Impact of ketone bodies on age-related inflammation and healthspan extension

项目摘要 衰老的特征是全身性慢性低度炎症。导致这一点的基本机制 炎症是未知的，因此不可能开发有针对性的疗法来预防慢性疾病 老年人。虽然这种炎症增加的确切来源尚不清楚，但一个主要的候选因素是 NLRP3炎症体。炎性小体的激活是一个高度调控的过程，需要两个信号 导致Caspase-1的激活和促炎症细胞因子IL-1β和IL-18的分泌 免疫细胞。NLRP3炎症体的异常激活与老年小鼠的慢性炎症有关 由于NLRP3基因缺失，可以防止与年龄相关的疾病，这些疾病限制了人们的健康寿命，包括 认知功能减退、代谢性疾病、骨质流失和免疫衰老。延长寿命的干预措施 如卡路里限制会降低NLRP3活性，且以代谢适应为特征 以增加酮体β-羟基丁酸酯(BHB)的产量。重要的是，bHb足以抑制 NLRP3在老年小鼠和人的先天免疫细胞中的激活。这一提议的总体假设 BHB对NLRP3激活的负调节作用可以减轻失调的炎症反应 在衰老过程中。这一假说将在两个目标上得到验证：(1)确定酮类化合物在体内的保护作用 内脏脂肪对感染或慢性无菌炎症的失调炎症反应(1a) 组织(1b)；和(2)定义在衰老过程中调节先天免疫炎症的细胞代谢变化。 急性炎症反应将在肺部感染或肺损伤模型中进行评估。无菌炎症 将在内脏脂肪组织中通过白细胞增多症、促炎免疫图谱和随后的 代谢健康将通过葡萄糖和胰岛素耐量测试进行测试。生酮途径正在成为靶点 通过条件删除天然免疫细胞亚群中的生酮酶，包括中性粒细胞和 宏页。该提案还寻求对候选人进行额外的实验方法科学培训， 包括体外实验、细胞周期分析和RNAseq分析。该提案还包括培训 专业发展，包括负责任地进行研究、教学经验、拨款撰写和 领导力机会。完成这些目标将使候选人非常适合获得 终身教职和成为一名独立科学家。这些研究将突出BHB作为一种 与免疫系统协调新陈代谢以抑制炎症的调节代谢物。长的- 这项申请的学期目标是为候选人过渡到独立的科学生涯做准备 研究先天免疫起源和衰老过程中炎症的调节，最终确定新的 治疗目标是减少与年龄相关的炎症，延长健康寿命。

Project Summary Aging is characterized by systemic chronic low-grade inflammation. The basic mechanisms leading to this inflammation are unknown, making it impossible to develop targeted therapies to prevent chronic disease in the elderly. While the precise source of this increased inflammation is not known, a primary candidate is the NLRP3 inflammasome. Activation of inflammasomes is a highly regulated process that requires two signals leading to activation of caspase-1 and secretion of the proinflammatory cytokines IL-1β and IL-18 from innate immune cells. Aberrant activation of the NLRP3 inflammasome contributes to chronic inflammation as old mice with genetic deletion of NLRP3 are protected from age-related diseases that limit healthspan, including cognitive decline, metabolic disease, bone loss, and immune senescence. Lifespan-extending interventions such as calorie restriction reduce NLRP3 activation and are characterized by a metabolic adaptation that leads to increased production of the ketone body β-hydroxybutyrate (BHB). Importantly, BHB is sufficient to inhibit NLRP3 activation in innate immune cells from aged mice and humans. The overall hypothesis of this proposal is that the negative regulatory effects of BHB upon NLRP3 activation can alleviate dysregulated inflammation during aging. This hypothesis will be tested in two aims: (1) Determine the protective role of ketones in dysregulated inflammatory responses against infection (1a) or chronic sterile inflammation in visceral adipose tissue (1b); and (2) Define cellular metabolic changes during aging that regulate innate immune inflammation. Acute inflammatory responses will be evaluated in lung infections or lung injury models. Sterile inflammation will be evaluated in visceral adipose tissue by leukocytosis, pro-inflammatory immune profiles, and ensuing metabolic health will be tested by glucose and insulin tolerance tests. The ketogenic pathway is being targeted by conditional deletion of ketogenic enzyme in innate immune cell subsets including neutrophils and macropages. The proposal also seeks additional scientific training for the candidate in experimental methods, including in vitro assays, CyTOF, and RNAseq analysis. This proposal also incorporates training in professional development including responsible conduct of research, teaching experience, grant writing, and leadership opportunities. Completion of these objectives will make the candidate ideally suited for obtaining a tenure-track faculty position and becoming an independent scientist. These studies will highlight BHB as a regulatory metabolite that coordinates metabolism with the immune system to dampen inflammation. The long- term goal of this application is to prepare the candidate for transition to an independent scientific career studying innate immune origins and regulation of inflammation during aging, ultimately identifying novel therapeutic targets to decrease age-related inflammation and extend healthspan.