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

非瑟酮可治疗衰老、肥胖和神经退行性疾病期间社区获得性病原体易感性

• 批准号: 10610378
• 负责人: CATHERINE M KOTZ
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610378
• 关键词: Acute; Adult; Affect; Age; Aging; Animals; Automobile Driving; Bacterial Infections; Beds; Behavior; Brain; Cell Aging; Cells; Chronic; Chronic Disease; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Communities; Community-Acquired Infections; Coronavirus; Dasatinib; Data; Disease; Elderly; Exposure to; Flavonoids; Fostering; Geroscience; Goals; Health; Healthcare Systems; Histopathology; House mice; Human; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Knowledge; Laboratory mice; Link; Longevity; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Products; Nerve Degeneration; Neurodegenerative Disorders; Nutraceutical; Obese Mice; Obesity; Parkinson Disease; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Physical Function; Physical activity; Physiological; Predisposition; Quality of life; Quercetin; Reproducibility; Resistance; Resources; Risk; Role; Specific qualifier value; Testing; Tissues; Transgenic Model; Trauma; Veterans; Virus Diseases; Vulnerable Populations; adverse outcome; age related; aged; aging population; alpha synuclein; brain cell; burn pit; cell age; cognitive ability; current pandemic; cytokine release syndrome; emerging pathogen; experience; fisetin; frailty; fruits and vegetables; germ free condition; high risk; human old age (65+); improved; in vivo; infection risk; microbial; military service; military veteran; mortality; mouse model; mutant; neuroinflammation; novel; pandemic disease; pathogen; pathogen exposure; pathogenic bacteria; pathogenic virus; pre-clinical; prevent; promote resilience; resilience; senescence; stressor; synucleinopathy; therapeutic target; transmission process

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.

衰老和与衰老相关的慢性疾病，例如肥胖和神经变性，并结合 兵役（创伤，燃烧坑曝光等）使老年退伍军人更容易受到社区的影响 病毒病原体。这降低了退伍军人的生活质量，并给我们的医疗保健带来了巨大的负担 系统。随着退伍军人人口的年龄，负担只会增加。因此，很有必要发现 衰老的基本机制，以制定理性策略来最大程度地减少老年退伍军人的脆弱性 病毒和细菌病原体。 GEROSCIENCE假设认为，治疗方法是针对基本的 衰老机制将在改善老年人口的健康方面产生更大的股息，而不是 将治疗与年龄相关的疾病，并赋予对病毒等压力源的抵抗力 感染。在衰老过程中，衰老细胞会积累，并可能对许多有机功能进行有毒。 消除使用鼻溶液药物消除衰老细胞已经促进了临床试验，在小鼠中，塞溶术 改善身体功能，组织健康并抑制全因死亡率。当前的大流行已经确定 那些在暴露于新病原体和社区时特别容易受到不利结果的人 获得的病毒感染已成为对包括退伍军人在内的年龄人口的紧急威胁。几乎没有 知道社区获得感染在脆弱人群中的影响，包括肥胖症的人群 和神经变性。 本项目的目的是确定fisetin是否（源自水果和蔬菜的鼻溶性化合物） 以及其他鼻孔剂，例如达沙替尼和槲皮素，可以降低肥胖症小鼠的发病率和死亡率 和具有神经变性的小鼠，暴露于正常微生物体验（NME），作为模型 社区获得了病毒感染。我们还将利用我们必须研究的知识和资源来研究 驱动老化，肥胖和帕金森氏症的小鼠模型的细胞衰老急性暴露 到NME。初步数据表明，具有大量衰老细胞负担的小鼠对 炎症挑战比没有衰老细胞的小鼠面临的挑战。此外，暴露于正常病原体 通过野生或宠物店的小鼠足以杀死在指定无病原体条件下容纳的旧实验小鼠， 但这不会杀死年轻的老鼠。在这里，我们建议使用这种实验范式来确定senoloticts是否， 专门杀死衰老细胞，抑制NME暴露老化肥胖小鼠的死亡率的药物以及小鼠 帕金森氏病的模型。直接目标是生成足够的临床前数据以支持临床 使用具有鼻溶性活性的营养素的试验，以防止退伍军人的不良后果 或感染后严重疾病。