Investigating the impact of peripheral senescent cells on the brain

研究外周衰老细胞对大脑的影响

• 批准号: 10670484
• 负责人: Yi Zhu
• 金额: $ 42.36万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670484
• 关键词: 3xTg-AD mouse; AP20187; Abdomen; Ablation; Adipose tissue; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Anxiety; Apoptotic; Attenuated; Autocrine Communication; Behavior; Blood; Brain; CDKN2A gene; Cell Aging; Cell Cycle Arrest; Cell Transplantation; Cell physiology; Cells; Central Nervous System Diseases; Chronic; Chronic Disease; Chronology; Cognitive; Cognitive deficits; Complement; Cytometry; Data; Development; Disease; Distal; Drug Targeting; Enzyme-Linked Immunosorbent Assay; Ependymal Cell; Functional disorder; Hippocampus (Brain); Impaired cognition; Individual; Inflammation; Inflammatory; Investigation; Lead; Link; Lipids; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Nerve Degeneration; Neuraxis; Neurocognitive; Neurodegenerative Disorders; Neuroglia; Nucleotides; Obesity; Outcome; Paracrine Communication; Pathogenesis; Pathologic; Pathology; Peptide Hydrolases; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Predictive Factor; Process; Proteomics; Risk; Role; Stimulus; Testing; Thinness; Tissues; Transgenic Mice; Transplantation; Work; age related; age related neurodegeneration; aged; aging brain; base; brain dysfunction; brain tissue; cytokine; diet-induced obesity; early onset; interest; middle age; mouse model; nervous system disorder; neurogenesis; neuroinflammation; neuropathology; neuropsychiatry; novel; novel strategies; oligodendrocyte progenitor; prevent; senescence; stem cells; systemic inflammatory response; tau Proteins; transplant model

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.

抽象的 自从发现与感应相关的秘书表型（SASP）以来 自分泌和旁分泌信号传导效应，以及证明 降低后代和年龄小鼠中的感觉细胞伯嫩，感官细胞的作用 在许多与年龄相关的慢性疾病的发病机理中，已广泛研究。结果，它 现在已经确定，感觉细胞通过促进局部炎症而积聚在组织中 组织老化和破坏，茎和祖细胞功能障碍，衰老的扩散 非阳性细胞。最近，感觉神经胶质细胞的有害影响，感觉脑 室室室室和感觉少突胶质细胞祖细胞各种神经系统 疾病引起了极大的兴趣。但是，这些研究都没有辨别 周围和中央感觉细胞。确实，周围感觉细胞对健康大脑的影响 衰老和与年龄有关的认知障碍仍然出乎意料。现有证据证明 外周组织中高度燃烧的感觉细胞在 多种年龄相关慢性疾病的发病机理，这是领先的预测因素 后来发展认知缺陷。我们推测外周感觉细胞连接慢性疾病， 大脑衰老和认知障碍。那我们假设在 周围组织有助于或加速与年龄相关的病理变化 海马，使大脑患有认知功能障碍。我们将使用三种不同的 传感相关模型以检验我们的假设。 AIM1是测试是否增加周围感应 细胞灼伤有助于年龄依赖年龄的认知缺陷。 AIM2是测试 如果肥胖驱动的周围感觉细胞有助于神经精神上的功能障碍和认知能力 缺陷。 AIM3是测试周围感觉细胞是否加速了年龄依赖性神经病理学 阿尔茨海默氏病模型小鼠的过程和认知缺陷。我们将应用我们最近的 开发了细胞移植模型，以测试外围移植的感觉细胞是否直接 原因或加剧衰老，肥胖和阿尔茨海默氏病的背景下的认知能力下降。 进一步研究周围感觉细胞如何影响大脑的可能机制 微环境，我们将检查由 使用新开发的质量细胞术（Cytof）方法，高外围感觉细胞燃烧燃烧 和其他完成方法。总体而言，我们的研究将回答一个关键问题，即是否减少 外周感觉细胞伯嫩对于治疗与年龄和疾病有关的神经系统是必需的 疾病和神经退行性疾病。

项目成果

Past and Future Directions for Research on Cellular Senescence.

细胞衰老研究的过去和未来方向。

• DOI: 10.1101/cshperspect.a041205
• 发表时间: 2024
• 期刊: Cold Spring Harbor perspectives in medicine
• 影响因子: 5.4
• 作者: Zhu,Yi;Anastasiadis,ZachariasP;EspindolaNetto,JairMachado;Evans,Tamara;Tchkonia,Tamar;Kirkland,JamesL
• 通讯作者: Kirkland,JamesL