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Hey everyone, it's Mikki here. You're listening to Mini Mikkipedia on a Monday. And today I want to talk about that mitochondrial molecule that everyone else is talking about. And that is Urolithin A. If you listen to any of the big health podcasts that are out there, you may have noticed more and more of them are being sponsored by a company that produces this mitochondrial molecule, Urolithin A. And if you're wondering whether or not it is just marketing hype,

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or there's something to it, I was wondering the same thing actually. So I thought that I would do a deep dive into the literature to shed some light into what makes the compound so fascinating, why scientists are excited, and also what does the research show and should we be forking out all of this money each month on it? So before we dive into Urolithin A, ideally we want to understand the problem that it's trying to solve. So mitochondrial dysfunction has emerged

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is one of the key hallmarks of aging. It's linked to numerous age-related diseases, including metabolic syndrome, neurodegenerative disorders, cardiovascular diseases, cancer, course, chronic fatigue, long COVID, all of that. Think of mitochondria as tiny power plants inside your cells. I know not all scientists think that like that. You have hundreds to thousands of them in each cell.

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they're converting the food that you eat and the oxygen you breathe into ATP. This is the energy currency that your body runs on. With advanced age, mitochondrial DNA volume, integrity and functionality decrease due to the accumulation of mutations and oxidative damage. In uh people of age, like me, mitochondria show impaired function including lowered oxidative capacity, reduced oxidative phosphorylation,

02:01
decreased ATP production, significant increase in reactive oxygen species generation, and diminished oxidant defense. In humans, aging generally begins after 30 as a result of physiological, psychological, and social changes leading to an overall decline in physical and mental wellbeing. It is course this gradual process and you don't, ideally, don't just fall off a sudden cliff.

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For what it's worth, been particular interest in mitochondrial health during perimenopause. Perimenopause begins at around eight to 10 years before menopause, when the ovaries gradually produce less estrogen. And research shows that immediately before the transition from perimenopause into menopause, which is kind of like walking through a door, if you like, there's this hypo metabolism in the brain, which is characterized by a reduction in glucose uptake and hexokinase activity. m

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accompanied by inactivation of complex 4-activity ampyruvate dehydrogenase. What that just means is that your brain just doesn't have the same energy. Studies comparing cognitively normal perimenopause and postmenopausal women versus age-matched men show that as women go through menopause, multiple imaging findings emerge including reduced brain glucose metabolism, increased amyloid B accumulation,

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and grey and white matter loss with patterns of brain hypermetabolism correlating with reduced mitochondrial activity. So this mitochondrial decline is real and it is measurable. This is one of the reasons why there is such interest in molecules that may help protect against this decline. another key issue is that with age, mitophagy, which is the autophagy lysosome system that degrades

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dysfunctional mitochondria was observed to decline. And this decline is associated with the accumulation of damaged mitochondria, advanced oxidative stress, and increase at-pop ptosis. So what that just means is like, it's like having this factory where broken machines keep piling up because the maintenance crew stopped showing up. And eventually those broken machines start causing problems for everything else.

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So mitophagy is the removal of that damaged mitochondria. So where does Urolithin A come in? Well, Urolithin A is a post-biotic metabolite which is derived from the microflora in your gut converting ingested illusia tannins and illusic acid, which are precursor molecules found in foods like pomegranates, strawberries, raspberries, and walnuts. So it's your gut bacteria

04:52
is taking these illusory tannins and converting them into Urolithin A. So if you eat a pomegranate or some walnuts or raspberries, your gut bacteria break these compounds down, called illusory tannins, into Urolithin A. It's not in the food itself, your microbiome creates it. However, having the right microbiome is required for this natural conversion. And this occurs in approximately 30 to 40 % of people at variable levels.

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with only a small percentage deriving Urelythin A from the natural exposure at substantial levels able to confer a health benefit. So what we're probably talking about here is that the Urelythin A supplements are providing these super high levels of Urelythin A compared to what our gut microbiome might naturally produce. Here's where it gets interesting. Urelythin A is known to stimulate mitophagy. That's it, selected removal of damaged mitochondria.

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and improve the muscle health in both animal models and preclinical studies of aging. just to be clear, the sort of relationship between that mitochondrial biogenesis, so the creation of mitochondria and those turnover pathways, it's critical for the cells to adjust their pull of that functional mitochondria in response to physiological or metabolic demands, stress, and other intracellular or environmental cues.

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And what Urelythin A does, it helps trigger that cleanup, that mitophagy. It does more than that though. It's part of this larger system that removes the old and damaged mitochondria, but it also helps promote the new mitochondria as well in that biogenesis. So it almost has this dual role. What preclinical trials show is that when administered to middle-aged mice for 16 weeks, Urelythin A increased markers of

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angiogenesis in skeletal muscle, activated pathways in elevated ATP and NAD plus levels. for those interested in the molecular details, Urethane A specifically activated the PGC1 alpha, which is our master regulator of mitochondrial biogenesis and the CERT1 protein that responds to cellular stress and helps coordinate the metabolic response.

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This pathway is the same one that's activated by calorie restriction and exercise, which are interventions we know extend lifespan in animals. So Urolithin A did the same thing. But what about human trials? There was what is sort of thought of as a landmark trial, like a randomized placebo controlled trial, administered Urolithin A at two doses for four months to middle-aged athletes

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they showed significant improvements in muscle strength of approximately 12%. That's quite substantial. So they were 88 untrained adults, aged 40 to 64. They were overweight with low physical endurance, and they were randomized to either a placebo or to ureolithin A at 500 mg or 1000 mg daily. This is for four months. So the study found clinically meaningful improvements on aerobic endurance,

08:14
and physical performance, though they did not notice significant improvements in peak power, which was one of their primary endpoints. They also had noted that there were levels of C-reactive protein were significantly lower, and that is a marker of systemic inflammation, with the urolithin A, which indicated higher mitochondrial efficiency and reduced inflammation. So that is a significant trial.

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that showed clinically meaningful outcomes in unfit, overweight adults, middle aged. So bear that in mind. There was another study with 66 subjects, found that two measures of muscle endurance were improved in the supplemented group, complete to placebo with Urolithin A, and endurance was measured through exercises involving the hand and the leg muscles. Interesting. The supplement was associated with significant reduction in several acylcannitines,

09:12
and ceramides, which are implicated in metabolic disorders involving mitochondria. If you have less of them, you're going to have less of that mitochondrial dysfunction. The finding with those acylcarnitides has also been found when they gave Urelythin A either as a single dose or as multiple doses over a four-week period to healthy, yet sedentary, elderly individuals. And not only did they find that had a

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favorable safety profile, there were reduced markers of mitochondrial damage. And this was found at doses of 500 milligrams or a thousand milligrams. So we are seeing changes in both molecular markers that suggest mitochondrial function is improving. And although there are some mixed results with those functional outcomes, so for example, there's been no sort of shift in peak power output or

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ATP production in some of these studies, there have been some other improvements. And then there was a systematic review conducted in 2024 that found in five studies that included 250 healthy individuals, doses of Urethane A for durations lasting from 28 days to four months showed a dose-dependent anti-inflammatory effect and upregulated some mitochondrial genes.

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markers of autophagy and fatty acid oxidation. Overall increased muscle strength and endurance, however, had no effect on anthropometrics, body size, cardiovascular outcomes and physical function. So there is a bit of a mixed bag. So what do we know? We know the safety profile is good and it has been granted for what it's worth, generally recognized as safe as stated by the FDA.

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the doses of between 250 to 1000 milligrams daily does increase my topology markers. There are some modest improvements in muscle function. It can reduce inflammatory markers and potentially will work better as a supplement than in dietary sources, which I'll talk about in a minute, particularly because only 30 to 40 % of people can naturally produce Urelythin A at meaningful levels. Whereas when you supplement a standard dose,

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This is going to bypass that variability. What don't we know? We don't know the long-term effects. So we don't know what happens beyond four months at this point. We don't know the optimal dosing. Studies use about 500 to 1,000 milligrams. So we don't know whether more might be better or is less as effective and therefore will it cost less? We also don't know who benefits most. And potentially, and this would make sense from a, just from a biology perspective,

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people with lower baseline mitochondrial function see bigger benefits and what about different age groups as well? A lot of the studies have been done in people, low fitness, overweight, older individuals, or at least middle-aged, which I don't mind, I'm middle-aged myself, but I don't really fall into those other categories. So we don't know who is gonna get the most benefit. And there may well be tissue specific effects as we know this about other molecules as well. So it would be interesting in

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particularly from a longevity perspective, and I talked about perimenopause in the brain to know better the implications for how this impacts the brain, our heart, our liver and other organs. And is there any sort of synergistic effect with Urelythin A and exercise, for example, or with other supplements? And what about in addition to a dietary intervention? And while there seems to be no firmly established mechanism by which Urelythin A acts,

13:03
to modestly improve mitochondrial function, it's generally presumed that it largely functions via improving that operation of morphology. So that activation of that new mitochondria being created and the clear out of the damaged mitochondria. And it would be super interesting to do studies looking in disease models. So there have been some studies in Alzheimer's disease mouse models showing that Urethane A treatment significantly improved learning and memory.

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olfactory function and synaptic function while reducing these amyloid beta and TOR pathways, but human trials for neurodegenerative diseases haven't yet been completed. And of course, I don't know, these are hype versus reality. SRS with everything, because you will see claims like mind blowing clinical trials and descriptions of mitochondria running on fumes, you know, and this is going to be the thing that saves them. But

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While the research is legitimate and promising, calling a 12 % improvement in muscle strength mind-blowing is hyperbole at best, really. Resistance training, for example, can increase coupled mitochondrial respiration by twofold. So that's 100%, not just 12%. High intensity interval training produces the most robust effects on mitochondrial health. Increasing mitochondrial area and size

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and promoting protein changes indicating increased mitochondrial fusion with these changes associated with improvements in mitochondrial respiration, insulin sensitivity, and cardio respiratory fitness. So exercise, which is free, produces effects that absolutely dwarf what we see in these Urelythin A studies. So be mindful of that too. And it's always going to be that cost consideration. Urelythin A supplements may cost between 60 to 100

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and $20 a month for effective doses. That's $720 to $1440 per year. That's US dollars for modest, though measurable, benefits. So I already mentioned just then that exercise does more and has known clinical benefits across the lifespan, different ages, different fitness levels, well more than what Uralithin does, and it can be free.

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And don't forget as well that there is research showing caloric restriction, although preclinical, and fasting also has similar benefits with mitochondria as well. Not that I'm recommending either of those particularly. So people who may benefit more from Urelythin A then would be people potentially who can't exercise due to poor muscle health or disease. Like they may well get a benefit here.

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middle-aged and older adults like us, but if you exercise then maybe not, hopefully you exercise. Those seeking an adjunct therapy, this is what could be interesting and I'm interested to see studies that supplement Urelythin A alongside as a complement to other lifestyle interventions. And then also here's the thing, people with confirmed low natural production and at present there's no simple at home test that is

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currently available to consumers to confirm or otherwise the production of urolithin A. But what we do know that in clinical studies, researchers testing production have used a standardized dose of those alugetanins, usually from pomegranate extract. They collect blood neurons samples at various time points, 24 to 48 hours post consumption. And they use sophisticated analytical techniques like high performance liquid

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chromatography mass spectrometry to detect and quantify Urelythin A metabolites. And then they classify people as producers or non-producers based on these detectable levels. But you can get some specialized microbiome testing. So certain gut bacteria species like Gordon Bacter Urelythin facins or Alujubacter iso-Urelythin facins are key to converting those

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allusia tannins into urethra A. And there are tests that analyze your stool for these bacteria or their metabolic output. So this is pretty niche, like Thorne's gut health test or other services like UBiome, although that's shut down. um They do offer these advanced microbiome sequencing. So they'll identify some bacterial profiles and may include some metabolite analysis. But currently those explicit tests to

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to determine whether or not you're a producer are not available just to consumers. And it's more of a research-based question. However, if you were interested to know, could I even just figure this out by how I felt? Well, yeah, you could. You could take a supplement to sort of see how you feel and whether it really makes a huge difference to you. Or this informal approach, which I've seen recommended, is that it's a little bit time consuming. However,

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You avoid pomegranates, berries and walnuts for a week. Then after that, for each day for three to four days, you consume a large amount of pomegranate, which is one to two whole fruits per day, or around 800 mLs or 16 ounces of juice daily for three to four days, and do a self-assessment. Some people report feeling increased energy or improved exercise recovery. If they're good producers, others won't.

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Clearly, this is highly subjective and susceptible to placebo effects. So this really won't tell you whether or not you're producing Urethra A or not, to be fair. And I mean, you can of course try and improve your microbiome's ability to produce Urethra A if you realize or discover that you're not a producer. And this is this consistent consumption of Alujetanin-rich foods, because regular exposure of your microbiome to these compounds might help

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favorable bacteria proliferate, your gut is really labelled to change, depending on what you feed it. Of course, fermented food and fiber and supporting your overall gut health through these diverse fiber um intake and fermented foods, like prebiotic fibers like inulin, chicory root, uh banana flower, resistant starch that is produced when you cook and pull potatoes and rice, things like that.

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and limiting factors that harm your microbiome diversity. So reducing unnecessary antibiotic use, limiting ultra-processed foods and managing stress. But at this point, all of that sort of self-testing and um is it a little bit theoretical? Although those tips that I just mentioned with improving your gut health, um pretty solid to be fair. And then finally, because of course this is super important, can you just get Urelythin A from food?

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Regardless of whether or not you produce it, you're just interested. You're like, look, I'll just, you know, hedge my bets that I do. I don't want to spend that much on supplements. Can I just get it from food? Well, you absolutely can. And if you enjoy eating things like pomegranates, walnuts and raspberries, there's no problem at all with it. However, it's pretty hard to get the dose that is used in the supplements themselves. And of course, do you produce it? Regardless, first thing,

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pomegranates. So the highest concentration of allusia tannins in pomegranates is actually in the husk and the membrane. So it's not actually in the juice. So if you're having pomegranate juice, you want to make sure the juice has the extract from the rind as well, because the pomegranate juice just by itself might contain some allusia tannins, but much less than the whole fruit. It's that white pith and outer rind. And that 500 to 1000 milligrams of allusia tannins daily

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translates to about one to two whole pomegranates, as I mentioned before. Or 30 to 60 grams of walnuts daily. So that's roughly a quarter to a half a cup. It's not a small amount of walnuts, is it? Or two to three cups of raspberries and berries. So these are the amounts of the foods that you eat to give yourself the best opportunity of converting those alooza tannins to that urolithin A in your gut. Okay, so to land this plane, what is the bottom line?

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Urelythin A is a legitimate science and it's not snake oil. So the mechanism makes biological sense. We can measure its effects at the molecular level. We see modest but real improvements in human clinical trials, but it is not a miracle compound. So the benefits are incremental, they're not transformative, and it's likely not going to fundamentally change your health span on its own. Surprise, because nothing ever will.

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always remains the gold standard for mitochondrial health to my mind. It produces effects that are larger, broader, and completely free if you choose for it to be. So if you're not exercising regularly, that needs to be your first priority. No supplement can replace it. And if you are doing everything right, right, I say in quotation marks, so you're exercising, you're eating well, you're managing sleep, you're managing stress, you're sleeping enough, and you have the disposable income,

22:37
then Urelythin A might be a reasonable addition to your regimen, especially if you're over 40 and experiencing some age-related decline in physical function. And of course, that cost-benefit calculation is entirely personal to you. Like, it's not necessarily the cost, it's like, what value will this provide? Two to three months of that supplement is going, or at least four months of that supplement is going to give you that answer. And what I find super exciting about this idea

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It's not necessarily Urolithin A itself, but really what it represents, because we're finally developing interventions that target the fundamental aging processes at the cellular level. Mitophagy activation is a validated target, and Urolithin A proves we can modulate it safely in humans. So this potentially opens the door for better compounds down the line. But of course, the future of healthspan medicine will not be a single magic bullet.

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It'll just be this combination of lifestyle interventions, targeted supplements for those who can afford it, and eventually more sophisticated therapies. These will all work together to keep our cellular machinery running smoothly for as long as possible. All right, team. So that is what I dug up on Neuralythin A. Keen to hear your thoughts with you take it. What do you notice? What don't you notice? Hit me up on Instagram, threads and X @mikkiwilliden. I'm on

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Facebook @mikkiwillidennutrition or head to my website mikkiwilliden.com and uh Send me an inquiry through form there. All right team you have the best week. See you later