Humanin: A Mitochondrial Peptide for Brain Health and Longevity
Humanin is one of those peptides most people have never heard of, but it might be one of the most important for healthy aging. It's an endogenous peptide, meaning your body already makes it. And when researchers look at people who live past 100, they consistently find higher humanin levels. Let's break down what it does and how to use it.
What is humanin?
Humanin is a 24 amino acid peptide encoded in your mitochondrial DNA, specifically the 16S RNA gene. It was first discovered in 2001 as a protective factor against Alzheimer's-related cell damage.
It's highly conserved across species, from worms to humans, which tells you it's biologically fundamental. Your mitochondria release it as a distress signal during stress, oxidative damage, nutrient deprivation, or toxic exposure.
Levels are highest in organs with the most energy demand. Brain, heart, muscle.
And like most things, humanin declines with age.
Think of it as a soldier peptide
Here's how I like to frame it. Two people can go through the exact same stressful situation in life and have completely different outcomes. One gets stronger, one breaks down.
Humanin is the body's natural response to that stress at the cellular level. When pro-apoptotic proteins like BAX, BID, and BIM try to punch holes in your mitochondria and trigger cell death, humanin physically binds to them and blocks them.
The cell survives. The mitochondria stay intact. You recover.
As humanin declines with age, your ability to respond to stress at the cellular level also declines. Supplementing it exogenously gives your body more of what it's losing.
How it works mechanistically
Humanin binds cell surface receptors and activates JAK/STAT, ERK1/2, and PI3K/AKT survival pathways.
It reduces inflammatory cytokines and increases antioxidant gene expression, similar to what GHK does across thousands of genes.
It also sequesters IGF-BP-3, which boosts IGF-1 survival signaling. That's something the other mitochondrial peptides don't do.
Where humanin shines compared to MOTS-c and SS-31
I get asked about this a lot. All three are mitochondrial peptides, but they hit different angles.
Humanin is your brain health and cytoprotective peptide. It's the first line of defense for mitochondrial brain health.
MOTS-c is the metabolic powerhouse. AMPK activation, glucose uptake, insulin sensitivity.
SS-31 is the synthetic tetrapeptide that stabilizes mitochondrial membranes and reduces reactive oxygen species. Now FDA approved for certain conditions.
Humanin still gives you metabolic benefits and SS-31 still gives you brain benefits. They overlap. But each one has a lane where it dominates.
The longevity data
This is where humanin gets really interesting.
In worm models, humanin overexpression extended lifespan by 30 to 40% and improved health span markers by 25 to 35%.
In mice, health span extended 15 to 20% and age-related decline was delayed by about 20%.
In humans, we don't have supplementation trials yet, but the observational data is hard to ignore. Children of centenarians have 2 to 3 times higher humanin levels. Cognitive decline rate was 50% slower in high-humanin individuals.
People with mitochondrial mutations that reduce humanin showed accelerated cognitive aging by about 2.5 years.
The APOE4 finding
The APOE4 gene is associated with higher Alzheimer's risk. But researchers found that APOE4 carriers who also had a P3S humanin variant (which produces higher humanin levels) had 40% lower Alzheimer's prevalence and 36% slower cognitive decline.
In mice with the same variant, amyloid plaque formation dropped by around 50%.
Higher humanin equals slower aging, better cognition, longer health span. Across every species studied.
Cardiovascular and metabolic benefits
From mouse studies:
- Myocardial fibrosis reduced 60 to 70%
- Cardiac apoptosis reduced 40%
- Left ventricular function improved 15 to 20%
- Infarct size reduced 30 to 50% after ischemia reperfusion
- Insulin sensitivity improved 30 to 35%
- Muscle glucose uptake increased around 40%
- Hepatic glucose production reduced about 35%
- Fasting glucose dropped 15%
Is it as metabolically powerful as MOTS-c? No. But it does work on those same pathways.
How to dose humanin
There's no official protocol yet, so this is what I recommend based on the similar mitochondrial peptides.
Dose: 1 to 2 mg per day Schedule: 5 days on, 2 days off Weekly total: 5 to 10 mg Cycle length: 8 to 12 weeks Route: Subcutaneous injection
Half-life is about 30 minutes, but tissue effects are cumulative, so you don't need to chase the half-life.
With a 10 mg vial, mix in 2 mL of bacteriostatic water. 1 mg = 20 units on an insulin syringe.
If someone has Alzheimer's or another serious neurological issue, you'd probably want to titrate up to the 5 to 10 mg per day range. For general longevity and brain health, 1 to 2 mg per day is plenty.
How I'd cycle it
I've talked before about rotating MOTS-c and SS-31 throughout the year. Going forward, I'm splicing humanin into that rotation.
My order would be SS-31 first, then MOTS-c, then humanin. Three month cycles each. That keeps you sensitized to each peptide and covers all the mitochondrial bases throughout the year.
You could run them concurrently, but I prefer sequence over stacking. Receptor sensitivity matters, and you get a stronger response when you cycle off and come back.
My take
Humanin is underutilized and underrated. The longevity correlation with centenarians is too strong to ignore, and the brain protective effects make it a must-have for anyone in their 50s or 60s who's thinking seriously about cognitive aging.
If you're building a brain health stack, this should be in the rotation alongside things like Cerebrolysin and P21. If you're already running MOTS-c and SS-31, add humanin as a third leg. Same mitochondrial benefits, slightly different mechanism, and you keep your receptors fresh.
We don't have human supplementation trials yet, but the genetic and observational data is compelling enough that I'm putting it in my own rotation going forward.
Full transcript click any paragraph to jump video
Hey everybody, this is Hunter Williams. I hope you're doing amazing wherever you might be in the world. Today I have a really cool video. Humanin is actually an endogenous peptide, meaning that we actually make humanin naturally in our body. And it was discovered recently, I'll talk about this a little bit in the background of the slides going through it, but it discovered within the last few
decades and we can actually now supplement with human in as we age. When it comes to mitochondrial peptides, obviously if we improve mitochondria health, it kind of has these ripple effects throughout the rest of the body. So there's tons of benefits of supplementing with mitochondrio peptide. When it comes to Huminen, there's gonna be a little bit of the MOTC side in it. There's going to be little of SS31 side of it, but what I think is cool about it especially as this becomes a larger and larger issue, is that it actually is a much larger player in terms of brain health.
So Huminnen, if we think about, it is going have more to do with the neurochemical side things and the neural health side, much more so than SS 31 and Motsi will. SS31 and MOTC do have brain benefits, obviously through the cascade of things they do in the body. But what's cool about humanin is that where it really shines, especially in relation to those other two mitochondrial peptides, is mitochondria health. And what is cool with human and we'll go through this in some of the research today, Is that when we look at people that have lived very long lives,
when they evaluate centenarians, which are people that have lived a hundred plus years, they actually have higher natural human and levels. So whether or not we have a lot of data around human in supplementation, we're not gonna have that at least to this point in humans, there's gonna be some rodent studies that we can look at. But when we look correlative things that relate to longevity human, and it's definitely an endogenous peptide that, that is much more present in people who have longer life spans and longer health spans.
I'm really excited about it. It's obviously one, it's been around in the research world for a while, but not a lot of people know about, not all people how to use it or the dosing. And we're going to cover that all today in this slides. As always, remember to hop over to the email list. That link will be down in description of wherever you're listening to this, whether it was iTunes or Spotify. Check that out, just make sure you're signed up for the email list so that you get all the updates of new videos that come out. Again, I don't spam you with anything like that. I just makes sure that I'm providing valuable updates on new video and any other research or other topics that i might be thinking about working on for
future videos and what not. Also to this is now live. We have the axion collective. So that is Taylor and myself's private group, or we have private coaching where you can come in and there is a forum where can network and communicate and talk with all the other group members. You can also message us privately and directly. and also till we do live coaching calls every night at Thursday or every Thursday night, at 8 p.m. We're doing live coach and call so you can come on and ask questions on those calls and we have very structured curriculum on these calls.
So you come in, check that out, see what it is. Obviously you watch all the recordings. You don't have to be on the call live, ask those questions, all that good stuff. Check it out. The link will be down for the description and that is called the Axion Collective. All right, without further ado, I'm gonna pull up my slides and today we are going to look at human All right, let's get into it today. We're going to talk about humanin, which is a mitochondrial peptide for longevity. It's a 24 amino acid peptides from our mitochondria and it could be one of the keys to healthy aging and an extended lifespan. Let's look a little bit at the background of human and It was originally discovered in 2001 as a Mitochondrial derived peptid that actually protects cells
from Alzheimer's related damage, obviously. That's a big thing in the world today, right? I've had personal family members suffer and pass away from Alzheimer's. It's something that at this point in world with how everything's going, you probably have someone in your family or at least a close friend that is someone that's suffered from Alzheimers or it might be in process of doing so. Again, it's the 24 amino acid molecule. That acts as a broad cell protective or cytoprotective factor. And when we're going to look at the research today, we are going find that it's linked to healthier aging.
It also extends lifespan in worms and mice while humans with exceptional longevity have higher human levels. Which brings up the point that we could potentially use it to aid in longevity as we look the concept of peptide replacement therapy which is replacing some of these endogenous peptides which obviously decline with age. Again, what is humanin? It's a mitochondrial peptide, it's encoded in mitochondria DNA's 16S RNA gene, not main cellular DNA. It is obviously highly conserved, is found across species from humans to worms, indicating fundamental biological importance,
again not just in humans. across tons of different other animals in the animal kingdom. It's also a signaling molecule that's released into cells and the bloodstream as a protective message during stress. And when we look at hormone replacement, peptide replacement a lot of these things especially if it's something like human that is endogenous to us. As we age, levels decline. When we look at environmental stress, whether that be from life or whether it is from physical things in the environment like toxins or whatever,
the body has a limit on how much stress it will be able to handle. And if we look at something like human end, what I like to think of is like, how can we use some of these peptides to improve our resilience to stress? I liked to always talk about the concept of you could have two people going through the exact same situation in life or the same environment and how one handles stress will actually determine the outcome of what that person does. Sometimes stress can make us stronger, can makes us better. Other times it can end up breaking a person and causing them illness, disease or what have you.
And that's what's cool about human and it is one of these peptides that comes in as a protector during stress. And if we're using human, and we can kind of think of it as, okay, I'm going through the stressful event. Human is going to come in, the body naturally releases it in stressful events. But if it declines with age, as we age we are not going be able to respond to those stressful. as appropriately as we may need to. Let's go into this a little bit more. It basically acts as a distress signal from the mitochondria. Basically, when cells face oxidative stress, nutrient deprivation, or toxic insults from pollutants or endocrine disrupting chemicals or what have you,
mitochondrias secrete human end to help these cells survive. Levels are highest in vital organs with high energy needs, meaning that the brain, muscle, and heart have the highest levels of humanium. And obviously human levels, like we've talked about, decline with age, which suggests that maintaining higher activity could benefit longevity, again, because it has this cell protective effect to keep cells from dying in the event of stress. Let's look through the mechanisms of human end, basically what happens when we inject it or we're producing or releasing it endogenously.
It binds to cell surface receptors which activates JAKSTAT, ERK1 and 2, and PI3K and AKT survival pathways. It also acts as an anti-inflammatory peptide. It reduces inflammatory cytokines and increases antioxidant gene expression. What else does that sound like? GHK. Anybody? G-H-K is very similar in that antioxidate gene-expression actually works on over 4,000 genes being GH-k. But it also what's unique about human and relative to some other peptides is a block cell death.
So it prevents pro apoptotic proteins from triggering mitochondrial damage. And when we look at some of these pro-apoptic proteins, what they end up doing is causing mitochondria damage, whereas human is going to block that. And again, I think when you look at humanin relative to the other mitochondrial peptides like SF31 and MOTC, obviously we'll talk about the brain protective effects of it, but it actually is very cytoprotective.
And that's where it is, very much different than those other peptide. Basically it physically binds pro-apodic proteins like BAX, BID, and BIM, which prevents them from damaging mitochondrial membranes. It also sequesters IGF-BP-3, which enhances IG-F1 survival signaling, Which is pretty cool, because we don't see that in those other peptides. Stress triggers apoptosis, and then BAX and BID proteins activate to punch holes in the mitochondria. And then basically what happens during that process is that huminin intervenes, it physically binds these proteins and blocks their destructive action.
So again, think of this as almost like a soldier peptide that as the stress is triggering cell death, it's actually coming in and stopping the death of those cells and the depth of the mitochondria of cells. And then when human comes in, the cell survives, that mitochondrial remain intact and that cell recovers from stress. Think about the natural process of human in the body is kind of this warrior peptide that is going in, stopping the cells from getting attacked from the environment and from stress in environment, and then preventing the death of the mitochondria and the cell.
And then when we obviously supplement it exogenously, it's going to help it even that much more. When we look at the benefits, what does this look like when it plays out in real life? Obviously, we have the neuroprotective benefits because human is so much more found in the brain. Basically, it blocks amyloid beta toxicity in Alzheimer's models. Age mice treated with human showed better memory and less cognitive decline. and lower levels were found in dementia patients. So that's where it's going to shine, especially relative to MOTC and to SS31.
And I think for someone that is building a brain health stack, if we are approaching the pillar of mitochondrial health in the brain, human aid is the first line of defense that I would go to. Obviously, there's other things we can use like cerebral liason, like P21, but human and definitely should be included. We have metabolic benefits, it improves insulin sensitivity, increases glucose uptake in muscles, reduces liver glucose production, and also activates AMPK pathways for better metabolic flexibility.
Now, does it do that as well as Matzi? No. It sounds like if I'm reading those benefits to you, right, that that would be chapter and verse what Matz does. And in fact it is. However, it does have those effects as. Well, in addition to the brain health benefits we're getting, we are also getting some of these metabolic benefits. Also, it's cardiovascular protective. It prevents heart fibrosis, reduces age-driven apoptosis of heart cells. it improves left ventricular function. Also protects against ischemia reperfusion injury.
And then when we look at longevity itself, It extends lifespan in worms, transgenic mice showed better health span, and children of centenarians have higher plasma human levels. This is one of those things as we get deeper into AI, discovering some of these things out there, we can look at a peptide like human and say, okay, this is correlative with people that genetically live longer. How can we actually extract that and maybe use it therapeutically to get the same effect? And again, when we look at the benefits, we're gonna see improved memory and physical performance.
We're going to have resistance to toxins and stress. I think that's what's also important is this one. If you are in a stressful environment, whether that emotional or psychological stress or even physical stress from pollutants or things of that nature is going help with that longer lifespan in certain cases. And it's going protect against Alzheimer's, diabetes and heart disease. Let's start looking at some of the longevity data around human. In worm models, there was 30 to 40% lifespan extension with human and overexpression in worms.
And then also 25 to 35% improvement in health span measurements, which were movement and stress resistant. When we look at mouse models, there was 15 to 20 percent extension of health span metrics, and then age-related decline delayed by around 20 in mice that were given humanin. When look look genetics, we don't have any human studies on the supplementation with human, but we looked at gene profiling of humans. Children of centenarians had two to three times higher human levels. Cognitive decline rate was 50% slower in high human and individuals and mitochondrial mutations reducing human accelerated cognitive aging by two and a
half years. Basically that means that people that had a mutated version of the mitochondria that reduced human in levels actually had more accelerated, cognitive decline. And then also too, I thought this was interesting. There's this idea of the APOE4 gene that basically is not a death sentence that you're going to get Alzheimer's, but there is increased risk or increased prevalence of people with this gene for getting Alzheimer. What's cool is they actually looked at this genetic mutation for people who have APo4, they also had a P30S or P3S mutation,
which means that their human and levels were actually higher. And those people had 40% lower Alzheimer's prevalence which is pretty statistically significant. They also had a 36% slower cognitive decline rate. Then in mice that also have this variant, amyloid plaque formation dropped by around 50% because of the higher human levels. Basically higher huminin equals slower aging, better cognition, longer health span across all species studied. When we look at the cardiovascular and metabolic side of things, obviously this is coming from mouse studies, myocardial fibrosis reduced by 60 to 70 percent
in mice, cardiac apoptosis reduced 40 percent, left ventricular heart function improved 15 to 20 percent and infarct size reduced 30 to 50 percent after ischemia reperfusion. When we look at metabolic benefits, insulin sensitivity improved by 30 to 35%, glucose uptake and muscle increased by around 40%, hepatic glucose production reduced by about 35% and fasting glucose dropped by 15%. Again, is it as powerful as Amatsi?
Metabolically speaking, no. However, what I love about this concept is that we can rotate Mozi SS31 in human and throughout the year, yield all of these amazing benefits and be hitting slightly different pathways, but still getting some of the benefits. And I think about it, okay, well, if I'm using MOTC and then I moved to Huminen, I love all those benefits of MotC, but now I've got to move to huminen because I want to cycle off. I wanna keep my receptor sensitive. However, we can still use a brand new peptide that we are completely resensitized to when we cycle of the MotsC in Huminnen and also get some of metabolic
effects in tandem, which is pretty cool. And again, when we look at some of the numbers, 25 to 30% memory improvement in age mice treated with human and analogs, 40 to 50% amyloid beta reduction in Alzheimer's mouse models, 30 to 35% better improvement and insulin sensitivity. And then again that one statistic which was pretty staggering is that children's of centenarians had two to three times higher human levels than those that were not, which is pretty cool.
When we look at dosage, this is where it's a little bit of the wild west right now. There's no official dosing. However, I would recommend a very similar protocol to MOTC and SS31, which is in the one to two milligrams per day range. This is what I like to do. So one to two milligrams of daily dose, and then five days on, two days off, just to keep you a little bit more sensitive to it over time, which ends up being a five to 10 milligram weekly dosage. The half-life is 30 minutes. However, the tissue effects end up cumulative, so you don't really have to worry about that.
You just want to make sure you're taking at least five or 10 milligrams per week over the course of a week and over eight to 12 weeks. that adds up. Again, it's going to be a subcutaneous injection. Typically, you're going see it come with a 10-milligram bottle, and then you would mix two milliliters of bacteriostatic water into it. And then if you wanted one milligram, that would be 20 units on that. I like everyday dosing five days on, two days off. and you should be good to go from there. Again, I think it's one of those things as with SS31, if there is a use case, so if we had someone with Alzheimer's, yeah,
you're probably going to want to be in that five to 10 milligram per day range. Obviously that becomes a little bit more costly. obviously you are going need more to get more of a therapeutic benefit. However, for longevity purposes for someone that may be like you or me that just wants to cover all the bases, that wants make sure they're doing everything they can to live long, live strong, I think the one to two milligrams per day is a great starting range. Obviously if there is chronic or acute issue that you're trying to solve, you are going to have to titrate that up higher to get more of a pronounced effect.
I did make a slide. I just wanted to go over how it differs from OTSI and SS31. Again, I know this stuff can be a little confusing sometimes. Obviously humanin is a natural mitochondrial peptide in the human body. It's a cell protective hormone, prevents apoptosis, reduces stress through signaling pathways. And again, right now we don't have any human trials on it yet, but there's lots of observational data about the benefits of supplementing with it. MotC is also a natural mitochondrial peptide. It's 16 amino acids, whereas humanin is 24 amino acid.
Its from a different gene. Is from the 12S RNA gene, where as humanins from 16S, RNA Gene. Mot C is much more of a powerful metabolic regulator. it activates AMPK, it improves glucose uptake and insulin sensitivity. Also, its kind of funny because like you say, we would say human in is more for brain health peptides as opposed to mot C, but we're still gonna get brain help benefits from motC. And so they do kind of play off of each other. And then there are early human trials taking place right now. Then we have SS31, obviously that just became FDA approved.
It is a synthetic tetrapeptide not encoded in our genome naturally. What SS 31 does is it binds a cardiolipin in mitochondrial membranes, stabilizes the cristae in the mitochondria and then reduces reactive oxygen species production. Obviously there use cases of SS-31 from heart failure to kidney disease. and other mitochondrial diseases like Barth syndrome, but that's how they're different. And what's cool is I think you could structure three month cycles of these throughout the year and pretty much cover your bases and still reap some sort
of mitochondria benefit at all times. Basically, I Think human is one of the more obviously underutilized peptides, particularly in the region of brain health and extending health span of We're looking at more of an early stage, so there's less data in supplementation than there is for MOTC and SS31, obviously. And obviously, in the research world, it's much less well-known. People don't really know the dosing. Hopefully, through this video, you've come to understand the benefits of it and how you could practically implement it in your own life.
And that is it for the slides. And, that IS everything you need to know, as least as it stands right now, about humanin. Again, I love humanine as an alternative to MotC or SS31. Mot C and SS 31 are pretty well tolerated. Some people, when they take the dosing up too high on Mot-C, they can get a little bit of an anaphylactic shock reaction. That's why I always recommend starting with one milligram of Motc and not the five to ten milligrams that some people see and decide to do. I love human and I think it should be in the rotation with Motzi and SS 31. I've talked about in past of just kind of rotating between Motze and Ss 31
throughout the year. My intention going forward is to actually splice in a human cycle. So to go from Motzie to human into SS31. If I was starting out, I would probably go SS 30 one first. Mozi second and then human and third and the move back to SS 31 after that. You could use it in tandem with those. It might be a little bit of overkill. I would prefer to use them in sequence, meaning that I will use one and move to the next and to next. However, you could probably use it with MATC or SS31 and still reap good benefit because it is working a slightly different pathway,
mechanistically is doing slightly things, but I just like cycling because I keep somebody sensitive to the peptide, meaning that when I go off of human and go back to SS 31, I'm going to be much more responsive to that SS-31. So you can use them in tandem, But I like to use the more in sequence that I would use concurrently at the same time. But I love human and it shows a lot of promise. And I think for someone that's probably in their fifties and sixties, and is getting to that point where they're becoming much more conscious of brain health and where, where things are headed over the next 20 years, I Think human is one that we are going to find shines and does really well in the future.
Again, that's it for this one in closing. Thank you guys so much. My heart goes out. I am overwhelmed with gratitude for everyone out there that supports the channel. To build out a new podcast studio so I can do more guest interviews, Taylor and I could do bigger and better live streams and the presentation hopefully is much higher quality for you. Again my mission is to bring the best information around peptides, hormones and health optimization to you each and every week. And in doing so, I want to make sure that the presentation is also the best.
Again, that would not be possible if it was not through the support of you guys through supporting, whether it's liking, commenting, subscribing, signing up for the email list, using my code to buy products. You guys have no idea how far that goes in supporting my operation to bring this to guys. I am so blessed to get to do what I do. It means the world to me that I have the supportive people and that to see the people's lives that are changed because of my work that warms my heart, but it also just means so much to me that I have the calling and then the responsibility to bring this to you guys.
So thank you so, much my heart overflows with gratitude, especially in the holiday season, as I reflect on the last year, I'm sure you are doing too. But thank, you, guys, that's it for this one and I will talk to, in, the next one. Peace.
