Systemic Cell Senescence as a Mediator of Brain Aging Through Circulation

项目总结 衰老是认知能力下降和痴呆症的最大风险因素。以基本衰老机制为目标 提供了有希望的新策略来对抗大脑功能障碍。最近的突破表明， 老年血液循环中的蛋白质机械地促进了大脑的加速衰老，以及衰老的细胞 (SCS)在衰老过程中积累，并可能部分通过促炎衰老推动组织恶化 相关分泌表型(SASP)。这项研究旨在测试孕酮SASP 全身性干细胞产生的蛋白质通过机械作用加速大脑衰老 血液循环。这一前提是基于已发表的研究结果，确定了老年人的血液循环和/或 直接给药孕激素血浆蛋白是推测的SASP因子，足以转移 幼龄小鼠脑加速衰老表型及我们的研究表明系统性SC 清除减少循环中的SASP，这与改善脑部炎症有关 参数和认知功能衰退。为了检验我们的中心假设，我们将结合循环交换 可以消除干细胞或产生干细胞蛋白质组的小鼠模型的方法 精确监测，这将使我们能够研究减少循环中的SASP是否足够 改善老年血液对脑内稳态的不利影响。我们将开发一种创新的 转基因小鼠模型，将使新生的p16+SC蛋白质组能够进行生物正交标记。这将是 使我们发现了年龄和组织特异性的p16+SC蛋白质组，它对 循环孕激素蛋白质组及其对SC清除的响应。生物正交法给药 标记老龄血浆+/-SC对幼鼠的清除将有助于发现候选SASP蛋白 负责加速老化的大脑表型，以进行进一步的机械化审讯。调理衰老血液 合成和靶向干细胞是目前积极寻求的改善年龄相关性衰退的治疗方法。 这个项目旨在机械地协同和推进这两个有希望的概念。我们的研究 临床前可能涉及全身SC清除，作为耗尽老年人孕激素影响的一种选择 血液，最终揭示了一种治疗或预防年龄相关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.