Can Senolytics Improve the Aged Response to Viral Infection

项目总结 流感(流感)是导致老年人死亡和残疾的所有传染病中最重要的， 尽管有广泛的疫苗接种计划。免疫系统中与年龄相关的变化导致了 人类和小鼠感染流感后产生高度保护性免疫反应的能力 模特们。随着年龄的增长，我们观察到病毒清除较慢，肺部炎症挥之不去，这可能 为继发性细菌感染做好准备。重要的是，老龄化几乎影响到适应能力的方方面面 免疫反应，包括产生病毒特异性的CD4和CD8T细胞效应器和高亲和力抗体 制作。虽然流感感染完全局限于肺部，但骨骼肌的功能减退 同时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，最终导致身体功能丧失。重要的是，流感感染对这些人的影响 随着年龄的增长，分子变化和整体功能下降更加明显和持续时间更长，表明 生理韧性下降。尽管已经做了很多研究，但这些问题的根本原因 与年龄相关的减退还没有被阐明。 衰老最显著的特征之一是衰老细胞的积累，在这个项目中 我们将探讨它们在应对流感感染的年龄相关变化中的作用。细胞衰老是 以细胞承受一系列压力时发生的不可逆转的生长停滞为特征的。数字 随着时间的老化，衰老细胞的数量增加，导致许多与年龄相关的病理和疾病。 衰老细胞分泌的因子也可以直接影响周围细胞驱动功能障碍和 影响细胞亚群分化。有趣的是，这些因素中有许多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。衰老细胞在肿瘤的发展过程中起着因果作用。 许多与年龄相关的疾病，表明衰老细胞的清除可能会减缓整个衰老过程 进程。重要的是，我们和其他人已经开始开发药物，这种药物可以特异性地杀死衰老细胞 (称为感觉剂)。间歇给药可以缓解一系列与年龄相关的疾病。 然而，目前尚不清楚增感剂对老年人群免疫系统功能的影响。 我们将在这项提案中提出的总体假设是，衰老细胞发挥着 与年龄相关的流感感染反应受损的因果作用。我们将通过删除以下内容来验证此假设 使用抗衰老药物的衰老小鼠的衰老细胞。这种方法将允许我们同时检查 细胞衰老在免疫应答受损及骨骼相关改变中的作用 在流感感染的老年小鼠模型中，肌肉和身体功能下降。

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.