No abstract

Osteoarthritis (OA) is the most common age‐related joint disorder with no effective therapy. According to the World Health Organization, OA affects over 500 million people and is characterized by degradation of cartilage and other joint tissues, severe pain, and impaired mobility. Mitochondrial dysfunction contributes to OA pathology. However, interventions to rescue mitochondrial defects in human OA are not available. Urolithin A (Mitopure) is a natural postbiotic compound that promotes mitophagy and mitochondrial function and beneficially impacts muscle health in preclinical models of aging and in elderly and middle‐aged humans. Here, we showed that Urolithin A improved mitophagy and mitochondrial respiration in primary chondrocytes from joints of both healthy donors and OA patients. Furthermore, Urolithin A reduced disease progression in a mouse model of OA, decreasing cartilage degeneration, synovial inflammation, and pain. These improvements were associated with increased mitophagy and mitochondrial content, in joints of OA mice. These findings indicate that UA promotes joint mitochondrial health, alleviates OA pathology, and supports Urolithin A's potential to improve mobility with beneficial effects on structural damage in joints.

Urolithin A is a gut microbiome derived postbiotic that has been shown to stimulate mitophagy, and improve muscle and mitochondrial health when administered orally to humans. In three separate randomized trials, we have now investigated the effect of topical administration of Urolithin A on skin aging features and on UVB-mediated photodamaged skin. Post-menopausal women with evidence of skin aging such as >Grade 3 wrinkle formation were included in a split-face/arm study design in the first trial (aging study 1; n=48), followed by a second larger trial (aging study 2; n=108) in middle-aged men and women focusing on wrinkle reduction. Healthy participants were included in the placebo-controlled, randomized UVB-induced trial (photo-damage trial; n=22). Participants were randomized to receive topical supplementation with either 0.5% Urolithin A cream or placebo for 8-weeks in a low-dose arm or 1% Urolithin A cream or placebo in the high-dose arm in the aging study 1. In the aging study 2 participants were randomized to receive 1% UA in a day-cream, a night cream and a serum, that were compared to the untreated site. For the photo-damage trial, topical patches containing either 0.5% or 1% UA or placebo cream were applied for 24-hours following UVB irradiation. The primary outcome in the aging study 1 was an impact on biological pathways linked to skin aging in skin biopsies, and an impact on skin barrier function after 8-weeks. Key secondary endpoints were a change in facial wrinkle appearance (crows feet area). The aging study 2 focused on wrinkle reduction as a primary outcome. In the UVB-mediated photo-damage study, the primary read-out was the change in erythema after application. Molecular analyses were conducted on skin biopsies and using ex-vivo systems to investigate the mechanism of action mediating skin protective effects of Urolithin A. In the aging study 1, Urolithin A at 1% significantly up-regulated collagen synthesis pathways in human skin biopsies and led to a decrease in wrinkle depth on facial wrinkles. The lower dose had no significant impact. There was no change on skin barrier function with both doses suggesting maintenance of a healthy skin barrier function. In aging study 2, topical application of Urolithin A at the 1% dose in different formulations (day-cream, night cream and serum) led to significant wrinkle reduction compared to the untreated side, confirming the previous findings. Skin hydration was improved significantly as well. In the third trial, investigating impact on photodamaged skin, Urolithin A application led to a significant decrease in UV-induced erythema (~14%) compared to the untreated area, while placebo and lower dose UA cream showed no benefits. Urolithin A topical administration was safe and well-tolerated in all studies. UA also inhibited collagen degrading and pro-inflammatory pathways and up-regulated gene expression of biomarkers linked to induction of mitophagy and autophagy in human skin cells. Taken together, these clinical studies support the topical use of Urolithin A to manage and prolong skin health longevity by acting at the cellular level, supporting collagen structure, reducing wrinkle appearance and protecting against photoaging.