Investigating the bidirectional interactions between senotherapeutic agents and human gut microbiota

Biological ageing is a time-dependent process that has implications for health and disease. Cellular senescence is a key driver in ageing and age-related diseases. Senotherapeutic agents have been shown to slow biological ageing by eliminating senescent mammalian cells. Given the increasing awareness of the gut microbiome in regulating human health, this study aimed to investigate the effects of senotherapeutic agents as pharmacological interventions on the human gut microbiota. In this study, the bidirectional effects of four senotherapeutic agents, quercetin, fisetin, dasatinib, and sirolimus, with the gut microbiota sourced from healthy human donors were investigated. The results revealed that quercetin was completely biotransformed by the gut microbiota within six hours, while dasatinib was the most stable of the four compounds. Additionally, metagenomic analysis confirmed that all four compounds increased the abundance of bacterial species associated with healthy ageing (e.g., Bacteroides fragilis, Bifidobacterium longum, and Veillonella parvula), and decreased the abundance of pathogenic bacteria primarily associated with age-related diseases (e.g., Enterococcus faecalis and Streptococcus spp.). The findings from this study provide a comprehensive understanding of the pharmacobiomics of senotherapeutic interventions, highlighting the potential of microbiome-targeted senolytics in promoting healthy ageing.