ザクロ由来化合物が免疫老化を逆転―新たな免疫強化法(Pomegranate-Derived Compound Strengthens Immune Defense)

2025-11-03 ゲーテ大学

<関連情報>

• https://aktuelles.uni-frankfurt.de/english/new-study-shows-pomegranate-derived-compound-strengthens-immune-defense/
• https://www.nature.com/articles/s43587-025-00996-x
• https://www.cell.com/immunity/fulltext/S1074-7613(22)00508-8

マイトファジー誘導剤ウロリチンAの加齢性免疫低下に対する効果:ランダム化プラセボ対照試験 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,Sibylle Loibl,Eric Verdin,Chris Rinsch & Florian R. Greten
Nature Aging  Published:31 October 2025
DOI:https://doi.org/10.1038/s43587-025-00996-x

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 (T_SCM) 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 CD56^dimCD16^bright NK cells, and nonclassical CD14^loCD16^hi 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.

ウロリチンA誘導マイトファジーによる優れた抗腫瘍免疫力を持つT記憶幹細胞の増殖 Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy

Dominic Denk ∙ Valentina Petrocelli ∙ Claire Conche ∙ … ∙ Pénélope A. Andreux ∙ Chris Rinsch ∙ Florian R. Greten
Immunity  Published:October 18, 2022
DOI:https://doi.org/10.1016/j.immuni.2022.09.014

Highlights

• UA induces Pink1-dependent mitophagy in CD8⁺ cells causing PGAM5 release
• Cytosolic PGAM5 augments Wnt signaling to drive T_SCM formation
• T_SCM induction augments anti-tumor immunity in vivo
• Urolithin can be used for ex vivo expansion of CAR-expressing T_SCM

Summary

T memory stem cells (T_SCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. T_SCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8⁺ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced T_SCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to T_SCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.