Icariin, a bioactive flavonoid from Epimedium, mitigates aging in female mice through gut microbiota-mediated sphingolipid metabolism

Female aging is characterized by hormonal imbalances and metabolic shifts, which significantly impact overall health. Icariin, a bioactive flavonoid derived from the functional herb Epimedium, has a long-standing history of use in traditional medicine and functional food products. Our previous research has demonstrated that icariin can enhance cognitive and motor functions in aged male mice and modulate the intestinal microbiota to resemble that of younger mice. However, its effects on female aging have remained largely unexplored. In this study, we aimed to investigate the anti-aging mechanisms of icariin in older female mice (24 months old). We employed a comprehensive approach, including behavioral tests, 16S rRNA sequencing, and multi-organ metabolic profiling. The results revealed that oral administration of icariin led to significant improvements in motor coordination and cognitive function. Additionally, icariin effectively reduced oxidative stress markers while simultaneously enhancing the activity of antioxidant enzymes. Gut microbiota analysis showed that icariin enriched beneficial taxa, such as <em>Akkermansia muciniphila </em>and <em>Dubosiella newyorkensis</em>, and suppressed pathogenic bacteria, including <em>Ileibacterium valens and</em> <em>Ruminococcus</em>. Non-targeted metabolomics identified sphingosine 1 phosphate (S1P) as a key mediator. Icariin administration resulted in an increase in serum S1P levels, which was positively correlated with the abundance of <em>Akkermansia</em>. Furthermore, S1P levels were positively associated with antioxidant activities and anti-inflammatory cytokines, while negatively linked to pro-inflammatory markers. Transcriptomics analysis further supported the role of S1P in suppressing the NF-κB pathway and enhancing neuroactive signaling. Based on these findings, our study positions icariin as a novel dietary candidate for mitigating female aging by restoring gut microbiota balance and sphingolipid metabolism. These results not only bridge the gap between traditional herbal medicine and functional food innovation but also offer a microbiota-targeted strategy for the management of menopausal health.