WGX ‐50 Promotes Healthy Ageing in Caenorhabditis elegans : A Combined Computational and Experimental Study

作者：Guihua Jia, Jiayi Li, Abbas Khan, Aman Chandra Kaushik, Diyi Wu, Hongyu Chen, Rongpei Li, Jian Wang, Chen Zhang, Adil Farooq, Xueying Mao, Aamir Mehmood, Weidong Zhang, Heng Wang, Dong‐Qing Wei · 发表于：Chemical Biology & Drug Design · 年份：2025 · DOI：10.1111/cbdd.70214 · 被引用次数：2 · 研究领域：Genetics, Aging, and Longevity in Model Organisms、FOXO transcription factor regulation、Telomeres, Telomerase, and Senescence

ABSTRACT WGX‐50, a previously reported drug candidate for Alzheimer's disease, is derived from Zanthoxylum bungeanum Maxim commonly called Sichuan pepper. Its pharmacological actions for the long run benefit of human health have been extensively investigated. However, in terms of its anti‐aging effect, it totally remains unexplored. In this work, WGX‐50 was first reported to promote healthy aging in Caenorhabditis elegans with insights from drug target prediction and molecular dynamics simulations. Further investigations have experimentally demonstrated that: Firstly, both daf‐16 and skn‐1 genes are causative to WGX‐50 mediated longevity. WGX‐50 failed to extend lifespan upon depletion of these genes in transgenic worms. Their orthologs Foxo1 and Nrf2 were also activated even in D‐galactose (D‐gal) induced aging and Zmpste24 −/− progeria mice intestines. Secondly, WGX‐50 inhibits IIS signaling via downregulating daf‐2 , and activating daf‐16 and skn‐1 genes, which thus enable downstream pro‐longevity effectors increasing stress resistance and promoting healthier aging. WGX‐50 increased expression levels of sod‐3 , ctl‐1 , gst‐7/8/12/33 , gsto‐1 , and heat shock protein genes such as hsp‐12.2 , hsp‐90 , F44E5.4/0.5 , T05E11.9 and their inducer hsf‐1 . In addition, the accumulation of lipofuscin, fat, and reactive oxygen species levels with age was decreased significantly upon WGX‐50 supplementation without physiological impairments. Thirdly, in progeria, D‐gal and naturally ag...