Could This Controversial, Newly Discovered "Dolphin Drug" Be A *Missing Key* To Longevity? The C15:0 Story, With Dr. Stephanie Venn-Watson

My name is Ben Greenfield, and on this episode of the Boundless Life Podcast, when we first made this link in the dolphins, we did 8 studies over 3 years. We showed that C15 is not only a beneficial and active saturated fat, but that it was meeting these rare criteria of being an essential fatty acid. And importantly, this is critical that over the last 24 months and really 12 months, 4 independent teams have now looked at the criteria of C15 being an essential fatty acid, including gold standard studies that were used back in 1929 and 1931. Really important follow-up from independent teams that have nothing to do with us, all concluding that yes, C15 meets the criteria of an essential fatty acid. So lots of exciting work on that frontier.

Welcome to the Boundless Life with me, your host, Ben Greenfield. I'm a personal trainer, exercise physiologist, and nutritionist, and I'm passionate about helping you discover unparalleled levels of health, fitness, longevity, and beyond.

My guest on today's podcast is a veterinary epidemiologist. That might be the longest multi-syllabic phrase I've used in quite a while. On my show, veterinary epidemiologist, Dr. Stephanie Van Watson. Welcome to the show.

Ben, it's great to be here. Glad to challenge you right out of the gate.

Right out of the gate. You wrote this book, "The Longevity Nutrient." This thing was intriguing for me because I'm always looking around for things that haven't been talked about yet in the whole nutrition and supplementation world. This definitely fit into that category and we'll talk about it. It's a fascinating book, by the way. If you guys want to check it out, go to BenGreenfieldLife.com/LongevityNutrient. C15, that's C-1-5. And I'll put all the show notes over there, which promise to be juicy for this one, or should I say fatty? Stephanie, what's a veterinary epidemiologist?

It's a nerd who loves animals, about as a short answer there. But so our job is to basically find patterns related to animal populations, remembering that humans are also animals. So veterinary epidemiologists tend to help not only in large population studies with non-human animals, but actually most of us are working for public health and other groups, so looking at human trends over time.

You mean you're studying humans or you're studying animals and figuring out if what you find in animals could be translated to humans?

Yeah, both, but the latter is obviously, is a good reason why we're chatting today. So, 'cause you know, it's like, as a veterinarian, you really come to understand there's a, there are so many so many more similarities between animals than there are differences. So that whole comparative approach has, you know, we're always thinking with regard to, you know, when we go to veterinary school, we learn about 12 species instead of 1. So it helps you understand the links between all of us.

Well, I was walking out to actually record this podcast out of the kitchen. My wife's like, "Have fun talking to the dolphins," because I told her last night I was going to be interviewing this dolphin researcher. And she's like, "Why the heck are you interviewing somebody about dolphins?" On Your Health podcast. So, I should let you answer that question, Stephanie, because I mean this whole story of how this book came to be started with, if I'm not mistaken, dolphins.

Yeah. So, there I was. I mean, this whole discovery, Ben, was an accident, which is wonderful and gifted to us by dolphins. So again, veterinary epidemiologist. I was recruited by the Navy about 24 years ago to help better understand health and wellness of aging Navy dolphins. The Navy has cared for this sustained population of about 100 bottlenose dolphins for over 60, 6-0, years. They live in the open ocean here in San Diego Bay, go out into the open ocean every day, every day they choose to come back. So it's a really amazing population. They get such good care, Ben, that while dolphins in the wild live to about 20 years old, Dolphins at the Navy are now routinely living into their 40s, 50s. And, I just learned last week when I stopped by for a visit, 2 of the dolphins are turning 60 years old this year. So, much older dolphins at the Navy.

I didn't know dolphins could even live that long. That's interesting that they come back. So, a dolphin is released into kind of its native habitat from this Navy base or whatever and they go out into the ocean, but then eventually just like show back up at the front door?

They do. And they live, you know, they live in the bay there. So they kind of have a home base in San Diego Bay. And so they'll go out in the bay, do their work, which is easy peasy. And then yeah, yeah, come back.

Do you guys count them? Is there ever like a rogue dolphin that doesn't come back?

It wouldn't work. So the program wouldn't work if dolphins went rogue. 'Cause if you can imagine, if you have 100 bottlenose dolphins, each one of those is, you know, a really valuable individual who you spend,, you know, decades training and working with and getting to know that if they just kind of went away, the program wouldn't be able to sustain. So it's really good population. Dolphins get really good care. And what we learned is as they were getting older, that about 1 in 3 older Navy dolphins were developing things that are going to sound really familiar, like insulin resistance, fatty liver disease, high cholesterol, anemia, chronic inflammation. And as we just published last week, the full suite of changes consistent with Alzheimer's. And so, really fascinating parallels between our large-brain long-lived mammals of humans and dolphins.

So obviously, a diabetic dolphin isn't necessarily eating, I don't know, seed oil Doritos or whatever it is people are blaming on diabetes these days or for diabetes. But, with these chronic diseases in dolphins, What is it that you were finding that's applicable to humans?

Right. And, you hit the nail on the head here, Ben, that this was a huge unlock. As I was reaching out to experts in the human space on, "Hey, how can we help dolphins? What are you doing in humans and how can we help dolphins?" They were flipping the conversation around immediately and saying, "Wait, wait a second, dolphins are getting fatty liver disease and Alzheimer's and all the chronic inflammation metabolic syndrome." Exactly like you're saying, without carbs, without trans fatty acids.

Right. Assuming they're not swinging by like a Navy SEAL tequila bar while they're out there on their journey when you let them loose. It's a pretty controlled diet and lifestyle, I'm assuming.

Exactly. Despite being Navy dolphins, they also are not heavy drinkers. So, we were given the good fortune to have Office of Naval Research funding. The Navy archives all of the serum that they collect on dolphins as part of their routine care. So we were able to go in and use an advanced technology called metabolomics to study thousands of small molecules that are present in the dolphins' archived serum, but also their all-fish diet, right? Because all they eat are fish. And we were then able to look for which small molecules predicted the healthiest aging dolphins. So those 2 and 3 that aged well, we thought it'd be omega-3s because all they eat are fish. And instead, right, they completely surprised us by showing that in fact, it was C15, this odd-chain saturated fat that predicted the healthiest aging dolphins and has emerged today, which we'll talk about, you know, as the first essential fatty acid to be discovered in over 90 years.

Okay. So, C15, you said it's a saturated fat?

Right. So, that's where we were confused too. We're like, wait a second, a saturated fat? We've all been taught our whole lives all saturated fats are bad, especially since our primary source of C15 isn't from fish, it's from whole fat milk and, you know, milk, but dairy fat. So, um, we— so C15 is, is called that because it is a fatty acid that has 15 carbons in it, hence C15. And then you'll see, even though we don't pronounce it, it's a colon zero. And the number after that colon tells you how many double bonds are in it. If they sat— if a fatty acid has no double bonds, it's a zero. That means it is a saturated fat, so it's particularly resistant to lipid peroxidation. Those double bonds love to get attacked by oxygen. So, um, it just ended up being this Goldilocks fatty acid that is a good saturated fat. We've learned that not all saturated fats are created equal. Those that have an odd number of carbons, like C15, C17, and C15 being the Goldilocks fat, have anti-inflammatory effects. We'll talk about all the many benefits of C15, um, and, and protective, while even-chain saturated fats like C16, C18 are pro-inflammatory, which is why we've, for so long, we've associated saturated fats with higher risk of type 2 diabetes, heart disease, fatty liver disease. We weren't wrong, we just are now understanding We've all known that not all fats are equal. We now know that not all saturated fats are created equal.

Okay. So, real quick, not to nerd out on this too much because it's probably not that high up on people's priority list, but thinking back to biochemistry. So, when you're saying C15, 15 refers to the number of double bonds?

Number of carbons. So, it'll tell you—

Number of carbons. Okay. So, there's 15 carbons, but because it's a saturated fat, every single bond between each of those 15 carbons is a double bond.

Is so— is a— is not a double bond.

So it's not a double bond.

Exactly.

Exactly. And when you say not a double bond, what does that mean?

So that's a good point. So it's a single bond. So if you like, we think back to our biochemistry days, right? You'll either see two bars go across almost like an equal sign versus one, a single bar. So a single bar means it's super sturdy. It means it can't bend. So if you think about in a fatty acid, structure. If it's a double bond, think of it as a hinge. So it allows the bond— allows that fatty acid to bend, which makes it flexible, which is why unsaturated fats that have double bonds, um, are oils at room temperature. So they're able to be flexible. But those double bonds can also be attacked by oxygen, which then leads to risk of lipid peroxidation and other things. So think about saturated and unsaturated fats as kind of like a yin and yang of the fatty acid world. Saturated fats are sturdy unsaturated fats are flexible, and we need both to maintain, you know, a balanced cell membrane. But specifically, we're learning that our cell membranes need C15. This odd-chain saturated fatty acid plays a very special role with regard to improving the integrity of our cells.

Yeah, it's a little bit counterintuitive, isn't it? Because you hear double bond and you think that a double bond would be more rigid, less flexible, twice as strong and unable to bend and more solid at room temp, right?

That's right. Yeah. So, it goes against, again, where all these things where it's like, "Wait, a saturated fat, that's good for us and double bonds are weaker." So, we're all learning together.

Okay. So, 15 carbons long, there's this fatty acid that you find in dolphins and you're saying that's the first essential fatty acid to be— how many years do you say, 90?

90 years since 1929, 1930.

Okay, walk me through that. What's that mean that it's essential, right?

So this is a big deal, right? So an essential fatty acid is a nutrient that our bodies must have in order to maintain our baseline physiological health. If we don't have enough of it, we— we'll see a deficiency syndrome. So, well, our health will fall apart. Importantly, our bodies can't make enough of this nutrient, of this fatty acid. Therefore, we have to get certain amounts routinely from our diet. So prior to our discovery with C15, there are two known essential fatty acids. One's an omega-3, alpha-linolenic acid, and one's an omega-6, linoleic acid, which were discovered way back when by George and Mildred Burr back in 1929 and 1931.

Okay. So, essential fatty acid doesn't mean you can't make it, it means you can't make enough of it.

Exactly.

Okay. Alright. So, when it comes to C15, 90 years is a long time. Why is it that you think this hasn't even been discovered before or looked into before? I mean, obviously, you'd expect for science to find new things as time progresses, but it just does seem like a long time with what we know about fatty acids for this not to have been identified as an essential fatty acid before this.

Yeah, you're exactly right. And then add on top of that, Ben, that I'm a dolphin veterinarian, right? So, so it's like we have people who spend their whole lives working on fatty acids. And so how is this not discovered before when we've we first made this link in the dolphins, we went to Dr. Ed Dennis, who is a global leader in fatty acids. He was the editor-in-chief for the Journal of Lipid Research for 15 years. So we're lucky that Ed was in San Diego, close to us. So we went and met with him and we said, hey, this is what we found in the dolphins. Do you think C15 might be beneficial? And he said, probably not, because we all know about C15. We've known about it since the 1950s. Is present at such low levels that we— and it's a biomarker of how much dairy fat we eat. Chances are we didn't miss this stuff, but the dolphin component is interesting. So here are the studies you would, you know, we would need to do to figure out is it bioactive, at what concentrations is it bioavailable, what activities does it have, like a whole slew of core questions that would need to be answered. So we did 8 studies over 3 years and the culmination of that of those studies we published in Scientific Reports with Ed Dennis as the senior author on this paper, in which we showed that C15 is not only a beneficial and active saturated fat, but that it was meeting these rare criteria of being an essential fatty acid. So we published that in 2020. And importantly, this is critical that over the last, you know, 24 months and really 12 months, 4 independent teams have now looked at the criteria of C15 being an essential fatty acid, including gold standard studies that were used back in 1929 and 1931, where you deprive, um, a pregnant mouse of C15, you let her have the babies, so now the babies are C15 deficient. They demonstrated nutritional deficiency syndrome, so poor growth. And when they gave the babies C15, their growth restored. So another study was done in worms showing that you could remove every nutrient, not just fatty acids, but every nutrient from a baby worm, and if you give it just C15, its normal growth will restore. So really important follow-up from independent teams that have nothing to do with us, all, uh, concluding that yes, C15 meets the criteria of an essential fatty acid. So Lots of exciting work on that frontier.

Well, I'm sure as a veterinary epidemiologist, you probably get this all the time. You just talked about dolphins earlier, and then rodents, and then worms, but what about, like, you know, people?

Right. There's that. So what's been important with people, like, so for example, in this, as far as infant development and growth, there are, there's a whole nother team. There are multiple teams working on the early stages of C15 in humans. Showing that even from the level of the oocyte, that the more C15 that's present, the better that oocyte multiplies. So it's signs of a healthier embryo for in vitro fertilization. Studies have shown that the more C15 mom has as a human, right, that the more C15 baby gets. And the more C15 baby gets, the better the fetal body growth and head, head circumference, which is brain development, the better the baby once it's born its growth and development. And there's a study done called the Éden Cohort Study in France that has followed kids all the way up to 6 years old, showing the more C15 they got from mom during and after pregnancy, the better the cognitive development of these children. So, you know, when all of these add up, these pieces that, you know, gets us to an essential fatty acid that, you know, is meeting the requirements and is relevant to humans, importantly.

A lot of the research I've seen on dairy seems to indicate, and this surprises a lot of people, maybe it's because of our built-in bias still about saturated fats being unhealthy, is that full-fat dairy seems to be where you get more of the benefits of dairy compared to nonfat or fat-free dairy. And, I've always wondered, is that because something about separating the fats from the proteins affects the dairy, something about the extra processing affects the dairy. I don't know if C15 could fit into the picture here, but is there any research that you know of on people eating full-fat dairy products being healthier and maybe some of those health benefits coming from the C15 composition of full-fat versus non-fat or fat-free dairy?

Right. So, yes. And in part, it's because C15 has been used as a biomarker of dairy fat. So it's almost like, you know, like we were saying before, how did people not discover this before? It's been right in front of us. It's just been the interpretation of people with higher C15 have a lower risk of developing type 2 diabetes, heart disease, fatty liver disease. But the reason why, you know, when you asked earlier, Ben Greenfield, like, why hadn't this been discovered before? People were just seeing C15 as a biomarker of dairy fats benefits, not that the fact that C15 itself may be beneficial. So when we isolated C15, right, and we took a look at how does C15 do compared to whole dairy fat, other folks have shown, like Bishop et al. did that study in mouse model of type 2 diabetes and fatty liver disease. And, you know, we had shown that C15 improves health, so decreases glucose, insulin, weight, body, body weight on a high-fat diet, lower inflammation. When Bishop et al. gave the same model, whole dairy fat, the mouse got worse. So, and it's because, and they attribute it to that whole dairy fat has much higher levels of C16 and C18 of these pro-inflammatory saturated fats. So kind of getting to the point where like Thorne et al. had talked about, how do we deal with whole dairy fat? It's kind of a mess. You do absolutely have studies saying whole dairy fat can be good for you. There's equal studies saying, you know, whole dairy fat or having these high levels of these pro-inflammatory fats could be bad for you. It's super confusing. And I think what we're getting to is understanding, like you said, different forms of dairy fat have different amounts of beneficial nutrients, which is why the Navy had funded us to say, "Hey, can we just take C15?

And if you're showing that it has these benefits, can we just put that to work absent kind of the confusion of dairy fat?" Ben Greenfield: Well, before we close the loop on dairy because I don't want to just leave people hanging and sitting there in front of their full-fat Greek yogurt now asking themselves, "Do I eat this? Do I not eat this?" What's your take on the dairy fat thing? Would you eat or would Would you drink full-fat milk? Would you eat full-fat yogurt based on what you know?

I do not shy away from whole dairy fat, but I do think it's in moderation. Like, we shouldn't make 90% of our diet dairy fat. If we look at the Sardinian population and the high longevity zone, they have swapped out cheese, specifically cheese for meat. So, eat a lot less meat, they eat a lot of cheese, and their cheese specifically has has 50% more C15 in it compared to other dairy fats. And so with regard to understanding fats that are good for us, it's dairy fat that comes from animals that are grass-fed have twice as much C15 in it than like cows, for example, that are fed corn. And so when I'm going for my whole dairy fat options, I go for cheeses that are from— if hopefully, you know, from grass-fed animals.

Okay. That's actually super important to know. So, in Sardinia, the cheese that they eat is special because that cheese is coming from grass-fed animals?

Yeah. And, even better, there's actually multiple studies showing not only is it about grass-fed animals and they use sheep and goats, it doesn't really matter if it's a sheep, a goat, or cow, but if they are fed not only grass but grass at high altitude, that has even more C15 in their milk. So, the Sardinian high longevity zone is in a mountainous region in Sardinia. So, they are hitting that sweet spot of grazing grass-eating sheep and goats at high altitude. And that's resulting in their cheese, one of which is Pecorino, which I love, has high C15 and it helps explain why people in this high longevity zone have 2 to 3 times higher C15 levels than the rest of us.

Ben Greenfield: Okay. We are rabbit holing big time, but why is it that a hypoxic Sherpa goat cheese would, because of some type of oxygen limitation, produce a cheese that's better than a goat at normal altitude?

Jessica Matthews: Yeah. I mean, I think you're heading down the right rabbit hole. I think C15's role is to be sturdy fatty acid that helps make things, living things, more resilient to stressors. And so, hypothesis, Ben, but not yet been tested is, are these high-altitude grasses and animals put at, you know, really having to leverage C15 to be able to make them more resilient? And again, in a hypoxic environment.

Kind of makes me wonder if any type of stress might induce upregulation of C15 because I have goats but I don't live at altitude, but I do have cold tubs. So, if I cold thermogenesis my goats, maybe I could induce higher C15.

You did not get that from me, but yeah, you're heading in the right direction.

I don't have mountains, but I have too many cold tubs around here.

Alright.

Well, we'll save that for another day. I'll let you guys know if I wind up cold plunging my goats. But, back to the longevity piece because Sardinia is obviously one of these longevity-enhanced blue zones apparently. You talk about longevity a lot in the book. You talk about a lot of these other chronic diseases, but specifically you talk about longevity and you describe these longevity must-haves that you've identified in terms of something that a molecule must cause for it to be a longevity must-have. Can you get into that a little bit?

I can. So, as we started learning about C15's role, its activities, how it works and what it's doing, Dr. Nicholas Schork, who's head of NIH's Longevity Consortium and has been playing that role for over 15 years. Nick came in and he's like, I'm reading all these studies. There are now over 100 peer-reviewed studies on C15 available at DiscoverC15.com for those who want to nerd out. And Nick said, Steph, like, C15 is— the evidence I'm seeing is that C15 is emerging as a geroprotector. And I said, great, what's a geroprotector? So that's where Nick described that a geroprotector is the holy grail of a longevity, a molecule, because it slows the rate at which we age to stem the onset of the diseases that kill us. Which means that if it's a true geroprotector, you're going to see clinically relevant benefits within months, right, in a person who's is already going through that process of aging. That's what excited Nick, because he's like, there's— we don't have that today, and this has the potential to have a meaningful effect. So we worked with Nick, and he came up with these 5 longevity molecule must-haves. And it— the molecule needs to show that it targets the human longevity-regulating pathway. It needs to show that it targets key hallmarks of aging. There needs to be evidence it slows the rate at which we age, that there are clinically relevant benefits seen within months and that there is strong evidence that the molecule can actually help prevent the onset of diseases. So what we do, we go through the book, is we show that C15 does all of that. It activates AMPK and inhibits mTOR, right? This is what metformin and rapamycin do, respectively. It targets 6 hallmarks of aging, including improving mitochondrial function and decreasing senescent cells and decreasing inflammaging. It has evidence of slowing the rate at which we age. There's a key biomarker of aging rate called red blood cell distribution width, or RDW. And C15 has been shown to reliably reverse that. So if it goes high, it's a faster aging rate. C15 has repeatedly shown to bring that down. And then we talked about, we'll talk about clinically relevant benefits through clinical studies, in vivo studies within months, having to do with liver health, metabolic health, cholesterol. And the last is there are meta-analyses, so studies of studies involving tens thousands of people over decades repeatedly showing that people with higher C15 have a lower risk of developing type 2 diabetes, heart disease, fatty liver disease. Lee et al. showed that for every 50% incremental increase in C15, the percentage that we have in our, um, in our cell membranes and in our blood decreases our risk of type 2 diabetes by 8% and our, our risk of getting coronary heart disease by 17%. So, when you bring all these pieces together, that's where you get to checking off these must-haves of a longevity nutrient.

Ben Greenfield: Kind of back to the "you are what you eat" type of idea or "you are what you eat ate." Is it because C15 is comprising our cell membranes with this more stable fatty acid? And, is it just that or is it doing other things? This is kind of a mechanism mechanism of action question, you know.

Absolutely. And this is so important, right? If you don't understand mechanism of action of something and what concentration, right, you need to achieve that mechanism of action, it's kind of like game over, right, Ben? It's like a lot of skepticism around like how does it really work. So you're spot on that C15 as a stable fatty acid goes into our cell membrane and it makes it more stable and resistant resistant to lipid peroxidation, which is a major driver of chronic diseases and aging. It is such a simple thing that it does, and we'll talk about it does more, but that is a core mechanism of action. In addition, you know, we and other groups have shown that C15 is a pleiotropic molecule, which means it does a lot of different things. And so I'm just gonna name off some acronyms, but we're not gonna go into detail, but it, you know, we know that it activates AMPK, AKT, MPAR alpha delta. We know that inhibits mTOR, JAK/STAT, HX6, lots of stuff.

Okay. So, by the way, those are all— I mean, interrupt you. You said AMPK, ACT, and PPAR. Those are all the same things that would get triggered via exercise. So, it sounds to me like you're saying it might act as a little bit of an exercise mimetic agent.

That is correct, yes, especially that PPAR delta. Yeah, AMPK. The fact that you're exercising while we're doing this, I'm incredibly impressed.

Yeah. In my opinion, most— sorry to interrupt— most exercise memetics and calorie restriction memetics are best combined with respectively exercise and calorie restriction if you're looking to maximize the benefits from those. You don't just pop a pill and watch Netflix.

Nope, you don't get any of that. You got to do both. And in fact, it helps a lot of people, even for myself, it helps me exercise. I'm able to exercise longer and it makes it more enjoyable for me.

Okay. So, I interrupted you as you were going down the alphabet letters.

Yeah. So, we've got— yeah, inhibits. When we talk about activates things, it inhibits things like mTOR, HDAC6, JAK/STAT. And so, it's like— and the core thing is if you look at all these different mechanisms and we just published last week that it inhibits these two things called FAAH and MAO-B. And it does by doing that, this is really critical to cognitive health. So, super exciting to help sustain higher, healthier dopamine levels and endocannabinoids, which we'll, we'll, we'll touch on in a little bit. So the point being, it's an essential fatty acid. Nature takes essential fatty acids and it has them do a lot of things, which is a big reason why we and dolphins and dogs have these receptors. It's because they're waiting for us to eat the right things and trigger these receptors and keep us balanced from a metabolic and immune standpoint. So, it all makes sense given the fact, again, that this is an essential nutrient that every mammal gets from birth.

Ben Greenfield: You mentioned modulation of mTOR. And then, earlier, of course, you're talking about diabetes. I think two darlings of the anti-aging industry as far as off-label drugs are metformin and rapamycin. How do you think about the head-to-head comparison of something like C15 with something like those, right?

So that's where Nick came in, and he had the same question you did, Ben, which is, hey, if we test C15 head-to-head against rapamycin, metformin, and then the third molecule called acarbose, which is also in that kind of anti-diabetic world—

isn't that like a negative glycemic index sweetener?

Yeah, exactly. We don't use it here as much. It's in Asian countries, is popular. And basically what it does, it prevents absorption of carbs.

Dr. Sandra Kaufmann, she's big into all these different ways to block glucose absorption. I think Acarbose is on her list of supplements. Okay. So, you're testing C15 against or at least comparing it against metformin, rapamycin, and Acarbose. And, what are you guys finding?

So, what we did is we used this panel that is industry standard for the pharmaceutical world. And, it's called BioMap. It's 12 human cell systems mimicking in various disease states, heart disease, liver disease, lung disease. And what you do is then you treat these diseases in a dish with 10 concentration— so, nope, let me take that back, 4 concentrations of each molecule. It measures 148 different biomarkers and it gives you a profile of how well does this molecule behave across many different human cell systems. So it's a great way to assess safety, but also efficacy. Efficacy. So, um, we did that with, uh, C15, pure C15, against these other longevity leaders, and we were able to show that C15 had the most cell, uh, longevity-enhancing cellular benefits than all of them, most closely mimicking rapamycin. And when you step back and you look at what we know rapamycin and C15 do, it's— they're anti-inflammatory, antioxidant, antifibrotic, so anti-scarring, antimicrobial, and anti-cancer. So it's this wonky set of tools that if you have these, you're going to live longer. And so the conclusion we came to in the paper that Dr. Shork and I, in this paper that we published in 2023, was, hey, maybe we didn't need to go to Easter Island for this molecule, right, that is grown in bacteria that grow in a faraway place, maybe what we've needed to support our longevity is, you know, C15, again, what all mammals get, and we've been taking out of our diets by reducing the amount of dairy fat we eat.

Yeah, this whole Biomap measuring thing that you use, I hadn't come across it before, but it's, it's kind of cool because, yeah, it's not like a double-blinded human clinical trial, you know, long-term in living people, but it's almost like kind of a cool algorithmic way of comparing things head-to-head. I hadn't heard of it before, but I think— let me find this section of the book. You actually say that you start with a handful of different human cell types like lung cells, white blood cells, vascular cells, and skin cells. Then, you expose them to a variety of factors that replicate a multitude of diseases. And so, you're getting a bunch of diseases in a dish that mimic things like heart disease, cancer, inflammation, arthritis, liver scarring, et cetera. And then, it gives you a comparison of what's going on in that dish based on what you test against these diseases, almost like a bunch of little miniature celebrity death matches in a Petri dish.

Hey, I love that. Yeah, I think Biomath is going to call you up and ask if they could use that as a description.

Yeah. It is really cool though. I mean, because again, I don't think you would say this either, this is not the same as a human trial, but it certainly gives you some pretty cool data to work with.

That's exactly right. And what I tell you, Ben, like, as the years have gone on since we first, you know, started using BioMap, I have become a huge believer in it. And it's because we've been able to see it, um, move forward, right? So it predicted, for example, that C15 would have, um, anti-cancer benefits in this dish. And then there's a group that then moved C15 forward in cancer studies in vivo, and that they were able to figure out what was the mechanism of action. So it was a JAK/STAT and HDAC6 inhibitor, which are anti-cancers. It mimicked gemcitabine and, uh, paclitaxel, which are two anti-cancer drugs. And most importantly, when they moved in vivo to a mouse model, that it decreased the tumor size, uh, of, uh, mice with breast cancer. So it's remarkably good at being a predictor of what activities it will have. And because these are human cell lines, it's a predictor of what's gonna be useful in humans. Again, this is used by the pharmaceutical industry and they are not gonna waste— this helps them be much more efficient at honing in on which molecules are most likely to make it across the line.

Yeah, yeah. A few minutes ago you mentioned the endocannabinoid system. Why, why were you talking about that?

Right, so this is a fun, um, component that, uh, you know, as people started, you know, taking Pure C15 and supplementation, we had about half of the people within 2 weeks reporting deeper sleep, calmer mood, and less joint pain.

Wait, I want to back up, interrupt you real quick. Were they like taking this right before bed or was this just kind of like chronic long-term use effects?

Yeah, like it was more like, and it's within 2 weeks. And so, you know, it takes a few, maybe a few days to, but let's say pretty reliably at 2 weeks, half of the people. And we're like, you know, hey, we understand C15's mechanism of action. You know, from what we understand today, that doesn't really line up with what we know about C15. But then the science continued and we learned that C15, that our bodies use C15 not only for all the things I just talked about, but our body uses C15 to make a second molecule, a metabolite called pentadecanoic carnitine. Which we'll just call PDC. And what we found was, again, the first step is, right, take the molecule, throw it against a bunch of receptors to understand, is it active? Is it activating relevant receptors? And so that's where we found that PDC fully activated CB1 and CB2 receptors, where CB stands for cannabinoid. So these are the receptors throughout our brain and body that respond to cannabis. Right? And, and they're named that because of cannabis, but we don't have those receptors because our bodies were waiting for humans to find cannabis and start using it, right? Like dogs have it and dolphins have these receptors.

So you're telling me weed is not an essential plant?

Weed is not, that was not the big discovery. So, but why are they there, right? And so what we showed is there's a, previously there was a one, um, called an endocannabinoid. So it's a cannabinoid that our bodies make that are intended to activate these receptors. Prior to our discovery, there was only one, uh, known, uh, full-acting endocannabinoid. This, uh, PDC was the second. So the second ever discovered, which then helped explain, aha, deeper sleep, calmer mood, less joint pain, all of which I have experienced myself. And now it's like, I get it. Like I'm understanding why, uh, those benefits.

So, the way that it's working on these receptors, you said it acts on CB1 and CB2 receptors or it upregulates this PDA which acts on those receptors.

Yeah, exactly. It's this metabolite that then activates these receptors.

Okay. So, if you're binding to those receptors, would you— and this is just a total thought experiment— and you smoked weed or had an edible, would you need more of it to actually work with those receptors because the receptor side is already occupied?

Yeah, that is an interesting question. If there's com— what we don't know is competition. That if, let's say, yeah, that the, uh, the phytocannabinoids, right, the non-ones that our body—

Right, non-endogenous cannabinoids, yeah.

Yeah, if they're stickier, right, to the receptor, then there may be a competition component. Um, the neat thing about endocannabinoids, which is fascinating, is that our bodies make it on demand. So we store C15, and then when our bodies need less pain, calmer mood, better sleep, our bodies will actually then make the, um, make the endocannabinoid. Versus if you take an edible, it just goes up at that time and then goes down based upon how long before when you had eaten it. So maybe they'll do a one-two punch that you can store it in your tissues, your tissues will use it when you need it, and then you have your edible is which will have its immediate effect at that time.

Yeah, interesting. If you— you said you store it in your tissues, what do you mean?

So C15, so as we eat C15, it goes into our cell membranes. This includes cells in all of our tissues. So we want to have C15 stored in our tissues because of, you know, all the things we talked about— anti-inflammatory, antioxidant— that keeps our liver, our heart, our brains healthy. But it also means we've got a store of C15 waiting so that when our body needs endocannabinoids when it needs to deal with pain, when it needs to deal with sleep, it's able to make those endocannabinoids and increase the levels upon demand, which again is something I learned while writing the book about endocannabinoids and just fascinating.

Ben Greenfield: Kind of makes me wonder too if you're kind of a pothead or you're too reliant on CBD or THC if you could kind of use some form of C15 to wean yourself off that or kind of taper off.

Yeah, that's the hypothesis. It helps.

Yeah, exactly. Interesting. So, if it's stored, is there a way to actually get a blood test or some kind of tissue sample or something that the average person could do to see how much C15 they actually have in their bodies?

Yes. And so, the good news is because C15 has been used as a biomarker for how much dairy fat we eat, The test has been used for decades reliably. So fatty acid panels, if you, you just, you can ask your doctor to do a fatty acid panel. Just make sure that they check and that C15 is included. Another reason why C15 wasn't discovered until recently is that fatty acid panels before the 1990s, for the most part, didn't include C15. So if we had done that dolphin study had it been 3 years earlier, we would have missed the entire discovery because C15 wasn't on the panel. So, a bit of luck came into play here. Ben Greenfield: Yeah.

But, if I ask my doctor for a fatty acid panel, I mean, I know doctors are smart, but maybe they're not trained in this specific type of panel. Usually, even a smart doctor is going to give me an omega-3, they'll order an OmegaQuant or something like that, Is there an actual test you could ask for or an at-home panel or do you literally just need to go to your doctor and say, "Hey, C15 is the one I want you to test for?" Yeah.

So, you can do the latter first. And, if they don't have it or they're like, "What are you? I don't even know what C15 is," and then you're going to give them the book. But, what we know is— so, we worked with Genova Diagnostics to develop an at-home blood spot test. So, if people don't have an option, and that's what I used, then you can get this at-home blood spot test. And then turn it in, you mail it in, and they send you your results.

Oh, easy. So, if I have an account at DirectLabs or whatever, would it be on there?

Yes, it should be on there.

Okay, easy. And, it's just at home? Yeah. Oh, most people, I mean, most of my listeners are going to do that because they just like to take it into their own hands.

I know, it's good.

I can't imagine that would be that expensive.

It's not, yeah. I mean, for people who are used to ordering tests and to be able to get results you know, that it's in the same realm as other tests. And so I use that one, and that's where I was able to show that my C15 levels in that test, right, that uses this, you know, a different reference range than maybe other tests. But this one showed from the concentration that I have the Sardinian level, so 0.46% and over 5 micrograms per mL.

So yeah, you're going to start talking like an Italian by hypoxic goat. Wow.

Yes, exactly. C is easy.

Okay. So, dolphins, you mentioned eat fish, they don't eat yogurt, but at least I don't think they do. I don't know what you're doing in the Navy if you guys have a Ben Jerry's there. But, the thing about fish oil, right, because fish oil is often called a source of some of these essential fatty acids that you named earlier, I think. How do you compare C15 to fish oil supplementation? Do you still use fish oil or what's your take on the fish oil?

Piece. I love fish. There's so much— there's so many studies, Ben, showing that the more fish we eat, if we eat 2 to 4 servings a week, that the better our health. So dolphins are on to something. So we know that fish are good for us. They contain a lot of important nutrients, including the omegas. So with regard to fish oil, you know, fish oil goes back to the 1800s. Industrial Revolution of— that's what's our cod liver oil was our main source of vitamin D, and it helped to get rid of— to cure rickets. I mean, so fish oils played a really important role in supporting our health. When we talk about— again, I think we talked about earlier the yin and yang, that omega-3s are important to keep our cell membranes flexible. They have some anti-inflammatory benefits. They the pure— this EPA, the omega-3 in that, in that supplement, or even better, the pharmaceutical, the better the outcomes in the longer-term studies because you just have more control over what was in that fish. Every fish has a different life, and that dictates the fatty acids that are in that fish's oil. So in comparison, C15, again, we talked about getting it from dairy fat, but that becomes complicated. So again, that's why the Navy funded us to isolate C15 and create a pure bioavailable form that you can control. And again, this was for the dolphins to control and supplement the dolphins' diets so they could get exactly the amount of C15 they needed. So it's a stable powder at room temperature versus an oil. So again, complementing each other. Um, uh, yeah, I'll leave it at that.

Okay. So they can complement each other. So So, DHA and EPA, if I look at a fish oil label, what is it, docosahexaenoic acid and eicosapentaenoic acid? Am I even close?

Yeah, that was it.

So, we nerded out before. I want to nerd out again just real quick just so people kind of understand this. So, C15 is 15 carbon atoms with a single bond. And then, EPA and DHA, what do those look like? If I were to look at a diagram or a picture of an EPA and DHA next to a Omega-3s versus omega-6s?

Yeah, so they have— They're polyunsaturated fatty acids, so that means they have multiple. So poly unsaturated means double bonds. Polyunsaturated means multiple double bonds. So it's a longer bigger kind of more complicated molecule that has lots of hinges and lots of bending points which is why they're oils at room temperature. It's why omega-3s are oils. And why they're more susceptible to oxygen. So, if you're, you know, like leave the oil out of the fish oil supplements, they can get rancid.

Or it gets shipped via Amazon and sits out in the summer heat for 90 degrees on your doorstep for 2 days while you're on vacation and you come back and put that in your fridge, it's still probably damaged.

Yeah, exactly. And so, that fishy smell you get is the oxidation of those fatty acids. So, it's not the manufacturer's fault, right? It's just— they're just molecules that are naturally more susceptible to attack by oxygen. The nice thing with, you know, with C15 is that whether in the bottle or in our bodies, its job is the opposite. It's meant to protect us against lipid peroxidation and shore up those membranes, but also be incredibly stable in the bottle.

Yeah, so it sounds to me like your take on fish oil is probably a little bit similar to mine. I love fish. On any day that I eat fish, I don't use fish oil. And so, that's on 3 days of the week. And then, on the other days, I take about 1 to 2 grams of a DHA/EPA blend that I keep in the refrigerator. And so, I kind of go back and forth. And I recently added C15 into the mix after reading your book. I decided to do— well, so far, I think I'm 2 months into kind of trialing using C15 via this supplement called Fatty 15. So, I've been taking, I think the label says 2, I've been taking 4 of those a day. Is that okay?

You know, 3 maybe, 3.

Okay. Alright, I'm an overachiever.

Well, you may be catching up. Maybe you're catching up. Because again, it's like—

I've been getting bigger. I'm almost 200 pounds now and I get a little bit of flack for this, but I don't purposefully keep my body fat low. But, I'm 4% body fat and 200 pounds, so I have a lot of muscle and I just feel like I need a little bit more than the average. I don't know if that's true.

Well, and also, I think it depends on a person's diet. If you don't eat a lot of dairy, then—

I don't. I'm pretty lactose intolerant. I forgot to mention that.

Yeah. So, it might be, again, maybe some catch-up, but we have people tell people start with one, work from there. And you have over 95% monthly retention rate. And it's not because, you know, people are just crossing their fingers and believing. It's that, you know, they're seeing and feeling benefits within months. And so those doses seem to be working for most people.

How many, like, milligrams is in one capsule?

100 milligrams.

And in the studies that you've done, you know, because I'm sure you're running this in the supplement industry, people will like make a supplement but it's nowhere near dosage that was actually used in the study or extrapolated to humans. How does the Fatty15 match up?

Yeah. So, it matches up. So, there have been multiple clinical trials. One of them used 200 milligrams. The other one did use 300 milligrams, but what we'll cover is that these clinical trials were done in people who were likely C15 and then we saw C15 deficient. So, again, kind of to your point, Ben, that if you're starting from a C15 deficient state, so people are purposely avoiding whole-fat dairy, then— or have a condition consistent with C15 nutritional deficiency, there's some catch-up that's needed. And I think there was a desire by the people who are running the study to say, like, we really want to kind of push it to a higher amount so that— because it's only for 12 weeks, it's not for 6 months or a year. So, they were pushing it higher to say, can we see benefits within in 12 weeks.

Ben: Okay, got it. Well, if people want to try the one I'm using, I'll put it in the shownotes at BenGreenfieldLife.com/C15. So, I want to kind of give you a little chance, maybe slightly lightning round-ish here, but you've had some people try and take down your research. And, I came across it. I do a little bit of stalking, a little bit of my own research in anticipation of these interviews that I do. So, there's a really popular podcast called The Proof. And, more or less, the summary of a YouTube video that they did was they said C15 is non-essential for humans and lacks strong evidence for metabolic health benefits and shows inconsistent absorption and effects in studies. What say you?

Well, it's easy to say things on YouTube, I'll say you that. It's a lot harder to get things published in peer-reviewed studies. So, we'll cover a couple of those things. You know, the— and I will say, Ben, I— my hope is that the intent of some of these, you know, takedown videos are not— it's because there's earned skepticism in the supplement industry. Right. There's a good reason for this. Right. And it's really hard to keep up with the latest C15 studies. Literally every 3 to 4 weeks, there's a new paper coming out around the world. So it's real hard unless you're spending all of your life like I do looking at the latest studies, which is one reason for writing the book, right, to have one resource for, for all of these studies. It's hard to keep on top of things. So my hope is it's not nefarious. It was just an unintentional misinformation that was provided. And so when we talk about, you know, there's no evidence that it has at all that it's essential, we already talked about not only did we show that it's essential, but now multiple teams have done the gold standard studies to show even beyond what omega-3 and omega-6 had to do to get their criteria of essentiality. We have surpassed that thanks to multiple teams coming in and revalidating it. So there is absolutely strong evidence for C15 as an essential fatty acid. So with regard to metabolic health, you know, when we talk about— if we walk our way up from mechanism of action, we know C15 activates AMPK and AKT. That was then showed in cell— and I should mention activating AMPK is the main mechanism of action of metformin, which is the top, you know, leading diabetes drug, right, for globally. When moved into cell lines, C15 at those concentrations of activating AMPK and AKT were shown to improve glucose uptake at the cells. Even interestingly, Fu et al. showed that C15 actually mimicked insulin. It not only improved insulin sensitivity, Ben, it actually did as well as insulin in these cell-based studies. Then we moved to in vivo efficacy studies. So then you treat a mouse that has type 2 diabetes, showing that it decreases insulin— I'm sorry, decreases glucose, you know, the whole suite of, of components of type 2 diabetes. Then you move into the human studies with regard to these large-scale human epidemiological studies. The higher C15, the lower the risk of developing type 2 diabetes. So we had a third party come in and actually review our claims for VADi15 and review the science and to say, are these substantiated? It's called CARSS process. And they absolutely said with regard to our claims including metabolic health that there's clear substantiated evidence that C15 plays a core role in supporting our metabolism.

Ben Greenfield: Right. And, I know that a lot of people will say, "Well, you showed that high levels of C15 in these models whether animal or human models is associated with all these benefits, but you haven't shown that taking your pill, your supplement, your Fatty 15 causes those same benefits. I've heard that. What do you think about that?

Yeah. So when it comes to clinical trials, right, so then you need a clinical trial in which people have the condition. And so with supplements, we haven't— that study, absolutely to your point, haven't been done yet. The studies to date on clinical trials have focused on fatty liver disease, and that's because the hypothesis is that fatty liver disease, which didn't non-alcoholic, or it's now called MAZLD, it's going through a rebrand, didn't exist before 1980. And so one of the hypotheses is that decreasing C15 levels that happened since the 1970s, and especially since the 1990s, have gone down population-wide, that then, um, these deficiencies may actually be causing fatty liver disease. So the clinical trials are being triaged based upon urgency. 1 in 3 people have fatty liver disease today. And so the 2 clinical clinical trials that have been done with C15 have been on people with fatty liver disease, history of fatty liver disease. The first one, which was 200 milligrams per day, had people go on it. And this clinical trial, Ben, was a home run. And the reason for that is 2 out of 3 of the people in the study, they were 18 to 24 years old, had what we defined as a nutritional deficiency, right? So they had C15 levels lower than this 5 micrograms per mL. So, so first of all, we're saying like, okay, 2 out of 3 people with this condition have what's defined by— through cell-based studies, from the dolphins, from the epidemiological studies, all rally around we need 5 micrograms per mL at least to not be deficient. So it showed that 2 out of 3 people met this criteria of deficiency. Then among the people who took C15 supplementation, and got their levels up and above that 5 micrograms per mil, they had lower liver enzymes of ALT and AST, which is improved liver function. And again, these people had high liver enzymes at the start of the study, and it also increased, uh, their hemoglobin, which again, kind of going back to the whole aging rate and stability of cells, includes red blood cells. This is a marker of improved red blood cell health, which was not the intent of the study but was really interesting, which leaves you with why did half of the people who got C15 not have an increase in their C15 levels?

Ben Greenfield: That's the other question I was going to ask you because Dr. Bill Harris of OmegaQuant, he came out with an article and said, well, half the people who took it didn't even see an increase. So, there's questionable aspects of the absorption effectiveness of it.

Right. And fair enough. I mean, so what's important is that a couple of things. The first is that extensive clinical trials, pharmacokinetic studies have been done on this pure free fatty acid C15 ingredient. This was done by Mascarenhas et al. and Stallings et al. And they did lots of people. They did adults, they did kids, they did people with and without cystic fibrosis. And Ben, what they showed across two papers, an extensive clinical trial, clinical trials were that this molecule is 100% bioavailable. So how much you ate reflects exactly how much was in your, your blood. So that leaves us with the question of what happened in this clinical trial. When you read more into the paper, what they showed was that the people who had the increase had a 95% adherence to the protocol. So they actually took the amount of C50.

Basically not doing their homework. Yeah.

Yeah. So, if— and it's there and it doesn't explain all of it, but a good portion is that it definitely— it was significant of people who actually took the C15 had higher C15 levels. And importantly, among that group that took— that adhered to the protocol, they had the increase and they increased their levels by 2 micrograms per mL, which exactly matches the 200 milligrams which is what the prior study showed that for every 100 milligrams you eat, you go up by 1 microgram per mil. So, when you look at that group, it was spot on. So, the big question is, well, if you don't take the supplement, you're not going to increase your C15. And, they were 18- to 24-year-olds. And, Jeff, it's kind of the worst group for adherence.

Okay. So, that was a 12-week study. So, what I'm getting from what you're saying is that there's probably still a need for longer-term human clinical trials of taking C15. But, the way I think about this is if somebody's listening in, I'm a total kind of n=1 guy, guinea pig stuff on myself all the time. Somebody could theoretically start taking this, you said 100 to a maximum of 300 milligrams a day, and then get pre and post bloods and maybe even this Genova Diagnostics C15 test to see what their absorption or what impact it has on the levels. Lots of people, especially my listeners who are smart cookies, know how to do that. They know how to get a pre-blood test, take a supplement for X amount of time, and then do a post-test to see what their levels are and see how it changed their biomarkers. But, the question I have for you is if somebody was going to do that, how long should they wait between the pre- and post-test for the C15 to build up or to have its effects based on what you know?

Yeah. So we do just like you said, we strongly recommend that every person before they start Fatty15, the supplement, to go get your bloodwork. C15 levels, great to assess, to look at. But what's more important is are we seeing clinically relevant improvements? Right. So start and get your baseline bloodwork, which includes— and sometimes you might need to ask for things like ferritin levels and your full red blood cell indices, because there are some special things like that RDW measurement that is kind of like bonus measurements of efficacy. But get your standard CBC and chem. Go back, we say, we recommend between 3 to 6 months later. And that's where, if you go to our reviews, and that's where, Ben, we're seeing again why people stay on Fatty 15 and retention is so high people are doing exactly this and they're seeing the benefits. I mean, science works like this is, you know, it's what Nick, you know, Shork, right? Dr. Shork, head of NIH's Longevity Consortium. It's why he has explained that there is no— of all, given the breadth of data across all these different aspects, he said there is no molecule that has more support as its role as supporting its role as a geroprotector or long-term health and wellness than C15. And this is Nick Shork saying this who has seen everything.

Yeah. Well, okay. So, 3 to 6 months, that's helpful. This whole thing has been helpful, by the way, and we barely even kind of broke the surface of everything that's in this book. I'm holding it up for the video, Longevity Nutrient. If you go to BenGreenfieldLife.com/C15, yeah, the letter C15, you can check out the shownotes, get the book. Check out the supplement, et cetera. Last question, Stephanie, from my kids and wife. Can you talk to dolphins? Do you speak dolphin?

I can speak dolphin by being a nerd that analyzes their data and I can tell you how that one's feeling. Gosh, I wish they could have told us from the beginning, "Hey, Steph, I slept better last night," or "My arthritis is feeling better." We had to figure that out down the road. But, there is new technology coming out that I think we're getting closer. To actually being able to interpret dolphin language, which is scary.

I do some turkey gobbles and some elk calls. And, I don't know, if they made a dolphin caller, I'd try it out. Ee, ee, ee, ee.

Something like that. Hey, you did that a lot better than me.

All right. I've got a little dolphin in me, I suppose.

I don't know.

I'll have to get a genetic analysis for that. Stephanie, this was great. Again, the shownotes for everybody listening in are BenGreenfieldLife.com/BenGreenfieldLife. Ben-greenfieldlife.com/C15. Dr. Stephanie Van Watson, the dolphin whisperer. Thank you so much for coming on the show.

Ben, it's been an absolute pleasure.

Thank you. Alright, folks, have an incredible week and try Fatty 15 if you want to. Leave the comments, questions, feedback in the show notes at ben-greenfieldlife.com/C15. Read the book too. It's great. And until next time, I'm Ben Greenfield along with Dr. Stephanie Van Watson signing out. Have an incredible week.

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