Advanced glycation end-product
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Advanced glycation end-products (AGEs) are proteins or lipids that become glycated after exposure to sugars.<ref name="hellwig">Template:Cite journal</ref> They are formed through a series of non-enzymatic reactions explained in further detail below, and their accumulation is associated with a variety of metabolic diseases such as diabetes, atherosclerosis, chronic kidney disease, age-related macular degeneration (even in non-diabetic animals), and Alzheimer's disease.<ref name="uceda">Template:Cite journal</ref><ref name=":5">Template:Cite journal</ref><ref name=":7">Template:Cite journal</ref><ref name=":0" />
Formation of AGEs
AGEs formation is initiated with the Maillard reaction which forms a reversible Schiff base between the carbonyl group of a reducing sugar — or its metabolites such as methylglyoxal — and a free amino group on a protein. This Schiff base undergoes oxidation and rearrangements to form Amadori products, which eventually lead to the formation of AGEs. AGEs affect nearly every type of cell and molecule in the body, are thought to be key contributors to the aging process,<ref name=":1" /> and are implicated in the development of some age-related chronic diseases.<ref name=":2" /><ref name=":3">Template:Cite journal</ref><ref name="pmid23867544">Template:Cite journal</ref> Notably, AGEs are believed to play a causative role in the vascular complications of diabetes mellitus and age related macular degeneration (AMD).<ref name=":4" />
Dietary sources of AGEs
Animal-derived foods that are high in fat and protein are generally rich in AGEs, and are especially prone to further AGE formation during cooking.<ref name="hellwig" /><ref name=":3" /> However, only low molecular weight AGEs are efficiently absorbed through diet. Interestingly, vegetarians have been found to have higher overall concentrations of AGEs compared to non-vegetarians.<ref name="pmid23867544" /> It is estimated that 10-30% of plasma AGEs come from the diet.<ref>Template:Cite journal</ref> This raises uncertainty about the role of dietary AGEs in disease and aging, whether they significantly contribute, or if only endogenously produced AGEs (those formed within the body) are relevant.<ref name=":6">Template:Cite journal</ref> Most endogenous AGEs are produced intracellularly, and their rates of production and accumulation increase in response to high glycemic index diets, extended exposure to glycating moieties in vitro, and aging in laboratory animals and humans<ref>Template:Cite journal</ref>- even in non-diabetics. AGEs also accumulate upon aging, which is explained in more detail below.<ref name=":5" /><ref name="pmid23867544" /><ref name=":6" />
Pathology
Shown to the right is a proposed mechanistic link between dietary sources of glycating moieties and AMD. It is probable that other diseases share similar mechanistic relations to dietary carbohydrate intake.
AGEs also play a role as pro-inflammatory mediators in gestational diabetes<ref name=":8" /> and have been implicated in Alzheimer's Disease,<ref>Template:Cite journal</ref> cardiovascular disease,<ref>Template:Cite journal</ref> and stroke.<ref>Template:Cite journal</ref> Additionally, AGE accumulation has been observed in the eye lens and retina of animals fed high glycemic index diets, as well as in HEK-293 and HELA cells exposed to methyglyoxal.<ref name=":5" /><ref>Template:Cite journal</ref>
In the context of cardiovascular disease, AGEs can induce crosslinking of collagen, which can cause vascular stiffening and entrapment of low-density lipoprotein particles (LDL) in the artery walls.<ref name="hellwig" /> AGEs can also cause glycation of LDL which can promote its oxidation.<ref name="pmid22314141">Template:Cite journal</ref> Oxidized LDL is one of the major factors in the development of atherosclerosis.<ref name="pmid23761786">Template:Cite journal</ref> AGEs can bind to RAGE receptors and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells.<ref name="hellwig" /><ref name="uceda" /><ref name="rung" />
A receptor nicknamed RAGE, from receptor for advanced glycation end products, is found on many cells, including endothelial cells, smooth muscle, cells of the immune system Template:Which from tissue such as lung, liver, and kidney.<ref name="hellwig" /><ref name="rung">Template:Cite journal</ref> This receptor, when binding AGEs, is under preliminary research to determine if it contributes to age- and diabetes-related chronic inflammatory diseases.<ref name="hellwig" /><ref name="uceda" />
The pathogenesis of this process is hypothesized to activation of the nuclear factor kappa B (NF-κB) following AGE binding.<ref name=hellwig/> NF-κB controls several genes involved in inflammation.<ref name=":1">Template:Cite journal</ref> AGEs can be detected and quantified using bioanalytical and immunological methods.<ref name=":2">Template:Cite journal</ref>
Effects
AGEs can be produced in the body and in manufactured foods.<ref name=hellwig/><ref name=uceda/><ref name=rung/> The accumulation of AGEs may have causative roles in several age-related diseases by forming adducts with proteins and lipids.<ref name=hellwig/><ref name=uceda/><ref name=rung/> In preliminary research, AGEs affect nearly every type of cell and molecule in the body, and may be a factor in aging<ref name=uceda/><ref name=":4">Template:Cite journal</ref> and some age-related chronic diseases.<ref name=hellwig/><ref name=rung/><ref name=":0">Template:Cite journal</ref> They are also believed to play a causative role in the vascular complications of diabetes mellitus.<ref>Template:Cite journal</ref>
AGEs may arise under certain pathological conditions, such as oxidative stress due to hyperglycemia in patients with diabetes.<ref name=hellwig/><ref name=rung/><ref name=BROWNLEE2005>Template:Cite journal</ref> AGEs may have a role as proinflammatory mediators in gestational diabetes.<ref name=":8">Template:Cite journal</ref>
In other diseases
AGEs have been implicated in Alzheimer's disease and cardiovascular diseases.<ref name=hellwig/><ref name=uceda/><ref name=rung/>
According to in vitro research, the mechanism by which AGEs may induce damage is through a process called cross-linking that causes intracellular damage and apoptosis.<ref name=uceda/><ref>Template:Cite journal</ref>
Pathology
In laboratory studies, AGEs have a range of pathological effects, such as:<ref name=GUGLIUCCI1996/><ref name=pmid17531120/>
- Increased vascular permeability
- Increased arterial stiffness
- Inhibition of vascular dilation by interfering with nitric oxide
- Oxidizing LDL
- Binding cells—including macrophage, endothelial, and mesangial—to induce the secretion of a variety of cytokines
- Enhanced oxidative stress
- Hemoglobin-AGE levels are elevated in diabetic individuals.<ref name="pmid19618662">Template:Cite journal</ref> Therefore, substances that inhibit AGE formation may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGE-mediated disease<ref name="Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. 1998 586–600">Template:Cite journal</ref><ref>Template:Cite journal</ref>
- AGEs have specific cellular receptors; the best-characterized are those called RAGE.<ref name=uceda/> The activation of cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers the generation of free radicals and the expression of inflammatory gene mediators.<ref>Template:Cite journal</ref> Such increases in oxidative stress lead to the activation of the transcription factor NF-κB and promote the expression of NF-κB regulated genes that have been associated with atherosclerosis.<ref name="Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. 1998 586–600"/>
As of 2024, there is no conclusive clinical evidence for AGEs having a pathological role in aging diseases, and no causality has been demonstrated between processed foods, AGEs, and onset of aging or age-related diseases.<ref name=hellwig/>
Clearance
In clearance, or the rate at which a substance is removed or cleared from the body, it has been found that the cellular proteolysis of AGEs—the breakdown of proteins—produces AGE peptides and "AGE free adducts" (AGE adducts bound to single amino acids). These latter, after being released into the plasma, can be excreted in the urine.<ref name=gugliucci>Template:Cite journal</ref>
Nevertheless, the resistance of extracellular matrix proteins to proteolysis renders their advanced glycation end products less conducive to being eliminated.<ref name=gugliucci/> While the AGE free adducts are released directly into the urine, AGE peptides are endocytosed by the epithelial cells of the proximal tubule and then degraded by the endolysosomal system to produce AGE amino acids. It is thought that these acids are then returned to the kidney's inside space, or lumen, for excretion. <ref name=GUGLIUCCI1996>Template:Cite journal</ref> AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent<ref name=GUGLIUCCI1996/> but accumulating in the plasma of patients with chronic kidney failure.<ref name=gugliucci/>
Larger, extracellularly derived AGE proteins cannot pass through the basement membrane of the renal corpuscle and must first be degraded into AGE peptides and AGE free adducts. Peripheral macrophage<ref name=GUGLIUCCI1996/> as well as liver sinusoidal endothelial cells and Kupffer cells <ref name="Smedsrød">Template:Cite journal</ref> have been implicated in this process, although the real-life involvement of the liver has been disputed. <ref name=Svistounov>Template:Cite journal</ref>
Large AGE proteins unable to enter the Bowman's capsule are capable of binding to receptors on endothelial and mesangial cells and to the mesangial matrix.<ref name=GUGLIUCCI1996/> Activation of RAGE induces production of a variety of cytokines, including TNFβ, which mediates an inhibition of metalloproteinase and increases production of mesangial matrix, leading to glomerulosclerosis<ref name=pmid17531120>Template:Cite journal</ref> and decreasing kidney function in patients with unusually high AGE levels.
Peptides and free adducts, the only breakdown products of AGE that are suitable for urinary excretion, are more aggressive than the AGE proteins from which they are derived, and they can perpetuate related pathology in people with diabetes, even after hyperglycemia has been brought under control.<ref name=GUGLIUCCI1996/>
Research
Ongoing studies are performed to specify mechanisms that selectively inhibit the glycation process, and to understand how glycated molecules could be protected from further deterioration, possibly by manipulating the glyoxalase enzyme system to detoxify AGEs.<ref name=uceda/>
Development of candidate drugs by the pharmaceutical industry includes compounds whose mechanism of action is to inhibit or revert the glycation process.<ref name=uceda/>