Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence

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

Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence

Hao Yang et al. Nat Aging. 2025 Mar.

. 2025 Mar;5(3):401-418.

doi: 10.1038/s43587-024-00795-w. Epub 2025 Jan 10.

Authors

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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. McClearn, G. E. et al. Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 276, 1560–1563 (1997). - PubMed - DOI
1. Hogg, R. E. et al. Gene–environment interactions and aging visual function: a classical twin study. Ophthalmology 116, 263–269 (2009). - PubMed - DOI
1. DeJong, E. N., Surette, M. G. & Bowdish, D. M. E. The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host Microbe 28, 180–189 (2020). - PubMed - DOI
1. O’Toole, P. W. & Jeffery, I. B. Gut microbiota and aging. Science 350, 1214–1215 (2015). - PubMed - DOI
1. Zhang, X. et al. Sex- and age-related trajectories of the adult human gut microbiota shared across populations of different ethnicities. Nat. Aging 1, 87–100 (2021). - PubMed - DOI

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Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence

Affiliations

Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials