A benzenesulfonamide GW8510 rejuvenates mice and yeast through interaction with p21-Activated kinases

Aging, a risk factor for many diseases, is largely attributable to cell senescence and impaired mitochondrial function. Here, we used connectivity map (CMAP) to predict the anti-aging effects of drugs based on age-related transcriptomic signatures. We found the kinase inhibitor GW8510 can extend lifespan of yeast, and C57BL/6J or ICR mice by 92.18%, 31.9%, and 142.9%, respectively. Mechanistically, GW8510 can ameliorate cellular senescence by enhancing mitochondrial function, decreasing SA-ß-gal staining, p21 and SASP marker expression, and rescues age-related histomorphological changes in mouse hippocampus, heart, kidney and liver. The GW8510 mode of action depends on STE20 (yeast PAK1 homolog), and binds to PAK1 with Kd of 0.82 µM. The crystal structure shows that GW8510 binds to the PAK1 ATP binding pocket. Furthermore, inhibition of PAKs can delay the effects of aging in mice. This work provides a valuable resource for mechanistic aging studies and suggests strong clinical potential for GW8510. Overall design: Using male ICR mice, a young control group (2 months), an elderly control group and an elderly treatment group (18 months old) were set up, and GW8510 (2mg/kg) was continuously intervened for 2 weeks from 18 months