Exercise alters transcriptional profiles of senescence and gut barrier integrity in intestinal crypts of aging mice

Abstract

Senescence is the gradual process of aging in tissues and cells, and a primary cause of aging-associated diseases. Among them, intestinal stem cells (ISCs) experience exhaustion during aging, leading to reduced regenerative capacity in the intestinal crypt, which impairs intestinal function and contributes to systemic health issues. Given the critical role ISCs play in maintaining intestinal homeostasis, preventing their senescence is essential for preserving intestinal function. Among the various strategies proposed to slow cellular senescence, regular exercise has emerged as one of the most well-known and widely accepted interventions. Here, we examined how exercise affects the small intestine in an aging mouse model. Using single-cell RNA sequencing, we found that signaling pathways and gene expression related to DNA replication and cell cycle progression were upregulated in ISCs. Additionally, genes promoting ribosome biogenesis showed increased expression in both ISCs and transit amplifying cells. Exercise also recovered Wnt signaling inhibition, potentially influencing ISC differentiation. Furthermore, exercise increased Reg3g expression in Paneth cells and improved gut barrier function, contrasting with findings from a diet-induced obese mouse model. This suggests that regular exercise helps inhibit the aging of ISCs in multiple ways, contributing to the maintenance of intestinal homeostasis. © The Author(s) 2025.