Unveiling the Molecule That Supercharges Your Mitochondria, Turns Back the Clock on Aging, and Battles Sleep Deprivation, With Dr. Anurag Singh from Timeline Nutrition.

My name is Ben Greenfield and on this episode of the Ben Greenfield Life.

Podcast, the 5 Best Ways to improve mitochondrial function. If I have to put a priority list, one would be regular physical activity. So try to do your 8,10,000 steps a day. Number two, in short of intermittent fasting, two meals a day with a very balanced nutrition profile probably does the trick. Stress, big impact of stress on circadian rhythms and sort of how it impacts mitochondrial health. Sleep, another big aspect that has a big impact on mitochondrial function at your cellular level. And then the fifth is what I would say sort of advanced nutritional supplementation, things like urotine. As we are chatting with or even hitting on some other well known autophagy boosters, you mentioned spermidine as one. You mentioned other ways to boost autopilot. So there's no one magic trick. It's really a concert with different tactics that you need to apply.

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People are talking about Urolithin A now, but I've never really unpacked in detail on a podcast what it is because there's some subtle nuances in terms of its sources, its bioavailability, its dosing, the research behind it. And it's such a popular supplement. And you're hearing about it all over the place now that I figured I should do a podcast on whether it's a reasonable thing to take in the first place, if you even need to supplement with it, and what exactly it is and how it works in the body. So I found a guy who knows a lot about Urolithin A. His name. And I hope I don't Butcher your name, Dr. Singh. Cause I got the last name S.

I, N G H, but is it Anurag?

Is that how you pronounce your first name?

Yeah, you got it correct. You can call me Dr. Singh.

Nailed it.

All right, we'll go with Dr. Singh.

So for everybody listening in, Dr. Singh is an MD in internal medicine, but he also has a PhD in immunology because he's a total underachiever. And he has worked with a bunch of different food companies, including Nestle and different startups, including one startup called Timeline, which has done a lot of this research and development of Urolithin A. And they actually claim Timeline does that. Urolithin A is backed by about 15 years of clinical research. And so we'll be be able to explore a little bit today about what exactly that research is and what Dr. Singh has found when it comes to Urolithin A, which again, like I'm now taking as a supplement. But I've never really done a deep dive into it. So this is going to be fun to get into Urolithin A.

You ready to talk all things.

All things urolithin, Dr. Singh.

Sure love to share it with the audience.

Cool.

What got you interested in it in the first place?

Well, I'm trained as an internal medicine doctor and for long I was practicing as they call modern medicine. And I realized basically that a lot of times when we were seeing people with different chronic conditions, it was too late in the sort of trajectory of health function and health dysfunction to intervene. And I started working with a lot of natural compounds as I was training to be a physician scientist. And yeah, from there the interest grew and we started looking at bringing the biotech approach to nutrition and stumble upon your lithium A. And it's really great area of health benefits.

So besides having a really weird name, what exactly is your lithium A?

Sure, yeah, it's a, it's a metabolite found from, you know, sort of. We all know the good foods that we eat, right? Things like pomegranate, walnuts, pecans, raspberries, all, all this red and blue looking stuff that we have, you know, for long said has packs a lot of antioxidants. Well, it does. So a lot of these antioxidants are polyphenols. They're natural compounds that are enriched in these fruits and nuts. But when we digest them, our gut microbiome releases this metabolite called URL. So it's basically a food metabolite.

Okay, what's that mean, the gut releases a metabolite? Would that mean like the bacteria that are already in your gut would consume these foods or, or ferment these foods and produce some kind of like, I think it's called a postbiotic compound. Is that kind of how it's working or what exactly is. Yeah, here that's going on?

Yeah. So these antioxidants or polyphenols are very complex sort of aromatic compounds. And so the, when you digest or you're taking a glass of juice or a bowl of berries, your, your gut microflora, basically we'll digest them and sort of break them down into smaller molecules that are more digestible, more well absorbed and have health benefits for the host. So that's. Yes, you're correct. This is what I would also call a postbiotic compared to a pro or prebiotic, which is essentially the gut microbiome and prebiotic the food that the gut microbiome needs.

Now, based on that, I guess I'm wondering, let's say I'm eating pecans and raspberries and pomegranate, weaving those into my diet so that I can then have the bacteria in my gut convert those into this metabolite, urolithin A. Is it going to Kind of vary the conversion efficiency based on my unique biome. Because you got companies now out there, like probably Viome is one of the most popular. I know Genova Diagnostics has a test for this, but they'll tell you, you know, the, the genetic composition of all the bacteria in your gut. And I'm curious if there's a way to know your, you know, kind of your, your potential for urolith and a production based on something like that.

Sure, yeah. So basically we have done a number of clinical trials all around the world. We've gone into French adult population, we've got into the Americans, the Canadians name it. And basically the best producers are the French. So they must be eating closer to the Mediterranean diet, rich in and I guess a lot of fruits and berries and nuts, but they're also eating a lot of cheese and wine and a lot of fermented stuff. So we do see about 30, 40% people in healthy adult population that have the correct gut microbiome. So you're right, you need to be eating healthy foods, but you need to have the right gut microbiome in the American population. We did a study we published a couple of years back. It's actually very low, it's like 10, 12%. And even those who will make it would make a very variable range. So in most cases it will be what I call sub optimal ranges that are hardly going to give you a health benefit. For example, we also have developed a test that can accurately measure just with a few drops of finger prick blood swabbing on a filter paper. We can tell you through very advanced mass spectrometry methods if your body is actually naturally producing or not and how much you need to be taking it. I can drink 6 liters of pomegranate juice. My body just refuses to make your lithium as an example that's interesting this.

This mass spec analysis that you can use on someone's blood, like with a blood spot test, is that looking at the genetic makeup of your gut or your, or is it looking at urolithin A presence in the blood or what exactly are you looking at?

Yeah, yeah. So it's exactly looking at the presence of urolithin A in the blood that you are probably exposed from diet. And it's a very precise test that we have developed. And the end goal of that whole thought of developing the test was basically this molecule, this postbiotic is sort of the natural way for the body that exists. So if you have a very well functioning gut, health, gut ecosystem and you're Eating right, you're probably going to make decent amounts of naturally ural today, but a lot of us don't. And so the tests you were mentioning that other companies such as Viome or others have, will tell you your microbiome sort of spread, whether it's favorable, whether it's rich and diverse. So we've actually done studies where we have looked at people who naturally produce and what's their gut microbiome look like and those who don't produce, such as me. And the answer really lies in the complex gut microbiome that you have to have a very rich and diverse gut microbiome. So you could do that analysis. But I think with our sort of end functional output, which is urolithin A, we can tell you if you're, you know, your body is making the end product or not.

Yeah, it sounds to me like you could skip a lot of the hassle with, with doing like a full biome test of the gut. If you can simply test your blood, you know, if you're already on a supplement that contains your lithium A, or I guess perhaps some kind of a probiotic that might result in urolithin A production, I would imagine you'd want to stop that and then you could just test what your levels naturally are and. No, but, but I'm just curious, do you think it's more that some people don't have the, the genetics from an overall like a whole genome standpoint to produce urolithin A? Or do you think that these, these Americans, for example, who you mentioned, are like 10 to 20% of them capable of producing adequate amounts of urolithin A, that it's more diet or epigenetic or environmental related, you know what I'm saying?

Yeah, I think actually it's more diet and environmental related. And what kind of exposure you had, for example? I trained, I grew up in India, a lot of antibiotic usage early on for everything, you know, there's a big practice to give antibiotics. My gut microbiome just basically I think was destroyed forever. And try as I might to eat a lot of fermented food and a lot of fiber, I don't seem to be able to rewire it. Now, those who are blessed, as I call them, those who are producing and eating the right foods to nourish, it doesn't, you know, they probably are getting the exposure to decent levels naturally.

Okay, got it. So would there be any advantage, and I realize this is probably kind of a question that you might be biased about, you know, working for a company that makes a product that supports urolithin a production. But would, would there be any advantage if you were getting, let's say adequate amounts from your diet and you're eating things like these raspberries and pecans and pomegranate and a wide variety of fermented foods so you have the bacteria to produce the urolithin of, of adding more like, like where's the benefit in supplementing with more? Have you guys kind of dug into the research behind that?

Yeah, we have. You know, I do work for a company but before I'm trained as a medical doctor and, and I always say diet and exercise are the two pillars of your key health to longevity. Right. So yes, I, I think if you're, if you can know that your body is producing enough URL of DNA, then you don't probably need to take a higher dose. You can probably just go on a maintenance dose and things like this because not, I assume, not everybody is juicing four to eight pomegranates every day to drink a glass or two glasses of pomegranate every day.

Exhausting.

Yeah. And you get the sugar exposure. A glass of juice is about 30 grams of sugar. So yes, people should eat raspberries and pecans and walnuts and other good sources. And if their body is producing your lithium A, then, you know, that's why we developed this test. They can actually, you know, develop a maintenance dose through dietary supplementation. Those who cannot, which is apparently a majority of us, then they need to rely on direct calibrated supplementation. You know, things like vitamin C. We all know our orange juice is good for you, has a lot of vitamin C, yet a lot of people take vitamin C supplementation. Right. And so that's, that's the way I look at it.

Yeah. Yeah. Back to similar reasons you outlined. Maybe somebody is watching their calories and doesn't want to have as much of the pomegranate juice or fructose containing foods, et cetera, which I know in the low carb community is kind of a thing, but you know, kind of a nerdy question, I suppose, but let's say I worked a test. Do you happen to know what reference ranges would be for adequate urolithin A levels that reflect some of the performance and recovery and mitochondrial benefits of something like elevated levels of urolithin A?

Yeah. So we've looked quite deeply both into the microbiome and exhaustively into the body blood levels both from let's say natural dietary exposure and with increasing Doses of direct supplementation. And we've published these in really top journals like Nature Metabolism. So we start seeing really big effects in different human sort of trial, randomized clinical trial settings at about 500 milligrams. So this compound hits your mitochondria and kind of rewires them from being poor looking mitochondria to healthy mitochondria. And we can tell that difference in four weeks through blood biomarkers, etc. But really the functional benefits, you start seeing it about two months of supplementation, we do see levels between let's say 10 to 100 nanograms per volume of let's say plasma that we can measure. It would be the dietary exposure about 2 to 5%. People do have higher than that. With let's say direct supplementation, you can't consistently reach that. 100 would be, let's say the lower limit. And you'll always get an average about 300, 400, which, you know, there's a concept called a therapeutic range that we call in medicine. So you always need to have enough exposure to the molecule in sufficient doses to sort of have the health output. And that's what I believe you always need to maintain your blood levels at.

Yeah, a lot of the research I was looking at leading up to this call, digging in a little bit, seemed to agree with what you just outlined in terms of around 500mg of daily supplementation being something that elicited a lot of these performance and recovery enhancing effects. And I even saw some, particularly in the muscle endurance and performance realm, albeit I think it was like with finger contractions and, and you know, in human models, which might not translate directly to like, you know, ironman triathlon or something like that, but they were up around a thousand milligra grams as far as the daily dosage goes. And I would love to get into some of the performance implications here in a little bit, but just backpedaling, what exactly is urolithin A doing from a, from an action mechanistic standpoint in the body?

Okay, great question. Yeah, so you, you touched upon it, you talked about NAD, you talked about Coq 10. They are mitochondrial boosters out there. So think about the life cycle of a mitochondria, right? We all are always our cells, typically highly energetic cells like your skeletal muscle which is always moving, which is always kind of climbing stairs, or a neuron cell which is always kind of active. These are cell types that have thousands of mitochondria. So they have a very high basically metabolic demand. And so there's always a flux of healthy and poor healthy or bad functioning mitochondria. But what happens is, is in the life cycle, healthy mitochondria accumulates what we call as oxidative stress becomes damaged, and then over time it becomes really crummy. Now with things like aging, or if you get injured and you're lying on a bed, you just shift the balance to more crummy looking mitochondria in your cells and in your system. And if you're not cleaning those faulty mitochondria, think of, you know, it as the trash bin in your house. If you're not cleaning your trash out regularly, your house is not going to smell. Right? And that's exactly what happens in muscle cells and neuron cells and hard cells. With aging or with obesity, for example, they just accumulate a lot of mitochondria. So you could do NAD supplementation, which is targeting what we call mitochondrial biogenesis, of trying to grow more healthy mitochondria. Or you could do things like coq tenor or L carnitine, which is just taking the pool of functioning mitochondria and trying to make them make more energy. But unless you clear out the waste and there's space in your mitochondria, and this is a process we call mitophagy, which basically is like autophagy of the mitochondria. So garbage disposal. So what urolithin A does is revs up mitophagy, cleans out the faulty mitochondria, and now you have basically newer building blocks for newer healthy mitochondria.

Okay, okay, got it. So with this mitophagy, then arguably most of the effects we're seeing with urolithin A in terms of its impacts for recovery or longevity or performance are based on enhanced health of the mitochondria due to mitophagy. Okay, does, does, does mitophagy result in, in greater amounts of mitochondrial density or number of mitochondria? Is it impacting simply the core quality of the already existing mitochondria or what exactly is going on there?

It's doing actually both. We do see higher mitochondrial abundance. Just because you're creating as a result of mitophagy, you, you will clean the waste out and you will see things impacting mitochondrial biogenesis so you will have more abundance of healthier mitochondria. But what you do see is mitochondrial quality go up big time. And just that just means that the cell is more energetic, your cellular health is more optimal. And that has implications beyond just improving mitochondrial Health into muscle performance and recovery as you said.

Yeah. I'm curious what you guys have actually seen or what you've seen in terms of the implications for this as far as enhanced mitophagy from something like let's say that standard dosage of 500 milligrams or so of urolithon A consumption.

Yeah. So we have run a number of randomized control trials, placebo controlled trials. We've run it in older adults about 65, 70 year olds. We've compared those even doing regular exercise, about those 70 year olds who are doing 60 minutes of running every day to the frail couch potato sedentary older adults. And we've given those sedentary older adults about 500 milligram or a gram of urolitin A and we've able to see basically a similar exercise mimetic like impact on mitochondrial and cellular health. And then we have gone into longer duration trials in for example 40, 50 year olds and even older adults again and really seen, I think you mentioned some of the results on the sort of hand contraction. Believe it or not, one of the first muscles that declines with aging is this one. So you know your grip strength basically is the first loss and that's why they say a handshake goes a long way to predicting your longevity. And it's basically that. So we have seen not just hand grip strength improve, but even leg endurance improve. And then we have put people on our ergometer and see and seen that they basically have a resistance to fatigue 20% more they, they walk more in the, let's say if you do a standardized walking test and yeah, most importantly you can measure it with a very simple test like Peak VO2 for example, goes up 10% in a non trained population. So these are some of the effects we have seen. In addition we have seen also some of inflammation markers. So as we all age or if we are not eating well, our bodies get inflamed and things like C reactive protein go up. Now there's a big interaction between mitochondria and immune health. And so what we see is actually down the road with longer a gram sort of supplementation, even other benefits coming out.

Interesting. So up to 1000mg or so you can see even greater benefits from a performance standpoint. Some of that research study I found.

Yeah, that's exactly what we are seeing now.

Any, any side effects? I mean I'm curious if this is causing a shift in the gut bacteria in terms of their postbiotic production. You know I, I took Some of the timeline stuff, namely I like that little powdered packet because I could just dump it into my morning smoothie. I know you guys have a whey protein as well as a, I believe a soft gel that contains some of these urolithin A precursors. But if, if you take it, do you ever notice anything like a, like gut side effects or any other side effects from a higher amount of URL with an A consumption?

That's a great question. So what safety? You know, we have really characterized the safety aspect very well. Before we actually went into humans, we did a whole battery of safety tests that we vetted with even the FDA through a process called as grass, which stands for generally regard as safe. And basically even in those experiments that we did early on, just even giving it like 5% equivalent in the diet didn't have any impact. And in the humans, of course we've done, gosh, about thousands of folks who have been in our randomized trials by now. And really this is a natural molecule. So as we were discussing, about 30, 40% of us have been making it. A lot of us were probably in the evolutionary tree when we were eating fresh food and eating out sort of in the wild with berries and nuts, we were all probably exposed to it. So it's a very safe molecule. We haven't really seen any product related adverse effects. Now certain people may have some allergenicity. You know, for example, a lot of people when they take the rice base or the berry based product may have some sensitivities to food ingredients. But as a compound it's. As a pure natural compound, it's very safe.

Now, based on the gut thing, I'm curious, you know, there's some companies out there, I would imagine some are competitors to timeline that make probiotics that promise to shift the gut bacteria in such a way that you naturally increase your own urolithin A production. I think that for example the, the seed symbiotic is one that I think I've seen that type of, that type of claim on for the urolith and a production. What's the difference between your product and a product that would be more of like a, like a bacterial based urolithinase support?

Yeah, I just think it's the, it's an indirect way. Right. And for example, I've been running clinical trials in the nutrition industry for 20 years. I started actually a lot of trials that you can probably pick up on. Probiotics are probably trials that I ran about a decade back. Problem with probiotics is if you're taking these billion CFUs, hoping that a certain percentage of them will colonize your gut. And we've looked at the gut. I spent a good amount of five, six years trying to study what is that bacteria. The gut microbiome is so complex. Right. It's never one bacterial strain or two bacterial strains attend. It's really the whole ecosystem needs to be there. So I think, as I said, if you can induce neurolithin A production through diet and probiotics or eating fermented foods, by all means do it. But I just think for a majority of us, that indirect way of supplementing will be imprecise and that will lead to a lot of variability in not just human clinical trial settings, but in real life with direct calibrated supplementation, 500 milligram or a gram, we know what we are giving and what levels we expect. And those are probably leading to more consistent clinical trials or real life results.

Yeah, I need to actually try this blood spot test that you mentioned because I take the seed probiotic, I take three of those little capsules when I get up in the morning. But then I've been putting the powder of urolithin A into my smoothie, which I have like five mornings a week. So it'd be interesting to actually test my levels both with and without the.

Sure.

The, the, the, the, the seed and then with and without the urolithin A, just to see, because I would imagine. I don't know what you think about this, but it seems to me like you could potentially do both, right. Support the gut bacteria and also supplement in the same way that you could eat a wide variety of fermented foods and then also weave in things like the pomegranate and the raspberries and pecans, et cetera. Have you ever thought about that?

Yeah, I agree. And that's why I said I really see this as part of the three pillars of human health. One is you need to be exercising regularly. You need to have a good diet rich in fiber, probiotics, vitamins and minerals, and, and then, you know, at the base of this is the third pillar which is really adding on sort of very advanced calibrated supplementation that is boosting your cellular health and will help, I don't know, better nutrient absorption, for example, or better cellular health that even, you know, you will have better additive effects. So I do think there's merit into doing, but complementary approach.

Yeah, you say advanced supplementation. How is, how is Timeline's product any different? I Guess I'm curious if you've somehow patented your process or if there's a special form of urolithin A that you use. Is there anything that particularly differentiates timeline or is it just these variety of delivery mechanisms like the protein or the capsule or the packet?

Well, one thing we know, the molecule in and out, as I mentioned, We've studied for 15 years. We have probably a whole array of patents protecting health benefits. But more importantly, it's how to deliver the molecule. Right. It absorbs well in sort of lipid medium chain triglyceride kind of matrices. So we have put it in soft gels that are sort of rich in these MCTs and that helps even enhance the bioavailability of this natural molecule. And so the, and of course we have proprietary ways to manufacture it from scratch. So we know that the purity of this molecule is over 99% and we do it with really the top manufacturers that of course are GMP compliant and very high quality.

Okay, that's interesting. So arguably taking it with lipids would be better. Like if I were to take it with fish oil in the morning or if I were to have other fats like you know, coconut milk or something like that in my morning smoothie, that's going to enhance the bioavailability.

Yeah, we've done even a head to head with, you know, it needs a sort of a food matrix protection. So you've done a trial with mixing it with high protein skewer like yogurt. So like Icelandic yogurt is very rich in whey protein and sort of branch in amino acids. And that gives it sort of a better effect in sort of protecting and the digestion of it. And that's one of the reasons why we blended it with the whey protein. If you mix it and blend it with the fiber, it also helps. But all the trials actually have mostly been run with the, with the MCT formulation and softgel. So I do think that gives it an edge in terms of a little enhanced absorption.

Okay, got it. Now what about the transdermal part of things? You know, I noticed that you guys have a skin product you sent me like a day lotion and a nighttime cream. Is that actual urolithin being applied to the skin?

Yeah, it is, it is. So for long, you know, when I would go to top conferences and presented top medical conferences, everyone was the first question everybody would ask me, well, what will I feel? You know, how do I measure mitochondrial health? And I would say, well, you would measure it kind of subjectively because you'll feel more energy, you'll feel less fatigue. If you really want to test it out, you. You'll measure your sort of VO2 max. And by going on into a special lab that can put you on a treadmill and hook you up with all kind of, you know, measuring instrumentation. So people say, well, but what will. My first thing. Will I see it in the mirror that I'm aging less? And I said, well, this is not you in a pill or exercise in a pill. This is improving, you know, hitting many of the pathways that are important for cellular health and recycling. And so that's. Those questions also triggered, well, what will it do? It's just not the muscle cells that are abundant. Mitochondria. Our skin cells have a lot of mitochondria. Our immune cells have a lot of mitochondria. So we started looking in these different verticals and really seeing if URL 10A. When we would sprinkle it on human skin cells, for example, from older donors, we started seeing the same effects as we were seeing in muscle cells. And that led to formulations in day creams and night creams. And now we have just run many randomized trials again that we are trying to publish in JAMA with the skin formulation. And what we see is basically improved cellular energy and less inflammation in the skin, which is practically what happens when we grow old is, you know, because of sun exposure, our skin gets inflamed and wrinkles start appearing. So we thought, you know, skin aging goes in parallel with longevity. And so now we have products that hit skin longevity.

That's interesting. So you see a difference between, say, oral consumption and the effect that would have on the skin versus direct sun transdermal application.

That direct comparison we have not done yet. It's something in the works to not compare direct, but to even combine the oral supplementation with the direct topical administration. Now, the reason is that when you take something orally, about 80% gets absorbed in GI and then probably disseminates. But then the 20% that comes in, some of it goes to the muscles, some goes to the brain, some gets taken up in plasma, hits your immune cells. So prob. Really, you know, all of it is not going to the skin. And so we thought, well, if we could do something synergistic and additive by applying direct, a very calibrated so that we're giving like 1% urlatine or mitopure in these topical products, then, you know, and we know it penetrates well in the skin and it hits a lot of the skin cells similar to the muscle.

So yeah, yeah, that's super interesting. And by the way, I'll link to this stuff if you go to BenGreenfieldLife.com TimelinePodcast BenGreenfieldLife.com Timelinepodcast because like I mentioned, they have a stick packet and a gel cap and the protein powder and then they also have these transdermal applications. So a lot of different delivery mechanisms for this urolithin A. But there's so many other things out there. I mean, Dr. Singh, you know, in the introduction and then you alluded to it, I mentioned NAD&C60 and fish oil and astaxanthin and all these other compounds. I recently interviewed Brian Johnson who takes like, I think he said he takes like 120 different supplements when he gets up in the morning. He runs that blueprint age reversal website. So I'm curious for you, you know, because it seems like you, you kind of have your, your ear to the ground for a lot of this stuff. Are there other compounds that you think would kind of like appropriately fall into an age reversal supplementation strategy that might go above and beyond urolithin? And if so, have you been particularly impressed with what you've seen on any of these?

Well, I think there's promise in the NAD field quite a bit, but I do think that there's sort of untapped synergy out there by combining a lot of people just blend in stuff. The problem with the nutrition field is oh, let's blend XYZ and hope miracle happens. I think there's a lot of interactions between molecules and so one needs to study that. Having said that, I think if people were to think, well, if you clean the waste away and then you apply something like an NAD booster on top, probably there's reason to believe that there will be synergy. So I do think there's merit in all these molecules, vitamin B3, nicotinamide, riboside or NMN that are kind of known to be biogenesis boosters. I like CoQ10 even though the literature is mixed because it's a molecule that directly goes into mitochondria and is important in the whole sort of energy metabolism pathway and that improves efficiency of whatever healthy pool of mitochondria you have. And then I think just the two best drugs ever developed to improve autophagy, mitophagy are regular exercise and intermittent fasting. So, you know, if people do want to boost autophagy and mitophagy, that's one additive way to do It.

Right.

And that's what I do. Practice also intermittent fasting myself.

Yeah. A few days ago on Twitter I published an interesting study showing that low dose aspirin, of course not only has some of the heart health benefits, particularly if you're careful not to combine it with a lot of other blood thinning agents, but seems to induce cellular autophagy mechanisms in a similar way that fasting does. And I kind of like some of these autophagy or mitophagy agents that particularly for lean active people, premenopausal females, et cetera, don't necessarily require hefty bouts of fasting, which I think can be overdone or particularly problematic for the endocrine system when combined with a lot of exercise or training for a triathlon or Marathon or CrossFit or something like that. And so I think that some of these things that you can do to improve mitophagy or autophagy separately from fasting can be a pretty good idea. I'm curious for you. You know, it sounds like you incorporate some of this stuff into your lifestyle. What, what a typical day would look like for you as far as some of the age reversal strategies or mitochondrial support strategies that you do in addition to using something like urolithin.

Well, I always say that probably the five best ways to improve mitochondrial function. If I have to put a priority list, one would be, first would be regular physical activity. So try to do your eight, 10,000 steps a day. Number two, eat. Eat. You know, you don't have to eat a lot, but in short of intermittent fasting, two meals a day with a very balanced nutrition profile probably does the trick. Stress, big impact of stress on circadian rhythms and sort of how it impacts mitochondrial health. Sleep, another big aspect that has a big impact on mitochondrial function at your cellular level. And then the fifth is what I would say sort of advanced nutritional supplementation, things like urotine. As we are chatting with or even hitting on some, you know, other well known autophagy boosters. You mentioned spermidine as one. You mentioned other ways to boost autophagy. So yeah, I think it's really a. There's no one magic trick. It's really a concert with different tactics that you need to apply.

Yeah, that's sound advice. I'd agree with all those principles. What do you do for sleep? How do you prioritize sleep or enhance your sleep? What's that look like?

I stop looking at my phone screen as I leave work and I play with my kids and that relaxes me And I go to bed around 10, 30, 11, and I mean everybody's different when it comes to sleep. I honestly myself, I was trained as a medical guy so I'm used to doing more with less sleep. So I just need about six to seven hours of sleep. But I think exercise whenever days when I do a 5 or 10k, I sleep the best. And I do think that even with things like Eroltin A and NAD supplementation, there is literature coming out that these have the potentials to sort of hit on some of the circadian rhythm through bioenergetic modulation and results in better sleep cycles and people have more wakefulness early on. So it needs to be studied further.

Yeah, NAD beyond the shadow of a doubt, particularly for me from an anecdotal standpoint, significantly combats any effects of sleep deprivation. I'll even use a heftier nad, oral dosage or a transdermal patch of nad. I get it from a company called Ion Layer when I need more nad. Or if I'm doing long haul flight and want to combat some of the DNA damage.

Oh sure.

And then creatine seems to act similarly, just a slightly higher dose of creatine. You know, usually I take 5 grams. If I'm sleep deprived I'll bump that up to about 6 to 8 grams. What about urolithin A? Have you noticed that that seems to have any type of effect either anecdotally or from a research standpoint? Yeah, anecdotally, sleep deprivation.

Yeah. We haven't run any randomized trials yet. There are some in the works. But anecdotally we've heard people waking up fresh, they're sort of, they feel like they wake up early and they are much more fresher early in the morning. But again, this is anecdotal. We are, you know, a lot of our studies are now kind of gearing up to. We've done a lot of studies, clinical trials in older adults and overweight middle aged adults. A lot of our new clinical research is moving towards more healthy. There's a study, for example, we are just doing an Elite athletes, believe it or not, you would think that their mitochondrial health is optimal. But the problem there is overtraining. Overtraining also induces mitochondrial dysfunction. And we are even in the works discussing to do a trial with the elite army professionals, the Green Berets, that have both sort of the cognitive decline with stress and hypoxia and the physical demand. So we are doing a lot of work that probably you'll hear about in the next Year or so. But I do think there's potential in those aspects.

Yeah, yeah. For sleep deprivation. I've noted that, noted that like acute dosing as soon as you get up in the morning, if we're looking at NAD and creatine seems to be best for timing. But you know, and I would imagine your oath and A might be similar, maybe take a thousand milligrams or something on a sleep deprived day and bump up your dosage when you first get up. And I'm actually going to experiment with that now that I know and I'm aware of its effects on that. But what about for something like a workout? You know, I know a lot of these studies have looked into performance, but what's the dosing? Well, we talked about the dosing, you know, 500 to up to a thousand milligrams. What about the timing? Is this something that chronically accumulates in the body like loading with creatine throughout the year or is it something that you can literally notice the acute effects of? If you were to, let's say take 500 milligrams for you tell me how long before workout.

Yeah, so the way the kinetics of absorption of this molecule works, the moment you take it, it takes about a few hours for it to start absorbing and it really peaks in your blood about six to eight hours after you've taken it. So most of our trials are done giving to individuals in the fasting state in the morning with or without breakfast. So that would be about let's say 7, 8 o' clock in the morning and would start beating, let's say midday, mid afternoon. That's where we see a lot of, let's say the acute effects. But then it has a kinetic where its half life is really about a day. So it kind of will peak at six to eight hours and then we'll start dipping down and go below what I call sub therapeutic or sub optimal levels of exposure to the molecule. So you would need to then again take it the next day or bump it up even to a lies after. So a lot of I with the gram. So a lot of the recovery workers with a gram. So I was just telling you about the study in athletes that was only focused on recovery. So a lot of these individuals before a big season of competition they go into training camps and they're all eating the same food, they're running downhill, they're kind of training in extreme conditions. What we are sort of seeing in some of this early data that is coming out is profound effects on recovery and Muscle damage. So I do think that even in, in sort of these settings, recovery will be boosted in these sort of populations with this molecule in a cute way. So during training or post workout would probably make more sense to take it.

Okay, got it. You know, when you look at creatine post workout, you know, co administering with caffeine seems to increase absorption a little bit. We talked about with urolithin A how co administration with either lipids or perhaps even some type of a ferment or probiotic might enhance the effects. But are there any other things? You know, a lot of my listeners like to stack stuff or know what combines best with what. Have you looked at any research or even just anecdotally yourself looked into stacks? Things that would go well when paired with your lithium A to either enhance bioavailability or enhance the mitophagy effect or, or anything else as far as kind of upgrading the urolithinase that you actually take.

Yeah, I know that there's sort of this bio optimization with the stacks and you know, taking a few things and then building on top of in the protocol sort of that people follow. You know, I'm a trialist and an evidence based person. So we have studied is things as you mentioned with lipid matrix like mcts probably that's probably going to. So if you're taking sort of a keto diet perhaps probably that would result in improved absorption. A lot of folks are taking high protein. High protein does seem to have a very sort of in, not in terms of enhancing but a protective effect around the molecules. So we when we give it with high protein shakes or things like high protein yogurts, we do see a bit slightly better sort of absorption of the molecule. And that could mean that it blends well with things like you know, branch and amino acids like leucine, isoleucine. So those would be my top two things to stack with. And as, as we mentioned, other mitochondrial optimizers probably are addictive as well. Things like Coq 10.

Yeah, I'm personally a bigger fan of essential amino acids than branched chain amino acids, which I think are kind of like overpriced flavored water because you just have the isoleucine, the leucine and the valine. I like the essentials because you get all nine of the amino acids.

Yep.

And I haven't done much experimentation. I've tried putting it in whey protein. You know what's funny is I haven't actually used your guys' whey protein, but I've used The kion protein before and combine that with urolithin A based on some of what you were explained explaining about it, seeming to perform pretty well when combined with protein. But your guys's whey protein, is that, is that something that you're just adding the urolithin to and just pure whey protein with urolithin?

Yeah, that's the blend with the whey protein. And we are developing alternative protein shakes as well as we speak. We are even running a head to head trial in sort of individuals who are immobilized. So think of an athlete who's got injured and we're giving them 20 grams of high protein supplementation, seeing the effect it has on muscle and comparing them to, you know, how, how it will be in that particular population if you were to supplement with high protein and the bioenergetic aspect with your lithium A. So we do think there's synergy in the two ideas to boost muscle mass and muscle quality and energetics.

Interesting. What else are you guys studying up right now at timeline because you have the transdermal products, the protein, the soft gel, the stick packets. What else are you looking at right now, if anything?

So I'm a trained immunologist and, and I do believe there's big impacts of the molecule on the immune, immune system. And so we, we have pretty good evidence already. But of course, you know, since the, the big discovery of the molecule about a decade back when we made and published our first papers, a lot of other top labs around the world have got interested into studying its effects on cognitive health. So I would put probably these two are the most at the top and getting in gut health because so much of it is getting absorbed in the gut that it must have and there are some top obligations. But for, for, for the time being, the trials we are running, one is in post cancer patients. So typically, let's say cancer patients have kind of cured themselves of cancer. After chemo and radiotherapy, they basically end up with also no immune system because the chemo and radio is hitting their functional healthy cells too. And so we are trying to see if we can rev up mitophagy in the stem cells that seed the immune system and that will lead to a better seeding of the immune system because stem cells get exhausted in this kind of both aging and post cancer. So that's one of the areas we're working and then we are working with National Institute of Aging on really looking at the impacts on cognitive health and how we can boost brain energetics with the molecule.

Do you think it would have any type of protective effect on stem cells? Let's ask because a lot of my listeners, they'll go out and do stem cell injections and I always advise against flying on an airplane for a couple of days after and engaging in some strategies to enhance stem cells help like, you know, PEMF and antioxidant rich diet, avoidance of vegetable oils, alcohols, all the things you do. If you had little tiny, fragile baby newborn cells floating around in your body. As far as urolithin a goes, do you think it would support or protect stem cells somehow in that type of context?

Yeah, I do believe absolutely. So there's a great paper we put out end of last year in, in probably the top immunology journal called Immunity and the data is pretty remarkable that it targets this sort of pool of stem cells that is always, you know, in our bone marrows, in all the organs where the immune cells and the stem cells are sort of, sort of hanging out and they're activating mitophagy in these pool of stem cells really resulted in better sort of receding of the immune system, you know, kind of even better muscle stem cells. So we do things. So we are studying, we have a lot of trials actually studying what you were just mentioning, the impact on stem cells.

Yeah, that's interesting. It's good to know. Maybe I'll throw it in my bag for my next, my next stem cell protocol and load up with it. You know, related to this concept of mitophagy, Dr. Singh, you know, there's a lot of people developing senolytics to prevent the accumulation of these so called zombie or senescent cells. But the idea is that quieting those senescent cells, particularly early in age when someone is going through growth phases, production of growth hormone, you know, higher amounts of anabolic type of activity that could be hampered by quieting cellular senescence. Too much dictates that you wouldn't want to overdo a senolytic compound and possibly even not do a lot of senolytics early on in life. When it comes to mitophagy, is it also like that? Like, is there a law of diminishing returns and you know, excessively turning over mitochondria and related to that, you know, an age at which that type of approach might not be advisable?

I don't think so. So, so basically the process of mitophagy is when mitochondria get stress and really damaged, they put out an eat me signal. So if this is A mitochondria, it puts out an eat me signal on the top of it its surface. And that's what basically when people are activating mitophagy through either URLs name or exercise or other things, that's what is those tagged mitochondria that get then put in the sort of garbage disposal machinery and then these become the building blocks of healthy new mitochondria. And that's a fundamental important thing to know is that you can overdo mitophagy. You can. Our cells are always in what I call mitoharmosis. So there's always a balance between good and sort of the yin and yang. So you will always just take those faulty tag mitochondria and then put them into more healthy mitochondria. Now, you know, mitophagy is always happening in sort of the. It just slows down with aging. It slows down with a lot of other things like prolonged immobilization. But we haven't really thought that over stimulating mitophagy. We haven't really seen that. I think it's more as what I call a modulator of mitochondria than approach than sort of overstimulating mitochondria.

Yeah, I've always wondered if the body will have a natural modulation mechanism to where mitophagy supporting compounds can present would not result in, let's say excess mitochondrial turnover just based on natural modulation. Although I don't know what the mechanism of action for that would be. The idea seems reasonable at least and I'm curious based on that kind of back to your blood levels of URL with an A. And this blood. By the way, where do you get that blood spot test kit? Do you guys mail it out from timeline?

No. So we are still prototyping it and there's a clinical study that I'm running with hundreds of folks just to make sure that, you know, we have the, the sort of the right test before we launch it. But happy, if you want to participate, we can send you a kit to some of your listeners if they are intrigued as well.

Yeah, that'd be interesting to test. I'd love to test based on what I was saying earlier. So yeah, I'll, I'll hunt that down and link in the show notes if you, if you send me over more information on it. And again, the show notes are Ben Greenfield BenGreenfieldLife.com timeline podcast but the reason I ask is have you compared what gets your urolithin A levels highest? The little soft gel that you guys make the stick packet or the whey protein. Have you broken that out at all?

So, so we have put them in those different matrices because we think all those different matrix help in the absorption. So we have studied, for example, independently the soft gels in a lot of trials and also studied the berry powder or now we're studying the protein shake. And I would say within a 10 percentile difference, they all in the similar levels of boosting, as I'm mentioning, to the therapeutic range of 300, 500, and some people even more depending on the dosing they're taking. So I think they're fairly equivalent, I would say.

Okay, have we not touched on any benefits or research that you're aware of about urolithin A that you think that would be important for people to know?

There's a lot of excitement, as you mentioned. We of course started doing the research 15 years back, but now I was approached by the National Institute of Aging that said, hey, we ran a library of thousands of natural compounds and repurposed drugs trying to study the best effects on neuron cells where typically in things like Alzheimer's disease, mitophagy declines. It's well known in neuron cells. And we think your compound is really one of the top inducers and really is neuroprotective. And so I think a lot of excitement now will come from these top professors. And Harvard has the same sort of research stream that I was told about. So I think that is the next big frontier. What are the levels that we can see in the brain getting into this molecule? If we can image sort of the ATP levels within six hours of peaking and look at brain energetic capacity, this is where I, I think a lot of research is headed now.

Interesting, you know, related to the brain. A lot of people take nootropics, they take smart drugs, they'll pop methylene blue, do red light therapy, do a lot of things that apparently increase activity of some of those cytochrome C oxidase pathways in mitochondria, resulting in enhanced production of ATP, mitochondrial biogenesis, et cetera. I'm curious if you've ever thought about or if you know anything about the idea of, well, if I'm making my mitochondria work harder, produce more energy, make more of them. If combining urolithin A with things like smart drugs, nootropics, some of these mitochondrial enhancing agents, in terms of things that kind of like push the gas pedal harder would be a good idea. Have you ever looked at that?

We haven't, but I do think it's a good idea and something we are exploring in the background. I, I do think there is potential in that to even combine it with certain amount of, for example even ketone bodies or ketone esters just to induce sort of better cognitive effects together where you can recycle the poor mitochondria neurons and then give them a sort of a alternative fuel supply to, to, to rewire them. So we are looking into that.

Yeah, I've come, I've kind of discovered the same thing. If I take DHA and choline to replenish a lot of nutrients that I'm burning through more quickly than ketone esters and NAD on any cognitively demanding day on which I might also be using, let's say, you know, methylene blue or psilocybin microdosing or some type of, of nootropic agent like you know, quality of mind or some of these newtopia products or something like that. I find that stacking choline, dhea, NAD and ketone esters to just blast through, let's say like a 16 hour creativity slash focus workday with some of these nutrients on board seems to help. But I haven't really brought in something like a mitophagy enhancing agent into that equation. It'd be interesting to experiment with.

Sure. Yeah. I think future research is headed that way.

Yeah. Well, this is fascinating, man. I really appreciate the research that you've done on your lithium A and with timeline. I, I know we have, we have discounts and codes and things like that for timeline. I'll hunt them down and put them in the show notes@bengreenfieldlife.com timeline podcast. That's BenGreenfieldLife.com timeline podcast. And over there if you'd like, you can also leave follow up questions, comments, feedback, etc. For Dr. Singh or myself. And we'd be happy to jump in and help reply and point you in the right direction. But in the meantime, Dr. Singh, I really appreciate you filling me in on all my silly questions about urolith and a because I've been fascinated by this for a while and kind of looking forward to getting you on the show and asking all these questions.

They're all great questions. So love chatting with you Ben.

Awesome. Awesome. Well, I'm excited to put this out. And folks, again the shownotes are at BenGreenfieldLife.com TimelinePodcast and until next time, I'm Ben Greenfield along with Dr. Anurag Singh signing out from BenGreenfieldLife.com have an amazing week.

More than ever these days, people like you and me need a fresh, entertaining, well informed and often outside the box approach to discovering the health and happiness and hope that we all crave. So I hope I've been able to do that for you on on this episode today. And if you liked it, or if you love what I'm up to, then please leave me a review on your preferred podcast listening channel, wherever that might be, and just find the Ben Greenfield Life episode. Say something nice. Thanks so much.

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