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Abstract
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 premature 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‐1β, IL‐1α, and INFγ 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.
Highlights
Cdc42 is a small RhoGTPase involved in multiple and diverse functions of eukaryotic cells, including actin cytoskeleton reorganization, cell polarity, and cell growth (Cerione, 2004; Etienne-Manneville & Hall, 2002)
Genetic deletion of Cdc42GAP in mice (Cdc42GAP knock out) results in an elevated level of Cdc42-GTP in every tissue. This constitutive increase of Cdc42 activity in young mice leads to a premature aging-like phenotype that affects several tissues and results in a decrease in lifespan (Wang et al, 2007)
We recently identified a specific small-molecule inhibitor of Cdc42 activity termed CASIN (Cdc42 activity-specific inhibitor) (Liu et al, 2019)
Summary
Cdc42 is a small RhoGTPase involved in multiple and diverse functions of eukaryotic cells, including actin cytoskeleton reorganization, cell polarity, and cell growth (Cerione, 2004; Etienne-Manneville & Hall, 2002). To determine whether a short-term systemic CASIN treatment of aged animals might influence lifespan, we administered CASIN i.p. every 24 h for 4 consecutive days to 75-week-old female C57BL/6 mice (Figure 1a).
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