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 Zmpste24progeria 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 aged mice, WGX-50 is incapable of inducing aging. Senescent genes and SASP factors were not produced at higher levels in livers and small intensities. No impact was observed on key organ indices, blood biochemistry parameters, and bone histomorphometry. WGX-50 perhaps prolongs lifespan through other mechanisms such as reducing fertility, inducing dietary restriction, and improving proteostasis with lowered levels of polyQ35 aggregates. Our findings thus provide primary insights for the potential medical use of WGX-50 in anti-aging and long-term healthcare. -/-
