Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
Protein Cell. 2024 Feb 1;15(2):98-120. doi: 10.1093/procel/pwad039.
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.
衰老会增加肝脏疾病和全身性衰老相关疾病的风险。然而，高等脊椎动物肝脏衰老的细胞类型特异性变化及其潜在机制仍不完全清楚。在这里，我们构建了灵长类动物肝脏衰老的第一个单细胞转录组图谱，其中我们解析了三个肝区带中肝细胞的细胞类型特异性基因表达波动，并检测到肝细胞和小生境细胞之间异常的细胞间相互作用。在深入剖析这个丰富的数据集后，我们发现脂质代谢受损和慢性炎症相关基因的上调与衰老过程中肝脏功能下降显著相关。特别是，固醇调节元件结合蛋白（SREBP）信号的过度激活是衰老肝脏的一个标志，因此，在人原代肝细胞中强制激活 SREBP2 可重现体内衰老表型，表现为解毒功能受损和细胞衰老加速。本研究扩展了我们对灵长类动物肝脏衰老的认识，并为肝脏衰老和相关疾病的诊断和治疗干预措施的发展提供了信息。
