Systemic Cell Senescence as a Mediator of Brain Aging Through Circulation

项目摘要 衰老是认知能力下降和痴呆的最大危险因素。针对基本衰老机制 为对抗脑功能障碍提供了有希望的新策略。最近的突破表明， 老年血液循环中的蛋白质在机械上有助于加速大脑衰老， (SCs)在衰老中积累，并可能部分通过促炎性衰老导致组织恶化 相关分泌表型（SASP）。本研究旨在检测早老性SASP是否 系统性SC产生的蛋白质通过以下机制促进大脑老化加速： 血液循环这一前提是基于已发表的研究结果，确定老年血液循环和/或 直接给予作为假定的SASP因子的早老性血浆蛋白足以转移 我们的研究表明，系统性SC 清除减弱循环中的SASP，这与脑炎症的改善有关。 参数和认知能力下降。为了检验我们的中心假设，我们将联合收割机的循环交换 使用小鼠模型的方法，其中可以消除SC或可以产生SC蛋白质组， 精确监测，这将使我们能够研究减少循环SASP是否足够 改善衰老血液对脑稳态的不利影响。我们将开发一种创新的 转基因小鼠模型，这将使生物正交标记的新生p16+ SC蛋白质组。这将 使我们能够发现年龄和组织特异性p16+ SC蛋白质组，其对 循环早老蛋白质组及其对SC清除的响应性。生物正交管理 标记的老龄血浆+/- SC清除到年轻小鼠将有助于发现候选SASP蛋白 负责加速老化的大脑表型，以便进一步进行机械研究。改善老化血液 组合物和靶向SC是积极寻求用于改善年龄相关衰退的治疗剂。 该项目旨在机械协同和推进这两个有前途的概念。我们的研究 可能临床前暗示全身SC清除作为一种选择，以消除老年人的早衰影响， 最终揭示了一种治疗或预防年龄依赖性认知衰退的新方法 和痴呆症。

PROJECT SUMMARY Aging is the strongest risk factor for cognitive decline and dementia. Targeting fundamental aging mechanisms offers promising new strategies to counter brain dysfunction. Recent breakthroughs have demonstrated that proteins in aged blood circulation mechanistically contribute to accelerated brain aging, and senescent cells (SCs) accumulate in aging and may drive tissue deterioration, in part, through the proinflammatory senescence associated secretory phenotype (SASP). This research is designed to test whether progeronic SASP proteins produced by systemic SCs mechanistically contribute to accelerated brain aging through blood circulation. This premise is based on published findings establishing that aged blood circulation and/or direct administration of progeronic plasma proteins that are putative SASP factors are sufficient to transfer an accelerated aging phenotype to young mouse brain and our research demonstrating that systemic SC clearance attenuates the SASP in circulation, which is associated with improvements in brain inflammatory parameters and cognitive decline. To test our central hypothesis, we will combine circulatory exchange methods with mouse models in which SCs can be eliminated or production of the SC proteome can be precisely monitored, which will enable us to study whether reducing the circulating SASP is sufficient to ameliorate the adverse influence of aged blood on brain homeostasis. We will develop an innovative transgenic mouse model that will enable bioorthogonal labeling of the nascent p16+ SC proteome. This will empower our discovery of the age- and tissue-specific p16+SC-proteome, its contribution to the circulating progeronic proteome, and its responsivity to SC clearance. Administration of bioorthogonally labeled aged plasma +/- SC clearance to young mice will facilitate discovery of candidate SASP proteins responsible for accelerated aging brain phenotypes for further mechanistic interrogation. Modifying aged blood composition and targeting SCs are therapeutics actively being pursued for ameliorating age-related decline. This project is designed to mechanistically synergize and advance these two promising concepts. Our research may preclinically implicate systemic SC clearance as an option to deplete the progeronic influence of aged blood, ultimately revealing a novel approach for treatment or prevention of age-dependent cognitive decline and dementia.