Urolithin A is a metabolite produced by gut bacteria, widely used as a dietary supplement, and has attracted attention from the aging research community for its positive effects on mitochondrial function. Of the various approaches to improving mitochondrial function with compounds classed as supplements, urolithin A is arguably the one that researchers know the least about when it comes to how exactly it functions, but equally there is stiff competition here. Knowledge of the exact mechanisms involved in translating the known immediate biochemical interactions of various compounds to better functioning mitochondria is sketchy at best for NAD+ upregulation, mitoQ, plastinquinones such as SkQ1, elamipretide, and so forth. Further, many of these do not appear to perform as well as exercise when it comes to measures of mitochondrial function.
The function of any one mitochondrion is complex and incompletely understood. Then there is the point that mitochondria exist in their hundreds in every cell, a dynamic population undergoing division, fusion, and transfer of component parts between one another. Further, mitochondria are policed by another incompletely understood set of mechanisms of quality control called mitophagy responsible for identifying and recycling damaged mitochondria. Strategies for improving mitochondrial function largely seem to improve mitophagy, but it isn't all that clear as to why this is the case, or whether it is the primary mechanism by which mitochondrial function is improved.
In today's open access paper, researchers focus on the anti-inflammatory properties of urolithin A. They provide evidence for this to occur in part by downregulating the inflammatory signaling generated by senescent cells. This connects to mitochondrial function because inflammatory signaling of this nature (and in non-senescent cells as well) can arise due to the mislocalization of mitochondrial DNA fragments. As mitochondrial function declines more such fragments of mitochondrial DNA are released into the cell, where they are mistaken for bacterial DNA, provoking the same inflammatory reactions as take place during infection. Less of this is a good thing.
Mitigating Pro-Inflammatory SASP and DAMP With Urolithin A: A Novel Senomorphic Strategy
Aging is associated with increased systemic sterile inflammation (inflammaging), which promotes several age-associated diseases. Key drivers of inflammaging include senescence-associated secretory phenotype (SASP) factors released by senescent cells. While the exact components of SASP vary between different senescent cells and tissues, core SASP factors include pro-inflammatory chemokines, matrix-degrading enzymes, and several damage-associated molecular pattern (DAMP) molecules. Pharmacological inhibition of SASP using small molecules known as senomorphics has been proposed as a potential intervention for age-associated diseases. However, such treatments include several flavonoid inhibitors of the p38 MAPK/NF-κB pathway, free radical scavengers, and Janus kinase (JAK) pathway inhibitors that are nonselective and broadly inhibit pathways also involved in homeostatic immune responses to various physiological challenges, thus limiting their systemic therapeutic application).
Here we present data indicating that the gut metabolite Urolithin A (UA) acts as a senomorphic compound. Senescent cells are known to contribute to aging and age-related diseases. One key way they influence aging is by secreting senescence-associated secretory phenotype (SASP) factors along with several damage-associated molecular pattern (DAMP) molecules. Consequently, inhibiting SASP and DAMP signaling (senomorphics) has emerged as a therapeutic strategy.
Digestive tract bacteria naturally produce UA through the metabolism of ellagitannins and ellagic acid, which are abundant in berries, nuts, and pomegranates. UA has been reported to be a potent anti-inflammatory agent, alleviating several age-related conditions in vivo. Preclinical studies have also shown its protective role against aging and age-related conditions affecting the muscles, brain, joints, and other organs. In a recent clinical trial, UA supplementation improved muscular endurance in older adults. Here we demonstrate that UA lowers the expression and release of pro-inflammatory SASP and DAMP factors, at least in part, by downregulating cytosolic DNA release and subsequent decrease in cGAS-STING signaling.
View the full article at FightAging
