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  3. Restoring circadian rhythms in the hypothalamic paraventricular nucleus reverses aging biomarkers and extends lifespan in male mice

Restoring circadian rhythms in the hypothalamic paraventricular nucleus reverses aging biomarkers and extends lifespan in male mice

  • Cell. 2026 Apr 2;189(7):2007-2023.e20. doi: 10.1016/j.cell.2026.01.016.
Haijiao Zhao 1,  Meimei Liao 2,  Ran Huo 3,  Ting He 4,  Hongni Tian 5,  Zeqi Li 6,  Chen Chen 7,  Ziqing Yu 7,  Juan Chai 7,  Xiaocui Song 7,  Ruichao Shao 7,  Shuhua Ying 7,  Wen Gao 5,  Ling Liu 5,  Di Sang 7,  Qi Li 3,  Haohong Li 8,  Fengchao Wang 9,  Dapeng Ju 10,  Eric Erquan Zhang 11
Affiliations

Affiliations

  • 1 College of Life Sciences, Beijing Normal University, Beijing, China; National Institute of Biological Sciences, Beijing, China.
  • 2 Department of Anesthesiology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Key Laboratory of Perioperative Medicine Innovation and Translation, Chongqing Education Commission of China, Chongqing, China.
  • 3 National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • 4 Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China; Department of Neurobiology, Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Department of Anesthesiology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 6 National Institute of Biological Sciences, Beijing, China; College of Biological Sciences, China Agriculture University, Beijing, China.
  • 7 National Institute of Biological Sciences, Beijing, China.
  • 8 Department of Neurobiology, Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 9 National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. Electronic address: [email protected].
  • 10 Department of Anesthesiology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Key Laboratory of Perioperative Medicine Innovation and Translation, Chongqing Education Commission of China, Chongqing, China. Electronic address: [email protected].
  • 11 College of Life Sciences, Beijing Normal University, Beijing, China; National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. Electronic address: [email protected].
PMID: 41785851 DOI: 10.1016/j.cell.2026.01.016
Abstract

Age-related circadian disruptions accelerate physiological decline and shorten lifespan. Enhancing circadian amplitude has emerged as a promising strategy for ameliorating age-associated disorders. Here, we show that the circadian-phase-optimized administration of 3'-deoxyadenosine (3dA) strengthens circadian amplitude in hypothalamic paraventricular nucleus (PVN) neurons, mitigates aging biomarkers, and extends mouse lifespan. 3dA restores clock synchrony and hormonal rhythms, including corticosterone, and reduces epigenetic age as measured by DNA methylation clocks. Transcriptomic, hormonal, and epigenetic profiling reveal robust increases in PVN circadian amplitude following timed 3dA administration, and the PVN-specific knockout of RuvB-like ATPase 2 (Ruvbl2) establishes its genetic necessity by abolishing 3dA's benefits. Similarly, chemogenetic PVN activation reproduces 3dA's metabolic and physiological benefits. These findings identify the PVN clock as a pharmacological node linking circadian amplitude to organismal aging, suggest that targeting RUVBL2-dependent circadian transcription enhances network synchrony, and indicate that circadian interventions are promising therapeutic candidates for delaying aging and improving healthspan in aged male mice.

Keywords

3′-deoxyadenosine; RUVBL2; aging; amplitude enhancement; circadian rhythms; paraventricular nucleus.

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