Heart Mind

: 2022  |  Volume : 6  |  Issue : 3  |  Page : 139--150

Exercise, Advanced Glycation End Products, and Their Effects on Cardiovascular Disorders: A Narrative Review

Saeedeh Hosseini Hooshiar, Helia Esmaili, AmirMohammad Taherian, Sadegh Jafarnejad 
 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran

Correspondence Address:
Dr. Sadegh Jafarnejad
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan


Lifelong accumulation of advanced glycation end products (AGEs) is linked to cardiovascular disease (CVD). As a result of AGEs, cardiovascular dysfunction develops and progresses via two main mechanisms: cross-linking AGEs with tissue proteins and binding of AGEs to their receptor for AGE (RAGE). In addition, the formation of atherosclerotic plaques in these patients may be due to increased oxidative stress, leading to an elevation in blood circulation and tissue AGEs. Increasing physical activity is a critical approach among the different strategies to manage the deleterious effects of these changes caused by disease. Exercise prevents the accumulation of AGEs and slows the progression of chronic disease sequels. Exercise reduces AGE levels through a reduction of insulin sensitivity, fat mass, inflammation, and RAGE expression. An improvement in glucose metabolism and glycemic control are also other possible explanations. Reduced peripheral insulin resistance may attenuate AGE accumulation. Physical exercise causes more antioxidant enzyme secretion and reduces oxidative stress. Antioxidant and anti-inflammatory endothelial function is improved by exercise. After exercise, subendothelial matrix stiffness decreases, and endothelial function is improved. In this current study, the association between AGEs and exercise and their interaction effects on CVD are discussed.

How to cite this article:
Hooshiar SH, Esmaili H, Taherian A, Jafarnejad S. Exercise, Advanced Glycation End Products, and Their Effects on Cardiovascular Disorders: A Narrative Review.Heart Mind 2022;6:139-150

How to cite this URL:
Hooshiar SH, Esmaili H, Taherian A, Jafarnejad S. Exercise, Advanced Glycation End Products, and Their Effects on Cardiovascular Disorders: A Narrative Review. Heart Mind [serial online] 2022 [cited 2023 May 29 ];6:139-150
Available from: http://www.heartmindjournal.org/text.asp?2022/6/3/139/357548

Full Text


Cardiovascular disease (CVD) is a significant cause of morbidity and mortality worldwide. It remains a considerable challenge for clinical treatments.[1] CVD has a complex etiology[2] and contributes to four behavioral risk factors, including tobacco smoking, alcohol abuse, physical inactivity, and an unbalanced diet. Long-term exposure to behavioral risk factors contributes to obesity, high blood pressure, hyperglycemia, and dyslipidemia. All of these factors cause inflammation, endothelial impairment, oxidative stress, and ultimately, vascular remodeling.[3] Increased oxidative stress is the initial core mechanism leading to diabetic CVD.[4] Nonenzymatic oxidative alteration of proteins could lead to increased levels of advanced oxidation protein products, endothelial nitric oxide synthase (eNOS), and advanced glycation end products (AGEs), which play an important role in the analysis of the prognosis of increased oxidative stress.[3]

AGEs are lipids or proteins that have been prolonged exposure to reducing sugars or short-chain aldehydes and/or have undergone significant oxidative stress. Furthermore, exogenous intake of standard diets could lead to increased AGE levels.[5] Food intake, smoking, and aging all contribute to the accumulation of AGEs in the body.[6] Plasma proteins from healthy subjects contain <3% glycated products.[7] However, the number of glycated products can increase by up to threefold in pathological conditions such as diabetes, leading to a pathological phenotype.[8] Under hyperglycemic conditions, for instance, in diabetes mellitus (DM), inflammatory conditions, and oxidative stress, AGE accumulation accelerates.[6] Levels of AGEs in the blood and tissue are closely associated with metabolic imbalance and chronic diseases, including CVD [Figure 1]. Vascular dysfunction can be caused by cross-linking AGEs with extracellular matrix (ECM) proteins (collagen and elastin). This leads to stiffness in blood vessels, diastolic dysfunction, and cardiac fibrosis.[9] Asymmetric dimethylarginine, the soluble form of vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 all show a correlation between elevated AGEs levels and inflammatory and endothelial cell injury indicators.[10]{Figure 1}

There is no international agreement regarding how to minimize the impact of AGEs by implementing an effective method. Consuming more vegetables, fruits, seeds, and nuts will enhance the quality of one's diet, and it has also been suggested that modifying cooking methods will reduce the total level of AGEs in the body.[9] The prevention of DM, CVD, chronic illnesses, and the buildup of AGEs with regular physical activity is another interesting field for investigation. A physical exercise program can reduce cardiovascular risk, improve endothelial function, and reduce arterial stiffness, among other benefits.[11] It has also been demonstrated that exercise reduces the levels of circulating AGEs.[12] According to various studies, physical activity can enhance systemic antioxidant activity. In rodent models, physical activity can decrease oxidative stress. Taking physical exercise in moderation could induce the expression of antioxidant enzymes and reduce oxidative stress. Physical exercise also decreases AGE levels of renal tissues in obese rats and positively affects glycemic control in diabetics.[13] In previous studies, AGEs are associated with exercise. Therefore, we aim to assess the correlation between AGEs and exercise among cardiovascular patients concerning the underlying cause of CVD.

 Advanced Glycation End Products and Their Involvement in Cardiovascular Disorders

AGEs are created endogenously, during aging and pathological conditions, and exogenously via food consumption or smoking.[14] AGEs can cause various pathophysiological changes in CVD, DM, cataract, renal, Alzheimer's disease, as well as other neurodegenerative diseases.[15] It is essential to consider that there are various forms of AGEs in vivo, all of which are highly heterogeneous. Typical AGEs include carboxymethyl lysine (CML), pentosidine, carboxyethyl lysine, pyralline, argpyrimidine, and cross-linked AGEs.[4] A disruption of the hemostatic control of AGEs in the serum may lead to pathological conditions with a chronic course. Thus, AGEs received considerable attention from researchers.[16] CVD is associated with AGEs. In diabetic patients with coronary heart disease, plasma AGE levels are higher compared to diabetic patients without coronary heart disease.[4] Circulating levels of AGEs, such as methylglyoxal-derived hydroimidazolones and CML, could display total mortality or CVD death among type 1 and type 2 diabetics, nondiabetic patients, patients with hemodialysis, and subjects with the acute coronary syndrome.[10] Growing evidence indicates AGEs contribution to the progression and development of cardiovascular dysfunction via two major mechanisms:[1] cross-linking AGEs with tissue proteins (e.g., intercellular proteins or ECM proteins) and[2] binding of AGEs to their specific cell surface receptor for AGE (RAGE).[17] In addition, elevated circulating and tissue AGEs can trigger oxidative stress, which in turn contributes to the development of atherosclerotic plaques in these patients.[18]

Cross-linking advanced glycation end products with tissue proteins in cardiovascular disorders

Cross-linking of ECM proteins (e.g., laminin, vibronectin, and collagen) is an essential physiological process to maintain tissue integrity and not compromise its flexibility. AGEs could change the physiological properties of ECM proteins via AGEs-AGEs intermolecular covalent bonds or cross-linking, a highly resistant to hydrolytic turnover.[5] Type IV collagen, laminin, and other ECM proteins could all be directly modified by AGEs. The production of vascular endothelial growth factor can be directly stimulated by AGEs, causing an increase in vascular permeability or edema in the vascular wall.[4] As a result, blood vessel structure and its function are disrupted, and cardiac fibrosis accelerates. The AGEs cause endothelial cell death as well as induce apoptosis and damage endothelial progenitor cells.[4] Cross-linking of AGEs with vascular collagen and/or myocardial results in decreased vascular elasticity, myocardial flexibility, and increased vascular and myocardial stiffness, thereby resulting in diastolic dysfunction. A cell's function is impaired as a result of glycation and cross-linking of intracellular proteins. Cross-linking of AGEs between the ryanodine receptor and sarco/endoplasmic retinaculum Ca2+ -ATPase (SERCA) can alter Ca2+ homeostasis.[5] Cardiomyocyte contraction depends on the release of Ca2+ from the sarcoplasmic retinaculum via the ryanodine receptor. In diabetic cardiomyopathy, AGEs could cause ryanodine receptor dysfunction, resulting in decreased cardiac contractility.[19] When SERCA is impaired by AGEs, it directly affects relaxation and leads to diastolic dysfunction.[5] AGEs can also cross-link with other proteins, including low-density lipoproteins (LDLs).[9] LDL is the number one responsible lipoprotein component for transferring exogenously and endogenously absorbed synthesized lipids to peripheral tissues. Biochemical modifications that affect LDL's structural and functional integrity are known to be central to atherogenesis. Advanced glycation causes a new class of chemical alterations that make it more atherogenic in addition to the oxidative modification that inhibits LDL clearance.[14] The infiltration of AGEs into endothelial cells results in the accumulation of oxidized LDL, a reduction in nitric oxide (NO) concentration, an increase in oxidative stress, and an increase in macrophage migration.[20] Atherosclerosis is caused by glycated LDL being absorbed by monocyte-derived macrophages, which stimulates the formation of foam cells.[9] According to recent research, the active component of endothelium-derived relaxing factor as well as NO action may be chemically hampered by AGEs produced in the vascular matrix. In addition, in vitro studies have demonstrated that AGE attached to moieties of collagen reacts directly with NO to inactivate its bioactivity. In addition, experimentally induced diabetes leads to faulty vasodilatory responses that have a pattern comparable with the subendothelial quenching of NO by AGEs.[14]

Binding of the advanced glycation end products with their receptors, receptor for advanced glycation end products, in cardiovascular disorders

The discovery of AGE receptors, RAGE, was reported in 1992 based on this molecule's ability to bind to nonenzymatic glycation products, oxidized proteins/lipids, and AGEs.[21] There is evidence that AGEs disrupt hemodynamic equilibrium and damage vascular walls in both receptor-dependent and nonreceptor-dependent ways. These effects eventually lead to vulnerable plaques, thrombosis formation, and acute coronary syndromes.[22] The interaction of AGE with RAGE results from endogenous AGE adducts and/or dietary sources of AGE. In both animal and human models, RAGE is expressed by a variety of cell types, including immune cells, vascular cells, cardiomyocytes, neurons, adipocytes, lung epithelial cells, glomerular epithelial cells, and a wide spectrum of altered cells.[21] In the atherosclerotic process, AGEs are believed to induce oxidative stress through receptor-mediated pathways, and RAGE is one of the most extensively investigated receptors.[17] Atrial fibrillation is more common in diabetic individuals, particularly in those with longer disease duration or poor glycemic control, and RAGE ligand AGEs, which enhance oxidative stress, fibrosis, and stiffness, contribute to this.[21] Further, RAGE inhibits the eNOS, leading to endothelial dysfunction,[23] atherosclerosis, and a variety of macrovascular and microvascular complications.[24]

Moreover, AGEs are recognized by RAGE, a member of the immunoglobulin superfamily, which induces oxidative stress in different types of cells and numerous tissues, contributing to the development of conditions associated with diabetes and aging, such as atherosclerotic CVD.[10] Recent evidence shows that a link exists between thrombotic disorders and several other proteins, including RAGE and its ligands, AGEs, High Mobility Group Box 1 (HMGB1), and S100/calgranulins. In case of thrombosis-related diseases such as stroke, coronary artery disease (CAD), peripheral artery disease, disseminated intravascular coagulation, and venous thrombosis HMGB1 expression increases. In obese patients, CML-AGE RAGE ligand and RAGE accumulate in adipose tissue.[21] It's noteworthy to note that RAGE is expressed in a variety of fat depots, which affects metabolism. It has been demonstrated that distinct fat depots play a role in cardiometabolic fate, including subcutaneous adipose tissue, brown adipose tissue, visceral adipose tissue, perivascular adipose tissue, and epicardial adipose tissue in animal and human models.[21] In addition, Cassese et al. showed that the creation of a multimolecular complex containing Insulin Receptor Substrate-1, RAGE, Src, and Protein Kinase C may have served as a mediator for the altered insulin action brought on by AGEs in muscles.[25] AGEs engage in interaction with their multi-ligand immunoglobulin superfamily receptor.[23] In addition, binding to AGEs, RAGE binds to other ligands, such as pro-inflammatory cytokine-like mediators of the S100/calgranulin family and high-mobility group protein B1, a nuclear protein that is produced during necrosis and, when extracellular, can exert pro-inflammatory functions. Despite its name, a multi-ligand receptor, RAGE plays a crucial role in inflammatory processes.[26] Blocking RAGEs reduces atherosclerosis and vascular oxidative stress.[4]

Advanced glycation end products, oxidative stress, and inflammation in cardiovascular disorders

AGEs can cause a vicious cycle of oxidative stress [Figure 2]. AGEs modify oxidative stress. Excessive oxidative stress could accelerate the generation of AGEs such as CML. All of these findings suggest that diabetic cardiovascular complications are strongly influenced by the crosstalk between oxidative stress and the AGE-RAGE axis.[4] AGEs can bind to endothelial cell receptors and trigger an intracellular cascade that increases the expression of genes linked to thrombosis, oxidative stress, inflammation, and leukocyte recruitment.[18] These factors could increase the risk of chronic diseases and endothelial dysfunction. Apoptosis, oxidative stress, and inflammatory response caused by RAGE activation via AGE, which has been linked to various macrovascular and microvascular complications in chronic kidney and diabetes disease.{Figure 2}

The AGEs-RAGE interaction releases inflammatory mediators and activates a nuclear factor-kappa B (NF-κB), with synchronous induction of atherosclerotic processes and oxidative stress.[20] The AGE-RAGE axis also interacts with the renin-angiotensin system (RAS), which is linked to the hypertrophy of cardiomyocytes and the growth of cardiac fibroblasts in diabetics, according to a recent study.[4] Reactive oxygen species (ROS) are produced when AGEs and RAGE interact, activating the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS plays an essential role in developing cardiac dysfunction by altering the function and structure of proteins, nucleic acids, and lipids, impairing excitation-contraction coupling at the cellular level.[5] Furthermore, AGEs could increase the activity and expression of NADPH oxidase in endothelial cells, which induces oxidative stress and inflammation in diabetic cardiovascular complications.[4] NADPH oxidase increase by AGEs-RAGE interaction is also related to stimulating NF-κB. In conclusion, AGEs should be considered an important mechanism contributing to ROS production and oxidative stress in the heart.[5] Increased ROS depletes cellular antioxidants such as glutathione, peroxidase, superoxide dismutase, and catalase.[4]

By activating NF-κB, AGEs could increase the expression of RAGE. The binding of activated NF-κB to particular DNA sequences controls the transcription of the associated genes and hastens the development of cardiovascular problems. Tang et al.'s research suggests that AGEs can activate NF-κB and encourage the expression of inducible NO synthase via RAGE/Ras Homolog Family Member A (RhoA)/Rho-associated coiled-coil-containing protein kinase (ROCK)-mediated and adenosine monophosphate-activated protein kinase (AMPK)-mediated signaling pathways, which promote the generation of NO in endothelial cells.[27] Finally, AGEs binding with RAGE could inhibit NO activity. AGEs can also reduce the eNOS, decreasing NO levels. AGEs could reduce the bioavailability of NO, leading to cardiac stiffness.[28] Finally, AGEs-RAGE interaction causes poor heart wall kinetics by increasing vascular permeability.[29],[30] There is evidence that AGE-RAGE interactions trigger the expression of VCAM-1 by generating intracellular oxidant stress and NF-κB.[31],[32] Long-term intervention studies indicated that as a marker of oxidative stress, the urinary concentration of isoprostanes increases after the high AGE meal.[33],[34] Nonenzymatic oxidative changes in proteins result in increased oxidation of protein products, AGEs, and e-NOS. They are closely linked with biochemical changes in increased oxidative stress conditions playing a vital role in the prognosis of risk factors.[35] Inflammatory factors such as intracellular adhesion molecule-1, VCAM-1, tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL-1a, and C-reactive protein (CRP) facilitate vascular inflammation and block the Renin-angiotensin-aldosterone system.[36] The S100A8 and S100A9 proteins have low molecular weights and consist of 93 and 114 amino acids, respectively, belonging to the S100 proteins superfamily. They are known as Calgranulin A and Calgranulin B due to their high expression levels in granulocytes and calcium-binding characteristics. They mostly occur as heterodimers due to stability concerns. S100A8/A9 is actively secreted from myeloid cells during inflammatory processes, and it functions as a mediator in immune responses. S100A8/A9 has also been characterized as a damage-associated molecular pattern molecule. It binds to RAGE or Toll-Like Receptor 4. S100A8/A9 is associated with inflammatory diseases and responds to treatment.[37] Biomarkers of oxidative stress measured by plasma CML and thiobarbituric acid reactive substances (TBARS) levels showed a partial decrease in the trained diabetic group (approximately 30% and 35%, respectively); thus, we might speculate that hyperglycemia could compromise endothelial function and result in significant AGE formation. AGEs could therefore directly inhibit NO, lowering endothelium-dependent relaxation responses.[38]

 Exercise and Cardiovascular Disorders

CVD is a disorder related to the heart and blood vessels. Coronary heart disease, rheumatic heart disease, cerebrovascular disease, and other conditions are some cases in point.[39] An increase in physical activity is considered one of the most effective strategies for reducing the harmful effects of CVD (often in conjunction with changes related to aging). Studies have demonstrated that physical exercise effectively prevents CAD and reduces the risk of death from CVD. Specifically, it provides a protective mechanism against any subclinical changes in the heart's structure. In patients with CVD, exercise may also improve endothelial function, diastolic function, and left ventricular distensibility.[40] According to studies, patients with heart failure (HF) who have a reduced exercise capacity (EC), especially those who have a peak oxygen uptake (peak VO2) under 14 mL/kg/min, have a higher mortality rate.[6] Poor stroke volume response, aberrant endothelial function, ventilatory dysfunction, inappropriate peripheral oxygen use, and chronotropic incompetence are all linked to low levels of physical activity.[41] Physical exercise may improve cardiovascular function by increasing cardiorespiratory fitness (CRF). By increasing CRF, patients with CVD may experience substantial health benefits, such as a reduced risk of HF associated with hospitalization later in life,[42] improvement of mortality rates after coronary artery bypass,[43] prevention of myocardial infarction, and decreased CVD.[44] It is regarded as the foundation of regimens for cardiac rehabilitation.[45] Extensive evidence exists regarding the benefits of aerobic exercise, including improvement of aerobic capacity, metabolic variables, cardiopulmonary and above all, the reduction of CVD risk factors. However, resistance training increases muscle mass, strength, and endurance to a greater extent. The purpose of exercises such as resistance training is always to complement aerobic exercise rather than replace it.[46] As well as improving glucose uptake, resistance training has also been shown to improve body composition, insulin sensitivity, and glycemic control.[47] Resistance training provides “cross-protection” from oxidative stress produced by aerobic exercise; combining resistance training with aerobic exercise may increase the effects on CVD risk factors and metabolic variables.[46]

Inflammation, oxidative stress, and endothelial dysfunction are all key pathophysiological components of metabolic dysfunction as well as CVD. A combination of these pathophysiological factors is responsible for exercise's effectiveness in preventing CVD. Numerous studies have shown that exercise is crucial to preserving cardiovascular health, especially when it comes to the intima layer.[48] Intimate collagen content decreases with exercise and returns to baseline following cessation of exercise. According to a meta-analysis, both aerobic and resistance exercise significantly improved physical indexes and a majority of cardiovascular risk factors.[49] Aortic content of N(ε)-CML, a dominant protein modification, increases with cardiovascular risk factors such as age, poor diet, and sedentary lifestyle. Following exercise, CML content in vessels decreases and returns to baseline following rest.[48] To conclude, exercise training combined with, or without, different drug intake alters collagen and RAGE immunoreactivity in a variety of methods. According to the data, exogenous factors may affect AGEs by modulating skeletal muscle fibers and ECM.[50] Most medical societies strongly recommend regular exercise to prevent CVD.[1] It is well established that exercise has beneficial effects on classic cardiovascular risk factors such as high-density lipoprotein (HDL), hypertension, insulin sensitivity, and obesity.[37] Without changing endothelial function or arterial stiffness, physical fitness increased noticeably after a year of exercise training and decreased the risk of getting CVD throughout the course of a person's lifetime.[11] In addition, physical activity results in increased mitochondrial size and number in skeletal muscle[51] as well as higher capillary density in muscle,[52] which may result in better biological adaptations of skeletal muscles and an increase in quality of life for patients with CVD.[53]

The effect of exercise on inflammation in cardiovascular disorders

Exercise may have anti-inflammatory effects based on biological evidence. CVD risk is associated with chronic low-grade inflammation. Observational studies and epidemiological data support the anti-inflammatory properties of exercise, which is shown by an inverse relationship between physical activity and classic markers of inflammation.[37] A 4-week exercise intervention significantly reduced the pro-inflammatory molecule S100A8/A9 and soluble RAGEs (sRAGEs). In addition, participants with heavier weights and higher baseline S100A8/A9 values reduced more after exercise. The results are consistent with studies that examined classic pro-inflammatory markers (mainly IL-6 and CRP), showing that subjects with higher body mass index (BMI) or higher baseline values showed greater reductions following exercise.[37] The health benefits of exercise training can also be attributed to the increased production of NO and/or its bioavailability to tissues. A decrease in NADPH oxidase gp91phox and p47phox subunit expression is also associated with these effects, which improve the relaxing response and reduce systemic pro-inflammatory mediator levels.[38] IL-1β plays an important role in initiating and perpetuating inflammation. In addition, it contributes to chronic diseases such as autoimmune disease, atherosclerosis, and diabetes. The results are consistent with the majority of the existing literature, indicating an anti-inflammatory effect of exercise through reducing IL-1β levels.[37]

According to a similar study, IL-6 levels were reduced in the subgroup with higher baseline levels, which is consistent with analogous investigations of CRP levels. Various studies and reviews have addressed the effects of exercise on IL-6 production, with a predominant theory indicating that exercising muscles produce IL-6, a myokine that acts as an anti-inflammatory. Due to this increase, the expected decrease in adipose-tissue-derived pro-inflammatory IL-6 is counterbalanced, resulting in a net anti-inflammatory effect of exercise via IL-6, despite unaffected serum levels of IL-6. For individuals with higher baseline IL-6 levels, exercise could result in a greater reduction of adipose-derived IL-6 than muscle-derived IL-6, resulting in reduced postexercise IL-6 levels.[37] Another study found that the 4-week exercise intervention did not significantly affect IL-6 levels. Data in the literature concerning the effects of an exercise intervention in healthy individuals on IL-6 are contradictory.[53] The results failed to demonstrate a significant effect of physical activity on IL-6, even though some indicated a significant reduction in CRP.[54] Chronic disease, especially long-term inflammation, is associated with AGEs and their cellular receptors (RAGE). Two different mechanisms are involved in sRAGEs production: proteolysis of RAGE's extracellular domain, or alternate mRNA splicing, resulting in endogenous secretory RAGEs (esRAGEs). As a whole, esRAGEs account for 20%–25% of total sRAGEs.[37] AGE can cause severe cellular damage in various tissues by activating RAGE.[38]

Exercise is thought to be a powerful inducer of NO production because it stimulates endothelial cells' mechanosensors, which are connected to intricate biochemical signaling pathways like rat sarcoma virus (Ras)/mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular-signal-regulated kinase (ERK), proto-oncogene tyrosine protein kinase (c-Src), and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt).[38] Earlier studies have shown that exercise training prevents eNOS expression and NO production reduces in both the femoral and coronary arteries of diabetic rats. It also demonstrated that exercise training fully prevented the increase in vascular ROS generation. On the other hand, only about 45% of the trained diabetic group's plasma NO × 2 levels were restored. This discrepancy between the full restoration of eNOS expression/NO production in vascular tissues and the partial recovery of NO production biomarkers (NO × 2 levels) may be explained by increased NO inactivation. As a result, exercise training causes shear stress, which repairs the imbalance between NO and ROS.[38] In diabetic animals, exercise training improved the relaxing responses to endothelium-dependent agonists in femoral and coronary arteries, which was directly related to a reduction in AGE formation.[38] Therefore, we can conclude that through its effect on inflammation, exercise can affect AGEs.

Exercise and the antioxidant effects

A wide consensus exists that physical activity increases systemic antioxidant activity.[55] Physical exercise can decrease oxidative stress in rodent animal models. Moderate physical exercise decreases oxidative stress by promoting the expression of antioxidant enzymes.[56] Exercise also reduces AGE levels in renal tissues of obese rats and improves glycemic control in diabetics. It is, therefore, possible that physical exercise can effectively combat AGE formation and AGE-related aging processes.[13] In particular, physical exercise inhibits ROS generation and enhances the activity of antioxidant enzymes.[57] Certain antioxidant enzymes, such as glutathione reductase, glutathione peroxidase, and catalase, are reduced by glycated modifications. Cellular oxidative stress is increased by altering the activities of these enzymes.[58] As a result of physical exercise, there may be more reactive intermediates available for glycation due to higher energy demand. The fundamental mechanism by which exercise contributes to antioxidant activity may be the suppression of AGE production since protein glycation processes are accelerated and driven by ROS. Moreover, efficient glycemic control can retard or attenuate AGE formation.[59] As a result, regular exercise attenuates AGE formation and accumulation in tissues by improving glycemic control.[13] Studies suggest that exercise may affect monocyte/macrophage activation, rather than their numbers. It is well documented that AGEs play an important role in the development of vascular dysfunction, renal fibrosis, and diabetic nephropathy. Regular moderate exercise may reduce AGE levels, which may account for exercise-associated renoprotection. A link is also highlighted between reducing AGE levels and reducing inflammatory status in persons with diabetes after regular physical activity. A bidirectional relationship exists between soluble AGE receptors, subsequent monocytes, and other inflammatory pathways.[60] Evidence suggests that regular exercise improves immune capacities and has an anti-inflammatory effect at a systemic level, as in DM.[61] According to some authors, the level of AGEs in diabetics is linked to an impaired oxidative stress mechanism, resulting in many chronic complications.[62] A person with a higher level of physical activity has a lower level of oxidative stress, resulting in a greater capacity for anti-oxidation, leading to a reduction in AGE levels.[63] As a result of resistance exercise, inflammation is inhibited, and endothelial function is improved; it also has a stronger function in lipid degradation.[12] In addition, aerobic exercise has been demonstrated to enhance anti-inflammatory, antioxidant, and glucose metabolism processes.[64]

 The Relationship between Advanced Glycation end Products and Exercise

Several authors suggested that regular exercise could reduce AGE serum levels.[16],[65] In addition, low physical activity is significantly associated with higher serum AGE levels. Drenth et al. examined this inverse relationship. Previous studies have shown that individuals who regularly engage in physical activity have lower levels of AGE on average than those who engage in little or no physical activity.[66] It is still unclear how exercise reduces the level of AGEs. Numerous possible explanations have been presented by some authors which reflect the complexity of the exercise effect on metabolic hemostasis.[16] As insulin resistance and fat mass decrease, exercise may decrease the sRAGE.[67] Most of the AGEs are believed to be present in the adipose tissues and are lost following regular physical activity with a loss in fat mass. This mechanism may explain why people who exercise regularly lose fat mass and have lower AGE levels.[16] In addition, the sRAGE also prevents the interaction between AGEs and their receptors.[68] The improvement in glycemic control could be another explanation. Generally, the lower the serum glucose level, the fewer the AGEs in body tissues, as these compounds are influenced by glycemic levels, which are greatly affected by regular physical activity.[13] An effect of this nature may be attributed to a noticeable reduction in the peripheral resistance to insulin, which may attenuate the accumulation of AGEs.[69] Recent animal investigations show that exercise training lowers AGE levels, especially in diabetic animals. As an example, Ito et al. have demonstrated that an 8-week exercise program could reduce the level of AGE precursors in the kidneys of diabetic rats.[70] In addition, Delbin et al. showed that following 8 weeks of aerobic activity, circulating levels of a particular AGE (N-epsilon-CML) in both coronary and femoral arteries decreased significantly, and vasodilation in response to acetylcholine significantly improved.[38] Finally, Gu et al. found that exercise training decreased oxidative stress, RAGE expression, inflammatory markers, and the concentration of highly reactive intermediates of AGE production in the aorta of older rats.[71] It was also shown in the studies that exercise had a positive effect on the accumulation of AGEs in the kidneys. In D-galactose-induced aging rats, exercise prevented renal AGE deposition.[13] Exercise-related decreases in circulation AGE levels in humans have also been shown, despite the fact that the majority of research demonstrating the positive effects of exercise training on AGEs has used animal models.[72] Yoshikawa et al. enlisted seventeen healthy women to take part in a 3-month lifestyle modification protocol that promoted physical activity in order to track changes in AGE levels. A lower level of CML was found in the treatment group than in the control group, and the level of CML changed in correlation with exercise intensity.[73]

Links between advanced glycation end products and muscle functions

The largest tissue in the body, the skeletal muscles, makes up about 40% of the total mass of the body. The skeletal muscles are crucial for metabolism and movement. Environmental factors, pathological diseases, physical activity, and nutrition all have an impact on skeletal muscle mass and function.[74] According to some studies, AGEs can alter the biomechanical properties of muscle tissue, which may lead to impaired muscle function caused by collagen cross-linking or increased inflammation caused by AGEs binding to their receptors [Figure 3].[75] The AGEs directly crosslink proteins, including muscle collagen and vascular collagen, causing the proteins to become dysfunctional. According to previous studies of AGEs and physical function, populations with high levels of AGEs tend to have decreased grip strength and slower walking speed.[76] Recent studies have linked AGE-rich diets to muscle dysfunction. A study found that consuming a diet high in AGEs (H-AGE) for 16 weeks caused CML to accumulate in skeletal muscle. Skeletal muscle mass, strength, and endurance all suffered as a result, along with other functions. Dietary AGE leads to AGE accumulation preferentially in fast-type fibers of the whole-body muscle, resulting in decreased muscular performance. However, studies have demonstrated that AGE concentrations were not different among fiber types in diabetic or elderly rats. Additional studies are necessary to determine whether AGE influences are dependent on fiber type. A higher level of AGE in blood or skin is also associated with lower muscle mass, lower grip strength, and lower walking speed in elderly and diabetic individuals. As a result, AGE is negatively correlated with skeletal muscle function.[74]{Figure 3}

Skeletal muscle dysfunction associated with AGE-enriched diets may be caused by failure of postnatal myogenesis and protein synthesis. Long-term exposure to an AGE-enriched diet inhibits skeletal muscle development and reduces postnatal growth.[74] Several foods that have been prepared at high temperatures generally contain AGE, as has been mentioned in previous sections. For this reason, animal models exposed to heat-treated foods are often used to study AGE's effects in vivo.[77] As a drawback, using these models may result in unexpected products in diets due to the heat applied to them. Thus, other products than AGE may also affect muscle dysfunction in this study. To further understand the direct link between AGE and muscle function, further research should be conducted using inhibitors of AGE accumulation.[74]

Skeletal muscle growth occurs when protein synthesis exceeds protein degradation. The protein synthesis is regulated by the mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) signaling pathway. The degradation of proteins is regulated by two major systems: autophagy and ubiquitin-proteasomes. Treatment with AGE induces autophagy in neonatal cardiomyocytes by suppressing the Akt/mTOR pathway.[74],[78] In addition, AGE treatment in C2C12 myotubes reduced Akt phosphorylation at Ser473, an indicator of Akt activity, while increasing atrogin-1, an enzyme in the ubiquitin-proteasome system. According to these findings, AGE inhibits protein synthesis in skeletal muscle while promoting protein degradation. In addition to affecting muscle mass, dietary AGE appears to impact muscle contractile properties. Several studies have demonstrated that myofibrillar proteins are subject to glycation modification.[74] Aging also leads to an accumulation of AGE-modified actin. Myosin and actin, muscle contractile proteins, may become less contractile due to modifications to these proteins.

In human skeletal muscle, connective tissue stiffness increases with age, but endomysial collagen concentration and enzyme-mediated collagen cross-linking have relatively little effect on it. However, other studies have shown an increase in collagen concentration, hydroxylysylpyridinoline cross-linking, and AGEs associated with stiffness and reduced muscle function as animals age.[50] Skeletal muscle growth requires both myogenesis and protein synthesis. It has been demonstrated in a previous study that AGE causes myotube atrophy by inhibiting the Akt pathway.[74],[79] The phosphorylation status of p70S6K Thr389 was lower in the extensor digitorum longus muscle of a diet H-AGE mice compared to a diet low in AGE mice, but the phosphorylation of Akt Ser473 did not change. In skeletal muscle, dietary AGE affects the mTOR/p70S6K signaling pathway independently of Akt. AGE probably modulate protein degradation, as previous studies have demonstrated that AGE treatment activated autophagy and ubiquitin-proteasome pathways in cultured cardiac and skeletal muscles. Consequently, AGE may deteriorate skeletal muscle growth by inhibiting protein synthesis.[74]

The effect of the advanced glycation end products on tissue damage and physical function

In addition to negatively affecting motor function (e.g. impaired muscles, walking impairments), AGE-induced tissue damage may also affect the amount of physical activity.[75] A decline in motor function, such as decreased muscle properties, declined walking abilities, and activities of daily living, are associated with AGEs in the aging population. According to a study, high AGE levels may contribute and serve as biomarkers to lower physical activity and functioning levels in the elderly. According to Drenth et al., aging contributes to the decline of motor function and, consequently, the level of physical activity.[75] Physical activity can reduce AGE formation to improve physical function, so it is essential for healthy aging.[80] Regular physical activity, on average, has been shown to reduce AGE levels more than hardly or no physical activity.[81] In addition, AGE accumulation has been shown to adversely affect the lung, cardiovascular, and musculoskeletal systems, which may negatively impact physical activity. Therefore, it is yet unknown whether the link between high AGE levels and a drop in physical activity is due to AGE damage to pertinent tissues, a decline in physical activity contributing to the accumulation of AGEs, or a combination of both variables.[75]

As a result of AGEs, tissues and cells may be damaged in three major ways: Firstly, AGEs could modify intracellular proteins; consequently, the cells will lose original functions. Secondly, by modification of ECM proteins, AGEs could cause abnormal interactions between these proteins and cells and cross-link between AGEs and the ECM, which decreases connective tissue elasticity. The third effect would be the generation of ROS, which results in altered cellular processes due to the activation of NF-κB.[82] In addition, the activation of pro-inflammatory and procoagulant cellular pathways, which boost the synthesis of adhesion molecules and cytokines like TNF-α and IL-6 and reduce NO bioavailability, is promoted by the binding of AGEs to their receptor, RAGE.[60] In addition, AGE accumulation in the central nervous system may impair physical performance. The accumulation of AGEs in brain tissue is associated with a reduction in gray matter volume.[83] AGE accumulation in specific motor-related brain regions may affect motor networks in the central nervous system and musculoskeletal structures.[75]

The relationship between hyperglycemia with exercise and its effect on advanced glycation end products

Hyperglycemic environments accumulate AGEs and contribute to age-related declines in the function of cells and tissues.[75] In many previous studies, physical activity has been shown to improve glycemic control, resulting in a reduction in AGE accumulation.[12] As a result of PE programs, AGEs are reduced as well as overall calorie intake is decreased. The reduction in overall energy intake will result in a lower glucose environment in the body and, as a result, a reduction in AGE substrates.[16] Despite improvements in glycemic control through regular exercise and physical activity, it is unclear if AGE accumulation also contributes to a loss of physical activity.[75] Physical activity may also contribute to a reduction in fat mass among those who engage in regular exercise. AGEs are believed to be primarily stored in adipose tissue and lost following regular physical activity accompanied by a reduction in fat mass. The negative relationship between fat mass and blood levels of AGEs and their receptors offers one explanation for this occurrence.[16],[84] There is inconclusive information addressing how exercise training affects serum AGE levels, despite the fact that exercise training has been demonstrated to enhance lipid profile and insulin resistance in participants.[72] Future studies should examine the connection between exercise and AGEs from this perspective.

 Advanced Glycation End Products and Exercise: the Interrelation Roles on Cardiovascular Disorders

Aside from the accumulation of AGEs with aging, other factors contribute to structural and functional changes in the cardiovascular system, including vascular stiffening, atherosclerosis, reduced central compliance, and endothelial dysfunction, all of which are exacerbated by diabetes, renal disease, and high blood pressure. Researchers are interested in investigating the role of exercise in preventing diabetes, CVD, some chronic diseases, and the accumulation of AGEs.[16] In certain chronic pathological conditions, such as arterial hypertension, dyslipidemia, obesity, and DM, exercise training is positively associated with better prognoses.[38] Research shows that exercise training improves endothelial function in healthy individuals and patients with increased cardiovascular risks, such as the elderly, obese, postmenopausal women, and dyslipidemic patients.[72] Exercise lowers AGE concentrations as well as highly reactive intermediates in the AGE pathway, like methylglyoxal, according to animal studies.[85] Several studies have also demonstrated that treadmill exercise minimizes the accumulation of CML and has renoprotective effects in aging mice and receiving natural anti-glycation therapy.[13] The contents of AGE cross-links in the patellar tendon of lifelong trained athletes were 21% lower than those of age-matched untrained individuals.[13]

The effects of 3 months of aerobic exercise alone on blood AGE levels have not been consistently demonstrated by several investigations.[12] The most notable improvements were seen in subjects who received both dietary and exercise recommendations. Not only did this group reduce serum AGEs and anthropometric parameters, but they also improved their lipid profile with a reduction of triglycerides and an increase in HDL levels. Recent studies have demonstrated that mixed resistance and aerobic training are more effective in the chronic modification of lipid profiles in overweight men. Although limited studies have been conducted regarding mixed exercises, additional research is needed to determine the exact effects of mixed exercises on AGE concentrations.[12] Several comparable results have been reported in the literature supporting the impact of regular physical activity on reducing AGEs in various chronic diseases, including CVD. A study by Russell et al. demonstrated improvements in BMI, glycemic control, and microvascular adaptation after intervention in type II DM patients.[86] There was a marked reduction in AGEs serum levels in patients with chronic diseases following exercise.[72] Exercising prevents the accumulation of AGEs and slows the progression of chronic diseases' sequels, especially when combined with other treatments that stabilize the underlying medical condition.[16] It has been suggested that a decrease in fat mass may explain the association between regular exercise, insulin sensitivity, RAGE expression, overall inflammatory status, and general body physiology.[16] Age and exercise have been demonstrated to have opposite effects on the rate of aortic CML throughout the whole artery.[87] Through its interaction as a ligand with the RAGE, CML modulates arterial stiffness as one of its main mechanisms.[88] CML content decreases with exercise in the aorta and returns to baseline following exercise cessation.[48]

After exercise, the collagen content of the intima decreases, whereas, after rest, the collagen content begins to increase.[48] Exercise also modulates the macro-scale compliance and stiffness of the arteries.[71],[89],[90] By reducing age-induced arterial stiffness, aerobic exercise contributes to cardiovascular health.[48] Data showed that stiffening of the subendothelial matrix decreased after exercise, but these effects did not persist.[48] Overall, studies indicate that exercise is essential for maintaining cardiovascular health, especially concerning the intima layer. The findings suggest that regular exercise is vital to preserving the subendothelial matrix's compliance. Wu et al. and Loimaala et al. demonstrated that people with diabetes have poorer diastolic function and EC than nondiabetics.[91],[92] Elevated AGEs are associated with reduced diastolic function and EC. Therefore, researchers looked at the relationship between elevated AGEs, reduced diastolic function, and aerobic EC among HF patients with and without diabetes.[46] The cross-linking of AGEs with collagen in the vascular wall alters its structural and functional properties, causing plaque formation and basement membrane hyperplasia.[93] A significant delay in calcium reuptake has also been reported as a consequence of exposure to AGEs, causing diastolic dysfunction.[46] Physical activity also promotes biological adaptations in skeletal muscle, including an increase in size and number of mitochondria,[51] and an increase in muscle capillary density,[52] all of which may have a positive synergistic effect on cardiovascular patients' survival.


The AGEs can accelerate the development of CVD by affecting the vascular wall, diastolic function, atherosclerotic plaques, and a certain number of parameters, including inflammation and oxidative stress. Exercise plays an important role in preventing CVD. According to recent studies, one of the reasons cited for this positive effect might be the effect of exercise on decreasing the concentration of AGEs and mediators of the AGEs pathway. Exercise reduces the expression of RAGE, inflammation markers, and oxidative stress. The improvement in glycemic control, insulin sensitivity, and fat mass could be another possible explanation. Exercise training improves endothelial function and stiffness of the arteries in healthy individuals and patients with increased cardiovascular risks. The most beneficial effects of exercise occur when aerobic and resistance exercises are combined. Additional research is needed to determine the exact effects of exercise on AGE concentrations. We need more detailed and future studies to prove more mechanisms in this regard. Furthermore, it is required to investigate the effects of AGEs on a variety of muscle fibers, especially heart muscle. More detailed studies are needed to find mechanisms of tissue damage caused by AGEs in motor function and to determine their effects.

Ethical Statement

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Conflicts of interest

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