Can Senolytics Improve the Aged Response to Viral Infection

Senolytics 能否改善老年人对病毒感染的反应

• 批准号: 10303445
• 负责人: Laura Haynes
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303445
• 关键词: Adaptive Immune System; Address; Age; Aging; Antibodies; Antibody Affinity; Antibody Formation; Antiviral Agents; Atrophic; Automobile Driving; Bacterial Infections; Body Weight decreased; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cause of Death; Cell Aging; Cells; Chronology; Clinical Trials; Communicable Diseases; Disease; Down-Regulation; Elderly; FOXP3 gene; Fast-Twitch Muscle Fibers; Functional disorder; Gait; Gene Expression; Generations; Genes; Growth; Histology; Immune response; Immune system; Immunization Programs; Immunologics; Impairment; Inflammation; Inflammatory; Influenza; Irrigation; Lung; Lung Inflammation; Molecular; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Pathology; Pharmaceutical Preparations; Phenotype; Physical Function; Physiological; Play; Process; Production; Recovery; Regulatory T-Lymphocyte; Research; Role; Serum; Skeletal Muscle; Stress; Testing; Time; Tissues; Up-Regulation; Viral; Virus; Virus Diseases; adaptive immune response; age related; aged; aging population; base; chemokine; cytokine; disability; effector T cell; experience; flu; functional decline; functional disability; functional outcomes; gene function; human model; human subject; immune function; immune system function; improved; influenza infection; loss of function; mortality; mouse model; muscle aging; new therapeutic target; preclinical study; prevent; resilience; response; senescence; side effect; walking speed

PROJECT SUMMARY Influenza (flu) is foremost among all infectious diseases causing death and disability in older adults, despite widespread vaccination programs. Age-related changes in the immune system contribute to declines in the ability to mount a highly protective immune response following flu infection in both humans and mouse models. With advancing age, we observe slower viral clearance and lingering lung inflammation, which could set the stage for secondary bacterial infection. Importantly, aging impacts almost every aspect of the adaptive immune response including generation of virus-specific CD4 and CD8 T cell effectors and high affinity antibody production. While flu infection is entirely localized to the lungs, functional decrements in skeletal muscle are also observed with upregulation of inflammatory and atrophy genes and downregulation of positive muscle regulators, ultimately resulting in loss of physical function. Importantly, the impact of flu infection on these molecular changes and overall functional declines is more pronounced and prolonged with aging, suggesting decreased physiologic resilience. Even though much research has been done, the ultimate cause of these age-related decrements has not been elucidated. One of the most prominent features of aging is the accumulation of senescent cells and in this project we will explore their role in the age-related changes in response to flu infection. Cellular senescence is characterized by irreversible growth arrest that occurs when cells experience a range of stresses. The number of senescent cells increases with chronological aging, resulting in many age-related pathologies and disease. Factors secreted by senescent cells can also have a direct impact on surrounding cells driving dysfunction and influencing cell subset differentiation. Interestingly, many of these factors are cytokines that are of vital importance for an effective anti-viral immune response. Senescent cells play a causal role in the progression of many age-related disorders, indicating that clearance of senescent cells might slow down the entire aging process. Importantly, we and others have started to develop drugs, which can specifically kill senescent cells (termed senolytics). Intermittent administration of senolytics can alleviate a range of age-related diseases. However, the impact of senolytics on immune system function in aged population has not yet been examined. The overall hypothesis that we will be addressing in this proposal is that senescent cells play a causal role in the age-related impaired response to flu infection. We will test this hypothesis by eliminating senescent cells in aged mice using senolytic drugs. This approach will allow us to simultaneously examine the role of cellular senescence in the compromised immune response and the associated changes in skeletal muscle and declines in physical function during flu infection in an aged mouse model.

项目摘要 流感（流感）是所有传染病中最重要的，导致老年人死亡和残疾， 尽管疫苗接种计划广泛。免疫系统与年龄相关的变化有助于下降 在人类和小鼠感染流感后，可以安装高度保护性免疫反应的能力 型号。随着年龄的增长，我们观察到病毒性清除率较慢和挥之不起的肺部炎症，这可能 为二次细菌感染设定了阶段。重要的是，衰老几乎会影响自适应的各个方面 免疫反应，包括生成病毒特异性CD4和CD8 T细胞效应子以及高亲和力抗体 生产。虽然流感感染完全位于肺部，但骨骼肌的功能降低是 还观察到炎症和萎缩基因的上调以及阳性肌肉的下调 调节器，最终导致身体机能丧失。重要的是，流感感染对这些影响 分子变化和整体功能下降更为明显，并且随着衰老的延长而延长 生理弹性降低。即使已经进行了很多研究，这是这些的最终原因 与年龄相关的减少尚未阐明。 衰老最突出的特征之一是衰老细胞的积累，在这个项目中 我们将探讨它们在流感感染的响应中与年龄相关的变化中的作用。细胞衰老是 当细胞经历一系列应力时，发生不可逆的生长停滞。数字 衰老细胞随时间衰老而增加，导致许多与年龄有关的病理和疾病。 衰老细胞分泌的因素也可能直接影响驱动功能障碍的周围细胞和 影响细胞子集分化。有趣的是，其中许多因素都是至关重要的细胞因子 对于有效的抗病毒免疫反应的重要性。衰老细胞在进展中起因果作用 许多与年龄有关的疾病，表明衰老细胞的清除可能会减慢整个衰老 过程。重要的是，我们和其他人已经开始开发药物，这些药物可以特别杀死衰老细胞 （称为Senolotics）。间歇性鼻孔剂可以减轻一系列与年龄有关的疾病。 但是，尚未检查鼻溶剂对衰老人群中免疫系统功能的影响。 我们将在此提案中解决的总体假设是，衰老细胞起着 因果关系在与年龄相关的对流感感染的反应受损中的作用。我们将通过消除来检验这一假设 使用鼻溶剂的老年小鼠中的衰老细胞。这种方法将使我们能够同时检查 细胞衰老在受损的免疫反应中的作用和骨骼的相关变化 老年小鼠模型中流感感染期间的肌肉和身体功能下降。