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: 9902309
• 负责人: Laura Jane Niedernhofer
• 金额: $ 57.03万
• 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/9902309
• 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 老龄化和与老龄化相关的慢性病给我们的医疗保健系统带来了巨大的负担， 降低老年人的生活质量。在接下来的三十年里，随着世界人口急剧老龄化， 负担只会增加。因此，迫切需要发现衰老的基本机制来发展 将老龄化对我们的健康和经济的影响降至最低的基本策略。 人们普遍认为，细胞自主机制有助于衰老。随着细胞损伤的增加 随着时间的推移，它们通过触发单个细胞的命运决定(例如，衰老和凋亡)来做出反应 最终会破坏组织的动态平衡，从而增加发病风险。然而，最近，有一些 大量证据表明，细胞的非自主机制也是至关重要的。 这些细胞非自主机制很可能更容易和更安全地作为治疗靶点。因此 确定和描述这些机制是当务之急。要问“老化”小鼠的一个组织是否足够 为了推动系统衰老，我们产生了一系列八种组织特异性突变动物，在这些突变动物中，DNA损伤， 衰老和组织功能障碍一次只在一种细胞类型或组织中增加。我们的初步数据 表明“老化”的免疫细胞在非自主性地驱动衰老过程中起着关键作用。只有在造血术中 细胞突变小鼠在出生的第一年就没有靶点，周围组织受到极大的影响，显示出 增加衰老、炎症和动态平衡的丧失。这个项目的目标是充分定义这部小说 免疫细胞介导的体内非自主衰老机制。该项目的目标是：1. 确定由“老化的”免疫系统驱动的次级衰老的时间顺序和程度。 衰老增加的特定免疫和非免疫细胞类型将通过qRT-PCR和 不同鼠龄小鼠的细胞周期。“衰老”免疫系统对外周组织功能的影响 动态平衡将通过测量特定疾病的终点和与年龄相关的组织病理学来确定。2. 确定最能推动全身衰老的免疫细胞类型(S)。这将会实现的 通过将脾细胞和分离的免疫细胞群移植到年轻的衰老报告鼠中， 然后是细胞类型特异性突变小鼠(例如，T、B、NK细胞或 亚群)。3.确定“老化”的免疫细胞驱动全身衰老的机制。这将是 通过将血清从造血型突变小鼠转移到年轻的衰老报告小鼠来实现 然后对分离的免疫细胞群体进行转录转录分析，以确定分泌因子。这些 推测的促老年因子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和表征一种新的细胞非自主衰老机制(S 由衰老的免疫系统驱动，这将有助于延长人类健康寿命的治疗靶向。