cells Review 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,* and Eloy Bejarano 1,5,* 1 Laboratory for Nutrition and Vision Research, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02155, USA; [email protected] (G.A.); [email protected] (S.R.); [email protected] (S.G.F.); [email protected] (E.A.W.); [email protected] (W.Y.); [email protected] (G.P.-V.) 2 Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02155, USA 3 Friedman School of Nutrition and Science Policy, Tufts University, Boston, MA 02155, USA 4 Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands; [email protected] 5 School of Health Sciences and Veterinary School, Universidad Cardenal Herrera-CEU, CEU Universities, Moncada, 46113 Valencia, Spain * Correspondence: [email protected] (A.T.); [email protected] (E.B.); Tel.: +1-617-556-3156 or +1-617-784-3199 (A.T.) 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 Citation: Aragonès, G.; Rowan, S.; tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age- Francisco, S.G.; Whitcomb, E.A.; related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic Yang, W.; Perini-Villanueva, G.; capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue- Schalkwijk, C.G.; Taylor, A.; Bejarano, dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic E. The Glyoxalase System in Age-Related Diseases: Nutritional targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, Intervention as Anti-Ageing Strategy. we summarize the current state of knowledge related to the protective mechanisms against glycative Cells 2021, 10, 1852. https://doi.org/ stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying 10.3390/cells10081852 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 Academic Editor: Taranjit Singh Rai 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 Received: 29 May 2021 for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid Accepted: 15 July 2021 protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to Published: 22 July 2021 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. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: glycative stress; glyoxalase system; aging; proteotoxicity published maps and institutional affil- iations. 1. Introduction: Glycative Stress and Unhealthy Aging A growing body of literature indicates that accumulation of damaged proteins is a Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. specific hallmark of aging and many age-related diseases, including type 2 diabetes, cancer, This article is an open access article neurodegenerative, cardiovascular, and eye-related disorders [1–7]. Aberrant proteins distributed under the terms and impair cellular homeostasis by forming non-functional and toxic aggregates and this leads conditions of the Creative Commons to the inactivation of not only the aberrant protein but can also impair the function of other Attribution (CC BY) license (https:// essential proteins due to the stress on—or insufficiency of—the protein quality control creativecommons.org/licenses/by/ machinery in the cell. One prominent mechanism that leads to aberrant molecules is modifi- 4.0/). cation by advanced glycation end-products (AGEs). Dicarbonyl compounds are generated Cells 2021, 10, 1852. https://doi.org/10.3390/cells10081852 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 28 Cells 2021, 10, 1852 2 of 26 is modification by advanced glycation end-products (AGEs). Dicarbonyl compounds are generated fromfrom different different metabolic metabolic pathways pathways (Figure (Figure 11)) that that involve involve dietary dietary sugar sugar and and carbohydrate carbohydratemetabolism metabolism to to form form AGEs. AGEs. These These dicarbonyl dicarbonyl compounds compounds interact interact with with biomolecules, bio- such molecules, suchas proteins, as proteins, lipids lipids and and nucleic nucleic acids acids in in a non-enzymatica non-enzymatic post-translational post-translational modification modificationcalled called glycation. glycation. The The major major glycating glycating dicarbonyls dicarbonyls agents agents are are methylglyoxal methylglyoxal (MG), glyoxal, (MG), glyoxal,or or 3-deoxyglucosone 3-deoxyglucosone [8 ].[8]. These These dicarbonyls dicarbonyls are are maintained maintained at at low low levels levels in in homeostatic homeostatic conditions,conditions, butbut thethe aging process increasesincreases thesethese glycatingglycating reagentsreagents toto pathologicalpatho- levels, logical levels,enhancing enhancing the the formation formation of toxicof toxic AGEs AGEs and, and, ultimately, ultimately, compromising compromising tissue tis- fitness. Given sue fitness. Giventhat the that formation the formation of AGEs of AGEs is dependent is dependent on glucose on glucose concentration, concentration, the consumption the of consumptionhigh of high glycemic glycemic diets diets or diabetic or diabet conditionsic conditions lead lead to a dramaticto a dramatic systemic systemic accumulation of accumulationAGEs. of AGEs. This This directly directly correlates correlates with with altered altered metabolism, metabolism, increased increased inflammation, inflam- and the mation, and progressionthe progression of severe of severe medical medica conditions.l conditions. Conversely, Conversely, the the intake intake of lowof low glycemic diets glycemic dietslimits limits AGE AGE accumulation accumulation and and is associated is associated with with the slower the slower progression progression of some of of these dis- some of theseeases diseases [9–13 [9–13].]. In this In context, this contex hyperglycemiat, hyperglycemia imposes imposes additional additional stress tostress the age-associatedto the age-associatedproduction production of glycated of glycated proteins proteins and exacerbates and exacerbates the detrimental the detrimental consequences con- of AGEs sequences ofdeposits AGEs deposits on organ on function. organ function. α Figure 1. SchematicFigure diagram1. Schematic of diagram-dicarbonyls of α-dicarbonyls formation and formation detoxification and detoxi pathwaysfication against pathways AGE-derived against AGE- damage in aging. The formationderived ofdamage highly reactivein aging.α -dicarbonylsThe formation such of ashighly methylglyoxal reactive α (MG)-dicarbonyls is through such non-enzymatic as methylglyoxal degradation of the glycolytic(MG) intermediates, is through includingnon-enzymatic dihydroxyacetone degradation phosphateof the glycolytic and glyceraldehyde intermediates, 3-phosphateincluding dihydroxy- and other sources, including aminoacidacetone and phosphate lipid metabolism. and glyceraldehyde In order to avoid3-phosphat AGEe damage, and other the sources, glyoxalase including system isaminoacid a primary and mechanism that limits thelipid synthesis metabolism. of AGEs, In converting order to avoid high AGE reactive damage, biomolecules, the glyoxalase such as system MG, into is a less primary reactive mechanism biomolecules (D- lactate). This processthat limits involves the synthesis the sequential of AGEs, activity converting of two high enzymes reactive GLO1 biomolecules, and GLO2 and such the as reduced MG, into form less of reac- gluthatione (GSH). Other detoxifyingtive biomolecules mechanisms (D-lactate). imply Th theis activity process of involves DJ-1, aldehyde the sequential dehydrogenases activity of (ALDHs), two enzymes aldo-keto GLO1 reductases and GLO2 and the reduced form of gluthatione (GSH). Other detoxifying mechanisms imply the (AKRs), and acetoacetate degradation enzymes. Once formed, AGEs can be cleared by two proteolytic pathways: the activity of DJ-1, aldehyde dehydrogenases (ALDHs), aldo-keto reductases (AKRs), and acetoacetate ubiquitin-proteasome (UPS) system and autophagy. These protective mechanisms (highlighted in green) decline under degradation enzymes. Once formed, AGEs can be cleared by two proteolytic pathways: the ubiqui- aging and contributetin-proteasome to the onset (UPS) of age-relatedsystem and diseasesautophagy. such These as neurodegeneration, protective mechanisms eye-related (highlighted