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.

衰老以及与衰老相关的慢性疾病，例如肥胖和神经退行性疾病，以及 服兵役（创伤、烧伤坑暴露等）使老年退伍军人更容易受到社区获得性感染 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。随着退伍军人人口老龄化，负担只会增加。因此，非常需要发现 老龄化的基本机制，制定合理的策略，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，治疗目标是基本的 老龄化机制在改善老年人口健康方面所产生的红利比 将治疗个体与年龄相关的疾病，并赋予对病毒等压力源的抵抗力 感染。在衰老过程中，衰老细胞不断积累，并对许多有机体功能产生毒性。 使用 senolytics 药物消除衰老细胞已经开展了临床试验，在小鼠中，senolytics 改善身体机能、组织健康并抑制全因死亡率。当前疫情已明确 那些在接触新病原体时特别容易遭受不良后果的人以及社区 获得性病毒感染已成为对包括退伍军人在内的老年人口的紧迫威胁。小的是 了解社区获得性感染对弱势群体（包括肥胖人群）的影响 和神经退行性变。 本项目的目标是确定非瑟酮（一种源自水果和蔬菜的抗衰老化合物）是否 和其他抗衰老药物，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 以及患有神经退行性疾病的小鼠，它们暴露于正常的微生物经验（NME），作为模型 社区获得性病毒感染。我们还将利用我们拥有的知识和资源来研究 细胞衰老导致老年、肥胖和帕金森病小鼠模型出现不良后果 到 NME。初步数据表明，具有大量衰老细胞负担的小鼠对 与没有衰老细胞的小鼠相比，炎症挑战。此外，接触正常病原体携带 野生或宠物商店的小鼠足以杀死饲养在特定无病原体条件下的老实验小鼠， 但它不会杀死幼鼠。在这里，我们建议使用这个实验范式来确定 senolytics 是否， 专门杀死衰老细胞、抑制暴露于 NME 的老年肥胖小鼠和小鼠死亡率的药物 帕金森病模型。近期目标是产生足够的临床前数据来支持临床 使用具有抗衰老活性的营养保健品预防高感染风险退伍军人出现不良后果的试验 或感染后患重病。