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。导致这种情况的基本机制 炎症是未知的，使得不可能开发靶向治疗来预防慢性疾病， 老人虽然这种炎症增加的确切来源尚不清楚，但主要候选者是 NLRP 3炎性小体。炎性小体的激活是一个高度调节的过程，需要两个信号 导致半胱天冬酶-1的活化和促炎细胞因子IL-1β和IL-18的分泌， 免疫细胞NLRP 3炎性体的异常激活有助于老年小鼠的慢性炎症 NLRP 3基因缺失的人免受限制健康寿命的年龄相关疾病的影响，包括 认知能力下降、代谢疾病、骨质流失和免疫衰老。延长寿命的干预措施 例如热量限制降低NLRP 3活化，且其特征在于代谢适应， 增加酮体β-羟基丁酸酯（BHB）的产生。重要的是，BHB足以抑制 来自老年小鼠和人类的先天免疫细胞中的NLRP 3活化。这项提议的总体假设是， BHB对NLRP 3激活的负调节作用可以减轻失调的炎症 在老化过程中。这一假设将在两个目标中进行检验：（1）确定酮在以下方面的保护作用： 内脏脂肪中针对感染（1a）或慢性无菌性炎症的炎症反应失调 组织（1b）;和（2）定义衰老过程中调节先天免疫炎症的细胞代谢变化。 将在肺感染或肺损伤模型中评价急性炎症反应。无菌性炎症 将在内脏脂肪组织中通过白细胞增多、促炎免疫特征和随后的 代谢健康将通过葡萄糖和胰岛素耐量测试进行测试。生酮途径被靶向于 通过先天免疫细胞亚群中生酮酶的条件性缺失，包括嗜中性粒细胞和 宏页面。该提案还寻求对候选人进行实验方法方面的额外科学培训， 包括体外测定、CyTOF和RNAseq分析。这项建议还包括以下方面的培训 专业发展，包括负责任的研究行为，教学经验，拨款写作， 领导机会。完成这些目标将使候选人非常适合获得 终身教职并成为独立的科学家。这些研究将突出BHB作为 调节代谢物，其协调新陈代谢与免疫系统以抑制炎症。很长的- 本申请的长期目标是准备过渡到一个独立的科学生涯的候选人 研究衰老过程中的先天免疫起源和炎症调节，最终确定新的 治疗目标是减少与年龄相关的炎症并延长健康寿命。

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.