Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial

Nov 1, 2025Nature aging

Urolithin A may slow age-related immune decline in a controlled trial

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Abstract

In a trial of 50 healthy middle-aged adults, urolithin A (UA) supplementation for 4 weeks led to a 0.50 percentage point increase in peripheral naive-like CD8 T cells.

UA supplementation was associated with a significant increase in CD8 fatty acid oxidation capacity, with a treatment difference of 14.72 percentage points.
Participants receiving UA showed augmented mitochondrial biogenesis in CD8 T cells and increased levels of peripheral NK cells and nonclassical monocytes.
Improvements were observed in T cell activation, specifically enhanced TNF secretion, and bacterial uptake by monocytes in the UA group.
Exploratory analysis indicated that UA influenced gene expression across immune cell types, affecting pathways related to inflammation and metabolism.
Findings suggest that UA could modulate immune cell composition and function, potentially addressing age-related immune decline.

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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 inducer, expands T memory stem cells (T) 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) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8fatty 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 CD8cells, increased peripheral CD56CD16NK cells, and nonclassical CD14CD16monocytes 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 . ClinicalTrials.gov registration number: NCT05735886 . SCM -1 + + + + dim bright lo hi

Key numbers

0.50 percentage points

Increase in

Change in percentage of naive-like after 28 days of intake.

14.72 percentage points

Increase in CD8 T Cell Fatty Acid Oxidation Capacity

Change in fatty acid oxidation capacity of after supplementation.

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Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial

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