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Advanced glycation end-product
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<h2 id="dietary-sources">Dietary sources</h2> <p>Animal-derived foods that are high in fat and protein are generally AGE-rich and are prone to further AGE formation during cooking.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> However, only low molecular weight AGEs are absorbed through diet, and vegetarians have been found to have higher concentrations of overall AGEs compared to non-vegetarians.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h2 id="effects">Effects</h2> <p>AGEs can be produced in the body and in manufactured foods.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> The accumulation of AGEs may have causative roles in several age-related diseases by forming <a href="/facts/Adduct/vBpTmotm">adducts</a> with proteins and lipids.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> In preliminary research, AGEs affect nearly every type of cell and molecule in the body and are thought to be one factor in aging<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> and some age-related chronic diseases.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> They are also believed to play a causative role in the vascular complications of <a href="/facts/Diabetes_mellitus/2xeHXbsI">diabetes mellitus</a>.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p><p>AGEs may arise under certain pathological conditions, such as <a href="/facts/Oxidative_stress/HX7dfUUb">oxidative stress</a> due to <a href="/facts/Hyperglycemia/HM8eNqfX">hyperglycemia</a> in patients with diabetes.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> AGEs may have a role as proinflammatory mediators in <a href="/facts/Gestational_diabetes/1Nn5kF5G">gestational diabetes</a>.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p><p>In the context of <a href="/facts/Cardiovascular_disease/HD420nMv">cardiovascular disease</a>, a possible AGE mechanism is to induce crosslinking of <a href="/facts/Collagen/KsyAb72K">collagen</a>, which can cause vascular stiffening and entrapment of <a href="/facts/Low-density_lipoprotein/R5VLPxAg">low-density lipoprotein particles</a> (LDL) in the artery walls.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> AGEs can also cause glycation of LDL which can promote its oxidation.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> Oxidized LDL is one of the major factors in the development of atherosclerosis.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> AGEs can bind to <a href="/facts/RAGE_(receptor)/JVNGnNEU">RAGE (receptor for advanced glycation end products)</a> and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p> <h3>In other diseases</h3> <p>AGEs have been implicated in Alzheimer's disease and cardiovascular diseases.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p><p>According to in vitro research, the mechanism by which AGEs may induce damage is through a process called <a href="/facts/Cross-link/zeQ9hEAA">cross-linking</a> that causes intracellular damage and apoptosis.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p> <h3>Pathology</h3> <p>In laboratory studies, AGEs have a range of <a href="/facts/Pathology/U9b18LJG">pathological effects</a>, such as:<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> </p> <ul><li>Increased <a href="/facts/Vascular_permeability/AnyAKbX2">vascular permeability</a>.</li> <li>Increased <a href="/facts/Arterial_stiffness/GlSgeYzJ">arterial stiffness</a>.</li> <li>Inhibition of <a href="/facts/Vasodilation/cjzrU8Ro">vascular dilation</a> by interfering with <a href="/facts/Nitric_oxide/UvhdvDzp">nitric oxide</a>.</li> <li><a href="/facts/Low-density_lipoprotein/R5VLPxAg">Oxidizing LDL</a>.</li> <li>Binding cells—including <a href="/facts/Macrophage/z7hkQu3o">macrophage</a>, <a href="/facts/Endothelial_cell/L4ENFVnw">endothelial</a>, and <a href="/facts/Mesangial_cell/rNWwqrkc">mesangial</a>—to induce the secretion of a variety of <a href="/facts/Cytokine/SdWpWABH">cytokines</a>.</li> <li>Enhanced <a href="/facts/Oxidative_stress/HX7dfUUb">oxidative stress</a>.</li> <li>Hemoglobin-AGE levels are elevated in diabetic individuals.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> 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.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a></li> <li>AGEs have specific cellular receptors; the best-characterized are those called <a href="/facts/RAGE_(receptor)/JVNGnNEU">RAGE</a>. The activation of cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers the generation of free radicals and the expression of inflammatory gene mediators.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> 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.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a></li></ul> <p>As of 2024, there is no conclusive <a href="/facts/Evidence-based_medicine/InK1lB9l">clinical evidence</a> for AGEs having a pathological role in aging diseases, and no causality has been demonstrated between foods, AGEs, and onset of aging or age-related diseases.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> </p> <h2 id="reactivity">Reactivity</h2> <p>Proteins are usually glycated through their <a href="/facts/Lysine/CEetgA9L">lysine</a> <a href="/facts/Residue_(chemistry)/xE6sUTDa">residues</a>.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> In humans, <a href="/facts/Histone/krb5VJfp">histones</a> in the <a href="/facts/Cell_nucleus/D7sFRa3c">cell nucleus</a> are richest in lysine, and therefore form the glycated protein <a href="/facts/N(6)-Carboxymethyllysine/f524Rfdf">N(6)-Carboxymethyllysine</a>.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> </p><p>A <a href="/facts/Receptor_(biochemistry)/tjTAC76a">receptor</a> nicknamed RAGE, from <a href="/facts/RAGE_(receptor)/JVNGnNEU">receptor for advanced glycation end products</a>, is found on many cells, including <a href="/facts/Endothelium/L4ENFVnw">endothelial cells</a>, <a href="/facts/Smooth_muscle_cells/mpcpTsHp">smooth muscle</a>, cells of the <a href="/facts/Immune_system/HRCTf1pb">immune system</a> [<i>which?</i>] from tissue such as lung, liver, and kidney.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> This receptor, when binding AGEs, is under preliminary research to determine if it contributes to age- and diabetes-related chronic inflammatory diseases.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> </p><p>The <a href="/facts/Pathogenesis/o9kHHK0U">pathogenesis</a> of this process is hypothesized to activation of the <a href="/facts/Transcription_factor/wro0DPHe">nuclear factor</a> kappa B (<a href="/facts/NF-%25CE%25BAB/qcpt5vuQ">NF-κB</a>) following AGE binding.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> NF-κB controls several <a href="/facts/Genes/e1swwPY6">genes</a> involved in <a href="/facts/Inflammation/Ura86MIy">inflammation</a>.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> AGEs can be detected and quantified using bioanalytical and immunological methods.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> </p> <h2 id="clearance">Clearance</h2> <p>In <a href="/facts/Clearance_(medicine)/RqI64paT">clearance</a>, or the rate at which a substance is removed or cleared from the body, it has been found that the cellular <a href="/facts/Proteolysis/GtQdv6J7">proteolysis</a> of AGEs—the breakdown of proteins—produces AGE <a href="/facts/Peptides/C4ltc7UG">peptides</a> and "AGE free <a href="/facts/Adducts/vBpTmotm">adducts</a>" (AGE adducts bound to single <a href="/facts/Amino_acids/WDxYwBny">amino acids</a>). These latter, after being released into the <a href="/facts/Blood_plasma/oHuwwugG">plasma</a>, can be excreted in the <a href="/facts/Urine/oNUYVtvX">urine</a>.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> </p> <p>Nevertheless, the resistance of <a href="/facts/Extracellular_matrix/kaHC5Ez8">extracellular matrix</a> proteins to proteolysis renders their advanced glycation end products less conducive to being eliminated.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> While the AGE free adducts are released directly into the urine, AGE peptides are <a href="/facts/Endocytosis/NJjChLNj">endocytosed</a> by the <a href="/facts/Epithelium/ecKHcHC3">epithelial cells</a> of the <a href="/facts/Proximal_tubule/mkezjse0">proximal tubule</a> and then degraded by the <a href="/facts/Lysosome/0mcrzJU9">endolysosomal system</a> to produce AGE amino acids. It is thought that these acids are then returned to the kidney's inside space, or <a href="/facts/Lumen_(anatomy)/3thJT4Hf">lumen</a>, for <a href="/facts/Excretion/mspsTfnv">excretion</a>. <a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> but accumulating in the plasma of patients with chronic kidney failure.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> </p><p>Larger, extracellularly derived AGE proteins cannot pass through the basement membrane of the <a href="/facts/Renal_corpuscle/A5tQAMan">renal corpuscle</a> and must first be degraded into AGE peptides and AGE free adducts. Peripheral <a href="/facts/Macrophage/z7hkQu3o">macrophage</a><a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> as well as liver <a href="/facts/Endothelium/L4ENFVnw">sinusoidal endothelial cells</a> and <a href="/facts/Kupffer_cell/h9rJeNqE">Kupffer cells</a> <a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> have been implicated in this process, although the real-life involvement of the liver has been disputed. <a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> </p> <p>Large AGE proteins unable to enter the <a href="/facts/Bowman%2527s_capsule/mvJx1IEJ">Bowman's capsule</a> are capable of binding to receptors on <a href="/facts/Endothelium/L4ENFVnw">endothelial</a> and <a href="/facts/Mesangial_cell/rNWwqrkc">mesangial</a> cells and to the mesangial matrix.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> Activation of RAGE induces production of a variety of <a href="/facts/Cytokines/SdWpWABH">cytokines</a>, including <a href="/facts/Tumor_necrosis_factors/5G0MA0dG">TNFβ</a>, which mediates an inhibition of <a href="/facts/Metalloproteinase/ShDT6dbf">metalloproteinase</a> and increases production of mesangial matrix, leading to <a href="/facts/Glomerulosclerosis/xIYHrtYN">glomerulosclerosis</a><a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> and decreasing kidney function in patients with unusually high AGE levels. </p><p>Although the only form suitable for urinary excretion, the breakdown products of AGE — peptides and free adducts — are more aggressive than the AGE proteins from which they are derived, and they can perpetuate related pathology in diabetic patients, even after <a href="/facts/Hyperglycemia/HM8eNqfX">hyperglycemia</a> has been brought under control.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Glycosylation/VYEeQCRz">Glycosylation</a></li> <li><a href="/facts/Glyoxalase_system/vcL6PNVB">Glyoxalase system</a></li> <li><a href="/facts/Methylglyoxal/S3WMsTcU">Methylglyoxal</a></li> <li><a href="/facts/Raw_foodism/142DEWBx">Raw foodism</a></li> <li><a href="/facts/N(6)-Carboxymethyllysine/f524Rfdf">N(6)-Carboxymethyllysine</a></li> <li><a href="/facts/Lipofuscin/CdJRWzug">Lipofuscin</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Hellwig M, Diel P, Eisenbrand G, et al. (September 2024). "Dietary glycation compounds - implications for human health". Critical Reviews in Toxicology. 54 (8): 485–617. doi:10.1080/10408444.2024.2362985. PMID 39150724. <a href="https://www.tandfonline.com/doi/full/10.1080/10408444.2024.2362985" target="_blank">https://www.tandfonline.com/doi/full/10.1080/10408444.2024.2362985</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Hellwig M, Diel P, Eisenbrand G, et al. (September 2024). "Dietary glycation compounds - implications for human health". Critical Reviews in Toxicology. 54 (8): 485–617. doi:10.1080/10408444.2024.2362985. PMID 39150724. <a href="https://www.tandfonline.com/doi/full/10.1080/10408444.2024.2362985" target="_blank">https://www.tandfonline.com/doi/full/10.1080/10408444.2024.2362985</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Flint B, Tadi P (4 January 2023). "Pathophysiology, Glycation. In: Physiology, Aging". StatPearls, US National Library of Medicine. Retrieved 27 June 2025. <a href="https://www.ncbi.nlm.nih.gov/books/NBK556106/#article-76059.s9" target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK556106/#article-76059.s9</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Rungratanawanich W, Qu Y, Wang X, et al. (February 2021). "Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury". Experimental and Molecular Medicine. 53 (2): 168–188. doi:10.1038/s12276-021-00561-7. PMC 8080618. PMID 33568752. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080618" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080618</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Hellwig M, Diel P, Eisenbrand G, et al. (September 2024). "Dietary glycation compounds - implications for human health". Critical Reviews in Toxicology. 54 (8): 485–617. doi:10.1080/10408444.2024.2362985. PMID 39150724. <a href="https://www.tandfonline.com/doi/full/10.1080/10408444.2024.2362985" target="_blank">https://www.tandfonline.com/doi/full/10.1080/10408444.2024.2362985</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Rungratanawanich W, Qu Y, Wang X, et al. (February 2021). "Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury". Experimental and Molecular Medicine. 53 (2): 168–188. doi:10.1038/s12276-021-00561-7. PMC 8080618. PMID 33568752. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080618" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080618</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Vistoli G, De Maddis, D, Cipak, A, et al. (August 2013). 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