Effect of Peripheral Cellular Senescence on Brain Aging and Cognitive Decline

We test the idea that peripheral cellular senescence is a major driver of age-related cognitive impairment, such that treatment with the brain impermeable senolytic, ABT-263, can preserve cognition and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12-18 months of age with quercetin + dasatinib or ABT-263 or vehicle and were compared to young (6 month). Senolytic treatments had similar effects in decreasing peripheral markers of senescence and the senescence-associated secretory phenotype (SASP), including plasma levels of several cytokines, rescued memory and hippocampal synaptic transmission, and decreased expression of immune response genes in the dentate gyrus (DG). Across senolytic treatment groups, differential DG gene expression was observed for cellular senescence and pathways linked to senescence, including negative regulation of cell death, ribosomes, and microglial activation consistent with differential access of dasatinib and ABT-263 to the brain. Finally, both senolytic treatments preserved the blood-brain barrier suggesting that leakage of clinically significant amounts of ABT-263 into the brain is unlikely. The results indicate that preserved cognition was due to removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, BBB breakdown, and impaired synaptic function.本研究验证了外周细胞衰老（peripheral cellular senescence）是年龄相关性认知障碍的主要驱动因素这一假说，即使用无法透过血脑屏障（blood-brain barrier）的衰老细胞清除剂（senolytic）ABT-263进行干预，能够保留认知功能，并改善被认为是认知衰退基础的脑衰老标志物水平。研究选取12至18月龄的雄性F344大鼠，分别给予槲皮素（quercetin）+达沙替尼（dasatinib）、ABT-263或溶媒（vehicle）干预，并以6月龄年轻大鼠作为对照。两类清衰剂干预均能有效降低外周衰老标志物及衰老相关分泌表型（senescence-associated secretory phenotype, SASP）水平，包括多种细胞因子的血浆浓度；同时可改善记忆功能与海马突触传递，并下调齿状回（dentate gyrus, DG）内免疫应答基因的表达。在不同清衰剂干预组中，齿状回内与细胞衰老及衰老相关通路（包括细胞死亡负调控、核糖体通路及小胶质细胞激活）相关的基因表达均存在差异，这与达沙替尼和ABT-263的脑组织摄取差异相一致。最后，两种清衰剂干预均能维持血脑屏障的完整性，提示临床剂量的ABT-263不太可能大量渗漏进入脑组织。研究结果表明，认知功能得以保留的原因在于清除了外周衰老细胞，从而减轻了通常会引发神经炎症、血脑屏障破坏及突触功能损伤的全身性炎症反应。