P21 The Brain Peptide

0:09 Hey everybody, this is Hunter Williams. I hope you're doing amazing wherever you might be in the world. Today's video is a long time coming. It's been one that I've wanted to do for a while. And just because of sourcing issues in research world, I had held off until now, but now we're good to go because there are plenty of companies that are selling it. This one is going to be about a peptide called P21. P 21 is much more of what I would classify as a brain peptide, I wouldn't necessarily call it a neutropic in the classical sense of neutropics,

0:41 but it is an amazing brain health peptides. I actually was turned onto this peptid years ago, probably two or three years, ago I got a couple of messages from parents of neurodivergent children. You can probably understand what I'm saying when I say that, or I'll just say it, autism. And some of these parents with autistic children had been using P21 as a nasal spray in their children and had an amazing success with some the autism symptoms that their kids had. And I was like, wow, that's pretty interesting.

1:11 Let me look more into it and kind of found a source for it. It's one of those ones that not a lot of people know about, therefore not all the companies sell it, found the source where I started playing around with myself and really noticed some positive benefits. If you know my content, you'll know I'm not the biggest nootropical. I think noOTropics have a place, but I am not someone that leans on neutropics all the time for performance. I think if you're doing everything right from a hormone standpoint and an overall metabolic health standpoint, you don't need too many neutropic compounds, although they can be fun to use from time to time.

1:46 I'll just say some bad effects long-term if you become dependent on those in order to perform, at least from a cognitive standpoint. Nonetheless, I've really liked my use of P21. It's not so much of a nootropic as it is an up regulator of BDNF in the brain, which is brain derived neurotrophic factor. Kind of like miracle grow for your brain. That's the old thing you've probably heard on podcasts about B D N F, but P 21 really seems to work well in that era or that area. of health and what I like about it is in the world that we live in today, cerebral liason is more or less the gold standard when it comes to neural repair

2:20 and brain repair, and helping with brain health. I think a lot of people make the assumption that cerebral isin is going to act as a nootropic. In some cases, it can have that effect if you have inflammation in the brain to lift brain fog and increase mental clarity, but it's not going be the limitless pill like from the old movie with Bradley Cooper. So all that to say is that P21 is not a neutropic, but I see it as an adjunct or maybe almost like a diet or light version of cerebral liason.

2:51 It's not the same thing, it's completely different, but, I notice a lot of the reduction in inflammation, some of same upregulation that I noticed from cerebral liaison. Again, completely, different molecules. But I think in a world we live in today where it is much harder to source cerebral, especially if you're not willing to use crypto, I think P21 is a great alternative. And I also think too, again cerebral isin is really powerful. I am not someone, even with the past of having concussions that needs to use cerebral iosin even every year, because my brain is in a really good place.

3:25 My brain age is the same as my biological age. I have very little signs of tau proteins or anything like that in my brain, which was a concern for me as someone that has had multiple and several concussions through my life. However, I see P21 is something that we can use as a lighter version of cerebral liason that's also going to have really good benefits in the long term for our health without us having to use something as strong as cerebral isin. It doesn't mean cerebral isn't bad. I just think with P21, we have easier access to it.

3:55 it's a little bit lighter. We can use it a bit more frequently than we would use cerebral, especially if someone's already in relatively good brain health. And again, I think it always comes down to the access question, right? And P 21 seems at least now to have much more access. But that's it. Let's get into the slides. As always, make sure you're on the email list, just in case I get deleted off of any of the other social platforms. Got deleted of YouTube, Instagram. I may be getting my Instagram back soon, so we'll see about that and hopefully my YouTube. But again, the best way to stay in contact with me is the e-mail list. And as always check out Axion Collective.

4:26 That is our private group. If you want to do live coaching calls on Thursday nights with myself and Taylor, And all the other wonderful members there, you can check that out. It's a really cool, fun place to be. You can also direct message me or talk to other amazing members in the forum. So let's get into it today. We're going to learn about P21. All right. Today we're gonna be learning about p21 in brain health and neuroscience. And really we want to see it shine in areas of memory enhancement and neurogenesis. Spoiler, we don't have that much human data on this other than what I can really talk about from my own perspective.

4:56 There are actually no human trials, but there is a good amount of animal data that we'll go over today. Just to give you a background, P21 is a small synthetic neurotrophic peptide derived from ciliary neurotrophy factor. And this is going to be a big theme in looking at P 21. This is abbreviated as CNTF and this modified pentapeptide includes an adamantane moiety greatly increasing its lyophilicity and blood brain barrier penetration. Basically what that means is that P21 is very effective at crossing the blood-brain barrier.

5:29 And unlike full-length CNTF, P 21 is stable in circulation and also orally active, which there's not anyone that I know that's making an oral version of P-21, but according to the molecular data that i could find on it, it actually is orly active and I think in some of the rodent data, that we'll look at today, but over 90% remains intact after 30 minutes in gastric fluid. It was developed by Fain's biotech as a potential disease modifying therapy for Alzheimer's. I don't know where that is at along the. phase one, phase two, face three trials, or even if it is in trials right now, but that's where it came from.

6:02 So there we see it. Let's talk about mechanisms of action. This is gonna be important. Basically P21, again, like I said, is a neurotrophic factor mimetic that interacts with the CNTF receptor pathway in the brain. In doing so, it activates the JAK-STAT3, MAPK, and PI3K slash AKT pathways to support neuronal survival, which is survival of neuron cells, in differentiation. We have what's called LIF inhibition, which is basically it's competitively blocking leukemia, inhibitory factor signaling.

6:33 It doesn't have anything to do with the disease leukemia, but it frees neuronal or excuse me, neural stem cells to form new neurons and promote neurogenesis. Again, helping to form new brain cells. It also works on BDNF upregulation, it increases BNN factor expression, triggering TRKB receptor signaling and PI3K-AKT pathway activation. And then it also work on the TAL protection level, and inhibits GSK3-beta via AKT mediated phosphorylation, which reduces pathological TALL hyperphosphorylation

7:07 and supports synaptic plasma plecticity. What that basically means is that it inhibits things that could lead to the formation of tau proteins, which again, when we talk about in the context of Alzheimer's, that's very important because a lot of times you look at someone with an Alzheimer or dementia brain, they have the formulation of these amyloid beta plaques, tau-proteins and whatnot that are causing issues that lead memory cognitive and ultimately neural decline. And that is very import when you are looking at P21. When we look at what it's actually doing, its effects on BDNF and the CREB cycle suggest enhancement of neuronal survival and plasticity programs.

7:43 The mechanism involves mimicking CNTF's neurotrophic signals while biasing them towards neurogenesis and synaptic maintenance. And by avoiding alternative receptor pathways that cause CNTF side effects, P21 achieves targeted action resulting in increased new neuron formation and improved synaptic protein levels, which then reduces neurodegenerative changes. And again, that means that basically we're going into the brain and kind of modulating some of these pathways to reduce any sort of inflammation there. but then also to up-regulate the formation of new things going on in the brain.

8:15 Now, does that mean, again, that it's going to have a massive nootropic effect? No, but I personally have noticed pretty good mental clarity. This comes from P21 without feeling like I'm taking a serious noo-tropic. Even something as gentle as like a dihexer or noopap, this feels much different. It feels more kind of like, a cleanse for the brains than it does more so like hardware upgrade. Let's look at the therapeutic advantages. We have enhanced cognitive function. There's improvements in learning and memory in normal mice and Alzheimer mouse models.

8:49 Chronic P21 therapy restored memory function to near normal levels with treated mice performing as well as wild mice in object recognition and spatial memory test. We also have neurogenesis and plasticity. It robustly promotes new neuron growth in the adult hippocampus. A 35-day treatment increased newborn neurons and elevated synaptic markers, such as synapotrophin and synapsin-1, in hippo-campal circuits, which enhance connectivity. Again, we're enhancing the connectivity between neurons via those synapse,s which is going to, again, help the brain fire and wire much more efficiently.

9:22 Then we also have neuroprotection. It reduces toxic Alzheimer's pathology, significantly lowering hyperfossilated tau and soluble alpha beta peptides. Prevents neuron loss and dendritic degeneration and traumatic brain injury models. I think this is also important, again, if you had a concussion, Obviously, cerebrolysis would be something you want to get your hands on. However, if can't for whatever reason, or if you wanted to use P21 in conjunction with that, this would absolutely be the first one I go to, even before C-Max or Solanke, BPC-TB500. All those things are great.

9:53 We see P-21 having much more of a direct effect, obviously on the memory enhancement side of things, but then on inflammation via traumatic brain injury. Let's look at some studies. There was a 2010 study, peripheral P21 administration via subcutaneous slow release pellets, significantly improved learning performance in healthy adults, enhancing both working memory and spatial memory task. And they also noticed around an 80% neurogenesis increase through higher incorporation of new neurons in the hippocampus versus the control mice.

10:25 And basically it found that clear pro neurogenic effects with nootropic benefits in normal healthy animals. And I know on some of those maze tests, they did a lot better. Now let's look at some Alzheimer's disease models in Alzheimer disease mice, which were developing both alpha beta plaques and talatangles. Chronic oral P21 treatment reduced cognitive deficits. Six months of P-21 at 16 animals a gram in their food allowed Alzheimer's disease mice to perform normally on object recognition memory equivalent to wild

11:01 type mice. Now, does that mean we're going to see the same things in humans? Maybe, maybe not. We haven't seen human trials. However, it is putting mice with Alzheimer disease on par with wild mice that have never had Alzheimer' disease. And so we look at the areas there, it's working on cognitive restoration. It's a normal object recognition and faster morse water maze learning in those mice. They had neurogenesis recovery. There was a four-fold increase in proliferating progenitor cells and new neurons, which normalized a neuroogenic deficit in the Alzheimer's disease mice,

11:32 and also worked on synaptic protection. there was synapto-trophism and MAP2 levels restored to healthy mouse levels. And there a reduction in pathology, significantly lowered the tau proteins, Inside of the Alzheimer's disease mice, which is pretty cool that it was reversing some of those things. There was another 18 month treatment study 2017 show the continuous P 21 treatment started in young adults. With Alzheimer disease or excuse me young adult mice with Alzheimer, disease prevented age related decline in synaptic proteins and memory.

12:04 By old age, treated mice maintained high PSD95 and glutamate receptor subunit levels, basically it preserved cognition over the lifespan. There was no development of typical learning impairments and it dramatically lowered the mortality rate. And again, in P21 treated mouse, there was an 87% survival rate of these Alzheimer's disease mice, whereas the untreated group only had a 41% percent survival rates. So what would that be like? A 46% increase in the survival race of the ones that were treated with P21. Again, both of these mice had Alzheimer's or they induced Alzheimer through whatever method they do it.

12:38 But it suggested that P 21 improved symptoms, but also could slow disease progression in Alzheimer mitals. Early P21 treatment in Down syndrome mice achieved normal developmental milestones, eliminated delays and prevented severe memory deficits into adulthood and brain BDNF levels doubled in the mice that were also noted to have the genetic mutation that ended up causing them to down syndrome. So pretty cool information there.

13:08 And again, I'm not extrapolating that to humans, but you could probably infer as to what could be going on mechanistically that is helping these mice that could translate into some human use cases. Again, there's no published human clinical trials at least that I could find out there in the research world. There is an NIH-funded project examining P21's effect on brain imaging and behavior in Alzheimer's disease model mice as a translational step. And then further toxicology and dosage studies needed before human trials, strong therapeutic signals in animals make P 21 a promising candidate.

13:40 Now we have noticed in the animal models, there have been no adverse safety signals emerged in rodents even after long-term exposure for up to 18 months continuously. Obviously in a peptide world, we're cycling on and off. which does bode well for eventual human testing. And obviously people in the research world are using this. I've used it myself on and off and had a really good effects with actually very, I would say for myself, zero side effects. Again, can't say that for everyone, but when we look at dosage, the mouse dosing, basically what they had is 16 animals of P21 per gram of food,

14:11 which is around 45 milligrams per kilogram per day. Obviously that's a higher dose than we're going to be doing as humans. but the sustained release pellets deliver around 25 nanomoles a day subcutaneously. Both oral and implanted routes produce significant memory enhancement and neurogenic effects. Again, I don't know of anyone making this orally, but from what we have from the rodent data, i'm not a chemist, from from rodents data it seems that it works oraly. How well does that translate to humans? I think you can err on the side of using it as an injection or even a nasal spray, Anyway, nonetheless, there was also doses around 500 nmol per kilogram

14:43 per day, which is around 0.3 mg per kg via oral gavages effect in aging studies and restored neurogenesis and prevented retinal degeneration over a three month treatment period. Now I will say this just to give a pause right here. Both my wife and I, Taylor have used this and we both love it as a peptide. I will say my vision, thank, you know, Thank God that I've always had really good vision and, I'd never had what I would say is like vision loss. So I have always been able to read from pretty far away.

15:14 And I don't ever find myself like having a squint and things like that. Now, yes, if I'm on a screen for a prolonged period of time, that does seem to make my mission a little bit less, but I try to do a good job of being outside and having far sight. toward my eyes, able to focus far away. Whereas a lot of times when we're looking at screens throughout the day, we kind of like up into a screen, which obviously is going to affect our eyesight. However, Taylor has worn glasses for most of her life and P21 for her, she always talks about the vision enhancement for it. So for all the people looking for an eyesight improvement peptide, I will say that P 21 does have some data to back it up in mouse studies that show that

15:51 it enhances retinal degeneration and prevented excuse me, prevented retinal degeneration and enhanced retina function. And in my own wife, again, I haven't noticed that much from a vision perspective, but I've also, the last times I'd been tested for vision, my vision was like 2015, 2020 in both eyes. I can't remember which one's which, because I know one is a little bit stronger. But Taylor, who has glasses, has worn glasses pretty much her whole life, and has contacts and everything has said that she notices her vision improves when she uses P21. And again, it makes sense, right?

16:22 If we are improving brain cells, we're improving those things. The eyes are near the brain and it's going to work there similar to how other mitochondrial peptides improve eye health because we were improving the mitochondria in the eyes. But when we look at a half-life pharmacokinetics, the plasma half life is over three hours in mice, highly stable in gastrointestinal conditions, which is kind of unique for a peptide, obviously, and supports the feasibility of oral administration despite being a peptide. Now, when talk about human administration, again, this is strictly theoretical. This is what I have come to as a conclusion based on my own use.

16:52 But for sub-Q injection, it's going to kind a wildly vary. I will say I started around the 100 to 150 micrograms per day dose. Worked my way up to 250 micrograms. That seemed to be a nice sweet spot. I've talked to other people that use 250. Micrograms, they don't notice anything. Not that I think you have to notice. Anything. But when they go up. To 500 micro grams and even potentially one milligram, it seems to have a more pronounced effect over weeks. I think cycling wise, it's fine to do it for eight weeks on, eight week's off. You could do every day, you could it four, five days on two days off, I thinking even in some cases, if you have any sort of stressful event going on in

17:28 your life, maybe travel for work, may be you're hungover or whatever it is, P21 is great to throw in those cases even just as a short term intervention. Now, when we talk about intranasal, like I mentioned earlier, this is one that definitely can be used intra nasally. And I would say for that dosing, you're probably going to want to go higher to get the same effect. So you could do around one to four milligrams per day in divided doses. I will probably not go over one milligram per spray when you are doing that, but you can do it multiple times throughout the day.

17:58 Obviously, it's going come in a five or 10 milligram vial in most cases. So you're probably going to go through it pretty fast. But I would say in the, what I've seen is nasally, you need to get a little bit higher dose, but I wouldn't start there. So probably start a bit lower. And again, maybe one day the potential exists for oral dosing. That would be pretty cool if we saw that. If P21 enters clinical trials, dose ranging studies will determine safe and effective human dosage. For right now, from what have seen in myself and then the people that I have worked with, Again, that 100 to 500 micrograms subcutaneous injection per

18:28 day seems to work well. I will even do that honestly when I'm cycling it for like three days a week and I still notice good effects. So you might not even need to use it every day. However, if you had a concussion or you feel like you're prone to Alzheimer's or something like that, or if feel you have a lot of brain fog, I would go ahead and use that every single day, but that would be my recommendations for the dosing. When we look at side effects and safety, as far as we can tell right now, again, from animal models and then just anecdotally what I've seen, it seems to be very, very safe and not have any sort of downside or immunogenicity.

19:02 Again, mice treated for 12 to 18 months showed no weight loss, tumors, or distress. And unlike CNTF protein therapy, which induced marked cachexia, P21 avoids catabolic effects. There are no behavioral deficits. I think this is one thing that's important. Six months of P21 had no negative impact on locomotor activity, anxiety-like behavior, grooming, or sensory motor reflexes in Alzheimer's disease model mice. What I have noticed too from my own experience using it, a lot of these nootropic peptides, if used too much, can kind of drive anxiety ish behavior to

19:37 which I don't want to go there, right? I want something might, what goes up must come down. So it might be good in the short term, but then the crash, you might have anxiety because of too much neurogenesis that is driven from those things. What I like about P21 is it seems to be much more of a modulator because of what it does with neurotransmitters. So when I come off, there's no weird downswing or weird crash, but it just seems to kind of continue with benefits for the long term. I also don't really notice a change in behavior at all.

20:09 Obviously some nootropics, you know, if you take modafinil, it's going to kind of turn you into a robot, which in some use cases might be a good thing, but you might not want to be that way all the time. So anyway, again, low immunogenicity. There are no anti-P21 immune responses noted. It's a small size amino acid and partial human sequence derivation. means there's low immunogenic potential and no neutralizing antibodies, which means, you know, we could probably use this a little bit longer than the typical eight to 12 weeks if needed. However, I think that's just kind of a good rule of thumb, especially when we don't have a lot of human data around it.

20:40 But again, maybe you'll get a slight injection reaction around the area. I will say sometimes I've had this sting a bit when I have injected it, but not anything terrible. Definitely not as bad as like a GHK. There's no gastric intolerance, GI side effects or nausea reported with, or administration. I didn't notice any of that. If anything, I will say for me, there could have been mild appetite suppression, but nowhere near even a microdose of a GLP. For me probably what it was doing similar to tesofensine is it's modulating neurotransmitters, obviously through this upregulation of BDNF,

21:15 which is probably modulated dopamine, for which for when I'm eating probably just means that I end up eating less, similar I wouldn't even say it's as strong as tesofensine, but I will say I noticed that I am less likely, much less like to overeat using P21. And I think kind of the same thing. This is just speculation on my part. I thing kind the thing is going on with like a teso-fensin to where it is modulating neurotransmitters to which, you know, for the purpose of modulated diet and appetite works really well. Again, not in the, same brute force way a GLP-1 would, But still noticeable nonetheless.

21:50 Just to sum up, P21 emerges from over a decade of research as promising neuro restorative peptide with the ability to enhance memory, stimulate brain regeneration and protect against neurodegeneration. Again, it was derived from CNTF and engineered for brain delivery. It operates by bolstering neurotrophic signaling by upregulating BNF and lifting restraints on neural stem cell growth. Again, we have a multifaceted therapeutic effect, improved cognitive function, increased neurogenesis, strengthened synaptic connectivity and reduced pathological

22:22 hallmarks in Alzheimer's disease models. And again, it shows benefit in rescuing impaired cognition and enhancing normal cognitive performance, suggesting potential nootropic uses. again that might be a dosing thing. I've never taken a dose super high over one milligram. And so, hey, maybe there is more of a strong effect at those higher milligram amounts. I don't know. But I do think when we look at this for any of the people interested for whatever reason in cerebral liason, I'm kind of defaulting to say, Hey, if you have a hard time sourcing it, or even if don t want to go with something as brute force as cerebral, let's try P 21 and see how it does.

22:57 Also too, I probably talked a little bit about one of my dogs a couple years ago started suffering from dementia. Obviously I've been injecting with him with testosterone. It completely changed his life, gave him a new lease on life basically, but I haven't given him P21. And although it is a bit harder to track dog's cognitive function for a 13 year old German shepherd, he seems to be doing really well and showing no signs of slowing down, which is pretty cool. I think in the context of just helping with Stimming the tide of neurodegeneration, this is absolutely one that even if that is already present in someone,

23:32 it can probably reverse a little bit of that. Now, how far along does that go? Could it be in a late stage thing? I don't know, but I think if the signs are there, I would absolutely have someone like that on P21. Again, has a strong safety profile, strong clinical and preclinical foundation. And I thing when we look at things to help the brain, is pretty unique in that sense because it's not, pharmaceutical drug. And it's kind of interesting because you hear this with cancer, you here with Alzheimer's, like, we got to fight this and we gotta come up with a treatment

24:02 for it. It's like some of this stuff is already there that we can use to have massive benefit in the regard of helping heal that type of disease. Obviously, I think with all timers, it is a little bit more on the metabolic side than most people realize, meaning that a lot of that has to do with the metabolic health of the end user that ends up causing that nerve degeneration. However, once that's there, we can use P21 to help reverse it and even before it gets there help just make sure the brain is operating on all cylinders and also think too in the case of someone with concussions is going to help drive new neuron growth, help repair any damaged ones that are there,

24:38 and obviously help the prevention and formation of those tau proteins that everyone knows ends up causing brain damage and dementia slash Alzheimer's. And I think that is it for the slides. And that's my presentation on P21. So like I said, a long time coming, but I this is one peptide that you can definitely harness the power of right away. Again, the sourcing is a little bit easier than cerebraliacin. I just think you could use it, just me personally, much more frequently than you would cerebroliacins. So maybe use it one week on, one we go off, eight weeks on eight, weeks off.

25:10 However, you ended up doing it. But even with more of that continuous use, as we see in the mouse models, there didn't seem to be any downside. Again, I think in a context of whether you're worried about Alzheimer's, or that's something that feels like it's on the horizon, Or you just want to make sure you have all your bases covered around your brain. I Think P21 has a use case and I do use It and will continue to use a periodically throughout the year, particularly for me in times of high mental stress, whether that's something that I've got a lot of work on my plate or something, that maybe even in the case of like a, a of emotional stress that can cause,

25:44 I wouldn't say damage, but some, some inflammation in the brain that you would be going through. I think P21 can definitely help with that. Again, I don't notice so much of like it being an anxiolytic, but maybe for people with inflammation that is driving their anxiety, it could be something cool too. So it's really cool, again, not something that it is going to turn your brain into a supercomputer, But it definitely will help. And I with repeated periodic use throughout the year, you will probably notice benefits to your long-term.

26:14 But that's it for this one. If you guys have used PB21 and you're watching this on Spotify, leave in the comments. It just helps the community there. And I would love to hear any of the feedback you have on this because again, I don't know of anyone else talking about this. So hopefully this gets the word out there and more people start to talk about it. More people get accustomed to it, more, people use it and see the benefits. With that in closing, thank you so much. My heart goes out with gratitude to you, guys. I truly have the best career slash job in the world to get to do this. I get excited every day to bring these messages to you and hopefully that comes through in material, but I don't exist without you guys.

26:48 So whether you like comment, subscribe, help share the video with friends or family, use my code at places, whatever shape or form it is. Thank you so much. And obviously too, if you're in my private group, thank you. That is what helps drive me and helps make this possible.