In a preprint examine, scientists from Lifespan Analysis Institute and the Buck Institute for Analysis on Growing old have revealed their findings that Urolithin A, a molecule that has garnered a variety of consideration within the longevity subject, potently reduces senescence-related markers in human fibroblasts [1].
Senolytic versus senomorphic
Mobile senescence is a well-documented facet of getting old [2], however the perfect technique to counter it stays a query. Senescent cells play an necessary position in growth, wound therapeutic, and anti-cancer defenses, however with age, as their numbers develop, they begin doing extra hurt than good.
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Whereas even in aged tissue, the relative prevalence of senescent cells is normally small, they wreak havoc by emitting damage-associated molecular patterns (DAMPs) in addition to the SASP. These set off extreme immune response and are documented to contribute to the systemic, age-related irritation generally known as inflammaging.
Clearing out senescent cells, one thing that the immune system ought to naturally do, varieties the idea of the senolytic method, which dominates right this moment’s analysis in academia and biotech. The duty is difficult, nevertheless, notably as a result of senescent cells are extremely heterogeneous and are additionally stuffed with dangerous molecules which are launched when the cell dies. One attractive different method is the senomorphic one, which entails altering senescent cells in a means that would go away them in place however make them much less dangerous.
Urolithin A may assist heal senescent cells
Urolithin A is a molecule that has gained reputation within the longevity group after demonstrating a number of healthspan and lifespan advantages in animal fashions and people. This metabolite is produced by our intestine micro organism from precursors present in meals like nuts, berries, and pomegranates, and it has been proven to lower irritation and enhance muscle perform in people. In animal fashions, it led to important will increase in lifespan. As an illustration, in a small examine from the Buck Institute for Analysis on Growing old, Urolithin A produced a 19% enhance in lifespan in mice, which is among the many finest outcomes for any intervention [3].
On this examine, the researchers induced two kinds of senescence in human fetal lung fibroblasts: one triggered by the chemotherapy drug doxorubicin and one other by mobile division (replicative senescence). Whereas the therapy had little impact on the 2 widespread senescence markers p16 and p21, it did considerably cut back the secretion of the most important pro-inflammatory SASP elements interleukin 6 (IL-6) and interleukin 8 (IL-8) in addition to the expression of the corresponding genes in each fashions of senescence.
This translated to decrease ranges of paracrine senescence, which happens when SASP from senescent cells induces senescence in neighboring cells. The researchers cultured wholesome fibroblasts within the presence of media collected from both management senescent cells or these handled with Urolithin A and located that the latter situation brought about much less paracrine senescence.
“Urolithin A has generated a variety of pleasure within the final a number of years based mostly on its potential use as an anti-aging therapeutic,” mentioned Dr. Julie Andersen of the Buck Institute for Analysis on Growing old, a co-author of this examine and the sooner one exhibiting that Urolithin A will increase lifespan in mice. “This consists of scientific knowledge demonstrating its potential to sluggish lack of muscle perform in older people. Our research display a novel mechanism of motion for the compound – suppression of persistent irritation related to mobile senescence, a significant contributor to a number of age-related illnesses. This affords a novel method for treating a variety of persistent illnesses which might enhance total high quality of life in later years.”
The mechanism
The researchers went one step additional and tried to elucidate the potential mechanisms behind these results. Mobile senescence has been linked to cytosolic DNA, that are fragments of DNA floating round within the cytosol as an alternative of staying the place they belong: within the nucleus and in mitochondria. Since it may be of viral or bacterial origins, cytosolic DNA is acknowledged by the cell as an indication of invasion, and the alarm is raised through the cGAS-STING pathway, which drives irritation.
Urolithin A considerably decreased the abundance of cytosolic DNA within the handled cells. The researchers counsel that this may need one thing to do with Urolithin A’s potential to induce mitophagy [4], the method of eliminating unhealthy mitochondria. Broken mitochondria leak DNA, and reducing their burden could be in step with the noticed discount in cytosolic DNA.
“We found that Urolithin A, a exceptional gut-derived metabolite considerably suppresses the expression and launch of pro-inflammatory SASP and DAMP elements,” mentioned Dr. Amit Sharma of the Lifespan Analysis Institute, the examine’s lead writer. “This impact is pushed, not less than partly, by decreasing cytosolic DNA launch and dampening the cGAS-STING signaling pathway – a central participant in persistent irritation.”
Is the hype actual?
Urolithin A has been making a variety of buzz recently, given its availability as a complement, which makes this pre-print notably well timed. “That is an thrilling examine because it opens up the potential for considering how intestine metabolites can affect irritation by modulating the SASP,” mentioned one other Buck researcher, Dr. Pankaj Kapahi, who was not concerned on this examine.
“The rising pleasure round Urolithin A as a potent anti-aging molecule is well-founded, and our findings take this a step additional, unveiling the exact mechanisms behind its anti-inflammatory energy,” Sharma famous. “This breakthrough offers a deeper understanding of how Urolithin A combats the hallmarks of getting old.”
Importantly, genetics dictate how we metabolize Urolithin A. In response to one examine, solely 40% of individuals are capable of produce it from pure precursors in significant portions [5]. Nonetheless, there are nonetheless not a variety of human research that contain Urolithin A.
“Our outcomes open new doorways for exploring Urolithin A as a focused and selective intervention towards inflammaging and its related illnesses,” mentioned Sharma. “Its distinctive potential to scale back irritation and deal with the foundation causes of inflammaging left us astonished. This molecule might redefine the combat towards age-related irritation and its devastating penalties.”
Literature
[1] Barkovskaya, A., Brauning, A., Chamoli, M., Rane, A., Andersen, J. Okay., & Sharma, A. (2025). Mitigating Proinflammatory SASP and DAMP with Urolithin A: A Novel Senomorphic Technique. bioRxiv, 2025-01.
[2] Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021). Mobile senescence in ageing: from mechanisms to therapeutic alternatives. Nature critiques Molecular cell biology, 22(2), 75-95.
[3] Ballesteros-Alvarez, J., Nguyen, W., Sivapatham, R., Rane, A., & Andersen, J. Okay. (2023). Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse mannequin of Alzheimer’s illness. Geroscience, 45(2), 1095-1113.
[4] Zhao, H., Track, G., Zhu, H., Qian, H., Pan, X., Track, X., … & Liu, C. (2023). Pharmacological Results of Urolithin A and Its Function in Muscle Well being and Efficiency: Present Data and Prospects. Vitamins, 15(20), 4441.
[5] D’Amico, D., Andreux, P. A., Valdés, P., Singh, A., Rinsch, C., & Auwerx, J. (2021). Impression of the pure compound urolithin A on well being, illness, and getting old. Developments in molecular drugs, 27(7), 687-699.
