The Estrogen Effect Nobody Talks About | Kiran Krishnan

There's a direct correlation between declining estrogen levels and declining nitric oxide response. So then vascular compliance is low, blood pressure goes up, and then that increases endothelial damage. women, you know, cardiovascular disease just meteorically rises, brain health drops. I mean just systemically, not just, you know, the end of our But much more bone health and on. I think we've gotten very stuck on let's drop LDL to 30 instead of.

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Head over to Calroy.com slash DRKF, that's Dr KF, to learn more. Hi everybody, welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine and of course Today is no exception. I am joined by Karan Kushnan. He is a research microbiologist and a familiar voice on this podcast. He's an all around

Brilliant guy, and actually really extraordinary athlete as well. If you've listened to him before, you know, he makes complex science feel clear and relevant. In this episode, we focus on women's health. So we're looking at the trio of calorie products.

through that lens, particularly the the transition from peri to menopause and the challenges that we're facing during that time and how this suite of products can just really have a broad influence and we can think about using them in very creative ways. You know, and this is going to be a conversation that I think you'll you'll really glean, you know, some things that will make you think. I hope you enjoy it.

Coran, it is always awesome to get to hang out with you and pick your brain. Just just yeah, we'll we'll mine your brilliance here and and and all of us, myself included, but the many clinicians listening will have some you know, some information to really use in practice. This is all about clinical app applicability.

Um we're talking about the dynamic duo of of cartogenics and basconox today and how they can be used synergistically and s and then we'll also talk about individually, but um I wanna start with y you know, this podcast th the overarching theme of this podcast is the trans the women's transition. So perimenopause, menopause,

This obviously applies beyond that group. Um, but let's talk about cardiovascular health, um, which in fact meteorically rises in, you know, women as we transition through perimenopause and into menopause. Um, but it impac influences obviously everyone. It's the number one it's the number one threat to health span and and longevity. All of us in clinical practice are always thinking about cardiovascular health of our patients and we've got better tools.

You know, better better labs, we've got better, you know, imaging is becoming more sophisticated. Um But one of the cool things that I think you all have really brought to the fore, brought to be right here for us to be thinking about with our patients is the endothelial glycocalyx and the essentiality of having that as a part of an overwhelm or thinking about the care of that as a part of an overall.

um health plan for our patients. So talk about it, you know, again, define it what it is and, you know, why is it so essential for cardiovascular health in in the in in this women's population, but more broadly. Yeah, well number one, thank you for so much for having me. It's uh this is such an important topic, right? Because um obviously it's still the number one killer. Um there are tools in place, but I think there are elements of the pathology that

we don't pay enough attention to. Um I think, you know, everyone is under s uh understands the atherogenic particles component of cardiovascular disease, right? But then when we start thinking about the actual physiology of the end the endothelium itself and what may be happening in that area. that creates so much risk once you hit your late forties, early fifties that wasn't there before when you were in your twenties.

Right. So then we have to really think about that physiological difference between the twenty, twenty five year old endothelium and the fifty year old endothelium. Right. So what is so different about it? And and really two things come to mind that that are significant, or really three things. Uh, but the first two are really important, which you you'd already touched on. Number one

is the the structure of the endothelial glycocalyx, right? This beautiful gel like barrier, if you will, on the endothelium that not only protects it in many ways, but then acts as a very active signaling uh structure. Then the second part of it is the uh the the response of nitric oxide in the vascular system, right? And then they actually marry together really well because one of the roles of the uh endothelioglycocalic.

is to take shear stress that's coming from blood movement and convert that shear stress into a signal, a biochemical signal to increase nitric oxide production. Right. And that is a really important aspect of vascular compliance. and protecting the the lining of the vessels from too much shear stress and exaggerated damage, right? From blood itself. Blood being a non Newtonian fluid.

It has a really big impact in terms of its viscosity, its shear stress, its movement, especially at the areas of the the arterial bifurcations, right? Where the blood runs into the bifurcations and then it bifurcates into the different uh vessels. All of those things have this mechanical stress element to it. That mechanical stress element is turned into biological signals by the endothelial gycochalic. And the response to that signal is the release and ma the pr production of nitric oxide.

Right. So that's it's such an important one two punch to protect the structural elements of the of the vascular system. Now as we age And as estrogen levels as women age and the estrogen levels go down, we know that nitric oxide response goes down. Right. There's a there's a direct correlation between declining estrogen levels and declining nitric oxide response and but nitric oxide production.

And so even if the endothelial glycocalyx is working fine and it's creating, it's transferring that stress signal into that that um fluid stress signal into nitric oxide activation, you're not responding by producing enough nitric oxide. So then vascular compliance is low, blood pressure goes up because there's more shear stress and more blood volume pressure on the vessels, right? And then that increases uh potential for endothelial damage. Then you look at

The uh the glycocalyx and its uh role in barrier function of the vascular system, right? Because it regulates permeability. And so when when the endothelial is intact, when the end endothelium glycocalyx is intact, it actually can reduce LDL uh migration into the intima, which is where those athrogenic particles can create havoc.

Right. And uh and and create the issues um uh around the the the gradient between the luminal side and then the the intima side. And so the glycocalyx plays an important role in that barrier system as well, right? So that's another role that it plays. Um, the glycocalyx also shields the vascular system from um you know drivers of of inflammatory mediation.

uh in in that in the intima layer as well. Um and so there's a number of structural elements that start to change as people age and the glycocalics start to dismantle and then the nitric oxide response reduces as well. So you see that vulnerability then of the um the endothelium as a result of that. Um

I would be I would be remiss not to mention the small roll of Arterocil here. Because, you know, obviously I think the the the three these three kind of the flagship products of Calroy, you know, can really work synergistically together. So Artericell supporting the patency of the endothelial glycocalic um, you know, the baskinox for increasing uh nitric oxide output. And we'll talk a little bit more about that mechanistically and what it does specifically in a minute. Um

And then I want to hear your thoughts on where cardogenic f cardogenics fits into the cardiovascular disease story. Yeah. Um But actually, Let's we can start there and then we'll move into talking about the f this extra this meteoric rise along with cardiovascular disease and joint pain that we see in the you know, in women transitioning. So first talk, you know, connect the dots.

with your thoughts around um Cardiogenics for cardiovascular and then we'll and then we'll move into joint pain more specifically in this population. Yeah, absolutely. So and and one more thing I want to mention because you you mentioned the synergy between the two products, right? So the the arterial cell and the vaskin oxygen. Um I talked about earlier how a healthy intestin uh endothelium glycocalyx uses the shear stress from blood movement to upregulate um nitric oxide production, which is

a really beautiful and elegant way of protecting vat the vascular system. The reverse is actually also true. The production of enos, right, uh the endothelial nitric oxide Um also in return helps preserve the endothelial glycocalic. uh by upregulating something called proteoglycan synthesis, right? And proteoglycan synthesis is the structural element that makes up the endothelo glycocalic. So The the glycocalyx stimulates nitric oxide production and nitric oxide production in turn protects

The endothelial glycoca like so they are absolutely synergistic, right? So you can see quickly how when one declines and with estrogen decline so so does uh an enos. And as a result of that, then you start to see a decline in the glycocalyx uh structure. And as a d as the glycocalyx structure declines, then you get less stimulus for more nitric oxide production and the cycle goes on and on and on. Right. So It's just y y you use the right word that when you said it's they're so synergistic.

And they absolutely are because both of these mechanisms kind of feed off of one another, right, to protect the overall structure. So it's it's it's such elegant biology that that takes place there. And then when you think about cartogenics and you go, okay We're really talking about joint regeneration or we're talking about cartilage regeneration as as it's been seen in in a couple of randomized controlled trials. How is that then related to cardiovascular disease? Well

Just looking at the epidemiology alone, right? So people with uh joint dysfunction, so whether it's osteoarthritis or rheumatoid arthritis, are two and a half to three and a half times more likely to develop cardiovascular. Um, there's a few different reasons for that. Number one, it's because a lot of them are using NSAIDs all the time to manage uh health, right? And manage joint health. Um NSAID use, continuous use especially is a risk factor for cardiovascular disease.

Um the second aspect of it is in all of these um individuals with joint dysfunction, you've got a anabolic, catabolic ba uh battle that's happening. So The anabolic side is trying to win out to rebuild the joints and and and rebuild tissue. But then as you age and you've got, you know, increasing amounts of inflammation, the catabolic component starts to win out. And now you've got a net degeneration.

That catabolic effect that is seen and and felt in the joints is also happening in other tissues. Right. And that whole anabolic-catabolic ba balance is a really elegant way of describing what happens with aging. Right. When we're younger, we've got a full on active anabolic system that can outrun any sort of catabolic function. But as we grow older, that starts to shift and then we lean much more catabolically.

But that happens in your muscles. This is why sarcopenia happens, right? That happens in your brain, neurodegenerative conditions, that happens in your cardiovascular system, um, you know, um your cardiac cells and all of those undergo the catabolic s uh you know uh shift. And so as a result of that, what we see the role of cardiogenics here is we're looking at it in the joint, but we're looking at it system uh systematically, right? So we're looking at

the markers of degradation versus um uh anabolic uh repair. We're looking at those in in this in the whole system, but we're also measuring the effect on the joint. So what we're seeing with cartogenics is this great profound shift in this anabolic-catabolic balance that's happening in the individuals. And we're using joint health as the proxy for understanding that that balance.

Because we're seeing the shift in those individuals and we can measure it in the joint, we can measure it systemically through biomarkers. where we're not making too much of a leap is to think that that same fight that same anabolic catabolic fight and if we start winning it, we start winning back the anabolic side, we're s improving the cardiovascular system, we're improving our muscles, we're improving everything else in the body.

that is damaged by that by losing that battle. Right. So I think I think that's a big part. And then the last part I would say is gets us active again. Right? Because the last thing you're thinking about when uh when your joints hurt is a going for a walk. Uh the last thing you're thinking about is doing exercise. Right. And so it the joint pain and the frequency of that

um does two big things. The first big thing it does is it creates a lack of mobility. And so we're not moving. We all know so well that mo movement is critically important for cardiovascular health. The second thing it does is it creates a lot of stress and anxiety, right? Chronic pain is a massive driver of stress and anxiety. Uh and stress and anxiety is really bad for cardiovascular health. Right. So I think I think the connection there becomes really clear.

Yeah, it's very it's fascinating the the three of them together to have um, you know, just a nice synergy and Yes, I can see just thinking about it overall the the fact that, you know, cardiogenic specifically in your investigation in in joint health was also associated with lower C R P and lower yep a lower IL six. It it you know, you've suspected in your publications that it's influencing inflammation sort of foundationally, but then you're witnessing these changes in the joint. Um

Yeah. And and and the key part of that is that those specific markers that you mentioned, right? So so if you look at HS C R P overall, um, but then you look at more refined, we look at I L six, T N F Alpha. um, you know, I L twelve, I L one, alpha and beta. So if you look at those very specific um you know cytokines and inoleukins, they are the culprits that drive the shift from anabolic to catabolic process.

Right. That's that is what is happening, right? So that it that changes cell types so so drastically, for example, in the joint itself, it changes the chondrocyte. that are designed to lay down uh um, you know, the c the cartilage and rebuild cartilage, it changes them not only from not rebuilding cartilage, but actually breaking down cartilage activity. by releasing enzymes like M MPs and so on, right? So so that battle, that catabolic anabolic battle is is I think not stated enough.

when we think about, you know, um functional medicine and and overall health, because it's at such a it's such a root cause driver of physiological changes in people that leads to dysfunction. Yeah, it's that's it's g it's a it's a great point. I mean we we're we're dialoguing about it now in the form of, you know, eat more protein all the time. Eat tons and tons of protein to sort of overcome that catabolic push um and support, you know, at maintaining muscle. But this is much more

This this is essential. This is this is this is very root. It's not yeah, it's not pounding back a couple of stakes, but it's it's tweaking the mechanisms that drives that drive the breakdown as we you know, as we age. Um and it drives the breakdown everywhere. You know, we're not talking just muscle, it's everywhere.

It's everywhere. Brain, gastrointestinal tract, you know, cardiovascular. everywhere. Can I just um I wanna just take a moment and just circle back to Cardigenics and the awesome research. We've already talked about it on this show. Uh, but it made me a believer. I mean, I just oh my gosh, the first time we talked, the product wasn't available yet.

Um, but I knew that I was gonna try'cause I've had this chronic knee pain um, like low grade. It doesn't inhibit well, you maybe it inhibit it was inhibiting my li was something that I was aware of and sort of a little bit anxious about to your p the stress point. Um but I could still function and walk and ride and all of that. Um but

you know, you guys showed such cool stuff. I mean, I was blown away by the fact that you showed, you know, cartilage regeneration on imaging in, you know, in a decently large cohort in in it was a uh it was a in a hospital setting. I mean you're you know, using Boswellia and um Celery seed. I mean sp and you can talk about they're special. They're special, but like they're you know, the bosuella is a pretty extraordinary form of boswella.

And also a drop in CTX, incredibly enough. We use this in practice. I'm sure most of the listeners are familiar with it as being kind of our one of our work horses. um markers of of you know bone loss or whether our intervention is working, we see that drop. We don't wanna have a high CTX that's evidence of cartilage turnover. So it I you know, again, I just wanna shout out

First of all, your commitment to science, um, Karan. I'm s always grateful for the and we'll link to these the previous podcasts so we everybody can hear the details around how you brought this. to market and your um efforts from from Encelica work on up to human beings. So cool! Um, and so you showed the regeneration of the droid space on imaging and then the side one of our original conversations was this is probably a surrogate marker of

biological age. You know, this is one measure'cause we all know that these these this joint these joint deterioration happens with the aging phenomena and I was just wondering, you know, how

what if you were able to put a biological age number to that change, what that might be. So I'm curious if you've ever circled back and and thought about that a little bit more. But I w I just wanted you to touch on that original science and and, you know, the components of the product and why they're special. Yeah, no, I it th that was actually a really good question and I'm gonna come back to that because you

illuminated that for us to think about from the first time we had this conversation. So um but to to review this the the study. So the these two components are quite unique and and the way we went about identifying the actives within these complex plants that could potentially do this. was through the in silico trial component of it, right? So uh what we were doing is first investment was really on um much more advanced analytical chemistry tools and capabilities because

M most of these plants, you know, celery seed and boswilla, the actives have been d defined for a long period of time, right? So Boswilia has the Boswillic acids and A K B A and so on. We know what those structures are. Um, same thing with celery. Uh we know what some of those structures are. But then again when you look at it and you go, Well, that was done fifteen years ago, analytical chemistry has improved quite a bit since then and we can decipher much more.

Right. And so that's that was the first layer of investment was okay, let's get, you know, six or seven really uh s uh great analytical chemists. Let's give'em all the equipment they need. Let's give them all the access that they need and resources and let them discover other activities.

within these plants. Um, and sure enough, they did. So then they came they come out with all these new compounds. They're able to quantify and look at the three dimensional structures and all that. Then the next step is That's great. Well, what do they do? Right. So then it goes down to the the biochemist groups that we work with and we said, All right, let's put this into an AI uh system and see what it can identify, what kind of receptors it may be able to activate and so on.

And we were able to narrow down biologically active components from the d from the mall the actives that we discovered. And in the in the uh Basilia, for example, serotol is one of them. And what's so interesting about serotol is it seems to play a role in um the tissue repair components of so uh activating of things like matrix metalloprotonases or down regulation of those uh you know catabolic enzymes and so on.

Um and so we said, Okay, so that's a really interesting component because we know Boswellia is already a LOX inhibitor, right? It's a it it reduces inflammation and so on. So we said let's look at the tissue repair component, potential tissue repair component with the serotol component. And then with the uh celery seed, we looked at other components that could be synergistic to this fun uh fact function.

And then we tested that in in in silico and saw that it likely has a strong synergy. So then you go into um the safety studies next just to make sure that these compounds don't have any sort of toxicity or any uh issues. And then once you pass the safety study then we went to the human trials and that's where it became super

Um, because there are trials on Boswilla, for example, on being able to provide alleviation on symptoms associated with joint dysfunction, right? But it's never been shown to actually start to create. cart uh cartilage, right? Like tissue regeneration. Um and and it's been thought for the longest time that once you wear down your your cartilage to a certain point and right, let's say you have bone and bone. That's it. Right. You can't

generated again. That didn't actually make sense to us because when you understand how cartilage is being generated, you've got cells that are sitting there called chondrocytes, that that's what they do. They make cartilage, right? And they're still there. When even when you have bone on bone, the chondrocytes are still there, they're still present.

And so there should be no reason you can't push them back into the anabolic state to start laying down cartilage again. Right. And so that was the the the crux of the research was showing not only uh both from a biomarker perspective, looking at cartilage degeneration and regeneration markers. Um, but also the imaging which which you had a chance to see where you could see bone on bone on these patients and then boom, joint space after ninety days, right?

Um, and when you brought that point up about looking at the joint space as a potential measure of of you know reversing biological age. We did that and and so what what we did is we uploaded a number of those images into an AI tool to try to read the joint space and and and get more and quantify it better. And we were getting some some actual initial readings, um, which was which was fantastic because what it validated was that number one, there are a number of studies.

Uh I think you know, and I don't know if you were familiar with the studies already, but you you have good instinct with that. There are a number of studies that actually show that joint space is a quantifiable measure of biological age. And so we we saw that and we referenced that and then we were getting some measurement. out of joint space increase, which is really exciting to see. What we'll probably have to do to make it usable information is standardize the um the x-rays better.

Um, we we did we use the X rays as just an add on just to see if we could visually see anything, right? That that that supports what we're seeing physically in people with their movements and their pain scales and all that. And so we didn't standardize the joint uh the the the X rays for joint imaging as well as we should, like meaning

putting people in the exact same position and so on from one to the other, right? To get the most accurate pictures. But I think that's something we would look to do next because What you mentioned about using that as a way of looking at biological aging, I think is it's it's really telling. Right. And and I've not seen it in anything else. I've not seen anything else show that regeneration of that important joint space. So it was a it was a great thing that you pointed out.

Well, I'm so glad that you're f pulling that thread. That's very satisfying. I'm so excited. I'm really excited to see what you find if you end up doing I I I certainly understand everything needs to be c controlled so exquisitely, but you You just got that really fabulous initial signal. And, you know, s you're starting to turn upside down the idea that bone on bone, you're you're done. God. You know, what a nice

What an extraordinary, you know, fallacy to do is just really disrupt. That's amazing. And, you know, kudos to you for you know, questioning it. I you know, in your in this journey. Um I just wanna say I I have two more thoughts uh around this and then uh and then we'll talk a little bit about, you know, what happens with the declining estrogen. First of all, I'm just curious

Using the AI tool, did that expedite the journey to identifying which compounds were like out that were um, you know, gonna be important? Right. I mean, was that as quick as pushing the chat GTP go button or I mean Yeah. is very much dependent on how good your prompts are. Right. Um and so so the people that are really good at w at working with chat and getting the maximal benefit out of it have become really great at the prompt.

And and understanding the limitations that it has and and and working through the limitations. Um, when you're doing in silico studies actually using um AI tools for modeling and modeling functional molecules. It's very similar to that, where it's really about how good you can be at use at at creating the right prompt. and creating the right uh input so that the AI can do what it does best. Um but yes, if you do it right, it is amazing at accelerating towards both safety and efficacy study.

It's pretty extraordinary. Right. Especially with plants, because plants are so complicated. They have so many components in there. And some of the components are going to be synergistic with actives that you know of in the plants. And some of them are going to be antagonistic. You know, and and you you would know you would typically learn that through like lots of effort of trials and right, dosing studies and v various w ways of extracting the actives. If we just think about

The thousands of years of Ayurveda, right? They learned how to extract certain tinctures that became efficacious. uh in in just through trial and error. And what they're effectively doing without knowing it is as they change the way they extract the tinctures, they're changing what they're actually pulling out. And so they find the most synergistic version of that extraction and then they use that.

Um, we can we could skip those years and just kinda go right to okay, these two things are gonna work really well together. Boom, let's let's uh let's study them now. So yes, it's a amazing tool and I and I Really, really hope more and more companies do that. That's now being done kind of in the probiotic space as well to a certain degree. And uh I I think it's gonna give us in the world of utilizing natural compounds a massive leg up. because we're starting from this m big mix

of compounds, right? Versus to the pharmaceutical side, you're starting with a single small molecule. Uh and you're adjusting that molecule based on the type of efficacy that you're looking for. Uh in in the from the plant world, we're starting with this massive barrage of molecules that you then have to narrow down to figure out what works. Uh

And to to that point, you know, you found some unique compounds in Boswalya that are not present in other forms. So all of us in functional medicine have prescribed Boswellya, I'm sure. I've been t I've been teaching about it as some as a you know, as a fabulous Lux inhibitor for my entire career at IFM. Going on I guess this is year thirteen. Long time. Um and of course it's been known time immemorial. Not

necessarily that it was a LOX inhibitor, but in Areveda, you know, they've had this idea. But the cool thing ab about about this journey that you took, you did identify some unique compounds that are efficacious in your particular product that um are are not present in other bus values that you've tested, right? That's exactly right. Yeah. I mean the the thing is it's in the plan.

Um but but in order to extract the the new compound like serotol, for example, which is part of our boswellian not found in anything else, um you actually have to completely alter the extraction methods because the polarity and the solubility and all of that of that particular active is different than the conventional actives within Boswilla. And we of course wanted all the conventional actives because they have been well established as as having functionalities, LOX inhibitors. We want that.

Uh so we have to be able to extract that in the known ways, but then alter the the preparation so that you actually get the additional actives out as well. Um so so then yeah, you know, uh so then the all the work doesn't stop once you identify the compound and identify that it can be efficacious in a unique way. Then you have the whole process of process development of like how do you commercially and in a in a financially feasible way alter the extraction process to get enough of this new app.

You know, and that's a whole other world of uh of of chemistry and biochemistry and um and so on. So it's it's it but it's it's super exciting to be able to do all that. Healthcare providers can join CalRoy for an informative expert panel on restoring metabolic resilience in the GLP1 era. Featuring women's health experts Monique Klasse, Ashley Kauf, Carrie Jones, and more. Friday, may twenty second, at twelve PM Eastern. Register at Calroy dot com slash panel.

It's really exciting. I love hearing about it. Um I'm just curious. And then I swear we're gonna change top. provocatively about identifying antagonistic compounds in your in silica work and I mean, have you are you intentionally avoiding certain compounds as you standardize your boswellia? Yeah, so, um... So so similar to lots of other things that that that clinicians have worked with, there Are

different levels of affinity for receptor sites, right? Yeah. Uh of compounds. And then so s so something might have a low affinity for the receptor site, but it could still be what we would call like either an allosteric or direct inhibitor of their receptor site. So it's taking up the space, but it's not then triggering the all of the downstream signaling.

And and because plants have so many different versions of a given compound, you take for example lycopene in a tomato, right? We think, oh lycopene, we know what that compound is, but a actual tomato has like two hundred different versions of lycopene. Right. And they have like s a certain amount of the structures very similar and then you've got all these side chains that'll be that'll change the the function of it.

And so one of the things that we're looking for are once we identify a potential receptor or signaling molecule that we want to activate. then we want to look for, you know, low affinity um agonist or antagonist of that function. Uh because what we don't want is to e extract something that potentially interferes.

Yes. With the with the ability of your target compound to function. Um so so that can be complicated because again p plants have all of these nutrients and anti nutrients. You know, they have like these these um components that can kind of compete. That's so fascinating. So so just trying to make sure you've got you know, you've got the best of what of what you need and, you know, minimizing what you don't.

Um, let's go back to thinking about um estrogen declining and all of the stuff that goes on. You know, you we talked about the endothelial glycocalyx and and um nitric oxide and it's interesting We know when estrogen declines, you know, as as clinicians we always see cholesterol go up and we see, you know, just all sorts of ab the abnormal c um lipid panels kind of start to emerge and

I think we've gotten very stuck on let's drop LDL to 30. You know, we've gotten really obsessed with that instead of thinking about the broader picture of what we can do to support optimal wellness. It's multifactorial. It's not just let's you know, cholesterol becomes a demon. Um But estrogen is this amazing compound that does tons of stuff. I mean it it helps our brain. I mean it controls inflammation. It just it it it and we see, you know, we just we and and and once it drops, we can see

um, inflammation increase in women, you know, obviously cardiovascular disease, just meteorically brain health drops. I mean just all s systemically. Yeah, we just see it everywhere. um not just, you know, the end of our menstrual cycle, et cetera, um, but much more bone health and on. Um, just you talk about cardogenics in pl playing a role there um as estrogen declines.

Yeah. But also too, I wanna just extend it to thinking about Vascinax as well and and and if you wanna throw our chair cell in there you could. Yeah, absolutely. So um one of the one of the things that that is maybe not spoken about enough is the role of estrogen in maintaining diversity in the gut microbiome.

Uh and as a result of that, intestinal permeability, right? So so one of the things that seems clear is that as estrogen declines in in perimenopause, you start to see a sh uh a reduction in diversity in the gut microbiome.

and and a dramatic increase in uh endotoxemia and that's uh intestinal permeability with an increase uh translocation and increase in serum LPS levels. Um right and that sets up this uh this um uh higher level of chronic low grade inflammation, the same kind of chronic low grade inflammation that creates uh a significant risk for cardiovascular health, uh bone loss. you know, um neurological damage, all of that, right? So Which is the c catabolic bias, yeah.

Exactly. It's all it's all starting to move move the catabolic bias. It's also one of the key reasons why Um, you know, anxiety and depression can increase. It's an another reason why um in insulin resistance increases as well. So for example, j just taking the role of what happens with LPS, right? So so as estrogen declines, LPS translocation increases in women, and you start to find higher concentrations of LPS in circulation.

Now, let's look at some studies that have looked at the what what that the impact of that is. So there's a study called the Netherlands Study on Anxiety and Depression. um this uh state sponsored study uh in the country of Netherlands looking at a nine year follow up on individuals that had, you know, basal level and then higher risks of anxiety and depression, a higher uh

confirmations of anxiety and depression. And then they looked at all kinds of biomarkers in these individuals to see which biomarkers were the most predictive of existing or onset or severity of anxiety and depression. And there was only one marker that in a nine year follow up period

what could predict not only the presence of anxiety and depression, but the severity of anxiety and depression depending on the concentration, and that was serum LPS levels, lipol polysaccharide levels, right? The one and only marker. That's um. Which is crazy. It's a nine year follow-up study, and they found that people who had anxiety and depression in the start of the study and a and elevated LPS as a as a result, uh w which the anxiety and depression is a result of that elevated LPS.

They followed these individuals over nine years for the individuals that that that reduced LPS levels and th and they didn't follow what they did to reduce it and all that. It could be a number of things, dietary changes, exercise, increasing fiber, a number of things, right?

But if your LPS levels reduced over time, so did your anxiety and depression. If it increased, so did your anxiety and depression. If it stayed the same, so did your anxiety and depression. So that's one effect of the presence of LPS. The second uh one i is shown in two different studies. One of the studies is the Cordiopreb study, which is a four hundred and eighty patients over sixty months. They were looking at pre-diabetics.

And then they were following pre-diabetics over the next sixteen months to see how many of them went from prediabetics to full on diabetes, following A one C, HOMO R and a number of things. At the same time they were following all kinds of markers to see which markers were predicted. for those who would go from pre-diabetes to diabetia, that was again only one marker that had greater than 95% confidence interval, and that was serum LPS level.

Right. And and then similar things have been shown in in the case of acne. Similar things have been shown in the case of central insulin resistance where an increase in LPS can actually increase inflammation in the hypothalamus and that inflammation in the hypothalamus creates something called central insulin resistance, which means your brain can't read your blood sugar levels. Right. Even your even if your pancreas and your isolate cells are producing enough insulin.

So so that is happening as estrogen declines, right? You're starting to see a higher amount of LPS and you're starting to see chronic low grade inflammation and all of these effects. from LPS, that becomes, you know, not only does it specifically drive the pathologies I was just talking about, but as you said, it also starts to shift women heavily and aggressively towards the catabolic confirmation.

Right. That is a massive driver of the catabolic anabolic battle and and causing the catabolic stress.

Um and and one of the things that we saw with cardiogenics when as we're looking at global markers in the body, not synovial markers in the joint specifically, we're looking at global markers, are markers of bringing back the the the battle towards the anabolic.

Right. So we are we're rescuing people to a certain degree from that catabolic shift and bringing them back. So just thinking about If you're a woman going through perimenopause, your gut is changing so significantly and the resulting endotoxemia is driving you towards catabolic state, that's a perfect time to really start thinking about how do we bring'em back.

Towards either balance or maybe even leaning more anabolic, right? So that we can rebuild, repair, do all the things that our body needs to do. So I think that's a really, really important role of of cardiogenic

in the entire system, um and and and directly tied to the impact of estrogen and uh estrogen decline um in the gut and in in this case in the gut. But but just tying in the the vascanox and the the uh arterial cell as well, you know, going back to the vascular system and remembering that as estrogen declines, so does nitric oxide signaling. And as a result of that, oxidative stress goes way up too, right? And we know oxidative stress plays a role in in cardiovascular pathology.

Um and and so and then and then as a result of n uh oxidative stress going up, the second thing that happens is you get more glycocalyx shedding. Right. So now that protective layer that's there that also plays a role in in nitric oxide signaling is getting shed faster. And as a result, you end up with endothelial permeability and more stiffness and lack of vascular compliance. Right. So that entire process is also happening quite rapidly as oxygen declines.

Right. So you've got this full array of things that you can you can target. The the reduction in nitric oxide, the shedding of the intestinal glycocalic. And the move towards k uh the catabolic function, because of all of those, because of the decline of estrogen, we could start to rescue all of those with cartogenics, with vascinox, with arterial.

So it's a it's such a perfect combination of products, right? At face value you look at it and go, Okay, how are these things related? Right. But then when you really start thinking about the mechanisms, you go, Wow, that is such an elegant way to support all of those systems. Yeah. And it gives us a it just expands our toolkit and, you know, again, there's a place and time for for addressing cholesterol of course, but we've been pretty myopic I think and this

zooms us out. I also want to talk about, you know, just mention the blood brain barrier enough endoglyc glycocalyx as well, endotheli glycocalyx and Um, you know, that's one of the things that I'm thinking about when I'm prescribing Artericell. So just bringing that back. And then the other thought that I had two other thoughts. One was

You know, long lived healthy people have really extraordinary varied microbiome. Like they maintain that. beautiful diversity. And I I have I I'm sure that it has to do with being able to maintain intestinal integrity and LPS is dropped. I mean it'd be interesting to do more broad investigations. There could be out there already, but

um, you know, we see dysbiosis as a driver of of aging. And I think, you know, just tying that back to to the drop in estrogen makes a ton of sense. Um, but then also, you know, giving us some ideas of how to think about it differently. Um I just wanted to briefly circle back to my own story'cause I said that I would mention it and I Yeah to I'm not gonna spend a lot of time on it. Basically my joint pain I mean you know, my knee pain went away and

It happened so subtly, Karan. Like you remember I was very excited to start the product and then I did and we had a webinar from when I had the I started it and one of my Um one of the people who who produced the webinar with me, her husband had this remarkable Turnaround. I don't know if you recall, she shared her story and she brought her to T Risk because it was such a big deal for him. And it happened quickly and it was profound.

And then you and I were in Vegas talking. We were doing a an interview and um I thought about my knee pain, you know, and those was many months later and I had that epiphany in our interview live that wow, yeah. My knee pain is gone, by the way. I just don't it's a non issue. So I um I was really excited and I and yeah, it was kind of a fun moment. Uh it's been very helpful.

And for you in that case, uh your your performance has increased as well, right? Because You know, you if I guess if you connect the two, it makes it easy to see that okay, even though you you found a way to n to to not allow the knee pain to kinda hinder you too much from the things you like to do and all that. it was likely hindering your ability to be the best version of yourself that you could

Yeah. Right. That's right. Yeah. Yeah. Yeah. It's exciting. It is exciting. Yeah. I've gone back to competitive cycling folks and um I'm just having a really a blast doing it. So It is part of my stack, you know, Cardigenics is a com I'm committed to it. It's only two a day. It's not a big deal. You can take it whenever. Like there's no there's no major effort in using it. But uh bascanox and arch aircell are all are also part of my stock. Um, as I've talked about before.

Uh anyway, moving on from that, um, just going back to what I thought was a was a creative thought, um

And that's medication delivery and HRT. So obviously a lot of our patients are using HRT. We're talking about what happens with a deficit of estrogen, but now let's talk about when we give our patients estrogen and, you know, whatever delivery system that might be. um or any other drug for that matter or supplement for that matter. It t we need healthy vasculature to deliver it. So, you know, maybe just talk a little a little bit about that.

Yeah, and I and I think that's a that's a part that maybe gets uh overlooked more often than it should. Um Because when you think about the vascular system, right, I mean number one, it's just i from a biological perspective, it is so elegant. I think I I can't forget the uh I I tend to forget the exact statistic but it's something like if we unraveled all our vessels in our body and we tied them end to end, right? We could wrap it around the earth.

uh th from one individual at least one time, maybe more than one. And so we just have so many miles of vasculature in our system. And of course So much of it is what we call microvasculature, right? There's such tiny little vessels that barely one blood cell can fit through at a time. And those are the terminal ends of the vascular system that finally deliver. the nutrients and the the compounds and all that to the tissues that need'em the most.

And one of the one of the big issues with aging, uh, and this can be measured quite quite easily, is what is that flow-mediated dilation? You know, how do your vessels respond to need? Um, can they im can they actually dilate enough? Can the microvasculature respond with enough dilation to actually deliver the nutrients that are needed to the sites of action? So then when we think about

Elderly individuals or, you know, you people we're talking about people in their seventies and eighties versus people even in their fifties and late forties that are in need of medication, that are in need of supplements. Are we really delivering that? Right. Doesn't mean it's necessarily getting to the target tissue because the highway in which it has to travel is compromised. And so we have to look at things from that from that uh systemic functionality perspective and ensure

that we're providing healthy uh nutrients for the vessels so that the vessels can be compliant and deliver it. And I think a great example of that is why diabetes. is such a massive risk for every other chronic condition, right? It basically having diabetes doubles and quadruples your risk for virtually every other quadr uh condition uh condition like cardiovascular disease, dementia, you know, Alzheimer's, all of those things.

What is it about diabetes that creates that significant risk? Well, I think at least one element is the decline in microbasculature function, right? You see that in blindness that occurs and all of that stuff. So so we cannot overstate the importance of as we getting as we get older to ensure that our vessels and our microvasculature

are structurally functioning so that we can deliver the nutrients that we need. And another nutrient that we've all talked about, that we continuously talk about, that we take for granted our getting to the site of action are amino acids.

Right. We talk about the importance of muscle mass and maintaining lean mass and and of course when the myogenic signals kick in at the site of action, which is at the muscle, because from the contraction and and the stress and all that from lifting You need to get the elements, uh the number one, the energy source, and then the amino acids to rebuild the muscles to the site and that all depends on the microbasculature. You know.

Um, we can measure, you know, w nitric oxide. We can take a y it's it's pretty easy to see whether, you know, we're producing enough. Yeah. I mean, do you do you uh do you check your mic do you check your nitri nitric oxide level? D I do just through those through the saliva swabs. Um and what's interesting is So I've been taking nitric oxide for a long time, right? And and my belief was those those silly little swabs didn't work.

Because for right, for like I remember starting to take nitric oxide fifteen years ago. Like you, I w I'm uh I I was a cyclist and I was a competitive cyclist. So to me, anything that can give me an edge, yeah. Right, without going to EPO and all of those things, yeah, uh, I'm willing to take. And so when I first heard about like the the nitric oxide from beets many, many years ago,

I was like, load me up, right? I need as much vascular dilation, right? So I would take it. I didn't I wouldn't really feel anything and I was someone that suit was very dialed in on my Cardiovascular performance and capabilities as you are, you know, and I I li uh we talked about earlier how I I like I measure everything. I mean I've been using a power meter for fifteen years. Awesome. Right. And I and I'm very dialed in because uh when you're racing

My biggest fear when you're racing is you get to the start line of your first race and you're under prepared and man you get just demolished, right? And it's so embarrassing as uh and you get dropped and left and you know, it like all that. So all those fears set in and in the uh in the early, you know, base training part of the season you're really doing everything you can so you're not la

in the first lace. And so popping nitric oxide, then I found those uh that was a company that was making those swabs and I kept trying them and they it wouldn't move the needle at all, right? Like the color never changed. Like as much as I would take those. Um, the first time I ever saw that color change and and and be able to maintain that color over a long period of time is when I started taking basket.

Right. I I I came into knowing uh calroid through arterial cell because my number one health goal is cardiovascular health. um because it's of family history and all that. Um but then when I started taking Vascinox was the first time I saw on those little color uh measurements on the tongue that it actually changed the color for me. Right? It moved it.

And you come to realize it's because it's a twenty-four hour upregulation of nitric oxide. When you take the nitrites and all that, they're fleeting. Right. They they they they they're used up. The gas is VATA goes away in in a matter of minutes. Uh but then providing the precursor. to nitrate to nitrite conversion and being able to show that it's sustained over a 24 hour period, that's where the key is.

to to this functioning. So so I'm excited to say that I constantly measure mine now and I'm I'm I like it makes me happy uh that I say that gives me like a little bit of a confidence, right? I was just uh skiing all week, uh, in in Vale and and there's always a part of me that's like, it's twelve thousand feet and you know, yeah, I I've I've raced in altitude before and I know that feeling and You know, I'm like, Oh but I got my nitric oxide, so I'm good. So you're good.

That's cool. That's really cool. You know, I I have my sticks at home to measure mine and I I I I just haven't been doing it that much, but maybe I'll jump on. And by the way, that's pretty cool that you were using a a a power meter way back in the day. I just started measuring mine and you you and I were talking about numbers before we started recording. I'm absolutely obsessed but It's'cause my bike has all you know, it's just like bikes now are are nuts.

Everything. Yeah. Yeah. Yeah. Yeah. Like it's it's funny, before I go on a ride I have to plug in my bike three different ways, right? One for the shifters, one for the pu with the the power meter, one for the uh computer. Like it's it's nuts. Yeah. And then check it all on your app. But yeah, I'm totally obsessed. That's very, very funny. So yeah, d so so so Vascanox, just a very uh an elegantly designed product.

um, has been shown and Dr. Houston's study actually shows it that it sticks around for up to twenty four hours, which is is absolutely game changing because nitric oxide is around for seconds and Um, I don't know. T I mean what are some of the the i I mean it's kinda a unique um collection of ingredients. You know, obviously there's there's beetroot in there, but maybe talk about, you know, some of the standouts, you know, and and what might be helping it stick around for so long. What are your

Yeah. Well so to me I think it's a it's a variety of of precursors uh for nitrate to nitrite um transition that have been provided. So when you look at things like uh the black garlic extract. uh that they have in there from the bulb specifically. Right. Um, which makes sense because the bulb of the of the black garlic extract is is the nutrient source of the garlic itself and so

Um, you know, the the the nitrate and nitrite uh precursors are in there at high concentration. Uh if you look at the things like the blue honeysuckle berry, the raspberry extract, the billberry extract, Um it's a it's a really nice variety of a number of stable nitrate sources. um that actually allow for that sustained release and conversion to nitrite. Um

It's uniquely di designed and I know I know they have a uh they have a pretty cool team over there. Uh that you guys have a a neat team over at um at Calroy designing stuff. So yeah, it is. It's a creatively designed product. Yeah. Um

I just want to talk about two in the home stretch. So we've touched on the the suite of cowboy products. Uh we've talked about muscle mass, we've talked about nutrient and you know, h HRT delivery, obviously nitric oxide and you know, in inflammation, joint space. Just and we we've we've gone the journey

Um massive in this conversation, massive in this space in in currently is um the use of GLP. I mean, we're prescribing it as clinicians in functional medicine. Of course, the more broad, the uh the broader medical community, the world is using a ton of GLP these days for many, many different, you know, indications off label. Um thoughts on how these might support using GLP or um yeah, I know you've you've you've spent some time pondering this.

Um yeah, so one of the one of the most important things I think about you know the use of GLP ones is is how do you set up your system so that you can come off Right. See nobody wants to be on GLP ones forever, nor is that a good idea. So they can give a boost, they can give an acceleration towards weight loss and and improving blood sugar control. But then the question becomes You know, how do we how do we set up the patient so that they can successfully come off the GLP water?

Right. Nobody wants to be on them for the rest of their lives. And and and what seems to be clear is is that, you know, in order to successfully be able to come off G L P ones we we have to make certain physical changes in the body. First of all, we have to maintain muscle mass.

or even try to increase muscle mass during that time. Uh, second of all, we probably have to increase movement in these patients, right? So we have to get them active again so that becomes a regular part of their lifestyle. And then and then third, we have to look at some of the structural elements that have likely been compromised.

in these patients even before they started GLP one. So when you look at the data, for example, the vast majority of people on GLP ones are uh larger body individuals, right? So they have uh increased BMI typically over thirty five. Uh, and then they are insulin resistant or full on diabetic. Um, there are two important characteristics that are very high prevalent in those individuals. Number one is that they tend to have much higher uh prevalence rate of joint.

Right, you're at four point seven times higher um i you know, frequency and prevalence of joint pain in people who have uh who are obese versus people who aren't. So the people who are starting GLP ones are already suffering from joint pain. So then how do you get them to move? Right? Uh of course the weight coming off is gonna help. but you still have to get them into the habit of moving and pain is a dramatic inhibitor of movement. The other aspect of it is they tend to have

significantly lower flow media dilation uh and greater microvascular uh abnormalities, right? Because th that's a profound characteristic of being insulin resistant and being diabetic and being overweight. So their their vascular system is already not functioning properly. And then on top of that, they've got increased joint pain, which makes it really hard to increase movement and exercise to rebuild muscle.

And so those two structural elements have to be addressed in your GLP one patient so that they can successfully come off the medication in a state in where their body can sustain activity, movement, resistance training. And also deliver nutrients and all that to all of the critical parts of the body, right? So I think uh anyone that has patients on GLP one should really be looking at cartogenic.

to get those patients' joints back to a healthy state so that they can sustain movement and they should also be looking at at least vascanox to improve the microvascular health so that we can get circulation. uh and transport of nutrients to the right places as well. Because those two components are uniquely compromised in GLP1 um, you know, uh qualifying patients. Right. Absolutely. And then of course a lot of them are gonna be dealing with, you know, some elements of of

cardiovascular disease processes and you know the endothelial glycocalyx is likely compromised. So I think it's worthy consideration for for our terracell as well if it um if it seems appropriate.

Well anyway, Kiran, it was awesome to spend some time with you today on New Frontiers. Thanks so much for joining me. This was a fun, kind of far ranging conversation on the suite of of really important tools and some kind of Different ways to think about, you know, why we would use these how and, you know, the m the the meaning behind them and and indications and so forth. But anyway, thanks for joining me. It's my pleasure. Thank you so much for having me.

As always, thank you so much for listening to this podcast. If this conversation has sparked ideas or shifts in how you're thinking about patient care, I would love to hear from you. This community is such an important part of what keeps this work evolving. The dialogue that we can share through your notes, through comments when you join us in the live setting is what keeps this work evolving. It keeps us engaged.

Don't forget to swing over to the show notes page. You will find the full transcript there. You'll find all the citations that we mentioned. You'll also find links. previous conversations that I've had with Karan and previous Cal Roy conversations as well. And it's all free, by the way. We'll see you next time on New Frontiers in Functional Medicine.

Cowboy advances human health by translating emerging scientific discoveries into breakthrough supplements that deliver real world outcomes people and practitioners can trust. From circulation to cognition, heart health to joint mobility, Calroid develops clinically validated supplements with patented ingredients that restore and protect the body's foundations. True vitality begins deep inside your body's system. Head over to Calroy dot com slash DRKF, that's doctor KF to learn more.

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