Body-wide multi-omic counteraction of aging with GLP-1R agonism

  • Cell Metab. 2025 Dec 2;37(12):2362-2380.e8. doi: 10.1016/j.cmet.2025.10.014.
Junzhe Huang  1 ,  Andrew J Kwok  2 ,  Jason Chak Yan Li  2 ,  Clement Lek Hin Chiu  2 ,  Bonaventure Y Ip  2 ,  Lok Yi Tung  2 ,  Roy C H Chan  2 ,  Danny C W Chan  2 ,  Ziyu Wang  2 ,  Xianyi Zheng  2 ,  Hoi Tung Chow  2 ,  Michelle P S Lo  2 ,  Zhongqi Li  3 ,  Nenghan Lin  2 ,  Manyu Wang  2 ,  Leo Y C Yan  2 ,  William K K Wu  4 ,  Kim Hei-Man Chow  5 ,  Wei-Jye Lin  6 ,  Yamei Tang  6 ,  Yun Zhang  7 ,  Weihong Song  8 ,  Billy Wai-Lung Ng  9 ,  Sunny H Wong  10 ,  Thomas W Leung  11 ,  Vincent C T Mok  12 ,  Ho Ko  13
Affiliations
  • 1. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. Electronic address: [email protected].
  • 2. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 3. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Neurology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China.
  • 4. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 5. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 6. Department of Neurology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong Province, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
  • 7. Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 8. Oujiang Laboratory, Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
  • 9. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 10. Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
  • 11. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 12. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. Electronic address: [email protected].
  • 13. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. Electronic address: [email protected].
PMID: 41265449 DOI: 10.1016/j.cmet.2025.10.014
Abstract

Identifying practical ways to counteract aging and associated degenerative disorders is urgently needed. We performed deep molecular profiling and functional assessments in aging male mice to show that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment broadly counteracts age-related changes. In mice treated with a GLP-1RA from 11 months for 30 weeks, we observed strong body-wide multi-omic age-counteracting effects and improved selected physical functions. Importantly, the effects were specific to aged mice, not young adults, and were attained with a relatively low dose that minimally affected food intake or body weight. With GLP-1RA treatment beginning at 18 months for 13 weeks, the molecular age-counteracting effects were even stronger and largely dependent on hypothalamic GLP-1R, pointing to a brain-body axis of aging modulation. Comparison with mammalian target of rapamycin (mTOR) inhibition, a proven Anti-aging strategy, revealed strong multi-omic similarities. Our findings have broad implications for the mechanisms behind GLP-1RAs' pleiotropic benefits, guiding clinical trials, and informing development of anti-aging-based therapeutics.

Keywords
GLP-1R agonist; aging; brain-body interaction; exenatide; mTOR inhibition; multi-omics; rapamycin.
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