Caloric restriction-driven immunometabolic checkpoints of inflammation

热量限制驱动的炎症免疫代谢检查点

• 批准号: 10656332
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 55.01万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656332
• 关键词: Acute; Adipocytes; Adipose tissue; Age; Aging; Alzheimer' s Disease; Ancillary Study; Animals; Anti-Inflammatory Agents; Biological Markers; Biopsy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Caloric Restriction; Cause of Death; Cell Nucleus; Cells; Cessation of life; Chronic Disease; Clinical; Clinical Trials; Data; Dietary Intervention; Disease; Energy Intake; Funding; Genetic Transcription; Goals; Growth; Health; Health Care Costs; Human; Human Volunteers; Immune; Immune response; Immune system; Immunity; Impairment; Individual; Inflammation; Inflammatory; Influenza; Interdisciplinary Study; Intervention; Long-Term Effects; Longevity; Measures; Metabolic; Modeling; Mouse Strains; Mus; Myeloid Cells; Outcome; Parasitic infection; Participant; Pathway interactions; Persons; Physiology; Plasma; Population; Primates; Protein Secretion; Proteins; Proteomics; RNA; Rana; Recording of previous events; Rejuvenation; Reproduction; Reproductive system; Risk Factors; Rodent; Role; Sampling; Serum; Signal Transduction; System; Technology; Testing; Therapeutic; Thymus Gland; Time; Tissues; West Nile viral infection; aptamer; arm; biomarker discovery; burden of illness; cellular targeting; clinically relevant; design; early onset; energy balance; extracellular; healthspan; human old age (65+); improved; insight; metabolome; mimetics; mortality; neuronal cell body; novel; polymicrobial sepsis; programs; public health relevance; response; single nucleus RNA-sequencing; theories; thymocyte; transcriptome; transcriptome sequencing

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.

项目概要： 到 2030 年，老龄化将首次成为美国历史上最大的疾病风险因素。 老年人的数量将超过 18 岁以下的人口。在未来 20-30 年里，超过 18 岁的人口数量将超过 18 岁以下的人口。 在美国，65 岁的人口将增加一倍，达到约 8000 万，相关的医疗费用预计将达到 2 万亿美元。 衰老引起的炎症是包括阿尔茨海默氏病在内的多种疾病的主要危险因素。 因此，抑制衰老炎症的内源性途径和代谢产物具有很高的临床应用价值。 动物的热量限制（CR）已被证明可以延长寿命和健康寿命。 CR 对免疫系统的影响以及人类炎症的免疫代谢控制尚不清楚。 该提案是对 PA-18-823“分析 CALERIE 数据和生物样本以阐明 热量限制 (CR) 对人类的影响的机制”。 减少能量摄入长期效果综合评估（CALERIE-II）临床试验 旨在测试 2 年适度 CR 对人体生理学的长期影响和预测因素 我们的初步数据证实了 CALERIE-II 免疫细胞的进一步分析。 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来发现 CR 机制并确定可针对与年龄相关的慢性疾病开发的目标。 该项目将测试以下中心假设：人类的能量负平衡将新陈代谢和 增强抗炎重编程并揭示临床相关 CR 模拟的免疫细胞 该项目的长期目标是发现减少炎症的 CR 模拟靶标， 增强免疫反应，促进健康寿命。