Can Senolytics Improve the Aged Response to Viral Infection

项目摘要 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。与免疫系统相关的变化有助于降低 在人类和小鼠感染流感后产生高度保护性免疫反应能力 模型随着年龄的增长，我们观察到较慢的病毒清除和挥之不去的肺部炎症，这可能 为继发性细菌感染创造条件重要的是，衰老几乎影响了适应性的各个方面。 免疫应答，包括病毒特异性CD4和CD8 T细胞效应子和高亲和力抗体产生 生产虽然流感感染完全局限于肺部，但骨骼肌的功能减退是 还观察到炎症和萎缩基因的上调以及阳性肌肉细胞的下调。 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 分子变化和整体功能下降更明显，并随着年龄的增长而延长，这表明 生理弹性下降。尽管已经进行了大量的研究，但最终的原因是 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，在本项目中， 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 其特征在于当细胞经历一系列压力时发生的不可逆的生长停滞。数量 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。 由衰老细胞分泌的因子也可以对周围细胞产生直接影响，从而驱动功能障碍， 影响细胞亚群分化。有趣的是，这些因子中有许多是细胞因子， 有效的抗病毒免疫应答的重要性。衰老细胞在衰老的进程中起着因果作用。 许多与年龄有关的疾病，表明清除衰老细胞可能会减缓整个衰老过程， 过程重要的是，我们和其他人已经开始开发药物，可以专门杀死衰老细胞 （称为Senolytics）。间歇性给予senolytics可以减轻一系列与年龄有关的疾病。 然而，senolytics对老年人群免疫系统功能的影响尚未得到研究。 我们将在本提案中提出的总体假设是，衰老细胞在衰老过程中发挥着重要作用。 在与年龄相关的流感感染反应受损中的因果作用。我们将通过排除 衰老细胞在老年小鼠使用衰老药物。这种方法将使我们能够同时检查 细胞衰老在免疫应答受损中的作用以及骨骼肌的相关变化 在老年小鼠模型中，流感感染期间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.