Fisetin as a treatment for community-acquired pathogen susceptibility during aging, obesity and neurodegenerative diseases

衰老和与衰老相关的慢性疾病，如肥胖和神经退行性疾病， 兵役（创伤、烧伤坑暴露等）使老年退伍军人更容易受到社区获得的 病毒病原体这降低了退伍军人的生活质量，给我们的医疗保健带来了巨大的负担。 系统随着退伍军人的老龄化，负担只会增加。因此，我们非常需要发现 老龄化的基本机制，以制定合理的战略，尽量减少老年退伍军人的脆弱性 病毒和细菌病原体。老年科学假说认为， 老龄化机制将在改善老年人口健康方面产生更大的红利， 将治疗个别与年龄有关的疾病，并将赋予抵抗压力，如病毒， 感染.在衰老过程中，衰老细胞积累并可证明对许多生物体功能有毒。 使用抗衰老药物消除衰老细胞已经促进了临床试验，在小鼠中， 改善身体机能、组织健康并抑制全因死亡率。目前的流行病已经确定 当暴露于新的病原体时特别容易受到不良后果影响的人，以及社区 获得性病毒感染已成为包括退伍军人在内的老年人面临的紧迫威胁。之甚少 了解社区获得性感染对脆弱人群（包括肥胖人群）的影响 和神经退化 本项目的目标是确定非瑟酮（一种来自水果和蔬菜的衰老清除化合物） 和其他senolytics，如达沙替尼和槲皮素，可以降低肥胖小鼠的发病率和死亡率， 和具有神经变性的小鼠，其暴露于正常微生物经历（NME），作为神经变性的模型。 社区获得性病毒感染。我们还将利用我们所拥有的知识和资源来研究 细胞衰老在急性暴露的老年、肥胖和帕金森小鼠模型中导致不良结局 到NME。初步数据表明，具有大量衰老细胞负荷的小鼠对衰老细胞的反应要差得多。 与没有衰老细胞的小鼠相比，此外，暴露于正常病原体 通过野生或宠物店小鼠足以杀死在特定的无病原体条件下饲养的老年实验小鼠， 但它不会杀死小老鼠。在这里，我们建议使用这种实验范式，以确定是否senolytics， 特异性杀死衰老细胞的药物，抑制暴露于NME的老年肥胖小鼠的死亡率， 帕金森病的模型。近期目标是生成足够的临床前数据，以支持临床 使用具有衰老清除活性的营养品预防高感染风险退伍军人不良结局的试验 或感染后出现严重疾病。

Aging and the chronic diseases associated with aging, such as obesity and neurodegeneration, combined with military service (trauma, burn pit exposure etc.) make old age Veterans more vulnerable to community-acquired viral pathogens. This reduces quality of life for Veterans and places a tremendous burden on our healthcare system. As the Veteran population ages, the burden will only increase. Hence, there is a great need to discover fundamental mechanisms of aging to develop rational strategies for minimizing the vulnerability of aged Veterans to viral and bacterial pathogens. The Geroscience hypothesis posits that therapeutically targeting fundamental mechanisms of aging would yield a larger dividend in terms of improving the health of the aged population, than would treating individual age-related diseases, and would confer resistance against stressors such as viral infections. During aging, senescent cells accumulate and can prove toxic to many organismal functions. Elimination of senescent cells using senolytic drugs have already fostered clinical trials, and in mice, senolytics improve physical function, tissue health and suppress all-cause mortality. The current pandemic has identified those who are particularly vulnerable to adverse outcomes when exposed to a new pathogen, and community acquired viral infection has emerged as an urgent threat to our aged population, including Veterans. Little is known about the effects of community-acquired infections in vulnerable populations, including those with obesity and neurodegeneration. The goal of the present project is to determine if fisetin (a senolytic compound derived from fruits and vegetables) and other senolytics such as dasatinib and quercetin, can reduce morbidity and mortality in mice with obesity and mice with neurodegeneration, that are exposed to normal microbial experience (NME), as a model of community acquired viral infection. We will also use the knowledge and resources we have to study the role of cellular senescence in driving adverse outcomes in aged, obese and Parkinson's mouse models acutely exposed to NME. Preliminary data indicate that mice with a substantial senescent cell burden respond much worse to inflammatory challenges than mice without senescent cells. Furthermore, exposure to normal pathogens carried by wild or pet store mice is sufficient to kill old experimental mice housed in specified pathogen-free conditions, but it does not kill young mice. Here, we propose to use this experimental paradigm to determine if senolytics, drugs that specifically kill senescent cells, suppress mortality in NME exposed aged obese mice, and in a mouse model of Parkinson's disease. The immediate goal is to generate sufficient preclinical data to support clinical trials using nutraceuticals with senolytic activity to prevent adverse outcomes in Veterans at high risk of infection or grave illness after infection.