The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy

Abstract

The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age-related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue-dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, we summarize the current state of knowledge related to the protective mechanisms against glycative stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying the reactive intermediates of glycation. This review focuses on glyoxalase 1 (GLO1), the first enzyme of the glyoxalase system, and the rate-limiting enzyme of this catalytic process. Although GLO1 is ubiquitously expressed, protein levels and activities are regulated in a tissue-dependent manner. We provide a comparative analysis of GLO1 protein in different tissues. Our findings indicate a role for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to delay the development of age-related diseases and summarize the literature that describes the current knowledge about nutritional compounds with properties to modulate the glyoxalase system.

In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration

“…Under homeostatic conditions, the AGE-precursors dicarbonyls are maintained at low levels due to the glyoxalase system. However, during aging the dicarbonyl levels increase, promoting the formation of AGEs [30]. Glyoxalase is a dicarbonyl-detoxifying system composed of two enzymes: Glyoxalase I (GLO1) and Glyoxalase II, (GLO2).…”

Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease

“…One of the most prominent ways cells detoxify MG is through the glyoxalase pathway, a highly evolutionarily conserved system that involves the activity of two enzymes: glyoxalase 1 (GLO1) and glyoxalase 2 (GLO2). 32 MG reacts nonenzymatically with glutathione (GSH) to form a hemithioacetal, which is recognized by GLO1 and converted into S - d -lactoylglutathione ( Figure 2 A). 33 GLO2 then converts S - d -lactoylglutathione into d -lactate, regenerating GSH ( Figure 2 A).…”

Autophagy and Glycative Stress: A Bittersweet Relationship in Neurodegeneration

“…For example, higher glyoxalase system activity has been seen in primary mouse astrocytes, as compared to neurons ( Bélanger et al, 2011 ). The glyoxalase system catalyzes the detoxification of glycation precursors ( Aragonès et al, 2020b ; Aragonès et al, 2021 ) and a weaker defense mechanism against glycation-derived damage in neurons leads to a higher susceptibility for glycation-induced neurotoxicity.…”

“…In order to avoid the glycation-derived perniciousness, our cells maintain non-toxic homeostatic levels of AGEs by deploying a battery of anti-glycation mechanisms that include detoxifying pathways that limit the synthesis of AGEs (glyoxalase system, Parkinson-associated protein DJ-1, aldehyde dehydrogenases, aldo-keto reductases, and acetoacetate degradation) and proteolytic AGEs elimination through UPS and autophagy ( Aragonès et al, 2021 ). Due to the irreversible nature of the glycation process, AGEs removal is the last line of defense against associated glycation-derived tissue malfunction ( Rowan et al, 2018 ; Taylor and Bejarano, 2022 ).…”