The impact of dietary AGEs on immune and energy metabolism parameters and muscle health

Advanced glycation end products (AGEs) are formed via a nonenzymatic reaction between an amino acid and sugar. Such AGEs can be formed either endogenously within the body, or exogenously in food and ingested via the diet. These AGEs are implicated in metabolic diseases like obesity and diabetes, but also neurodegenerative diseases like multiple sclerosis. AGEs can bind to the receptor for advanced glycation end products (RAGE) which leads to inflammation and oxidative stress. However, the mechanism leading to AGE-RAGE induced inflammation and immune responsiveness is not yet clear. Moreover, it is not clear how this AGE-induced inflammation and oxidative stress may effect functional parameters, such as energy metabolism and ultimately skeletal muscle function. Objectives: The overall aim of this project is to investigate the impact of endogenously formed and diet-derived AGEs on immune - and energy metabolism and how this relates to skeletal muscle performance markers in healthy aging humans. Approach: We will perform a series of in vitro mechanistic-experiments on the receptor binding profile and downstream signalling routes of several endogenous and dietary-derived AGEs. Next, we will study the effect of the AGE compounds on macrophage polarization and their metabolism, including the functioning of mitochondria. With the intervention study we will investigate the relation between AGEs, immune-and muscle health, and possible differences between men and women. We will recruit middle aged participants who will undergo an oral glucose tolerance test in combination with short exercise breaks in the postprandial period. Measurements will include blood drawing at several different timepoints, muscle function measurements, and a muscle biopsy. This project will gain insight in the molecular mechanism linking AGE-induced inflammation to immune and energy metabolism and the acute impact of a high glycolytic flux on AGE derived signaling in circulation, and skeletal muscle function