In vivo transformations and maintaining health

Chairperson

Summary  WG5

Bio-reactive AGEs alter the structure and function of molecules in biological systems, increase oxidative stress being responsible for the ageing process. These adverse effects of both exogenous (e.g. dietary AGEs) and endogenously derived AGEs (formed in the human organism by reaction of proteins/aminophospholipids with various glycating agents) have been implicated in the pathogenesis of diabetic complications and changes associated with aging including atherosclerosis, renal, eye, and neurological disease. Specific AGE receptors (e.g. RAGE) and nonreceptor mechanisms contribute to these processes but also assist in the removal and degradation of AGEs. The final disposal of AGEs depends on renal clearance.

Until recently, it was thought that AGE formation involves primarily long-lived extracellular proteins and occurs as a function of time, thus representing a form of molecular senescence. It is now clear that AGEs arise on short-lived molecules as well, including circulating plasma proteins and lipids, and that their levels are significantly elevated in diabetic patients and in patients with impaired renal clearance and/or liver cirrhosis. It is also recognised that they can form on cytoplasmic proteins and nucleic acids. Such AGE modification of short- and long-lived molecules is known to involve oxidation of proteins and lipids, to disrupt molecular conformation, to reduce degradative capacity, and to result in abnormal recognition and clearance by receptors. Recent studies indicate that AGEs introduced to biological systems from diet may have significant impact on disease mechanisms. Proteins and the products of lipoxidation (e.g., glyoxal, 2-nonenal, malondialdehyde) undergo similar chemistry to proteins and sugars leading to the formation of advanced lipoxidation endproducts (ALEs). Indeed, some intermediates (e.g., glyoxal) are common to both lipoxidation and sugar autoxidation, leading to common products, e.g., N-epsilon-carboxymethyllysine (CML).

The main objectives of this WG will be:

• to elucidate the effects of diet (high-AGE, low-AGE) on protein modification in vivo and the implications for health/disease and aging; to study the effects of endogenous glycation on the functionality of various enzymes and proteins

• to investigate the impairment of angiogenesis in diabetes mellitus by e.g. glycation of the fibroblast growth factor 2.

Tasks  WG5

5.1. Food AGEs and health

5.2. Protein glycation in vivo

Links  WG5