Caloric restriction-driven immunometabolic checkpoints of inflammation

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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.