Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68⁺ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.

我们最近的研究表明，年轻的血液因子对于哺乳动物组织的全身再生不是因果关系，也不是必需的。相反，一种称为中性血液交换 (NBE) 的程序通过稀释旧血浆将信号环境重置为促再生状态，增强肌肉和肝脏的健康和修复，并在 2 年内促进更好的海马神经发生。老老鼠 (Mehdipour et al., Aging 12:8790–8819, 2020)。在这里，我们扩展了 NBE 的恢复表型，重点放在大脑上。也就是说，我们的结果表明，在一次 NBE 之后，老老鼠在新物体和新纹理（晶须辨别）测试中表现得更好，同时伴随着神经炎症减少（较少激活的 CD68 ⁺小胶质细胞）。反对外周衰老相关分泌表型 (SASP) 的衰减/稀释作为 NBE 背后的主要机制的证据是，senolytic ABT 263 对神经炎症的影响有限，并且不会增强老年小鼠的海马神经发生。有趣的是，外周作用的 ABT 263 和 NBE 都减少了旧脑中的 SA-βGal 信号，表明外周衰老传播到大脑，但 NBE 比 ABT 263 更能恢复活力，这表明恢复活力不仅仅是通过减少衰老。为了解释 NBE 对大脑产生积极影响的机制，我们的比较蛋白质组学分析表明，稀释旧血浆会增加小鼠和人类大脑维护和修复的决定因素。