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Causes of Immune Cell Senescence in Aging Humans

老年人免疫细胞衰老的原因

基本信息

批准号：
10160743
负责人：
PATRICIA FITZGERALD-BOCARSLY
金额：
$ 19.6万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160743
关键词：
ATAC-seq Age Aging Alzheimer&apos s Disease Antibodies Area Atherosclerosis Biological Assay Blood Blood donor CD8-Positive T-Lymphocytes CDKN2A gene Cell Aging Cell Lineage Cell physiology Cell surface Cells Chromatin DNA Damage Data Degenerative polyarthritis Development Disease Elderly Embryo Embryonic Development Environment Flow Cytometry Fluorescence Functional disorder GLB1 gene Gene Expression Genomics Goals Health Human Immune Immune response Immunofluorescence Immunologic Immunologic Surveillance Impairment Intervention Malignant Neoplasms Mammalian Cell Mammals Modeling Mus Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Obesity Organism Papio Pathology Pattern Peripheral Blood Mononuclear Cell Permeability Pharmacology Phenotype Play Population Pulmonary Fibrosis Role Signal Transduction Spiders Stains Stress T-Lymphocyte Techniques Telomere Shortening Testing Therapeutic Intervention Tissues adaptive immune response age related base beta-Galactosidase biological adaptation to stress cell age epigenome fitness healthspan immune function improved juvenile animal novel paracrine response sarcopenia senescence targeted treatment tau Proteins telomere therapeutic evaluation tissue repair transcriptome transcriptome sequencing

项目摘要

Cellular senescence is a stable proliferative arrest that is encountered by mammalian cells in response to cell extrinsic and intrinsic stresses, such as telomere dysfunction. In mammals, this stress response not only functions to suppress cancer development, but it also plays important roles during tissue repair and embryonic development. Cellular senescence, therefore, evolved to benefit the organism. The persistence of senescent cells in tissue, however, also has a substantial negative impact on health and fitness. For example, senescent cells accumulate with advancing age in various mammalian tissues and this accumulation of senescent cells has recently been show to be a major contributing factor to aging and the development of age-associated pathologies in mice. The aging-associated accumulation of senescent cells, however, is surprising, given that they can be efficiently cleared from tissue by innate and adapted immune responses under different circumstances in young animals, such as during tissue repair, as well as during embryonic and cancer development. One model that could explain why senescent cells accumulate with advancing age in mammalian tissue is that immune cells themselves increasingly become senescent as we age, thereby increasingly weakening immune responses that would otherwise clear senescent cells from aged tissue. This proposal tests the hypothesis that aging causes various subsets of human circulating immune cells to increasingly undergo telomere dysfunction-induced cellular senescence with advancing age, thereby resulting in an age-associated overall loss of immune cell function. Using a novel technique to detect senescent cells by flow cytometry, we propose to identify specific populations of human peripheral blood mononuclear cells (PBMCs) that increasingly undergo cellular senescence with advancing age. Additionally, we will characterize the transcriptome and epigenome of senescent PBMCs by RNA-seq and ATAC seq, respectively, not only to better define the senescence state of specific PBMC populations, but also to uncover potential targets for therapeutic interventions to modulate senescence responses of human PBMCs. Lastly, using immunofluorescence analysis and ex-vivo cultures of human PBMCs, we will reveal the causes and functional consequences of PBMC senescence in humans and test strategies to suppress them, with the overall goal of reducing immune cell senescence, improving immune function, and suppressing age-associated diseases.

细胞衰老是哺乳动物细胞响应细胞衰老而遇到的稳定的增殖停滞。外在和内在的压力，如端粒功能障碍。在哺乳动物中，这种应激反应不仅功能抑制癌症发展，但它也在组织修复和胚胎发育过程中发挥重要作用。发展因此，细胞衰老的进化有利于生物体。衰老的持续性然而，组织中的细胞也对健康和健身具有实质性的负面影响。例如，衰老细胞随着年龄的增长在各种哺乳动物组织中积累，最近被证明是一个主要的因素老化和发展的年龄相关的小鼠的病理学。然而，与衰老相关的衰老细胞积累是令人惊讶的，因为它们可以通过先天性和适应性免疫应答从组织中有效地清除，例如在组织修复期间，以及在胚胎和癌症期间，发展有一个模型可以解释为什么衰老细胞随着年龄的增长而积累，哺乳动物组织的一个重要原因是，随着我们年龄的增长，免疫细胞本身也会逐渐衰老，免疫反应越来越弱，否则会从衰老组织中清除衰老细胞。这项提议验证了一个假设，即衰老导致人类循环免疫细胞的各种亚群，随着年龄增长，越来越多地经历端粒功能障碍诱导细胞衰老，从而导致与年龄相关的免疫细胞功能的全面丧失。使用一种新的技术来检测衰老细胞，流式细胞术，我们建议确定特定人群的人外周血单核细胞随着年龄的增长，越来越多的人外周血单个核细胞（PBMC）经历细胞衰老。此外，我们将描述分别通过RNA-seq和ATAC seq对衰老PBMC的转录组和表观基因组进行分析，不仅更好地定义特定PBMC群体的衰老状态，但也揭示了潜在的靶点，治疗干预以调节人PBMC的衰老应答。最后，使用通过对人PBMC的免疫荧光分析和离体培养，我们将揭示其原因和功能。人类PBMC衰老的后果和抑制它们的测试策略，总体目标是减少免疫细胞衰老，提高免疫功能，抑制年龄相关疾病。