Life-span-dependent transcriptional dynamics of the human heart

  • Sci Adv. 2026 Jun 19;12(25):eaeg2614. doi: 10.1126/sciadv.aeg2614.
Hao Jia  1  2  3 ,  Xiao Chen  3 ,  Yuan Chang  1 ,  Yifan Wang  1  2  3 ,  Eric L Lindberg  4  5  6  7 ,  Hao Cui  2  3 ,  Yihang Feng  3  8 ,  Ningning Zhang  3 ,  Xiulin Zhang  2  3 ,  Mengda Xu  1 ,  Dan Shan  3 ,  Yixuan Sheng  3 ,  Fengxiang Wei  9 ,  Xiumeng Hua  1 ,  Han Mo  10 ,  Yuhong Hu  1  3 ,  Xijia Shao  1 ,  Han Han  1  2  3 ,  Daniel Reichart  4  5  6  7 ,  Jiangping Song  1  2  3  10  11
Affiliations
  • 1. Department of Cardiac Surgery, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Fuwai Hospital, Beijing, China.
  • 2. Beijing Key Laboratory for Xenotransplantation, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3. State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Fuwai Hospital, Beijing, China.
  • 4. Department of Cardiology, University Hospital, LMU Munich, Munich, Germany.
  • 5. Gene Center Munich, LMU Munich, Munich, Germany.
  • 6. Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU), LMU Munich, Munich, Germany.
  • 7. Partner Site Munich Heart Alliance, DZHK (German Centre for Cardiovascular Research), Munich, Germany.
  • 8. National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 9. The Genetics Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City, Longgang Maternity and Child Institute of Shantou University Medical College, Shenzhen, China.
  • 10. Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China.
  • 11. Department of Cardiac Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, China.
PMID: 42308288 DOI: 10.1126/sciadv.aeg2614
Abstract

The human heart undergoes continuous transcriptional remodeling from development through aging, yet the cellular and regulatory features governing this process remain incompletely defined. Here, we generated a single-nucleus RNA Sequencing atlas of 442,239 nuclei from 54 nonfailing myocardial tissues of 29 individuals spanning development, adulthood, and aging, covering left and right ventricles. Across all major cell types, we uncovered coordinated yet cell type-specific transcriptional trajectories that converge on progressive loss of gene expression homeostasis, stress responses, and inflammatory signaling over the life span. Cardiomyocytes displayed distinct age-associated transcriptional states enriched for senescence- and disease-related signatures. Regulatory network analysis identified PRDM16 as a transcriptional regulator whose activity declined with age in cardiomyocytes. Functional perturbation of PRDM16 in human cardiomyocyte models induced senescence, metabolic dysfunction, and stress responses, whereas its rebalancing in aged mouse hearts improved cardiac function and partially reversed aging-associated transcriptional programs. Last, leveraging life-span-resolved single-nucleus data, we constructed cardiac transcriptomic age prediction models that closely tracked chronological age in nonfailing hearts and revealed deviations consistent with accelerated aging in cardiomyopathies. Together, this study provides a comprehensive single-nucleus resource of the human heart across the life span and delineates cellular and regulatory features associated with cardiac aging.

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