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Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.

Type 2 diabetes mellitus (T2DM) is a very complex and multifactorial metabolic disease characterized by insulin resistance and β cell failure leading to elevated blood glucose levels. Hyperglycemia is suggested to be the main cause of diabetic complications, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for health care systems. Therefore, and to counteract the continually increasing prevalence of diabetes, understanding the pathogenesis, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence that oxidative stress has an important role in hyperglycemia-induced tissue injury as well as in early events relevant for the development of T2DM. The formation of advanced glycation end products (AGEs), a group of modified proteins and/or lipids with damaging potential, is one contributing factor. On the one hand it has been reported that AGEs increase reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. Thus, AGEs contribute at least partly to chronic stress conditions in diabetes. As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications—if they are causal or simply an effect—is only partly understood. This review will highlight the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications.

Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. Future Directions: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 23, 1144–1170.

Protein oxidation in vivo is a natural consequence of aerobic life. Oxygen radicals and other activated oxygen species generated as by-products of cellular metabolism or from environmental sources cause modifications to the amino acids of proteins that generally result in loss of protein function/enzymatic activity. Oxidatively modified proteins can undergo direct chemical fragmentation or can form large aggregates due to covalent cross-linking reactions and increased surface hydrophobicity. Mammalian cells exhibit only limited direct repair mechanisms and most oxidized proteins undergo selective proteolysis. The proteasome appears to be largely responsible for the degradation of soluble intracellular proteins. In most cells, oxidized proteins are cleaved in an ATP-and ubiquitin-independent pathway by the 20 S "core" proteasome. The proteasome complex recognizes hydrophobic amino acid residues, aromatic residues, and bulky aliphatic residues that are exposed during the oxidative rearrangement of secondary and tertiary protein structure: increased surface hydrophobicity is a feature common to all oxidized proteins so far tested. The recognition of such (normally shielded) hydrophobic residues is the suggested mechanism by which proteasome catalyzes the selective removal of oxidatively modified cell proteins. By minimizing protein aggregation and cross-linking and by removing potentially toxic protein fragments, proteasome plays a key role in the overall antioxidant defenses that minimize the ravages of aging and disease.

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Oxidized cytoplasmic and nuclear proteins are normally degraded by proteasome, but accumulate with age and disease. We demonstrate the importance of various forms of the proteasome during transient (reversible) adaptation (hormesis), to oxidative stress in murine embryonic fibroblasts. Adaptation was achieved by ‘pre-treatment’ with very low concentrations of H2O2, and tested by measuring inducible resistance to a subsequent, much higher ‘challenge’ dose of H2O2. Following an initial direct physical activation of pre-existing proteasomes, 20S proteasome, immunoproteasome, and PA28αβ regulator, all exhibited substantially increased de novo synthesis during adaptation over 24 hours Cellular capacity to degrade oxidatively damaged proteins increased with 20S proteasome, immunoproteasome, and PA28αβ synthesis, and was mostly blocked by 20S proteasome, immunoproteasome, and PA28 siRNA knock-down treatments. Additionally, PA28αβ knockout mutants achieved only half the H2O2 induced adaptive increase in proteolytic capacity of wild-type controls. Direct comparison of purified 20S proteasome and immunoproteasome demonstrated that immunoproteasome can selectively degrade oxidized proteins. Cell proliferation and DNA replication both decreased, and oxidized proteins accumulated, during high H2O2 challenge, but prior H2O2 adaptation was protective. Importantly, siRNA knock-down of 20S proteasome, immunoproteasome, or PA28αβ regulator blocked 50–100% of these adaptive increases in cell division and DNA replication, and immunoproteasome knock-down largely abolished protection against protein oxidation.