35% Off Limitless (Code EP20) + Your Blood Is Making Anti-Aging Molecules 🧬

Happy Tuesday, Friends! 👋

I've been buried in papers for the last couple of weeks, and honestly, some of what's come out in the last year is the most interesting stuff I've read since I started this newsletter. Three things today: a Limitless sale, some bad news on the YouTube front, and eight papers that are worth your full attention.

All the studies are listed below, and every one of them is linked. If you want to go read the full papers yourself, just click straight through.

Let's get into it.

Limitless has a sale running right now, up to 35% off with code EP20. It's on select items, not sitewide, but they've put a genuinely large chunk of the catalog on sale, way more than "select items" usually means with these guys.

They've also got some unique stuff you don't see everywhere, capsules, nasal sprays, and more. And they've been a vetted vendor in this community for close to 9 years now, so if you've been on the fence about trying them, this is a good excuse.

🎟️ Code EP20 at checkout for the discount.

Research Use Only! ⚠️

Not the update I wanted to write, but here it is straight: our YouTube channel is gone. We appealed, no dice, that's it, permanently deleted. That sucks, plain and simple, especially with how much video we had built up there.

We're working on a self-hosting solution so we're never at the mercy of a platform like that again, but that's going to take some time to build properly. In the meantime, we're posting video on X/Twitter and Rumble instead, and hoping there's a bit more free speech runway on both of those than there was on YouTube.

So if you want the videos, follow us there:

The paper: A pathway to next-generation mast cell stabilizers identified through the novel Phytomedical Analytics for Research Optimization at Scale data platform, Jansen, Rice, Wooton et al., Chaminade University and University of Hawai'i.

What a mast cell stabilizer actually is: a drug that stops mast cells from dumping their contents in the first place, which is a completely different job from what an antihistamine does.

Simply explained: imagine a mast cell is a water balloon filled with a hundred different things that make you feel awful. An antihistamine is a towel, it mops up one of the things that spilled out. A mast cell stabilizer makes the balloon harder to pop, so nothing spills in the first place. That's why stabilizers matter so much for complex cases, they address the whole mess instead of one puddle.

The problem the authors call out: the stabilizers we actually have are frustrating. Cromolyn sodium, nedocromil, ketotifen, tranilast. The authors say plainly that these are held back by poor bioavailability (your body barely absorbs the drug, so most of what you take never gets where it needs to go), frequent dosing, long lags before you feel anything, and what they call enigmatic mechanisms of action.

Simply explained: we've been using cromolyn since the 1960s and we still don't fully know how it works. It just does, sort of, sometimes. That's a wild thing to admit about a drug that's been in clinics for sixty years, and it's exactly why building a better one has been so hard.

What they did: here's the cool part. Cromolyn didn't come from a lab, it came from a plant. It's a modified version of khellin, from Ammi visnaga, the khella seed, which Middle Eastern, African and Indian medicine used for asthma and allergy for centuries. So the team asked the obvious follow-up question nobody had systematically asked: if one plant gave us our best stabilizer, what's hiding in all the other traditional medicine systems?

They built a platform called PhAROS that maps traditional and contemporary non-Western pharmacopeias against compounds, targets and conditions. The network they describe runs to over 6.9 billion pairwise linkages and 3.1 billion multicomponent paths connecting formulations, indications, organisms and compounds. Then they scored and ranked candidates on how druggable they look and what they hit.

Simply explained: they took every plant remedy that humans have ever written down for rashes, swelling, wheezing and hives, fed it all to a computer, and asked it to find the patterns. Which plants keep showing up, across cultures that never talked to each other, for the exact problems mast cells cause? Because if twelve unrelated traditions independently landed on the same plant for hives, that plant is probably doing something.

They explicitly name MCAS in the keywords, so this is a group of researchers openly aiming at our problem, and it's the first genuinely systematic attempt to find the next cromolyn instead of waiting to stumble on it.

The paper: Mast Cell Tryptase Potentiates Neutrophil Extracellular Trap Formation, Pejler, Alanazi, Grujic et al., Journal of Innate Immunity 2022;14(5):433-446.

Tryptase is the most abundant protein stored in mast cell granules, and it's the thing your doctor measures to prove a mast cell went off. Simply explained: it's the confetti. When the balloon pops, tryptase is what covers the floor, and it's how we know a balloon popped at all.

NETosis is a form of cell death where a neutrophil, a first-responder immune cell, throws its own DNA outside itself as a sticky web to trap bacteria. The webs are called neutrophil extracellular traps, or NETs. Simply explained: a soldier cell rips out its own insides and throws them like a net to catch invaders, and it dies in the process. That's a brilliant trade when there's an actual infection, and a real problem when there isn't one.

What they found: tryptase markedly increases how many of these nets get thrown. It binds to the nets, chews up the histone proteins in them, and pushes neutrophils to dump more of their granule contents.

And here's the part that made me sit up. They showed that the DNA in the nets feeds back and holds tryptase in its active four-part form. Tryptase normally falls apart and switches off once it's outside the cell, but the net DNA keeps it switched on.

Simply explained: the confetti tells the soldiers to throw nets, and the nets then grab the confetti and stop it going stale, so the confetti stays sticky and keeps telling soldiers to throw more nets. It's a loop that keeps itself running without anyone pressing the button again.

Where clotting comes in: NETs are heavily documented as pro-clotting, showing up in thrombosis and in coronary plaques. Separately, tryptase acts on PAR-2 receptors on the cells lining your blood vessels and makes them leaky and inflamed. A 2026 review in Current Vascular Pharmacology by Manolis and colleagues walks through the mast cell and cardiovascular disease connection more broadly.

If the coagulation side of things has been your particular flavor of hell, this is the mechanism to bring to a clinician who knows mast cell disease.

The paper: Progress in mast cell activation syndrome: the global consensus-2 diagnostic criteria at six years, Afrin, Blitshteyn, Bluestein, Dempsey, Maxwell, Miller, Nagy, Nugent, Schofield, Weinstock, Xi, Molderings. Diagnosis, June 4, 2026.

That author list is basically everybody. If you've read anything credible about MCAS in the last decade, you've read one of these names.

The background: there are two competing sets of rules for diagnosing MCAS. Consensus-1 from 2012 is stricter, Consensus-2 from 2020 is broader. This is the six-year check-in on how the broader criteria have performed in the real world.

Simply explained: two groups of doctors disagree about how wide the door should be. One group says only let people through with very specific, very high proof. The other says that door is so narrow that people who obviously have the problem are stuck outside with nothing. This paper is the second group coming back six years later to show what happened when they widened it.

What they report: recognition of MCAS has grown significantly. Consensus-2 has brought diagnosis and effective treatment to many patients previously labeled with unexplained inflammatory syndromes, or misdiagnosed as somatization or other primary psychiatric disorders. And critically, the fear that broader criteria would cause overdiagnosis has not been realized.

Somatization, simply explained: it means a doctor decided your physical symptoms were coming from your mind rather than your body. It means being told it's anxiety, it's stress, it's in your head, go home. If you've lived through that, you know exactly why that one sentence in a medical journal matters so much.

The paper: Utility of glucagon-like-peptide-1-receptor agonists in mast cell activation syndrome, Afrin, Weinstock, Dempsey, Aschenbrenner, Blitshteyn, Schofield. American Journal of the Medical Sciences, 2025 Oct;370(4):377-382.

Given how much we talk about GLP-1s here for weight, this one is a genuine plot twist.

The numbers: 47 patients with MCAS who had already failed conventional treatment. Mean age 39, range 15 to 71, 89% female. 89% showed clinical benefit on a GLP-1 receptor agonist, across inflammatory, allergic, neurologic, gastrointestinal and autonomic symptoms.

Why would a diabetes drug touch mast cells? Mast cells carry GLP-1 receptors. A receptor is a docking port on the outside of a cell that only accepts one shape of key.

Simply explained: the mast cell has a keyhole on it that nobody thought was important. Turns out the GLP-1 drug is a key that fits that hole, and turning it seems to calm the cell down. Everyone assumed that keyhole was only about blood sugar, and it looks like they were wrong.

The proposed mechanisms are the NF-κB pathway, a master switch that turns inflammation genes on, and the cAMP-PKA pathway, an internal messaging line that tends to tell cells to settle. Simply explained: one is the light switch for the alarm system, the other is the intercom telling everyone to calm down, and the drug appears to dim the first while turning up the second.

The paper also notes relapse was common on stopping, and symptoms often returned between doses if dosing wasn't frequent enough, with adjustments to dose frequency or formulation restoring control. Worth knowing if you go down this road with your doctor.

Two papers here, because this is actually two separate discoveries that fit together.

Paper A: Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis, Cell, Kaplan lab, University of Pittsburgh.

A specific subset of sensory nerves in your skin, marked by a receptor called MrgprD, sits right next to your mast cells and constantly holds them down as an actual ongoing job. When researchers removed those nerves, mast cells switched on a whole set of activation genes and became far more likely to degranulate. When they stimulated those nerves, the mast cells quieted back down. The chemical doing the talking is glutamate.

Simply explained: there's a nerve sitting next to every mast cell whispering stay calm, stay calm, stay calm, all day, every day. Take the whisperer away and the mast cell gets jumpy and starts popping at things it used to ignore. Nobody knew that whisperer existed until recently.

Paper B: Sensory neurons promote immune homeostasis in the lung, Cell.

This is the vagus one. Sensory neurons in the vagus nerve need an enzyme called JAK1 to properly produce a neuropeptide called CGRPβ. That CGRPβ suppresses allergic inflammation in the lung by calming down ILC2s, immune cells that drive allergic responses. Cut those nerves and lung inflammation gets worse.

Simply explained: the vagus nerve is the big cable running from your brain down through your chest and belly, and it doesn't only carry signals upward. It also sprays out a calming chemical that tells the allergy cells in your lungs to settle, which makes it far more of an active participant than a passive wire.

Put them together and you get the real, mechanistic reason vagal tone keeps coming up in this community. Your nervous system is actively holding inflammation down, at multiple sites, using multiple chemicals.

Worth knowing that nerves cut both ways here. Substance P, another nerve chemical, clearly triggers mast cells through MRGPRX2, so which nerve and which chemical and which tissue all change the answer.

The paper: led by Professor Hakuto Kageyama at Meijo University, Japan, published in Bioscience, Biotechnology, and Biochemistry, January 2026. Summary here.

Mycosporine-like amino acids (MAAs) are compounds made by seaweed and cyanobacteria that absorb UV radiation. Simply explained: algae float at the top of the ocean getting blasted by sun all day and can't move into the shade, so they make their own sunscreen inside their bodies. That's what these are.

They compared two: porphyra-334, pulled from dried edible seaweed, and GlcHMS326, a modified version isolated from a cyanobacterium in a Thai hot spring. Four things came out:

Simply explained: a molecule whose entire job was blocking sunlight turns out to also press one of the main buttons controlling how hard your heart has to push. It's a bit like finding out your umbrella also works as a phone.

One edible, natural, multi-mechanism compound doing UV protection, anti-wrinkle, anti-glycation and cardiovascular work at once is a rare profile. I'm watching this one closely.

The paper: Discovery and Biosynthesis of Indole-Functionalized Metabolites from the Human Blood Bacterium, Paracoccus sanguinis, and Their Anti-Skin Aging Activity, Lee, Ahn, Lee, Park, Kim, Lee, Lee, Kim. Journal of Natural Products, DOI 10.1021/acs.jnatprod.4c01354.

Paracoccus sanguinis was only identified in 2015. It lives in human blood, which is one of the least explored places in the entire microbiome world. We've mapped the gut half to death and barely touched the blood.

What they did: grew a big batch for three days, pulled out everything it produced, and used spectrometry, isotope labeling and computational analysis to identify 12 distinct indole metabolites. Six had never been documented by anyone, ever.

Metabolites, simply explained: the stuff a living thing makes and leaves behind while going about its business. Like how a bakery makes bread but also fills the whole street with smell. The bacteria are living, and these molecules are what they give off.

Then the test: they stressed human skin cells to jack up reactive oxygen species, unstable molecules that cause inflammation and wreck collagen. Simply explained: they deliberately made the skin cells rusty and angry. Then they added each of the 12 molecules and watched.

Three of the twelve worked, including two of the brand new ones. They lowered reactive oxygen species, lowered two inflammatory proteins, and lowered a protein involved in collagen breakdown.

Simply explained: there are tiny creatures living in your blood right now, and some of them are quietly producing chemicals that protect your skin from getting old. They came with you, free of charge, and nobody knew they were doing it.

Mining your own body's microbes for skin compounds instead of synthesizing them from scratch is a genuinely new direction.

GHK-Cu searches have exploded this year, and the peptide crowd has known about it for a long time. Here's what's actually underneath the hype.

GHK-Cu is a three amino acid peptide, glycine, histidine and lysine, bound to a copper ion. Your body makes it naturally. At 20 you're running about 200 ng/mL of it, and by 60 you're down to around 80.

Simply explained: it's a tiny repair signal your body sends out when tissue gets damaged, telling cells to build here and fix this. You make loads of it when you're young and less and less as you get older, which is a big part of why a cut heals in three days at 15 and three weeks at 60.

The head-to-head: the study everybody in the peptide world quotes is Abdulghani, Sherr, Shirin, Solodkina, Tapia, Wolf and Gottlieb, 1998, in Disease Management and Clinical Outcomes. They put copper peptide cream up against tretinoin (prescription retinoic acid, the strongest retinoid there is), vitamin C cream, and melatonin cream, then took actual skin biopsies to look at what happened underneath.

The result that made GHK-Cu famous: copper peptide improved collagen production in roughly 70% of the women treated. Vitamin C came in around 50%. Retinoic acid around 40%. The copper peptide beat the retinoid.

Simply explained: four creams went head to head to see which one made the skin build new scaffolding underneath. They didn't just ask people whether they looked better, they took tiny samples of skin and examined them under a powerful microscope, which is a lot harder to fudge than a before-and-after photo. The copper one came out on top.

Why that matters more than the raw number: tretinoin is the gold standard, the thing dermatologists have prescribed for decades and the benchmark every new ingredient gets measured against. It also comes with peeling, redness, irritation and sun sensitivity, which is why so many people quit it. GHK-Cu got a better collagen response here without any of that.

Simply explained: retinol works by being a little bit mean to your skin, stripping and irritating it to force a rebuild. Copper peptide gets there by sending a message that says build here, and letting the skin do the work itself, which is why it doesn't come with the sandpaper.

Fair to say what this study was: a pilot with a small group, and the authors were clear that not every individual responded. Their own conclusion is that tretinoin, vitamin C, melatonin and copper peptide creams all enhanced dermal collagen synthesis, just not in everybody. It remains the only real head-to-head anyone has run.

The rest of the human evidence: Watson et al., 2009, British Journal of Dermatology, a double-blind randomized controlled trial in photoaged skin showing improvement in fine wrinkles, mottled pigmentation and roughness. Finkley, Appa and Bhandarkar ran 67 women aged 50-59 over 12 weeks. Carey and Pickart used high-resolution ultrasound on 21 subjects over 3 months and measured increases in subdermal density, which tracks collagen and elastin.

The gene thing: Broad Institute Connectivity Map analysis found GHK shifts expression of roughly a third of analyzed human genes, with the net effect pushing age-shifted patterns back toward younger profiles. That is a genuinely unusual amount of reach for a molecule this small.

The catch, and it's the whole ballgame, is skin permeation. GHK-Cu loves water and your skin barrier is essentially greasy, and the two don't mix.

Simply explained: imagine trying to push a wet sponge through a greasy wall. There's nothing wrong with the sponge, the wall is the problem. That's why the dish results on this peptide look spectacular while topical results are all over the place, the molecule is fine and getting it in is the hard part.

This is why delivery method matters more than the percentage printed on the bottle. Copper complexation and palmitoylation (Pal-GHK) both improve permeability, and microneedling as pretreatment is being looked at for the same reason.

(Not advice, just my own system for research peps.) I've shared this before, but it's worth revisiting:

I use a Dymo labeler, but tons of labeling machines work great for this. You can also just use a pen and mark the sticker on the vial. Anxiety-free prep! ❄️

A closing thought. The thread running through almost all of these is that mast cells are not a standalone problem. They're wired into your nerves, your clotting system, your gut, your blood vessels, and even the skin research keeps circling back to the same inflammatory machinery. The science is finally catching up to what a lot of you have been living for years.

More real movement on mast cell disease in the last eighteen months than in the previous ten years. I'll take it.

⚠️ Research Use Only.

Disclaimer: This email is provided for informational purposes only and does not constitute medical or legal advice. Products discussed are intended for research use only, are not approved for human consumption, and should be handled in accordance with applicable laws and regulations. Nothing here is a protocol to follow. If you think you may have MCAS or any condition discussed above, work with a licensed clinician who knows mast cell disease.

Stay Curious 🕵️

Tk - Exploring Peptides