Luna Adrian, Chou Kai-Neng, Wragg Kathleen M, Worley Matthew J, Paruchuri Nikhil, Zhou Xiaofeng, Blin Muriel G, Moore Bethany B, Salmon Morgan, Goldstein Daniel R, Deng Jane C
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
Aging Cell. 2025 Apr;24(4):e14437. doi: 10.1111/acel.14437. Epub 2025 Jan 3.
Aging is a major risk factor for poor outcomes following respiratory infections. In animal models, the most severe outcomes of respiratory infections in older hosts have been associated with an increased burden of senescent cells that accumulate over time with age and create a hyperinflammatory response. Although studies using coronavirus animal models have demonstrated that removal of senescent cells with senolytics, a class of drugs that selectively kills senescent cells, resulted in reduced lung damage and increased survival, little is known about the role that senescent cells play in the outcome of influenza A viral (IAV) infections in aged mice. Here, we tested if the aged mice survival or weight loss IAV infections could be improved using three different senolytic regimens. We found that neither dasatinib plus quercetin, fisetin, nor ABT-263 improved outcomes. Furthermore, both dasatanib plus quercetin and fisetin treatments further suppressed immune infiltration than aging alone. Additionally, our data show that the short-term senolytic agents do not reduce senescent markers in our aged mouse model. These findings suggest that acute senolytic treatments do not universally reverse aging related immune phenotype against all respiratory viral infections.
衰老是呼吸道感染后预后不良的主要风险因素。在动物模型中，老年宿主呼吸道感染最严重的后果与衰老细胞负担增加有关，这些细胞会随着年龄的增长而逐渐积累，并引发过度炎症反应。尽管使用冠状病毒动物模型的研究表明，使用一类能选择性杀死衰老细胞的药物（衰老细胞溶解剂）清除衰老细胞可减少肺部损伤并提高存活率，但对于衰老细胞在老年小鼠甲型流感病毒（IAV）感染结果中所起的作用知之甚少。在此，我们测试了使用三种不同的衰老细胞溶解方案是否能改善老年小鼠IAV感染后的存活率或体重减轻情况。我们发现，达沙替尼加槲皮素、非瑟酮或ABT - 263均未改善预后。此外，与仅衰老相比，达沙替尼加槲皮素和非瑟酮治疗均进一步抑制了免疫浸润。此外，我们的数据表明，短期衰老细胞溶解剂不会降低我们老年小鼠模型中的衰老标志物。这些发现表明，急性衰老细胞溶解治疗并不能普遍逆转与衰老相关的针对所有呼吸道病毒感染的免疫表型。
