Reviewing AGEs and ALEs in Oxidative Stress and Aging

Advanced glycation end products (AGEs) and the less discussed advanced lipoxidation end products (ALEs) are an interesting topic in the context of aging. There are in fact two distinct topics here. The first is the presence of persistent cross-links, in which glucosepane AGEs form links between extracellular matrix molecular, degrading the structural properties of tissue, particularly elasticity. These cross-links, arising from the normal operation of metabolism, are resilient and not broken down by our biochemistry. Some form of biotechnology, such as therapies based on enzymes mined from bacterial species that can metabolize glucosepane, will be required to remove their contribution to the aging process.

The second topic is that a menagerie of many different short-lived AGEs and ALEs emerge in greater numbers in the aged or diabetic metabolism, and cause chronic inflammation via their interaction with the receptor for AGEs, RAGE. They also produce other significant changes for the worse in cellular behavior. There is also some debate over whether or not AGEs and ALEs in the diet are important in these processes, with evidence for either answer to that question. It isn't clear as to what might be the best approach to this side of the problem, but researchers are considering targeting RAGE as a single influential point of intervention.

Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging.

Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF-κB, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases. The accumulation of ROS under oxidative stress conditions results in the induction of lipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivativesm, giving rise to advanced lipoxidation and glycation end products (ALEs and AGEs, respectively).

Both ALEs and AGEs play key roles in cellular response to oxidative stress stimuli through the regulation of a variety of cell signaling pathways. However, elevated ALE and AGE production leads to protein cross-linking and aggregation resulting in an alteration in cell signaling and functioning which causes cell damage and death. This is implicated in aging and various age-related chronic pathologies such as inflammation, neurodegenerative diseases, atherosclerosis, and vascular complications of diabetes mellitus. In the present review, we discuss experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions. We focused on the implications of ALEs/AGEs in aging and age-related diseases to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.


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