Upregulation of the Cdc42 GTPase limits replicative lifespan in budding yeast

Cell polarity underlies various cellular processes, including cell proliferation and asymmetric cell division. Cdc42, a conserved Rho GTPase, plays a central role in polarity establishment in yeast and animals. While cell polarity is critical for the asymmetric division of budding yeast, whether Cdc42 impacts lifespan is not clear. Here, we show by live-cell imaging that the active Cdc42 level is sporadically elevated in wild-type cells during repeated cell divisions but rarely in the long-lived bud8 deletion mutant. Remarkably, mild overexpression of Cdc42 causes premature aging with frequent symmetric cell divisions despite no harmful effects on young cells. Furthermore, deletion of BUD8 rescues the short lifespan of an rga1 mutant, which lacks a Cdc42 GTPase activating protein, and Bud8 competes with Rga1 for localization to cytokinesis remnants. Collectively, our findings suggest that upregulation of Cdc42 is a proximal cause of cell death in old yeast cells and that Bud8 counteracts Rga1 in modulating the Cdc42 activity to limit replicative lifespan.