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. 2019 Aug 14;2019:3085756.
doi: 10.1155/2019/3085756. eCollection 2019.

Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases

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Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases

Nurbubu T Moldogazieva et al. Oxid Med Cell Longev. .
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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 derivatives such as glyoxal, methylglyoxal (MG), malonic dialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE) 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.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this paper.


Figure 1
Figure 1
Schematic KEGG map representations of signaling pathways involved in Alzheimer's disease (a), Parkinson's disease (b), and amyotrophic lateral sclerosis (c). Oxidative stress-induced alterations in signaling pathways, which cause mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and dysregulation of the ubiquitin-proteasome system (UPS) and the autophagy/lysosomal protein quality control machinery, followed by neuronal death, are also shown. Here, → indicates stimulating effects and indicates inhibitory effects. (a) AD is characterized by the formation of amyloid precursor protein-derived amyloid β-peptide (Aβ), a major component of senile plaques, which forms oligomers to induce pathways initiated by the following receptors: (i) LRP, an apoE receptor; (ii) amyloid precursor protein (APP), an integral membrane protein, mutations of which cause susceptibility to familial AD; (iii) TNF-α receptor (Fas/TNFR) to activate caspases; (iv) GNAQ (Gq)/G-protein-coupled receptor (GPCR) to stimulate phospholipid C (PLC) followed by the activation of inositol-3-phosphate receptor (IP3R) and ER stress; (v) N-methyl-D-aspartate receptor (NMDAR) to cause hyperphosphorylation of tau receptors, and (vi) voltage-gated (dependent) calcium channels (VDCC) followed by neuronal damage through mitochondrial dysfunction and disruption of calcium release from ER. Presenilin 1 and 2 (PSEN1 and PSEN2) proteins belong to γ-secretases that generate Aβ. (b) PD results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNs). Normally, dopamine active transporter (DAT) pumps dopamine out of the synaptic clefts into the cytoplasm. The early onset of PD is associated with mutations in synuclein-alpha (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), PTEN-induced kinase 1 (PINK1), leucine-rich repeat kinase 2 (LRRK2), mitochondrial serine protease 2 (HTRA2), parkin, and parkin-associated protein DJ1 involved in oxidative stress. (c) ALS is a lethal disorder characterized by the death of motor neurons in the brain and spinal cord. Mutations in SOD1 may interfere with the neurofilament heavy polypeptide (NEFH) and the translocation machinery, the translocase of the inner/outer membrane (TIM/TOM) that is involved in familial ALS. Proapoptotic THFα acts through its receptor, TNFR, to induce inflammation and apoptotic cell death. The main glutamate transporter protein, excitatory amino acid transporter (EAAT2), is inhibited by ROS produced by mitochondria. Glutamate acts through its receptor (GluR) to increase calcium release from ER and to enhance oxidative stress and mitochondrial damage. Permission 190019 for usage of the following KEGG pathway images was kindly granted by Kanehisa Laboratories [141]: map05010—Alzheimer's disease; map05012—Parkinson's disease; map05014—amyotrophic lateral sclerosis (ALS).

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