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Review
. 2021 Jul 22;10(8):1852.
doi: 10.3390/cells10081852.

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

Gemma Aragonès  1 , Sheldon Rowan  1   2   3 , Sarah G Francisco  1 , Elizabeth A Whitcomb  1 , Wenxin Yang  1 , Giuliana Perini-Villanueva  1 , Casper G Schalkwijk  4 , Allen Taylor  1   2   3 , Eloy Bejarano  1   5
Affiliations
Review

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

Gemma Aragonès et al. Cells. .

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.

Keywords: aging; glycative stress; glyoxalase system; proteotoxicity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram of α-dicarbonyls formation and detoxification pathways against AGE-derived damage in aging. The formation of highly reactive α-dicarbonyls such as methylglyoxal (MG) is through non-enzymatic degradation of the glycolytic intermediates, including dihydroxyacetone phosphate and glyceraldehyde 3-phosphate and other sources, including aminoacid and lipid metabolism. In order to avoid AGE damage, the glyoxalase system is a primary mechanism that limits the synthesis of AGEs, converting high reactive biomolecules, such as MG, into less reactive biomolecules (D-lactate). This process involves the sequential activity of two enzymes GLO1 and GLO2 and the reduced form of gluthatione (GSH). Other detoxifying mechanisms imply the activity of DJ-1, aldehyde dehydrogenases (ALDHs), aldo-keto reductases (AKRs), and acetoacetate degradation enzymes. Once formed, AGEs can be cleared by two proteolytic pathways: the ubiquitin-proteasome (UPS) system and autophagy. These protective mechanisms (highlighted in green) decline under aging and contribute to the onset of age-related diseases such as neurodegeneration, eye-related diseases (AMD, cataract, DR), nephropathies, metabolic syndrome, and cancer. GLO1: glyoxalase 1; GLO2: glyoxalase 2; GSH: glutathione.
Figure 2
Figure 2
Mechanisms of glyoxalase 1 (GLO1) regulation. GLO1 activity can be regulated through multiple mechanisms, including transcriptional regulation and post-translational modifications. The Glo1 promoter contains various regulatory elements, such as antioxidant response (ARE), metal-response (MRE) and insulin-response (IRE) elements, and binding sites for AP-2α and E2F. In normal conditions, the nuclear factor erythroid 2-related factor 2 (NRF2) is complexed with KEAP1, a substrate adaptor protein for cullin-3-dependent E2 ubiquitin lipase complex, directing NRF2 for degradation by the ubiquitin proteasome system (UPS). Oxidative stress leads to the destabilization of the complex NRF2-KEAP1, causes the detachment of NRF2 that is translocated to the nucleus where triggers the upregulation of different antioxidants genes. Binding of NRF2 to the Glo1-ARE increases expression of GLO1. Under hypoxia conditions Glo1 expression is inversely regulated by hypoxia-inducible factor 1α (HIF1α). Different post-translational modifications in the cytosol can impact GLO1 stability.
Figure 3
Figure 3
A comparative analysis of GLO1 protein and activity in ocular and non-ocular tissues. (A) GLO1 activity was assayed in non-ocular tissues and retinal tissues from WT mice as previously described [29] and activity was expressed as percentage (%) compared to liver. (B) Liver and (C) retina representative Western blot analysis of WT and Glo1 overexpression transgenic mice (Glo1 Tg+/+) using a monoclonal antibody (non-commercial) and polyclonal antibody for Glo1 (commercial, GeneTex) [36,103,104]. (D) Representative Western blot analysis of non-ocular tissues extracts (50ug) of WT mice using a monoclonal antibody for Glo1 (non-commercial) and (E) protein quantification of GLO1 normalized to control loading (Ponceau staining). (F) GLO1 activity was performed in ocular tissues (Retina, RPE/Choroid, and Lens) from WT mice as previously described [29] and activity was expressed as milliunits per milligram of protein. Values are mean ± SEM. Sample size is n = 4 from the GLO1 protein and activity assays.
Figure 4
Figure 4
Immunohistochemistry of GLO1 in mouse retinal tissues. (A) Cross-sectional, cellular schematic of the retina illustrating its three primary layers comprised of the ganglion cell layer (GCL), containing retinal ganglion cells (RGC), inner nuclear layer (INL), hosting interneurons of amacrine, bipolar and horizontal cells as well as Müller glial cells, and outer nuclear layer (ONL), housing rod and cone photoreceptors. The sensory tissue, or neuroretina, is connected to the retinal-pigmented epithelium (RPE). Red arrows indicated the RPE layer. (B) Representative picture of GLO1 immunostaining in retinal samples from WT mice. (C) Mean intensity fluorescence of GLO1 normalized to the value in the RPE. Data shown are mean ± standard errors of the means (SEM).
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References

    1. Prasad C., Imrhan V., Marotta F., Juma S., Vijayagopal P. Lifestyle and Advanced Glycation End Products (AGEs) Burden: Its Relevance to Healthy Aging. Aging Dis. 2014;5:212–217. doi: 10.14336/AD.2014.0500212. - DOI - PMC - PubMed
    1. Rowan S., Bejarano E., Taylor A. Mechanistic targeting of advanced glycation end-products in age-related diseases. Biochim. Biophys. Acta. Mol. Basis Dis. 2018;1864:3631–3643. doi: 10.1016/j.bbadis.2018.08.036. - DOI - PMC - PubMed
    1. Kandarakis S.A., Piperi C., Topouzis F., Papavassiliou A.G. Emerging role of advanced glycation-end products (AGEs) in the pathobiology of eye diseases. Prog. Retin. Eye Res. 2014;42:85–102. doi: 10.1016/j.preteyeres.2014.05.002. - DOI - PubMed
    1. Semba R.D., Nicklett E.J., Ferrucci L. Does accumulation of advanced glycation end products contribute to the aging phenotype? J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2010;65:963–975. doi: 10.1093/gerona/glq074. - DOI - PMC - PubMed
    1. Taylor A. Mechanistically linking age-related diseases and dietary carbohydrate via autophagy and the ubiquitin proteolytic systems. Autophagy. 2012;8:1404–1406. doi: 10.4161/auto.21150. - DOI - PMC - PubMed

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