Enhancing Quercetin Bioavailability Attenuates Aging Phenotypes via the Gut Microbiota-Intestinal Barrier Axis in...

Aging is characterized by progressive functional decline associated with alterations in gut microbiota, epithelial barrier dysfunction, and cellular senescence. Although quercetin has been proposed as a potential anti-aging compound, its clinical application is limited by poor bioavailability. In this study, we investigated whether enhancing quercetin bioavailability using EubioQuercetin (EQN) modulates aging-related phenotypes through the gut microbiota-intestinal barrier axis.

Male C57BL/6J mice were treated with EQN or conventional quercetin (CQN) for 12 weeks. External aging phenotypes were assessed using a composite aging score based on hair glossiness, hair loss, and the presence of white hair. Gut microbiota composition was analyzed via 16S rRNA sequencing with centered log-ratio transformation, and intestinal gene expression was assessed by quantitative reverse transcription-polymerase chain reaction.

EQN significantly reduced the aging score compared with the control group (median 4.5 vs. 8, p < 0.01), while CQN also showed a moderate reduction. Microbiota analysis identified taxa positively associated with aging (Lactobacillus, Romboutsia, Desulfovibrio, and Lachnoclostridium) and negatively associated taxa (Akkermansia and Christensenellaceae). EQN suppressed aging-associated taxa and partially increased taxa linked to a healthier microbiota profile. At the intestinal level, EQN downregulated senescence-associated genes (p21, PCNA, and Lgr5) and upregulated the tight junction gene claudin-1. In contrast, systemic inflammatory markers and short-chain fatty acids were not significantly associated with the aging score.

These findings indicate that enhancing quercetin bioavailability attenuates externally assessed aging phenotypes in aged mice and is associated with coordinated changes in gut microbiota and intestinal gene expression. Modulation of the gut microbiota-intestinal barrier axis may represent a potential mechanism underlying these effects.