Could *This* Molecule Be the KEY To Reversing Immune Aging & “Supercharging” Your Mitochondria? With Dr. Anurag Singh

My name is Ben Greenfield, and on this episode of The Boundless Life Podcast, 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 in, in inside the immune cells, they get recharged and they kind of propel the immune system at a much better way.

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 to discover unparalleled levels of health, fitness, longevity, and beyond.

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My podcast is with Dr. Singh.

We're going to be talking about, drum roll please, you're about to find out, for boosting muscle and endurance and reversing immune aging. So, The show notes are going to be at BenGreenfieldLife.com/TimelineReplay. That's BenGreenfieldLife.com/TimelineReplay. Let's jump in.

Dr. Singh, welcome back, man.

Pleasure, Ben. Absolute pleasure to be back on.

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 to 1,000 milligrams 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. 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?

Sure. So, just as a reminder, you know, this is 15 years of very in-depth biotech research that basically discovered this postbiotic molecule, correct? So, urolithin A 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, urolithin 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 urolithin A or Mitopure is that the damaged mitochondria get sort of recycled into healthier ones that basically produce more energy. 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 2 to 4 months, we see in healthy adults, whether it's 40s, 50s, 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, the scope and depth of the trials we had talked about lately.

There is— and just to interrupt real quick, was that at about 1,000 milligrams?

Yeah. So we have studied, we studied what is called as dose-finding clinical studies, and we find that the sweet spot is between 500 milligrams to about a gram. 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, and we can talk about it, uh, more impact on systemic aging and systemic organs such as immune aging with that.

Yeah, 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 1,000-milligram that you're finding to have the most effects on human performance.

Yeah. Yeah. So, 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. It will give you 500 milligrams equivalent.

Okay. So, so 1,000 milligrams, basically you're juicing 60 pomegranates.

Yeah, 60. Yeah, you'll need to drink about 10, 10, 12 glasses of pomegranate juice and that'll give you a lot of sugar as well.

Okay.

Yeah, yeah.

It's carpal tunnel syndrome and a lot of sugar.

Yeah. Yeah, true. So what we see is in the, in the sort of the healthy Mediterranean diet cultures, we see about 1 in 3 in Canada and the US we see 1 in 10. So only 10, 12% of healthy adults who, 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, uh, 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. 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.

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

Yeah, so, so I'm a trained immunologist. Uh, after my MD, I, I did further training in immunology. So immune aging to me is Everything you just mentioned, immune aging is, is sort of the sequelae. And there are 3 key hallmarks to this sort of, uh, phenomena. One is inflammaging, which means as we're getting older, our cells are getting fatigued, damaged, and these sort of damaged zombie-like cells become triggers of inflammation in our, in our cells and organs and body. And that kind of keeps increasing as we age. So from our 30s, 40s, to our 50s, 60s, our bodies, as my professor would say, is swimming in a sea of, or blue of, these soluble factors that we call immune cytokines. And these are basically damaging our organs. So that is inflammaging 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, and the most potent immune cells it makes is something called T cells. Immunologists are not very creative people. They just thought about few cells and they call them A, B, C, D, 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. 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 metabolic capacity to keep fighting cancer or keep fighting infection. And so that's sort of all-encompassing into immune aging.

Ben Greenfield: Okay. So, when we talk about longevity and anti-aging, and I'm not one of those guys who 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?

So, I mean, we've all talked about and probably it has been talked about in your podcasts 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 2 or 3 key in these. There, 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 as in our cells. But the 2 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 strawberry-flavored longevity gummies.

Are you kidding me? They're the Mitopure gummies jam-packed with the active ingredient urolithin, which is essential for your mitochondrial health. So, these little gummies each contain about 250 milligrams of urolithin A. So, 4 gummies would get you the dose dose that has been shown in studies now to improve strength and improve endurance and, of course, support the renewal of mitochondrial function, a key driver of healthy aging. So, these gummies, the way I do it, I keep them in my freezer. I'm just saying I might be breaking the rules here and I might get in trouble with Mitopure for telling you this, but I do. I keep them in my freezer because I like them really, really chewy. My dentist probably hates that also, but this is just what I do. And, I put them on top of my smoothie, as like a really chewy thing that I got to get through as I eat my morning smoothie. And, uh, it's nice to know that I'm also filling my body with something backed by more than 15 years of research in mitochondrial health. So if you want to try these gummies or anything Mitopure-ish from Timeline, uh, you can visit timeline.com/Ben and get up to 39% off your Mitopure gummies.

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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, and they're very closely linked: mitochondrial health and immune health.

So why is it that, um, 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?

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, and inside the cells and the neighboring cells, they're talking to each other. And so what they're almost like a surveillance program, this immune system. And what happens is as soon as the, the cellular health declines, okay, so as, 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 and it starts to survey deeper. And, 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 healthspan decline. And as soon as we hit our 30s, 40s, and, 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, 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. So the, the policemen in this case, the immune cells need energy to, to, 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 re-energizing or rewiring the immune system by boosting the mitochondria. And that's the connection.

Ben Greenfield: 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?

Yeah. So, Urotonate, from the time you take it orally, will hit mitochondrial health in every cell that has mitochondria. And all, all our cells except the red blood cells have cellular mitochondria. Now, the more metabolic ones, like the neurons or the skeletal muscle cells, they get hit hard the, the most. So, the, 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 the sequelae to things like Alzheimer's. I believe it's, you know, when, when you take urolithin 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. But what we are discovering is that the mitochondria in, in 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, at a, at a much better way. And so that kind of links to aging and mitochondrial health.

Okay, got it. Let's, let's get in the mechanism of action here. You use 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 urolithinate doing to the mitochondria?

Yeah. So, you can power up your mitochondria 3 ways today or at least 3 known ways to scientists and doctors. One is a process we call mitochondrial biogenesis. So, this is the sort of pathway if you're hitting exercises well-known, way to induce mitochondrial biogenesis, which it means just create new healthy mitochondria that create more new energy, more healthier energy, and you power yourselves 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. You know, I see you're exercising, so you're already inducing biogenesis. But how do you keep these healthy mitochondria, uh, up and running and become more efficient? And that, these are things like creatine, CoQ10. Now what Urolithin A Mitopure is doing is hitting what I started describe 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 damaged because they just can't keep up with For example, all the viruses and bacteria, they have to— the onslaught that happens with aging and 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. 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 PGC-1 alpha or biomarkers linked to better mitochondrial health starting to show up in, in, in these immune cells. And when we put, for example, these immune cells with bacteria, they kill them better. So that's the, you know, sort of biology that we are seeing happen, which is really mitophagy. We had started with muscle cells and we, we, 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-induced inflammation. We're seeing that get blunted. So, that's the connection.

Okay.

I've actually never heard it explained that way before. So, you have mitophagy, that's one of the 3 things that you said. That's the last one that urolithin A focuses on, the mitochondrial cleanup. You said mitochondrial biogenesis. I think you said that one's more triggered by things like exercise.

Yeah, exercise, fasting, known modulators.

Yeah. Okay. And, what was the third one?

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 of cleaning up shows up, uh, and cleans the waste. And now that is recycled and, and triaged and put back as recycling, you know, building blocks of new healthy mitochondria, which is biogenesis in many ways.

Okay. So like in an ideal scenario, you're, 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.

Yeah. And that is actually, I described it one after the other, but I 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. Mitophagy or autophagy is, you have to clean out the damaged cell, the damaged cellular machinery. And, and that again gives way to real estate, and now you can do the building blocks. So we have thought about it. We've combined urolithin. We've tested in different models of, of aging where we have combined exercise with urolithin A. We get a better augmented response. We've combined caloric restriction with Urolithin A supplementation, we've got a better response. We've actually done now 2 or 3 randomized trials in athletes where people are training and, and they're finding in, in these different trials, some of them are published, some are not, that Urolithin A actually augments even the, the, the performance of exercise or the impact of exercise.

Yeah, that's actually what I wanted to ask you about, cuz like 3 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.

Yeah. So, this is a long collaboration with two of the pioneers in the field of studying immune aging. One is Professor Eric Guerdin who's the CEO of the Buck Institute of Aging and has been studying immune health and the impact of immune aging on healthspan 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, you know, the cancer-prone cells because of mitophagy issues. So, mitophagy decline and cancer incidents 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. And so he published actually 2, 3 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, with urolithin A, he saw that he saw basically better immune system and more mitochondria in the immune cells that would then lead to sort of better cancer survival in these models. And so 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. So 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, and we gave them, we randomized them into two groups. Now, the way top-tier clinical trials are done is you, you do, 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 of, of, of urolithin A, Mitopure. And, and we did serial blood draws. So we, before they started the supplementation, we took their blood and we ran something called as, as complete immune profiling. Now, this is not what your standard medical doctor will do, but you're, 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 Wardah, he profiled them. And what we saw was really shocking was that we almost saw the 50-year-old person's, who was 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 would look like.

Wait, and these, when you see immune cells, these are the T cells?

Yeah.

So you, okay.

You, you take the, when you do a blood draw, you get total blood cells. What, and you can take the, the red blood cells out and what you're left with is what we call white blood cells or, or leukocytes. Now these are, you know, the, 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, and, and these are another 20, 30%. And then there are cells called neutrophils, which are like, you know, the, the, they're not the police, but they are kind of the, the first responders. And so they kind of, they, they, they 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're always surveilling whatever infection or cancer, you know, prone cells are, are loitering around. So we actually profiled all of them. And amazingly, the mitochondria in all of them went up, uh, which means now the immune system has more energy to function. But what struck was two kinds of cells that, uh, 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, uh, 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. So, these are the 3 key findings from this trial.

You know, a lot of people, this just makes me think about this, whether for cancer or— I mean, I've done this just as almost like a longevity play. They'll go overseas and do killer cell infusions. Have you heard of this?

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 thousandfold higher. And that's these cytotoxic T cells and the killer cells. The killer cells are about 1% to 2% in your body., and we see them, their mitochondria also getting recharged, and we see the increase in what these NK cells, or the natural killer cells, and cytotoxic. So as an immunologist, I think these are the two main cells you have. And so of course what you are seeing today is, uh, 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.

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 urolithin A. Yeah.

And so, the way I see it is we are finding— so first, we found the impact on muscle health. Now, we're finding the impact in immune health. I think the real, the missing piece of the puzzle is, is, is the impact urolithin A has on cognitive health, which a lot of groups have started to, to, to, to publish in different models of, of neurocognition decline with aging. And I see these three as, as the, 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 a $100 million prize called XPRIZE dedicated to this, is to find a solution that simultaneously hits, improves muscle health, immune health, and cognitive health by 10 years.

Oh, I didn't realize those are the 3 that he's combined.

Interesting. Yeah. So, you, in a, in a randomized clinical trial, you need to show improvements in all 3 organ systems. And we were actually one of the, one of the selected, uh, finalists of this competition, which is now engaging in a long-term trial to see the effect of Mitopure long-term on all these 3 organs. And so what we are actually describing, this Mitomean trial, is just a part of the puzzle, which is how does it work on 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 brain cells.

Okay. And, I might have missed it, you might have said it, but for the Mitohormone trial for the T-cell piece, what was the dosage?

It's a gram. So, sometimes it's serendipity. So, in all the 3 trials we did, the older adult population, the first trials which I came to your podcast 2 years or 2.5 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 3 trials, we took the blood and we looked in, in, in the blood and plasma what was changing. And, you know, 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, that, 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. Now, that could be because of fatigue, it could be because of cellular damage.

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I think these are all, as I mentioned, these are not hallmarks that exist in isolation. It's like a metro station and I believe multiple metro stations and the common big one is is the immune system, and that's where they all come in. And that's how I see the, the, 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. Okay. The cancer, uh, uh, problematic cells stay away. And so that has a bigger benefit on the whole body, uh, as an impact, uh, And that's where I think immune cells, the Mitomune story is so cool, but it's at a gram.

Yeah.

Yeah.

Did you guys ever try like a dose response to like 1.5 grams, 2 grams? Like, do the, do the positive effects keep improving?

Long back. So the way we came to this dose was, uh, we actually brought in, uh, a cohort of older adults. We gave them 250 milligrams. We saw Mitopure come in the blood, uh, and as we started talking. You know, you needed to drink 3, 4 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 PGC-1α. So we went a little higher, we went to 500 milligrams, and in 4 weeks when we did the blood work, when we took the muscle biopsies, we saw the, 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, and we saw a beautiful increase in dose response. But when we jacked it up to 2 grams, we did not see the, the linearity of the response. So now what does that mean? It means is the, that the body can only absorb a certain amount, uh, at a given time. So I haven't done 500 split in 2 doses in a day. Uh, for a gram total, or having done a gram in the morning and a gram in the evening to keep sort of the response.

Yeah, I was gonna say like, like spread out the dosage to see if you could absorb it.

Yes, we haven't done that, but to, to answer your 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 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.

Yeah. Or your next product needs to be the urolithin IV or patch.

Yeah, I know that's getting a lot of traction in the vitamin infusions and the NAD therapies.

I mean, in all seriousness though, could you do that with urolithin? Like, is it something you could get intravenously?

Yeah. So, it will only be soluble in, in, in a few matrix. It likes MCTs a lot. So that's why we put it in these soft gels. It likes protein or, or, so it likes good fat, which is MCTs. It likes protein or things like this to, to, to mix. So IV, you would need to, in a sterile IV, you'll need to mix it in water. And I think that's one of the limitations, but there are workarounds we, we, 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.

Might have implications though for the whole cancer research T-cell piece.

Yeah. So there's a fascinating publication, doesn't come from us. And, and, and they actually screened about 4,000 medical drugs and 4,000 more natural compounds. Which are soda supplements, they only found 2 that could recharge CAR T cells and, 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 2 compounds that they find, one of course is, is on the supplement side is urolithin A, and on the medicine side is GLP-1, which is tris-zerptidide. So they actually find, and both, it makes sense, both are hitting metabolism, right? Uh, trisepatide, and it's not really—

Yeah, you mean, uh, you mean, um, uh, tirzepatide?

Yeah, the Ozempic kind of drugs. So they, they have an impact on, on metabolism like crazy. People haven't really gone to the, the details of cellular biology, but they know, and they've done these trials where people rapidly lose, uh, weight and, and fat. And so I think there is and this is a new field, that the immense metabolic shift causes the immune system, system to wake up. So the— and we can go a bit nerdy here— this, 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, it just uses fatty acids more than, than it would use glucose, and that shift kind of causes a a rejuvenation effect. And it's in every cell type.

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.

Yeah, but fascinating idea. I mean, we haven't thought about an IV formulation yet, but I mean, probably question mark is the regulatory, uh, way.

Obviously not, not as palatable either for, for a direct-to-consumer. So a few logistical questions. 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? Have you guys compared them as far as absorption?

We have. 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 bioequivalence clinical testing. And what that means is you take 12 to 15 healthy adults in one group, 12 to 15 healthy adults in a second group, and, and a third group potentially. And we give one group the powder containing 500 milligrams of urolithin A, which is one sachet. And second group, we give them two soft gels, each soft gel being 250 milligrams for a total dose of 500. And then we have these gummies, each gummy given 250 milligrams, and we give them two. So they get also 500. And then we let these people take the product and then I bleed them. Well, sounds like, you know, but basically I take a small amounts of blood over time and, and I look at the absorption of urolithin A in the blood and I wanna see that the kinetics are identical. And that's what it is. The powder, the gummy, and the soft gel, they're all identical and they all give, you know, between a plus 9, 10% sort of range, which is or 20%, which is the rain, 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 impact.

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

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're healthy and you're eating a bowl of berries and nuts every day or drinking as we discussed just, you know, 6 to 10 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 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. I mean, if you want or your listeners want, they can sign up and I can 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. And or not, and if you do, what levels. And then you'll also get one shot of, of the urolithin 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 are just testing it in a clinical study and not commercially.

So, it sounds to me like you can see the test results acutely, meaning as soon as I take it, I could see it increase in my blood.

No, you'll have to send the filter card with your blood spot to lab and you'll get it in the same—

Oh, what I mean is acutely after dosing, you would see an increase. Yeah.

Of course, you'll see the full chain.

Yeah. Earlier, you were saying you still see, gosh, I don't remember if you said 2 to 4 weeks or 2 to 4 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.

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 1 or 2 shots you suddenly, you know, uh, induce, uh, years and years of cellular health damage. I think the turnover and, and the impact on mitochondria takes about 2 to 4 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, 2 to 4 months is when we start seeing whole body effects that are, we discussed that improved strength, endurance. What I really wanna do is now go longer. And that's the, 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? Now, I've heard a lot of people on it say, oh, I feel within a few days, uh, more energy and better recovery from exercise. And that may be possible, it's just that we haven't done the trials yet.

So, okay, yeah, all right, got it. I, 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 gets stronger, would you tend to see, from an effect standpoint, would you tend to get sick less or get sick more? Does a stronger immune system mean you have better sentinels and you get a fever and flu-like reaction, congestion, et cetera, more readily as you get better at fighting something off? Or would it mean you're more resistant to infection?

Yeah. So, the immune system itself is a double-edged sword. So, you're correct there. So, if you have too 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, kids having their immune system. I remember 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.

Same thing with our kids. You know, we had the little bulb to get the boogers out of their nose and the constant congestion.

Yeah. 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 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. And so that's when it will trigger.

Now, right, that's where you'd see things like lupus, MS, myasthenia gravis, like arthritis.

These are some of the common. Now, both are two real extremes of the immune system. And what I believe is, you know, my, my, you know, 25, 30 years back when I was training as an immunologist, uh, my professor who not only looked like Santa Claus, but actually was in behavior. He would always tell me, uh, anorexic, 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, to the middle. And when, for example, and, and there are many publications coming out on, on, on models of multiple sclerosis. There's a fascinating paper on, 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 talk about police and elite forces a lot, it kind of keeps the police in check. That's the word. So, it's like an immune modulator.

Similar to how to reishi or rhodiola adaptogens might help to modulate stress by increasing or decreasing cortisol. Urolithin is almost a little bit adaptogenic regarding the immune system.

You got it. Yeah.

Okay, interesting. This is fascinating. And, 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 that at BenGreenfieldLife.com/TimelineReplay.

Play.

But in the meantime, Dr. Singh, is there any other research, anything else that people should know at this point about urolithin A?

Well, they should know that, you know, 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, with caloric restriction, with what is the additive effect of urolithin A. But I think the research that really excites me, and we talked about it, is this sort of the, the healthspan research. How long can, can I, you know, with being on this particular intervention that is hitting the two central hallmarks, you know, can I be 80-year-old but with this be behave like a 70-year-old? And that's really where the research is going. We are partnering with a company called True Diagnostic 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 phenoage and, grim age, we are reversing this just in 4 weeks. So, maybe longer, perhaps, perhaps. You mentioned Peter Diamandis, his vision is not too far. So, that's where I see, but I think cognition and showing benefits in cognition is really key and that's where we are headed.

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 1,000 milligrams a day bandwagon. I'll link to all that at BenGreenfieldLife.com/TimelineReplay 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. Perfect. Always pleasure to be back and happy to come back when we have more data. All right, thanks for listening, everybody.

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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