Ulcerative colitis (UC) is a chronic and recurrent gastrointestinal disease that affects millions of humans worldwide and imposes a huge social and economic burden. It is necessary to find safe and efficient drugs for preventing and treating UC. The aim of this study was to determine whether ganoderic acid (GA), the main bioactive components of Ganoderma lucidum, has preventive and therapeutic effect on UC in a dextran sulfate sodium (DSS)-induced UC mouse model. Our experimental results showed that GA significantly ameliorated the body weight loss and disease activity index (DAI) of UC mice. GA significantly restored 11% of the colon length and 69% of the spleen index compared to UC mice. GA significantly decreased the intestinal inflammatory response and improved the barrier function of the intestine by upregulating the tight junction proteins Zonula occludens-1 (ZO-1), occludin and claudin-1. A co-housing experiment showed that gut microbiota accounted for the therapeutic activity of GA on UC, which was confirmed by fecal microbiota transplantation from GA-treated mice to the UC mice. Furthermore, 16S rDNA high-throughput sequencing of fecal bacteria showed that GA significantly enriched the abundance of Lactobacillus, Oscillospira, Odoribacter and Ruminococcus, which were positively correlated with colon length. Furthermore, this study found the functional metabolites, including Indole-3-acetaldehyde (IAAld), Glutamine (Gln) and Glutathione (GSH), reduced barrier damage in the Caco-2 cell model. In conclusion, this study suggests that GA could ameliorate UC by improving intestinal barrier function via modulating gut microbiota and associated metabolites.

Cognitive frailty (CF), characterized by concurrent cognitive and motor decline, is a major challenge to healthy aging, yet effective interventions remain limited. Klotho, an anti-aging protein that declines with age, has been implicated in both hippocampal function and skeletal muscle homeostasis. In this study, we investigated whether aerobic exercise combined with multisensory stimulation training (CT) ameliorates age-related CF through systemic Klotho signaling. A 16-month-old mouse model of age-related CF was assigned to aerobic training, multisensory stimulation, or combined training, and behavioral, electrophysiological, histological, and molecular assessments were performed. To examine the mechanistic role of Klotho, dual-route shRNA delivery was used to inhibit systemic Klotho expression. CT significantly improved cognitive and motor performance compared with either intervention alone. CT also increased hippocampal dendritic spine density and long-term potentiation, reduced collagen deposition in gastrocnemius muscle, and upregulated Klotho, FGF19, and FGFR1 expression in both hippocampus and muscle, accompanied by elevated serum Klotho levels. Klotho knockdown attenuated these beneficial effects, reduced PSD95 and GluN2B expression, and increased MuRF3 and TNF-α levels. These findings suggest that CT alleviates cognitive frailty and that systemic Klotho is a key mediator linking hippocampal synaptic function and skeletal muscle homeostasis.