Key points are not available for this paper at this time.
ABSTRACT Intestinal senescence is an important factor in systemic aging and age‐related diseases; however, detailed studies have been limited due to the lack of robust experimental models. In this study, we established cellular senescence models of human small intestinal organoids using two senescence‐inducing agents: butyrate (an endogenous microbial metabolite) and cisplatin (an exogenous chemotherapeutic agent). Both molecules induced senescence‐associated features, including increased p16INK4a , CDKN1A , IL8 , and TNF expression, as well as SA‐β‐Gal activity. RNA‐sequencing revealed that cisplatin, but not butyrate, activated the p53 signaling pathway, whereas both downregulated various nutrient absorption and metabolism‐related pathways. These models exhibited reduced nutrient transporter expression, diminished glucose uptake, and decreased vitamin D responsiveness, thus recapitulating the features of aged or damaged intestinal tissue. In cisplatin‐treated organoids, epithelial to mesenchymal transition (EMT)‐related gene ontologies were enriched based on RNA‐sequencing. The induction of EMT through cisplatin‐induced senescence was further confirmed by EMT marker gene expression, which decreased following the inhibition of TGF‐β signaling, a canonical EMT‐inducing pathway. Notably, TGF‐β signaling inhibition attenuated senescence‐induced inflammation and nutrient dysfunction, which suggests the importance of EMT as a target for preventing intestinal senescence. Our models provide a novel platform for examining the intestine‐specific molecular mechanisms of senescence associated with distinct senescence‐inducing mechanisms and for developing strategies to prevent age‐related intestinal dysfunction.
Ayabe et al. (Fri,) studied this question.