Fan Yanling, Zheng Yandong, Zhang Yiyuan, Xu Gang, Liu Chun, Hu Jianli, Ji Qianzhao, Zhang Shuo, Fang Shuaiqi, Lei Jinghui, Li Lan-Zhu, Wang Xing, Xu Xi, Wang Cui, Wang Si, Ma Shuai, Song Moshi, Jiang Wenjian, Zhu Junming, Feng Yijia, Wang Jiangang, Yang Ying, Zhu Guodong, Tian Xiao-Li, Zhang Hongjia, Song Weihong, Yang Jiayin, Yao Yan, Liu Guang-Hui, Qu Jing, Zhang Weiqi
China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Nat Cardiovasc Res. 2025 May;4(5):602-623. doi: 10.1038/s44161-025-00635-z. Epub 2025 Apr 29.
Elucidating the regulatory mechanisms of human cardiac aging remains a great challenge. Here, using human heart tissues from 74 individuals ranging from young (≤35 years) to old (≥65 years), we provide an overview of the histological, cellular and molecular alterations underpinning the aging of human hearts. We decoded aging-related gene expression changes at single-cell resolution and identified increased inflammation as the key event, driven by upregulation of ARID5A, an RNA-binding protein. ARID5A epi-transcriptionally regulated Mitochondrial Antiviral Signaling Protein (MAVS) mRNA stability, leading to NF-κB and TBK1 activation, amplifying aging and inflammation phenotypes. The application of gene therapy using lentiviral vectors encoding shRNA targeting ARID5A into the myocardium not only mitigated the inflammatory and aging phenotypes but also bolstered cardiac function in aged mice. Altogether, our study provides a valuable resource and advances our understanding of cardiac aging mechanisms by deciphering the ARID5A-MAVS axis in post-transcriptional regulation.
阐明人类心脏衰老的调控机制仍然是一项巨大的挑战。在此，我们使用了来自74名年龄从年轻（≤35岁）到年老（≥65岁）个体的人类心脏组织，概述了人类心脏衰老背后的组织学、细胞和分子变化。我们在单细胞分辨率下解码了与衰老相关的基因表达变化，并确定炎症增加是关键事件，这是由RNA结合蛋白ARID5A的上调驱动的。ARID5A通过表观转录调控线粒体抗病毒信号蛋白（MAVS）的mRNA稳定性，导致NF-κB和TBK1激活，放大衰老和炎症表型。将编码靶向ARID5A的短发夹RNA的慢病毒载体用于心肌的基因治疗，不仅减轻了炎症和衰老表型，还增强了老年小鼠的心脏功能。总之，我们的研究通过破译转录后调控中的ARID5A-MAVS轴，提供了有价值的资源，并推进了我们对心脏衰老机制的理解。
