Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial
Dominic Denk, Anurag Singh, Herbert G. Kasler, Davide D’Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M. Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J. Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, S. Loibl, Eric Verdin, Chris Rinsch, Florian R. Greten
Abstract
Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day−1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 . Immune aging fosters multimorbidity and compromises control of infection and cancer. In a phase 1 randomized controlled trial in middle-aged adults, Denk and colleagues administer the mitophagy inducer urolithin A and profile cellular and metabolic aspects of immune aging.