This FASCINATING Molecule Originally Boosted Muscle & Endurance But Is *Now* Being Shown To Reverse Immune Aging?! Urolithin A With Dr. Anurag Singh

Ben Greenfield [00:00:00]: My name is Ben Greenfield, and on this episode of the Boundless Life podcast...

Dr. Anurag Singh [00:00:04]: You know, when, when you take urolithin A, not only are you hitting mitochondria in your skeletal muscle cells, but what we are discovering is that the mitochondria inside the immune cells, they get recharged and they kind of propel the immune system at a much better way.

Ben Greenfield [00:00:21]:Welcome to the Boundless Life with me, your host, Ben Greenfield. I'm a personal trainer, exercise physiologist and nutritionist. And I'm passionate about helping you discover un parallel levels of health, fitness, longevity and beyond.

Ben Greenfield [00:00:40]: Well, it's apparently one of the hottest days in Switzerland, so don't worry if you're watching the video and you see my guest sweating profusely. He's not nervous. He actually knows a lot about what he's talking about. It's just hot. And Dr. Singh, having actually been in Europe and in Switzerland specifically during the, I think it was like the 107 degree heat craze a few years ago, I know exactly what you're going through. As a matter of fact, I have a quick, funny story. I was staying at a health clinic in Switzerland called the Swiss Mountain Clinic and was visiting with the doctor there about cancer, hyperthermia.

Ben Greenfield [00:01:21]: And I found it such a fascinating discussion. I said to her, hey, is there a way I could actually try your hyperthermic unit to see what it feels like? They agreed, but of course, since this was during the heat craze, not only was it even more warm than I had anticipated, especially based on the rectal probe that they had up my butt to analyze my body temperature, which went through the roof, but afterwards I was disappointed to find out I wasn't allowed to jump in a lake or a cold shower and that I had to just lay in my bed sweating profusely for like five hours in a hyperthermic unit, induced fever all afternoon. It was a rough go. So hopefully you don't have to do that today.

Dr. Anurag Singh [00:02:05]: No, no, I'm just. Yeah, surprised. Switzerland used to be the, you know, the destination people ran away from when it was too hot. It's becoming more and more warm here. So anyway.

Ben Greenfield [00:02:17]: Yeah, yeah, well, hopefully. Hopefully, the ski resorts don't all shut down due to the global warming effect in Switzerland. So Dr. Singh, for those of you not familiar with him, he's been on the podcast before. We talked back when this very interesting compound, Urolithin A, was catching a lot of attention about this newly studied molecule at the time that kind of supercharged the mitochondria and seemed to turn back the clock on aging somewhat and battle sleep deprivation. And Dr. Singh, who works with Timeline nutrition, went into depth in terms of how this stuff works and why it's so intriguing, especially in the longevity and anti-aging sector right now.

Ben Greenfield [00:03:00]: He's authored 50 plus articles for different science journals, has 20 patents or more. He's led over 50 randomized clinical trials, and much of his research is on this urolithin A, which is something Timeline produces in the form of what they call Mitopure. Well, since our last show, new research has been emerging, especially in the realm of the immune system. I'm so intrigued with the immune system and the link between that and aging. Something I haven't really talked about a lot in the show that I wanted to get Dr. Singh back on. Everything that you hear us talking about, you can find the show notes for it. BenGreenfieldLife.com TimeTimeMunity that's BenGreenfieldLife.com/timelineimmunity Dr. Singh, welcome back, man.

Dr. Anurag Singh [00:03:46]: Pleasure, Ben. Absolute pleasure to be back on.

Ben Greenfield [00:03:48]: Yeah, yeah. And in our last show, we talked a lot about the human performance-enhancing effects of urolithin A, especially related to strength and endurance. I've been supplementing with it at about 500-1,000mg a day since I talked with you. Fortunately, it's a little tastier now. I'm kind of addicted to these little 250 milligram gummies that you guys make. These strawberry gummies. I just had them in my smoothie.

Ben Greenfield [00:04:15]: But now it appears there is immunity data. I want to dive into that. But just for people who didn't hear our last podcast, what is the scope of the effects in terms of human performance when you look at something like urolithin A?

Dr. Anurag Singh [00:04:31]: Sure. So just as a reminder, this is 15 years of very in-depth biotech research that basically discovered this postbiotic molecule. Correct. So your urolithin A is, is the molecule, and Mitopure is sort of its branded name. And so 15 years in a snapshot, what we started finding was that this postbiotic urolothin A activates a process within our bodies that slows down with aging. And this process is called mitophagy, which is basically cleaning up of damaged zombie mitochondria similar to autophagy at the cell, right? And so what happens with this sort of reactivation of mitophagy if you're supplementing with your urolothin A Mitopure is that the damaged mitochondria get sort of recycled into healthier ones that basically produce more energy.

Dr. Anurag Singh [00:05:24]: And so instead of getting fatigued, instead of having poor endurance with aging, what we see across species and in multiple randomized trials now is that regular supplementation for up to two to four months we see in healthy adults, whether it's 40s, 50, 60 year olds or even older adults, we see primarily a big benefit on improved muscle strength in the legs. And we see better endurance, so better peak VO2, better recovery from exercise, et cetera. So that's the scope and depth of the trials we had talked about lately.

Ben Greenfield [00:05:59]: And just to interrupt real quick, was that at about 1,000 milligrams?

Dr. Anurag Singh [00:06:04]: Yeah. So we have studied, we studied what is called dose finding, clinical studies, and we find that the sweet spot is between 500 milligrams to about a gram. A 500 milligram dose is where we start seeing the activation of mitophagy and the improvement in mitochondrial health, and longer term usage and improvements in strength. But the gram dose really takes it up a notch in terms of the benefits we start seeing. In addition to the strength benefits, we see better endurance. And we can talk about it—more impact on systemic aging and systemic organs, such as immune aging with—

Ben Greenfield [00:06:40]: Yeah, I want to talk about that. I know some people might be wondering, well, why would I need to pop a pill? Could you find this stuff in nature? I believe I've heard before pomegranates would be one source. Describe to me how much is in food sources, especially comparative to this 1000 milligram that you're finding to have the most effects on human performance.

Dr. Anurag Singh [00:07:02]: Yeah, yeah. So we, we did this clinical study, and I've looked at Italians, French, Canadians, Americans, even my country of birth in India and, and the variability of exposure of this molecule from diet is, is very variable. So French and Italians, a lot of Mediterranean diet, fermented foods. We see about 1 in 3 adults, healthy adults, already getting it from diet, whether they're getting enough? That really depends. If you're eating a bowl of berries or a bowl of nuts or, or, for example, 30 pomegranates, which is probably the equivalent of juicing 30 pomegranates, will give you 500 milligrams, equivalently.

Ben Greenfield [00:07:40]: Okay, so, so a thousand milligrams, basically you're juicing 60 pomegranates.

Dr. Anurag Singh [00:07:44]: Yeah, 60. Yeah. You'll need to drink about 10 - 12 glasses of pomegranate juice and that'll give you a lot of sugar as well.

Ben Greenfield [00:07:51]: Okay. Yeah. It's carpal tunnel syndrome. And a lot of sugar.

Dr. Anurag Singh [00:07:54]: Yeah, yeah, true. So what we see is in the, in sort of the healthy Mediterranean diet cultures, we see about one in three. In Canada and the U.S., we see one in 10. So, only 10- 12% healthy adults who think they're eating right or whatever, we see about 1 out of 10 having circulating levels of urolithin A, which could be giving health benefits. So it's really two-pronged. One, you need to be eating, as we discussed enough, pomegranates, berries, or nuts, which have the precursors that our gut microbiome will generate urolithin out of, or you need to have the right gut microbiome, which is, having now studied my home country, a lot of it is seeded early on in life and at rapid antibiotic usage in some of these countries takes away a lot of this beneficial gut microbiome.

Dr. Anurag Singh [00:08:46]: So what we see is very variable responses. And yeah, not everybody is getting exposed to it. So we need to supplement, and that's why we created a supplement.

Ben Greenfield [00:08:56]: Okay, got it. Now, I want to address the elephant in the room here, just because I think it's important people understand immune aging before we talk about urolithin A and what it has to do with that. So how do you describe immune aging? And I hear terms like inflammaging and immune senescence, and immune cell exhaustion. Can you walk us through what all these things actually mean?

Dr. Anurag Singh [00:09:18]: Yeah, so. So I'm a trained immunologist. After my MD, I did further training in immunology. So, immune aging, to me, is everything you just mentioned. Immune aging is sort of the sequela, and there are three key hallmarks to this sort of phenomenon. One is inflammation, which means as we're getting older, our cells are getting fatigue damage, and these sort of damaged zombie-like cells become triggers of inflammation in our cells and organs and body. And that kind of keeps increasing as we age.

Dr. Anurag Singh [00:09:57]: So from our 30s, 40s, to our 50s, 60s, our bodies, as my professor would say, is swimming in a sea of these soluble factors that we call immune cytokines. And these are basically damaging our organs. So that is inflammation in sort of broad context. Then there is these terms like immunosenescence, which really means your immune system just does not have the ability to, you know, be what it was in our 20s and 30s. And that's primarily because we have this organ called thymus, you know, up right here. And around our 20s, it starts involuting, means shrinking. And as it shrinks, and that's the organ that makes a lot of immune cells.

Dr. Anurag Singh [00:10:43]: And the most holding immune cells it makes is something called T cells. Immunologists are not very creative people. They just thought about a few cells and they call them ABCD all the way till T. And so these are T cells, which stands for basically think of them as the elite forces of the army of the immune system. And they are patrolling all the organs for when is the next big threat coming, whether it's autoimmunity or an infection or even cancer. And so these kind of disappear and become very fatigued. And that's the phenomena called immunosenescence. And then there's a third term called immune resilience or immune sort of fatigue.

Dr. Anurag Singh [00:11:20]: What happens is that these immune cells, T cells, B cells, all the, you know, sort of alphabetical names that come with these immune cells, they have mitochondria that over time get fatigued. And they just don't have enough metabolism, metabolic capacity to keep fighting cancer, keep fighting infection. And so that's sort of all encompassing into immune aging.

Ben Greenfield [00:11:44]: Okay, so when we talk about, you know, longevity and anti aging, and I'm not one of those guys who, you know, endorses the idea of just trying to live no matter what, to 200 years old, I'm more in the camp of live as healthy as possible, as close as possible to the day that you die. But when we talk about the immune system, how much of an impact does that actually have on longevity? Like declining immune health? Because you hear about declining mitochondrial health or declining brain health. How big of an impact does declining immune health have on longevity?

Dr. Anurag Singh [00:12:19]: So, I mean, we've all talked about, and probably it has been talked about in your podcast before, this whole idea of hallmarks of aging, right? So biological hallmarks of aging are these very interconnected biological pathways that all decline together with aging. And I believe there are two or three keys in these. There are 12 of them now. You know, they range from our genes getting altered or the environment impacting our genes, or poor nutrient absorption in our cells. But the two main ones, I believe, are mitochondrial dysfunction and chronic inflammation or inflammaging or immune aging. And I think they're really linked together very closely. And when I say linked together very closely, I mean I personally believe that immune aging is sort of the central piece, and that's the trigger for a lot of these hallmarks of aging. So if you slow down immune aging, immune cells are in all organs, and if they go problematic, then you're impacting what I call the organ rate of aging or cellular aging. We are finding evidence that things like changing exercise regimens or diet or even mitochondrial interventions actually alter these two key hallmarks.

Dr. Anurag Singh [00:13:37]: And they're very closely linked, mitochondrial health and immune health.

Ben Greenfield [00:13:42]: So why is it that? I mean, you say that immune aging and mitochondrial health are kind of very much related, but. But why is that? What's the link between the two?

Dr. Anurag Singh [00:13:55]: Yeah, so, you know, as I was starting to mention, that immune system, the way I see it, it's almost like a, you know, like a policeman of the entire body, all the organs, the immune cells are everywhere. So when something goes wrong in a bigger picture, who comes in? The police comes in, right? And so as we age, when the cells in our organs are not optimally functioning, the immune cells kind of come in to survey if everything's going all right, if, you know, all the organelles are, et cetera, inside the cells and the neighboring cells, they're talking to each other. And so they're almost like a surveillance program, this immune system. And what happens is as soon as the cellular health declines, okay, as soon as all the different hallmarks start declining, the immune system is the first to put its hand up and say, hey, there's something going wrong.

Dr. Anurag Singh [00:14:56]: And it starts to survey deeper, and at a certain point, it cannot because it just gets overwhelmed. And so I believe the immune system is like the sentinel of our health span decline. And as soon as we hit our 30s, 40s, and the first wave of, you know, biological changes happens, the immune system is the first one that fires that shot and says, problem. Okay? And so it, and the connection between mitochondrial health and immune cells and immune health is there are. It's a field we call immune metabolism.

Dr. Anurag Singh [00:15:34]: So the policemen, in this case, the immune cells, need energy to be able to survey all the organs, the key metabolic organs that decline with aging. And so they run out of gas, and they run out of fuel because mitochondria powered them up. And so one of the fixes, we think, is by sort of reenergizing or rewiring the immune system by boosting the mitochondria. And that's the connection.

Ben Greenfield [00:16:02]:Okay, so in the case of urolithin A, then does it have more an impact on the mitochondria, or is it working on some other element of the immune system?

Dr. Anurag Singh [00:16:11]: Yeah, so urolothin A, from the time you take it orally, will hit mitochondrial health in every cell that is mitochondria. And all our cells, except the red blood cells, have cellular mitochondria. Now, the more metabolic ones like the neurons or the, the skeletal muscle cells, they get hit hard the most. So the things that happen the most frequently with aging is problems getting up from a chair, problems walking. And that's mostly because your muscle cells do not have the right energy source, which is mitochondria able to power them up. Same with neurons. The first thing that will happen is decline in cognitive health and sequela to things like Alzheimer's. I believe it's, you know, when you take urolitin A, not only are you hitting mitochondria in your skeletal muscle cells, theoretically in your neuron cells, and you can even target brain health via that.

Dr. Anurag Singh [00:17:07]: But what we are discovering is that the mitochondria inside the immune cells, these T cells and B cells, they get recharged and they kind of propel the immune system to start surveillance at a much better way. And so that kind of links to aging and mitochondrial health.

Ben Greenfield [00:17:26]: Okay, got it. Let's get into mechanism of action here. You used the word like hitting the mitochondria, recharging the cell. But in terms of a little bit more of a scientific explanation of what that means, like hitting, recharging, et cetera. What is urolithin A doing to the mitochondria?

Dr. Anurag Singh [00:17:42]: Yeah, so you can power up your mitochondria three ways today, or at least three known ways to scientists and, and doctors. One is a process we call mitochondrial biogenesis. So this is the sort of pathway you, you if you're hitting exercise is well known way to induce mitochondrial biogenesis. Which means just create near healthy mitochondria that create more near energy, more healthier energy, and you power your cells up. That's one way. And there are compounds like NAD modulators, things like resveratrol. These are all known mitochondrial biogenesis agents. The second pocket is you have your healthy pool of mitochondria.

Dr. Anurag Singh [00:18:23]: You know, I see you're exercising, so you're already inducing biogenesis. But how do you keep these healthy mitochondria up and running and become more efficient? And these are things like creatine, CoQ10. Now what your lithin a Mitopure is doing is hitting what I started described process called mitophagy, which is basically damaged zombie mitochondria. So as we are aging, our immune cells are aging, their mitochondria are getting more and more damage because they just can't keep up with for example, all the viruses and bacteria. They have to the onslaught that happens with aging or cancer sort of mutations that start happening. And so they need to be recycled. And that's what we are seeing when we take the immune cells, these T cells, out from people who are, who are aging or 70, 80 years old.

Dr. Anurag Singh [00:19:15]: We see exhaustion in these immune cells. And what that means is basically the mitochondria are not able to induce properly the energy currency, which is ATP. When we give them Mitopure, whether in, you know, in our randomized trial, which we can talk about, or in cell culture, we see more PGC1 alpha, or biomarkers linked to better mitochondrial health starting to show up in these immune cells. And when we put, for example, these immune cells with bacteria, they kill them better. So that's the sort of biology that we are seeing happen, which is really mitophagy. We had started with muscle cells, and we focused on endurance and performance and strength benefits. But what we are actually discovering now as a sort of additional benefit is that you lower inflammation, you recharge your immune system. And even in, you know, athletes, for example, athletes are well known to have a lot of overtraining, induces inflammation. We're seeing that get blunted. So that's the connection.

Ben Greenfield [00:20:19]: Okay. I've actually never heard it explained that way before. So you have mitophagy. That's like one of the three things that you said. That's the last one that URL A focuses on, like the mitochondrial cleanup. You said mitochondrial biogenesis. I think you said that one's more triggered by things like exercise.

Dr. Anurag Singh [00:20:36]: Yeah, exercise, fasting, known modulators. Yeah.

Ben Greenfield [00:20:40]: Okay. And what was, what was the third one?

Dr. Anurag Singh [00:20:42]: The mitochondrial efficiency. So this process, you know, you always have in your cells this yin and yang of healthy mitochondria and damaged mitochondria and this sort of balance in between. And that's always going on, you know, even when we're healthy, young, we always have this process continuing. But what happens with aging is mitophagy slows down, biogenesis slows down. And so you're basically shifting that balance towards all damaged mitochondria. And so what we see is mitophagy is the actual trigger to clean out that waste. Almost like the Pac-Man an of cleaning up shows up and cleans the waste. And now that is recycled and.

Dr. Anurag Singh [00:21:26]: And triaged and put back as recycling building blocks of near-healthy mitochondria, which is biogenesis in many ways.

Ben Greenfield [00:21:33]: Okay. So, like, in an ideal scenario, you're exercising, you're fasting, you're doing things for mitochondrial biogenesis. You're getting some fuel in with things like NAD, creatine, healthy diet, et cetera, for the mitochondrial efficiency. And then for the mitophagy, you're introducing a component like urolithin A.

Dr. Anurag Singh [00:21:49]: Yeah, and that is actually, I described it one after the other, but I think think of a little town, right? Or think of a little town where you have x amount of buildings you can have. Unless you clean the damaged buildings or the damaged portion out, you can't really build new stuff. And that's what mitophagy or autophagy is. You have to clean out the damaged cell, the damaged cellular machinery, and that again, gives way to real estate. And now you can do the building block. So we have thought about it. We've combined urolithin A, we've tested in different models of aging where we have combined exercise with urolithin A.

Dr. Anurag Singh [00:22:31]: We get a better augmented response. We have combined caloric restriction with urolithin A supplementation, we've got a better response. We've actually done now two or three randomized trials in athletes where people are training and they're finding in these different trials, some of them are published, some are not, that urolithin A actually augments even the performance of exercise or the impact of exercise.

Ben Greenfield [00:22:57]: Yeah, that's actually what I wanted to ask you about because, like, three months ago, you guys sent me the new RCT. I think it was called MitoImmune. That's what got me interested in this whole topic of mitochondrial and immune aging in the first place. Tell me about this RCT.

Dr. Anurag Singh [00:23:13]: Yeah, so this is, you know, this is a long collaboration with two of the pioneers in the field of studying immune aging. One is Professor Eric Verdin, who's the CEO of the Buck Institute of Aging and has been studying immune health and the impact of immune aging and health span for the last 35 years. And the other is actually a cancer researcher who many years back came to us and basically in different models of cancer, what he saw was that actually the immune system was failing. And it was failing in part of what I was describing, surveilling the cancer prone cells because of mitophagy issues. So mitophagy decline and cancer incidence in these models went up. So he came to us and he said, you've published, and at that time, you've just published that urolithin A was a mitophagy agent and enhancing muscle health. But he was very interested in using it as a way to sort of recharge the immune system in the fight against in these models of cancer.

Dr. Anurag Singh [00:24:20]: And so he published actually two, three years back, actually, when we first spoke In a very prestigious journal. But it was an animal study, in a model of colorectal cancer. When he supplemented with urolithin A, he saw basically better immune system and more mitochondria in the immune cells that would then lead to better cancer survival. In these models we said, well, we don't want to do cancer yet. Let's start and see what happens with this molecule in healthy middle-aged adults. Because we had seen the effects on muscle in middle aged adults, we ran a trial where we selected from hundreds of people about 50, 60 years of age. They were a bit overweight, some of them were exercising, some were sedentary.

Dr. Anurag Singh [00:25:08]: And we gave them, we randomized them into two groups. Now the way top-tier clinical trials are done is you have a control group, a placebo group. So we took 25 participants, we gave them placebo and 25 participants, we put them on a gram of urolitin A Mitopure and we did serial blood draws. So before they started the supplementation, we took their blood and we ran something called as complete immune profiling. Now this is not what your standard medical doctor will do, but this is a technology that was from a small amount of blood, I can profile all your immune cells in your body and there are trillions of them. And I can see the immune age score of all these cells basically. And so what this professor, we are collaborating, the CEO of the Buck institute of Aging, Professor Verdin, he profiled them. And what we saw was really shocking was that we almost saw the 50 year old persons with healthy immune cells that were fatiguing, that were inflamed, they almost reversed back to probably what a 30, 40 year old person's immune system will look like.

Ben Greenfield [00:26:21]: And these, when you see immune cells, these are the T cells?

Dr. Anurag Singh [00:26:24]: Yeah. So, okay, when you do a blood draw, you get total blood cells and you can take the red blood cells out and what you're left with is what we call white blood cells or leukocytes. Now these are, you know, let's say the main cell immune cells in our body are the T cells. They're about 10 to 20% of your immune cells. Then there are the B cells which make antibodies, and these are another 20, 30%. And then there are cells called neutrophils which are like, you know, the, they're not the police, but they are kind of the first responders. And so they kind of give the first shout out to these immune cells. And there's something called dendritic cells, which are basically immune cells, but with tentacles and they are always surveilling whatever infection or cancer, you know, prone cells are loitering around.

Dr. Anurag Singh [00:27:18]: So we actually profile all of them, and amazingly, the mitochondria in all of them went up, which means now the immune system has more energy to function. But what struck was two kind of cells that are needed to fight cancers and are needed to or decline very fast in aging process. These are the T cells. These are the, what we call the cytotoxic T cells. They fight cancer, they fight flu, they fight any virus that you have growing up. You have lots of them, and as you age, you kind of lose all of them. And so we see them kind of coming back to the, you know, almost like repopulating in the body. And then the inflammation was much subdued in these people.

Ben Greenfield [00:28:01]: So these are the three key findings from this trial.

Ben Greenfield [00:28:04]: You know, a lot of people, this just makes me think about this. They, whether for cancer, I mean, I've done this just as almost like a longevity play, they'll go overseas into killer cell infusions. Have you heard of this?

Dr. Anurag Singh [00:28:17]: Of course. Yeah. So, you know, I didn't want to get too nerdy, but we look at something called natural killer cells, which is abbreviated to killer cells. So the two main cells, if your body just loses them, your chance of getting cancer is like thousand-fold higher. And that's these cytotoxic T cells and the killer cells. The killer cells are about a percent to 2% in your body. And we see them, their mitochondria also getting recharged. And we see the increase in these NK cells or the natural killer cells and cytotoxic.

Dr. Anurag Singh [00:28:49]: So as an immunologist, I think these are the two main cells you have. And so, of course, what you are seeing today is if you go all the way to cancer treatment, is two kind of therapies. As you were saying, NK cell or killer cell infusions or something called CAR T cell infusion, which is basically where you take a T cell and you artificially put the cancer sort of signal on it, and then you inject it into the cancer patient. And because now they have seen it in a dish, they'll multiply and they'll kill off the cancer. So these are the two main cells. We're seeing the effects.

Ben Greenfield [00:29:29]: Yeah. Tony Robbins and Peter Diamandis described that CAR T cell infusion, or protocol when I interviewed them about their book, Life Force. It's fascinating. But, I mean, I guess where my mind is going now is if that were not doable for somebody, whether financially, logistically or otherwise. They could potentially at least support something like NK cells with urolothin A.

Dr. Anurag Singh [00:29:53]: Yeah, and, and so the way I see it is, is we are finding. So first we found the impact on muscle health, now we're finding the impact on immune health. I think the missing piece of the puzzle is the impact your urolithin A has on cognitive health, which a lot of groups have started to publish in different models of neurocognition decline with aging. And I see these three as the key organs - muscle, immune, brain - as the three key organs that you can hit to improve healthspan. And Peter Diamandis, you mentioned that he has 100 million poll price called X prize dedicated to this is to find a solution that simultaneously, it improves muscle health, immune health and cognitive health by 10 years.

Ben Greenfield [00:30:46]: I think I realized those are the three that he's combined. Interesting.

Dr. Anurag Singh [00:30:49]: Yeah, so in a randomized clinical trial, you need to show improvements in all three organ systems. And we were actually one of the selected finalists of this competition, which is now engaging in a long-term trial to see the effect of Mitopure long term on all these three organs. And so what we are actually describing, this Mitoimmune trial is just a part of the puzzle, which is how does it work in the immune system? And it doesn't work that differently than what we are seeing on muscle cells. It activates mitophagy, clears the damaged mitochondria out, the cells have more fuel, they function better, whether it's muscle or immune. And I hope in the future, when we are now conducting our cognition trials, we see the same in the, in the brain cells.

Ben Greenfield [00:31:36]: Okay, and I might have missed it, you might have said it. But for the mitoimmune trial, for the T cell piece, what was the dosage?

Dr. Anurag Singh [00:31:43]: It's a gram. So, you know, sometimes it's serendipity. So in all the three trials we did, the older adult population, the first trials, which I came to your podcast two years or two and a half years back, one trial was done in 70, 80 year olds, one trial was done in 40 to 60 year olds and one trial was done in athletes. All these three trials we took the blood and we looked in the blood and plasma, what was changing. And of course people were, you know, strength was better, endurance was better. But when we did, there was one biomarker that moved across in every trial and it moved at the 1 gram dose and that was C reactive protein, which is, you know, to a medical doctor, they've heard about it, they track it regularly as a Marker of whole body inflammation. But to me, what it means is that your body is inflamed, it's stressed.

Dr. Anurag Singh [00:32:40]: Now that could be because of fatigue, it could be because of cellular damage. I think these are all, as I mentioned, these are, you know, these are not hallmarks that exist in isolation. It's like a metro station and I believe, you know, multiple metro stations. And the common big one is the immune system. And that's where they all come in. And that's how I see the whole cellular health and how urolithin A, Mitopure is hitting is it gets the immune cells surveilling, policing better. Everybody else stays in check. The cells are behaving with each other.

Dr. Anurag Singh [00:33:14]: Okay. The cancer problematic cells stay away. And so that has a bigger benefit on the whole body as an impact. And that's where I think immune cells. The MitoImmune story is so cool, but it's at a gram.

Ben Greenfield [00:33:28]: Yeah, yeah. Did you guys ever try like a dose response? Like one and a half grams, two grams, like do the, do the positive effects keep improving?

Dr. Anurag Singh [00:33:36]: Long back. So the way we came to this dose was we actually brought in a cohort of older adults. We gave them 250 milligrams. We saw Mitopure come in the blood. And as we started talking, you know, you needed to drink three, four glasses of pomegranate juice and that was the equivalent. But it took a while to see the effects on mitochondrial turnover and biogenesis markers like PGC1 alpha. So we went a little higher, we went to 500 milligram. And in four weeks, when we did the blood work, when we took the muscle biopsies, we saw the mitochondrial sort of machinery just turned on and there was more healthier mitochondria, there was more energy. And so we went again, third time around with a gram and we saw a beautiful increase in dose response.

Dr. Anurag Singh [00:34:23]: But when we jacked it up to 2 grams, we did not see the linearity of the response. So now what does that mean? It means is that the body can only absorb a certain amount at a given time. So I haven't done 500 split in two doses in a day for a gram total or I haven't done a gram in the morning and a gram in the evening to keep sort of the response.

Ben Greenfield [00:34:50]: Yeah, I was gonna say like, like spread out the dosage to see.

Dr. Anurag Singh [00:34:53]: Yes, we haven't done that. But to, to answer a question, for, for, you know, did we increase beyond a gram? We did, but sort of the body, you know, has to absorb and then take away whatever it doesn't need and sort of that response plateaus out. And so that's what I. I think. But, you know, back to what we were just saying, or you were saying, maybe we split out the dose and we will get better response.

Ben Greenfield [00:35:15]: Yeah, yeah. Or your next product needs to be the urolith IV or patch.

Dr. Anurag Singh [00:35:20]: Yeah, I know that's getting a lot of traction in, in the vitamin infusions and the NAD therapies.

Ben Greenfield [00:35:28]: I mean, in all seriousness, though, could you do that with urolithin? Like, is it something you could get intravenously?

Dr. Anurag Singh [00:35:33]: Yeah. So it will only be soluble in a few matrix. It likes MCTs a lot, so that's why we put it in these soft gels. It likes protein, so it likes good fat, which is MCTs. It likes protein or things like this to mix. So iIV you would need to—in a sterile IV, you need to mix in water. And I think that's one of the limitations.

Dr. Anurag Singh [00:36:02]: But there are workarounds that we are thinking about right now. It's just what would be the regulatory status of an IV infusion? It's probably like a drug, probably.

Ben Greenfield [00:36:11]: Might have implications, though, for the whole cancer research T cell piece.

Dr. Anurag Singh [00:36:16]: Yeah. So there's a fascinating publication. Doesn't come from us and they actually screamed about 4,000 medical drugs and 4,000 more natural compounds, which are soda supplements. They only found two that could recharge CAR T cells and induce better tumor responses. There's a study that just came out a few weeks back. They haven't done the trial, but it's all done in a dish. And the two compounds that they find, one, of course, is on the supplement side is urolithin A and on the medicine side is GLP1, which is tirzepatide. So they actually find.

Dr. Anurag Singh [00:36:51]: And both. It makes sense, both are hitting metabolism. Right. Tirzepatide and it's not really known.

Ben Greenfield [00:36:59]: You mean tirzepatide?

Dr. Anurag Singh [00:37:02]: Yeah, those are big kind of drugs. So they have an impact on metabolism like crazy. People haven't really gone to the details of cellular biology, but they know and they've done these trials where people rapidly lose weight and fat. And so I think there is, and this is a new field, that the immense metabolic shift causes the immune system to wake up. And we can go a bit nerdy here. The shift of fuel from using glucose to more burning fat has a shift in kind of waking. And that's what Mitopure does. We look at muscle cells.

Dr. Anurag Singh [00:37:40]: It just uses fatty acids more than it would use glucose and that shift kind of causes a rejuvenation effect and it's in every cell.

Ben Greenfield [00:37:50]: Yeah, that's interesting too considering it combines well with MCT oil, which is going to push you into a little bit more ketone utilization as well.

Dr. Anurag Singh [00:37:56]: Yeah, but fascinating idea. I mean we haven't thought about an IV formulation yet, but I mean probably question mark is the regulatory way to-

Ben Greenfield [00:38:06]: Obviously not. Not as palatable either for a direct to consumer. So a few logistical questions. You know, you described how you have the powder, you have a soft gel, now you have the gummies. That's been my preferred delivery mechanism. Any advantage of one versus the other. Like have you guys compared them as far as absorption?

Dr. Anurag Singh [00:38:25]: We have. You know, I'm an evidence-based person and I wouldn't let our commercial marketing friends put out any product until I have clinically tested them. So we use something called bioexcellence clinical testing. And what that means is you take 12 to 15 healthy adults in one group, 12 to 15 healthy adults in the second group, and a third group potentially. And we give one group the powder containing 500 milligrams of urolithin A, which is one sachet. In second group, we give them two softgels, each soft gel being 250 milligrams for a total dose of 500. And then we have these gummies, each gummy given to 50 milligram and we give them two so they get also 500. And then we let these people take the product and then I bleed them.

Dr. Anurag Singh [00:39:13]: Well, sounds like, you know, but basically I take the small amounts of blood over time and I look at the absorption of urolithin A in the blood and I want to see that the kinetics are identical. And that's what it is. The powder, the gummy and the softgel, they're all identical and they all give, you know, between a plus 10% sort of range, which is, or 20%, which is the range. But we get very good data in all of them and that's what convinces me. And then I'm also looking at, I'm doing a thorough blood biochemistry and safety profile of all formats and that's how we call them bioequivalent, meaning one product is replaceable with the other and you can kind of mix and match whatever and they'll give you the same, same impact.

Ben Greenfield [00:39:59]: Okay, got it. Another practical question. Let's say I wanted to test my levels. I seem to recall at one point you guys had sent me a blood test. Yeah, I've seen urolithin A on stool panels before as well. If someone wanted like the gold standard measurement for urolithin A, what do you recommend?

Dr. Anurag Singh [00:40:17]: So there are some companies that are starting to either tell you that you may or may not have a certain group of bacteria that are involved in, let's say, urolithin A transformation. If you know, if you're healthy and you're eating a bowl of berries and nuts every day or drinking, as we discussed, you know, six to ten glasses of juice every day. The second is nobody yet has a great test to tell you the precise levels of urolithin A in blood, urine or stools. We have developed a, a blood based test which is using finger prick. So with a few drops of blood that you blot on a small filter paper, you know, it's a test. It's not yet a commercial test. We are still testing its sort of reproducibility in different subjects over time. And so this is a trial.

Dr. Anurag Singh [00:41:12]: I mean, if you want or your listeners want, they can sign up and I can send, send the link to this clinical study. You'll get a kit, you'll get a glass of juice, you drink the juice and you can do the finger prick. It will tell you if you make urolithin A or not, and if you do what levels. And then you'll also get one shot of the urolitin A powder and you mix it in your smoothie and you drink it the next day and you'll be able to see the impact it has. But we are on that path. It just requires a bit more sort of clinical validation and, and I'm pretty confident we'll have a test soon. I mean we have a, we're just testing it in a clinical study and not commercially.

Ben Greenfield [00:41:55]: So it sounds to me like you can see the test results acutely, meaning as soon as I take it, I could see an increase in my blood.

Dr. Anurag Singh [00:42:01]: No, you'll have to send the filter card with your blood spot so lab and you'll get it in the same way.

Ben Greenfield [00:42:06]: What I mean is acutely after dosing you would see an increase.

Dr. Anurag Singh [00:42:09]: Of course you'll see the full check.

Ben Greenfield [00:42:12]: Yeah. Earlier you were saying you still see, gosh, I don't remember if you said two to four weeks or two to four months for some of the effects on the immune system, strength, endurance, et cetera. Is that correct, that you kind of have to dose over time to see the actual mitochondrial effects versus just the acute levels in the bloodstream?

Dr. Anurag Singh [00:42:28]: So the acute effects will be just the Absorption effects. Right. So you take one shot, you see your blood levels are here, you take it, your blood cells go, go this high. It takes about. And then this is not a magic pill that in one or two shots you suddenly, you know, induce years and years of cellular health damage. I think the turnover and the impact on mitochondria takes about two to four weeks to have an impact. And that's when we start picking all these changes in immune cells or muscle cells. When we do biopsy longer out two to four months is when we start seeing whole body effects that are we discussed that improve strength, endurance.

Dr. Anurag Singh [00:43:11]: What I really want to do is now go longer. And that's the healthspan study that we are doing now is beyond just the muscle effect, beyond just the immune effect, beyond just the mitochondrial effect. What is the long term effect? I've heard a lot of people on it say, oh, I feel within a few days more energy and better recovery from exercise. And that may be possible. It's just that we haven't done the trials yet. So.

Ben Greenfield [00:43:36]: Yeah, all right. Got it. I would be remiss to have an immune expert on the podcast and not ask what might be a stupid question, but I'm going to ask it anyway. So as your immune system.

Ben Greenfield [00:43:47]: As your immune system gets stronger, would you tend to see like, like from an effect standpoint, would you tend to get sick less or get sick more? Like, like does a stronger immune system mean you have better sentinels and you, you know, you get a fever and you know, flu like reaction, congestion, et cetera, more readily as you, as you get better at fighting something off or would it mean you're like more resistant to infection?

Dr. Anurag Singh [00:44:13]: Yeah, so the immune system itself is a double edged sword. So you're correct there. So if you have two weak immune system, you're going to be sick all the time, you're going to have a lot of runny nose. And you see that with kids, you know, kids haven't their immune system... I remember my, my little one when she was going to daycare, every week she was sick, she would bring it. You know, the immune system's still getting educated.

Ben Greenfield [00:44:39]: Same thing with our kids. You know, we had the little, little bulb to get the boogers out of their nose, the constant congestion. Yeah.

Dr. Anurag Singh [00:44:44]: So that's, it's still learning. It's still learning what's out there. And you know, same with old people. I always say the immune system, what it was in the first year of life is probably the same when you're 75, 80 year old it's, it's lost its ability to recognize or surveillance. So it's weak and if you stimulate it it will now become better surveillance. But the immune system is when I say that's a double edged sword. In certain cases it may overreact. And if it triggers an overreaction then it could induce things what we call autoimmunity as an immunologist which means it gets so much, so much wired in that it even recognizes your own, some of parts of your own body as foreign.

Dr. Anurag Singh [00:45:32]: And so that's when it will trigger.

Ben Greenfield [00:45:35]: Now that's where you see things like lupus, MS, Ms. Arthritis.

Dr. Anurag Singh [00:45:40]: These are some of the common. Now both are two real extremes of the immune system. And what I believe is, you know, 25, 30 years back when I was training as an immunologist, my professor who not only looked like Santa Claus, but actually was in behavior, he would always tell me Anurag, the immune system just needs to be in what we call a homeostatic state. And that word homeostasis means if you can find compounds that can maintain the balance of the immune system. And so I see urolithin A and we talked about it quite a lot as an immune modulator. When it's weak, the immune system is fatiguing. It kind of shifts the balance back to the middle. And when for example and there are many publications coming out on models of multiple sclerosis.

Dr. Anurag Singh [00:46:36]: There's a fascinating paper on inflammatory bowel disease with urolithin A. When it goes in autoreactive mode it kind of brings it back in check. So it is like you talked about police and elite forces a lot. It kind of keeps the police in check. That's the word, you know. So it's like an immune modulator.

Ben Greenfield [00:46:54]: Similar to how to reishi like rhodiola adaptogens might help to modulate stress.

Dr. Anurag Singh [00:46:58]: Exactly. That's the word: adaptogen. 

Ben Greenfield [00:47:00]: Or decreasing cortisol. Urolithin is almost like a little bit adaptogenic regarding immune system. Okay, interesting. This is fascinating and you know a lot here in terms of the science and the previous chat that we had, I guess it was a couple of years ago, time flies. I'm going to link to [email protected]/timelineimmunity. But in the meantime, Dr. Singh, is there any other research, anything else that people should know at this point about urolithin A?

Dr. Anurag Singh [00:47:29]: Well, they should know that there's a lot of upcoming research and we started to get into it on brain health and cognitive decline. And I really think as a trialist, as a physician scientist, for me that yes. You know, and again there is no one magic pill. So the way I see it is there'll be more and more trials with multi pronged interventions. We'll be doing trials with exercise, with caloric restriction, with what is the additive effect of your urolithin A. But I think the research that really excites me and we talked about it is this sort of the health span research. How long can I with being on this particular intervention that is hitting the two central hallmarks - can I be 80 year old but would this behave like a 70 year old? And that's really where the research is going. We are partnering with a company called TruDiagnostic and something, you know, where we are looking at immune cells at an epigenetic level on what this immune age is and we are seeing in all the clocks that we are having an effect, things like pheno age and grim age.

Dr. Anurag Singh [00:48:40]: We are reversing this just in four weeks. So maybe longer perhaps. Perhaps. You know you mentioned Peter Diamandis. His vision is not too far, you know, so that's where I see. But I think cognition and showing benefits and cognition is, is really key and that's where we are headed.

Ben Greenfield [00:48:59]: Well in the meantime, if you're listening in and you want to try the gel caps, the powder, the gummies are my go to for a morning in my smoothie. They taste good, not too sweet, but they're actually fantastic and strawberry flavored. So that's really got me on the 1000mg a day bandwagon. I'll link to all that at BenGreenfieldLife.com/timelineimmunity where you can leave your questions, your comments, your feedback and let Dr. Singh and I know what you think and any other questions that you have. Dr. Singh, thank you so much for doing this and for the pleasure Ben, for the research that you're putting into this fascinating little molecule.

Dr. Anurag Singh [00:49:36]: Perfect. Always pleasure to be back and happy to come back when we have more data.

Ben Greenfield [00:49:41]: All right, thanks for listening everybody.

Ben Greenfield [00:49:43]: To discover even more tips, tricks, hacks and content to become the most complete, boundless version of you, visit BenGreenfieldLife.com.

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