Protein restriction reprograms the multi-organ proteomic landscape of mouse aging

Tian Lu¹, Yuting Xie¹, Yingrui Wang¹, Xiling Lin², Xue Cai¹, Yuqi Zhang¹, Zongxiang Nie¹, Chang Su³, Wanglong Gou⁴, Hong Zhang⁵, Jing Wang⁵, Yan Zhong⁵, Zeyin Lai⁶, Jingjing Xiang⁶, Peng-Fei Shan², Ju-Sheng Zheng⁷, Huijun Wang³, Yi Zhu⁸, Tiannan Guo⁹

Affiliations

¹ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China.
² Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
³ National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China; NHC Key Laboratory of Public Nutrition and Health, Beijing 100050, China.
⁴ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou 310024, China.
⁵ Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China; Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
⁶ Department of Pathology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou 310006, China.
⁷ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou 310024, China.
⁸ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China. Electronic address: zhuyi@westlake.edu.cn.
⁹ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China. Electronic address: guotiannan@westlake.edu.cn.

PMID: 41138729
DOI: 10.1016/j.cell.2025.10.004

Protein restriction reprograms the multi-organ proteomic landscape of mouse aging

Tian Lu et al. Cell. 2025.

. 2025 Oct 24:S0092-8674(25)01133-X.

doi: 10.1016/j.cell.2025.10.004. Online ahead of print.

Authors

Affiliations

¹ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China.
² Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
³ National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China; NHC Key Laboratory of Public Nutrition and Health, Beijing 100050, China.
⁴ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou 310024, China.
⁵ Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China; Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
⁶ Department of Pathology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou 310006, China.
⁷ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou 310024, China.
⁸ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China. Electronic address: zhuyi@westlake.edu.cn.
⁹ Westlake Center for Intelligent Proteomics, State Key Laboratory of Medical Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang Province, China; Affiliated Hangzhou First People's Hospital, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou 310024, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China. Electronic address: guotiannan@westlake.edu.cn.

PMID: 41138729
DOI: 10.1016/j.cell.2025.10.004

Abstract

Population aging is accelerating, yet the multi-organ aging process and the geroprotective effects of dietary protein restriction (PR) remain poorly understood. Here, we conducted comprehensive proteomic analyses on 41 mouse tissues during male mouse aging and PR. Our findings identified tissue-specific aging hallmarks, including widespread changes in immunoglobulins and serine protease inhibitors across multiple tissues. PR mitigated age-related tissue-specific protein expression, epigenomic states, and protein phosphorylation patterns, and it significantly improved adipose tissue functions. These findings were supported by independent reduced representation bisulfite sequencing (RRBS), phosphoproteomics, and pathological analyses. Furthermore, analysis of plasma samples from mice and humans confirmed the cardiovascular benefits of PR. We identified sexual and temporal variations in the impact of PR, with middle age being the optimal intervention period. Overall, our study depicts the multi-organ aging process and provides valuable insights into the geroprotective potential of PR.

Keywords: aging; epigenomics; geroprotective; human; mouse; multi-organ; protein restriction; proteomics; thermogenesis.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests T.G. and Y.Z. are shareholders of Westlake Omics Inc.

LinkOut - more resources

Full Text Sources
- Elsevier Science
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Protein restriction reprograms the multi-organ proteomic landscape of mouse aging

Affiliations

Protein restriction reprograms the multi-organ proteomic landscape of mouse aging

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Research Materials