Wei Rui, Peng Yuling, Luo Yamei, Wang Xinyuan, Pan Zhenzhong, Zhou Ran, Yang Huan, Huang Zongyao, Liu Yaojia, Dai Lunzhi, Wang Yuan, Zhang Yan
State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Proteomics-Metabolomics Platform of Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
PLoS Genet. 2025 Mar 31;21(3):e1011648. doi: 10.1371/journal.pgen.1011648. eCollection 2025 Mar.
Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drug(s) can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative, rescues age-associated AS defects and extends lifespan. Combining bacterial DNA sequencing, proteomics, metabolomics and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate drug's functions through complex interplay among drug, bacteria and host.
衰老与可变剪接（AS）缺陷相关，这些缺陷对与衰老相关的疾病具有广泛影响。然而，尚未系统地探索哪种药物能够挽救与年龄相关的AS缺陷并延长寿命。我们使用双荧光剪接报告系统在秀丽隐杆线虫中进行了大规模化合物筛选。在筛选出的最佳药物中，氟尿苷（一种氟嘧啶衍生物）可挽救与年龄相关的AS缺陷并延长寿命。结合细菌DNA测序、蛋白质组学、代谢组学和三元筛选系统，我们进一步揭示细菌核糖核苷酸代谢在氟尿苷的转化和功效中起着至关重要的作用。此外，氟尿苷增加细菌代谢产物如亚油酸和胍丁胺的产生，以延长宿主寿命。总之，我们的研究结果确定氟尿苷是一种有效的先导化合物，可用于挽救与衰老相关的AS缺陷并延长寿命，并通过药物、细菌和宿主之间的复杂相互作用阐明了该药物的功能。
