How To Reap The Anti-Inflammatory and Longevity Benefits Of Astaxanthin - Transcript

Introduction: Coming up on this episode of The Doctor's Farmacy. David Watumull: Importantly, astaxanthin actually crosses the blood-brain barrier, so it gets to the brain, gets into the cells, and helps to reduce oxidative stress and inflammation. Dr. Mark Hyman: Welcome to The Doctor's Farmacy, I'm Dr. Mark Hyman. That's farmacy with an F, a place for conversations that matter. If you're interested in longevity and natural molecules, and how they interact with their biology to activate longevity pathways, I think you're going to find this conversation interesting, because it's about a particular molecule, widely found in nature that has remarkable properties called astaxanthin. You might have heard about it or maybe you haven't, but you certainly have eaten salmon, which is orange, and that's what you're eating. That's what's in there. Today, we have as our guest, David Watumull, who's had more than 20 years of experience in developing this product and this product development. In understanding astaxanthin as a powerful and safe, naturally occurring antiinflammatory compound that can upgrade our health. He's the co-founder and CEO of AX3 Life, which is a consumer longevity company that's formed to help people be their best selves. AX3 Life targets inflammaging, one of the core hallmarks of aging you've heard me talk about on the podcast, that I've written about in Young Forever. The core of that product is astaxanthin, BioPure Astaxanthin. He's also the COO of Cardax, a life sciences business focused on advancing pharmaceutical and nutraceutical applications of astaxanthin. Well, welcome, David. David Watumull: Thanks, Mark. Great to see you again. Pleasure to be here. Dr. Mark Hyman: All right. Great. Well, it was great to have you on, because I think obviously our audience is really interested in longevity and some of the biology of what goes on underneath the hood. A couple of things seem to be pretty universal as we get older, one is inflammation and that is one of the hallmarks of aging or inflammaging. And oxidative stress, which isn't actually a hallmark of aging, but it indirectly is, because a lot of it is about mitochondria and mitochondrial function. How that plays a role with the development of reactive oxygen species and oxidative stress that gets out of control. Oxidative stress, when it's too much, will actually cause a downstream cascade of damaging cells, tissues, organs and accelerating aging. Can you talk a little bit about how oxidative stress and inflammation impact health and age? What can we do on a practical level daily to unlock our key to longevity by addressing these two key components of aging? David Watumull: As you've outlined, oxidative stress and inflammation drive a lot of issues as we age with our health outcomes. As you've advocated in your book and on your podcast and everything, diet is a foundational role, exercise, lifestyle modifications, but supplements do play an important role in managing health. We've been really focused on astaxanthin as a naturally occurring supplement that can help you safely address oxidative stress and inflammation at the source. Because as you talked about, if you have oxidative stress and inflammation that's left to go awry, it can manifest itself into different types of things, that may downstream appear to be different types of issues. But if you can really focus on the root causes and restore health at that basic cellular level, that's something that really is worth pursuing. Dr. Mark Hyman: Yeah. It's really this ubiquitous process that we're constantly navigating. It's not that all inflammation is bad or all oxidative stress is bad, it's when they get out of control it's a problem. As part of ongoing research and actually new research at the NIH, scientists have been looking at how do we address this through various natural or synthetic compounds? Astaxanthin is a powerfully occurring plant compound that is found in algae and oceans, and essentially can have powerful effects in protecting us for many reasons. We'll talk about some of the NIH research and some of their programs that they have around looking for molecules that are in either pharmaceutical stock or in nature, that actually can activate many of these beneficial longevity pathways. But let's talk about astaxanthin particularly and how it helps fight some of the key hallmarks of aging, like mitochondrial dysfunction, inflammaging, cell signaling. Talk about and just get into the weeds a little bit about how it works on some of these fundamental mechanisms that we now know underlie all aging. We talked about this before in the podcast, but if you address, for example, heart disease and cancer and get rid of them from the planet, your life expectancy might increase five to seven years. If you address all the hallmarks of aging, which underlie all the chronic disease of aging, you could extend your life by 30 or 40 years, which means living to be 120. That's a big difference. Can you talk about particularly how astaxanthin targets some of these key hallmarks of aging? David Watumull: Yeah. In order to do that, we can really look at what astaxanthin does in the cell. First of all, when you ingest it orally, it's distributed systemically. It is distributed throughout your body to all your tissues and gets into the cells. In particular, gets into the cellular membranes and including not just the plasma membrane, but importantly the mitochondrial membranes, nuclear membrane. Given its structure with its polar headgroups and Poly backbone, it perfectly spans and anchors into the membranes. With that, it's a great scavenger of reactive oxygen species, free radicals, both inside and outside the membranes. As it's sitting there at that key site, say at mitochondrial membrane. Mitochondria, of course, our body's energy plants, and as a byproduct of energy production, of course, you have oxygen free radicals that are created and need to be addressed. Astaxanthin is perfectly situated to sit there in the mitochondria, and address the excess reactive oxygen species that can lead to oxidative stress. As you talked about, trigger inflammatory pathways. Looking at say inflammaging, by reducing excess oxidative stress, you can prevent the pathological activation of inflammatory pathways, like NF-kappa B and it's downstream cytokines like TNF alpha, COX-1, COX-2, IL-1, IL-6, and prostaglandin I2. A lot of the targets of lot of the anti-inflammatory drugs, but instead working upstream at the pathway activation level. In terms of inflammation working upstream to prevent the pathological activation of these inflammatory pathways, we think plays a major role in mitigating the effects of inflammation. Then if you transition to say mitochondrial function, again, being situated in the mitochondrial membrane, astaxanthin has demonstrated impacts on membrane stability in the mitochondria, reductions of oxidative stress, lipid peroxidation in the mitochondria. There's been studies showing increased ATP production, say in young and geriatric dogs, for example. It plays a fundamental role at the mitochondrial level. In addition to impacting inflammatory pathways, it impacts other cell signaling pathways related to aging, such as AMPK. We've seen impacts on AMPK and age-related pathways, so the sirtuins, FOXO3, even mTOR target of rapamycin. With impacts on all of these pathways, you get impacts on autophagy and mitophagy, and mitogenesis and all these critical roles that are part of the aging process. Dr. Mark Hyman: That's amazing. Okay. I'm going to unpack that because there was a lot and a lot of acronyms in there. I don't think people necessarily know what they are, but I'm going to help you unpack that. I think the question really was how does this molecule impact some of these ancient preserved longevity pathways? These receptors and mechanisms that are designed to keep us alive, to keep us alive longer, and are survival mechanisms. I talk a lot about them in Young Forever, these key longevity switches, things like the nutrient-sensing pathways. mTOR, which is basically regulating autophagy by being a fasting. When you fast, you basically inactivate mTOR, you inhibit mTOR. That allows your cells to clean up and do self-cleaning and repair, which is autophagy, which is so important to clean up all parts and recycle things. You said astaxanthin also impacts AMPK, which is another regulatory pathway as part of our nutrient-sensing pathway, that's very involved in blood sugar control and mitochondrial function in regulating inflammation, even activating sirtuin pathways. Then sirtuin pathways also you mentioned, are involved in the interplay between astaxanthin and aging. As sirtuins are involved in DNA repair and inhabiting inflammation, you mentioned things like COX-2 and NF-kappa B, these are compounds in the body that are regulating inflammation. When you have high levels of NF-kappa B or COX-2, basically you're driving inflammation and astaxanthin works on these mechanisms. For example, NF-kappa B is involved in regulating gene transcription for all these inflammatory cytokines, some of them which you mentioned. We have this really amazing interplay between these natural molecules and our biology to regulate these essential pathways. You mentioned FOXO, which is another really important one I want to get into, but that is involved in regulating a lot of our antioxidant pathways and our antioxidant enzymes. Basically, we call these compounds pleomorphic. Pleomorphic means it has many, many, many activities. For example, if you take a blood pressure drug like an ACE inhibitor, it inhibits this angiotensin converting enzyme, which regulates your blood pressure. That's it basically. Whereas these compounds work on multiple pathways across multiple receptors, and multiple mechanisms that affect our aging process. It's amazing to me how nature and humanity have co-evolved to help regulate these essential, biological processes without any side effects, which is amazing. Because a lot of these drugs that we use like Advil, for example, which can cause all kinds of side effects. Or even Celebrex, which is a COX-2 inhibitor, has these side effects, but we don't want those side effects. We want effects that are beneficial and that's what's really exciting. Whether it's regulating inflammation, regulating oxidative stress, regulating autophagy, regulating mitochondrial function, regulating DNA repair, astaxanthin works across all these. That's why it has broad effects across your health, from your brain to your heart, to your immune system, to your eyes. Across the board, it's beneficial. I think it's an amazing story. There are many molecules in nature that do this, but astaxanthin is one of the, I think, superstars. Tell us about some of the benefits. I just mentioned a few of them, but tell us about some of the research that's been done. This is a very, very well researched compound. Tell us about some of the health benefits, and we'll go through some of them. What do they do and what are the highlights of how astaxanthin optimizes our health? David Watumull: Sure. Like you said, a lot of other agents and therapies are addressing downstream and manifestations of problems, so like you've said, it's like whack-a-mole medicine. In the case of astaxanthin, it's working at a more fundamental level, really restoring cellular function, homeostasis. When you're doing that, you can have this broad effect on all these things that appear to be different, but in fact, are very similar at the molecular level. Like you said, this results in a wide variety of health impacts. We look at both, like you've talked about, healthspan and lifespan types of applications. Looking at lifespan, there's been a variety of studies in model organisms looking at lifespan. We've seen extension of life in the C. elegans, the roundworm models, also in yeast and fruit flies. That's led to research at the NIH funded Interventions Testing Program, looking at lifespan in mice. We can talk a little bit more about that later as well. But this is something that has been demonstrated across species to impact lifespan, which makes sense given its impact on age-related pathways and mechanisms as we've talked about. Then in terms of healthspan, you don't just want to live longer. You want to live longer and feel better and be healthy throughout that lifespan, so healthspan is really important. Things like joint and muscle health, the things that you think about as you age, what happens? Your joints, you slow down physically, mentally, et cetera. With joint and muscle function, we've seen impacts certainly on the mechanisms of joint health. If you look at what are the top-selling rheumatoid arthritis drugs treating? They're going after TNF alpha. We've seen reductions of TNF alpha. In fact, we had a head-to-head study versus prednisolone looking at reduction of TNF alpha, and reduced that to the same extent as prednisolone at the same dose. It's very potent from an anti-inflammatory perspective. Targets a lot of the same cytokines that say other agents may be addressing for say, joint issues. Certainly, in the community of individuals that have been taking astaxanthin, there's been wide reports of improved joint muscle function. But certainly, if you also look at say, animal studies. There's been an osteoarthritis model in rabbits, and saw benefits in cartilage degradation, for example. Or in the areas of sarcopenia with muscle deterioration, obviously a major issue as people age. There's been studies in both humans and animals showing benefits there. Dr. Mark Hyman: Amazing. David Watumull: Certainly from a physical standpoint, joint muscle function, we've seen a lot of benefits there. Then you look at the leading cause of death, cardiovascular issues. First of all, astaxanthin again gets to heart tissue and really helps prevent oxidative stress and inflammation, which a lot of people think of heart disease as too much cholesterol. But as everyone now knows, it's not just about the cholesterol or lipids, it's about the quality of those lipids. But it's also say inflammation where studies say like CANTOS from Novartis in recent years, showed that even if you have no impact on LDL, but all you do is reduce inflammation, you can have a major impact on major adverse cardiovascular events. We've shown benefits on both reductions of inflammation, as measured by say hsCRP, but we've also shown benefits for lipids. We've seen reductions in LDL cholesterol and importantly, oxidized LDL cholesterol. Really, the quality of the lipids, reductions of triglycerides, increases in HDL. Interestingly, in research that we worked on with our collaborators, we demonstrated in a mouse model that you could reduce the plaque built up in the arteries. We had imaging and we showed in the control versus the treated groups, the actual reduction of the plaque in the aortic arch, which was really cool to see. We also showed reduction of blood clots in multiple species in both dogs and rodents, so both thrombosis and rethrombosis types of settings. Pretty profound impacts on cardiovascular health. Blood pressure has been reduced as well, so we think that's obviously a huge benefit for long-term health. Then if you transition say to brain health, cognitive health, the role of oxidative stress and inflammation is definitely demonstrated for your brain and mental health. Importantly, astaxanthin actually crosses the blood-brain barrier, so it gets to the brain, gets into the cells, and helps to reduce oxidative stress and inflammation. You can imagine all the benefits it could have there. There'd be a lot of great studies that could be done in terms of cognitive health. But say in humans, there have been studies looking at cognitive performance and Maze tests and things showing benefits for memory and attention, and information processing. In animals, there's been benefits showing neurogenesis, neuroplasticity, et cetera. There's been a lot of amazing research in the brain health space, which again makes sense given its impacts on oxidative stress and inflammation at that cellular level. You go on and on, like you said, there's a lot of research. You look at things like skin health, eye health, again, the same story, reducing oxidative stress and inflammation in those locations has really important benefits. Then if you say look at immune health, you think about anti-inflammatories. Often if you look at what are prescribed as anti-inflammatories, they're going to have immune issues. You may have immune suppression, and so you're battling this, "I'm reducing inflammation, but now my immune system is no longer functioning in a way that actually allows me to fight off infections and wound heal." With astaxanthin, we've actually seen not only no immune suppression, but actually fewer infections, for example, in animals. We really think it's the different mechanism of attacking inflammation by working at the source, allowing normal functions. Your immune system can function normally, but not in a pathological way in a chronic, long-term, low-grade inflammation type of deciding, which is not what we want. Dr. Mark Hyman: It's quite amazing. There's just such a vast array of research on all these various things. The reason it works across all these problems and diseases, is because it works on some of these underlying mechanisms that have to do with all disease. What we talk about in functional medicine, is the fundamental, physiological systems or the biological networks, or the hallmarks of aging. It almost seems too good to be true, but actually when you look at the data, pretty impressive. Talk about also where do we find this in nature? This is one of the carotenoids, right? We've heard about carotenoids, the oranges in carrots, sweet potatoes, beta-carotene and all this stuff. It works as a plant's defense system against environmental stresses, but talk to us about how it shows up in nature. Talk to us about how it plays a role in the marine food system and the chain. Even with salmon, why it's so important for salmon, which is when we see the orange color, why it's so important for them as opposed to other fish, for example. David Watumull: Yeah. Yeah, the whole story of carotenoids and astaxanthin is really interesting. Carotenoids actually co-evolved with photosynthesis, so they're a key component of photosynthesis and help to protect plants from photooxidative damage. It played a fundamental role in evolution there. In the marine environment, astaxanthin is produced by microalgae, like you said, as a defense mechanism against UV light from the sun. These are green algae that when stressed by the sunlight, produce astaxanthin as a defense mechanism and then turn bright red. It plays this vital role in dealing with severe environmental stress. Then microalgae are then consumed up food chain, so into crustaceans, krill, crab, lobsters, shrimp, up through salmon. Other fish, whales, obviously huge part of their diet is krill. It's been this really important nutrient throughout the marine environment. To take one example with salmon. Salmon, of course, are not just swimming around in the ocean, they also migrate, they swim upstream to reproduce. It's amazing feats of endurance and strength to do that, but the way they are able to do that is because of astaxanthin. They are loaded up on astaxanthin in their flesh, and that really helps them deal with the consequences of that upstream journey. Without astaxanthin, salmon would not only be gray instead of the beautiful pink color that we all know, but they would be smaller, they'd be weaker, they're prone to infections, but they wouldn't be able to swim upstream. It's a really amazing role that astaxanthin plays in nature. Like you said, we've all consumed it through salmon or crustaceans, shrimp, et cetera, but certainly it's hard to get a high enough level on a consistent basis. Just like the salmon, we would like to benefit in the same way. Certainly, nature has come up with something that has really worked to have really important protections against environmental stresses. With carotenoids, if you look at the evolution, they went through a series of steps and ultimately went through different carotenoids. Like you said, beta-carotene is an example of a commonly known carotenoid. But astaxanthin is a particular type of carotenoid called a xanthophyll carotenoid that was later in the evolutionary process, that was optimized in the apex or king of the carotenoids. Importantly, it has oxygenated headgroups, so it has a hydroxyl group on each end of the molecule and a ketone group. That gives the molecule polarity so that when it spans the membrane. We actually done studies with our collaborator at Harvard, showing that astaxanthin spans the membrane and doesn't disrupt the membrane. In this same study you looked at say beta-carotene, which can also get into the membrane but is not polarized, doesn't have the hydroxyl groups, for example. Then it just sits and perturbs or disturbs the membrane. Not every antioxidant is the same, not every carotenoid is the same. We think nature came up with astaxanthin is the optimal carotenoid, and certainly been demonstrated throughout the natural environment and certainly with humans in the last 20 years. Dr. Mark Hyman: That's amazing. How is it different than other antioxidants? You're talking about vitamin C or vitamin E or other ones, so how does it compare? David Watumull: There's a few different things. One you can look at, it's antioxidant capacity of performance. You can look at things like singlet oxygen quenching. In those types of studies, we've seen that it's 6,000 times stronger than vitamin C, or 550 times stronger than vitamin E or 40 times stronger than beta-carotene. You can have a performance benefit in terms of scavenging free radicals, for example, but as in real estate location, location, location, that really matters. The fact that astaxanthin gets to your cells but actually gets into the membrane of the cells, and like I just said, the fact that it stands and stabilizes the membranes, distinguishes it from other antioxidants. And that it gets to not only say the plasma or outer membrane of the cell, but to the mitochondrial membranes. Getting to those privileged locations is something that not every antioxidant does. You want to get to the cells, you want to get to the mitochondria, you want to get into the membranes, not disturb the membranes, and sit there and protect the membranes from oxidative stress. That's something that really sets astaxanthin apart from other antioxidants. Dr. Mark Hyman: Interesting. Let's talk a little bit about now the FOXO gene, FOXO3, which is a really important gene. Maybe you can explain what it is, what its role is in the body, and how it plays a role in longevity and what astaxanthin does to FOXO3 pathways. David Watumull: Yeah. The FOXO3 gene is really interesting and our collaborators here in Hawaii, helped to actually uncover the link between FOXO3 and human longevity. You may be familiar with the Honolulu Heart Program, which was started in the 1960s with 8,000 Japanese American men. This amazing program followed these men for decades with doctor's visits and blood tests, and looked at all the reasons that their health declined or why they died. It created this amazing database of doctors' visits, records, but also biological specimens. Our team in Hawaii here looked at that, and discovered that FOXO3 was something that when assayed in these individuals, was associated with those that lived the longest and the healthiest. If you have the right version of the FOXO3 gene, which would be the GG allele, that you would actually have the best chances of living to 100 healthy. If you don't have that version, if you have the TT or the GT versions, then you're less likely to live that long healthy. The difference between those different versions of the FOXO3 gene is how active they are. With astaxanthin, with the same group in Hawaii, we did a study in mice and we showed that astaxanthin actually increased activation of the FOXO3 gene, as measured by the mRNA expression or mRNA levels. This was actually in the heart tissue of the mice. We demonstrated that you could increase FOXO3 activation in the heart tissue of the mice. This was really amazing and it also confirmed that in the roundworms and the C. elegans where we saw life extension results, if you knocked out the roundworms version of the FOXO3 gene, the ortholog-16, the lifespan benefit went away. It looks like in the roundworms that the mechanism of extending life was via their version of FOXO3. We know in humans that FOXO3 is one of the key anti-aging genes associated with longevity. We demonstrated in mice that we have activated FOXO3. This was really amazing research that actually led to the National Institutes of Health or National Institute on Aging, they have a program that they fund called the Interventions Testing Program. They actually selected astaxanthin to be included in this program to look at lifespan in mice. Prior to this, lifespan was just like I said, examined in model organisms, but not yet in mammals. The ITP, as it's called, the Interventions Testing Program, an NIA funded program, has been running for the last 20 or so years. Every year they take a cohort of a few promising longevity agents, and there's a lot of well-known agents that have been tested in this program. Rapamycin is probably the agent that has been tested the most and demonstrated efficacy in multiple cohorts. But obviously, rapamycin has side effects and has prompted people to look at different types of dosing and rapalogs or analogs of rapamycin. But even things like resveratrol, there was a lot of hype around resveratrol 2006, 2007. It was included in the cohort back then. It actually did not extend lifespan in this model. Metformin has been tested. It also did not show benefit. The NAD precursor NR was tested, did not show benefit. There's only been a handful of agents that have shown benefit in this model. Interestingly, it's highly, highly rigorous. It's conducted three different sites, the University of Michigan, the Jackson Lab, and the University of Texas Health Sciences. They have specially bred mice that are designed to not have confounding variables that you might find in typical laboratory in bred mice. They have specially bred mice, they run it at three different sites in parallel, literally thousands of mice in each cohort. We were fortunate to be selected to supply the astaxanthin to this study. Dr. Mark Hyman: This is the NIH study? David Watumull: Yeah. Yeah, this is a NIH funded study. It's called the Interventions Testing Program. The study for our cohort started back in 2019, and actually just wrapped up this year. We've been working with the ITP team to get the manuscript drafted. It's in the process of being submitted for publication. We're going to be really excited to be talking about those results as soon as they come out, hopefully in the next few months. The thing that we think is really important when looking at this is, first of all, can you demonstrate efficacy in a model like this? But what is the practical application of this? Something like I said, like rapamycin which has demonstrated lifespan benefits in this model, doesn't really have the utility in humans that we would like because of its limitations on safety and tolerability. Whereas with the case of astaxanthin, because of its mechanism and because of just all the data that we've demonstrated, it's exceptionally safe. Both because we've consumed it in our diet, we've had decades of experience as a dietary supplement, but it turns out that astaxanthin is actually a major component of the animal feed. Farm-raised salmon, despite having poor living conditions and other things, they're actually fed astaxanthin to make them pink just like they would get it in the wild. It's a really important nutrient in their feed, but also other animal feed utilizes astaxanthin. In order for the FDA to allow astaxanthin to be used as an additive for animal feed, there was a very extensive set of safety studies that were done, the likes of which would be done for pharmaceutical development. So long-term toxicity studies, carcinogenicity studies, et cetera, and showed at very high levels and very long durations, literally thousands of milligrams per kilogram of body weight. Compared to what human dosing is, which is fractions of a milligram per kilogram or a couple milligrams per kilogram, depending on how high you want to dose, it's orders of magnitude difference between these animal studies and human studies. We showed or third parties showed that there were no side effects of clinical significance in any of those studies. That's something that when we look at longevity applications, you want to have something you can take every day for the rest of your life that that's safe. That's what we think really sets astaxanthin apart. Dr. Mark Hyman: That's impressive. Just to clarify for people, the NIH folks is looking for screening molecules that may have potential for longevity and it doesn't test very many and it's just had a few. This is a big deal to get astaxanthin tested in this way, and to look at its effect on longevity and many of the longevity pathways. Very excited to see that study and the latest science around that. There's so much more data. In 1998, there were 200 papers, now there's over 3,000 papers on astaxanthin. Are there any other interesting new data that's coming out that you want to share with us? David Watumull: It's just like you said, it's been an explosion of research. When we started with this back in the late '90s, there was less than 200 peer-reviewed papers. 15 years later, it was up to 1,000 peer-reviewed papers. 10 years further on now to present dates, it's more than 3,000 papers. I think we'll see over the next few years just a further explosion in the research with astaxanthin. It's been well studied and well known in the scientific community, and starting to get more and more traction. But it really has not been known in the general public setting. The research is something because it's a naturally occurring molecule, unlike a proprietary pharmaceutical, research can be conducted throughout the world by various academic institutions and others in a private sector. What we've seen in recent years, is just further research looking at elucidating the mechanisms of action. Say we've seen impacts like we talked about on AMPK and other age-related pathways, but things like, "Well, does astaxanthin impact autophagy?" You can find papers on autophagy. Really, further elucidating the ways it works, because we know that it works through nature, through evolution and through the studies have been done in humans and animals. But further understanding how it works is something that research is taking place at this time. Also, further clinical studies, there's been more than 50 or 60 human clinical studies. These are smaller pilot types of studies, but areas of cardiovascular health, metabolic liver health. I think continuing to expand in those areas, is what's really exciting and what we'll continue to see in the coming years. Dr. Mark Hyman: That's amazing. In terms of the next steps for astaxanthin as a molecule of interest in longevity, where do you see this going? David Watumull: Well, I see a couple of things. I do think that astaxanthin will become part of the dialogue around longevity. There's a lot of talk around various other agents that have a lot of promise, NAD precursors, et cetera, et cetera. We think astaxanthin should be right there in that conversation and at the forefront of it. Because it has these profound impacts on aging, healthspan, lifespan, it's super safe, it's commercially available, so it's accessible. This is something that if you can imagine, snap your fingers, everyone taking astaxanthin, you would have a much healthier society. This is something that why wouldn't you do it? It's safe, it reduces oxidative stress and inflammation at this core cellular level. It's something that we frankly believe everyone should be taking. We think that that's going to be the next steps, is really making astaxanthin a household name and something that is associated with longevity. That's really the next steps is building this public dialogue, this community around astaxanthin and healthy aging. Then on the flip side, there's also pharmaceutical applications. You could look at, for instance, higher doses for disease states, which hopefully through diet, exercise, lifestyle supplementation with compounds such as astaxanthin, you're healthy. But the reality is people will develop issues. If you can have agents like astaxanthin that are put through the FDA clinical trial process and approved as a pharmaceutical for certain disease applications. Analogous to say the omega-3 or the fish oils where you have prescription versions and you have supplement versions and we could see that as well. We have a pharmaceutical version of the molecule that we've developed and would look advance in future years as well. Dr. Mark Hyman: Yeah. What's interesting is when you think about, "Okay, this would be great. It's going to be a great molecule. It's maybe going to be good for a billion people and it affects joint pain and muscle function, and cognitive health and heart health, and lifespan and many, many things." The problem is supply, right? If you're looking at where it comes from, it comes algae in the ocean and doesn't seem like a really sustainable way to get that much astaxanthin. Can you talk about the difference between the synthetic versions, the kind that are synthesized in the lab, versus the natural astaxanthin? How they're different and why maybe even this synthetic might be better? Because typically people think, "Synthetic, that's not good. I want the natural form." Can you explain that a little bit? David Watumull: Sure. We've actually worked with both forms. My father and I, who I've worked with for the last 25 years here with astaxanthin, both started with a company that was producing microalgae. It was on the big island of Hawaii. It was literally in the lava fields. You dig out ponds in the lava fields and grow microalgae, which it's a great environment for growing the microalgae and stressing them with the sunlight to produce astaxanthin. But like you said, it's a very difficult process to scale. Takes a lot of land, but also it's not the most pure. You have contamination issues. In the case of that location, you're next to the volcano, so you could have vog. You're next to the airport, so you could have jet vapor from the fuel, you can have just other elements externally. It's essentially farming and so you're going to have potential contamination. It also takes a lot of energy, a lot of water. In terms of impact on the environment, it's something that is not optimal. We thought that, like you said, if you want to bring this to the world, to the mass market, you need something that's scalable, that's sustainable, that's pure, that's consistent. We transitioned to natural product total synthesis. That is where you are in the laboratory taking chemical building blocks, and constructing the molecule step by step and arriving at the exact molecule you find in nature, but without any other components. With the microalgal form, you not only have to grow the microalgae in the first place, but then you have to extract the astaxanthin from the microalgae. You can't get just the astaxanthin out, you're going to have maybe 5% or 10% astaxanthin, and the rest is other microalgal matter, which probably it doesn't hurt you, but you don't need that. That's not the active ingredient. Actually, gives it a fishy smell and aftertaste, which is not the astaxanthin, it's the other content from the algae. With the synthetic form, we have something where it's just the naturally occurring molecule, exact same chemical formula, exact same structure. Whether the algae synthesize it internally or we synthesize it in the lab, you're arriving at the same place. But in our case, we're doing it now with very high purity, very high consistency. Something that in studies has been shown to actually be much more environmentally sustainable, because it uses less land, less water, less energy. We think that is a huge, huge benefit for the synthetic form. Like you said, obviously there are some negative views on synthetic types of products, but in this case, we believe you have the best of both worlds. Synthesis is what's used to produce most of your small molecule drugs. The manufacturing rigor of drugs is not what's in question, it's how they act biologically and their side effects. If you can produce a naturally occurring molecule, make a nature identical form, you have the pharmaceutical-like manufacturing purity and control, but you have the benefits of this natural product. Those are some of the key benefits. The final benefit is we have a special formulation of the synthetic astaxanthin, which if you don't formulate it or esterify in the case of the pharmaceutical form, it's not bioavailable. We specially formulate the astaxanthin, and we actually conducted a head-to-head study versus a leading microalgal astaxanthin product on the market. It was a human study crossover design. We gave a group of human volunteers the microalgal astaxanthin product, and then measured their blood levels over the course of 24 hours. Had them wash out for an entire week without any astaxanthin supplements or food. Then provided them with the synthetic form with our special formulation. Demonstrated over the course of that same 24-hour period, both a maximum concentration or Cmax as well as the total concentration, the total area under the curve over the full 24 hours of three times the blood levels of astaxanthin. There's a very significant bioavailability difference. A lot of people don't realize, you swallow a capsule, you think it all goes in your body, but it doesn't necessarily. Some can pass right through you, which is a shame. In this case, having the superior three times bioavailability is the third key component, in addition to the environmental sustainability and the increased PRD. Dr. Mark Hyman: There's benefits to the synthetic version then. That is what you're saying? David Watumull: Yes. Dr. Mark Hyman: That's great. David Watumull: Exactly. Dr. Mark Hyman: Now there's a lot of astaxanthins on the market. How is this one different? David Watumull: Yeah. Almost every astaxanthin product on the market comes from microalgae or some downstream version, say like krill, which can ultimately consume astaxanthin in nature derived from microalgae. The issues with these products are what I've described, in terms of the supply to scale and serve the world is challenging. The purity, the consistency, the bioavailability, those are all the challenges with these products. Whereas our form, like we talked about, is the synthetic nature identical form. We believe it's something that's helped our professionals like yourself would understand the benefits of the rigor of delivering this naturally occurring product, but with the synthetic production. That's really the key difference that sets us apart. We also believe that no one has really created a conversation around astaxanthin. That's something that we're looking to do here, is actually communicate the benefits of astaxanthin to the world. One important note I'd like to make, is that there's a lot of research out there with both synthetic and natural forms of the product. The safety studies I referenced, the very high dose, long-term studies, those were with the synthetic form. A lot of the animal studies, a lot of the in vitro studies are done with the synthetic form. The human studies, most of them have been done with the microalgal forms because those have been the forms that have been on the market longer. But in recent years, we, for example, have done clinical studies showing benefits in the cardiovascular, real-world, cardiovascular patient population that was on all the cardiovascular meds. But we still showed benefits on top of that in terms of reductions of lipids and oxidized LDL, blood pressure, et cetera. There will be more studies going forward with the synthetic form, but there's been a lot of research with both synthetic and natural. Biologically, astaxanthin is astaxanthin. You can look at the literature and the benefits of astaxanthin are applicable to both synthetic and natural, but the real difference is how you make it, how you deliver it. That's really where we distinguish ourselves. Dr. Mark Hyman: That's amazing. Well, this is just such a great conversation. I think it's important for everybody to understand that living healthy and long requires the foundations, which is healthy eating, exercise, sleep, stress management. The right basic, foundational, social fabric that you're embedded in that keeps you healthy and connected and alive. Then supplements take a role. I just want people to understand that they're called supplements, not replacements, but I think this is a very promising molecule and I'm very excited to hear about the research on this, David. Particularly, I want to see the data from the NIH trial because I think that's going to be a very compelling story. I thank you so much for your work over the years, for bringing this product to market. I think people can learn more about it. They can go to AX3.life and then learn more about it and how to look at the research and the data. All the studies are there if you want to look at getting it, there's a great availability as well. Thank you so much for being on the podcast. I hope you've enjoyed this time. I hope y'all listening, have enjoyed the podcast. Please share with your friends and family. We'd love to hear comments on how you've learned to regulate your lifestyle and inflammation in general. Subscribe wherever you get your podcasts, and we'll see you next week on The Doctor's Farmacy. Closing: Hi, everyone. I hope you enjoyed this week's episode. Just a reminder that this podcast is for educational purposes only. 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