The Estrogen Effect Nobody Talks About | Kiran Krishnan

Cardiovascular disease is the number one threat to healthspan and longevity. But, aging in women doesn’t follow the same trajectory as it does in men. Alongside perimenopause, as the protective effects of estrogen wane, dyslipidemia, metabolic dysregulation, and weight gain arrive in a rush. This transition still catches even our healthiest patients (and their clinicians) off guard. The downstream effects are vast–brain, bone, microbiome, joints, and barriers (including intestinal and endothelial) all become compromised. Cardiovascular risk can skyrocket.

Kiran has become one of my favorite people to think through these challenges out loud with, and we scaffold this episode of New Frontiers around the underlying perimenopause- and (more broadly) age-related dismantling of the endothelial glycocalyx, nitric oxide signaling, microbial integrity, and cartilage health. These underlying mechanisms are hugely relevant, regardless of whether a patient is on HRT, GLP-1s or even statins. And it’s always a refreshing escape from the myopic fixation on LDL targets without attention to the underlying systems biology.

I think you’ll find this conversation will shift your thinking. – DrKF

In this episode of New Frontiers in Functional Medicine, Dr. Kara Fitzgerald sits down with Kiran Krishnan to explore the compounding biological vulnerabilities that emerge with aging – and what we can actually do about them. The conversation moves across the biology of vascular and joint aging, connecting the dots between the gut, the endothelium, the joint space, and the cardiovascular system. Kiran and Dr. Fitzgerald discuss how the Calroy trio of Arterosil, Vascanox, and Cartigenix can be deployed synergistically to address these overlapping mechanisms, and why that matters for virtually every patient from early midlife forward. This is a wide-ranging, clinically grounded conversation that will shift how you think about vascular health, the anabolic-catabolic balance, and the clinical tools available to us right now.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: 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 Kiran Krishnan. He is a research microbiologist and a familiar voice on this podcast. He’s an all-around brilliant guy and actually a really extraordinary athlete as well. If you’ve listened to him before, you know, he makes complex science feel clear and relevant.

Dr. Kara Fitzgerald: In this episode, we focus on women’s health. So we’re looking at the trio of Calroy Health Sciences products through that lens, particularly the transition from perimenopause to menopause, the challenges that we’re facing during that time, and how this suite of products can just really have a broad influence. We can think about using them in very creative ways. This is gonna be a conversation where I think you’ll really glean some things that will make you think. I hope you enjoy it.

Dr. Kara Fitzgerald: Kiran, it is always awesome to get to hang out with you and pick your brain. Just, yeah, we’ll mine your brilliance here and all of us, myself included, but the many clinicians listening will have some information to really use in practice. This is all about clinical applicability. We’re talking about the dynamic duo of Cartigenics and Vascanox today and how they can be used synergistically and then we’ll also talk about individually, but I want to start with, you know, the overarching theme of this podcast is the women’s transition. So perimenopause, menopause, this obviously applies beyond that group. Let’s talk about cardiovascular health which, in fact, meteorically rises in women as we transition through perimenopause and into menopause. But it influences everyone. It’s the number one threat to health span and longevity. All of us in clinical practice are always thinking about the cardiovascular health of our patients. And we’ve got better tools, better labs. Imaging is becoming more sophisticated.

Dr. Kara Fitzgerald: But one of the cool things that I think you have really brought to the fore, brought to 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 overall, or thinking about the care of that as a part of an overall health plan for our patients. So talk about it. Again, define it, what it is, and why is it so essential for cardiovascular health in this women’s population, more broadly.

Kiran Krishnan: Yeah, well, number one, thank you so much for having me. This is such an important topic, right? Because obviously it’s still the number one killer. There are tools in place, but I think there are elements of the pathology that we don’t pay enough attention to. I think everyone understands the atherogenic particles component of cardiovascular disease, right? But then when we start thinking about the actual physiology of the endothelium itself and what may be happening in that area that creates so much risk once you hit your late 40s, early 50s that wasn’t there before when you were in your 20s. So then we have to really think about that physiological difference between the 20, 25 year old endothelium and the 50 year old endothelium.

Kiran Krishnan: So what is so different about it? And really two things come to mind that are significant, or really three things, but the first two are really important, which you’d already touched on. Number one is the structure of the endothelial glycocalyx. 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 structure, then the second part of it is the response of nitric oxide in the vascular system. Then they actually marry together really well because one of the roles of the endothelial glycocalyx is to take shear stress that’s coming from blood movement and convert that shear stress into a biochemical signal to increase nitric oxide production. That is a really important aspect of vascular compliance and protecting the lining of the vessels from too much sheer stress and exaggerated damage. Including 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 arterial bifurcations, where the blood runs into the bifurcations and then it bifurcates into the different vessels.

Kiran Krishnan: All of those things have this mechanical stress element to it. That mechanical stress element is turned into biological signals by the endothelial glycocalyx. And the response to that signal is the release and the production of nitric oxide. So that’s such an important one to punch, to protect the structural elements of the vascular system.

Kiran Krishnan: Now, as we age, and as estrogen levels as women age and estrogen levels go down, we know that nitric oxide response goes down. There’s a direct correlation between declining estrogen levels and declining nitric oxide response, and nitric oxide production. And so even if the endothelial glycocalyx is working fine and it’s creating, it’s transferring that fluid stress signal into nitric oxide activation, you’re not responding by producing enough nitric oxide.

Kiran Krishnan: So then vascular compliance is low, blood pressure goes up because there’s more shear stress and more blood volume pressure on the vessels. And then that increases potential for endothelial damage. Then you look at the glycocalyx and its role in the barrier function of the vascular system, because it regulates permeability. When the endothelial glycocalyx is intact, it actually can reduce LDL migration into the intima, which is where those atherogenic particles can create havoc, right? And create the issues around the gradient between the luminal side and then the intima side. And so the glycocalyx plays an important role in that barrier system as well. So that’s another role that it plays.

Kiran Krishnan: The glycocalyx also shields the vascular system from drivers of inflammatory mediation in the intimal layer as well. And so there’s a number of structural elements that start to change as people age and the glycocalyx starts to dismantle and then the nitric oxide response reduces as well. So you see that vulnerability then of the endothelium as a result of that.

Dr. Kara Fitzgerald: I would be remiss not to mention the small role of Arterosil here because, you know, obviously I think the three flagship products of Calroy, you know, can really work synergistically together. So Arterosil supporting the patency of the endothelial glycocalyx, Vascanox for increasing nitric oxide output. And we’ll talk a little bit more about that mechanistically and what it does specifically in a minute. And then I want to hear your thoughts on where Cartigenix fits into the cardiovascular disease story. We can start there and then we’ll move into talking about this meteoric rise along with cardiovascular disease and joint pain that we see in women transitioning. So first, connect the dots with your thoughts around Cartigenix for cardiovascular health and then we’ll move into joint pain more specifically in this population.

Kiran Krishnan: Yeah, absolutely. So, and one more thing I want to mention because you mentioned the synergy between the two products, right? So the Arterosil and the Vascanox. I talked earlier about how a healthy endothelium glycocalyx uses the sheer stress from blood movement to upregulate nitric oxide production, which is a really beautiful and elegant way of protecting the vascular system. The reverse is actually also true. The production of nitric oxide by eNOS – endothelial nitric oxide synthase – also, in return, helps preserve the endothelial glycocalyx by upregulating something called proteoglycan synthesis. Proteoglycan synthesis is the structural element that makes up the endothelial glycocalyx. The glycocalyx stimulates nitric oxide production and nitric oxide production in turn protects the endothelial glycocalyx. They are absolutely synergistic.

Kiran Krishnan: We can see quickly how when one declines and with estrogen decline, so does eNOS. And as a result of that, then you start to see a decline in the glycocalyx structure. And as the glycocalyx structure declines, then you get less stimulus for more nitric oxide production and the cycle goes on and on and on. You used the right word there when you said they’re so synergistic and they absolutely are because both of these mechanisms kind of feed off of one another to protect the overall structure. It’s such elegant biology that takes place there.

Kiran Krishnan: Then when you think about Cartigenix and you go, okay, we’re really talking about joint regeneration, we’re talking about cartilage regeneration as it’s been seen in a couple of randomized controlled trials. How is that then related to cardiovascular disease? Well, just looking at the epidemiology alone: People with joint dysfunction, whether it’s osteoarthritis or rheumatoid arthritis, are two and a half to three and a half times more likely to develop cardiovascular disease. 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 health. And manage joint health. NSAID use, continuous use especially, is a risk factor for cardiovascular disease.

Kiran Krishnan: The second aspect of it is in all of these individuals with joint dysfunction, you’ve got an anabolic/catabolic battle that’s happening. The anabolic side is trying to win out to rebuild the joints 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 felt in the joints is also happening in other tissues.

Kiran Krishnan: That whole anabolic/catabolic 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. That happens in your muscles – this is why sarcopenia happens, right? That happens in your brain, neurodegenerative conditions, that happens in your cardiovascular system – your cardiac cells and all of those undergo the catabolic, you know, shift.

Kiran Krishnan: And so as a result of that, what we see in the role of Cartigenix here is we’re looking at it in the joint, but we’re looking at it systematically. So, we’re looking at the markers of degradation versus anabolic repair. We’re looking at those in the whole system, but we’re also measuring the effect on the joint. So what we’re seeing with Catigenix 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 battle.

Kiran Krishnan: Because we’re seeing the shift in those individuals, and we can measure it in the joint, we can measure it systemically through biomarkers, we’re not making too much of a leap to think that that same fight, that same anabolic-catabolic fight, if we start winning it, we start winning back the anabolic side, we’re improving the cardiovascular system, improving our muscles, we’re improving everything else in the body that is damaged by losing that battle. So I think that’s a big part.

Kiran Krishnan: Then the last part I would say is it gets us active again. Because the last thing you’re thinking about when your joints hurt is going for a walk. The last thing you’re thinking about is doing exercise. And so the joint pain and the frequency of that 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 movement is critically important for cardiovascular health. The second thing it does is it creates a lot of stress and anxiety – chronic pain is a massive driver of stress and anxiety in people, and stress and anxiety is really bad for cardiovascular health. So I think the connection there becomes really clear.

Dr. Kara Fitzgerald: It’s fascinating. The three of them together have just a nice synergy. I can see just thinking about it overall the fact that Cartigenix specifically in your investigation in joint health was also associated with lower CRP and lower IL-6. You’ve suspected in your publications that it’s influencing inflammation foundationally, but then you’re witnessing these changes in the joint.

Kiran Krishnan: Yes, and the key part of that is those specific markers that you mentioned. So if you look at hsCRP overall, but then you look at more refined (biomarkers), we looked at IL-6, TNF-alpha, IL-12, IL-1 alpha and beta. So, if you look at those very specific cytokines and interleukins, they are the culprits that drive the shift from anabolic to catabolic processes.

Kiran Krishnan: That is what is happening. That changes cell types so drastically, for example, in the joint itself. It changes the chondrocytes that are designed to lay down the cartilage and rebuild cartilage. It changes them not only from not rebuilding cartilage, but actually breaking down cartilage actively by releasing enzymes like MMPs and so on. So that battle, that catabolic-anabolic battle is, I think, not stated enough when we think about functional medicine and overall health, because it’s such a root cause driver of physiological changes in people that leads to dysfunction.

Dr. Kara Fitzgerald: It’s a great point. mean, 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 and support, you know, maintaining muscle. This is much more, this is essential. This is very root. It’s not it’s not pounding back a couple of steaks, but it’s tweaking the mechanisms that drive that drive the breakdown as we, you know, as we age. And it drives the break down everywhere. You know, we’re not talking just muscle. It’s everywhere. You know, it’s brain gastrointestinal, you know, cardiovascular everywhere.

Dr. Kara Fitzgerald: I want to just take a moment and just circle back to Cartigenix and the awesome research. We’ve already talked about it on this show. But it made me a believer. I mean, I just, my gosh, the first time we talked, the product wasn’t available yet. But I knew that I was gonna try it, because I’ve had this chronic knee pain, like low grade. doesn’t inhibit, well, maybe it was inhibiting my life. It was something that I was aware of and sort of a little bit anxious about to your stress point. But I could still function and walk and ride and all of that. But you you guys showed such cool stuff. I was blown away by the fact that you showed cartilage regeneration on imaging in, you know, in a decently large cohort in a hospital setting. I mean, you’re, you know, using Boswellia and celery seed. I mean, they’re special – the Boswellia is a pretty extraordinary form of Boswellia.

Dr. Kara Fitzgerald: And also (you saw) a drop in CTX, incredibly enough. We use CTX in practice. I’m sure most of the listeners are familiar with it as being kind of one of our workhorse markers of bone loss or whether our intervention is working – seeing that drop. We don’t want to have a high CTX. That’s evidence of cartilage turnover. But anyway, for me, it was so exciting, the science that you were doing and the images.

Dr. Kara Fitzgerald: So again, I just wanna shout out, first of all, your commitment to science, Kiran, I’m always grateful for the, and we’ll link to these, previous podcast so everybody can hear the details around how you brought this to market and your efforts from in silica work on up to human beings. So cool.

Dr. Kara Fitzgerald: So you showed the regeneration of joint space on imaging. And then my side note in one of our original conversations was that this is probably a surrogate marker of biological age. You know, this is one measure, because we all know that this joint deterioration happens with the aging phenomena. And I was just wondering, you know, 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 thought about that a little bit more, but I just wanted you to touch on that original science and the components of the product and why they’re special.

Kiran Krishnan: Yeah, no, that was actually a really good question. I’m going to come back to that because you illuminated that for us to think about from the first time we had this conversation. But to review the study, so these two components are quite unique. 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. So, what the first investment was really on much more advanced analytical chemistry tools and capabilities because most of these plants, you know, celery seed and Boswellia, the actives have been defined for a long period of time, right? So Boswellia has the Boswellic acids and AKBA and so on. We know what those structures are. Same thing with celery. We know what some of those structures are.

Kiran Krishnan: But then again, when you look at it and you go, well, that was done 15 years ago, analytical chemistry has improved quite a bit since then and we can decipher much more. And so that was the first layer of investment was, okay, let’s get six or seven really great analytical chemists. Let’s give them all the equipment they need. Let’s give them all the access that they need and resources and let them discover other actives within these plants.

Kiran Krishnan: 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. What do they do? So then it goes down to the biochemist groups that we work with. And we said, all right, let’s put this into an AI system and see what it can identify, what kind of receptors it may be able to activate and so on.

Kiran Krishnan: And we were able to narrow down biologically active components from the of the actives that we discovered. And in the Boswellia, for example, seratol is one of them. And what’s so interesting about seratol is it seems to play a role in the tissue repair components. So, activating of things like matrix metalloproteinases or down regulation of those catabolic enzymes and so on. So we said, okay, so that’s a really interesting component because we know Boswellia is already a LOX inhibitor. It reduces inflammation and so on. So we said, let’s look at the tissue repair component, potential tissue repair component with the seratol component. And then with the celery seed, we looked at other components that could be synergistic to this function.

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

Kiran Krishnan: Because there are trials on boswellia, for example, on being able to provide alleviation of symptoms associated with joint dysfunction. But it’s never been shown to actually start to create cartilage, like tissue regeneration. And it’s been thought for the longest time that once you wear down your cartilage to a certain point, and let’s say you have bone and bone, that’s it. You can’t generate it 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. 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.

Kiran Krishnan: So that was the crux of the research was showing not only both from a biomarker perspective, looking at cartilage degeneration and regeneration markers, but also the imaging, which you had a chance to see, where you could see bone on bone on these patients and then boom, joint space after 90 days.

Kiran Krishnan: When you brought that point up about looking at the joint space as a potential measure of reversing biological age – we did that and so what we did is we uploaded a number of those images into an AI tool to try to read the joint space and quantify it better. And we were getting some actual initial readings, which was fantastic because what it validated was that number one, there are a number of studies that actually show that joint space is a quantifiable measure of biological age. And so we saw that and we referenced that and then we were getting some measurements out of the joint space increase, which is really exciting to see.

Kiran Krishnan: What we’ll probably have to do to make it usable information is standardize the X-rays better. We use the X-rays as just an add-on just to see if we could visually see anything 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 X-rays for joint imaging as well as we should – putting people in the exact same position and so on from one to the other 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, think it’s really telling. 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 great thing that you pointed out.

Dr. Kara Fitzgerald: Well, I’m so glad that you’re 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 certainly understand everything needs to be controlled so exquisitely, but you just got that really fabulous initial signal. And you’re starting to turn upside down the idea that bone on bone, you’re done.

Dr. Kara Fitzgerald: You know, what a nice, what an extraordinary, know, fallacy to just really disrupt. That’s amazing. And, you know, kudos to you for, you know, questioning it in this journey.

Dr. Kara Fitzgerald: I just want to say, I have two more thoughts around this, and then we’ll talk a little bit about 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 gonna be important? I mean, was that as quick as pushing the ChatGPT go button?

Kiran Krishnan: Similar to ChatGPT. If anyone’s used ChatGPT, they know that what you get out of it is very much dependent on how good your prompts are. So the people that are really good at working with ChatGPT and getting the maximal benefit out of it have become really great at the prompts and understanding the limitations that it has and working through the limitations. When you’re in silico studies actually using AI tools for modeling and modeling function of molecules, it’s very similar to that where it’s really about how good you can be at creating the right prompts and creating the right input so that the AI can do what it does best.

Kiran Krishnan: But yes, if you do it right, it is amazing at accelerating towards both safety and efficacy studies. Especially with plants, because plants are so complicated. They have so many components in there. 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 would typically learn that through lots of effort of trials and dosing studies and various ways of extracting the actives. If we just think about the thousands of years of Ayurveda – they learn how to extract certain tinctures that became efficacious 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. We can, we could skip those years and just kind of go right to, okay, these two things are going to work really well together – Boom, let’s study them now.

Kiran Krishnan: So yes, it’s an amazing tool 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 I think it’s gonna give us in the world of utilizing natural compounds, a massive leg up because we’re starting from this big mix of compounds, right, versus the pharmaceutical side, you’re starting with a single small molecule. And you’re adjusting that molecule based on the type of efficacy that you’re looking for. 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.

Dr. Kara Fitzgerald: Yes. And to that point, you found some unique compounds in (your form of) Boswellia that are not present in other forms. So all of us in functional medicine have prescribed Boswellia, I’m sure. I’ve been teaching about it as a fabulous LOX inhibitor for my entire career at IFM going on, I guess this is year 13. A long time! And of course it’s been known time immemorial, not necessarily that it was a LOX inhibitor, but in Ayurveda, they’ve had this idea.

Dr. Kara Fitzgerald: The cool thing about this journey that you took, you did identify some unique compounds that are efficacious in your particular product that are not present in other Boswellias that you’ve tested, right?

Kiran Krishnan: That’s exactly right. Yeah, I mean, the thing is it’s in the plant. But in order to extract the new compound like seratol, for example, which is part of our Boswellia, not found in anything else, 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 Boswellia.

Kiran Krishnan: And we, of course, wanted all the conventional actives because they have been well established as having functionalities, LOX inhibitors. We want that. So we have to be able to extract that in the known ways, but then alter the preparation so that you actually get the additional actives out as well. So then all the work doesn’t stop once you identify the compound and identify that it can be efficacious in a unique way.

Kiran Krishnan: Then you have the whole process of process development – how do you commercially and in a financially feasible way – alter the extraction process to get enough of this new active in? And that’s a whole other world of chemistry and biochemistry and so on. But it’s super exciting to be able to do all that.

Dr. Kara Fitzgerald: It’s really exciting. I love hearing about it. I’m just curious. And then I swear we’re going to change topics. You talked provocatively about identifying antagonistic compounds in your in silica work. I mean, are you intentionally avoiding certain compounds as you standardize your boswellia?

Kiran Krishnan: Yeah. Similar to lots of other things that clinicians have worked with, there are different levels of affinity for receptor sites of compounds. Something might have a low affinity for the receptor site, but it could still be what we would call either an allosteric or direct inhibitor of the receptor site. It’s taking up the space, but it’s not then triggering all of the downstream signaling.

Kiran Krishnan: 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 an actual tomato has like 200 different versions of lycopene. And they have like a certain amount of the structure is very similar, and then you’ve got all these side chains that’ll change the function of it.

Kiran Krishnan: And so one of the things that we’re looking for is, once we identify a potential receptor or signaling molecule that we want to activate, is a low affinity agonist or antagonist of that function. Because what we don’t want is to extract something that potentially interferes with the ability of your target compounded function. So that can be complicated because again, plants have all of these nutrients and anti-nutrients. They have these components that can kind of compete with each other.

Dr. Kara Fitzgerald: Yes. That’s so fascinating. So just trying to make sure you’ve the best of what you need and minimizing what you don’t.

Dr. Kara Fitzgerald: Let’s go back to thinking about estrogen declining and all of the stuff that goes on. We talked about the endothelial glycoglycerides and nitric oxide and it’s interesting. We know when estrogen declines, as clinicians, always see cholesterol go up and we see just all sorts of abnormal lipid panels kind of start to emerge. And I think we’ve gotten very stuck on let’s drop LDL to 30. 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 cholesterol becomes a demon.

Dr. Kara Fitzgerald: But estrogen is this amazing compound that does tons of stuff. I mean, it helps our brain. I mean, it controls inflammation. And we see, you know, we just, and once it drops, we can see inflammation increase in women, obviously cardiovascular disease just meteorically rises, brain health drops, I mean just all systemically, we just see it everywhere. Not just the end of our menstrual cycle, et cetera, but much more bone health and on. Talk about Cartigenix playing a role there as estrogen declines.

Dr. Kara Fitzgerald: But also too, I wanna just extend it to thinking about Vascanox as well, and if you wanna throw Arterosil in there, you could.

Kiran Krishnan: Yeah, absolutely. One of the things that is maybe not spoken about enough is the role of estrogen in maintaining diversity in the gut microbiome. And as a result of that (decline) – intestinal permeability. So one of the things that seems clear is that as estrogen declines in perimenopause, you start to see a reduction in diversity in the gut microbiome and a dramatic increase in endotoxemia. And that’s intestinal permeability with an increased translocation and increase in serum LPS levels. And that sets up this higher level of chronic low-grade inflammation, the same kind of chronic low-grade inflammation that creates a significant risk for cardiovascular health, bone loss, neurological damage, all of that.

Dr. Kara Fitzgerald: It pushes the catabolic bias, yeah.

Kiran Krishnan: Exactly. It’s all starting to move the catabolic bias. It’s also one of the key reasons why anxiety and depression can increase. It’s another reason why insulin resistance increases as well. So for example, just taking the role of what happens with LPS. 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 what the impact of that is.

Kiran Krishnan: So, there’s a study called the Netherlands study on anxiety and depression. It’s a state sponsored study in the country of Netherlands looking at a nine year follow up on individuals that had, know, basal level and then higher risks of anxiety and depression, higher 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 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, lipopolysaccharide levels. The one and only marker.

Dr. Kara Fitzgerald: Wow, that’s crazy.

Kiran Krishnan: 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 had elevated LPS – the anxiety and depression is a result of that elevated LPS. They followed these individuals over nine years. For the individuals that reduced LPS levels – 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. 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.

Kiran Krishnan: The second one is shown in two different studies. One of the studies is the CORDIOPREV study, which is 480 patients over 60 months. They were looking at pre-diabetics. And then they were following pre-diabetics over the next 60 months to see how many of them went from pre-diabetics to full-on diabetes, following A1C, HOMA-IR, and a number of things. At the same time, they were following all kinds of markers to see which markers were predictive for those who would go from pre-diabetes to diabetes. That was, again, only one marker that had greater than 95% confidence interval, and that was serum LPS levels.

Kiran Krishnan: Then similar things have been shown 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 anymore. Even if your pancreas and your insulin cells are producing enough insulin.

Kiran Krishnan: So that is happening as estrogen declines. 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. 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 conformation. That is a massive driver of the catabolic-antibolic battle and causing the catabolic stress.

Kiran Krishnan: One of the things that we saw with Cartigenix, as we’re looking at global markers in the body, not synovial markers in the joints specifically, we’re looking at global markers, are markers of bringing back the battle towards the anabolic side. So 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 them back towards either balance or maybe even leaning more anabolic. So that we can rebuild, repair, do all the things that our body needs to do. I think that’s a really, really important role of Cartigenix in the entire system and directly tied to the impact of estrogen and estrogen decline in the gut.

Kiran Krishnan: Tying in the Vascanox and the Arterosil as well, 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. And we know oxidative stress plays a role in cardiovascular pathology.

Kiran Krishnan: Then as a result of oxidative stress going up, the second thing that happens is you get more glycocalyx shedding. So now that protective layer, that also plays a role 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. So that entire process is also happening quite rapidly as estrogen declines.

Kiran Krishnan: So you’ve got this full array of things that you can target – the reduction in nitric oxide, the shedding of the intestinal [correction: endothelial] glycocalyx, and the move towards the catabolic function. Because of all of those, because of the decline of estrogen, we could start to rescue all of those with Cartigenix, with Vascanox, with Arterosil. So it’s such a perfect combination of products. At face value, you look at it go, okay, how are these things related? 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 and rescue them.

Dr. Kara Fitzgerald: Right. Yes. And it just expands our toolkit. You know, again, there’s a place and time for addressing cholesterol, of course, but we’ve been pretty myopic, I think, and this, you know, just zooms us out. I also want to talk about, you know, just mention the blood brain barrier and endothelial glycocalyx as well. You know, that’s one of the things that I’m thinking about when I’m prescribing Arterosil. So just bringing that back.

Dr. Kara Fitzgerald: And then the other thought that I had two other thoughts. One was – long lived healthy people have a really extraordinarily varied microbiome. They maintain that beautiful diversity. And I’m sure that it has to do with being able to maintain intestinal integrity and LPS has dropped. I mean, it’d be interesting to do more broad investigations. There could be out there already, but you know, we see dysbiosis as a driver of aging. And I think just tying that back to the drop in estrogen makes a ton of sense. But then also giving us some ideas of how to think about it differently.

Dr. Kara Fitzgerald: I just wanted to briefly circle back to my own story, because I said that I would mention it then I completely forgot to. I’m not going to spend a lot of time on it. Basically, my knee pain went away. It happened so subtly. Kiran, you remember I was very excited to start the product. And then I did. And we had a webinar around when I started it and one of the people who produced the webinar with me, her husband had this remarkable turnaround. I don’t know if you recall, she shared her story and it brought her to tears because it was such a big deal for him. And it happened quickly and it was profound.

Dr. Kara Fitzgerald: And then you and I were in Vegas talking. We were doing an interview and I thought about my knee pain. This 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 was really excited, and yeah, it was kind of a fun moment. So it’s been very helpful.

Kiran Krishnan: That’s awesome. Well, and for you in that case, your performance has increased as well, right? Because, you know, I guess if you connect the two, makes it easy to see that, okay, even though you found a way to not allow the knee pain to kind of 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 be. So yeah, that’s exciting.

Dr. Kara Fitzgerald: Right. Yeah, that’s right. It is exciting. I’ve gone back to competitive cycling folks and I’m just having a blast doing it. So it is part of my stack, now, Cartigenix. 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 Vascanox and Arterosil are also part of my stack as I’ve talked about before.

Dr. Kara Fitzgerald: Anyway, moving on from that, just going back to what I thought was a creative thought. 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 whatever delivery system that might be, or any other drug for that matter, or a supplement, we need healthy vasculature to deliver it. So maybe just talk a little bit about that.

Kiran Krishnan: Yeah, and I think that’s a part that maybe gets overlooked more often than it should. Because when you think about the vascular system right now, number one, it’s just from a biological perspective, it is so elegant. 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 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 compounds and all that to the tissues that need them the most.

Kiran Krishnan: One of the big issues with aging, and this can be measured quite easily, is what is that flow-mediated dilation? How do your vessels respond to needs? 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 people we’re talking about people in their 70s and 80s versus people even in their 50s and late 40s that are in need of medication that are in need of supplements are we really delivering them to the site of action just because we’re taking them right doesn’t mean it’s necessarily getting to the target tissue because the highway in which it has to travel is compromised.

Kiran Krishnan: And so we have to look at things from that systemic functionality perspective and ensure that we’re providing healthy 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? Basically having diabetes doubles to quadruples your risk for virtually every other condition like cardiovascular disease, dementia, Alzheimer’s, all of those things. What is it about diabetes that creates that significant risk? Well, at least one element is the decline in microvascular function. You see that in blindness that occurs and all of that stuff.

Dr. Kara Fitzgerald: Yes. Yes. Of course, massive.

Kiran Krishnan: So we cannot overstate the importance of 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 getting to the side of action, are amino acids.

Kiran Krishnan: We talk about the importance of muscle mass and maintaining lean mass. Of course, when the myogenic signals kick in at the site of action, which is at the muscle because from the contraction and the stress and all that from lifting, you need to get the elements – number one the energy source, and then the amino acids to rebuild the muscles to the site – and that all depends on the microvascular chart.

Dr. Kara Fitzgerald: You know, we can measure nitric oxide. It’s pretty easy to see whether we’re producing enough. I mean, do you check your nitric oxide level?

Kiran Krishnan: Yeah. I do just through those through the saliva swabs. And what’s interesting is… So I’ve been taking nitric oxide for a long time, right? And my belief was those silly little swabs didn’t work. Because for, right? Like I remember starting to take nitric oxide 15 years ago. Like you, I was a cyclist and I was a competitive cyclist or to me, anything that can give me an edge. Right, without going to EPO and all of those things. And so when I first heard about like the nitric oxide from beets many, many years ago, I was like, load me up, right? I need as much vascular dilation as possible. So I would take it. I wouldn’t really feel anything. And I was someone that was very dialed in on my cardiovascular performance and capabilities as you are, you know, and I, we talked about earlier how I measure everything.

Kiran Krishnan: I mean, I’ve been using a power meter for 15 years. And I, and I’m very dialed in because when you’re racing, your biggest fear is you get to the start line of your first race and you’re underprepared and man, you get just demolished, right? And it’s so embarrassing and you get dropped and left and you know, all that. So all those fears set in and in the early, you know, base training part of the season, you’re really doing everything you can so you’re not last in the first race. And so popping nitric oxide. Then I found those, there was a company that was making those swabs and I kept trying them and it wouldn’t move the needle at all, right? Like the color never changed, like as much as I would take those. The first time I ever saw that color change and be able to maintain that color over a long period of time is when I started taking Vascanox.

Kiran Krishnan: I came into knowing Calroy through Arterosil because my number one health goal is cardiovascular health because of family history and all that. But then when I started taking Vascanox, that was the first time I saw on those little color measurements on the tongue that it actually changed the color for me. It moved it. And you come to realize it’s because it’s a 24-hour upregulation of nitric oxide when you take the nitrites and all that, they’re fleeting, right? They’re used up, the gas is volatile – it goes away in a matter of minutes. But then providing the precursors 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 this functioning. So I’m excited to say that I constantly measure mine now and it makes me happy.

Kiran Krishnan: It gives me like a little bit of a confidence. I was just skiing all week in in Vail and and there’s always a part of me that’s like it’s 12,000 feet and you know, yeah I’ve raced in altitude before and I know that feeling and you know, I’m like, but I got my nitric oxide. So I’m good.

Dr. Kara Fitzgerald: So you’re good. That’s really cool. You know, I have my sticks at home to measure mine and 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 power meter way back in the day. I just started measuring mine and you and I were talking about numbers before we started recording. I’m absolutely obsessed, but it’s because bikes now are nuts.

Kiran Krishnan: They’ve got everything. Yeah. It’s funny, before I go on a ride, I have to plug in my bike three different ways. One for the shifters, one for the power meter, one for the computer. It’s nuts.

Dr. Kara Fitzgerald: Yeah. And then check it all on your app. But I’m totally obsessed. Vasconox is just a very elegantly designed product. And Dr. Houston’s study actually shows that it sticks around for up to 24 hours, which is absolutely game changing because nitric oxide is around for seconds. It’s kind of a unique collection of ingredients. Obviously, there’s beetroot in there. But maybe talk about you know, some of the standouts and what might be helping it stick around for so long. What are your thoughts on that?

Kiran Krishnan: It’s a variety of precursors for nitrate to nitrite transition that have been provided. So when you look at things like the black garlic extract – that they have in there from the bulb specifically. Which makes sense because the bulb of the black garlic extract is the nutrient source of the garlic itself. so, you know, the nitrate and nitrite precursors are in there at high concentration. If you look at the things like the blue honeysuckle berry, the raspberry extract, the bilberry extract, it’s a really nice variety of a number of stable nitrate sources that actually allow for that sustained release of the final conversion of nitrate to nitrite.

Dr. Kara Fitzgerald: It’s uniquely designed and I know they have a pretty cool team over there. You guys have a neat team over at Calroy Health Sciences designing stuff. So yeah, it is a creatively designed product.

Dr. Kara Fitzgerald: So we’ve touched on the suite of Calroy products. We’ve talked about muscle mass, we’ve talked about nutrient and HRT delivery, obviously nitric oxide and inflammation, joint space. We’ve gone the journey. Massive in this conversation, massive in this space currently is the use of GLP. I mean, we’re prescribing it as clinicians and functional medicine. Of course, the broader medical community the world over is using a ton of GLP these days for many, many different indications off label. Thoughts on how these might support using GLP?

Kiran Krishnan: Yeah, so one of the most important things I think about, you know, the use of GLP-1s is how do you set up your system so that you can come off of them, right? Obviously nobody wants to be on GLP-1s forever, nor is that a good idea. So they can give a boost, they can give an acceleration towards weight loss and improving blood sugar control. But then the question becomes how do we set up the patient so that they can successfully come off the GLP-1s? Nobody wants to be on them for the rest of their lives.

Kiran Krishnan: What seems to be clear is that in order to successfully be able to come off GLP-1s, 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. Second of all, we probably have to increase movement in these patients. So we have to get them active again, so that becomes a regular part of their lifestyle. 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-1.

Kiran Krishnan: When you look at the data, for example, the vast majority of people on GLP-1s are larger body individuals. So they have increased BMI typically over 35. And then they are insulin-resistant or full-on diabetic. There are two important characteristics that are very highly prevalent in those individuals. Number one is that they tend to have a much higher prevalence of joint pain. You’re at 4.7 times higher prevalence of joint pain in people who are obese versus people who aren’t. So the people who are starting GLP-1s are already suffering from joint pain. So then how do you get them to move? Of course, the weight coming off is going to help, but you still have to get them into the habit of moving and pain is a dramatic inhibitor of movement.

Kiran Krishnan: The other aspect of it is they tend to have significantly lower flow-mediated dilation and greater microvascular abnormalities. Because that’s a profound characteristic of being insulin resistant and being diabetic and being overweight. So 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.

Kiran Krishnan: And so those two structural elements have to be addressed in your GLP-1 patients so that they can successfully come off the medication in a state 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 anyone that has patients on GLP-1s should really be looking at Cartigenix 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 and transport of nutrients to the right places as well. Because those two components are uniquely compromised in GLP-1 qualifying patients.

Dr. Kara Fitzgerald: Right, absolutely. And then, of course, a lot of them are gonna be dealing with some elements of cardiovascular disease processes and the endothelial glycocalix is likely compromised, so I think it’s worthy consideration for Arterosil as well if it seems appropriate.

Dr. Kara Fitzgerald: Well, 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 really important tools and some kind of different ways to think about, you know, why we would use these how and, you know, the the meaning behind them and indications and so forth. Thanks for joining me.

Kiran Krishnan: It’s my pleasure. Thank you so much for having me.

Dr. Kara Fitzgerald: 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.

Dr. Kara Fitzgerald: We’ll see you next time on New Frontiers in Functional Medicine.

Kiran Krishnan is a research microbiologist and a health and wellness expert who aims to make complex information understandable to all. He has founded a number of successful health and supplement companies over the last 20 years including co-founding and leading Microbiome Labs, the preeminent, microbiome therapeutics focused brand among healthcare professionals. He is currently a co-founder and partner in 3 other companies that aim to revolutionize wellness care. He has conducted and published several research studies in scientific journals, has published chapters in scientific textbooks/reference books, has global patents and is a sought after speaker on human health and the microbiome.

Kiran Krishnan

Calroy Health Sciences

Cartigenix HP

Arterosil HP

Vascanox HP

Related Conversations on New Frontiers

What New Research Says About Cartilage Regeneration and Joint Longevity

Innovative Approaches to Cardiovascular Care: A Deep Dive with Dr. Mark Houston

Mastering Cardiovascular Longevity: Glycocalyx and Biohacking for Optimal Heart Health

How to Fix the Vascular Health Crisis: The Endothelial Glycocalyx

Cartilage Regeneration Research

NSAID sparing effect of celery seed and Boswellia serrata in osteoarthritis

Clinical effectiveness and tolerability of celery seed and Boswellia serrata in osteoarthritis

RCT (double-blind) Boswellia serrata and Apium graveolens for osteoarthritis and cartilage degeneration

Nitric Oxide Research

Garlic extract and Dietary Nitrate Formula on Blood Pressure and Salivary NO (Mark Houston study)

Endothelial Glycocalix Research

Nutrition and Lifestyle for endothelial glycocalyx

Regeneration of endothelial glycocalyx after high glucose damage

Microbiome/Lipopolysaccharide Research

LPS and Anxiety in The Netherlands Study

LPS Predicts T2DM in the CORDIOPREV Study

LPS-Induced Central Insulin Resistance

Declining Estrogen Effects

Estrogen and nitric oxide/eNOS

Estrogen and gut microbiome diversity – a two-way street

Podcast: Moving Beyond Glucosamine: The Future of Functional Joint Care

Bio Age Self Assessment Quiz

Younger You book

Better Broths and Healing Tonics book