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Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence

Yang, Hao, Wang, Tongyao, Qian, Chenglang, Wang, Huijing, Yu, Dong, Shi, Meifang, Fu, Mengwei, Liu, Xueguang, Pan, Miaomiao, Rong, Xingyu, Xiao, Zhenming, Chen, Xiejiu, Yeerken, Anaguli, Wu, Yonglin, Zheng, Yufan, Yang, Hui, Zhang, Ming, Liu, Tao, Qiao, Peng, Qu, Yifan, Lin, Yong, Huang, Yiqin, Jin, Jianliang, Liu, Nan, Wen, Yumei, Sun, Ning, Zhao, Chao·2025·Nature Aging
DOI 10.1038/s43587-024-00795-w
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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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Metadata

Authors
Yang, H., Wang, T., Qian, C., Wang, H., Yu, D., Shi, M., Fu, M., Liu, X., Pan, M., Rong, X., Xiao, Z., Chen, X., Yeerken, A., Wu, Y., Zheng, Y., Yang, H., Zhang, M., Liu, T., Qiao, P., Qu, Y., Lin, Y., Huang, Y., Jin, J., Liu, N., Wen, Y., Sun, N., & Zhao, C.
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2025-01-10
Volume
5
Issue
3
Pages
401-418
ISSN
2662-8465
DOI
10.1038/s43587-024-00795-w
Cited by
86
References
18
Language
en
Licence
Funders
  • Program of Shanghai Academic Leader for health the National Key Research and Development Project of China Grant from National Clinical Research Center Innovation of Fudan University
  • the National Key Research and Development Project of China the Shanghai Municipal Science and Technology Major Project

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