Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain-of-activity mouse model presents with a pre-mature aging-like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75-week old) female C57BL/6 mice with a Cdc42 activity specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN-treated animals displayed a youthful level of the aging-associated cytokines IL-1b, IL-1a and INFg in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells.  Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan.