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000305613 1001_ $$00000-0002-4887-1492$$aDenk, Dominic$$b0
000305613 245__ $$aEffect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
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000305613 520__ $$aMitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day-1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 .
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000305613 7001_ $$aSingh, Anurag$$b1
000305613 7001_ $$aKasler, Herbert G$$b2
000305613 7001_ $$00000-0002-8499-9514$$aD'Amico, Davide$$b3
000305613 7001_ $$aRey, Julia$$b4
000305613 7001_ $$00009-0009-9928-9388$$aAlcober-Boquet, Lucía$$b5
000305613 7001_ $$aGorol, Johanna M$$b6
000305613 7001_ $$00000-0001-6991-9910$$aSteup, Christoph$$b7
000305613 7001_ $$aTiwari, Ritesh$$b8
000305613 7001_ $$00000-0002-1850-6611$$aKwok, Ryan$$b9
000305613 7001_ $$00000-0001-9785-3883$$aArgüello, Rafael J$$b10
000305613 7001_ $$aFaitg, Julie$$b11
000305613 7001_ $$aSprinzl, Kathrin$$b12
000305613 7001_ $$0P:(DE-HGF)0$$aZeuzem, Stefan$$b13
000305613 7001_ $$aNekljudova, Valentina$$b14
000305613 7001_ $$aLoibl, Sibylle$$b15
000305613 7001_ $$00000-0003-3703-3183$$aVerdin, Eric$$b16
000305613 7001_ $$aRinsch, Chris$$b17
000305613 7001_ $$00000-0002-3928-6080$$aGreten, Florian R$$b18
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