Autophagy suppresses mitochondrial metabolism to preserve hematopoietic stem cells (HSCs) in mice. However, the mechanism by which autophagy regulates hematopoietic aging, in particular in humans, has largely been unexplored. Here, we demonstrate that reduction of autophagy in both hematopoietic cells and their stem cells is associated with aged hematopoiesis in human population. Mechanistically, autophagy delays hematopoietic aging by activating the downstream expression of Sirt3, a key mitochondrial protein capable of rejuvenating blood. Sirt3 is the most abundant Sirtuin family member in HSC‐enriched population, though it declines as the capacity for autophagy deteriorates with aging. Activation of autophagy upregulates Sirt3 in wild‐type mice, whereas in autophagy‐defective mice, Sirt3 expression is crippled in the entire hematopoietic hierarchy, but forced expression of Sirt3 in HSC‐enriched cells reduces oxidative stress and prevents accelerated hematopoietic aging from autophagy defect. Importantly, the upregulation of Sirt3 by manipulation of autophagy is validated in human HSC‐enriched cells. Thus, our results identify an autophagy‐Sirt3 axis in regulating hematopoietic aging and suggest a possible interventional solution to human blood rejuvenation via activation of the axis.

中文翻译：

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自噬-Sirt3 轴减缓造血衰老。

自噬抑制线粒体代谢以保护小鼠的造血干细胞 (HSC)。然而，自噬调节造血衰老的机制，特别是在人类中，很大程度上尚未被探索。在这里，我们证明造血细胞及其干细胞中自噬的减少与人群中的老年造血功能有关。从机制上讲，自噬通过激活 Sirt3 的下游表达来延缓造血衰老，Sirt3 是一种能够使血液恢复活力的关键线粒体蛋白。Sirt3 是富含 HSC 的人群中最丰富的 Sirtuin 家族成员，尽管它随着自噬能力随着年龄的增长而下降。自噬的激活上调野生型小鼠的 Sirt3，而在自噬缺陷的小鼠中，Sirt3 的表达在整个造血系统中被削弱，但在富含 HSC 的细胞中强制表达 Sirt3 可减少氧化应激并防止自噬缺陷导致的加速造血老化。重要的是，通过操纵自噬来上调 Sirt3 在人类富含 HSC 的细胞中得到验证。因此，我们的结果确定了自噬-Sirt3 轴在调节造血衰老中的作用，并提出了通过激活该轴来实现人类血液年轻化的可能干预解决方案。