Blood circulating microRNAs (c-miRs) are potential biomarkers to trace aging and longevity trajectories to identify molecular targets for anti-aging therapies. Based on a cross-sectional study, a discovery phase was performed on 12 donors divided into four groups: young, old, healthy, and unhealthy centenarians. The identification of healthy and unhealthy phenotype was based on cognitive performance and capabilities to perform daily activities. Small RNA sequencing identified 79 differentially expressed c-miRs when comparing young, old, healthy centenarians, and unhealthy centenarians. Two miRs, that is, miR-19a-3p and miR-19b-3p, were found increased at old age but decreased at extreme age, as confirmed by RT-qPCR in 49 donors of validation phase. The significant decrease of those miR levels in healthy compared to unhealthy centenarians appears to be due to the presence of isomiRs, not detectable with RT-qPCR, but only with a high-resolution technique such as deep sequencing. Bioinformatically, three main common targets of miR-19a/b-3p were identified, that is, SMAD4, PTEN, and BCL2L11, converging into the FoxO signaling pathway, known to have a significant role in aging mechanisms. For the first time, this study shows the age-related increase of plasma miR-19a/b-3p in old subjects but a decrease in centenarians. This decrease is more pronounced in healthy centenarians and was confirmed by the modified pattern of isomiRs comparing healthy and unhealthy centenarians. Thus, our study paves the way for functional studies using c-miRs and isomiRs as additional parameter to track the onset of aging and age-related diseases using new potential biomarkers.

中文翻译：

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循环 miR-19a-3p 和 miR-19b-3p 表征人类衰老过程，它们的 isomiRs 与极端年龄的健康状态相关

血液循环中的 microRNA (c-miRs) 是追踪衰老和寿命轨迹的潜在生物标志物，可用于识别抗衰老疗法的分子靶点。根据一项横断面研究，对 12 名捐赠者进行了发现阶段，他们分为四组：年轻、年老、健康和不健康的百岁老人。健康和不健康表型的识别基于认知表现和进行日常活动的能力。在比较年轻、年老、健康的百岁老人和不健康的百岁老人时，小 RNA 测序确定了 79 个差异表达的 c-miR。两种 miR，即 miR-19a-3p 和 miR-19b-3p，在老年时增加，但在极端年龄时减少，这在 49 名验证阶段的供体中得到了 RT-qPCR 的证实。与不健康的百岁老人相比，健康人群中这些 miR 水平的显着降低似乎是由于存在 isomiRs，而这些 isomiRs 无法通过 RT-qPCR 检测到，而只能通过高分辨率技术（如深度测序）检测到。在生物信息学上，miR-19a/b-3p 的三个主要共同靶点被确定，即 SMAD4、PTEN 和 BCL2L11，它们汇合到 FoxO 信号通路中，已知在衰老机制中具有重要作用。这项研究首次显示老年受试者血浆 miR-19a/b-3p 的增加与年龄相关，但百岁老人减少。这种下降在健康的百岁老人中更为明显，并且通过比较健康和不健康的百岁老人的 isomiRs 的修改模式证实了这一点。因此，