Urolithin A

[Sue (Ayt)]

So, I listened to Clif High’s substack Here
called “Energy, in old age, & with cancer - Biohacking...learn it.”
Listened to it twice, actually, so I could write down and research his hints. As most know, Clif battled cancer for quite a while, and appears to have won. (which is kind of unusual and I tend to take heed when I hear from real people who are doing well with their health.)

Anyway, Clif listed 4 key supplements that he took to restore his cancer-wasted body, after he had tackled his disease, and he continues to take. They are:
Chaga
C-60
Urolithin A
Plasmalogens

I have read about Chaga and C-60 and we have some info on the forum about them, but the 2nd two were new to me. So, I did a search on the forum for urolithin and the only hit I got was a post I had made myself! (but my post included a bunch of substances besides that one.)
https://projectavalon.net/forum4/sho...=1#post1561712

Hmmm - pomegranates…
Anyway, a further google search brought up a lot more interesting info about it.
This article I found particularly interesting:
https://www.cell.com/trends/molecula...914(21)00118-0
It makes it sound like almost a miracle substance, but not all people produce it at healthy levels, and it tends to fall as we age. Plus, it does many other good things besides restore our muscular strength and endurance. Eating pomegranates (and some other healthy foods) apparently is the precursor for Urolithin A, BUT not everyone converts the pomegranates to Urolithin A no matter how many they eat.

Here are a couple of other research links about it, but there are many more.
https://www.nature.com/articles/s42255-019-0073-4
https://www.liebertpub.com/doi/abs/1.../rej.2018.2066

_____
So, for Part II of my story… I saw this seemingly unrelated article today :
A Secret in the Blood: How PF4 Restores Youth to Old Brains
https://www.ucsf.edu/news/2023/08/42...uth-old-brains

and it reminded me of Vicus’ post about this article https://projectavalon.net/forum4/sho...=1#post1543745
‘Young Blood’ Anti-Aging Drug Discovered By Columbia University"

Well, giving young blood to aged folks does NOT sound like anything remotely appealing in my opinion, but then a search of PF4 (from Vicus' article) connected it to … urolithin A!

https://www.forbes.com/sites/william...h=1def0e02cc32

ha - The elites can have their baby blood, but reading these links prompted me to share this info here on Avalon, where maybe we can delve deeper into Urolithin A. So far, I have found nothing at all harmful about it reported. (I need to get my muscles back in shape for gardening!) Urolithin A is available on Amazon and elsewhere, by the way.

[Mike]

I've been taking urolithin A for about 3 months. It's one of the most powerful supplements I've ever taken (And I've taken alot!).

Navigating the brands is a little tricky. I began with Mitopure, which is the real deal but absurdly expensive and not sustainable.

From there I tried a couple other brands (cheaper) that literally had no effect at all. The difference was so profound that I feel fairly certain there was no urolithin A in those brands at all.

Finally I found an affordable brand that delivered the goods: Neurogan. I highly recommend it.

https://www.amazon.com/Neurogan-High...0a008b07e78d49

[Vangelo]

Urolithin A Unveiled: Exploring Its Potential for Longevity
By Allison Krug, MPH
Updated on February 22, 2024
Fact checked by
Linas Černiauskas, PhD Candidate
source:

Urolithin A has attracted interest from longevity enthusiasts for its potential to optimize mitochondrial efficiency. These powerhouses of the cell must be maintained for optimal health by producing new mitochondria and recycling the old mitochondria. This process involves complex pathways of gene regulation that can malfunction with aging. It is thought that urolithin A supplementation could optimize mitochondrial efficiency, but how much science is there to support this notion, and how safe is it?

The growing interest in longevity has prompted research on a wide variety of supplements to decelerate the aging process. Much of the research has focused on the mitochondria. These complex, sausage-shaped structures are the power plants of human cells and are found in nearly every cell of the human body. Some cells, such as muscle and nerve cells, which require more energy, have thousands of mitochondria.

In addition to energy supply, the mitochondria serve other critical functions, such as storing calcium ions, which are needed for blood clotting and muscle contraction. Mitochondria also contain enzymes needed to produce heme, which is required for red blood cells to transport oxygen. In addition to driving all these life-sustaining functions, mitochondria are responsible for triggering cell death (autophagy) and the recycling of older, dysfunctional mitochondria (mitophagy).

The process of mitophagy is important to maintaining mitochondrial function. Removing and recycling damaged mitochondria produces new, fully functional mitochondria. If this process of mitophagy is impaired, cell health can be negatively affected, leading to age-related chronic diseases, such as Parkinson’s disease, Alzheimer's, cardiac disorders, osteoarthritis, and cancer.

Understanding urolithin A
Urolithin A (UA) is an important postbiotic produced by your gut microbiome that influences mitochondrial function. Foods that contain the polyphenols needed to produce urolithin A include walnuts, strawberries, pomegranates, and raspberries. Some studies suggest that only a fraction (perhaps 15–40%) of older adults can produce UA reliably from a regular diet.

Animal studies, often on mice, have suggested that urolithin A can promote optimal mitochondrial function, and recent clinical studies on humans suggest that supplementation can improve mitochondrial health and muscle function in older individuals. Urolithin A appears to promote the recycling of mitochondria by triggering a pathway that first causes the degradation of older mitochondria and then stimulates the production of new, healthy mitochondria.

Potential benefits for longevity
In addition to supporting mitochondrial turnover, urolithin A supplementation in animal models such as worms and mice shows promising effects in reducing inflammation, supporting nerve growth and memory, spinal disc and joint tissue repair, muscle strength and endurance, intestinal lining integrity, and kidney function.

Is there science behind urolithin A?
The first randomized clinical trial of urolithin A was a two-part study that evaluated various doses of the supplement. Part one of the study was a single dose at 250 mg, 500 mg, 1,000 mg, or 2,000 mg among 24 healthy middle-aged participants (aged 50). In part two of the study, 36 participants were randomly assigned to 28 days of a daily supplement at 250 mg, 500 mg, or 1,000 mg. The results revealed that urolithin A was absorbed and detectable in the blood and muscle tissue.

Another randomized placebo-controlled trial, ATLAS, took the testing a step further by randomizing 88 overweight, middle-aged (40–64) participants to three equal groups: placebo, 500 mg, or 1,000 mg per day over four months. No significant differences were found between the three groups for the pre-specified primary endpoint: peak power output. However, hamstring strength improved in both the 500 mg and 1,000 mg groups, and hand grip strength, aerobic capacity, and walking distance each improved in the 1,000 mg group compared to placebo.

Additional tests were conducted to evaluate whether urolithin A supplementation supports mitophagy and muscle metabolism. These tests focused on measuring acylcarnitines in the blood to evaluate mitochondrial efficiency. The 500 mg group experienced reductions in the acylcarnitines, which are linked to increased mitochondrial efficiency, while no changes were detected in the 1,000 mg group.

Measures of inflammation, such as C-reactive protein (CRP) and pro-inflammatory cytokines, were evaluated to detect whether urolithin A offers any anti-inflammatory potential. The 1,000 mg dose showed a statistically significant reduction in CRP and reductions in some of the pro-inflammatory cytokines. Because the inflammatory markers were already low at baseline in this population, Urolithin A showed a mild anti-inflammatory effect.

Overall, the ATLAS trial found that long-term dosing was safe and well tolerated and that leg muscle strength and mitochondrial health improved in the 500 mg group while leg muscle strength and aerobic capacity increased in the 1,000 mg group. However, the pre-defined outcome of interest (peak power output) did not differ between the placebo and treatment groups.

A study among 66 older adults (65–90), again over four months, compared a placebo to 1,000 mg daily supplementation of urolithin A. This study did not find any difference in the 6-minute walk test or cell energy production (ATP) but did find improvements in muscle endurance and plasma biomarkers.

What is the recommended dosage?
When considering a supplement, it is important to remember that these dietary products are not regulated by the Food and Drug Administration (FDA). Manufacturers need only advise the FDA that they are releasing the product. Consumers can check the FDA website for updates and advisories on reported issues, but there is no government oversight for effectiveness or quality control.

The FDA released a Generally Recognized as Safe (GRAS) notice in 2018 for typical use at 250 mg up to 1,000 mg. While there is no recommended dosage, urolithin A is available for purchase in a wide array of dosages, including at least the following: 500 mg, 700 mg, 800 mg, 1,000 mg, and 2,000 mg.

What are the possible side effects and safety precautions?
Although the ATLAS study sample sizes were small, careful investigation of the supplemental information on adverse events suggests a possible dose-response relationship with headaches. In other words, the 1,000 mg group had a higher frequency of headaches than the 500 mg group or placebo group, but this difference did not reach statistical significance. According to the study investigators, other adverse events were likely associated with the muscle biopsies performed to measure mitochondrial gene expression.

Individuals who are taking medications should always check with their primary care clinician before starting a supplement. Your clinician will want you to keep a list of all the supplements you are taking (and the date you started taking them) so that if any new symptoms arise, you will have an idea of when you started the supplement that you can compare to the onset of new symptoms.

How to incorporate urolithin A into my longevity strategy
The best longevity strategy incorporates good sleep, nutrition, movement, relationships, exposure to sunlight and the outdoors, and good oral and gut health. Taking a longevity supplement is not likely to correct for deficiencies in these other areas. However, if taking a supplement gets you excited about focusing on your health in a new way, then it may be worth considering.

For instance, would learning about urolithin A rejuvenate your appreciation for the gut microbiota producing important postbiotics? Given that the safety profile seems reasonable at the lowest dose tested (500 mg), there may be a net benefit with short-term use. Lower doses (e.g., 250 mg) are available commercially as well. On the other hand, many of the benefits noted, such as strength and endurance, can be gained with old-fashioned conditioning programs that have no downsides. Consider what has worked well for you in the past and find ways to build on those wins.

Conclusion
Overall, the current research suggests that supplementation with urolithin A among older and middle-aged adults seems to be safe, but the proper dosing is uncertain, and the real-world benefits are difficult to measure because improvements are not dramatic. Some benefits were detected at the 500 mg dose, but some adverse events were also observed. The cautious consumer might consider starting with the lowest dose available and keep an eye on unusual cardiovascular or neurological symptoms. Set some goals for your strength and endurance, and start a program that builds up gradually.

FAQ
Who would benefit most from urolithin A?
According to clinical trials, middle-aged and older individuals may experience benefits in muscle strength and endurance with Urolithin A supplementation.

Should athletes take urolithin A?
The clinical trials are so far on middle-aged and older individuals; there is little information on the impact of this supplement on athletes.

Can urolithin A support joint health?
One of the most common challenges of aging is joint pain. There is some evidence that urolithin A can help reduce tissue damage and pain in the joints.

How safe is urolithin A?
The clinical trials are small and short-term, so the safety data is very limited. It is always best to start at a low dose and track any adverse effects.

Is it possible to be an elite strength athlete without supplementation?
Yes, many elite strongmen and strength athletes avoid supplements and prefer to be all-natural ('natty').

[ThePythonicCow]

Posted by Sue (Ayt) (here)
(I need to get my muscles back in shape for gardening!) Urolithin A is available on Amazon and elsewhere, by the way.

This article claims that Urolithin B does more for muscles: What Is Urolithins And Its Functions?

[Sue (Ayt)]

Would love to hear more about how you feel it has helped, Mike.

I ordered some, and have been taking it for 6 days now, and have been feeling quite, um... uplifted, clear, vibrant, or ?. Just generally good well-being at the moment. It's nice.
Thanks

Posted by Mike (here)
I've been taking urolithin A for about 3 months. It's one of the most powerful supplements I've ever taken (And I've taken alot!).

Navigating the brands is a little tricky. I began with Mitopure, which is the real deal but absurdly expensive and not sustainable.

From there I tried a couple other brands (cheaper) that literally had no effect at all. The difference was so profound that I feel fairly certain there was no urolithin A in those brands at all.

Finally I found an affordable brand that delivered the goods: Neurogan. I highly recommend it.

https://www.amazon.com/Neurogan-High...0a008b07e78d49

[Mike]

Posted by Sue (Ayt) (here)
Would love to hear more about how you feel it has helped, Mike.

I ordered some, and have been taking it for 6 days now, and have been feeling quite, um... uplifted, clear, vibrant, or ?. Just generally good well-being at the moment. It's nice.
Thanks

Posted by Mike (here)
I've been taking urolithin A for about 3 months. It's one of the most powerful supplements I've ever taken (And I've taken alot!).

Navigating the brands is a little tricky. I began with Mitopure, which is the real deal but absurdly expensive and not sustainable.

From there I tried a couple other brands (cheaper) that literally had no effect at all. The difference was so profound that I feel fairly certain there was no urolithin A in those brands at all.

Finally I found an affordable brand that delivered the goods: Neurogan. I highly recommend it.

https://www.amazon.com/Neurogan-High...0a008b07e78d49

Hi Sue, same here: uplifted, vibrant, energetic (by my standards anyway).

Maybe the biggest improvement is in mental energy. And I'm only taking 1 capsule a day (700mg). Perhaps today I'll try taking two capsules.

It acts directly on the mitochondria, so it's going to have an overall uplifting effect for everyone, while also offering specific support for individual problem areas (for me it's the heart).

It's a little pricey but worth it. I don't waste money on supplements I can't feel working almost immediately. This stuff gets to work right away.

[Pam]

Sue, this is a great thread, I am glad I checked it out. Mike, thanks for a personal testimonial. I did find a brand for Plasmalogens from Japan (funny, I now try to buy any products that I ingest I can from outside the US which used to be the opposite).The product name is Rememory if anyone wants to check that brand out. The product you recommended, Mike' recommendation,has a lab certification so that is promising.

I know I am going a bit off topic here but we are talking about brain well being and clarity for the brain, I have to give a strong shout out to methylene blue, which as a nootropic potentiates mitochondria, it also has anti anxiety, antidepressant qualities as well as the other benefits of fortifying the functions of mitochondria. I find it so effective that I do it at night otherwise I feel so relaxed...but it plays a great role in mental clarity.

Of course, with any of this, we have to do our own research, and Sue did a bunch for us.

[Mike]

Posted by Pam (here)
Sue, this is a great thread, I am glad I checked it out. Mike, thanks for a personal testimonial. I did find a brand for Plasmalogens from Japan (funny, I now try to buy any products that I ingest I can from outside the US which used to be the opposite).The product name is Rememory if anyone wants to check that brand out. The product you recommended, Mike' recommendation,has a lab certification so that is promising.

I know I am going a bit off topic here but we are talking about brain well being and clarity for the brain, I have to give a strong shout out to methylene blue, which as a nootropic potentiates mitochondria, it also has anti anxiety, antidepressant qualities as well as the other benefits of fortifying the functions of mitochondria. I find it so effective that I do it at night otherwise I feel so relaxed...but it plays a great role in mental clarity.

Of course, with any of this, we have to do our own research, and Sue did a bunch for us.

Hi Pam, I always say - whatever brand you go with, make sure they have a full refund policy!

It's a great way to save money. I broke my own rule with urolithin A and wasted 70 or so bucks on some useless brands

Let us know how Rememory works for you! Maybe we can create a little list of legitimate urolithin A brands here so people don't make the same mistake I did.

[ExomatrixTV]

• Impact of the Natural Compound Urolithin A on Health, Disease, and Aging

• Impact of the Natural Compound Urolithin A on Health, Disease, and Aging

[Sue (Ayt)]

Saw this article in "Medical News Today", so thought to add it here.

'Rejuvenating' mitochondria may help fight toxic proteins in Alzheimer's
May 22, 2024

"Although scientists still do not know the exact cause of Alzheimer’s disease, most agree that the clumping of certain proteins — beta-amyloid and tauin the brain characterize the disease.

“The unifying feature of neurodegenerative diseases of aging is the accumulation of large protein clumps in the brain which we term insoluble protein aggregates,” Edward Anderton, PhD, a postdoctoral researcher at The Buck Institute for Research on Aging in California and co-first author of a study recently published in the journal GeroScience, explained to Medical News Today.

“In Alzheimer’s disease, the [beta-amyloid] protein forms aggregates called plaques, and these are tightly associated with areas of neuronal death and brain inflammation causing disease,” he noted.

However, Anderton added, these plaques contain hundreds of additional proteins which have been largely ignored until now.

For this reason, he and other researchers from The Buck Institute for Research on Aging in California decided to examine how the accumulation of insoluble proteins, in general, might accelerate Alzheimer’s disease.

Using a worm model, scientists found that both the natural aging process and beta-amyloid drive other proteins to become insoluble.

Researchers then used a compound to boost the quality of mitochondrial health in the proteins that had become insoluble, effectively delaying the toxic effects of beta-amyloid.

Mitochondria, the so-called powerhouses of the cell, have recently become a focus point in Alzheimer’s research, as scientist have been trying to see whether “repairing” mitochondria that stop functioning well with age might help preserve brain health."

What is protein clumping?

According to Manish Chamoli, PhD, research scientist at The Buck Institute for Research on Aging in California and co-first author of this study, proteins are like tiny machines in our cells that need to be a specific shape to work correctly.

“Imagine if you had a key that got bent and no longer fit into its lock — that’s similar to what happens when proteins lose their shape,” Chamoli explained to MNT. “These misshapen proteins start sticking together and form insoluble protein aggregates. Proteins can lose their shape due to various factors like stress, aging, or damage.”

“Our cells have evolved ways to either refold the proteins into the correct shape or degrade them when they’re too damaged to be refolded,” he continued.

In conditions such as Alzheimer’s disease, however, the brain does not correctly dispose of such proteins.

“In laboratory organisms, such as the microscopic worm Caenorhabditis elegans, our lab and other labs around the world have observed that, as these worms age, they accumulate clumps of insoluble proteins,“ Chamoli told us.

“Likewise, it’s well established that Alzheimer’s disease patients’ brains accumulate protein aggregates,” he added.

Why do proteins clump in the brain?
As insoluble proteins do accumulate in the brain during normal disease-free aging, Chamoli, Anderton, and their team wanted to know what was the connection between brain protein clumps in normal aging and Alzheimer’s disease.

Using a worm model, scientists discovered that beta-amyloid causes a massive amount of insolubility in other proteins, especially in a subset of proteins researchers called “the core insoluble proteome.“

According to researchers, the insoluble proteins found in the core insoluble proteome have already been linked to other neurodegenerative conditions including Parkinson’s disease and Huntington’s disease.

“Data suggest there may be a causal role for the insoluble proteome in Alzheimer’s disease pathogenesis,” Anderton said. “For example, insoluble protein extracts from old but not young animals accelerate the aggregation of [beta-amyloid].”

“We questioned if the reverse was also true: Can [beta-amyloid] drive the insolubility of proteins that tend to aggregate during aging? Our data are consistent with the notion that [beta-amyloid] and age-related changes interact in a destructive feedforward cycle, leading to an acceleration of protein insolubility in Alzheimer’s disease.”

Can boosting mitochondrial health prevent toxic aggregate formation?
Next, researchers wanted to find a way to potentially reverse how beta-amyloid helps drive the insolubility of proteins.

As many mitochondrial proteins become insoluble during natural aging and beta-amyloid influence, they hypothesized that boosting mitochondrial protein quality might reverse some of beta-amyloid’s negative effects.

“Mitochondria contain a specialized energy-producing complex of proteins called the electron transport chainTrusted Source, which is the primary way our cells use food to produce energy,” Chamoli said. “We found that the proteins of the electron transport chain were driven to become insoluble when we exposed them to [beta-amyloid].”

“It has been known for some time that mitochondria can be negatively impacted by [beta-amyloid] but we show that this is likely due to protein insolubility,” he continued. “Luckily, cells possess a way to recycle damaged mitochondria through a process called mitophagyTrusted Source. Our lab and others study a small molecule that boosts mitophagy to rejuvenate mitochondria.”

To do this, they chose urolithin A a metabolite compound found in the gut microbiome. Pomegranates, walnuts, strawberries, raspberries, chia seeds, hemp seeds, and almonds are all foods rich in urolithin A.

“We reasoned that using a pharmacological approach to clear away the insoluble proteins from mitochondria could prevent some of the toxic effects of [beta-amyloid] and that’s exactly what we found,” Anderton said.

Potential for new therapeutic interventions for Alzheimer’s
more at link:
https://www.medicalnewstoday.com/art...for-Alzheimers
------------

Anyway, this was a fairly long article, and I kept reading it to determine what this new compound they are researching might be, and turned out it was Urolithin A.

This Link was found in the article above, and included references and citations from pubmed.

[Sue (Ayt)]

Dietary Urolithin A Suppresses Lung Cancer via Gut Microbiota-Mediated Autophagy Activation

Author
Jiayin Zhang, Rong Zhang, Lemei Sun, Bingqi Chen, Xiaohan Li, Jing Duan

Cite
https://doi.org/10.1016/j.jnutbio.2025.110080

Highlights

• Urolithin A exhibits potent anti-lung cancer activity in both in vitro and in vivo models.
• Autophagy is activated by Urolithin A through targeting the PI3K/AKT/mTOR signaling cascade.
• Urolithin A combats lung cancer by modulating gut microbiota (Lactobacillus↑/Desulfovibrio↓).

ABSTRACT

Urolithin A (UA), a gut microbiota-derived metabolite of ellagic acid, exhibits diverse biological activities. Emerging evidence suggests its anti-tumor potential, possibly mediated through gut microbiota modulation, yet its role in lung cancer remains unclear. In this study, UA dose- and time-dependently suppressed lung cancer cell proliferation. Mechanistically, UA triggered autophagy, as evidenced by increased LC3-II protein levels, and transcriptome analysis revealed this effect was mediated through inhibition of the PI3K/AKT/mTOR pathway. In vivo, UA supplementation markedly inhibited tumor growth in H1975 xenograft models, concomitant with enhanced autophagy and downregulation of associated proteins. Notably, 16S rRNA sequencing demonstrated that UA modulated gut microbiota composition, increasing Lactobacillus while decreasing Desulfovibrio abundance. Spearman’s correlation analysis further linked these microbial shifts to altered expression of autophagy-related genes. Collectively, our findings highlight UA as a promising gut microbial metabolite for lung cancer intervention via coordinated autophagy induction and microbiota remodeling.

More at Link:
https://www.sciencedirect.com/scienc...55286325002426

[Sue (Ayt)]

And Bill - here's one to share with your neighbor, Noem.

Sports Med
. 2025 Aug 21.

Evaluating the Impact of Urolithin A Supplementation on Running Performance, Recovery, and Mitochondrial Biomarkers in Highly Trained Male Distance Runners

Conclusions: Our results show that 4 weeks of daily UA supplementation facilitates recovery by downregulating inflammatory pathways and indirect markers of muscle damage. However, despite a reduction in rating of exertion and increased aerobic capacity, UA supplementation did not further enhance performance in highly trained male endurance athletes.
https://pubmed.ncbi.nlm.nih.gov/40839339/

(suggest that Noem eat lots of pomegranates!)