Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.

中文翻译：

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单核转录组学揭示了 FOXP1 在灵长类动物心脏衰老中的看门人作用。

老龄化是心血管疾病的主要危险因素，心血管疾病是老年人死亡的主要原因。然而，心脏老化背后的细胞类型特异性变化远未明确。在这里，我们对年轻和年老食蟹猴的左心室进行了单核 RNA 测序分析，以确定与年龄相关的不同细胞类型的细胞组成变化和转录组学改变。我们发现，老化的心肌细胞在细胞数量上经历了巨大的损失，在转录谱上发生了深刻的波动。通过转录调控网络分析，我们发现 FOXP1 是器官发育的核心转录因子，是衰老心肌细胞的关键下调因子，伴随着与心脏功能和心脏病相关的 FOXP1 靶基因的失调。始终如一，FOXP1 的缺陷导致人胚胎干细胞衍生的心肌细胞肥大和衰老表型。总而言之，我们的研究结果以单细胞分辨率描述了心室老化的细胞和分子景观，并确定了灵长类动物心脏老化的驱动因素和干预心脏老化及相关疾病的潜在目标。