Urolithin A’s Secret to YOUTHFUL ENERGY and the Fight Against Inflammaging : 1225

The more CD8T cells you have, the better your longevity. Health predictor. This is the number one intervention that has been shown to sort of reverse a lot of these immune aging decline. Mitopure is your cellular health glue or your lubricant. Biologists have described nine biological hallmarks of aging. If I were to redraw these hallmarks, I would put one in the middle, and that will be.

You're listening to the Human Upgrade with Dave Asprey. Today we're going to talk about mitochondria. Good God. How many times am I going to talk about mitochondria on the show? An infinite number of times. One for each number of mitochondria in your body. Okay, not really, but I've become increasingly convinced over the last, oh, 25 years of studying my mitochondria and mitochondria in general, that they are at the foundation of our interface with reality and that they control a lot more in our bodies than we're aware of. And that science, every single day is figuring more and more out, like, oh, let's study the brain. Oh, let's study neurons or glial cells. Oh, look, there's mitochondria behind them. Let's study athletic performance. Oh, look, mitochondria. Sex hormones, mitochondria. So this is why you keep hearing about them on the Human Upgrade. It's because they matter and because all the different tools you can use will make you live longer and make you perform better at whatever it is you want to do as a human being. And on that note, we're going to talk about some things with mitochondria in your skin today and your immune system. And we're going to talk about a compound called urolithin A that you may have heard about on the show today. Our guest is Dr. Anurag Singh, who's chief medical officer at Timeline Nutrition, and he's a top mitochondrial and cellular health expert and has an MD in internal medicine with a PhD in immunology, has led 50 clinical trials and written 40 plus scientific articles and has 15 patents. In other words, this is a guy who is steeped in mitochondria because they kind of run everything in your immune system and. Right. Is that actually true? Do mitochondria really run everything in your immune system or am I being hyperbolic?

Well, mitochondria, they are in every cell type except your red blood cells. So they are, of course, greater abundance in metabolic cells like our muscle cells and brain cells and heart cells, but they're very, very Important to what I call immune fatigue with aging. So, as with aging, you know, our immune system declines, and principally now the science is showing that the key driving factor is mitochondrial dysfunction.

I've done a lot of work on reversing aging in the cells. I recently did another thing to change the central aging clock in my brain. Did a whole podcast on that and using stem cells and focused ultrasound. But the one area that I'm most concerned about from aging is immune system aging. To address that, years ago, I did cultured natural killer cells. I took mine out, amplified them, and put them back in.

Yep.

Which is all I could find to really do this at a heavy level. But it turns out there's some things we might be able to do to lessen the effect of the immune system on aging. In my case, because I had chronic fatigue, I've had autoimmune issues probably for my entire life. This is one of my big risk factors.

Yeah.

What do we know about inflammaging? What is it? And what do mitochondria have to do with it?

Yeah. So I've spent 20 years studying mitochondria, and even a greater time studying the immune system. And. And funny enough, the two roads are now converging, so chronic inflammation and sort of these leaky cells. So, you know, the more as we age, these cells become what they're calling zombie cell or senescent cells or leaky cells. They start releasing these fragments of cellular debris, and that causes sort of a chronic inflammation, you know, and as we age, this inflammation rises, and that's the term we've called inflammaging. And that's a broader part of what I call the three hallmarks of immune aging. One is inflammaging, as I just described. It's like this increasing chronic inflammation with aging. The second is immunosenescence. So you started with a very technical term. NK cells, natural killer cells. So with aging, we. We lose our lymphocytes. So our body shifts from these, you know, trillions of immune cells where we have more lymphocytes, like, which are what I call the. The third arm of our. The elite forces of our immune system aging, and that's immune senescence. And third is really, you know, this concept of immune resilience. And that's where we can talk about mitochondrial health and how that is key for boosting your immune system.

If we look at all of the different causes of aging, and my book a superhuman on longevity, I identified about 7. Some people identify up to 12. How important is Immune aging compared to all the other things that happen.

So, you know, these are whether seven biologists have described nine biological hallmarks of aging. And now we've actually expanded that universe and included three more. And these three are actually, I think these are the foundational pillars of what causes these other things. And these three are chronic inflammation, gut dysbiosis, and a loss of what they call macroautophagy, which is basically, you know, mitophagy and lysophagy, things that allow you to clean yourself. So I think if I were to redraw these hallmarks, I would put one in the middle and that will be inflammaging and chronic inflammation. And they all can converge on this one because I think poor nutrient sensing or epigenetic modifications or mitochondrial dysfunction. You can explain all of them with this concept of inflammaging. And that's what biology and scientists and clinical clinicians are finding.

Now, if your immune system is working perfectly, you would have very little inflammation except from exercise or something like that. Right. What percentage of people have immune systems that work in, you know, that work really well these days? It seems like it's almost impossible.

Yeah, I mean, listen, the more sedentary we are, the more processed food we eat, the more artificial dyes that we are getting in our processed foods, you know, things like this. And then all the chronic exposure of stress, sleep, all these are causing inflammation in a background. And there is a very thin line between good and bad inflammation. A little inflammation is good. As you mentioned, exercise causes a little low grade inflammation. That is good. But over time, if, you know, with all the cellular systems not working in perfect harmony, this leads to really an accumulation of inflammation and the body can't control it. And so what I see, actually we've looked at a lot of. And if you look at all these longevity stud studies and blue zones, et cetera, you'll find that they have very low grade C reactive protein or interleukin 6. These are factors that are in our blood that are made by immune cells. And these are signs of if you have good inflammation or not. And so the more C reactive protein you have, the more cardiovascular diseases you have, the more brain degeneration you have. So you can actually link just by one marker or two markers, the entire sort of longevity landscape.

So if we wanted to measure the number one thing, it would be C reactive protein.

I think that's the old school. So I trained in that medical school where they said inflammation is crp, Right? That's probably the one Tool. And the second maybe you can do what is called as a total leukocyte count. So you can count the number of your lymphocytes and your neutrophils and all these other cell types. These were the two things that probably even till today the clinicians are using. Now. Science is progressing at such a high speed that with little drop of blood we can look at more than just CRP. So interleukin, all these interleukins, like interleukin 1 beta, TNF, alpha, these are all factors. When the cells get stressed, the immune cells, they, they, they release a lot of these factors. And so you can measure with a tiny drop of blood a lot of these factors and then with a little drop of blood I can actually look at millions and millions of cells in the blood which will give you like an atlas of your immun. Sounds a bit Star Trekkie, but it's coming in. Let's say the clinicians will know more about it and start using it in the next five years, 10 years timeframe.

And this is different than like DNA methylation, true age kind of things or is it related?

Yeah, so true. Yeah, true diagnostic or looking at epigenetic age. You're just looking at methylation patterns inside immune cells or any other kind of cells. Here you're using a technique called as flow cytometry. So you take, let's say 1mL of blood that you take, go for your regular blood checkup, about 5 to 10 million immune cells. So you take these and you run them on a very high throughput machine called a flow side emitter and you can using dyes, recognize every part of your immune system. So you know your first line of defense. These are what I call the police forces. These are things like neutrophils and other cells that help in wound healing. Then the second line of defense is your antibody producing and the third is really what you are calling these T cells and NK cells that are these like I call the elite forces of the immune system. And so using this panel we can tell who has low immune cells, T cells, low NK cells, who has more of. Yeah, and I think this is known to correlate the more CD8 T cells you have, the better your longevity health predictor.

So how do I have more of the CD8 cells?

So even in the CD8 T cells you have two kinds. One are what we call the memory T cells. These, these are, that's where vaccines are given. So you give a vaccine which is like a attenuated part of A virus or whatever. And these cells remember, so the next time they see a virus or a cancer, part of a cancer cell, they attack it. But these viruses or cancer cells are very smart. They fatigue these immune cells. And so you get basically a lot of bad goodies in your body over time and over aging. And so what you really need is these naive STEM cell, like CD8T.CE of us can make it because we have an organ here called the thymus that after a 20, starts going, you know, involuting and becomes smaller and smaller. So we can make. And that's the term t cell comes from, because they all educated in the thymus. So if there are strategies to boost these knife CD8T cells, then we can reverse partially immune aging.

One of the things that happens as we age is our thymus goes away. Why does it go away?

It's funny you say that. I think it's like a programmed. If you talk to folks like Dave sinclair, they'll tell you these are, you know, the whole immune system is like a compact disc. It's all written. And the thymus has a certain, what we call in the immunology field, a sequence of patterns that it can recognize. A pattern of viruses, pattern of cancer cells. And once around in our. It peaks in our middle teenage and twenties, it feels like it's done enough. It automatically starts receding. And there is a lot of effort being put in this field to keep the thymus around long time. So there are hormones that, you know, people can give thymus then or other. There's even efforts to reconstitute the thymus to regrow the immune system. So there are these strategies out there. But why exactly it it involutes? I think it's just programmed in our aging, and I don't think there's a clear answer why it involutes.

Today I've looked at protocols that regrow the thymus that seem to make people much younger. And these are complex things with growth hormone and metformin and things like that.

Yep.

Those are relatively extreme. And there's risks from taking growth hormone.

Yep.

What are some things we could do to help with this inflammating that are a little bit more affordable and accessible?

So fasting, believe it or not, this is the number one intervention that has been shown to sort of reverse a lot of these immune aging decline. There have been studies done by walter lungo and colleagues that show that not only do you reverse this biological age that you were talking about this methylation pattern, but you actually induce deep immune changes. So these CD8T cells come back. And we have been, you know, I'm a trained immunologist, and all the data we have been seeing with certain nutritional interventions, and we can talk about one of them, called urolithin A or gut metabolites, points to a deep connection between our gut and our immune system. A lot of immune cells are actually in our gut. They are educated also in the gut. And so what we are seeing now is that a lot of these mitochondrial boosters can be used to rewire and rejuvenate the immune system and get more of these NK cells, get more of these CD8 T cells.

One of the things that you're most known for is urolithin A, the things you're doing with timeline. And for listeners, if this is the first time you've heard me interview Anurag, I've been using timeline since it first came on the market because there's 10 years of really profound research in this postbiotic technica, is what you could call it, for doing all sorts of good things for mitochondria, including dealing with inflammaging. So what is the role of urolithin A with or without fasting, in affecting the CD8 cells or the thymus or just inflammaging?

Yeah. So I think about a year and a half back, there was a very fascinating podcast you had with a collaborator of mine. Actually it was an oncologist, Dr. Dominique Denk, and he's a very young clinician. He has been studying the immune system for a long time. And he's been studying cancer and cancer models, colorectal cancer, in models like this. And what they started seeing in cancer patients and in these colorectal model cancer models was that the immune cells had depleted mitochondria. These, these sort of, these elite force equilibrium. These, these are, are stem cell, like CD8T cells and K cells, et cetera. And they started looking for interventions that could boost mitochondria inside these T cells and in these models. And what they found, actually that in both these models and in a dish where they took out human cells and they cultured them with this postbiotic URL atin A, they could boost the more the abundance and the quality of the mitochondria. And so when he showed me that data, and I think he came on your podcast about a year and a half back, we said, hey, you know, we have to, you know, we have to run a randomized clinical trial in healthy folks to see if, you know, from Our furry animals. Whatever you're seeing in these models can be translated into humans. And at the time I was running trials with urolithin A in healthy folks, more on the muscle side. But we will always look at blood biomarkers and crp as we started talking about C reactive protein would always be dampened, whether it was older adults or a bit overweight middle aged adults. So we did this trial, we ran this with the Buck Institute of Aging, which is one of the top research institutes where they have this technology to really do a deep immune phenotyping. And after a month of taking urolitin A, we already start seeing significant reversal of this immune decline that I started to tell you about. So the inflammation is dampened. This inflammation is dampened. We see more youthful CD8T cells and a lowering of these fatigue memory cells. And. And then the fascinating, which I've always believed is the two roads meeting that I was saying is now these immune cells have much about a 20, 30% more mitochondria and if you throw a virus on them, they kill it about 20% better. So now you have a better chance. You have given yourself this sort of rejuvenated immune system that has the resilience to fight infections or whatever.

What kind of dose of urolithin A is necessary to do this?

So this randomized clinical trial was done with a gram of erolithin A. And as a trialist I always go with where we have the most evidence. So in our previous trials we see the 500 milligram and a gram both impact mitochondrial health and muscle health. The gram does impact more of the inflammation and inflammation related endpoints in the earlier trials. So we went ahead with that approach and we tested only the gram. And now we have plans to repeat the same study with the 500 milligram but a bit longer because I think it's really a kinetic of the time thing. The 500 milligram, those you will need to intervene a bit longer.

And that's four timeline pills, is one gram.

So each pill is 250 milligram and that's four timeline pills or two powders. You know, one powder has 500 milligram.

Is it better to do 500 in the morning, 500 at night, or just one gram in a single dose?

Fascinating question. And that's the randomized. I think you've asked me this before, that's a trial and I always say I need to do it, but this time I'm actually going to do that trial. So a lot of folks. Most of our trials are done with intake in the morning because just easier from a compliance perspective in a randomized trial to tell hundreds of folks to take it all in the morning. But we do think that the half life of the compound is about a day and it peaks about eight hours after you take it. So it could make sense as you're saying to split the dose, maybe take one 500 in the morning and then 500 in the late afternoon or early evening so that your exposure in your body the levels are always high. And that's a trial we need to run. And I will, next time I come back we'll have data.

I keep hearing this over and over. Yeah, no, I'm just kidding. So if someone's taking four either capsules or two of the powders in the morning with or without food.

So we've done that one. So we have done the comparison where we've given a heavy breakfast meal with the powder or the pill or an a fasted state. The absorption is identical. So by that I mean you get the same levels on a fasting versus a non fasted state. And so I think it's the only reason we say take it in the fasted state is that potentially you may even argument some of the response because people fast overnight and a lot of folks I don't eat breakfast, for example, my first meal is a lunch so I fast 18 hours. And so you're actually boosting a lot of that autophagy that is being induced by fasting. And then you take mitopure or urolitin A which I think is the foundation which will even boost fasting or even exercise responses. That's how I approach it.

For me it's 12:30 in the afternoon. I haven't had anything but danger coffee and a handful of supplements including four of the timeline your lithon A capsules. But is the the surface or the encapsulation material, is that enough to mess with the fast?

No, the capsules have zero calories. The powders maybe have some caloric because they're fruit flavor.

Is there a gelatin or something in them? I didn't look at what rmhcp no.

They'Re vegan so they have a vegan shell and the caloric value is absolutely zero. I have one of them in front.

It can't be zero aspect one calorie. I mean there's something in there unless it's not digestible.

So they have so ural today needs a fatty matrix so they have mcts.

Okay. So yeah, the mcts alone accelerate fasting and give you more ketosis. So you've got some MCTs, you've got a little bit of capsule material.

Yeah.

Which is probably hydroxy cellulose, which isn't actually. That's a prebiotic anyway, so it's not going to have any calories unless your gut bacteria turn it into propionic acid or something like that. Okay, so totally fasting compatible. Yeah, I do this every morning and sometimes I take a couple more at night. Do we have studies of weirdos like me who are willing to do six or eight because we're traveling or something?

Studies on, On. You mean fasting that.

No, not fasting, just studies of taking a timeline or urolithin A. So sometimes I'll do a gram in the morning, but then like, that was a long day, I'm traveling or something. I'll do another 500 at night just because. Well, why not?

Yeah. So we've gone till a 2 gram and you get the same effects. But it's not like every time you double the dose, you'll get more bioavailability. I think the body needs time to absorb and clear out the excess nutrients. So having said that, 500 milligrams thrice a day, this is something, as I said, or twice a day we have to test it out.

Got it. So I love this. It's not tested, but I mean, conjecture is at the base of science, right?

Yeah. I mean, I could argue. I mean, it's a hypothesis. That's why I say research is two words. Re and search. You always have an educated guess, Right. In research. So you have to go back to the drawing board and you're making me think and making me go to the drawing board.

Got it. I love the elegance with which you dance away from answering that question. It's all right.

Good.

Scientists say, well, we don't really know. And I'm like, well, guess, because you know more than someone who is just flipping a coin. But I'm going to guess that. Actually I couldn't even guess when I think about it. I mean, maybe having a big, big spike and then having a break, you know, maybe arrhythmic pulsing is better than constant dosing. But I. I could see that being really hard to do.

Yeah. In all our studies in, in. In the different species that were published in 10 years back, I mean, you talked about 10 years of research. It. It's really, you know, intake every few hours. These furry rodents are taking it all the time. So after a while, and this is Back to. Is it always going to be inducing mitophagy? Well, you're gonna clean the waste out, and then the body will allow for more healthier mitochondria to seed in. And we see that. We see PGC1 Alpha, we see more biogenesis, whether it's the immune cell or the muscle cell. So. So we need to figure out kind of how we pulse it and that can we induce mitophagy faster? I think it's a great idea. I'm taking quick notes.

I'm intrigued. You know, do like a mega dose during a fast. You know, take 20 grams and see what happens. And then, like, who knows what would happen? Maybe you get a big senolytic effect. Who heck knows? But I'm. I'm the guy who would probably try that. And then either, like, what happened or not, like, what happened. I'm not recommending anyone do that, by the way. I'm just, like, curious. Okay. I'm gonna get into skin health and, and urolithin A in a minute here. But part of the recommendations that I make for people and that you have as well is you should have a lower inflammation diet for inflammaging. And one of the primary measures of inflammation is the omega 6 or of the inflammation in the fats from the diet is omega 6 to omega 3 ratio. So one of my companies that's part of Upgrade Labs is called Axo Health. And I just got my results back, and we include an omega 6 to omega 3 ratio, and mine's at 2.6. And the longevity, people say it should be 4 to 1. That means you have four omega 6s for every omega 3 you have. But a lot of Americans are at 40 or 45 to 1, which means they're just getting crazy amounts of canola and corn. So it means you eat at restaurants, basically, or you don't know how to order at restaurants. So is there an ideal omega 6 to omega 3 ratio that you like to target? And what does urolithin A have to do with the inflammation levels when you're messing with your fatty acids?

So it's a good question. I. I don't think there is evidence of combining omega 3 with urolithin A, for example, in literature. What I can tell you is that your lithin A will increase the absorption of most nutrients. We have seen, for example, we know it improves magnesium absorption, and magnesium and mitopure together are really a potent combo. Omega 3 we haven't really studied, Dave, to be honest, together, and we haven't Looked the effect of urolithin A or mitopure on this ratio. But something we can do actually in our recently completed trial that we just completed, we can easily measure because it's easy to measure this ratio. But on other markers of inflammation we have a whole panel. As I mentioned, Interleukin 6 is down. TNF Alpha is down, IL1 beta is down. These are all very potent pro inflammatory factors that are made by immune cells that will damage your gut lining, will damage your skin barrier, will probably disrupt your omega 3 to 6 ratio that you were talking about. And so so chronic intake of mitopure dampens these inflammatory factors. So if you have another marker like this sounds like it's a very innovative one. We can take a look. In our clinical study, I'm really interested.

In all of the things you can do to suppress inflammation without taking too many antioxidants because literature shows you make energy with oxidation. So if you take too many antioxidants, you don't get benefits from exercise. You don't, you actually suppress good things in the body. Does urolithin A have that same effect of suppressing the benefits of exercise?

No. So we've actually run a randomized clinical trial with exercise in conjunction in actually elite runners, some of them which were Olympian level middle distance runners. And what we saw in the trial that again giving mitopure with this exercise training regiment, it improved sort of their performance measures up to a certain extent. But the real dramatic effect was really blunting this exercise induced inflammation and muscle damage. So most athletes with overtraining, they get this real big spike of CRP of interleukin 6 and they have an increase of a muscle damage factor called creatine kinase. We see all of them blunted when given in conjunction with exercise. So that's where I see really a value in the recovery field of mitopure with exercise.

Okay. So we don't run the risk of taking too much timeline or urolithin A with exercise cause it helps exercise. But if you were to take vitamin EE or even CoQ10, which I'm a huge fan of, if you're doing that with exercise, it actually might blunt the responses of exercise.

So there are some things like as you mentioned that are blunted. They're blunt these elite exercise responses in runners and cyclists. We ran this study exactly with one of the top sports researchers for that reason because a we wanted to see the absorption. A lot of nutrients are not studied. Most athletes or well trained folks absorb things differently than let's Say the regular Joes. And so what we see is similar levels of exposure and we see that we blunt the muscle damage and we really have an anti inflammatory response in these folks. Well, in fact, any population, any trial I've looked, I've seen that anti inflammatory aspect of urolithin A.

Okay, that's pretty cool. I would say that this is one of those foundational longevity and performance supplements that I just truly believe in. And one of the reasons is that there isn't a risk of, of taking away benefits from exercise or other beneficial stressors in the body. Which is why I'm. That was one of the many reasons that just as a longevity guy, I think this stuff is pretty cool. Let's talk about skin. So what does urolithin A do specifically for skin repair?

Yeah, so this started as a weakened idea. Not, not that we didn't have a lot of work already in our regular, you know, with a lot of the scientists here in timeline, we said, well, this stuff gets in the body, has all these great effects. What if we actually put it in a cream and actually looked at what the effects are directly on skin cells? And a lot of times in the longevity field, people were asking me, well, what does improving mitochondrial function mean? Should I feel more energy? What do I see on my face every morning? And so a lot of yes, you can look at energy, VO2 max and strength measures. But that led to that idea, well, what can people see on their face? Well, let's put it on a cream and see the effects. And so we started actually studying skin cells from young and old people. I couldn't believe that the exact same hallmarks of aging were going down. So you had chronic inflammation because of excessive UV damage in the skin cells. You had photo damage taking place causing inflammation. You had the mitochondria in the skin field are very poorly studied. And we started looking at young fibroblasts versus old fibroblasts. And the number one feature that was down was poor mitochondrial health in these skin cells that are called fibroblasts. And so we started of course adding uretinae mitopure into and seeing if you could reverse it. And we did see the same reversal we were seeing, for example, on muscle and immune cel. And that led to a whole plethora of randomized clinical trials where we designed the topical creams. We took volunteers that were men, women with wrinkles, poor skin hydration, poor skin barrier. And these folks applied these skin creams for up to two months. And we took skin biopsies as well, just to really go deep into the biology. And we saw a reversal to a certain extent of the skin wrinkles, better hydration. And the real key finding was that we urolithin a mitopure topically applied, stop these collagen degrading enzymes that are existing in our skin cells called matrix metalloproteinases. These are called mmps that really go up with skin aging. And that was blunted. So I think this is sort of a two prong approach. There's things like retinol, Right. In the skin aging field that do attack wrinkles, but they are. They leave your skin sensitive and a bit irritant. And so I think this is a very natural, safe way to counteract different features of skin aging.

All right, you talked about a Super nerdy topic. MMPs, they're one of my favorite unknown longevity factors. Define MMPs. Talk a little bit more about what they do in the body and outside the body and where they come from.

Yeah. So, you know, wherever there's collagen, whether in our joints or skin or, you know, collagen is. People don't realize a lot of the collagen and proteins and things also get synthesized in their mitochondria. So if you think about it, collagen with aging levels decline. And you have all these collagen supplements that people are selling, but these are like proteins that will get chopped into amino acids. So the holy grail in the whole aging field is to attack these set of enzymes called mmps, which stands for matric metalloproteinases. And there are several of them. These are enzymes that basically go up with aging. And so they keep chopping collagen and degrading collagen. And so the good collagen never stays around with the aging process. And that leads to, you know, loose skin that you think that comes with, you know, the saggy skin, the wrinkling of the skin. And. And so there are ways out there. If you can attack the activity of these enzymes and prevent the degradation of collagen, then you have a natural way to counteract skin aging. And that's what we are seeing with our. We see an effect on MMP1 and 2 and other MMPs on. And they're different kind of skin cells. Right. So you have the first layer, which is the. Which makes melanin. That's the pigmentation cells. Then you have the keratinocytes. And then you have a deeper level. You have the fibroblasts. So these are the three main skin cell types. And they all, most of the collagen is coming from the deeper layers. And so we see the keratinocytes and fibroblasts. And when we pull biopsies from these middle aged fol. Extressive wrinkles, after a while we see wrinkles go away. But the expression of mmps in skin has gone down. And I think that's phenomenal because now you have a biology to explain how your compound works for a certain health benefit.

MMPs seem like they're a part of aging throughout the body, not just in collagen, because of the fascia throughout the body. I had a recent experience where I ate a bad oyster in Las Vegas. And there's two kinds of toxins or bacteria you'll find in oysters. The paralytic one that everyone is, is probably you've heard about, that's really bad. But the other kind of bacteria that you'll find in oysters creates high levels of MMP in the body. And I sweated through the sheets that night, took some charcoal, but that wasn't enough. And I felt like a, a truck hit me the next day. Every site I've ever had an injury and sites I haven't even just absolutely sore and just felt really, really awful. And so I did the research. Oh yeah, I have high MMP levels that overnight went to all these sites in the body where there probably has already disrupted collagen and things. And it's normal to take about two weeks before you recover from that sort of thing. And it's rough on the liver as well. Well, so I said, well, what can I do? What do I know that affects mmp? Well, there's timeline. And then one of my other companies called Wasabi Method, which is a unique kind of pressure wave therapy, it's a device that practitioners can use to regenerate tissues. So I took a bunch of timeline and I did the Wasabi method all over, but especially in those areas to raise the enzyme that breaks down mmp, the proteinase. And I was only sore for like a couple days compared to what would have been a much longer time time. So regulating MMPs regularly seems like a good move because we know some of them are made in the gut and some of them are just made as we age. Is there a good way of measuring MMPs? Is this part of any longevity panel? Like, how do you guys study that?

This is using a very standard assay called elisa. So you're looking for, for their levels in either plasma, in blood, or when we do the biopsies. I Think more and more you will start seeing these assays come up in a longevity panel because these MMPs where I see the researches, as you were pointing out, they're actually driving a lot of I believe cellular senescence as well. And so a lot of these so called senolytics will be used to look at the effects, will be used to look at the effect on mmps.

So not something that most of us are going to get measured, but something that seems like it's, that's more implicated in tissue aging than, than most of us talk about. So guys, I have a pretty good track record of calling it early. So wait five years and look at MMP in the field of aging and I bet you'll find a bunch of cool stuff. I bet you'll find a lot more about urolithin A and you'll probably see Dr. Singh's name on some of the papers. Am I right?

Yeah, absolutely. Yeah. It's a Bible, 15 years of research.

So yeah, that's, that's super cool. That's just a walk into, into what's going on. Now. I do use timeline on my skin. I use a lot of other stuff too. To be clear. I don't use this one product. I have ridiculously like supple skin. I also have a lot of skin because I used to weigh 300 pounds. Like so I have like a lot, which is why like you can see I have these whatever they're called marionette lines. But the, the tissue quality is, is just really, really good. Especially if you account for the amount of sunshine that I've had growing up in New Mexico. And you account for the fact that the calendar thinks that I'm slightly over 50, even though my lab tests don't agree. So how long does it take if someone starts putting urolithin A on their skin to see a difference? And what difference do they see?

Yeah, so this is not a, again, this is not a magic pill or magic cream. So it, it does. We start seeing the earliest changes are after two weeks on the skin. So better hydration so the skin looks more moisturized and things like this at about four to eight weeks. And it's really eight weeks where we see the real hallmarks of skin aging. Like if less redness. I mean there are pictures I've seen of people with really eczema in our trials and red inflamed skin and that goes away. And of course the wrinkles is, well people call it wrinkles. It's really looking at the loss of skin elasticity and you know how good the topographic of the skin is. So we studied skin roughness and, and we see the wrinkles go down. We see skin roughness being improved and, and the skin being more elastic and yeah, I mean that all these are, can be linked to better yet if you block mmps as we were discussing.

Okay, interesting. That might be one of the ways aside from just helping mitochondria that you're seeing an effect on skin. So it takes, you know it a couple months of regular application.

Yeah.

Do you need to use it once or twice a day?

So in our trials we have done both. So we have a suit of products. So we have the, you know, we have the face creams that are used with the daily application and we have the clinical data on it that is published now. And then we have the serum which is really like a more twice a day application and a lot of folks love that one and we have clinically studied that too as well.

Will timeline. You guys spent 10 years figuring out all the science behind your Lethan a before you came out with one of the new longevity molecules. And to be really clear, I, I think this is at least as important as NAD which is really well known in the longevity field. So I'm, I'm a big fan just based on the science and that can't be the only thing you're working on. I don't think you're a one hit wonder. So what?

No.

What's in the pipeline here?

So the pipeline is, you know, we've been lifting the cross for a long time and now the buzz, the buzz is going to other scientists. So we were just at an aging conference and there were folks talking about brain health and how you know, this is after fasting and mcts. This, this compound is inducing similar benefits in models of brain decline, for example. So on one aspect we, our main focus today remains unlocking more newer benefits of this compound because as we started off saying mitochondria everywhere. So it has to have more than just effects on your skin or your muscles. So we are unlocking that. We are running a study in pre diabetics looking at metabolic health in GLP1 production. I mean this is a postbiotic. It has to influence the gut microbiome where GLP1 is mostly made that a lot of folks don't understand. And then we are kind of exploring synergies with other compounds which have a similar scientific rigor and where we can hit different pathways of the all hallmarks of aging. So stay tuned on that one. We'll be running a lot of new trials and coming out with new products.

A little bit more specific.

Yeah, my IP intellectual property guy will not like it.

But no, no, I don't want. You guys have to have filed some patents and stuff. I'm not asking for roadmap for the future here.

I'll give you an example. Brain health. Right, Brain health. We are running two or planning to kick off two new studies. One is looking at folks, believe it or not, mid-40s, mid-50s, who all have sleep disorders. They have something called as REM sleep disorders. And it has been shown that in multiple longitudinal studies that 95% of these folks who have sleep disorders will turn into some form of cognitive neurodegenerative disorder. So whether it's dementia, Alzheimer's, Parkinson's, whatever. So we want to catch them early in their 40s and 50s when they start having these REM sleep disorders. And so we are running this trial to improve brain bioenergetics. These are the same folks that have actually looked at NAD as a way to modulate the brain and improve brain health. And so we now have data that urolutein A or some other scientists have shown that urotine actually also boosts Nadia levels by sort of the recycling mechanism. So we're exploring that, and then we are looking at brain aging. So, for example, there are nutrients like selenium, okay, that are known to decline with aging. There are nutrients like magnesium that everybody takes for recovery, but nobody really has studied the interaction with other supplements or other bioactives. And so the way I see it is that mitopure is your cellular health glue or your lubricant that you put motor oil that you put in your fast car, and it revs up other things. So now if you're taking an Omega 3, you'll absorb Omega 3 better. If you're taking magnesium, you'll absorb not just because all your cellular machinery is working so much more efficiently. So that's something we are exploring. And yeah, we are looking at other actives that are similar to URL 10A as well.

Well, the big hypothesis behind my book, Headstrong, which is kind of the cognitive enhancement Bible as far as I'm concerned, is is one of my really successful books. It was that step one, upregulate mitochondrial activity in the brain, which drives down inflammation and improves cognitive function just because you have more power. And then step two would be increase BDNF because this increases neuroplasticity. So now you have more power in a brain that can Change more easily. Therefore, medit will work better and focusing will work better and just everything works better. It stands to reason that since mitopure, the timeline, flagship urolithin A stuff, since that does increase mitochondrial function, if all the research in my book is right, then I would expect cognitive effects. And this is the first trial that you're, you're looking at to study cognitive effects for urolithin A. Yeah.

So this is the first randomized clinical trial we are leading. There are trials underway by other investigators who, who partner with us, but then they run their own trials. These are famous professors all around the U.S. and outside the U.S. and, and so there are other trials happening.

Yeah, we also have this idea of polypharma and in the pharmaceutical industry we study different combinations of drugs and to see what, what do they do when they're stacked. And in biohacking, of course, we stack things because we're results oriented. Oh, you wanted something to happen. Do everything that's likely to make it happen, get the result and then back off like that. That's, that's the how do I change myself most quickly way of doing it. But I've seen very few companies transition this idea of studying multiple compounds over into cognitive enhancement. And in the supplement industry, and it sounds like you're going down that path. You're looking at combining urolithin with things that will amplify its effect.

Yeah, I mean, you have to understand the biology of brain decline. Right. There's mitochondria at one of the hallmarks. Then you have you talked about, about inflammaging and inflammation. So you need something that can be additive to mitopure. Then, you know, things like the B vitamins and things like selenium and magnesium, they decline, you know, because their transport to the blood brain barrier declines. And, and maybe the old folks are also not eating well. And so can you add other nutrients and other bioactives and other pathways. So, so something that can regenerate your myelin sheath, for example, and potentiate a phospholipid, for example. So that's how we are approaching it. So you will see multiple targeted nutrients all studied together and validated in a clinical trial, randomized trial, and then we launch these products.

I do greatly appreciate the level of rigor that you guys have. The 10 years of research to bring out your lithium A was impressive. And when I look at my 150 supplements a day and I it's not always 150. That's when I'm traveling at my most Extreme like I have to be on. But most days it's you know, 50 to 150. Timeline is one of the things that's always there just because of the, the strong research on, on baseline mitochondria. And it's one thing to take a nootropic that does a specific thing for a neurotransmitter that's very high level compared to just having better base machinery that's running. Are there other compounds that you like to take? Even if it's something that you don't, you guys don't manufacture that you like to take regularly?

Yeah, I'm a big fan of Omega 3. I did a lot of that research before in my former life. These omega 3s do become processed, broken down into our body into something called resolvins. And so I studied resolvents a lot and so I know the anti inflammatory aspect of these molecules. Plus heart health is a big one. We are all in that age group where we need to think about our heart health. So I love taking Omega 3, a good brand, at least 2 grams plus because most of the brands sell it at less than a gram and most of the clinical data is 2, 3 grams plus real efficacy. So I take that and I take MCTS. I take some ketones, ketone esters as well. Well they really have this effect on cognition but sometimes they give me a little GI upset, but that's just a matter of dozing. But those are my top three stacks.

Have you played with ketone dial versus ketone esters?

No. Which would that be? Which company would be selling this?

Ketone iq.

Ketone iq. Okay, that one I haven't tried.

Those are interesting because the esters seem to place a load on the liver because they have to to it has to process them and they uncontrollably raise ketone ketone dial. The body still can regulate, but you can get up to about 1.5 on a ketone meter. And MCTs will get to in my experience, like the C8 stuff that I popularized when I was at Bulletproof, we'll get to about 05, maybe 07 on an empty stomach with coffee. And coffee is an amplifier of ketosis. So I've found I take mcts regularly and I'll take some when I want extra ketones. I go for the dials now and I do take that with urolithin A. Is there an effect on amplifying ketosis when you take urolithin A?

Yeah. So you know, we, we urotinate loves being in a Matrix of fat and mcts and it just absorbs much better. So that there's that one angle that ketosis will more. A certain amount of mcts will help you absorb more of urolithin A. And we have certainly looked at the amplification and just through biomarkers, but I think proper trials on cognitive function need to be designed. But fundamentally, yes, on mitochondrial function, we have evidence on cell based systems that if you add MCT or ketone bodies, you get better effects on inflammation, anti inflammatory effects of mitopure, or if you add things like CoQ10, you get even better mitochondrial function. So they are additive angles to chase. I agree.

What I would hypothesize here, and I want to run this pastor's scientific brain. There's still, I'm going to call them the keto bros. These are people who, you know, maybe read the bulletproof diet. Oh, ketosis is the best thing ever. And I'm never going to eat a carb again. And they'll sort of compete to have the highest possible ketone levels. And I always feel like that's the same as competing to have the highest possible blood glucose levels. It means the body's not burning ketones if your levels are super high. So I would hypothesize that anything that enhances mitochondrial function is gonna make the mitochondria better at pulling energy substrates out of the blood.

Absolutely.

That that means if you took some exogenous ketones like mcts or ketone IQ or ketone esters or BHB salts, whatever you're using, using that you might have lower blood sugar levels or lower ketone levels. If you take mito pure because your mitochondria worked better and they were better able to burn whatever was present. Does that make sense?

Absolutely. In, in all our studies, when we look at this, what we call a substrate switch, so you can actually look at is your cell now needing glucose or is it needing fats? And we always see the switch to more fatty acid oxidation from a gluc glycolytic energy pathway with your lutein A. Now that means now you're utiliz fats more and more. And so I think that makes total sense to test even in a randomized trial.

It really does make sense. And for listeners, if you're in a keto phase and hopefully if you've read the bulletproof diet, you recognize cycle in and out of ketosis, for God's sake, don't stay in it forever. It's not a good idea. But if you're worried that your ketones aren't high enough. It could just be that you're fat adapted because people who regularly experience ketosis have lower ketone levels because their mitochondria can better burn ketones. And if you enhance mitochondrial function with mito pure and your ketone levels drop by 0.2 or something, it's probably because you're using the ketones again. We don't have data for that, but it just makes sense. You want mitochondria that can vacuum blood sugar or ketones out of the blood and turn it into heat or electricity or other compounds your body needs, right?

Yeah. I mean this is something I've thought about long, long time, late evenings, nights, how to combine it. The problem is, is most people like popping pills and gummies. And to get that effect, at least with MCTS, you need a lot, right? You need what, 20 grams of MCTS. So it's really a powder based proposition that you have to think about rather than trying to put too much in a pill. So that's the only challenge on the commercial side, I think. But otherwise, hypothesis, the scientific and clinical rationale is very small, solid. As we were just discussing.

Got it. You mentioned Omega 3s since you studied them extensively and you know a thing or two mitochondria, I'm going to pick your brain about those Y with or without taking mure. So we have epa, we have dha, and there's also dpa. Talk to me about how much of each of those you like to get and whether you even pay attention to dpa.

I don't. All I to make sure is I get enough EPA and DHA and then they are. There's a lot of research now on alternatives. I think that's some very exciting stuff coming out. There's fatty 15, there's other derivatives, similar resolvents. You have to look into the resolvents as well. These are fascinating compounds as well, much like metabolites of like, of omega 3s. So I just go with the EPA DHA content.

And what ratio do you like between the two of those?

So I think it's something like 2 to 1 in the whole field of, of omega 3. They say take 3 grams and I think you want to target getting 25, 30% of, of that to be EPA, DHA. I think that's where they are all headed at.

Okay, that, that makes sense. I've been kind of tortured by this since I wrote my first book on fertility, which is my very first book book. We know that babies like dha no for sure.

All the infant formulas have that.

Yeah, it's. And it's important for moms. Even before pregnancy, a lot of women like, oh, no, I have fat on my, my thighs and my butt. I'm like, yeah, that's your DHA sore and your first baby's going to drain that for you. You know, your body's getting ready for that if you decide to have kids. But adults, it feels like we need a little bit more EPA than dha.

Yep.

And. And so there's probably some age appropriate thing there. And, and again, I would stack all of these things with mito pure because better mitochondria equals better results. And I, I also appreciate you mentioned Coq10. I take that as well. So, so this is a nice stack. Some EPAs, some Mito Pure, and some CoQ10, and you're probably gonna get good results.

I, I think you Back to my. And this is something again, another trial I need to run is I need to take the stack of vitamins and minerals and supplements and then add mitopure and show that now you're getting even better exposure to all these. Just like we were saying with ketosis or, you know, just because now your cellular machinery is so optimal to absorb these nutrients. I think this is a, this is something we need to.

It is. And I love that you said minerals and things like that. So there's vitamin D and Minerals101 are two of the things I focus on.

Yeah.

As foundational. Because mitochondria, even if they have mito pure, if they're lacking zinc and copper and all the other minerals, they just don't work very well because they have no building blocks. So you start with building blocks, do your mito pure and just keep going up the stack. So I, I appreciate being able to share this information in, in a usable way. If you're listening to the show going, you know, supplements are expensive. Yeah, they are. They're not that expensive compared to what you likely spend on going out for drinks. And if you're not going out for drinks, they're still less expensive than a single doctor's appointment. And so I, I just look at this as the first place that I invest after eating food that's low in toxin. Anything else we should know about how to use mito pure to get better mitochondria?

I think we covered all the basis. You know, I think it. Again, a lot of people say, what dose should I start with? Is it 500 milligram or a gram? That's probably the, the trickiest thing. And I put my, you know, again, as a trained doctor, we weren't trained to think about, you know, prevention and go early to delay aging. I think if you are fatigued, if you feel like your body is sort of under stress and inflamed, and if your blood labs are showing that inflammation, then a gram makes sense to start off and you can always bring it down. I mean, we talked about that. You know, this could be seen as an expensive supplement, even though it's like taking a coffee a day or even cheaper. But, but it's again, if you, you are already doing all the good stuff like fasting and exercise and taking a lot of vitamins and other CoQ10 mother mitochondrial boosters, then 500mg is the dose we see already hits the cellular energy and the recycling of these bad zombie like mitochondria. So, yeah, that's probably the only last top parting thought.

Okay, I do have an addition on that one. And it's take a gram. If you've never taken it before, do it. Instead of taking 500 milligrams a day for a month, do a gram for two weeks. So you'll feel it. And you might not feel it when you start taking it, but at the end of two weeks when you stop taking it and you go back to the way you used to feel, then you'll really notice it.

Yeah, this is so true. Absolutely. So. Well, I also invented a test that allows you to know if your body can actually make the postbiotic URL atin a. My body doesn't. And I'm running a study actually in my home country, India. And I realize in Europe, in the French and the Italians that are kind of eating the good Mediterranean diet, we see 30, 40% in the US and I ran studies, we see only 10, 20% people have this molecule. India, it's less than 5%. And I don't know why. I don't know why. It's probably a lot of antibiotic exposure. And even growing up, I got so much antibiotics for everything. They give you antibiotics probably. That's my hypothesis. But my body, I feel it, I need to take a gram and when I switch to 500, I feel a little crash. So, yeah, got it.

And for some people listening, well, that means there's something wrong with you. No, it doesn't. It means that when your body's running at its full efficiency, it's probably not going to do that without help. Even if you were a caveman and living in nature and all that stuff, your body doesn't want to attempt to expend the resources to do that. And if you use biohacking, you take control of what goes into your body. You can make it so your body has everything it needs to do that, and then it's going to do it and you're going to like how you feel. So one group of people say, well, that's cheating. Or that means you're addicted to it. I'm like, well, going outside makes you feel better because of sunshine. Exercising makes you feel better. Like all of these things are just things you do to function better, feel better, and have control of your biology. So I think this is just awesome stuff and I'm grateful to you for sharing some of your knowledge of what stacks well with your lithon A and I also want to call out for people who are on GLP1 drugs like semaglutide. We have a whole episode talking about using Timeline, Mito Pure and how important mitochondrial function is if you're on one of those weight loss medications. So you definitely want to check that episode out as well. And because we want to save you some money, go to timeline.com Dave they'll give you 10% off your order. This stuff is just worth it and I want to make everything as affordable as possible. So thanks for sponsoring the episode and just sharing real unbiased data guys. If you're all into the the super famous things like NAD or testosterone therapy, both of which I'm a fan of and use, this is something that is equally important. It's that big of a deal. So I appreciate you just doing the hard research and sharing it again. Timeline.com Dave Sa Some money and get some results. See you next time on the Human Upgrade Podcast.

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