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.

中文翻译：

---

灵长类动物肝脏衰老的单核转录组图谱揭示了 SREBP2 在肝细胞中的促衰老作用。

衰老会增加患肝脏疾病的风险以及对衰老相关疾病的全身易感性。然而，高等脊椎动物的细胞类型特异性变化和肝脏衰老的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核转录组景观，其中我们解决了三个肝脏分区中肝细胞中细胞类型特异性基因表达的波动，并检测了肝细胞和生态位细胞之间的异常细胞间相互作用。经过对这一丰富数据集的深入剖析，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功能下降显着相关。特别是，过度激活的甾醇调节元件结合蛋白（SREBP）信号传导是衰老肝脏的一个标志，因此，人原代肝细胞中SREBP2的强制激活再现了体内衰老表型，表现为解毒受损和细胞衰老加速。这项研究扩展了我们对灵长类动物肝脏衰老的认识，并为肝脏衰老及相关疾病的诊断和治疗干预措施的发展提供了信息。