Peptides: The Ultimate Body Hack?
Peptides: The Ultimate Body Hack?
Science Vs podcast
Peptides are Everywhere Right Now
Hi I'm Wendy Zukerman and this is Science Vs. The show that pits facts against internet PHENOMENA… today on the show.. PEPTIDES
Here are the top five peptides I'd recommend to glow up before summer and flex on your ex, respectfully.
You know that peptides are everywhere right now.
Peptides! You want to know more about peptides? Look at my stash. I'm really into peptides.
Peptides are huge right now. No matter what you are struggling with – an annoying injury that won't heal?? Belly fat that's pissing you off? Low energy? Gut issues?? There is a peptide for you. People are buying this stuff off the internet, injecting themselves with it – saying it's life changing
I have never been this confident, felt this good, looked this good. You wanna be on these.
For the uninitiated there's many different peptides that people are injecting –but one of the biggest and most popular is called BPC 157. It's a fan favourite of Joe Rogan. Andrew Huberman has injected it into his back… People often take it alongside another peptide in what's known as the Wolverine Stack… not so much because it makes you hairy - I wish! - but because it's supposed to help heal injuries fast
There's one peptide that seems to be good for everything, and that's BPC-157.
BPC 157 it’s primarily known for healing … but it has a massive ability to heal your gut as well
GB: It's so effective, I can't even begin to tell you
Another popular peptide out there is called MOTS-c - folks on it are saying they're losing weight, getting energy and they reckon it's even going to make them live longer.
There’s a peptide that works like a workout you never actually did and it’s called MOTS-c
You are leaner, you are more vascular, and your muscle definition is better.
My eyes are open, my brain is firing, I am so clear
Guys, it's like you have ... unlimited energy.
But not everyone is so excited about peptides… There are the peptide heretics. That say … you are injecting what now??? This is a BAD and potentially dangerous idea… that could apparently increase your risk of cancer
"Those peptides are gonna kill you!" Those peptide are gonna KILL YOUUUUUUUU
What are you even doing and where did this come from? And who told you this was a good idea?
Every time I log in there's another influencer in my feed raving about some compound they probably heard about on a podcast three weeks ago.
A podcast?! Who me?! Today on the show – Can peptides heal you??? Will they really put a pep(tide) in your step? And the truth is that away from the internet hype there is actually a potential revolution happening in medicine around peptides. So today on the show – we are going to find out
When it comes to peptides there's a lot of
And then there's Science…
Science Vs peptides is coming up! After the break
BREAK
What are peptides?
Welcome back, today on Science Vs: peptides. And the first thing you have to know is what on earth they are. Peptides are short chains of amino acids strung together, you can think of them as small proteins, in fact some scientists call them "microproteins". There's thousands of peptides in your body and some do very important things – like insulin ... That is peptide. Another peptide?
GLP-1s. The blockbuster weight loss drugs. They mimic an important peptide in our bodies that regulates blood sugar and helps make us feel full[1]
The peptide revolution in medicine
So peptides are real things in science – but to know more about the current hype… and what scientists are pumped about here… we need to meet this guy[2]…
HC Hey there.
WZ: Hi.
HC My name is Hassy Cohen.
Hassy Cohen is a Professor of Gerontology at the University of Southern California[3].
and he thinks we're at the cusp of revolution when it comes to peptides. And to understand why … we need to go back... to a time when you felt like you were personally victimized by Regina George … Lose My Breath by Destiny's Child is playing on your MySpace page… Maroon 5 isn't quite so irritating.. and the human genome has just been decoded... That's right. It's 2004. An international team of researchers announces that after 13 years… they've found all the genes hidden in our DNA…
And if you need some biology 101, genes are instructions that tell your body to make proteins, like hemoglobin, or collagen…and Hassy remembered finding out just how many genes there were in the human body [4].
HC People said there are 20,000 genes. That's it. And they do everything, which I always found to be a little bit mysterious. I didn't really think this could be true.
Hassy figured – humans are so complicated, some 20,000 genes?! To make EVERYTHING in your muscles, bones, brain, eye ball, sphincters .... Even at the time - one headline said this was "unexpectedly low"[5] And back then, there were clues that there's more to us than that. So when you look at our entire DNA… you roll it out like toilet paper… Those 20,000 genes are a tiny fraction of the roll.
HC: They're 3% of the DNA. 97% of the DNA[6] until 20 years ago, they used to refer to as Junk DNA.
WZ: Ah! That's where these peptides are coming from, the so-called junk DNA?
HC: Many of them[7].
WZ: That’s so cool! Because some of the famous peptides that people know about – Insulin, GLP1s, they're not from junk DNA –
HC: Right
WZ but this new peptide revolution, where we're discovering new, cool peptides – some of those are coming from junk DNA?
HC: Yes yes!
For years that so-called junk DNA – and more generally the parts of our DNA that didn't code for proteins – was like a cipher … that many scientists, including Hassy, were trying to decode… And over years, they worked out that these mysterious chunks in our DNA do loads of important stuff… including -coding for – not big complicated proteins – but little baby proteins… peptides[8].
HC: Nobody expected a small protein to come out of that.
But fast forward to today and Hassy's team has found a bunch of peptides hanging out in weird parts of our DNA. His lab likes to give them Yiddish names
WZ: Please tell me there's one called chutzpah
HC: We don't have chutzpah yet. But we have mensch …
WZ: Mensch?
HC Schlep, schmooze, we have one called Mazel, like Mazel Tov, Putz. … We're just having fun.
Hassy's lab – has found these peptides in what's called our mitochondrial DNA. Mitochondria are known as the powerhouse of our cells, they kinda look like carpet beetle larvae, but what they do is pump out fuel for our body to use for energy. And in humans, different versions of Hassy's mitochondrial peptides have been linked to lowering our risk of various diseases
HC: Alzheimer's[9][10], Parkinson's[11], diabetes, obesity, cancer[12]…
In lab and animal studies these peptides can affect muscle growth, metabolism, oxidative stress, insulin sensitivity and cognition[13]. And we keep finding more peptides, a study published in May this year, found more than 3000 peptides hiding in these mysterious chunks of our DNA, and we're not sure what many of them even do[14].
Hassy is excited that there is this a whole new world of tiny proteins, actors, in the human body that we didn't even know existed …… and he reckons it could change the way we understand some diseases, possibly opening the door to different kinds of medicine[15].
HC And what this microprotein revolution really embodies is the fact that instead of 20,000 genes, we probably have a million genes.
WZ: Wow
HC: Expanding the human genome by two orders of magnitude — that is the revolution.
WZ: Yeah, wow.
HC: That is the transformative change.
Another researcher told me – maybe we're not going to find that many peptides… he thought it's more like 20,000, maybe 30,000… but still!! That's a lot of peptides!
MOTS-c: Should you take it?
And one of the peptides that Hassy's team discovered… has completely bolted into internet fame. MOTS-c. That's right! The peptide from the start of the show – that people are taking to lose weight, and get energy - it's one of the top five peptides that you should try to glow up before summer and flex on your ex, respectfully…. is Hassy's baby[16]
HC MOTS-c is having a moment.
WZ Is having a big mom–
HC And over the last few months, I realized, this is not just kind of a curiosity: Tens of thousands of people are taking MOTS-c.
Now, if you are racking your Yiddish trying to work this one out… It actually from a Hebrew Prayer..
HC: You say, Hamotzi lechem min haaretz[17]
Get it? MOTS-c. So let's get into the science … and find out if you should start taking it. So when Hassy's team first discovered this little peptide, 16 amino acids all stuck together …
HC: We had no idea what it did. And the post-doc who was working on it just started putting it on things and injecting it into mice and, you know, let's see what happens kind of thing.
And one of the things they did ... is put some mice on a high fat diet ... which would usually make them put on weight... and then they injected some MOTS-c into them …
HC: Lo and behold, they did not gain any weight! Instead of gaining weight, like they should on a high-fat diet, they didn't get any weight[18][19][20]. And MOTs-c completely prevented 100% accumulation of fat in the liver of those mice.
WZ: Whoa!
HC: That was a big deal.
Fat in the liver can be dangerous[21] - it can muck up the liver itself, but also lead to things like stroke[22]. So the idea that this peptide could prevent that happening - even when the mice were eating all these calories - was potentially big. The team kept testing it. They gave older mice MOTs-c and they lived longer than the mice on a placebo[23].
HC: You give mice MOTS-c and you put them on a treadmill, they can run a lot longer.[24]
Hassy's team worked out that MOTS-c might protect muscle, by blocking the activity of a molecule that can break down muscle. One study found that in men, having a mutated form of Mots-C increased their risk of type 2 diabetes, and having more visceral fat[25]. Another study found that type 2 diabetics with low MOTS-c had a higher risk of having a life threatening cardiac event.[26] Hassy thought he really had something here.
So he started a company with a friend[27], they raised $80 million and ran a small trial[28] of MOTS-c. They got a people with a high BMI and quite a bit of fat around their liver[29], had them come to a lab.
HC: Four weeks, 20 people, you get injected typically in your tummy subcutaneously. For 30 days.
The people were injected with either MOTS-c or a placebo. And Hassy wanted to know would those getting MOTS-c lose more weight? Would they lose some of the fat around their liver?
Here's what happened. When it came to weight loss and fat around the liver… The MOTS-C group maybe did a little better, but it wasn't statistically significant… They did see some more exciting stuff though. There are these liver enzymes that tend to go up in people with fatty liver…
HC: Those went down. Blood sugar went down, which is great.[30].
And it was pretty safe. The biggest issue is that some people had a bit of skin irritation around the site of injection
HC: Which is not a complete deal breaker, but it was a little bit annoying for the people who used it.
So things were going pretty good. Hassy thought, maybe this would really be a drug. He was starting to dream of larger trials[31]… but soon. A rival peptide entered the field …
HC: Ozempic became the most successful drug in history. It was a weekly drug, and our version of MOTS-c at the time was a daily injection.
Investors told Hassy…
HC: This is not going to make money.
And ultimately, the company folded. But since then Mots-C has taken on a life of its own… you can buy it online - supposedly just for “research purposes” … and inject yourself with it. And people are going bananas for it … Just off the back of a bunch of mouse studies, one small clinical trial… and a whole lot of hype…
HC That created this crazy black market use of MOTS-c. And I've spoken to some people who swear that they see their athletic performance improve on MOTS-c.
WZ: Is that surreal for you? Is it so strange?
MC It is, it is surreal, it is surreal.
People are saying they’re losing fat, building muscle, amping up their energy … Hassy says… sure based on the mice studies he's done… maaaaybe you could make a case here, after all – those mice ran longer on the treadmill… but up against the hype - the research cupboard is pretty bare.
After the break - we go further down the peptide rabbit hole… We'll look into BPC-157… Plus… could peptides really give you cancer?
Coming up.
BREAK
BPC-157: Can it heal you?
Welcome back. Now, let's get into one of the most popular peptides on the market – BPC 157…This is the so-called Wolverine peptide – that people say can help you recover from injuries… fast. So where does it come from… and should you try it?
BPC 157 stands for Body Protective Compound-157… so you know immediately that it was not discovered by Hassy's team. It was isolated from gastric juice in the early 1990s by a Croatian lab[32][33]... And what's curious, is that humans don't make BPC 157, you can't find it in our DNA… so the going theory is that maybe a gut bug makes it[34]??? We don’t know. But the big question is of course can it heal you?
For this I called up Keith Baar[35], a Professor of Molecular Exercise Physiology at University of California Davis, he told me that recently ...
KB So I started getting a lot of emails from people asking me, so I, you know, I inject BPC-157 into my tendons and they're feeling better. You know, this is a magical thing and like, oh, that's really cool. So let's go test it.
Yes! He wanted to see if BPC 157 can heal tendons and ligaments, which can be really difficult injuries to treat. So it would be great if all you needed was an injection… And here's what Keith did. His first step is basically building a little tendon in a lab.
KB: We take cells from people who basically rupture their Achilles, they come to our medical center to get their Achilles tendon repaired. And what we do is we take the little broken piece.
Keith's team takes the roughed up, broken cells of the human tendon, embeds them in a gel … puts it all on a tiny bone-like scaffolding[36], yada yada yada… the cells will start to replicate.
KB They make more cells and so from that one ACL, that one ruptured ACL, I can make about a thousand little engineered human ligaments.
WZ: Wow, that's so cool.
The model will grow to about the size of a toothpick, and then he's ready to test it. His team exposes the tendon to, say, different peptides and sees what happens… And he told me it's often pretty obvious if it's doing something.
KB: If you wiggle it normally, you'll see it move a little bit. If it's stronger, it'll stay nice and stiff. If it's really weak, it will flop around. So you can see that these things — these drugs or these treatments — are really either having an effect on the tissue or they're not.
And they’ve seen this with another peptide, called Insulin-like Growth Factor 1. Some body builders use IGF1 to get stronger – and in high doses it's not safe, it can increase your risk of heart disease[37] and cancer[38], but it's been studied for a long time and it can help build a bit of muscle and make you bigger[39]… In fact, not just you..
KB: So IGF-1? That's the difference between say a Great Dane and a Chihuahua.[40]
WZ Wait, so if you gave a Chihuahua insulin growth factor 1 at a critical point in development —
KB: When it's very, very young and in developing still, it will get bigger and it will become a big Chihuahua, yeah.
But away from the Chihuahua…. what happened when Keith put these peptides on his lab grown tendons?
KB: And so when we treat it with IGF-1, they get stronger[41], but when we did the exact same thing with BPC-157, it had absolutely no effect.
WZ: No effect?!
KB: It wasn't better, but it wasn't worse.
Keith tested BPC 157 a different way, bathing some human cells in it – to see if they replicated faster… And again, it didn't do anything.
This doesn't totally put the kibosh on BPC 157, Keith has just started studying this, he hasn't even published this data yet – wants to keep running tests, and he says just because BPC 157 might not do anything to his tendon in a dish…
KB: It doesn't mean that it doesn't do something when you put it into a body.
So for example, other researchers found evidence in rats and basically petri dish studies, that BPC 157 might promote something called angiogenesis[42]
KB: Or the production or the making of new blood vessels. It's supposed to increase the ability to get blood flow to whatever tissue that you're trying to regenerate.
And Keith says you wouldn’t see new blood vessels popping up on what’s basically a disembodied tendon in a dish… to find out if this peptide really does increase angiogenesis… or more broadly help you heal you need to test it in a human body… Not just in human flesh. So what studies do we have here? Let me tell you. In 2015, a placebo controlled safety trial for BPC 157 was registered on the US Government website for clinical trials… but the results were never published[43]. Another study from 20 years ago...of 46 people with ulcerative colitis, either got a BPC 157 enema, or placebo each day for 2 weeks - and it looked like maybe the BPC 157 group did better overall, but most of the findings were not significant[44].
Then there's a doctor[45] who — by the way — wrote a book called "THE FOUNTAIN OF YOUTH WITH PEPTIDES" , and has a clinic in Florida where he injects people with peptides. He asked 12 of his patients who he'd injected with BPC 157[46] because of their knee pain, do you remember how bad your pain was? And is it better now? 9 out of the 12, roughly 75%, said that 3 months to a year later, the pain was better. We have no idea if the peptide improved their knees, or the passing of time.. which is y'know supposed to heal all wounds.. or perhaps the placebo effect!? I talked about this with Dr. Dhruv Khullar[47], a physician and health policy researcher at Weill Cornell Medicine in New York… who told me the placebo effect can be huge, particularly when it comes to knee pain.
DK: We know placebo effects are very powerful. People who have a fake knee surgery, they have better outcomes.
Yeah. There are studies where doctors give someone an anesthetic… slice them open… stare at the ceiling for a bit and sew them back up… And those patients felt better, to the same degree, as if they'd gotten real surgery.[48]
DK: There are studies that suggest that, you know, the more expensive you think a drug is, even if it's a placebo, the more effective it seems to be for you.[49] And that's true for things like Parkinson's,[50] which you wouldn't expect. In this case, you're going through the trouble of ordering something online. There's a bunch of syringes. It's kind of scary. You inject yourself. It's expensive, it's painful. You really want this to work.
So, if all we've got are some uninspiring studies in people… why are folks online going through all this trouble for BPC 157? Where are all the claims coming from?! It heals your tendons and ligaments… you'll become Wolverine?! Well… it's been used in certain online spaces for a while now, so there's a lot of lived experience, anecdote… whatever you want to call it… But if you're looking for science – all the claims about BPC 157 are from studies in rats. And the vast majority of the studies from this one particular lab-- the lab that first discovered the peptide in Croatia. It's the same lab that's linked to that study from 2015 that never published the results. But for three decades this lab they have published scores of studies where they'll get a rat, cut its quadricep[51] or ligament[52], slice its cornea[53], damage its nerves[54][55]... you get the picture, and then give one group of rats a placebo, while another gets BPC 157. And over and over again this team finds that the rats injected with BPC 157 do better. I called up the professor that heads up the lab
Ring… Ring…
But he wouldn't go on the record to talk – and once I started asking why didn't he publish the clinical trial from 2015, he ghosted me completely.
[Translated Croatian: The user is currently unable to accept the call. Please try again later.]
So that's BPC-157, and like I mentioned, there are other peptides out there that are supposed to help you hulk up and recover faster… But a review paper[56] looking into some of the most popular ones out there… basically concluded: there's no good evidence in humans for this. I spoke to one of the authors of that paper, Dr Cory Mayfield, a resident at the Keck School of Medicine USC.
CM: It was more shocking on that front to learn how little research there had actually been.
WZ: Going in, what did you think you were going to find?
CM: We had thought there would probably be more, at least, evidence supporting the use of these. I don't think there's really any other therapy that we see that has less evidence that's more used.
So here's where we are at. Online you'll read about and see these amazing stories … of people juicing up with peptides and healing so quickly from injuries, popping with muscles, having all this energy … but if you're looking for scientific evidence that the peptides are doing that magic, not the placebo … you're going to be bitterly disappointed. As I kinda was…
What are the risks?
But this takes us to the last question of the episode… what are the risks? If you've got some knee injury, or you want to build extra muscle fast… and want to give this stuff a go… are there any downsides?
Well if you try this - you will be injecting yourself. So you need to be careful, because you could get a nasty infection. And there is the odd case report of bodybuilders using unclean needles to inject steroids and getting infected with Hepatitis C[57][58], or HIV[59]. And on Reddit you'll see people injecting themselves with peptides, some body part swelling up like mad… and needing antibiotics.[60] Also, if you're giving yourself repeated injections you also need to worry about lipohypertrophy - which is a build up of fatty, rubbery lumps under the skin[61]. Away from needles another issue is… how do you know what's in the vial? Right now, in the US you can't buy a lot of these peptides at a pharmacy, you get them online… And Dr Dhruv Khullar[62], the physician at Weill Cornell Medicine in New York, recently bought some peptides to find out exactly what was in them. It was for an article he wrote for the New Yorker[63]. Oddly, on one of the peptide websites, they gave him a little bonus.
DK: And when I was checking out, they just a dded 30 capsules of this synthetic hormone called demoxytocin[64] for no reason, which, you know, doctors usually use for inducing labor or treating postpartum bleeding.
WZ: WHAT?!
DK: And just like, here, you might, some other drugs you might like, I guess.
No matter, within a week, the peptides started arriving.
WZ: What did it look like when it arrived?
DK: Oh, it was just, it's usually just a white powder. You know, it looks maybe like some flour or cocaine. You know, depending on what you're most familiar with.
WZ: Yeah! Dhruv, I didn't know you'd make that joke. I was ready to make it, but you got in there out in front of me.
DK: All right
He took the peptides into a lab that tested what was inside. The results found that one of the vials had the right peptide at the right dose. Another vial contained endotoxins – bits of bacteria, possibly from contaminated water in the manufacturing process, another had less than half the advertised dose. And?
DK: I got one vial with lead in it. I prefer my medications without lead.
Yes, lead - and then people would be injecting it into themselves — not great. This is, of course, just Dhruv's experience; maybe he got unlucky. We don't have studies analysing what's contained in the peptides people are buying online – researchers are on the case – but we do have studies on a similar illicit market: anabolic steroids[65]. One Australian study of more than 100 samples, found that 22% were mislabelled.[66]. And they could also be contaminated with heavy metals in them – from lead to arsenic[67]. I asked Dhruv what the lab he tested his peptides in was seeing.
WZ: Broadly what did they tell you about how many of the peptide samples that they tested have issues?
DK: They estimated between 10% to 20% of the samples had significant issues, dosing or purity. When you're ordering these unapproved drugs online, you don't really know what you're getting.
WZ: It's just like a box of chocolates.
DK Exactly, exactly.
Basically right now – in this unregulated market - these peptides are coming from factories… where the quality control is not up to snuff. This may change in the US soon, the FDA is meeting in July to talk about letting compounding US pharmacies[68][69] make a handful peptides - including Mots C and BPC 157[70] - and sell them directly to the public — of course that won't make them effective, just less likely to have lead in them… But there is one more risk that we need to talk about and that is around cancer. Like I mentioned, some peptides are supposed to work by encouraging blood vessels to grow…. and this in theory could increase your risk of cancer, because giving cancer cells a blood supply – gives them the nutrients to survive and spread.[71] I talked about this with Dr. Cory Mayfield.
WZ: I know, anyone who would have had a scan for some weird thing in their body. One of the tests for — is that weird thing cancerous? — is: are there blood vessels around it or not?
CM: Correct. Yeah, that's the main thing we look for is, you know, is it getting blood? Is it new blood? That's like, is it pulling in its own blood supply? And that's what we worry about.
We don't know for sure if it is a risk – or even if some of these peptides increase angiogenesis in the first place – but the thing is that if the peptides actually do what people are saying they can – if they can modulate your body in all these different exciting ways, they probably will have some side effects. I mean think of the peptides that we have good research on … GLP-1s for example – they work really well – but if you're losing a tonne of weight, you need to worry about muscle loss, and they can also cause nausea and diarrhea, and rarely, gut paralysis"[72]… IGF 1, like I mentioned, can increase your risk of cancer[73] and heart disease.
None of the doctors and researchers you heard from in this episode – Dhruv, Cory, Keith and Hassy - inject themselves with peptides. I talked to Hassy about why he's not injecting MOTs C
HP: And let me say that I am coming of age and I'm very worried about my muscle loss, my sarcopenia. I'm worried about this. If MOTS-c was approved, I would take it right now. Will I ever take it? I don't know. At the moment, I'm not taking it.
WZ: Why not?
HP: Because I don't trust I don't trust the stuff that people are taking out there. I don't know where they're getting it, how it's mixed, how it's prepared.
WZ: But you could, you could act- you're one of the few people out there that could actually get MOTs-c and know you're getting MOTS-c, but you still don't take it.
HC: It's true, it's true.
WZ: Why not?
HC Because I'm an old-fashioned traditional guy. And you know, when you're raised with values as a physician-scientist, you know, all the supplement universe is something that you really disrespect. And the majority of the supplements is a multibillion-dollar business. Almost all of them don't work. And I've always said to myself, why are people doing it? They don't know, there's no evidence. So I come from a place of a traditional, old-fashioned physician-scientist who believes there's a right way to do it and a wrong way to it.
And while I get the impulse to want to be your best self, I know how frustrating it is when injuries take a long time to heal, and I also think the potential peptide revolution happening in science-land is super cool… But injecting yourself with stuff some influencer – or worse, podcaster - is selling you online…as Hassy would say – it's the wrong way to do it. I guess I'm old fashioned too…
That's Science Vs.
This episode has 73 citations
This episode was produced by me, Wendy Zukerman, with help from, Rose Rimler, Ekedi Fausther-Keeys, Meryl Horn and Michelle Dang. We’re edited by Blythe Terrell. Fact checking by Diane Kelly. Video editing and sound mix by Bobby Lord. Music written by Bumi Hidaka, Peter Leonard, Emma Munger and Bobby Lord. Thanks to the researchers I spoke to for this episode including Dr Dana Lis, Dr Pouya Faridi and Dr Timothy Piatkowski, as well as the Australian science media centre. A big thanks to Joseph Lavelle Wilson and the Zukerman family.
Science Vs is a Spotify Studios Original. Listen for free on Spotify or wherever you get your podcasts. Follow us and tap the bell for episode notifications.
[1] GLP-1 (glucagon-like peptide-1) is a hormone naturally produced in the gut after eating. It helps regulate blood sugar by stimulating insulin, suppressing glucagon, and slowing digestion. Pharmaceutical versions amplify these effects, reducing appetite and promoting satiety, or a feeling of fullness.
[3] https://gero.usc.edu/faculty/cohen/ Research: The emerging science of mitochondrial-derived peptides including, 1. humanin, a peptide encoded from the mt-16S-rRNA which is a novel, centrally acting, insulin sensitizer and metaboloprotective factor representing a new therapeutic and diagnostic target in aging, diabetes and related disease. 2. MOTS-c, a second peptide encoded from a small ORF in the 12S region of the mitochondrial chromosome, that has potent anti-diabetes and anti-obesity effect, acting as an exercise-mimetic. 3. SHLP2, a peptide encoded from the light strand of the mt-16S-rRNA region whose levels correlate with prostate cancer
[4] 2004: The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. …The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000-25,000 protein-coding genes.
[6] Despite how useful this coding sequence is, it only makes up about 2% of the total DNA in a cell. The remaining 98% of the DNA is noncoding sequence and is interspersed within and between genes.
[7] Small open reading frames (small ORFs/sORFs/smORFs) are potentially coding sequences smaller than 100 codons that have historically been considered junk DNA by gene prediction software and in annotation screening; however, the advent of next-generation sequencing has contributed to the deeper investigation of junk DNA regions and their transcription products, resulting in the emergence of smORFs as a new focus of interest in systems biology. Several smORF peptides were recently reported in non-canonical mRNAs as new players in numerous biological contexts;
[9] Utilizing an APOE4‐centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin.
[11] SHLP2 (small humanin-like peptide 2) is a newly discovered MDP that is coded from the MT-RNR2 (Mitochondrially encoded 16S rRNA) gene in mitochondrial DNA (mtDNA)
[12] Described here https://pmc.ncbi.nlm.nih.gov/articles/PMC9057581/
[13] After the discovery of humanin, seven additional mitochondrial microproteins were identified. Six of these, named small humanin-like peptides 1 to 6 (SHLPs 1–6), are encoded from the 16S rRNA region and share some biological features with humanin (60). For example, SHLP2 protects cells from amyloid β–induced toxicity and age-related macular degeneration (61). SHLP2 also has been characterized as a chaperone, because it bound IAPP species and blocked amyloid seeding (62). This chaperone-like activity might link its cytoprotective roles, suggesting that SHLP2 has potential as a metabolic therapeutic. Moreover, administration of SHLP2 and SHLP3 promotes mitochondrial biogenesis, reduces reactive oxygen species, and decreases mtDNA oxidation (60). Unlike these cytoprotective SHLPs, SHLP6 was shown to induce apoptosis in multiple cell lines (60). Much remains to be learned about the mechanisms of these SHLPs through future experimentation.
[14]Overall, we found 3,116 peptides mapping to 1,785 out of 7,264 Ribo-seq ncORFs (24.6%).This indicates that peptides produced from ncORF-encoded microproteins are most often sourced from the intracellular pool of protein translation products and are less likely from extracellular sources, in contrast to canonical proteins
[15] their promise to advance medical science is manifested in their contributions to the genetic basis of disease, mechanisms of cancer biology, and cancer-restricted and HLA-presented cryptic antigens targetable by immunotherapy.
[16] Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis.
[18] Here we report a sORF within the mitochondrial 12S rRNA encoding a 16 amino acid peptide named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA -c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat diet-induced insulin resistance, as well as diet-induced obesity….Although MOTS-c treatment had no effect on body weight in mice fed a normal diet, it remarkably prevented obesity when administrated to mice fed a HFD (Figure 6A). This difference in body weight was not attributed to food intake, as caloric intake was identical between the groups (Figure 6B-C). Additionally, MOTS-c treatment prevented HFD-induced hyperinsulinemia, indicating improved glucose homeostasis (Figure 6D-E). Hepatic lipid accumulation was dramatically reduced in HFD-fed mice treated with MOTS-c (Figure 6F).
[19] MOTS-c was first described as an exercise mimetic peptide because it prevented weight gain in mice with high-fat diet–induced obesity, improved insulin sensitivity, and increased exercise capacity in both obese and old mice
[20] High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. (The effect was not seen in female mice).
[22] Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and affects a considerable proportion of the general population. NAFLD is independently associated with increased risk for cardiovascular events, particularly coronary heart disease. Importantly, even though NAFLD is more prevalent in patients with major cardiovascular risk factors (e.g., type 2 diabetes mellitus, obesity and hypertension), the association between NAFLD and cardiovascular disease appears to be independent of these risk factors. However, NAFLD also appears to increase the risk for ischemic stroke, a leading cause of mortality and long-term disability worldwide.
[23] Ultimately, LLII (late life intermittent) MOTS-c treatment showed a trend towards increased median (6.4%) and maximum (7.0%) lifespan and reduced hazard ratio (0.654); P = 0.05 until 31.8 months (Fig. 4m). Larger cohorts will be needed to confirm the broader significance of MOTS-c treatment on overall longevity. These data suggest that LLII MOTS-c treatment improves overall physical capacity in old mice and may compress morbidity and increase healthspan.
[24]A treadmill running test confirmed that MOTS-c treatment can enhance physical performance. Because MOTS-c is a regulator of metabolic homeostasis that prevented high-fat diet (HFD)-induced obesity and insulin resistance, we tested if MOTS-c also improved running performance under metabolic (dietary) stress. We fed young mice (CD-1) a HFD (60% calories from fat) and treated them with 2 doses of MOTS-c (5 and 15 mg/kg/day; IP; Supplementary Fig. 3a). Mice on the higher dose of MOTS-c showed significantly superior running capacity (Fig. 2a–c) and power output (joules; Supplementary Fig. 4a) following 10 days of treatment, but not following 7 days of treatment (Supplementary Fig. 5a). Notably, 7 days of MOTS-c treatment significantly improved skeletal muscle insulin sensitivity in young and older C57BL/6J mice also fed a high-fat diet. We progressively increased the treadmill speed to test both endurance and speed. The final stage, which required mice to sprint (23 m/min), was reached by 100% of mice on the higher dose of MOTS-c, but only 16.6% in the lower dose and control (vehicle) groups (Fig. 2d).
[25] Here, we elucidated the association between T2D and m.1382A>C in Japanese individuals and established the abnormal biological effects of the K14Q MOTS-c peptide variant – a consequence of the m.1382A>C polymorphism – on insulin action and adiposity in vitro and in vivo….K14Q MOTS-c has a dramatically diminished action as an insulin sensitizer compared to WT MOTS-c….Meta-analysis of the three cohorts showed that the m.1382A>C polymorphism significantly increases the prevalence of T2D (p < 0.01) in males but not in females …we found that MOTS-c SNP carriers exhibited significantly higher visceral fat compared to controls matched for age and BMI (p < 0.05, Figure 4A). This result suggests that the MOTS-c polymorphism could lead to abdominal obesity and participate in the pathogenesis of T2D in East Asians.
[27] CohBar Inc.(was) a biotechnology company focused on the research and development of mitochondria-based therapeutics (MBTs) to treat age-related diseases and extend healthy lifespan. The company works on discovering and developing novel peptides encoded within the mitochondrial genome, which have the potential to regulate various biological processes and address a wide range of age-related conditions such as obesity, type 2 diabetes, cancer, and cardiovascular and neurodegenerative diseases. CB4211 recently completed phase I clinical trials as a treatment for obesity. Joseph J. Sarret MD, JD, is the current CEO.
[28] Part C https://clinicaltrials.gov/study/NCT03998514 Part C is a randomized, double blind, placebo controlled, multiple dose, parallel group study evaluating the safety, tolerability, PK, and PD of once daily SC doses of CB4211 over 28 days in subjects with NAFLD….CB4211 Dose TBD (N=10) Placebo (N=10) Subcutaneous injection once daily for 28 days
[29] Part C Inclusion Criteria: Body mass index ≥30.0 kg/m2, and body weight ≤115 kg at Screening; History of Fatty Liver Index (FLI) score >60, FLI score >60 at Screening, or documented history of fatty liver with imaging results (eg, standard positive ultrasound or Fibroscan controlled attenuation parameter (CAP) >300 decibels (dB)/m) indicating liver fat >10% within 6 months of Screening. A formal diagnosis of nonalcoholic fatty liver disease (NAFLD) is not required; Liver fat content ≥10% as determined by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) within 14 days prior to Check in. One repeat Baseline MRI-PDFF will be allowed if the first value is below 10%, but greater than or equal to 9.5%; Glycosylated hemoglobin A1c <7.0 % at Screening.
[30] CB4211, a Novel Analog of MOTS-c, Improves Markers of Liver Injury and Metabolism in Obese Subjects with Nonalcoholic Fatty Liver Disease: a Multicenter, Double-Blind, Randomized, Placebo-Controlled Study. Poster presented at AASLD The Liver Meeting
[32] Body Protective Compound-157 (BPC-157) in the context of musculoskeletal healing… Originally isolated from human gastric juice by Dr. Predrag Sikiric in 1993, BPC-157 has demonstrated regenerative properties in animal models, promoting the healing of tendons, ligaments, muscles, nerves, bones, teeth, corneas, and the endothelium
[33] A new gastric juice peptide, Mr 40 000, named BPC, was recently isolated. Herein, a 15 amino acid fragment (BPC 157), thought to be essential for its activity, has been fully characterized and investigated
[34] BPC 157 is a pentadecapeptide with the amino acid sequence of Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val and a molecular weight of 1419.55 daltons, which was first introduced and described by Sikiric and colleagues in 1993 [27]. Although it was isolated as part of the peptide from human gastric juice [28], it shows no sequence homology with known intestinal peptides [29]
[35] The goal of my laboratory is to understand the molecular determinants of musculoskeletal development and the role of exercise in improving health and performance. To achieve this goal, we work on muscle, tendon, and ligaments from 2- and 3-dimensional tissue culture, in vivo wild type and genetically modified animals, and humans.
[36] The goal of this work was to rapidly engineer ligament equivalents in vitro that contained both the soft tissue sinew and a hard tissue bone mimetic. This goal was achieved using cast brushite (CaHPO4·2H2O) anchors to mimic bone and a fibrin gel embedded with fibroblasts to create the sinew. The constructs formed within 7 days.
[37] https://pubmed.ncbi.nlm.nih.gov/36810801/ In this large prospective study using a nationally representative sample from UK Biobank, we found that both low and high serum IGF-1 concentrations were nonlinearly associated with increased risk of incident CVD and mortality.
[38] https://pmc.ncbi.nlm.nih.gov/articles/PMC2987015/ Higher IGF1 circulating levels significantly increased 15% of cancer risk (odds ratio (OR), 1.15, 95% confidence interval (CI), 1.03–1.29), especially among prostate, pre-menopausal breast and colorectal cancer patients, whereas higher concentrations of IGFBP3 significantly decreased the risk of advanced prostate cancer by 56% (OR, 0.44, 95% CI, 0.25–0.77).
[39] https://pmc.ncbi.nlm.nih.gov/articles/PMC4665094/ / It's not dramatic though: https://www.health.harvard.edu/diseases-and-conditions/growth-hormone-athletic-performance-and-aging "We found that although growth hormone significantly increased lean body mass and was associated with a near-significant trend toward decreased fat mass, it did not result in gains in biceps and quadriceps strength."
[40] https://www.science.org/doi/abs/10.1126/science.1137045 we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs….
[41] The effect of IGF-1 and rapamycin was determined independently and interactions between the two treatments were tested. Grafts were treated for 6 days before mechanical testing and analysis of collagen content. Following 8 days of treatment, mechanical properties increased 34% with IGF-1 and decreased 24.5% with rapamycin. Similarly, collagen content increased 63% with IGF-1 and decreased 36% with rapamycin.
[42] As demonstrated by the chick chorioallantoic membrane (CAM) assay and endothelial tube formation assay, BPC 157 could increase the vessel density both in vivo and in vitro, respectively. BPC 157 could also accelerate the recovery of blood flow in the ischemic muscle of the rat hind limb as detected by laser Doppler scanning, indicating the promotion of angiogenesis. Histological analysis of the hind limb muscle confirmed the increased number of vessels and the enhanced vascular expression of vascular endothelial growth factor receptor 2 (VEGFR2) in rat with BPC 157 treatment.
[43] In 2015, a Phase I clinical trial conducted on 42 healthy volunteers (both sexes, aged 18–35 yrs.) was started. This study aimed to determine the safety and pharmacokinetic profile of the BPC 157 peptide (NCT02637284) [105]. Unfortunately, in 2016, the researchers cancelled submission of the results./ More details here / https://undark.org/2026/02/03/bpc-157-peptide-fda/
[44] N= 46 Unlike placebo, PL 14736 induced a statistically significant decrease of the DAI at the end of a 2-week treatment period. The mean change of the DAI was -3.2 points (95%CI –5.58, -0.82) in the PL 14736 group and –1.6 (95%CI -3.86, 0.67) in the placebo group. The estimated difference between groups was 1.6 points(95%CI –4.84, 1.62). The single components of the DAI showed no significant differences between the treatment groups, however, there was a favorable trend for PL 14736, which
in contrast to placebo reduced the mean stool frequency, improved stool consistency, and had beneficial effects on histopathological findings.
[46] https://pubmed.ncbi.nlm.nih.gov/34324435/ 2021 Patients were asked to rate their pain prior to injection, the length of time the peptides helped ease the pain and the degree to which the injection helped them. No specific tools were used to measure their improvement in function, quality of life, stiffness or activities of daily living. The survey's main goal was to determine whether BPC157 helped with multiple types of knee pain in a primary care setting.
[48] A total of 180 patients with osteoarthritis of the knee were randomly assigned to receive arthroscopic débridement, arthroscopic lavage, or placebo surgery. Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope. Patients and assessors of outcome were blinded to the treatment-group assignment. Outcomes were assessed at multiple points over a 24-month period with the use of five self-reported scores — three on scales for pain and two on scales for function — and one objective test of walking and stair climbing. A total of 165 patients completed the trial. At no point did either of the intervention groups report less pain or better function than the placebo group (all reported drops in pain scores - Table 2).
[51] Regularly, quadriceps muscle completely transected transversely 1.0 cm proximal to patella presents a definitive defect that cannot be compensated in rat. BPC 157 (10 µg, 10 ng, 10 pg/kg) is given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice. It consistently improves muscle healing throughout the whole 72-day period.
[52] After MCL transection BPC 157 was effective in rats when given once daily intraperitoneally (10 microg or 10 ng/kg) or locally as a thin layer (1.0 microg dissolved in distilled water/g commercial neutral cream) at the site of injury
[53] We made a penetrant linear 2-mm incision in the paralimbal region of the left cornea at the 5 o'clock position with a 20-gauge MVR incision knife at 45° under an operating microscope. Medication was BPC 157 (2 pg/mL, 2 ng/mL, and 2 μg/mL distilled water, two eye drops/left rat eye) immediately after injury induction and then every 8 h up to 120 h; controls received an equal volume of distilled water. In contrast to the poor healing response in controls, BPC 157 significantly accelerated the healing process in 2 μg and 2 ng BPC 157-treated eyes,
[54] (Sci Hub) We focused on the healing of rat transected sciatic nerve and improvement made by stable gastric pentadecapeptide BPC 157 (10 microg, 10ng/kg) applied shortly after injury (i) intraperitoneally/intragastrically/locally, at the site of anastomosis, or after (ii) non-anastomozed nerve tubing (7 mm nerve segment resected) directly into the tube. Improvement was shown clinically (autotomy), microscopically/morphometrically and functionally (EMG, one or two months post-injury, walking recovery (sciatic functional index (SFI)) at weekly intervals). BPC 157-rats exhibited faster axonal regeneration
[55] Therefore, BPC 157 therapy was administered by a one-time intraperitoneal injection (BPC 157 (200 or 2 μg/kg) or 0.9% NaCl (5 ml/kg)) 10 min after injury. The injury procedure involved laminectomy (level L2-L3) and a 60-s compression (neurosurgical piston (60–66 g) of the exposed dural sac of the sacrocaudal spinal cord).
[56] A comprehensive literature search was conducted using PubMed to identify biochemical and clinical studies on the most popular types of injectable peptide therapy. Key peptides evaluated included BPC-157, TB-4, TB-500, CJC-1295 + ipamorelin, tesamorelin, and GHK-Cu.BPC-157 demonstrated potential benefits in tendon and muscle repair, but these findings are largely unvalidated in human trials.
[57] https://pubmed.ncbi.nlm.nih.gov/11841901/ To measure exposure to the hepatitis C and B viruses and HIV among Victorian steroid injectors and evaluate associations between exposure and risk behaviour, and report other characteristics of the study group….Hepatitis C virus exposure was associated with heroin injection, imprisonment, sharing needles to inject other drugs, number of tattoos, and hepatitis B virus exposure. No significant differences existed in the steroid-related risk behaviour of exposed and non-exposed individuals. Hepatitis B virus exposure was associated only with hepatitis C virus exposure, past imprisonment and age of first injection.
[58] One hundred and forty-nine participants who had injected anabolic steroids in the previous month were identified from 1991-6, contributing 1.4% of all participation episodes in the survey. Rates of needle and syringe sharing by steroid users were low. Three of the 149 (2.0%) had anti-HBc and none had anti-HIV in their salivary specimens. The prevalence of anti-HBc in steroid injectors was significantly lower than in heroin injectors, 275/1509 (18%) (P < 0.001), or in amphetamine injectors, 28/239 (12%) (P < 0.001). The risk of blood borne virus transmission amongst these steroid injectors is low, probably due to hygienic use of injecting equipment and low levels of sharing. It is important to distinguish steroid injectors from other IDUs because they are a distinct group in terms of lifestyle and injecting practice.
[59] We report a case of acquired immunodeficiency syndrome (AIDS) virus transmission by intramuscular injection. A 26-year-old white male bodybuilder requested tests for AIDS. He was asymptomatic but said that for the past 3 years he and a fellow bodybuilder had been taking black-market anabolic androgenic steroids in cycles. To administer the intramuscular injectable steroids, primarily testosterone cypionate and testosterone proprionate, they shared a hypodermic needle on approximately 60 occasions without sterilization. No other individuals used their needle or syringe.
[60] https://www.reddit.com/r/bpc_157/comments/16pd7zn/bpc157_pain_swelling/ / https://www.reddit.com/r/bpc_157/comments/1dpve08/swelling_post_injection_help/
[62] Associate Professor of Population Health Sciences, Population Health Sciences , Weill Cornell Medical College 2024 -
[63] https://www.newyorker.com/magazine/2026/04/13/why-are-people-injecting-themselves-with-peptides Health and wellness influencers are hawking unapproved treatments on the gray market. The future of the F.D.A.—and the health of consumers—is at stake.
[65] 80% of AAS seized from French bodybuilders were incorrectly labelled: All dietary supplements and pharmaceuticals seized from the black market and addressed to the laboratory for a qualitative and quantitative analysis between January 2016 and December 2019 were included in the study. A screening was carried out by gas chromatography-mass spectrometry and liquid chromatography-high resolution mass spectrometry….Among the pharmaceuticals, 25/75 (33%) were substandard (dosage not on the acceptable range defined for original products), 24/75 (32%) were counterfeit (qualitative formulation does not match the label) and 14/75 (19%) were original (qualitative formulation and levels of active ingredients fully matches the declared formulation. The analysis of the 12 remaining products revealed a correct qualitative content for 11/75 (15%), but quantitation could not be carried out because of the lack of reference standards at the time of the analysis. Fifty-four pharmaceuticals contained anabolic-androgenic steroids (AAS). Four out of 54 (7.4%) AAS were found as original, 8/54 (15%) could not be quantified (one with wrong active ingredient), corresponding to 43/54 (80%) AAS being non-original.
[66] As part of Wave 3 of a Steroid Testing Trial (2024), community members in Queensland, Australia, submitted AAS samples for laboratory analysis. Using advanced forensic techniques, we tested these samples for compound presence and dosage accuracy….Of 105 AAS samples analysed, 22% were mislabelled and 50% were underdosed.
[67]Analysis of 28 AAS samples (16 injectable, 10 oral, 2 raw powders) revealed that 15 samples were mislabelled or mis-sold. When considering the 21 samples with clearly defined expected labelled dosages, 4 of these were within a ±5% deviation of the expected purity. Twelve heavy metals were detected in injectable and oral products, with mean concentrations ranging from 0.07 to 62.54 μg/mL in injectables and 1.94–47,901 μg/g in orals….The current study also revealed heavy metal contamination in all product types. Although metal contamination is well documented in supplements [18, 19], it remains largely overlooked in AAS.
[68] Compounded drugs are not FDA-approved. This means the agency does not review their safety, effectiveness or quality before they are marketed. Compounded drugs can serve an important medical need for patients. However, if a compounded drug does not meet appropriate quality standards – such as if a drug is contaminated or contains too much active ingredient – it could cause serious injury or death. Additionally, the labels on compounded drugs may not include important information such as adequate directions to help ensure the drugs are used safely. The agency seeks to strike a balance between preserving access to lawfully-marketed compounded drugs for patients who have a medical need for them while protecting patients from the risks associated with compounded drugs that are not produced in accordance with applicable federal law.
[69] State-licensed physicians and pharmacists that compound under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) may only compound drug products using bulk drug substances that:
In addition, bulk drug substances must be accompanied by a valid certificate of analysis and must have been manufactured by an establishment registered with FDA under section 510 of the FD&C Act.
[70] On July 23, 2026, the Committee will discuss the following bulk drug substances being considered for inclusion on the 503A Bulks List: BPC-157-related bulk drug substances (BPC-157 (free base)/ BPC-157 acetate), KPV-related bulk drug substances (KPV (free base)/ KPV acetate), TB-500-related bulk drug substances (TB-500 (free base)/ TB-500 acetate), and MOTs-C-related bulk drug substances (MOTs-C (free base)/ MOTs-C acetate). The chart below identifies the use(s) FDA reviewed for each of the bulk drug substances being discussed at this advisory committee meeting.
[71] As BPC 157 has been found to stimulate angiogenesis [14,85], this is likely to have some undesirable consequences. Angiogenesis is a well-known four-stage process of new blood vessel formation that occurs in healthy individuals (e.g., during the menstrual cycle or muscle growth) but also in immune diseases [106]. Although the proper development of the vascular network enables gas exchange and transport of metabolic products in the organs, angiogenesis also occurs in many pathological conditions [107]. This also applies to cancer, as the formation of blood vessels during carcinogenesis enables oxygen supply to the tumor and enhances its proliferation, diffusion, and metastasis
[72] The most common side effects of GLP-1 agonists include: Loss of appetite, Nausea., Vomiting, Diarrhea.
[73] Higher IGF1 circulating levels significantly increased 15% of cancer risk (odds ratio (OR), 1.15, 95% confidence interval (CI), 1.03–1.29), especially among prostate, pre-menopausal breast and colorectal cancer patients,