A new clinical study published in Nature Aging reports that Urolithin A (UA), a naturally occurring postbiotic compound, may significantly reverse key aspects of immune aging in healthy adults. The randomized, double blind, placebo-controlled trial enrolled 50 participants aged 45 to 70 years, who received 1,000 mg of UA daily for 28 days. Researchers found that the supplement reprogrammed immune cell metabolism and restored mitochondrial function, addressing two major hallmarks of age-related immune decline.
The team observed that UA activates AMPK, inhibits mTOR, and increases the expression of PGC 1α, a central regulator of mitochondrial biogenesis. It also boosts sirtuin, FOXO, and Nrf2 signaling pathways, which help reduce oxidative stress and inflammation. By promoting mitophagy and increasing glutathione S transferase activity, UA improved mitochondrial quality, respiration, and energy efficiency, offering potential benefits for longevity and health span.
One key feature of immune aging is the loss of naive T cells, driven by chronic inflammation and mitochondrial dysfunction. UA supplementation increased naive like CD8⁺ T cells and improved their metabolic flexibility, shifting their energy use toward healthier fatty acid and amino acid oxidation. These changes were associated with higher PGC 1α levels, lower TOX expression (a marker of T cell exhaustion), and better mitochondrial biogenesis.
Natural killer cells and monocytes also showed notable improvements, including increased energy utilization and better bacterial clearance, without triggering systemic inflammation. Levels of IL 2 decreased, and pro inflammatory cytokines remained stable, suggesting that UA supports immune function without overstimulation.
Single cell transcriptomic analysis showed that UA increased the expression of genes linked to T cell memory and stemness, such as TCF7, LEF1, and IL7R, while reducing the activity of exhaustion related pathways including NR4A2 and CREM. These patterns suggest a broad rejuvenation of immune signaling networks.
UA demonstrated good safety and bioavailability, with no significant adverse effects compared with placebo. However, researchers noted that larger and longer duration trials are needed to confirm whether these cellular benefits translate into better resistance to infections or stronger vaccine responses.
Additional evidence from work by D’Amico and colleagues supports these findings. Their studies show that Urolithin A (Mitopure) enhances mitophagy and mitochondrial function in chondrocytes, reducing inflammation, cartilage degeneration, and pain in osteoarthritis models. This suggests wider protective benefits of UA across age related diseases.
Overall, the new study positions Urolithin A as a promising food derived therapeutic candidate for restoring mitochondrial health and rejuvenating the aging immune system. If confirmed in larger studies, UA could offer a safe and natural approach to strengthening immune resilience in midlife and beyond.
Reference
- Denk D, Singh A, Kasler HG, D’Amico D, Rey J, Alcober-Boquet L, et al. Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial. Nat Aging. 2025 Oct 31;1–14.
- Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019 Jun;1(6):595-603.
- D’Amico D, Olmer M, Fouassier AM, Valdés P, Andreux PA, Rinsch C, et al. Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell. 2022;21(8):e13662.
- D’Amico D, Andreux PA, Valdés P, Singh A, Rinsch C, Auwerx J. Impact of the Natural Compound Urolithin A on Health, Disease, and Aging. Trends in Molecular Medicine. 2021 July 1;27(7):687–99.