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

酮体对年龄相关炎症和延长健康寿命的影响

基本信息

批准号：
10116685
负责人：
Emily Lauren Goldberg
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116685
关键词：
Ablation Acute Acute Lung Injury Adipose tissue Adult Age Aging Anti-Inflammatory Agents Antiinflammatory Effect Atherosclerosis Bacterial Infections CASP1 gene Caloric Restriction Cell physiology Cells Chronic Chronic Disease Coenzyme A Data Development Disease Educational process of instructing Elderly Enzymes Esters Faculty Fatty Acids Fatty acid glycerol esters Fibrosis Genetic Genus Hippocampus Glucose Glucose tolerance test Goals Grant Health Hepatic Host Defense Human Immune Immune Targeting Immune response Immune system Impaired cognition Impairment In Vitro Individual Infection Infiltration Inflammaging Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-18 Intervention Ketone Bodies Ketones Ketosis Label Leadership Leukocytosis Link Longevity Lung Lung infections Lyase Measures Mediating Metabolic Metabolic Diseases Metabolism Methods Modeling Mus Myelogenous Nutritional Outcome Parabiosis Pathology Pathway interactions Population Positioning Attribute Process Production Regulation Risk Factors Role Scientist Signal Transduction Source Staphylococcus aureus Starvation Sterility Testing Tissue Model Tissues Training Virus Diseases Visceral Writing age related aged antimicrobial autocrine base beta-Hydroxybutyrate bone loss career cell age cytokine cytotoxicity experience experimental study feeding functional decline glycemic control healthspan improved in vitro Assay in vivo insulin tolerance ketogenic diet ketogentic lung injury macrophage metabolic rate mimetics mouse model neutrophil new therapeutic target novel novel therapeutics preference prevent programs protective effect protein complex response responsible research conduct senescence targeted treatment tenure track transcriptome sequencing uptake

项目摘要

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.

项目摘要衰老的特征是全身性慢性炎症。导致此的基本机制炎症是未知的，使得无法开发针对性疗法以预防慢性病较早的。虽然尚不清楚这种增加感染的确切来源，但主要候选人是 NLRP3炎症体。激活炎症是一个高度调节的过程，需要两个信号导致caspase-1的激活和促炎细胞因子IL-1β和IL-18的分泌免疫细胞。 NLRP3炎性体的异常激活会导致慢性炎症，因为老鼠 NLRP3的遗传缺失受到保护，免受与年龄相关的疾病，这些疾病限制了健康状况认知能力下降，代谢疾病，骨质流失和免疫感应。延长寿命的干预措施例如卡路里限制减少NLRP3激活，并以代谢适应为特征重要的是，BHB足以抑制来自老年小鼠和人类的先天免疫小球中的NLRP3激活。该提议的总体假设是，BHB对NLRP3激活的负调节作用会减轻注射失调在衰老期间。该假设将以两个目的进行检验：（1）确定酮在内脏脂肪中针对感染（1a）或慢性无菌感染的炎症反应失调组织（1b）; （2）在调节先天免疫炎症的衰老过程中定义细胞代谢变化。将在肺部感染或肺损伤模型中评估急性炎症反应。无菌炎症将通过白细胞增多，促炎性免疫特征在内脏脂肪组织中评估，并确保代谢健康将通过葡萄糖和胰岛素耐受性测试测试。生酮途径是针对的通过有条件地删除了先天性免疫小球子集中的生酮酶，包括中性粒细胞和宏观。该提案还寻求针对实验方法的候选人的其他科学培训，包括体外测定，Cytof和RNASEQ分析。该建议还包括专业发展，包括负责任的研究，教学经验，赠款写作和领导机会。这些目标的完成将使候选人非常适合获得终身教师职位并成为独立科学家。这些研究将重点介绍BHB作为调节代谢物，可与免疫系统互动以抑制炎症。长期该应用程序的任期目标是为候选人做好过渡到独立科学职业的准备研究先天免疫的起源和衰老期间炎症的调节，最终确定了新型治疗靶标可减少与年龄相关的感染并扩展健康范围。