Investigating the impact of peripheral senescent cells on the brain

摘要 自从发现衰老相关分泌表型（SASP）具有有效的抗衰老作用以来， 自分泌和旁分泌信号传导作用，以及 减少早老性和按时间老化的小鼠中的衰老细胞负荷，衰老细胞的作用 在许多与年龄相关的慢性疾病的发病机制中的作用已被广泛研究。结果它 现已确定衰老细胞通过促进局部炎症而在组织中积累， 组织老化和破坏，干细胞和祖细胞功能障碍，以及衰老的蔓延， 非衰老细胞。最近，衰老的神经胶质细胞，衰老的大脑 室管膜细胞和衰老的少突胶质细胞祖细胞在各种神经系统中， 疾病已经引起了极大的兴趣。然而，这两项研究都没有发现 外周与中央衰老细胞。事实上，周围衰老细胞对健康大脑的影响 衰老和与年龄相关的认知障碍仍然未被探索。现有证据表明 外周组织中衰老细胞的高负荷在这一过程中起着可能的因果作用。 多种与年龄相关的慢性疾病的发病机制，这是主要的预测因素， 之后会出现认知缺陷我们推测外周衰老细胞与慢性疾病有关， 大脑老化和认知障碍因此，我们假设，高衰老细胞负荷， 外周组织有助于或加速与年龄相关的病理变化， 海马体，使大脑容易出现认知功能障碍。我们将使用三种不同的 衰老相关模型来检验我们的假设目的1是测试是否增加外周衰老 细胞负荷导致按时间顺序老化的小鼠中的年龄依赖性认知缺陷。Aim2测试 如果肥胖驱动的外周衰老细胞导致神经精神功能障碍和认知功能障碍， 赤字目的3是测试外周衰老细胞是否加速年龄依赖性神经病理学变化。 过程和认知缺陷的阿尔茨海默病模型小鼠。我们将在最近申请 建立了细胞移植模型，以测试外周移植的衰老细胞是否直接 在衰老、肥胖和阿尔茨海默病的背景下，导致或加剧认知能力下降。 进一步探讨外周衰老细胞影响脑功能的可能机制 微环境，我们将检查海马体中的细胞和分子变化， 高外周衰老细胞负荷使用新开发的质谱细胞仪（CyTOF）方法 和其他补充方法。总的来说，我们的研究将回答一个关键问题， 外周衰老细胞负荷对于治疗年龄和疾病相关的神经系统疾病是必要的 疾病和神经退行性疾病。

Abstract Ever since the discovery of the senescence-associated secretory phenotype (SASP) having potent autocrine and paracrine signaling effects, together with the demonstration of beneficial effects of reducing senescent cell burden in progeroid and chronologically aged mice, the role of senescent cells in the pathogenesis of many age-related chronic disorders has been extensively studied. As a result, it has now been established that senescent cells accumulate in tissues by promoting local inflammation, tissue aging and destruction, stem and progenitor cell dysfunction, and the spread of senescence to non-senescent cells. More recently, the detrimental effects of senescent glial cells, senescent brain ependymal cells, and senescent oligodendrocyte progenitor cells in various kinds of neurological disorders have attracted significant interest. However, neither of these studies discerns the effects of peripheral vs. central senescent cells. Indeed the impact of peripheral senescent cells on healthy brain aging and age-related cognitive impairment remain unexplored yet. Existing evidence demonstrates that a high burden of senescent cells in peripheral tissues plays a possible causal role in the pathogenesis of multiple age-related chronic diseases, which is the leading predictive factor for developing cognitive deficits later. We speculate that peripheral senescent cells link chronic diseases, brain aging, and cognitive impairment. Thus, we hypothesize that high senescent cell burden in peripheral tissues contributes to or accelerates age-related pathological changes in the hippocampus, predisposing the brain to cognitive dysfunction. We will use three different senescence-associated models to test our hypothesis. Aim1 is to test if increased peripheral senescent cell burden contributes to age-dependent cognitive deficits in chronologically aged mice. Aim2 is to test if obesity-driven peripheral senescent cells contribute to neuropsychiatric dysfunction and cognitive deficits. Aim3 is to test if peripheral senescent cells accelerate age-dependent neuropathological processes and cognitive deficits in Alzheimer’s disease model mice. We will apply our recently developed cell transplantation model to test whether peripherally transplanted senescent cells directly cause or exacerbate the cognitive decline in the context of aging, obesity, and Alzheimer’s diseases. To further investigate the possible mechanisms of how peripheral senescent cells affect brain microenvironments, we will examine cellular and molecular changes in the hippocampus resulting from high periphery senescent cell burden using the newly developed mass cytometry (CyTOF) approach and other complement methods. Overall, our studies will answer a critical question of whether reducing peripheral senescent cell burden is necessary for treating age- and disease-related neurological disorders and neurodegenerative diseases.