Impact of Urolithin A supplementation, a mitophagy activator on mitochondrial health of immune cells (MitoIMMUNE) - A randomized, double-blind, placebo-controlled trial in healthy adults

Mitochondrial dysfunction and stem cell exhaustion are hallmarks of aging, driving inflammaging and limiting immune function. Likewise, cancer is characterized by repression of mitochondrial dynamics in tumor-infiltrating leukocytes that fosters terminal T cell exhaustion. Yet, interventions to reliably improve immune function are still lacking. Urolithin A (UA) is a postbiotic known to improve muscle function in aged adults upon oral intake. We have recently shown that UA induces mitophagy in human CD8+ cells to induce formation of T memory stem cells, as well as sensitizing murine cancer to immunotherapy.

We here present results from a randomized, placebo-controlled trial in 50 aged adults where we administer UA (NCT05735886) over four weeks. The primary end points were changes in peripheral CD3+ cells, as well as alterations in mitochondrial activity in select immune populations. Intake of UA was safe and well-tolerated in the intervention cohort of 25 participants. Performing a complete immunophenotyping via spectral flow cytometry, we found that UA elicits immune remodeling characterized by broad changes of immune surface markers and mitochondrial measurements. We also assessed transcriptomic changes in PBMCs and alterations in circulating cytokines.

Collectively, our study constitutes an unprecedented intervention-based assessment of immune aging that globally characterizes the effect of UA on the immune system, proposing further validation in cancer.