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-β-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. 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

衰老作为多种疾病的高危因素，在很大程度上可归因于细胞衰老与线粒体功能损伤。本研究基于衰老相关转录组特征，借助连接图谱（Connectivity Map, CMAP）预测药物的抗衰活性。本研究发现激酶抑制剂GW8510可分别将酵母菌、C57BL/6J小鼠及ICR小鼠的寿命延长92.18%、31.9%与142.9%。从机制角度而言，GW8510可通过增强线粒体功能、降低衰老相关β-半乳糖苷酶（Senescence-associated beta-galactosidase, SA-β-gal）染色水平以及p21蛋白与衰老相关分泌表型（Senescence-Associated Secretory Phenotype, SASP）标志物的表达，改善细胞衰老状态，并逆转小鼠海马体、心脏、肾脏与肝脏中与衰老相关的组织形态学改变。GW8510的作用机制依赖于STE20（酵母PAK1同源蛋白），其与PAK1的结合解离常数（Kd）为0.82 μM。晶体结构解析结果显示，GW8510可结合于PAK1的ATP结合口袋。此外，抑制PAK家族蛋白可延缓小鼠的衰老进程。本研究为衰老机制研究提供了宝贵的科研资源，同时证实GW8510具有显著的临床转化潜力。本研究选用雄性ICR小鼠，设置2月龄年轻对照组、老年对照组与18月龄老年给药组，自18月龄起连续2周以2mg/kg的剂量给予GW8510干预。