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.

摘要

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