Everything You Need To Know About Urolithin A

Dr. Anurag Singh joins Ben Greenfield to discuss Urolithin A, the molecule that supercharges your mitochondria, turning back the clock on aging.

Podcast

Ben Greenfield Life

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Unveiling the newly studied molecule that supercharges your mitochondria, turns back the clock on aging, and battles sleep deprivation from Timeline Nutrition.

Topics covered

  • What makes Urolithin A interesting for longevity
  • What is Urolithin A
  • The health benefits of supplementing with Urolithin A
  • How does Urolithin A work in the body
  • Safety and efficacy of Urolithin A
  • Urolithin A from diet vs supplementation
  • The topical benefits of Urolithin A on skin health
  • Dr. Singh’s daily longevity strategies
  • Protocol for supporting workout activities with Urolithin A
  • What to stack with Urolithin A for longevity
  • Exciting Urolithin A clinical studies underway
  • Impact of Urolithin A on brain health
Transcript
Ben Greenfield
My name is Ben Greenfield. On this episode of the Ben Greenfield Life Podcast…
Dr. Anurag Singh
The five best ways to improve mitochondria function, if I have to put a priority list, one would be regular physical activity. Try to do your 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. Big impact of stress on circadian rhythms and how it impacts mitochondrial health.
Dr. Anurag Singh
Sleep, another big aspect that has a big impact on mitochondrial function at your cellular level. Then the fifth is what I would say advanced nutritional supplementation, things like Urolithin A, as we were chatting with, or even hitting on some other well-known autophagy boosters. You mentioned spermidine as one. You mentioned other ways to boost autophagy. There's no one magic trick. It's really a concert with different tactics that you need to apply.
Ben Greenfield
Faith, family, fitness, health, performance, nutrition, longevity, ancestral living, biohacking, and a whole lot more. Welcome to the show. Summer. I feel like that snowman out of Frozen. Summer. It brings warmth and sunshine and mud puddles and energizing opportunities to reconnect and move and play and a fair amount of sweat. Sweat, sweat, sweat. That dilutes you. It gets minerals out of your bloodstream and that can lead to headaches and poor sleep and all sorts of nasty effects. Drinking water helps, especially mineral-rich water, but you need the right fluid to electrolyte balance and that's a science. When I get that science right, I feel amazing, especially on hard workout days.
Ben Greenfield
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Ben Greenfield
Well, folks, you've probably heard me talking before about something called Urolithin A. You can find it in things like pomegranate and walnuts and raspberries. My guest on today's show might know some other fringe sources of it. But it seems to be becoming one of these darlings of the age reversal and healthy aging community right up there with the things you hear people talking about like NAD and C60 and astaxanthin and spermidine and fish oil and peptides and stem cells.
Ben Greenfield
People are talking about Urolithin A now, but I've never really unpacked in detail on a podcast what it is. Because there are some subtle nuances in terms of its sources, its bioavailability, its dosing, the research behind it, and it's such a popular supplement. 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.
Ben Greenfield
I found a guy who knows a lot about Urolithin A. His name, and I hope I don't butcher your name, Dr. Singh, because I got the last name, S-I-N-G-H, but is it Anurag? Is that how you pronounce your first name?
Dr. Anurag Singh
Yeah, you got it correct. You can call me Dr. Singh.
Ben Greenfield
Nailed it. All right, we'll go with Dr. Singh. For everybody listening in, Dr. Singh is an M.D., in internal medicine, but he also has a PhD in immunology. He's a total underachiever. He has worked with a bunch of different food companies, including Nestlé, and different startups, including one startup called Timeline, which has done a lot of this research and development of Urolithin A.
Dr. Anurag Singh
They actually claim, Timeline does, that Urolithin A is backed by about 15 years of clinical research. We'll 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, I'm now taking as a supplement, but I've never really done a deep dive into it. This is going to be fun to get into Urolithin A. You're ready to talk all things urolithin, Dr. Singh?
Dr. Anurag Singh
Sure. I'd love to share it with the audience.
Ben Greenfield
Cool. What got you interested in it in the first place?
Dr. Anurag Singh
Well, I'm trained as an internal medicine doctor. For long, I was practicing, as they call modern medicine. I realized basically that a lot of times when we were seeing people with different chronic conditions, it was too late in the trajectory of health function and health dysfunction to intervene. I started working with a lot of natural compounds as I was training to be a physician scientist. From there, the interest grew and we started looking at bringing the biotech approach to nutrition and stumbled upon Urolithin A, and it's a really great area of health benefits.
Ben Greenfield
Besides having a really weird name, what exactly is Urolithin A?
Dr. Anurag Singh
Sure. It's a metabolite found from… We all know the good foods that we eat, things like pomegranate, walnuts, pecans, raspberries, all those red and blue looking stuff that we have for long, say it packs a lot of antioxidants. Well, it does. 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 Urolithin A. It's basically a food metabolite.
Ben Greenfield
What does that mean, the gut releases a metabolite? Would that mean the bacteria that are already in your gut would consume these foods or ferment these foods and produce some kind of… I think it's called a postbiotic compound. Is that how it's working? What exactly is conversion here that's going on?
Dr. Anurag Singh
These antioxidants or polyphenols are very complex aromatic compounds. When you digest or you're taking a glass of juice or a bowl of berries, your gut microflora basically will digest them and break them down into smaller molecules that are more digestible and more well absorbed and have health benefits for the host. 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.
Ben Greenfield
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 vary the conversion efficiency based on my unique biome? Because you got companies now out there, probably biome is one of the most popular. I know Genova Diagnostics has a test for this, but they'll tell you the genetic composition of all the bacteria in your gut. I'm curious if there's a way to know your potential for Urolithin A production based on something like that.
Dr. Anurag Singh
Sure. Basically, we have done a number of clinical trials all around the world. We've got into French adult population, we've got into the Americans, the Canadians, name it. Basically, the best producers are the French, so they must be eating closer to the Mediterranean diet rich in, 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.
Dr. Anurag Singh
We do see about 30, 40% people in healthy adult population that have the correct gut microbiome. 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%. Even those who would make it would make a very variable range. In most cases, it will be what I call suboptimal ranges that are hardly going to give you a health benefit.
Dr. Anurag Singh
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 Urolithin A, as an example.
Ben Greenfield
That's interesting. 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 is it looking at Urolithin A presence in the blood, or what exactly are you looking at?
Dr. Anurag Singh
It's exactly looking at the presence of Urolithin A in the blood that you are probably exposed from diet. It's a very precise test that we have developed. The end goal of that whole thought of developing the test was basically, this molecule, this postbiotic, is the natural way for the body that exists. 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 Urolithin A, but a lot of us don't.
Dr. Anurag Singh
The test you were mentioning that other companies such as Viome or others have, will tell you your microbiome spread, whether it's favorable, whether it's rich and diverse. We've actually done studies where we have looked at people who naturally produce it and what's their gut microbiome look like, and those who don't produce, such as me. The answer really lies in the complex gut microbiome, that is you have to have a very rich and diverse gut microbiome. You could do that analysis. But I think with our end functional output, which is Urolithin A, we can tell you if your body is making the end product or not.
Ben Greenfield
It sounds to me like you could skip a lot of the hassle with doing a full biome test of the gut if you can simply test your blood, if you're already on a supplement that contains Urolithin A, or I guess perhaps 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 know.
Ben Greenfield
But I'm just curious, do you think it's more that some people don't have the genetics from a whole genome standpoint to produce Urolithin A? Or do you think that these Americans, for example, who you mentioned are 10-20% 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?
Dr. Anurag Singh
I think actually it's more diet and environmental related and what exposure you have. For example, I trained, I grew up in India. A lot of antibiotic usage early on for everything. There's a big practice to give antibiotics. My gut microbiome just basically, I think, was destroyed forever. 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, they probably are getting the exposure to decent levels naturally.
Ben Greenfield
Okay, got it. Would there be any advantage, and I realize this is probably a question that you might be biased about working for a company that makes a product that supports Urolithin A production. But 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 food so you have the bacteria to produce the urolithin of adding more? Where's the benefit in supplementing with more? Have you guys dug into the research behind that?
Dr. Anurag Singh
Yeah, we have. I do work for a company, but before I'm trained as a medical doctor, and I always say diet and exercise are the two pillars of your key health to longevity. Yes, I think if you can know that your body is producing enough Urolithin A, then you don't probably need to take a higher dose. You can probably just go on a maintenance dose and things like this. As you know, not everybody is juicing four to eight pomegranates every day to drink a glass or two glasses of pomegranate every day and then-
Ben Greenfield
That sounds exhausting.
Dr. Anurag Singh
You get the sugar exposure. A glass of juice is about 30 grams of sugar. Yes, people should eat raspberries and pecans and walnuts and other good sources, and if their body is producing Urolithin A, then that's why we developed this test. They can actually 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. Things like vitamin C. We all know orange juice is good for you. It has a lot of vitamin C, yet a lot of people take vitamin C supplementation. That's the way I look at it.
Ben Greenfield
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 fruit just containing foods, etc, which I know in the low carb community is a thing. But a nerdy question, I suppose. But let's say I were to 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?
Dr. Anurag Singh
We've looked quite deeply both into the microbiome and exhaustively into the blood levels, both from, let's say, natural dietary exposure and with increasing doses of direct supplementation. We've published these in really top journals like Nature Metabolism. We start seeing really big effects in different human randomized clinical trial settings at about 500 milligrams. This compound hits your mitochondria and rewires them from being poor-looking mitochondria to healthy mitochondria. We can tell that difference in four weeks through blood biomarkers, etc.
Dr. Anurag Singh
But really, the functional benefits, you start seeing in about two months of supplementation. We do see levels between, let's say, 10-100 nanograms per volume of plasma that we can measure it, would be the dietary exposure. About 2%-5% people do have higher than that. With direct supplementation, you can't consistently reach that. 100 would be the lower limit, and you'll always get an average about 300-400, which there's a concept called a therapeutic range that we call in medicine. You always need to have enough exposure to the molecule and sufficient doses to have the health output. That's what I believe you always need to maintain your blood levels at.
Ben Greenfield
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 500 milligrams of daily supplementation being something that elicited a lot of these performance and recovery-enhancing effects. I even saw some, particularly in the muscle endurance and performance realm, albeit I think it was with finger contractions and in human models, which might not translate directly to Ironman Triathlon or something like that, but they were up around 1,000 milligrams as far as the daily dosage goes. 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 an action mechanistic standpoint in the body?
Dr. Anurag Singh
Great question. You touched upon it. You talked about NAD, you talked about CoQ10. They are mitochondrial boosters out there. Think about the life cycle of a mitochondria. Always our cells, typically highly energetic cells, like your skeletal muscle, which is always moving, which is always climbing stairs, or a neuron cell which is always active. These are cell types that have thousands of mitochondria, so they have a very high, basically metabolic demand.
Dr. Anurag Singh
There's always a flux of healthy and poor healthy or bad functioning mitochondria. But what happens is in the life cycle, healthy mitochondria accumulates what we call as oxidative stress, becomes damaged, and then over time it becomes really crummy.
Dr. Anurag Singh
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. If you're not cleaning those faulty mitochondria, think of 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. That's exactly what happens in muscle cells and neurons, cells and hard cells with aging or obesity, for example. They just accumulate a lot of their mitochondria.
Dr. Anurag Singh
You could do an NAD supplementation, which is targeting what we call mitochondrial biogenesis of trying grow more healthy mitochondria, or you could do things like CoQ10 or L-carnitine, which is just taking the pool of functioning mitochondria and trying to make them make more energy.
Dr. Anurag Singh
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 a garbage disposal. 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.
Ben Greenfield
Okay. Got it. 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. Does mitophagy result in greater amounts of mitochondrial density or number of mitochondria? Is it impacting simply the quality of the already existing mitochondria? What exactly is going on there?
Dr. Anurag Singh
It's doing actually both. We do see higher mitochondrial abundance just because you're creating, as a result of mitophagy, you will clean the waste out and you will see things impacting mitochondria biogenesis, so you will have more abundance of healthier mitochondria. But what you do see is mitochondrial quality go up big time. 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.
Ben Greenfield
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 Urolithin A consumption?
Dr. Anurag Singh
Yeah. We have run a number of randomized control trials, placebo control trials. We've run it in older adults, about 65, 70-year-olds. We've compared those even doing a 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 Urolithin A.
Dr. Anurag Singh
We've able to see basically a similar exercise in my medic like a impact on mitochondrial and cellular health. Then we have gone into longer duration trials in, for example, 40, 50-year-olds and even older adults again. And really seeing that, I think you mentioned some of the results on the hand contraction. Believe it or not, one of the first muscles that declines with aging is this one.
Dr. Anurag Singh
Your grip strength basically is the first loss. That's why they say handshake goes a long way to predicting your longevity. It's basically that. We have seen not just hand grip strength improve, but even leg endurance improve. Then we have put people on our ergometer and seen that they basically have a resistance to fatigue 20% more. They walk more.
Dr. Anurag Singh
Let's say if you do a standardized walking test… Most importantly, you can measure it with a very simple test like PPO2. For example, those are 10% in the non-trained population. These are some of the effects we have seen. In addition, we have seen also some of the inflammation markers. 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. What we see is actually down the road with longer grams supplementation, even other benefits coming out.
Ben Greenfield
Interesting. Up to 1,000 milligrams or so, you can see even greater benefits from a performance standpoint? Some of the research study I found.
Dr. Anurag Singh
Yeah. That's exactly what we are seeing now.
Ben Greenfield
Any side effects? I'm curious, if this is causing a shift in the gut bacteria in terms of their postbiotic production. 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, I believe, a softgel that contains some of these Urolithin A precursors. But if you take it, do you ever notice anything like gut side effects or any other side effects from a higher amount of Urolithin A consumption?
Dr. Anurag Singh
That's a great question. What safety? 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 read it with even the FDA through a process called as GRAS, which stands for generally regarded as safe. 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. In the humans, of course, we've done, gosh, about thousands of folks who have been in randomized trials by now.
Dr. Anurag Singh
Really, this is a natural molecule. 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 in the wild with berries and nuts, we were all probably exposed to it. It's a very safe molecule. We haven't really seen any product-related adverse effects.
Dr. Anurag Singh
Now, certain people may have some allergenicity. For example, a lot of people when they take the rice-based or the berry-based product, may have some sensitivities to food ingredients. But as a compound, as a pure natural compound, it's very safe.
Ben Greenfield
Now, based on the gut thing, I'm curious, 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 seed symbiotic is one that I think I've seen that type of claim on for the Urolithin A production. What's the difference between your product and a product that would be more of a bacterial-based Urolithin A support?
Dr. Anurag Singh
I just think it's an indirect way. For example, I've been running clinical trials in the nutrition investor for 20 years. I started actually a lot of trials that you can probably pick up and probiotics are probably trials that I ran about a decade back.
Dr. Anurag Singh
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. It's never one bacterial strain or two bacterial strains attend. It's really the whole ecosystem needs to be there.
Dr. Anurag Singh
As I said, if you can induce Urolithin 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 precise and that will lead to a lot of variability in not just human clinical trial settings, but in real life. With direct calibrated supplementation of 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.
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Ben Greenfield
I need to actually try this blood spot test that you mentioned because I tell 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. It'd be interesting to actually test my levels both with and without the seed and then with and without the Urolithin A just to see.
Ben Greenfield
Because I would imagine, I don't know what you think about this, but it seems to me like you could potentially do both; 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 the pecans, etc. Have you ever thought about that?
Dr. Anurag Singh
Yeah, I agree. 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. Then at the base of this is the third pillar, which is really adding on very advanced calibrated supplementation that is boosting your cellular health and will help better nutrient absorption, for example, or better cellular health that even you will have better, a bit of effect. I do think there's merit into doing a complementary approach.
Ben Greenfield
You say advanced supplementation. How is Timeline's product any different? 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?
Dr. Anurag Singh
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. It absorbs well in lipid medium-chain triglyceride matrices. We have put it in softgels that are rich in these MCTs, and that helps even enhance the bioavailability of this natural molecule. And of course, we have proprietary ways to manufacture it from scratch.
Dr. Anurag Singh
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 at very high quality.
Ben Greenfield
Okay, that's interesting. Arguably, taking it with lipids would be better. If I were to take it with fish oil in the morning, or if I were to have other fats like coconut milk or something like that in my morning smoothie, that's going to enhance the bio-availability?
Dr. Anurag Singh
Yeah. We've done even a head-to-head with… It needs a food matrix protection. You've done a trial with mixing it with high protein Skyr like yogurt. Icelandic yogurt is very rich in whey protein and branching amino acids. That gives it a better effect in protecting and the digestion of it. That's one of the reasons why we blended it with the whey protein.
Dr. Anurag Singh
If you mix it and blend it with the fiber, it also helps. But all the trials actually have mostly been run with the MCT formulation and softgel. I do think that gives it an edge in terms of a little enhanced absorption.
Ben Greenfield
Okay. Got it. Now, what about the transdermal part of things? I noticed that you guys have a skin product. You send me a day motion and a night time cream. Is that actual urolithin being applied to the skin?
Dr. Anurag Singh
Yeah, it is. For long, when I would go to top conferences and presented top medical conferences, the first question everybody would ask me, "Well, what will I feel? How do I measure mitochondrial health?" I would say, "Well, you would measure subjectively because you'll feel more energy, you'll feel less fatigue. If you really want to test it out, you'll measure your V02 max. And by going into a special lab that can put you on a treadmill and hook you up with all kinds of measuring instrumentation."
Dr. Anurag Singh
People say, "Well, but what was my first thing? Will I see it in the mirror that I'm aging less?" I said, "Well, this is not a youth in a pill or exercise in a pill. This is improving, hitting many of the pathways that are important for our cellular health and recycling."
Dr. Anurag Singh
Those questions also triggered, "Well, what will it do?" It's just not the muscle cells that are abundant in mitochondria. Our skin cells have a lot of mitochondria. Our immune cells have a lot of mitochondria. We started looking in these different verticals and really seeing if Urolithin A, 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. That led to formulations in day creams and night creams.
Dr. Anurag Singh
Now we have just run many randomized trials, again, that we are trying to publish in JAMA with the skin formulation. What we see is basically improved cellular energy and less inflammation in the skin, which is practically what happens when we grow old is because of sun exposure, our skin gets inflamed and wrinkles start appearing. We thought skin aging goes in parallel with longevity. Now we have products that it's skin longevity.
Ben Greenfield
That's interesting. You see a difference between oral consumption and the effect that would have on the skin versus direct transdermal application?
Dr. Anurag Singh
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 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.
Dr. Anurag Singh
Probably all of it is not going to the skin. We thought, "Well, if we could do something synergistic and additive by applying direct, very calibrated so that we're giving a 1% Urolithin A and MitoPure in these topical products." We know it penetrates well in the skin and it hits a lot of the skin cells similar to the muscle.
Ben Greenfield
That's super interesting. By the way, I'll link to this stuff if you go to bengreenfieldlife.com/timelinepodcast, because like I mentioned, they have a stick pack and a gel cap and the protein powder. Then they also have these transdermal applications, so a lot of different delivery mechanisms for this Urolithin A.
Ben Greenfield
But there's so many other things out there. Dr. Singh, in the introduction, and then you alluded to it, I mentioned NiD, and C60 in fish oil, and astaxanthin, and all these other compounds. I recently interviewed Bryan Johnson, who I think he says he takes 120 different supplements when he gets up in the morning. He runs that Blueprint age reversal website.
Ben Greenfield
I'm curious for you because it seems like you have your ear to the ground for a lot of this stuff. Are there other compounds that you think would appropriately fall into an age reversal supplementation strategy that might go above and beyond urolithin? If so, have you been particularly impressed with what you've seen on any of these?
Dr. Anurag Singh
Well, I think there's promise in the NAD field quite a bit. But I do think that there's untapped synergy out there by combining. A lot of people just blend and stuff. The problem with the nutrition field is, "Oh, let's blend X, Y, Z and hope miracle happens." I think there's a lot of interactions between molecules, and so one needs to study that.
Dr. Anurag Singh
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. I do think there's merit in all these molecules, vitamin B3, nicotinamide mononucleotide, or NMN that are known to be biogenesis boosters.
Dr. Anurag Singh
I like CoQ10, even though the literature is mixed because it's a molecule skill that directly goes into mitochondria and is important in the whole energy metabolism pathway. That improves the efficiency of whatever healthy pool of mitochondria you have. Then I think just the two best drugs ever developed to improve autophagy, mitophagy, or regular exercise and intermittent fasting. If people do want to boost autophagy and mitophagy, that's one additive way to do it. That's what I do practice also intermittent fasting myself.
Ben Greenfield
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.
Ben Greenfield
I like some of these autophagy or mitophagy agents that particularly for lean, active people, premenopausal females, etc, 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. 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.
Ben Greenfield
I'm curious for you, it sounds like you incorporate some of this stuff into your lifestyle. 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?
Dr. Anurag Singh
Well, I always say that probably the five best ways to improve mitochondrial function, if I have to put a priority list, first would be regular physical activity. Try to do your 8,000, 10,000 steps a day. Number two, 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. Big impact of stress on circadian rhythms and how it impacts mitochondrial health.
Dr. Anurag Singh
Sleep, another big aspect that has a big impact on the mitochondrial function at your cellular level. Then the fifth is what I would say advanced nutritional supplementation, things like your Urolithin A, as we are chatting with, or even heading on some other well-known autophagy boosters. You mentioned spermidine as one. You mentioned other ways to boost autophagy. There's no one magic trick. It's really a concert with different tactics that you need to apply.
Ben Greenfield
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?
Dr. Anurag Singh
I stop looking at my phone screen as I leave work and I play with my kids and that relaxes me. I go to bed around 10:30, 11:00. Everybody is different when it comes to sleep. Honestly, myself, I was trained as a medical guy, so I'm used to doing more with less sleep. I just need about 6-7 hours of sleep. But I think exercise, when there were days when I do a 5 or 10K, I sleep the best.
Dr. Anurag Singh
I do sit and think that even with things like Urolithin A and NID supplementation, there is literature coming out that things have the potential to hit on some of the circadian rhythm through bionic energetic modulation and results in better sleep cycles and people have more wakefulness early on. Needs to be studied further.
Ben Greenfield
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 hefty or like NAD oral dosage or a transdermal patch of NAD. I get it from a company called IonLayer when I need more NAD, or if I'm doing long haul flight and want to combat some of the DNA damage.
Dr. Anurag Singh
Oh, sure.
Ben Greenfield
Then creatine seems to act similarly, just a slightly higher dose of creatine. I usually take five grams. If I'm sleep deprived, I'll bump that up to about six to eight grams. What about Urolithin A? Have you noticed that that seems to have any type of effect, either anecdotally or from a research-based standpoint on the sleep deprivation?
Dr. Anurag Singh
Yeah, we haven't run any randomized trials yet. There are some in the works. But anecdotally, we've heard people making a fresh… They feel like they wake up early and they are much more fresher early in the morning. But again, this is anecdotal. A lot of our studies are now gearing up to… We've done a lot of studies, clinical trials in older adults and overweight middle-age adults.
Dr. Anurag Singh
A lot of our new clinical research is moving towards more healthy… There's a study, for example, we are just doing in 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. We are even in the works discussing to do a trial with the elite army professionals of the Green Berets that have both the cognitive decline with stress and hypoxia and the physical demand. We're 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.
Ben Greenfield
Yeah. For sleep deprivation, I noted that 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. I would imagine Urolithin A might be similar. Maybe take 1,000 milligrams or something on a sleep-deprived day and bump up your dosage when you first get up. I'm actually going to experiment with that now that I know and I'm aware of its effects on that.
Ben Greenfield
But what about for something like a workout? I know a lot of these studies have looked into performance, but what's the dosing? Well, we talk about the dosing, 500 to up to 1,000 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?
Dr. Anurag Singh
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. It really peaks in your blood about 6-8 hours after you've taken it. Most of our trials are done giving to individuals in the fasting state in the morning with or without breakfast. That would be about, let's say, seven, eight o'clock in the morning. It would start peaking, let's say, midday, mid-afternoon.
Dr. Anurag Singh
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. It will peak at 6-8 hours and then we'll start dipping down and go below what I call subtherapeutic or suboptimal levels of exposure to the molecule. You would need to then again take it the next day or bump it up even 12 lives after.
Dr. Anurag Singh
A lot of the recovery work is with a gram. I was just telling you about the study in athletes that was only focused on recovery. 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 training in extreme conditions. What we are seeing in some of this early data that is coming out is profound effects on recovery and muscle damage. I do think that even in these settings, recovery will be boosted in these populations with this molecule in acute way. During training or post-workout would probably make more sense to take it.
Ben Greenfield
Got it. When you look at creatine post-workout, co-administrating with caffeine seems to increase absorption a little bit. We talked about with your Urolithin A, how co-administration with either lipids or perhaps even some type of a ferment or probiotic might enhance the effects.
Ben Greenfield
But are there any other things? A lot of my listeners like the stack stuff or know what combines best with what. Have you looked in any research, or even just anecdotally yourself, looked into stacks, things that would go well when paired with your Urolithin A to either enhance bioavailability or enhance the mitophagy effect or anything else as far as upgrading the Urolithin A that you actually take?
Dr. Anurag Singh
I know that there's this bio-optimization with stacks and taking a few things and then building on top of in the protocol that people follow. I'm a trialist and an evidence-based person. We have studied things, as you mentioned, the lipid matrix, like MCTs probably, that's probably going to… If you are taking a keto diet, perhaps, probably that would result in improved absorption.
Dr. Anurag Singh
A lot of folks are taking high protein. High protein does seem to have a very, not in terms of enhancing, but protective effect around the molecule. When we give it with high protein shakes or things like high protein yogurt, we do see a bit slightly better absorption of the molecule. That could mean that it blends well with things like branch and amino acids like leucine, isoleucine. Those would be my top two things to stack with. As we mentioned, other mitochondrial optimizers probably are additive as well, things like CoQ10.
Ben Greenfield
I'm personally a bigger fan of essential amino acids than branched-chain amino acids, which I think are 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. I haven't done much experimentation. I've tried putting it in whey protein.
Ben Greenfield
You know what's funny is I haven't actually used your guys' whey protein, but I've used the Kyan protein before and combined that with the Urolithin A based on some of what you were explaining about. It seemed to perform pretty well when combined with protein. But your guys' whey protein, is that something that you're just adding the urolithin to and it's just pure whey protein with urolithin?
Dr. Anurag Singh
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 individuals who are immobilized. 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 how it will be in that particular population if you were to supplement with high protein and the bioenergetic aspect with Urolithin A. We do think there's synergy in the two ideas to boost muscle mass and muscle quality and energetics.
Ben Greenfield
Interesting. What else are you guys studying up right now at Timeline? Because you got the transdermal products, the protein, the softgel, the stick packets. What else are you looking at right now, if anything?
Dr. Anurag Singh
I'm a trained immunologist and I do believe there's big impacts of the molecule in the immune system. We have pretty good evidence already. But of course, since 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 and cognitive health.
Dr. Anurag Singh
I would put probably these two are the most at the top and gut health because so much of it is getting absorbed in the guts that it must have. They are some top obligation. But for the time being, the trials we are running, one is in post-cancer patients. Typically, let's say cancer patients have secured themselves with 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.
Dr. Anurag Singh
We're trying to see if we can ramp 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 both aging and post-cancer. That's one of the areas we're working. Then we're working with National Institute on Aging on really looking at the impacts on cognitive health and how we can boost brain energetics with the molecule.
Ben Greenfield
Do you think it would have any type of protective effect on stem cells? I just ask because a lot of my listeners, they'll go out and do stem cell injections. I always advise against flying on an airplane for a couple of days after and engaging in some strategies to enhance stem cells health, like PEMF and antioxidant-rich diet, avoidance of vegetable oils, alcohol, all the things you'd 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?
Dr. Anurag Singh
Yeah, I do believe. Absolutely. There's a great paper we put out last year in probably the top immunology journal called Immunity. The data is pretty remarkable that it targets this pool of stem cells that is always in our bone marrow and all the organs where the immune cells and the stem cells are hanging out. Activating mitophagy in these pool of stem cells, really resulted in better seeding of the immune system, even better muscle stem cells. We do things, we are studying. We have a lot of trials actually studying what you were just mentioning, the impact on stem cells.
Ben Greenfield
That's interesting. It's good to know. Maybe I'll throw up my bag for my next stem cell protocol and load up with it. Related to this concept of mitophagy, Dr. Singh, there's a lot of people developing senolytics to prevent the accumulation of these so-called zombie or senescent cells.
Ben Greenfield
But the idea is that quieting those senescent cells, particularly early in age when someone is going through growth phases, production of growth hormone, 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? Is there a law of diminishing returns and excessively turning over mitochondria? Related to that, an age which that type of approach might not be advisable?
Dr. Anurag Singh
I don't think so. Basically, the process of mitophagy is when mitochondria get stressed and really damaged, they put out a eat-me signal. This is a mitochondrion. It puts out a eat-me signal on the top of its surface. That's what basically when people are activating mitophagy through either Urolithin A or exercise or other things. It's those tagged mitochondria that get then put in the garbage disposal machinery. Then these become the building blocks of healthy new mitochondria.
Dr. Anurag Singh
That's a fundamental important thing to know, is that you can't overdo mitophagy. Our cells are always in what I call mitohormesis. There's always a balance between good and the yin and yang. You will always just take those faulty tagged mitochondria and then put them into more healthy mitochondria.
Dr. Anurag Singh
My topic is always happening in 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 overstimulating mitophagy. We haven't really seen that. I think it's more what I call a modulator of mitochondria than approach then over stimulating mitochondria.
Ben Greenfield
I've always wondered if the body will have a natural modulation mechanism to where our mitophagy-supporting compounds 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. I'm curious, based on that, back to your blood levels of your Urolithin A and this blood… By the way, where do you get that blood spot test kit, do you guys mail it out from Timeline?
Dr. Anurag Singh
Yeah. We are still prototyping it and there's a clinical study that I'm running with hundreds of folks just to make sure that we have 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. We can offer that as well.
Ben Greenfield
That'd be interesting to test. I'd love to test based on what I was saying earlier. I'll hunt that down and link in the show notes if you send me over more information on it. Again, the show notes are in bengreenfieldlife.com/timelinepodcast. But the reason I ask is, have you compared what gets your Urolithin A levels highest? The little softgel that you guys make, the stick packet, or the whey protein? Have you broken that out at all?
Dr. Anurag Singh
We have put them in those different matrices because we think all those different matrix help in the absorption. We have studied, for example, independently, the softgels in a lot of trials and also studied the berry powder, or now we're studying the protein shake. I would say within a 10 percentile difference, they all in the similar levels of boosting, as I've been mentioning to the therapeutic range of 300, 500 and some people even more, depending on the dosing they're taking. I think they're fairly equivalent, I would say.
Ben Greenfield
Have we not touched on any benefits or research that you're aware of about Urolithin A? Do you think that would be important for people to know?
Dr. Anurag Singh
There's a lot of excitement, as you mentioned. We, of course, started doing the research 15 years back. I was approached by the National Institute on Aging that said, "Hey, we ran a library of thousands of natural compounds ..."
Dr. Anurag Singh
I think a lot of excitement now will come from these top professors and Harvard has the same research stream that I was told about. 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 the ATP levels within six hours of peaking and look at brain energetic capacity, this is where I think a lot of research is headed now.
Ben Greenfield
Interesting. 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, etc.
Ben Greenfield
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 your Urolithin A with things like smart drugs, nootropics, some of these mitochondrial enhancing agents in terms of things that push the gas pedal harder would be a good idea. Have you ever looked at that?
Dr. Anurag Singh
We haven't, but I do think it's a good idea and something we are exploring in the background. 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 better cognitive effects together where you can recycle the poor mitochondria in neurons and then give them an alternative fuel supply to rewire them. So we are looking into that.
Ben Greenfield
I've discovered the same thing. If I take DHA and Choline to replenish a lot of nutrients that I'm burning through more quickly, then Ketone esters and NAD on any cognitively demanding day on which I might also be using, let's say, methylene blue or silicide and micro-dosing or some type of nootropic agent like quality of mind or some of these Newtopia products or something like that.
Ben Greenfield
I find that stacking Choline, DHA, NAD, and Ketone esters to just blast through, let's say, a 16-hour creativity/focus work day with some of these nutriates on board seems to help. But I haven't really brought something like a mitophagy-enhancing agent into that equation. It'd be interesting to experiment with.
Dr. Anurag Singh
Sure. Yeah, I think future research is headed that way.
Ben Greenfield
Yeah. Well, this is fascinating, man. I really appreciate the research that you've done on Urolithin A and with Timeline, I know we have discounts and codes and things like that for Timeline. I'll hunt them down and put them in the show notes at bengreenfieldlife.com/timelinepodcast. That's bengreenfieldlife.com/timelinepodcast.
Ben Greenfield
Over there, if you'd like, you can also leave follow-up questions, comments, feedback, etc, for Dr. Singh and 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 Urolithin A. I've been fascinated by this for a while and looking forward to getting you on the show and asking all these questions.
Dr. Anurag Singh
They're all great questions. I love chatting with you, Ben.
Ben Greenfield
Awesome. Well, I'm excited to put this out. Folks, again, the show notes are bengreenfieldlife.com/timelinepodcast. Until next time, I'm Ben Greenfield, along with Dr. Anurag Singh, signing out from bengreenfieldlife.com. Have an amazing week.
Ben Greenfield
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Well, first of all, let me say, it is even though it might look like it from outside appearances, not just me. I'm nothing special. There is an amazing team of individuals who surround me, who support me, who co-found things with me, who basically make what I do look really good because I, after all, am just a glorified personal trainer.
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These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. References: *Nutrition studies: 500mg Mitopure® have been shown to (1) induce gene expression related to mitochondria function and metabolism and (2) increase the strength of the hamstring leg muscle in measures of knee extension and flexion in overweight 40-65 year olds. Data from two randomized double-blind placebo-controlled human clinical trials. **Nutrition NOURISH Study: 500mg Mitopure® have been shown to deliver at least 6 times higher Urolithin A plasma levels over 24 hours (area under the curve) than 8 ounces (240ml) of pomegranate juice in a randomized human clinical trial.

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