Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence

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

doi:10.1038/s43587-024-00795-w

Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence

Nat Aging. 2025 Jan 10. doi: 10.1038/s43587-024-00795-w. Online ahead of print.

Authors

Hao Yang^#¹, Tongyao Wang^#¹, Chenglang Qian^#¹, Huijing Wang^#², Dong Yu^#³, Meifang Shi^#⁴, Mengwei Fu¹, Xueguang Liu⁵, Miaomiao Pan¹, Xingyu Rong⁶, Zhenming Xiao¹, Xiejiu Chen¹, Anaguli Yeerken¹, Yonglin Wu¹, Yufan Zheng⁷, Hui Yang⁷, Ming Zhang¹, Tao Liu⁴, Peng Qiao¹, Yifan Qu¹, Yong Lin¹, Yiqin Huang⁸, Jianliang Jin⁹, Nan Liu¹⁰, Yumei Wen¹, Ning Sun^{11

12}, Chao Zhao^{13

14

15}

Affiliations

¹ National Clinical Research Center for Aging and Medicine, Huashan Hospital and MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
² Institute of Wound Prevention and Treatment, Shanghai University of Medicine and Health Sciences, Shanghai, China.
³ Department of Precision Medicine, Translational Medicine Research Center, Naval Medical University and Shanghai Key Laboratory of Cell Engineering, Shanghai, China.
⁴ Department of Clinical Laboratory, Youyi Road Community Health Service Centre for Baoshan District, Shanghai, China.
⁵ Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
⁶ Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁷ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
⁸ Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China.
⁹ Department of Human Anatomy, Research Centre for Bone and Stem Cells; Key Laboratory for Aging and Disease; The State Key Laboratory of Reproductive Medicine; Nanjing Medical University, Nanjing, China.
¹⁰ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences and Shanghai Key Laboratory of Aging Studies, Pudong, Shanghai, China.
¹¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. sunning@jiangnan.edu.cn.
¹² Wuxi School of Medicine, Jiangnan University, Jiangsu, China. sunning@jiangnan.edu.cn.
¹³ National Clinical Research Center for Aging and Medicine, Huashan Hospital and MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. czhao@fudan.edu.cn.
¹⁴ Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China. czhao@fudan.edu.cn.
¹⁵ Engineering Research Center of Intelligent Healthcare for Successful Aging, Ministry of Education, Fudan University, Shanghai, China. czhao@fudan.edu.cn.

^# Contributed equally.

PMID: 39794469
DOI: 10.1038/s43587-024-00795-w

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.