Advanced glycation end-product
Advanced glycation end products (AGEs) are proteins or lipids that become
Dietary sources
Animal-derived foods that are high in fat and protein are generally AGE-rich and are prone to further AGE formation during cooking.[3] 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.[4] Therefore, it is unclear whether dietary AGEs contribute to disease and aging, or whether only endogenous AGEs (those produced in the body) matter.[5] This does not free diet from potentially negatively influencing AGE, but potentially implies that dietary AGE may deserve less attention than other aspects of diet that lead to elevated blood sugar levels and formation of AGEs.[4][5]
Effects
AGEs affect nearly every type of cell and molecule in the body and are thought to be one factor in aging
AGEs arise under certain pathologic conditions, such as oxidative stress due to hyperglycemia in patients with diabetes.[11] AGEs play a role as proinflammatory mediators in gestational diabetes as well.[12]
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. AGEs can also cause glycation of LDL which can promote its oxidation.[13] Oxidized LDL is one of the major factors in the development of atherosclerosis.[14] Finally, AGEs can bind to RAGE (receptor for advanced glycation end products) and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells.[13][14]
In other diseases
AGEs have been implicated in Alzheimer's Disease,[15] cardiovascular disease,[16] and stroke.[17] The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis.[18] They form photosensitizers in the crystalline lens,[19] which has implications for cataract development.[20] Reduced muscle function is also associated with AGEs.[21]
Pathology
AGEs have a range of pathological effects, such as:[22][23]
- Increased vascular permeability.
- Increased arterial stiffness
- Inhibition of vascular dilation by interfering with nitric oxide.
- Oxidizing LDL.
- Binding cells—including .
- Enhanced oxidative stress.
- Hemoglobin-AGE levels are elevated in diabetic individuals[24] and other AGE proteins have been shown in experimental models to accumulate with time, increasing from 5-50 fold over periods of 5–20 weeks in the retina, lens and renal cortex of diabetic rats. The inhibition of AGE formation reduced the extent of nephropathy in diabetic rats.[25] 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.[26][27]
- AGEs have specific cellular receptors; the best-characterized are those called RAGE. The activation of cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers the generation of free radicals and the expression of inflammatory gene mediators.[28] 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.[26]
Reactivity
Proteins are usually glycated through their lysine residues.[29] In humans, histones in the cell nucleus are richest in lysine, and therefore form the glycated protein N(6)-Carboxymethyllysine (CML).[29]
A
Clearance
In
Nevertheless, the resistance of extracellular matrix proteins to proteolysis renders their advanced glycation end products less conducive to being eliminated.[34] 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. [22] AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent[22] but accumulating in the plasma of patients with chronic kidney failure.[34]
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[22] as well as liver sinusoidal endothelial cells and Kupffer cells [35] have been implicated in this process, although the real-life involvement of the liver has been disputed. [36]
Large AGE proteins unable to enter the
Although the only form suitable for urinary excretion, the breakdown products of AGE—that is, 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 hyperglycemia has been brought under control.[22]
Some AGEs have an innate catalytic oxidative capacity, while activation of
In diabetics who have an increased production of an AGE, kidney damage reduces the subsequent urinary removal of AGEs, forming a positive feedback loop that increases the rate of damage. In a 1997 study, diabetic and healthy subjects were given a single meal of egg white (56 g protein), cooked with or without 100 g of fructose; there was a greater than 200-fold increase in AGE immunoreactivity from the meal with fructose.[37]
Potential therapy
AGEs are the subject of ongoing research. There are three therapeutic approaches: preventing the formation of AGEs, breaking crosslinks after they are formed and preventing their negative effects.
Compounds that have been found to inhibit AGE formation in the laboratory include
Studies in rats and mice have found that
Compounds that are thought to break some existing AGE crosslinks include
There is, however, no agent known that can break down the most common AGE, glucosepane, which appears 10 to 1,000 times more common in human tissue than any other cross-linking AGE.[51][52]
Some chemicals, on the other hand, like
See also
References
- PMID 16894049.
- S2CID 207517855.
- PMID 20497781.
- ^ PMID 23867544.
- ^ PMID 22254007.
- PMID 30184484.
- PMID 19409449.
- PMID 19448391.
- PMID 19023277.
- PMID 18331228.
- PMID 15919781.
- S2CID 3186554.
- ^ S2CID 8471652.
- ^ PMID 23761786.
- S2CID 207158367.
- S2CID 30264495.
- PMID 7731977.
- S2CID 37510479.
- PMID 18673320.
- S2CID 9260375.
- PMID 17901242.
- ^ PMID 8635666.
- ^ PMID 17531120.
- S2CID 23150519.
- ^ Ninomiya, T.; et al. (2001). "A novel AGE production inhibitor, prevents progression of diabetic nephropathy in STZ-induced rats". Diabetes. 50 Suppl. (2): A178–179.
- ^ PMID 9659442.
- ^ Thornalley, P.J. (1996). "Advanced glycation and the development of diabetic complications. Unifying the involvement of glucose, methylglyoxal and oxidative stress". Endocrinol. Metab. 3: 149–166.
- S2CID 7208198.
- ^ PMID 21725160.
- ^ PMID 7893666.
- .
- PMC 5661633.
- doi:10.1002/iub.1450.
- ^ PMID 17118352.
- PMID 9065778.
- PMID 15582139.
- PMID 9177242.
- ^ PMID 27773573.
- PMID 17210450.
- PMID 16177476. Archived from the original(PDF) on 2009-04-17. Retrieved 2009-04-16.
- ^ A. Gugliucci, "Sour Side of Sugar, A Glycation Web Page Archived July 1, 2007, at the Wayback Machine
- PMID 17383766. Retrieved 2013-11-13.
- PMID 1540533.
- PMID 16181134.
- ^ PMID 14568010.
- PMID 10903896.
- PMID 24614199.
- PMID 15607432.
- S2CID 4366953.
- .
- S2CID 27507321.
- PMID 16706655.