Aging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA-associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA-based analyses uncover depleted cardiac-specific processes, among other relevant functions, that are undetected by CA. Twenty BA-related microRNAs are identified, and two of them highly heart-enriched that are present in plasma. We describe a microRNA-gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research.

中文翻译：

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人类左心室心肌的时间和生物学老化：microRNAs贡献分析

衰老是心血管疾病的主要危险因素。在人类中，心脏衰老的特征仍然很差。大多数研究都是基于实足年龄（CA）而忽略了生物学年龄（BA），即实际生理年龄（器官结构和功能的老化率的结果），从而产生潜在的不完美结果。破译心室衰老的分子基础，尤其是通过 BA，可能会导致心脏研究取得重大进展。我们的目标是根据 CA 和 BA 描述人类衰老左心室 (LV) 的转录组动力学，并描述关键转录调节因子 microRNA 的贡献。BA 使用两个 CA 相关转录标记测量：CDKN2A表达，细胞衰老标志物和表观年龄（AppAge），一个高度复杂的转录指数。对 132 个 LV 样本的生物信息学分析表明，CDKN2A表达和 AppAge 比 CA 更能代表转录组变化。两种 BA 标志物都在与心脏功能障碍相关的衰老表型、心脏纤维化量方面进行了生物学验证。基于 BA 的分析揭示了 CA 未检测到的耗尽的心脏特异性过程以及其他相关功能。鉴定了 20 种与 BA 相关的 microRNA，其中两种高度富含心脏，存在于血浆中。我们描述了一个与心脏过程相关的 microRNA 基因调控网络，该网络在体外得到了部分验证以及来自活体捐赠者的 LV 样本。我们证明了 BA 在解释衰老心肌转录组变化方面比 CA 具有更高的敏感性，并报告了对人类 LV 生物衰老的新分子见解。我们的结果可以在未来的治疗和生物标志物研究中找到应用。