Année : 2025

In a preprint study, scientists from Lifespan Research Institute and the Buck Institute for Research on Aging have published their findings that Urolithin A, a molecule that has garnered a lot of attention in the longevity field, potently reduces senescence-related markers in human fibroblasts [1].

Senolytic versus senomorphic

Cellular senescence is a well-documented aspect of aging [2], but the best strategy to counter it remains a question. Senescent cells play an important role in development, wound healing, and anti-cancer defenses, but with age, as their numbers grow, they start doing more harm than good.

While even in aged tissue, the relative prevalence of senescent cells in the tissue is usually small, they wreak havoc by emitting damage-associated molecular patterns (DAMPs) as well as the SASP. These trigger excessive immune response and are documented to contribute to the systemic, age-related inflammation known as inflammaging.

Clearing out senescent cells, something that the immune system should naturally do, forms the basis of the senolytic approach, which dominates today’s research in academia and biotech. The task is tricky, however, particularly because senescent cells are highly heterogeneous and are also full of harmful molecules that are released when the cell dies. One enticing alternative approach is the senomorphic one, which involves altering senescent cells in a way that would leave them in place but make them less harmful.

Urolithin A might help heal senescent cells

Urolithin A is a molecule that has gained popularity in the longevity community after demonstrating several healthspan and lifespan benefits in animal models and humans. This metabolite is produced by our gut bacteria from precursors found in foods like nuts, berries, and pomegranates, and it has been shown to decrease inflammation and improve muscle function in humans. In animal models, it led to significant increases in lifespan. For instance, in a small study from the Buck Institute for Research on Aging, Urolithin A produced a 19% increase in lifespan in mice, which is among the best results for any intervention [3].

In this study, the researchers induced two types of senescence in human fetal lung fibroblasts: one triggered by the chemotherapy drug doxorubicin and another by cellular division (replicative senescence). While the treatment had little effect on the two popular senescence markers p16 and p21, it did significantly reduce the secretion of the major pro-inflammatory SASP factors interleukin 6 (IL-6) and interleukin 8 (IL-8) as well as the expression of the corresponding genes in both models of senescence.

This translated to lower levels of paracrine senescence, which occurs when SASP from senescent cells induces senescence in neighboring cells. The researchers cultured healthy fibroblasts in the presence of media collected from either control senescent cells or those treated with Urolithin A and found that the latter scenario caused less paracrine senescence.

“Urolithin A has generated a lot of excitement in the last several years based on its potential use as an anti-aging therapeutic,” said Dr. Julie Andersen of the Buck Institute for Research on Aging, a co-author of this study and the earlier one showing that Urolithin A increases lifespan in mice. “This includes clinical data demonstrating its ability to slow loss of muscle function in older individuals. Our studies demonstrate a novel mechanism of action for the compound – suppression of chronic inflammation associated with cellular senescence, a major contributor to multiple age-related diseases. This offers a novel approach for treating a wide range of chronic diseases which could improve overall quality of life in later years.”

The mechanism

The researchers went one step further and tried to elucidate the potential mechanisms behind these effects. Cellular senescence has been linked to cytosolic DNA, which are fragments of DNA floating around in the cytosol instead of staying where they belong: in the nucleus and in mitochondria. Since it can be of viral or bacterial origins, cytosolic DNA is recognized by the cell as a sign of invasion, and the alarm is raised via the cGAS-STING pathway, which drives inflammation.

Urolithin A significantly decreased the abundance of cytosolic DNA in the treated cells. The researchers suggest that this might have something to do with Urolithin A’s ability to induce mitophagy [4], the process of eliminating unhealthy mitochondria. Damaged mitochondria leak DNA, and lowering their burden would be consistent with the observed reduction in cytosolic DNA.

“We discovered that Urolithin A, a remarkable gut-derived metabolite significantly suppresses the expression and release of pro-inflammatory SASP and DAMP factors,” said Dr. Amit Sharma of the Lifespan Research Institute, the study’s lead author. “This effect is driven, at least in part, by reducing cytosolic DNA release and dampening the cGAS-STING signaling pathway – a central player in chronic inflammation.”

Is the hype real?

Urolithin A has been making a lot of buzz lately, given its availability as a supplement, which makes this pre-print particularly timely. “This is an exciting study as it opens up the possibility of thinking how gut metabolites can influence inflammation by modulating the SASP,” said another Buck researcher, Dr. Pankaj Kapahi, who was not involved in this study.

“The growing excitement around Urolithin A as a potent anti-aging molecule is well-founded, and our findings take this a step further, unveiling the precise mechanisms behind its anti-inflammatory power,” Sharma noted. “This breakthrough provides a deeper understanding of how Urolithin A combats the hallmarks of aging.”

Importantly, genetics dictate how we metabolize Urolithin A. According to one study, only 40% of people are able to produce it from natural precursors in meaningful quantities [5]. However, there are still not a lot of human studies that involve Urolithin A.

“Our results open new doors for exploring Urolithin A as a targeted and selective intervention against inflammaging and its associated diseases,” said Sharma. “Its exceptional ability to reduce inflammation and tackle the root causes of inflammaging left us astonished. This molecule could redefine the fight against age-related inflammation and its devastating consequences.”

Literature

[1] Barkovskaya, A., Brauning, A., Chamoli, M., Rane, A., Andersen, J. K., & Sharma, A. (2025). Mitigating Proinflammatory SASP and DAMP with Urolithin A: A Novel Senomorphic Strategy. bioRxiv, 2025-01.

[2] Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature reviews Molecular cell biology, 22(2), 75-95.

[3] Ballesteros-Alvarez, J., Nguyen, W., Sivapatham, R., Rane, A., & Andersen, J. K. (2023). Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse model of Alzheimer’s disease. Geroscience, 45(2), 1095-1113.

[4] Zhao, H., Song, G., Zhu, H., Qian, H., Pan, X., Song, X., … & Liu, C. (2023). Pharmacological Effects of Urolithin A and Its Role in Muscle Health and Performance: Current Knowledge and Prospects. Nutrients, 15(20), 4441.

[5] D’Amico, D., Andreux, P. A., Valdés, P., Singh, A., Rinsch, C., & Auwerx, J. (2021). Impact of the natural compound urolithin A on health, disease, and aging. Trends in molecular medicine, 27(7), 687-699.

Cyclarity Therapeutics, a biotechnology company based at the Buck Institute in California, has launched its first human clinical trial.

Its primary candidate cyclodextrin drug, UDP-003, focuses on 7-ketocholesterol, an oxidized cholesterol variant that builds up in cells as we age. Atherosclerosis involves the accumulation of plaque within arteries, and it primarily results from this oxidized form of cholesterol.

Heart disease is the leading cause of death worldwide. If successful, this drug could potentially help 70 to 80 percent of people that have heart disease and are at risk of having heart attacks.

Current treatment of heart disease includes lifestyle and dietary interventions, statins, and surgery. However, these are not that effective, and there is currently no effective way to reverse the condition. If UDP-003 is a success in the coming years, it will be a game changer.

Not only will it transform how we treat heart disease, it will be a clear demonstration of how tackling the root causes of aging can lead to proper solutions to age-related diseases.

Trials and tribulations

The original plan had been to launch the trials in Cambridge, UK working with the MHRA (similar to the FDA in the USA), but, unfortunately, there were setbacks.

Regular readers may recall our last interview with Dr. Matthew O’ Connor from Cyclarity, CEO of Scientific Affairs, where he explained the delay:

The bad thing is that post Brexit, it seems that the MHRA has gotten a bit backlogged and isn’t able to keep up with our current demands on their time. It takes too long to get meetings and responses to applications currently. We’ve had to take our first human clinical trial to Australia, where it’s a faster, more streamlined, and cheaper process.

While this has led to a delay in starting trials for this potentially transformative therapy, it is great to see it finally moving forward.

Dr. Matthew O’ Connor was previously the Vice President of Research at the SENS Research Foundation for nine years (now the LRI, of which Lifespan.io is part), where initial research for what was to become UDP-003 was conducted. This trial is a proud moment for both Cyclarity and our organization.

Australia is leading the charge

This research will now take place at CMAX, a leading clinical research center in Australia, in partnership with Monash University. The trials will proceed under the guidance of Dr. Stephen Nicholls, the Director of the Monash Victorian Heart Institute in Melbourne and a Professor of Cardiology at Monash University.

In the recent Cyclarity press release, Dr. Matthew O’Connor said: “We are excited to be working with Dr. Nicholls on a groundbreaking advancement in cardiovascular care. As we advance into being a clinical stage company, Cyclarity is focused on bringing truly disease-modifying treatments for the world’s deadliest disease into reality.”

The Phase 1 clinical study will include a section featuring single ascending dose and multiple ascending dose methodologies as well as a unique segment involving 12 patients suffering from acute coronary syndrome.

This trial is intended to assess the safety of UDP-003 in patients with pre-existing plaque and to collect initial insights on its efficacy.

Cyclarity has already finished the manufacturing process for the human-quality drug material in what’s known as the Current Good Manufacturing Practice (the CGMP). They have human-grade material packaged and in sterile, single-use vials ready for patients to receive.

Thorough studies necessary for investigational new drug approval have been completed, showing no expected toxicity issues and ensuring a safe route for clinical advancement. All essential documents for trial authorization have been submitted and accepted, which means that the clinical trial should commence in the very near future.

We will be interviewing Dr. Matthew O’ Conner from Cyclarity and finding out more about this exciting development, so stay tuned for that in the next week. Finally, we wish to congratulate the Cyclarity team on this important milestone for our field. Perhaps this will lead to more acceptance of the idea that to tackle age-related diseases, we need to tackle the underlying reasons we age.

Researchers have discovered that intermittent fasting increases myelin in aged mice, leading to better neural function and coordination.

Crucial proteins and a well-known intervention

Normally, neuronal axons are coated in a protein sheath made of myelin, which is necessary for their proper function [1]. Myelination is most known to be impeded by multiple sclerosis, but it also decreases with aging [2]. It is predominantly formed from two key proteins, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) [3], and previous work has found that upregulating the expression of these proteins has a beneficial effect on myelination [4].

Other work has found that myelination can be affected by diet and nutrition [5]. However, that work did not focus on these researchers’ chosen intervention: intermittent fasting, which has been found in substantial previous research to have metabolic and anti-inflammatory benefits, particularly in the context of aging [6].

Fasting for 18 hours a day

For their experiments, the researchers used three groups of mice: ten young mice, ten older mice, and eight older mice that had undergone intermittent fasting fof ten weeks, in which they were only allowed to eat for six hours a day. The researchers first began by testing overall markers of physical function: on the wire hanging test, the fasting mice were able to hold on for longer than the old control group, and they trended towards being able to run faster and longer than this group as well.

In a balance beam test, the fasting proved exceptionally potent: the fasting group was able to perform just as well as the young mice, far outpacing their same-aged counterparts. However, cognitive function was found to be unaffected: there was no benefit according to a Y maze test.

Stronger motor signals

A closer look at the mice’s muscles may have revealed why. While the maximum electrical signal strength going from the nerves to the muscles was not significantly affected, the treatment group had higher average signal strength. Looking at the frequency ranges involved revealed that the treatment group could exert more force and could react more quickly than similarly aged mice that were fed freely.

The brain was affected as well. Measuring whole-brain connectivity, the researchers found that the brains of the treated mice were less connected in ten areas but more connected in seven, particularly in places related to motor function and sensory input. Comparing these connection differences to the physical tests, the researchers concluded that these changes may also be responsible for the improvements they found.

Myelin was directly improved

Finally, the researchers looked directly at the myelin in the brain. Interestingly, and possibly of concern, the fasting group had reduced axonal diameters compared to the aged control group, suggesting an increase in degeneration. However, they had substantially more myelin, particularly on their smaller axons. These findings were true for both motor and non-motor portions of the brain, and the researchers note that this has been documented to occur in other animals, including people, who are recovering from demyelinating diseases [5].

Both MBP and MAG were positively affected. The treated mice had significantly more of both proteins in both of the tested areas, although there was no significant increase in MAG in the motor cortex. Myelinated fibers were found to trend towards being more common and longer in the fasting group. Overall, these results suggest that fasting somewhat changes the brain, and the researchers hold that these changes are beneficial.

While this is only a mouse study, it is in line with previous research showing that such dietary interventions may have beneficial effects on the brain. Furthermore, while it may not be appropriate for everyone, intermittent fasting is a freely available intervention. More studies may reveal whether or not it has beneficial effects on the myelin, and muscle coordination, of older people.

Literature

[1] Almeida, R. G., & Lyons, D. A. (2017). On myelinated axon plasticity and neuronal circuit formation and function. Journal of Neuroscience, 37(42), 10023-10034.

[2] Nickel, M., & Gu, C. (2018). Regulation of central nervous system myelination in higher brain functions. Neural plasticity, 2018(1), 6436453.

[3] Deng, S., Shu, S., Zhai, L., Xia, S., Cao, X., Li, H., … & Xu, Y. (2023). Optogenetic stimulation of mPFC alleviates white matter injury‐related cognitive decline after chronic ischemia through adaptive myelination. Advanced science, 10(5), 2202976.

[4] Zhang, Q., Zhu, W., Xu, F., Dai, X., Shi, L., Cai, W., … & Hu, X. (2019). The interleukin-4/PPARγ signaling axis promotes oligodendrocyte differentiation and remyelination after brain injury. PLoS biology, 17(6), e3000330.

[5] Langley, M. R., Triplet, E. M., & Scarisbrick, I. A. (2020). Dietary influence on central nervous system myelin production, injury, and regeneration. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1866(7), 165779.

[6] De Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. New England Journal of Medicine, 381(26), 2541-2551.