Immune cells as a driver of cell non-autonomous aging

免疫细胞是细胞非自主衰老的驱动因素

• 批准号: 9765815
• 负责人: Laura Jane Niedernhofer
• 金额: $ 61.2万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765815
• 关键词: Adoptive Transfer; Affect; Age; Age-Months; Age-Years; Aging; Agreement; Animals; Aorta; Apoptosis; Automobile Driving; Biological Assay; CDKN2A gene; Cardiovascular Diseases; Cell Differentiation process; Cells; Cellular Stress; Characteristics; Chronic; Chronic Disease; Cytometry; DNA Damage; DNA Repair Endonuclease; Data; Degenerative polyarthritis; Dementia; Diabetes Mellitus; Disease; ERCC1 gene; Elderly; Endothelial Cells; Enzymes; Event; Functional disorder; Generations; Genes; Goals; Health; Health Care Costs; Healthcare Systems; Hematopoietic; Histopathology; Holoenzymes; Homeostasis; Human; Immune; Immune response; Immune system; Impairment; In Vitro; Individual; Inflammation; Kidney; Knowledge; Lead; Life; Liver; Luciferases; Lung; Lymphopenia; Measurement; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Natural Killer Cells; Organ; Peripheral; Persons; Phenotype; Plasma; Play; Population; Proteinuria; Proteomics; Quality of life; Quantitative Reverse Transcriptase PCR; Reporter; Risk; Role; Series; Serum; Signal Transduction; Solid; Sorting - Cell Movement; Splenocyte; Syndrome; Time; Tissues; Transplantation; Validation; Wild Type Mouse; age related; aged; burden of illness; cell age; cell injury; cell type; experimental study; functional loss; healthspan; immune clearance; immune function; immunosenescence; in vivo; monocyte; mortality; mutant; normal aging; novel; perforin; premature; promoter; recombinase-mediated cassette exchange; regenerative; repaired; resilience; senescence; targeted treatment; therapeutic target; transcriptomics; young adult

Project Summary Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system and reduce quality of life for the elderly. As our world population ages dramatically over the next three decades, the burden will only increase. Hence, there is a great need to discover fundamental mechanisms of aging to develop rationale strategies for minimizing the impact of aging on our health and economy. There is general agreement that cell autonomous mechanisms contribute to aging. As cells accrue damage over time, they respond by triggering individual cell fate decisions (e.g., senescence and apoptosis) that ultimately disrupt tissue homeostasis and thereby increase risk of morbidity. However, more recently, there are numerous lines of evidence indicating that cell non-autonomous mechanisms are critically important as well. These cell non-autonomous mechanisms are likely much easier and safer to target therapeutically. Therefore identifying and characterizing these mechanisms is a priority. To ask if “aging” just one tissue in mice is sufficient to drive systemic aging, we generated a series of eight tissue-specific mutant animals in which DNA damage, senescence and tissue dysfunction were increased in only one cell type or tissue at a time. Our preliminary data indicate that “aged” immune cells play a key role in driving aging non-autonomously. Only in the hematopoietic cell mutant mice were non-targeted, peripheral tissues dramatically affected in the first year of life, showing increased senescence, inflammation and loss of homeostasis. The goal of this project is to fully define this novel mechanism of immune cell-mediated, non-autonomous aging in vivo. The aims of the project are to: 1. Determine the temporal order and extent of secondary senescence driven by an “aged” immune system. The specific immune and non-immune cell types with increased senescence will be identified by qRT-PCR and CyTOF at different mouse ages. The functional impact of the “aged” immune system on peripheral tissue homeostasis will be determined by measuring disease-specific endpoints and age-related histopathology. 2. Identify the immune cell type(s) that is most potent at driving systemic aging. This will be accomplished by transplanting splenocytes and isolated immune cell populations into young senescence reporter mice, followed by generation and characterization of cell-type specific mutant mice (e.g., T, B, NK cell or subpopulations). 3. Identify the mechanism by which “aged” immune cells drive systemic aging. This will be accomplished by serum transfer from the hematopoietic mutant mice into young senescence reporter mice followed by transcriptomic analysis of isolated immune cell populations to identify secreted factors. These putative pro-geronic factors will be validated by proteomics and functional validation. Completion of these aims will identify and characterize a novel mechanism(s) of cell non-autonomous aging driven by an aged immune system, which will lend itself to therapeutic targeting for extending human healthspan.

项目摘要 衰老和与衰老有关 降低年龄较大的生活质量。随着我们世界人口在接下来的三十年中的巨大年龄， 负担只会增加。因此，迫切需要发现衰老的基本机制 为了最大程度地减少衰老对我们健康和经济的影响的辩护策略。 人们普遍认为，细胞自主机制有助于衰老。随着细胞的损害 随着时间的流逝，它们通过触发单个细胞命运决定（例如，感应和凋亡）来做出反应， 最终破坏组织稳态，从而增加发病率的风险。但是，最近有 大量证据表明细胞非自治机制也至关重要。 这些细胞非自主机制可能更容易，更安全地靶向治疗。所以 确定和表征这些机制是一个优先事项。询问小鼠中只有一个组织“衰老”是否足够 为了推动全身衰老，我们产生了一系列八个组织特异性突变动物，其中DNA损伤， 一次仅在一种细胞类型或组织中增加感应和组织功能障碍。我们的初步数据 表明“衰老”的免疫细胞在非自动驱动衰老中起关键作用。仅在造血 细胞突变小鼠在生命的第一年中未靶向，周围组织受到巨大影响，显示 增强感受，影响和稳态的丧失。该项目的目的是完全定义这本小说 免疫细胞介导的非自治衰老的机理。该项目的目的是：1。 通过“老化”的免疫系统确定次级感应驱动的临时顺序和程度。 QRT-PCR和 在不同小鼠年龄的细胞。 “老化”免疫系统对外周组织的功能影响 稳态将通过测量特异性终点和与年龄相关的组织病理学来确定。 2。 确定最有潜力驱动全身性衰老的免疫小球类型。这将完成 通过将脾细胞和分离的免疫细胞群体移植到年轻的感应报告小鼠中 其次是细胞类型特异性突变小鼠的产生和表征（例如T，B，NK细胞或 亚群）。 3。确定“老化”免疫细胞驱动全身衰老的机制。这会 可以通过从造血突变小鼠中的血清转移到年轻的感应报告小鼠中来完成 然后对分离的免疫细胞群进行转录组分析，以鉴定分泌的因素。这些 推定的促性因素将通过蛋白质组学和功能验证来验证。 这些目标的完成将识别并表征细胞非自治衰老的新机制 在老化的免疫系统的驱动下，这将使自己能够用于扩展人类健康状况的治疗靶向。