Caloric restriction-driven immunometabolic checkpoints of inflammation

项目概要： 衰老是疾病的最大风险因素。到2030年，美国历史上第一次，65岁和 老年人将超过18岁以下的人。在未来的20-30年里， 在美国，65岁的老年人将翻一番，达到8000万，相关的医疗保健费用预计将达到2万亿美元。 衰老引起的炎症是包括阿尔茨海默病在内的多种疾病的主要危险因素。 因此，使衰老炎症失活的内源性途径和代谢产物具有高临床应用价值。 冲击动物的热量限制（CR）已被证明可以延长寿命和健康。但 CR对免疫系统影响和人类炎症的免疫代谢控制尚不清楚。这 该提案是对PA-18-823“CALERIE数据和生物样本分析以阐明 热量限制（CR）在人类中诱导效应的机制。中心假设。因此 减少能量摄入长期效果的综合评估（CALERIE-II）临床试验 旨在测试2年中度CR对人体生理学的长期影响以及 健康和长寿。我们的初步数据确定CALERIE-II免疫细胞的进一步分析 在我们的研究中收集的样本、血浆和脂肪组织活检是一种富有成效的方法， CR的机制，并确定可以针对年龄相关慢性疾病开发的目标。这 该项目将测试中心假设，即-负能量平衡在人类整合代谢和 增强抗炎性重编程并揭示临床相关CR模拟物的免疫细胞 目标的该项目的长期目标是发现减少炎症的CR模拟靶点， 增强免疫反应，促进健康。

PROJECT SUMMARY: Aging is the single biggest risk factor for disease. For the first time in US history, by 2030, people aged 65 and older will outnumber individuals under the age of 18. Over the next 20-30 years, the number of people over the age of 65 will double to ~80 million in the US with associated healthcare costs projected to be 2 trillion dollars. Aging induced inflammation is the major risk factor for multiple diseases including Alzheimer's disease. Therefore, the endogenous pathways and metabolites that deactivate inflammation of aging have high clinical impact. Caloric restriction (CR) in animals has been shown to extend lifespan and healthspan. However, the impact of CR on immune system, and immunometabolic control of inflammation in humans is unknown. This proposal is in response to the PA-18-823 “Analyses of CALERIE Data and Biospecimens to Elucidate Mechanisms of Caloric Restriction (CR)-Induced Effects in Humans”. The central hypothesis. Therefore, the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE-II) clinical trial was designed to test the long-term effects of 2 years of moderate CR on human physiology and predictors of healthspan and longevity. Our preliminary data establishes that further profiling of CALERIE-II immune cell samples, plasma and adipose tissue biopsies collected in our study is a fruitful approach to discover mechanism of CR and identify targets that can be developed against age-associated chronic diseases. This project will test the central hypothesis that – negative energy balance in humans integrates metabolic and immune cells that enhances anti-inflammatory reprogramming and reveals clinically relevant CR-mimetic targets. The long-term goal of this project is to discover CR-mimetic targets that reduced inflammation, enhance immune response, and promote healthspan.