This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.

这项工作将之前关于血液异时性的动物研究推广到人类，并建立了一种新颖的生物年龄直接测量方法。我们的结果支持这样的假设：与小鼠类似，人类衰老是由年龄造成的系统性分子过剩驱动的，其减弱会逆转生物年龄，在我们的工作中将其定义为 10 种新型蛋白质生物标志物的失调（噪音）。关于生物年龄的结果得到了数据的有力支持，这表明多轮治疗性血浆置换（TPE）促进了全球向年轻的系统蛋白质组的转变，包括年轻恢复的促再生、抗癌和凋亡调节因子以及年轻的特征循环细胞中的骨髓/淋巴标记物，可减少细胞衰老并降低 DNA 损伤。从机制上讲，JAK-STAT、MAPK、TGF-β、NF-κB 和 Toll 样受体信号通路的循环调节因子通过 TLR4 的正常化变得更加年轻平衡，我们将 TLR4 定义为这种分子年轻化的节点。我们的研究结果的重要性通过大数据基因表达研究得到了证实。