Deleting the mechanosensitive channel Piezo1 prevents gut motility decline in aging mice

In mice, aging slows whole gut and colonic transit, increases regional stiffness, and reduces smooth muscle contractility, according to a new preprint. Researchers investigated how physical tissue changes drive this functional decline. Inducible smooth muscle cell deletion of the mechanosensitive channel Piezo1 preserved youthful gut transit and force generation in older mice, while activating Piezo1 in young mice caused transit delays. Using single-cell transcriptomics, RNA velocity, stiffness-controlled cell and tissue cultures, and pharmacological tools, the team found that Piezo1 couples tissue stiffening to calcium-calcineurin-NFAT signaling. This cascade silences contractile gene programs, promoting a shift from contractile to synthetic smooth muscle cells and increasing gut wall stiffness. Human intestinal smooth muscle cell assays supported this pathway, and human carriers of PIEZO1 gain-of-function variants showed a trend toward delayed colonic transit.