety signals like organ toxicity, lab abnormalities, or ECG changes noted compared to placebo. Overall, this indicates that SS31 is well tolerated for at least up to several months of use. Now, I would recommend cycling on and off, but I do know people that have run this for over a year at a time and still had cumulative benefits to stack up. The more mitochondrally unhealthy someone is, the longer they can stay on it. And so far, no dose limiting toxicity have emerged.

34:25 Again, this is one that you can take up pretty much to a higher dose that would be cost prohibitive for most people. Matzi, same thing, clinical safety data is sparse given the lack of large human trials, but the CB4211 is a better glimpse into human safety and the analog was safe in healthy adults over the short term, only mind effects like nausea and injection site issues were One consideration like I talked about with insulin is the interaction with other drugs. So Matzi's potential to interact with metabolic drugs since Matzzi activates AMPK and improves insulin sensitivity if a patient is also on anti-diabetic medication.

35:02 Like metformin, which also activates AMPK or insulin, the combination might have additive effects. So just be careful. You'd be totally fine taking met formin. And you're not going to lower your blood sugar too low. But if for whatever reason you are from the bodybuilding world side of things and you were taking exogenous insulin just, be with Matzi because I did go hypo one time when using both things together. and again, it was a very low dose of insulin. I think it's like two I use. It wasn't more than four I used. Cause I've never, I never used more that four IU's of Insulin at one. time, but in summary, Matz's safety profile of fuel appears very favorable at this stage.

35:35 Now, let's look at some of the synergies between the two. So because ESSA 31 and MOTC work via distinct pathways, a natural question is whether they could be combined for additive benefits. SS31 acts inside the mitochondria to immediately stabilize bioenergetics, whereas MOTC acts at the cellular and organism level to induce longer-term adaptation. So these approaches could be very synergistic. For example, in a patient with mitochondrial dysfunction, SS 31 might provide acute relief, while the MotC could work in parallel to improve the metabolic body.

36:08 In essence, S 31 rescues distressed mitochondrion, and MotsC promotes the growth of a new healthy mitochondrium and efficient fuel use. They also can kind of help fill in each other's gaps. So because they work on different mechanisms, when you use them together, it could address the mitochondrial quality and systemic metabolic context in the body. And as far as cautions go, Both of them reduce oxidative stress via different pathways, and this likely results in an added reduction in oxidant damage. So there's little direct redundancy because one doesn't block the other's route.

36:41 One theoretical caution is that MOSI requires a bit of mitochondrial stress to activate AMPK. An aggressive mitochondria protectant like SS31 might slightly blunt this AMPk signal. However, given Matzi primarily acts via the folate ICAR route, which SS31 doesn't touch, we don't really have to worry about that. So in severe mitochondrial diseases or age-related frailty, a combination therapy could be envisioned together, and Matzie could address the diabetes root cause while SS 31 protects the heart when we're looking at metabolic disease. We definitely could use these two together.

37:11 The question, though, is which one, if I'm going to use, should I use first if i'm doing one or the other? It's a loaded question. And the answer kind of depends on the user. So for acute or severe mitochondrial stress, if the immediate issue is acute, for example, an ischemic event like a heart attack or kidney injury, definitely want to use SS31 first. It's rapid direct action on mitochondria can quickly stabilize cell bioenergetics and prevent cell death. and a scenario where time is of the essence to a person's health is more likely to yield prompt benefits.

37:44 And in situations like Barth syndrome, obviously you want to use it. In MOTC, by contrast, works with gene expression and metabolic shifts that take time to manifest. Now, for chronic metabolic dysfunction and prevention in conditions such as type 2 diabetes, metabolic syndrome or general age-related decline, Motsy might be a more logical first strategy. Again, there is no right or wrong. We're just looking at use cases here. So it addresses the underlying metabolic inflexibility and insulin resistance that characterizes these conditions. For instance, an individual with obesity, pre-diabetes, and fatigue might benefit more from MAT-C's systemic effects.

38:14 Using MATC first could improve the overall metabolic processes going on in the body, which in turn will benefit mitochondrial function indirectly throughout the rest of the bodies. And then if needed, SS31 can be later added for specific organ support. So essentially in a scenario of whole body mild mitochondria dysfunction starting with the hormonal approach of Matzi is going to be a good idea. Now, cardiovascular disease, like I talked about, SS31 has a more direct benefit. So again, if the bleeding neck problem is cardiovascular, disease SS 31 is gonna be what I'm gonna go to first.

38:47 And then Matz could come in afterwards. After that, neurodegenerative disease. I think SS-31 hands down is actually what you want to use. Matzie could but absolutely we want to use SS31 first. So that's going to be the first line of defense for neurodegenerative disease among other things like cerebral isin. For muscle, performance, and exercise, MATC is definitely going to be what you want to go to. If performance enhancement is the goal, better endurance, cardio, glucose, you take an uptake in utilization, MatC hands down is going be better.

39:17 It could enhance the benefits of physical therapy or exercise programs by molecularly jumpstarting those pathways. Now SS31 can also help and you probably will notice a little bit of a benefit, but I think MATS is gonna be much more pronounced. And then when we have metabolic disorders, MAT-C's direct actions on insulin sensitivity and weight make it the favorite option for a first try. So again, if there's no outstanding acute disease, other than just being overweight and being obese, I think MATC is gonna be better first. However, If you are mitochondrally impaired and you're obese it would be to use SS31 first, so once glycemic control is improved with MAT C adding SS 31,

39:56 might also help remedy complications by repairing mitochondria in affected tissues. So you can see how it can be kind of different. Now, when we look at practical availability, obviously in the research world, we can readily access both of these compounds. SS-31 is farther along in development from the pharmaceutical side of things, and we probably won't see MOTC pharmaceutically prescribed anytime soon. But at the end of the day, it depends on the context. If we were going to use both of them together, you could start with MOTC in an aging patient to broadly improve mitochondrial health across tissues,

40:31 and then assess if specific issues remain that require targeted SS31 therapy. Alternatively, in a mitochondria diseased patient, start SS 31 to get acute symptom relief, then we could introduce MotC to maintain and further improve function. What we use first depends on the context. SS-31 is poised for acute targeted mitochondrial rescue and is nearer to clinical use, and MOTC is ideal for chronic metabolic enhancement and prevention. So we can definitely use them to benefit each other. Now, the question, too, people are going to have is, can I use the both together?

41:03 You absolutely can. I don't see any issue with that. Don't any negative side effects that would come from that, but I would not use right alongside each other. Personally, I would use one versus the other, and again, depending on what your goal is, that's going to kind of lead you to what you want to start with first. Now, to look at dosages, the MATC beginner dose is going be one milligram per day, sub-Q, or IM, in the morning for eight to 12 weeks. You could actually do it intramuscularly to help with the absorption. I think you get a more performance-enhancing benefit from that. The intermediate dose, it's gonna be two milligrams per, day and, again this is gonna, when I say intermediate, mean that you need more energy and more

41:38 fat loss. And then the advance is going to be five milligrams per day. You could definitely do that if you need a lot of fat loss. I personally wouldn't go that high, but I'm not trying to lose a bunch of body fat. SS-31, funny enough, dosage is pretty much the same. Again, a of people that ask me, Hunter, your dosing for SS 31 is all over the place. It's because there's different use cases. Kind of like saying how much water you'd need. That's like how dehydrated are you? You need to sip or you needed a whole bottle. The beginner, for someone that's already healthy, one milligram per day is good. Intermediate, five milligrams per today. The more mitochondrial impaired you are, the more you're going to need.

42:10 And then obviously the advanced, which would be someone who is severely mitochondrion impaired, you'll need to go up to 10 milligrams a day. So again, dosage depends on the end route. Just to sum these up, mitochondria are crucial for energy. When they malfunction, it contributes to aging and diseases like heart failure, Alzheimer's, and diabetes. An SS-31 and MOTC are very powerful compounds that we can use. SS-31 is a small synthetic peptide drug that goes straight to the mitochondria. This is mitochondrial protective shield, so it sticks to inner wall of the myocondria and helps mitochondrion work properly.

42:42 So this reduces harmful oxygen radicals oxidative stress inside cells. It keeps cells energy production running smoothly along the electron transport chain. it prevents the Mitochondrial from releasing the signals that kill the cell and ensure to protect cells from damage or death during stress like heart attack or toxic injury. Conversely, Matzi is a tiny protein naturally made by our mitochondria already. It is like a built-in helper, otherwise known as a mitochond, and it is fitness trainer for your cell's metabolism. Everyone knows I love the analogies and this is kind of more like the trainer.

43:15 What Matzzi does is it activates AMPK that tells the cell to produce energy and burn fat or sugar, similar to what happens during exercise or fasting. Improves how the body uses insulin, thus lowering blood sugar and increasing insulin sensitivity. is even sent out into the blood, acting like a hormone that can boost muscle and other organs. For example, it can increase muscle endurance and bone strength, and it's even been linked to better memory in lab studies. And it boosts the body's natural stress defenses and metabolism. So similar goals, different tactics. SS31 MOTC ultimately help mitochondria make energy with less stress.

43:50 Whereas MATSI does it by adjusting the cells and body settings from without. So again, like I said, SS31 is a hardware upgrade, MATSII is the software upgrade. Who will get the most from what? Someone with acute injury or known mitochondrial disease is going to benefit much more from SS31. Someone, with general aging issues, pre-diabetes or wanting to improve metabolic health, might start with MOTC. However, you could end up using both together at various times. So, SS 31 immediately to protect organs and Motsy to build long-term resilience because one fixes the mitochondria now and the other makes them stronger

44:27 for the future they could be a powerful one-two punch so matzi is like giving our mitochondrial armor and or excuse me ss-31 is giving your mitochondrion armor, and matz is, like, giving them a workout plan to get fit for long term so there you have it folks that is it for slides and that's my comparison video of matzie vs s31 so hopefully that was helpful to you guys I may have been beating a dead horse a little bit, but hopefully now you have a comprehensive framework of how and when to use either of these compounds. I think they are both great, I personally use both of them throughout the year.I didn't mention SLU PP332 and BAM15 in this context,

45:03 because I want to reserve this just as a conversation. i do have the video on mitochondrial cycling that you can look up on my channel that explains how to us these in conjunction with SLUPP333 and even a bit of BAN15 so you could check that out. I would say at the end of the day, when we look at different pathways that we can optimize, we obviously have our hormones. We have the insulin pathway. we have all these things. When we looked at mitochondria, these are the two go-to staples for mitochondrial health for the long-term. And I think really younger people can benefit from doing this when look performance, and then older people are going to benefit when they look just at

45:35 anti-aging and longevity from that perspective. So I hope this was helpful to you guys. I look forward to your feedback on this one. Again, I can't respond to all the comments and emails and everything I get, but I appreciate you so much. And those really helped drive the direction of where this is because again, I was able to make this video because I saw all of the questions and responses and everything I got about how to use Mozi versus S31, which one should I use and all the confusion around that. So hopefully that was helpful to you guys. I really appreciate you. Thank you, guys, so much. And I like to close out every with you saying from the bottom of my heart, absolutely nothing but gratitude for you guy.

46:08 be able to bring this content to you and hopefully improving your life, improving, your education, and improving the ability that you have to manage and be the proactive scientists of your own health. So thank you guys so much. I love you, guys, from the bottom of my heart. Don't forget to check out the links, which are down in the