Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence.

IF 17 Q1 CELL BIOLOGY Nature aging Pub Date : 2025-01-10 DOI:10.1038/s43587-024-00795-w

Hao Yang, Tongyao Wang, Chenglang Qian, Huijing Wang, Dong Yu, Meifang Shi, Mengwei Fu, Xueguang Liu, Miaomiao Pan, Xingyu Rong, Zhenming Xiao, Xiejiu Chen, Anaguli Yeerken, Yonglin Wu, Yufan Zheng, Hui Yang, Ming Zhang, Tao Liu, Peng Qiao, Yifan Qu, Yong Lin, Yiqin Huang, Jianliang Jin, Nan Liu, Yumei Wen, Ning Sun, Chao Zhao

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Abstract

Gut microbiota plays a crucial role in the host health in the aging process. However, the mechanisms for how gut microbiota triggers cellular senescence and the consequent impact on human aging remain enigmatic. Here we show that phenylacetylglutamine (PAGln), a metabolite linked to gut microbiota, drives host cellular senescence. Our findings indicate that the gut microbiota alters with age, which leads to increased production of phenylacetic acid (PAA) and its downstream metabolite PAGln in older individuals. The PAGln-induced senescent phenotype was verified in both cellular models and mouse models. Further experiments revealed that PAGln induces mitochondrial dysfunction and DNA damage via adrenoreceptor (ADR)-AMP-activated protein kinase (AMPK) signaling. Blockade of ADRs as well as senolytics therapy impede PAGln-induced cellular senescence in vivo, implying potential anti-aging therapies. This combined evidence reveals that PAGln, a naturally occurring metabolite of human gut microbiota, mechanistically accelerates host cellular senescence.

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