Enhancing Quercetin Bioavailability Attenuates Aging Phenotypes via the Gut Microbiota–Intestinal Barrier Axis in Aged Mice

Aging is characterized by a progressive decline in physiological functions driven by cellular senescence, chronic inflammation, and alterations in the gut microbiota. Quercetin is a potential anti-aging compound; however, its clinical application is limited by low bioavailability. In this study, we investigated whether enhancing quercetin bioavailability using EubioQuercetin (EQN) improves aging phenotypes by modulating the gut microbiota–intestinal axis. Male C57BL/6J mice were treated with EQN or conventional quercetin for 12 weeks. 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 evaluated via quantitative reverse transcription-polymerase chain reaction. Notably, EQN significantly reduced the aging score compared to the control (median = 4.5 vs. 8; p < 0.01), with greater efficacy than conventional quercetin. Microbiota analysis identified taxa that were positively (Lactobacillus, Romboutsia, Desulfovibrio, and Lachnoclostridium) and negatively (Akkermansia and Christensenellaceae) associated with aging. EQN selectively suppressed aging-associated taxa and increased the abundance of beneficial bacteria. It also downregulated the expression levels of senescence-related genes (p21, proliferating cell nuclear antigen, and leucine-rich repeat-containing G protein-coupled receptor 5) and upregulated those of tight junction genes (claudin-1 and -6), indicating improved intestinal barrier function. No significant associations were observed between the aging score and levels of short-chain fatty acids or most circulating proteins. Overall, these findings suggest that enhancing quercetin bioavailability amplifies its anti-aging effects through the coordinated modulation of gut microbiota and intestinal barrier function. Therefore, targeting the gut microbiota–intestinal axis via bioavailable dietary polyphenols represents a promising strategy for promoting healthy aging.