A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes
Shanshan Yang1,3,6, Chengyu Liu4,7, Mengmeng Jiang2,8,9, Xiaoqian Liu4,8,9, Lingling Geng1,3, Yiyuan Zhang2,9, Shuhui Sun2,8,9, Kang Wang2,7, Jian Yin2,7, Shuai Ma2,8,9, Si Wang1,3, Juan Carlos Izpisua Belmonte11, Weiqi Zhang5,7,8,10(), Jing Qu4,7,8,9,10(), Guang-Hui Liu1,2,3,6,7,8,9,10()
1. Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China 2. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 3. Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China 4. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 5. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China 6. Xuanwu Hospital Capital Medical University, Beijing 100053, China 7. University of Chinese Academy of Sciences, Beijing 100049, China 8. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China 9. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China 10. Aging Biomarker Consortium, Beijing 100101, China 11. Altos Labs, Inc., San Diego, CA 94022, USA
Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized. Here, we constructed the first single-nucleus transcriptomic landscape of primate liver aging, in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell–cell interactions between hepatocytes and niche cells. Upon in-depth dissection of this rich dataset, we identified impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark of the aged liver, and consequently, forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes, manifesting as impaired detoxification and accelerated cellular senescence. This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.
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