Scientists Discuss Brand New Heart Health Studies (ft Mike Mutzel)

Patients really relied on their doctor's direction. Now, with the explosion of social media and freedom to access information, patients get curious.

When people think like, "Oh, I'm depressed, I should just go get an SSRI," and not change their diet or their exercise or their lifestyle, we're really missing the bigger picture here.

Simple things like amino acids that we have in our protein-rich foods affects everything from diabetes to heart disease to brain health. Metabolic health. Underpins all of this evidence base does not line up with what actually might be the best practice. Is it possible if you're upwards of 50 that apple cider vinegar could protect your endothelium from undergoing senescence? One therapeutic could be fecal transplant. So if you're young and healthy, you might be able to sell your poo in 10 years to old rich people, who knows? All right, I'm back with the third program in our interview series. Now here with Mike Mutzel from the High Intensity Health Channel. You probably know it. If you don't, you definitely should check it out. Mike earned his bachelor's in science from Western Washington University in biology and then got his master's in health and nutrition from the University of Bridgeport. Given our shared interest in cardiovascular health and how much he covers it on his channel, I thought he'd be a really fun person to unpack some breaking research findings in the area of cardiovascular health. So we're gonna have two parts to this interview. The rule for part one is we can only focus on on new 2025 research covered in top basic science journals. So actually from Nature, Nature Aging, and Cell Reports Medicine. We're going to go through 3 studies, and then part 2, we're going to talk about a study in particular that I found really shocking. It excited me and shocked me. You're going to hear all about it. I'm interested to get, uh, Mike's take since I shared it with him as well. It was something that I consider the most overlooked study of, uh, 2024, and and we'll see if we can live up to that hype. But with that, Mike, thanks for joining us.

Nick, it's great to be here. Really appreciate you extending this invite. And yeah, I'm very excited to dive into all things gut microbiome as it is interfaced with the etiology of cardiovascular disease. I think this is really underrecognized, but really important to explore. And I like that you're relegating this to very recent articles because we're going to dive into some complex pathophysiology.

Yeah, well, you gave a teaser. So, two of the studies have to do with the gut-heart axis, covering a couple hot molecules. One's called, and brace for jargon, imidazolepropionate, and the other's called phenylacetic acid. But before we get to those, I just want to start off with like some high-level questions. So to start us off, my impression as both a scientist but also as a recent medical school graduate is that Cardiology and lipidology is moving away from the ApoB/LDL-centric view. I know a lot of people still beat that drum, but I think the aperture of focus is changing. From your perspective as a scientist and a content creator, do you agree or disagree?

Hmm, Nick, it's a great question. I would respectfully disagree in terms of clinical practice. And I say this with experience having been on the sales side for advanced lipoprotein particle testing. I got— just quick backstory— I got into sales, and that's how I got into, you know, marketing and, uh, and, and then producing this content because I would interview my customers back in 2014. And I started selling advanced lipoprotein particle testing back in 2007 for a company called Spectracell. And even back then, like, I was really excited about the prospect of using what's called ultracentrifugation to look at the different phenotypes of LDL, remnant lipoprotein, VLDL, and so forth. And back then, you know, a lot of doctors really didn't care and see the clinical value of even doing that. And I think the narrative is changing a little bit in clinical medicine, but I think still most mainstream practitioners are now just starting to look at ApoB to ApoA-1 ratios and maybe do some, you know, other esoteric tests, fibrinogen and Lp-PLA2, and possibly look at plaque with Cleerly, for example. But I think, you know, I love all these new, you know, articles and mechanistic findings that help us better understand the etiology of disease, but I have found just being on the other side that it takes a very long time for, practicing clinicians and the healthcare apparatus to adopt these new things. So that's my perspective. Now, I'm not out working knee-to-knee with doctors anymore. This was in 2007 to 2011. But again, I think, you know, working with clients, I help people with their blood work all the time, and they'll go to Kaiser and these big HMOs and send me their labs. And Nick, you wouldn't believe it, they're omitting very basic biomarkers like GGT or ALT, just looking at AST, the 3 liver function tests. You know, sometimes they'll have iron but not ferritin, right? Or they'll have glucose and maybe A1C but not insulin or, you know, fructosamine. So I just see this cost-cutting when it comes to testing and trying to, you know, really squeeze in as many patients as humanly possible in a short period of time. So that's just my perspective, but I could be wrong.

Yeah, I love the perspective, and thank you for respectfully pushing back. I think there's a lot of truth to what you say. I'll posit one more thing. Which I find interesting, or I'll play the devil's advocate, which is in medical training you're taught don't order a lab if you don't know what to do with it. So that brings up the question of actionability, which is dictated by what tools are available, including medications. And so when you have these biomarkers that can be acted upon with potentially lifestyle interventions, even if skeptical, and we'll get into this in a moment. So it's kind of, you know, the border on like, do we have data that this intervention actually changes this biomarker with, you know, outcome efficacy? Um, versus what has been proven in the most, quote, rigorous clinical trials. So it's at a very high level the limitations of evidence-based medicine, because you need to check certain boxes to be considered standard of care, which doesn't necessarily mean the best care. But, and, and we can circle back to this later because I want to get into the, the new papers, but one thing I'm finding— I'll see if you agree with this— is that, you know, 10 years ago even, patients really relied on their doctor's direction. Now with the explosion of social media and freedom to access information, including from content creators and scientists who are speaking about it freely publicly, like you and me, it forces some bottom-up change whereby like patients get curious about data, different biomarkers, and then can go request that their physician work with them based on what's interesting. So I'm sensing a little bit of a shift that is a unique bottom-up shift as the general public and like academic medicine are having this incursion. We can table that, but I have an optimistic bend. I just want to get your reaction to that. And then I'm going to jump into the first paper.

For sure. No, I wholeheartedly agree with that, Nick. I think many patients are actually driving the expansion of medicine. And now with ChatGPT, you know, and AI using tools like that, I know many friends family members who are into functional medicine who just throw in their labs and their symptoms into ChatGPT. Not saying that that is the best tool, but they are— and then taking that information and helping, um, you know, the clinicians start to consider more testing or more tools that could be helpful in ameliorating their condition. So yeah, this bottom-up approach is really nice. Yeah, um, podcasts and all that, the democratization of science and information. And I think younger generations don't have that same appeal to authority that older generations did when it comes to practitioners. Um, and so yeah, and we can get labs now and go to anylabtestnow.com, and even Quest and LabCorp are just opening up their accessibility to just patients ordering their own labs.

There's so much direct-to-consumer and so much like biomonitoring technology that I think is going to make huge advances. Maybe that's for another time, but I do want to get into these studies. So the first one we're going to talk about was a new study that just came out in Nature about a molecule called imidazolepropionate. Now, I know we both read this paper. Just to give people a high-level overview, imidazolepropionate is a microbiome-derived metabolite that is made from histidine, which is an essential amino acid, and it has been linked to atherosclerosis in humans in a dose-dependent manner. So they looked at two different human cohorts in this study, including, I think it was the PESA cohort and the IGT cohort, and there was a dose response effect whereby higher, uh, IMP levels were associated with worse atherosclerosis on CACs and vascular ultrasound. And then they did mouse models atherosclerosis and treated them with IMP and saw a pretty impressive progression of atherosclerosis that was cholesterol independent. So that, that's my high-level summary. Are there things you saw in this paper that— like, first of all, let me just ask What were your main takeaways, and did you find this paper compelling overall?

Yeah, I thought it was really interesting, um, to consider that short-chain fatty acid-like metabolites, or this acetic acid, which we'll talk about later, propionate, butyrate, all these compounds, um, ultimately impact, you know, this inside-out level control within the gastrointestinal microbiome and the intestinal lining, but also systemic physiology, and contribute, as you mentioned, the— to the etiology of atherosclerotic plaque formation. So to me, I think this is really incredibly fascinating, and it helps us better understand conceptualize food. I think we really think about food in terms of calories and macronutrients and don't think about the quality of food, the fermentation, how it's prepared, whether, you know, bread has been properly fermented or, you know, risen via yeast and things like that. It helps us better understand the importance of eating healthy, whole, unprocessed, unfried, unadulterated foods for improving just overall systemic diversity of the microbiome in there. And as a benefit of that, you're going to get better levels of these various short-chain fatty acid-like metabolites. So that to me was, was really exciting. Um, this particular paper I didn't dive into as much detail as the other ones, but I think it really then sort of dovetails into, in my opinion, the ketogenic diet and the idea that beta-hydroxybutyrate and butyric acid from the small— or sorry, large intestine— there is some crosstalk and interconversion between those two compounds. And so to me, I just think it's another exciting mechanism that we can look to in terms of amelioration of not only gastrointestinal issues but also systemic atherosclerotic cardiovascular disease.

Yeah, so I'll give a little bit more detail on this paper and then ask some high-level questions since we were kind of getting there, which was my impression, you can correct me if you had a different reading, but that the way in which IMP causes atherosclerosis was through inducing basically inflammation and insulin resistance, in particular insulin resistance This was a molecule that was actually, you know, commented on in the literature in a paper in Cell back in 2018 as a cause of insulin resistance and diabetes. And the mechanism had to do with basically blocking insulin signaling at the level of the insulin receptor. I know a lot of jargon, but the thing I want to highlight here, which I find interesting, is you have the same molecule popping up in different metabolic disease states. And I think we often look at different diseases as very siloed. Metabolism is very siloed. But to see the same Gut-derived microbe popping up as potentially causal in multiple diseases makes a lot of sense to me in terms of an integrated model of mental health— I mean, metabolic health. Often these papers are like novel discoveries that aren't yet actionable, and people want the 'what do I do?' So my question to you is, based on this literature, what can we say actually helps? What can we say, you know, is speculative, and where might people get trapped into misleading conclusions?

Yeah, that's a good question, Nick, and that's sort of where I struggle with this paper because, you know, this is a histidine-derived metabolite as far as I recognize and interpreted. And of course that is going to be synthesized via the breakdown of more proteinaceous foods that are in lower— of lower glycemic index and things like that. And most people have improved their health by consuming more high protein, low carb foods, especially our audiences, right? So that's where it's a little bit, um, of a mental incongruence for me when reading some of these papers and not getting overly excited about some of these gastrointestinal derived— you know, there was the whole thing about TMAO several years ago, you know, for example, and then there's endotoxin, and that was a huge story for a lot of years. And so I just— with some of these, you know, new articles, I think it's very interesting for sure, But interesting on a high level that we should be eating a whole foods omnivorous style diet to help to balance out the overall gastrointestinal ecology. That's, that's kind of where I look at this, unless one day we do get a biomarker or a test where looking at short-chain fatty acids in the stool, you know, then we can really be more precise about which foods we do or don't eat. But I do see, or have seen over the years, some conflicting information about propionic acid to fecal acetate ratios as it's linked with obesity and things of that sort. But yeah, so back to your question, I struggled with the conclusion of this because essentially they— the authors insinuate that it was protein-rich foods that are causing the increase in the histidine metabolism that preferentially forms the IMP, which then of course is linked with diseases. So yeah, pitch it back to you. What, what are your thoughts on that conclusion?

I had a different read. I had to read— so this is one of those situations where like I saw what the author said and then what was being said on social media, and I saw a big discrepancy, which is not the fault of the author. So, um, to your point, this is a histidine-derived metabolite. So what I saw first and foremost is actually how it came to my attention is, you know, when something's happening in our community that let's just say the bulk of the audience isn't happy with, they poke you to respond. And the thing that was popping up was there was a lot of very plant-based people saying— or plant-based people, not very plant-based people, you're plant-based or not, I guess. Um, actually, that's not true. There was a lot of people in the plant-based community that were suggesting that this proves meat causes cardiovascular disease. That came up several times because their logic was— and people probably can follow why this seems logical— all right, meat, it's high in protein, it's high in essential amino acids, Therefore it has cysteine, which can be derived or turned into IMP, therefore heart disease. So what appears at first to be like a reasonable conclusion really starts to degrade when you start to look at the literature. So for example, first of all, even plant-based proteins have all 9 essential amino acids. So right there, your argument is kind of like falling apart when you're looking at meat in particular. But there's an assumption built in that I don't think most people see, which that histidine is actually limiting. So in any, you know, process, there are limiting factors, there are non-limiting factors. And if you actually look at the human literature, there is none whatsoever association between dietary histidine and IMP levels. And I raise this because it's one of those things where you want to draw conclusions, but you actually have to go into the broader literature to try to validate whether or not your, like, speculations make sense. And in this case, there was a really good paper where the authors, I don't think, drew inappropriate conclusions per se, they noted some associations like Mediterranean-style diet, healthy user bias there, but with lower IMP levels, fine. But then the internet went berserk about, oh, you know, histidine meat heart disease. And I have nothing more to say than I guess— I guess my question for you is, how should people buttress against, and I guess put like airbags on, for inappropriate speculation from new breaking science? When it's cool to speculate about new breaking science and it's fair, but it can also lead you to very inappropriate conclusions. So how do people grapple with that?

Yeah, this is a great question. I think we just see history repeat itself.

Now that history is to repeat itself.

When there is one particular biomarker that is associated or elevated and is linked causally with another disease process. And as I mentioned, the TMAO thing, this was a huge story in like 2014, 2015, and everyone said, see, this is why we should not be consuming red meat, because red meat forms this trimethylamine oxide, and so does seafood and so forth, and that, that is linked with atherosclerotic cardiovascular disease and all this. And so there's always these one-off, you know, biomarkers, but I think there's so much about the gut and the microbiome that we still don't even know. And so really kind of monomaniacally focusing on these one-off biomarkers, as seductive as they are, and as interesting as it is finding that different metabolites can systemically make their way throughout the body and initiate disease processes that are very common like heart disease, I think it's seductive and really interesting, but we still can't really measure these, you know, in clinical practice. So that's why I just, again, go back to this idea of eating an omnivorous diet, whole foods, not, you know, eating a lot of fried, you know, refined carbohydrates and things like that because overall eating an omnivorous style diet as well as exercise will improve the diversity of the microbiome support the intestinal lining and contribute to an ecosystem that is much more healthy. And we're not going to, you know, focus just on one esoteric biomarker. Instead, look at the collective, you know, holistic. So that's my perspective.

First of all, great use of the terms monomaniacally and seductive. I'm going to get on to our next paper about the microbiome and, um, and heart health. But before I do, you were just talking about generally— I mean, I, I like how you're bringing it back and giving broad, generally good principles. So I'll just tangent for a minute and I'll plug this to you because this is going to be something you want to cover. I found a paper on Cell Metabolism this morning. It was actually from last year, 2024. Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity. So people can look this up anyway. Um, this is mental health, not necessarily cardiovascular health, but it plays on the same themes of amino acids. So in this case, tyrosine is the precursor to this homovanillic acid. It's in the dopamine synthesis pathway. And then ecosystem, like you're talking about fostering the right ecosystem. And so in this case, they found that basically in human depression, there was a deficit in this homovanillic acid, which is a neurotransmitter made by the gut that can actually cross the blood-brain barrier. So to differentiate from where people say like, oh, 90% of serotonin is made in your gut— yeah, that can't cross the blood-brain barrier. This can. It's depleted in human depression. And then when they did several mouse models, they were able to show that replenishment directly of the homovanillic acid or the bacteria that produce it, a Bacteroides species, was actually able to reverse depression in multiple mouse models across multiple tests. So that's a topic for another time, but I just think it plays into this theme of whole body systemic health and how simple things like amino acids that we have in our protein-rich foods can interact with our individual microbiomes to produce very— a very complex web biomolecules that affects everything from diabetes to heart disease to brain health. And all these things are interconnected. I'll let you react to that first. I didn't prime Mike on this paper, so it's not fair to get him to respond on it. But before we go on to our next paper, that was— yeah, no, I think this morning—

that's awesome. And that reminds me of another related serotonin metabolite, an enzyme that is responsible for metabolizing various serotonin derivatives and so forth, indoleamine-2,3-dioxygenase, or IDO. And that has been a big story for a while as well. And basically it dovetails into what you were just saying there, Nick, and that is that whole body and reducing systemic inflammation can actually improve neurotransmitter levels in the brain as well. And so this metabolite has been shown to selectively or preferentially pull serotonin and use that to create more inflammatory-like compounds. And so there's a researcher in the UK, Michael Ash, he's spoken on this a lot, and I think it's just incredibly fascinating and it just When people think like, "Oh, I'm depressed, I should just go get an SSRI," and not change their diet or their exercise or their lifestyle, we're really missing the bigger picture here. And that is if there is pathological microorganisms or dysbiosis or intestinal permeability or chronic low-grade inflammation, then of course the whole body, including the brain, would be imbalanced. And so we gotta get back to the basics here.

Yeah, no, that's a great point. Now we're going off on a tangent, but just because you bring it up, you like mentioned SSRIs. Like, something interesting about SSRIs is what are they? They're selective serotonin reuptake inhibitors, so they boost serotonin levels. But clinical improvements don't necessarily line up with how the serotonin levels are increased, so it's more complex than that. There was a recent paper that I can send you. Basically what they were showing was that different antidepressants— so they looked at ketamine and SSRIs in this case— converge on a basic metabolic process, autophagy, which in depression is dysfunctional in a depression region of the brain. So what ends up happening is, um, levels of the receptor for the brain's main excitatory neurotransmitter called glutamate build up in the depression center of the brain. So your brain literally gets biochemically like despair and depression tuned up. And then what the antidepressants do, as well as other things that could modulate autophagy, is they bring this back into balance. So you have the appropriate balance of excitatory and inhibitory neurotransmitters in those key brain regions. So again, the theme is metabolic health underpins all of this. It's sometimes just really hard to dissect. The brain is a good case of a black box. And then it's in tension with modern medicine, which requires a very specific set of criteria in order to prescribe something as standard of care. Speculation and physiology isn't good enough to be, quote, evidence-based. But that also means evidence-based does not line up with what actually might be the best practice, including for the individual. So my soapbox there. I do want to get on to this next paper about, um— now before we move on, a quick tangent. I want to thank the sponsor of this video, Chapter. I know sponsor messages can feel like a pill, but bear with me, this one's important and could save your life, or your parents' lives. First, here's a transparency statement from me. After 2 doctorates and over a decade of higher education, the US healthcare system and insurance markets are still the most complex thing in the universe to me. It's more complex than if the Krebs cycle swallowed the chronic cascade and chased it down with a glass of quantum biology. But here's why this really matters: the right health insurance can literally improve all cause mortality. And that's not just a correlation, there's causal evidence for this. The methods are kind of complicated, and you can see this Nuance Note letter for more. I've linked it in the caption. Anyway, that is why Chapter exists. It was founded by people whose parents were scammed by sleazy Medicare brokers, and they vowed to fix the system, and actually built a model that does just that. They search every Medicare plan to match you with the right fit. For you. And Chapter is fully independent. It searches every Medicare plan available to find the one that truly fits your needs and priorities. And you'll always talk with a real human, too. And their advisors aren't compensated based on steering you to a particular plan. That means the results are savings for you in 3 currencies: money— the average user saves $1,100 per year— savings in stress— it's always nice to talk to a real human and have them handle it for you— and even maybe savings in life years. Now, if this could help you or a loved one, we've set up a phone line, 815-STAY-CURE, as in stay curious. That's 815-782-9287. Metabolic health is life insurance of a form, but you also need the right real health insurance. Thanks for listening. Back to your main program. I do want to get on to this next paper about phenylacetic acid. So you're talking about inflammation. There was a new paper out I think was Nature Aging. So phenylacetic acid links aging to cardiovascular dysfunction. In particular, what happens is with age, there's a microbiome change. We talk about the microbiome. Levels of this phenylacetic acid increase, and then it causes damage directly to the blood lining, the endothelium, in particular causing oxidative stress, inflammation, and ultimately endothelial senescence, which is a hallmark of aging. They prove that causal mechanism in animal models. Again, in humans, PAA levels do increase with age, and PAA levels are dose-dependently associated with major adverse cardiovascular events. So again, taking what we can from the human literature and then building mouse models to, you know, prove a causal mechanism. What did you think of this paper?

This was really exciting to me, um, because I quite like this understanding pathophysiologic drivers of cellular senescence. And I know this is sort of a big, you know, multi-syllabic word and people aren't totally familiar with it, but the way that I think about cellular senescence is like rusty cells, cells that should apoptose and die, but they're stuck and they start to recruit other cells to misbehave via this secretory-associated senescence phenotype, or the SAS, which is really problematic. So a friend explained to me, you know, to conceptualize this. You know, when we were younger in high school and, you know, maybe middle school, our parents were like, hey, don't hang out with those kids because they're bad and they'll cause you to do bad things, you know, steal, you know, getting involved in criminal activity and so forth. Well, it turns out senescent cells recruit normal healthy cells to behave more, more badly, and they start releasing just low-grade smoldering inflammation that can compromise the function of the healthy cells. And it turns out that this you know, microbe-derived, you know, phenylacetic acid metabolite, PAA, does exactly that via epigenetic mechanisms, which I think is really particularly interesting. So it causes cells to epigenetically— it changes not the hardware of the cell, but the software governing the function of the hardware to then cause it to function, you know, more in a, in a reduced compromised state, a senescent cellular state. And that dovetails into what you're just talking about with serotonin, Nick, and that is autophagy. And one of the reasons why autophagy is this really sought-after mechanism that may be ascribed to healthier aging is it may decrease the formation of senescent, or cells that should apoptose and die, by, through various mechanisms. So to me, I think this is really exciting and helps us better, again, understand the diseases or ways to ameliorate aging. But the specifics on that, I want to pin back to you and sort of ask you what your thoughts are there. But yeah, this is a really interesting mechanism to me.

Sure. Yeah, I like that analogy, rusty cells. And the way you were describing it also sounded almost like a zombie apocalypse. Like the— I'm imagining I Am Legend and all these zombie senescent cells infecting everybody. But autophagy is an interesting potential therapeutic. I'm actually not expert in autophagy at the endothelial level and whether or not that can function to improve the endothelium. Somebody might— more knowledgeable than me might be able to comment there. I guess to your question, other mechanisms— well, based on the kind of causal cascade, so aging in particular was associated with changes in certain Clostridium species. I think one was ASF356, not very creatively named. But, um, if it is microbiome in origin, so age-related microbiome changes, then What about fecal transplants? I mean, we already have pretty decent data on, like, say, plasma transfers for reducing biomarkers of aging. In particular, there was a paper out, I think, last year, and also Nature Aging, about— they, they were able to identify the component in plasma, in young plasma, that was rejuvenating. There were these, um, small extracellular vesicles. In fact, it was so conserved that you could do human-to-mouse plasma transfers with these small extracellular vesicles in order to rejuvenate the mouse. So you could take an old human or a young human and rejuvenate the mouse based on, you know, taking the young human, not the old human. So it's quite interesting, and I think, you know, has to do with some microRNA signaling and epigenetic modification. But what I'm saying is one therapeutic could be fecal transplant. So if you're young and healthy, you might be able to sell your poo in 10 years to old rich people. Who knows? Um, that's one idea. Uh, I have a few others. What do you think about that though?

Yeah, um, FMT I think is amazing. I've had several people that I know who had a lot of antibiotics and things like that as a child who got, uh, you know, FMT from a healthy donor, a young donor that had never received antibiotics and was, you know, vaginally birthed and breastfed and the whole thing. That to me is an amazing intervention. I also think Helminth Therapy, or, you know, non-pathogenic parasites as a, as a therapeutic tool Have you ever read the book "Epidemic of Absence" by Moses Balikwesmanoff?

No. Cool name though.

Amazing book, everyone needs to read this. And it's basically this idea that humans, ancestral humans, we evolved and grew up, you know, and were raised and lived among rats. You know, if you think about, if you walk around London or Manhattan, you see rats everywhere. And our immune system evolved to have a, sort of resilience about in relation to the parasites that we would be exposed to from the rats that would be living among us. And now that we are so clean, we don't have rats around. I mean, they're, they're, you know, in their, our, you know, basements and they're on the streets, but they're not in our vicinity as they were several hundred years ago. And that is causing our immune system to be a little bit overactive and changes the T regulatory cell phenotype or setting, which can worsen Autoimmune Disease and Chronic Inflammation. So, um, great book for folks to, to check out. But, um, yeah, I think FMT is amazing, and as well as Helminth Therapy, there's some pretty good research on that. So if someone has the opportunity, especially if someone has had a lot of surgical procedures, antibiotics, um, weren't breastfed, weren't vaginally delivered, you know, FMT can be a great tool.

That hits home with me. I was actually— you might not know this, my audience probably doesn't know this, but I was C-section birthed, then almost immediately given IV antibiotics, which not good for your microbiome as a neonate. It actually can increase your risk of ulcerative colitis by up to 500%, which I then developed in my 20s. So yeah, microbiome recovery with FMT is really promising. I will caution and caveat that it's not as simple as just like doing a, you know, choosing your host and doing a one-time like feces enema. You have to like collect, store, prime, which does mean throwing antibiotics at your microbiome, which is not necessarily a safe thing. And then you have to do routine treatments. I think right now it's only approved FMT for C. diff infections. So hopefully it's the next frontier or a next frontier, but right now it is risky. So I'm not saying don't do it because I've been at the level where like I kind of wanted to, but even then with my resources, I couldn't figure out what was a good protocol, so I never ended up going through with it. But something for future. Quickly, before we do more on PAA, um, you're wearing a shirt that says, I think, something like pet dogs. I know you're zoomed in now, but you were talking about exposures. And, um, I did some content recently, I released a video. But in terms of like our exposures priming our immune system, there was a paper, jaw-dropping, I'll send it to you. It was, um, they were looking at, uh, newborns, infants at 3 months and whether they were exposed to like pets in the home, particularly dogs. And there was, get this, a 90% reduction in food allergies when kids were exposed to dogs in future life, which is not that surprising. But like, yeah, being overly sterile is not good for our immune systems, especially during early development, during the critical period. So that's a theme. Um, quickly I'll throw out while it's on my mind, so This phenylacetic acid again goes to the endothelium, causes oxidative stress, um, and senescence. One of the things they showed in the paper, which we heretofore haven't mentioned but I'm guessing we both picked up on, was, uh, in their animal models they could treat with acetate. And acetate actually dampened the effects of the PAA and helped reduce senescence. This is interesting because acetate's a short-chain fatty acid made by the microbiome, but you can also consume it other ways. So like if you have vinegar, shots of apple cider vinegar. It's 5% acetic acid. Speculating, but that could actually offset age-related increases in PAA. What I'm saying, to be very direct, is, is it possible if you're upwards of 50 that apple cider vinegar can protect your endothelium from undergoing senescence? What do you think?

I think that it sounds amazing. Um, and coffee as well. I think you, you highlighted some of that. Yerbamate. I think that's fascinating to me. You know, there is sort of this allure to apple cider vinegar, right? I mean, Tim Ferriss talked about, about this in his book, and, and this has been around for a long time. People would say, like, you know, if you have indigestion, consume like a couple tablespoons of apple cider vinegar, lemon juice, things like that, you know, before a meal and even before bed to enhance sleep. And I think sleep deprivation was linked with higher PA levels, if I'm not mistaken. So yeah, all these things I think are really interesting. And again, going back to, well, what is apple cider vinegar? It's a whole food, right? And so that is exciting to me.

Yeah.

Um, mechanistically though, the, the caffeine, the coffee and the yerba mate, how is that affecting PAA?

I think there's a different system. So for example, an antioxidant system called NRF2 is activated by chlorogenic acid, which is in coffee and yerba mate. In this particular instance, I do think that the acetate is probably going to have a more potent effect since it was actually like commented on in the paper and directly intersects with the pathway in question. But I think just like high level, what me and Mike are both saying here, not to speak for you, but I think you're going to agree with what I say, is that these mechanisms are fascinating. And based on understanding the physiology, you can speculate fairly as to what holistic lifestyle interventions or, you know, like whole foods interventions might genuinely converge on this pathology. Now, there's like two important things to note here. One is it's really hard to prove. I get people all the time in my comment section saying, "Oh, but this portion of the paper is just a mouse model." I'm like, "Yeah, but you can't like, you know—" I did the content yesterday and it was about retinal damage from blue light. And they're like, that's just a mouse model. I'm like, yeah, but are you going to volunteer for a study where the researchers then pluck your eyeballs out to like look at your retina after the fact? No, you're not going to do that. So it's the same with, you know, this study. You can't just like rip out the endothelium, um, in humans to look at it. So there's limitations on the type of data we can collect. And that's important not only because it does add a caveat to what conclusions we can make, but it makes it really difficult to translate what actually might be a very powerful intervention into standard of care. Because it doesn't meet those criteria that modern medicine requires for your physician to have it, say, in their training and then to recommend it to you in the clinic. So just the high-level, high-level thought there. Anything else on phenylacetic acid? You did mention, by the way, um, correctly, that there are data on lower PAA, or more in particular, I think it's like, um, it's derivative PGLN levels with sleep deprivation. So another way in which, like, sleep deprivation can increase this molecule PAA, which can then damage your endothelium, causing, in essence, theme, diet, sleep, all these things like change your physiology in a way that genuinely makes a difference on, uh, these, these disease processes. And the answer is not necessarily just pills, but addressing the root cause phenomenology. Incredibly fascinating.

Um, one thing that I do personally now is I test my blood pressure first thing in the morning. There's a new, um, gosh, the name of the cuff, um, I could send it to you, but Yeah, I found, and if I, cause I travel a lot from my work, I have a manufacturing facility in Arizona. So I go down there all the time and I'll notice Nick, and this is related to this cellular senescence and endothelial dysfunction. If I have circadian rhythm disruption, or if I don't get decent sleep, my blood pressure is significantly elevated, particularly my diastolic levels. Normally my blood pressure would be like 110 over 70. And like, you know, this week my sleep has been off going from the East Coast to the West Coast. Now my diastolic jumped up to like, you know, I think it was like 110 over 85, and so— or 84. So it got up. So I just think it's important for people to understand. Now, why are we talking about blood pressure? Well, this can be a reflection of endothelial dysfunction, among other things. So I think, um, yeah, it's just important for folks to have these different wearables and tools to know where they are in the spectrum, because of course endothelial dysfunction is linked with erectile dysfunction, which is problematic for, for a lot of men. Um, so having these things to test is really important. Yeah, so many tangents.

I have to do this one. Forgive me, audience, but I do, because you mentioned blood pressure. There's another paper I was just reading— I'll send it to you— but about how— and we're going to talk about this for the next paper— fat tissue alters your responses to different things in the environment. There's data showing that leptin released from fat tissue can change the vasculature, actually thicken the vasculature at the blood-brain barrier around the hypothalamus, and thereby downstream cause increased sympathetic tone and increased blood pressure. And it actually aligns with some very interesting studies, like including in the New England Journal of Medicine, um, and other studies where they found a link between obesity and, say, salt sensitivity. There is a mechanism by which basically like excess adiposity and the hormones released from fat tissue via acting on the central nervous system could change someone's salt sensitivity. So it starts to piece together, but like just the basic physiology here— I don't ever mean to like fearmonger, but I do think the awe and humility, it does help inspire lifestyle change and deeper understanding than just platitudes like, you know, salt is bad. You know, like maybe some people are more sensitive. Why might people be more sensitive? Maybe they have metabolic dysfunction and excess leptin that's changing their blood-brain barrier. So with fat tissue, one of the papers I know we, we corresponded about was this one about myeloperoxidase, which is a biomarker you can measure. So I'm going to hand this off to you to tell me about this myeloperoxidase paper and why it was so freaking cool.

Yeah, this was really exciting to me because as you mentioned, Nick, is like, this is something we can actually measure. And I do recommend my clients look at myeloperoxidase levels. You know, you can look at Cleveland Heart Lab, Boston Heart Lab, some of these more esoteric, uh, advanced lipoprotein particle type testing, you know, outfits will also look at these ancillary biomarkers. But it turns out that myeloperoxidase is made by the perivascular adipocytes, or fat cells surrounding the vascular tissue, and it tends to then cause endothelial dysfunction among other things. So again, it's, it's an adipocytokine-like compound. You mentioned leptin, so So there's a direct correlate— correlation with adiposity or levels of body fat and leptin levels. The higher your body fat percentage, the higher leptin levels you will have. And it turns out that the, uh, levels of myeloperoxidase tend to correlate with BMI and body fat percentage. And it seems that there are some regional or proximal, uh, pathophysiologic changes here when the, the fat tissue around the endothelium and the perivascularity, the myeloperoxidase, I think it increases hydrogen peroxide and other free radical and basically oxidative stress, which is going to cause endothelial dysfunction, which could lead to hypertension and stenosis and narrowing of the arterioles and capillaries. So yeah, this to me is really exciting. And I think, you know, there was— did they look at individuals that had undergone bariatric surgery noting reductions in— Yeah.

Just to— I want to define for the audience, I realize we haven't— what exactly myeloperoxidase is. As Mike mentioned, it's made in different places regionally, including from immune cells, and it is an enzyme itself. And one of the things it helps does is like kill things with, you know, help produce like oxidative bursts. So hypochloric acid, I think it's HOCl, you know, very cytotoxic. And this does have a purpose, but it can oxidize things around it. Including, say— so there's multiple ways it can work, but oxidizing LDL, it's one thing that does generate oxidized LDL and oxidized phospholipids on LDL. But like you mentioned, that's like— I'm trying to explain this in a way that captures how cool this is. You have myeloperoxidase like inside the blood vessel, so there's like an inside-out, from in the lumen to like out pathology. So you're damaging the blood vessel lining directly and you're oxidizing LDL. But what this paper showed, which is so cool, Mike mentioned something that you guys might have missed, which was perivascular adipose tissue, or PVAT. So there's fat, like subcutaneous, like visceral, around your blood vessels. And in addition to the, the MPO, myeloperoxidase pool, like, you know, in your circulation, which you can measure, it is correlated with that myeloperoxidase that is made outside your blood vessels. So there's like an inside-out and an outside-in, like, pincer maneuver. On the vessels. And some of the things that the myeloperoxidase does from outside, as, as Mike was alluding to, was, um, it decreases a hormone called adiponectin. And Mike was talking about like hypertension and stiff blood vessels. Adiponectin is kind of like yoga class for your blood vessels. It helps with their flexibility. And myeloperoxidase decreases adiponectin. And adiponectin decreases myeloperoxidase. So basically what you end up with is if you have excess fat tissue around the vessels, you know, in obesity, you get myeloperoxidase, which decreases adiponectin, then adiponectin can't decrease myeloperoxidase, so it just spirals. And you can get stiffer blood vessels. And if you look in humans, you'll have a positive association between body fat and myeloperoxidase, and that negatively associates with markers of vascular function. So one is flow-mediated dilation. So it all fits together really, really nicely. And then there's like vicious cycles on vicious cycles. So another thing that myeloperoxidase inhibits is the browning or beiging of fat tissue. So this is in a mouse model, but basically they showed that the higher myeloperoxidase led to diet-related weight gain, um, because it decreased energy expenditure from this fat tissue, which means then you gain more fat which means then you have more myeloperoxidase, and you see how these vicious cycles compound.

Kind of scary. What's really wild, and I think the other thing that is important to mention here, Nick, and you talked about it, not to get too granular, but the perivascular adipose tissue that we've been talking about, fat around the vessels, they get infiltrated with obesity. Adipocytes in general, whether they're in the visceral adipose tissue or around the blood vessels, get an infiltration of various immune cells. And in this particular context, it was the neutrophils, to the best of my recollection, that increased the that synthesize the myeloperoxidase, right? And so I think that's important to recognize that the more body fat that you accumulate from eating processed foods, not exercising, sleep and circadian rhythm disruption, the more pro-inflammatory your adipose tissue or fat tissue becomes. And then you get all the systemic consequences of this. And the least of which, you know, that we're talking about here would be endothelial dysfunction and beyond. But the other part about adiponectin, and I wanna, you know, ask you this, and this is just me thinking. On the fly here is we know there's an inverse correlation with adiponectin and insulin sensitivity. It's really been well recognized that adiponectin, unlike leptin— leptin you generally want to have lower levels of, and this is an adipocytokine or fat-related signal molecule derived from fat tissue— leptin— adiponectin is more favorable and is positively correlated with insulin sensitivity. So it's quite interesting that we, you know, a lot of us have been talking about the connection between insulin resistance and atherosclerotic cardiovascular disease. And here we have within the endothelial tissue itself a reduction in leptin, and that could— or sorry, adiponectin, which could lead to more insulin resistance, at least in the vessel. And I don't know what the systemic consequences of that are. Um, but yeah, it's super interesting how all these mechanisms are interconnected.

Yeah, I, I guess it sounds like you were posing the question, or you were speculating on this mechanism. One thing I wasn't clear about, and I don't know the answer to this question, is I do believe adiponectin is associated with insulin resistance. Is there a causal link between them? Do you know?

Yeah, I think it affects— adiponectin affects the insulin receptor. Okay. Yeah, I mean, and like PI3 kinase in that.

Yeah, no, no, I believe it. I guess the level of complexity I would leave people to consider as we wrap up part 1 here is what we're talking about here is not just hormones interacting with other hormones. But hormones interacting with other hormones in a very particular metabolic context at a very particular site that is tissue and organ dependent. So when we talk about things like, you know, generally lower leptin is better, or you, you want like, you know, better insulin sensitivity or leptin sensitivity, it is all very tissue specific. And that is actually, well, one, what makes it beautiful and elegant, but also what makes the pathophysiology so complex because Take insulin resistance, is something people are familiar with. In insulin resistance, what happens? Your body makes more insulin. You're hyperinsulinemic because it's trying to compensate for the body's tissues not responding to insulin. So you would think, okay, if that's the case, then up until a point, shouldn't your body be able to just match the insulin resistance? So you become insulin resistance, like becoming a little bit more deaf, your body just shouts louder and louder. Can it actually kind of like match it as it increases? The answer is no, because what happens is insulin resistance isn't the same across tissues. So some tissues become very insulin resistant, and even despite higher insulin levels, they don't get the signal. Other tissues remain insulin sensitive, then they get too much signal because your body's trying to compensate. So you end up with different tissues— be this leptin, adiponectin, insulin— getting too much or too little, but never the right amount, like never the Goldilocks of a hormone signal. I want people to just muddle on that because that is the beauty and complexity of metabolism, one of the reasons that it's really hard to just pharma solutions to these problems because you really do need to address the underlying pathophysiology in order to reverse the disease process rather than just addressing the downstream manifestations. So, Mike, thank you for part 1. Do you have anything to add before we leave people on a cliffhanger and then come back to talk about the most overlooked study of 2024.

Yeah, it was a study related to what you were just saying there, Nick, and I was smiling the whole time because I wanted to— I hope to have the ability to articulate this. So the researchers in Denmark did a study, I want to say it was in 2014, where they looked at the regional insulin sensitivity in the upper versus lower body musculature, looking at the arms, uh, the musculature in the arms, and they did an insulin-glucose clamp type study to look at the glucose uptake and so forth. And this was in type 2 diabetics. And this was really interesting to me, finding that the skeletal— I mean, ultimately diabetes is a complex disease, but foundationally we can ascribe diabetes to be characterized by an inability of skeletal muscle to uptake glucose, among other things. That's one of the early pathophysiologic features of diabetes. In these individuals, um, that were type 2 insulin-dependent diabetic, the leg tissue was— the musculature in the legs was particularly resistant to glucose, to insulin. You know, the ability of— with the glucose clamp, um, and insulin mediation, you know, in diabetics, their leg tissue is not absorbing much glucose in the presence of insulin. In contrast, the musculature of the arms and the, and the upper body musculature remained relatively glucose and insulin sensitive, even in diabetics. So to me, that just highlighted— like, I love weightlifting and exercise in general, so I train my legs pretty much every day, whether that's some air squats or some sprints or the Concept2 rower, hiking, walking. I make sure to move my legs because I think— and I talked with Ben Bikman about this several years ago— um, the leg tissue, the musculature in the legs— humans naturally evolved to just move our legs a lot. And so I just want to leave people with that to remember that, you know, a few lunges, Bulgarian split squats, air squats, you know, sprints, all these things are very beneficial for maintaining and preserving the insulin sensitivity in the leg tissue.

That's awesome. That's a very functional tip. I'm going to be evil and leave people on a cliffhanger that they'll have to chase. But, uh, Mike, how many types of type 2 diabetes are there?