Advanced Glycation End Products in Disease and Aging
Advanced glycation end products (AGEs) result from a reaction between reducing sugars and amino groups on proteins, lipids, or nucleic acids. This reaction takes several steps, and the last steps are very hard to reverse . This is why AGEs are so difficult to remove from the body.
This reaction was discovered in 1912 by Louis Camille Maillard . Initial interest in the Maillard reaction was driven by food chemists, as AGEs are used as flavor enhancers, such as the outer surface of a honey-baked ham or Thanksgiving turkey. AGEs form rapidly on the outer surface of meat that is cooked with dry heat .
John Hodge determined the steps of the Maillard reaction in 1953 . Fifteen years later, Samuel Rahbar discovered glycated hemoglobin, also known as HbA1c . The implications of this finding were stunning. If hemoglobin could undergo the Maillard reaction, then any protein in the body could.
A flurry of interest in the world of physiology followed this discovery. In 1976, Anthony Cerami recommended that HbA1c be used as a diagnostic tool for diabetes [6,7]. At this time, Cerami and his colleagues first used the term “advanced glycosylation end products”. In 1981, a paper from China translated into English made the first reference to advanced glycation end products .
Since the end products of this reaction are irreversible, AGEs often take up permanent residence in the body . This is especially true of AGEs like glucosepane, which forms on collagen , the most abundant protein in the human body. Collagen also has a very slow turnover rate, with a half-life of between 95 and 215 years .
Other AGEs may be slowly cleared from the body. Protease enzymes break down proteins , and enzyme systems undermine AGE formation from AGE precursors .
How AGEs drive inflammatory disease
Biochemically, AGEs cause oxidative damage and inflammation, which leads to the mechanical effects of stiff tissues, alterations in gene expression, and neurological impairment [14,15,16]. AGEs also drive the development of many diseases, such as diabetes, cancer, cardiovascular, Alzheimer’s, and kidney disease .
This occurs through the activation of the receptor for advanced glycation end products (RAGE). AGE-RAGE binding kicks off a cascade of signaling events inside the cell, which drive inflammation and oxidative stress . Two of the most important molecules that receive RAGE signals are NOX and NFkB.
NOX, when signaled, captures molecular oxygen and turns it into reactive oxygen species (ROS) . ROS, in turn, cause damage to almost everything they encounter.
For instance, when ROS oxidizes LDL cholesterol, its propensity to cause damage skyrockets. In this state, LDL readily passes into the arterial wall to drive atherosclerosis and perpetuate oxidative damage .
Activated NFkB moves into the nucleus of the cell. There, it cues DNA to initiate the production of inflammatory cytokines. After these cytokines are made, they migrate out of the cell and attract immune cells .
The infiltration of immune cells leads to the release of more inflammatory molecules. This increases ROS and retriggers NFkB. The result is a vicious cycle of inflammation and oxidative damage.
Constant inflammation drives neighboring cells to cancer, senescence, and apoptosis. Lost cells are replaced by extracellular matrix tissue, potentially resulting in fibrotic disease and a progressive loss of function . RAGE also signals a host of other molecules that play roles in specific disease processes to become active.
General mechanism for AGE-RAGE inflammation and ROS production: (1) AGE attaches to RAGE and contributes to arterial stiffening through the creation of molecular cross-links. (2) RAGE activates NOX. (3) NOX converts molecular oxygen into ROS. (4) ROS oxidizes LDL to oxidized LDL and causes general free radical damage. (5) LDLox infiltrates the arterial wall to promote atherosclerosis. (2b) RAGE activates NF-kB. (3b) Activated NFkB enters the nucleus and (4b) prompts DNA to send plans for making cytokines to the cytoplasm and activates cancer-causing promoting genes related to cell growth, proliferation, and apoptosis. (5b) Inflammatory cytokines are made in the cytoplasm and released from the cell to attract other immune cells. (5b2) Cancer- promoting proteins are produced in the cytoplasm. (6b) Cytokines promote immune cell infiltration. Immune cells release ROS and stimulate NFkB, creating a cycle of inflammation.
AGEs and diabetes
AGEs develop more quickly in diabetics, as higher blood sugar means more glucose to react and form AGEs. This is not the whole story, though. Most AGEs are not churned out by the direct reaction of glucose with proteins and fats.
Glucose is split into two fragments during the process of energy production. Normally, these fragments undergo more enzymatically driven changes that ultimately result in the production of ATP. This process unintentionally produces methylglyoxal (MG) and 3-deoxyglucosone (3-DG), which form AGEs very quickly. MG forms AGEs 20,000 times faster than glucose .
When blood sugar is abnormally high, enzyme shortages result in the formation of increased amounts of MG and 3-DG. This is why the AGE burden in diabetics is so dramatically high.
Additionally, the AGE burden is further increased by abnormal dependence on the polyol pathway, which first turns glucose into sorbitol and then to fructose . Diabetics process approximately 30% of their glucose in this way.
The problem is that this process depends on an enzyme called sorbitol dehydrogenase. The kidneys, nerves, and eyes don’t normally make a lot of this enzyme . When the system is overloaded by diabetes, shortfalls in sorbitol dehydrogenase are even greater.
Sorbitol buildup creates osmotic pressure that causes the kidneys, nerves, and eyes to swell . Additionally, the overabundance of fructose leads to the production of 3-DG and MG once again.
The collective effects of excess sorbitol and AGEs is devastating. It causes kidney disease, nerve degeneration and pain, and loss of eyesight . The destruction of the kidneys further increases the AGE burden in diabetics. This is because we depend on our kidneys to eliminate AGEs in concert with glyoxalase defense systems [27,28].
Scientists are investigating the downstream effects of high blood sugar, such as AGE formation, which they hypothesize may be prime drivers in the complications of diabetes .
The role of advanced glycation end products in cancer
As AGEs accumulate in tissue, their ever-increasing interaction with RAGE drives inflammation. When RAGE is stimulated by an AGE, numerous signaling pathways in the cell are activated. RAGE-NFkB and RAGE-NOX are two such pathways that are strongly associated with both cancer and atherosclerosis .
Many cancer-related genes are activated by NFkB, such as TNF-alpha, IL6, BCLXL, BCL2, BCLXS, and XIAP. The proteins associated with these genes prevent apoptosis (programmed cell death) and promote uncontrolled cell growth, division, and metastasis [30,31].
Advanced glycation end products in atherosclerosis, hypertension, and heart failure
The lesions that form as a consequence of increased blood pressure initiate an immune response. This causes the spaces in the arterial wall to open up, allowing oxidized cholesterol to easily pass through. Oxidative damage caused by this oxidized cholesterol results in more inflammation and cytokine release from affected cells.
This, in turn, attracts immune cells called macrophages, which move into the arterial wall and gobble up oxLDL cholesterol. This results in the formation of foam cells, which make up the bulk of arterial plaque .
Additionally, when AGEs dock on RAGEs in the arterial wall, additional inflammation occurs, further damaging the artery . AGE-promoted arteriosclerosis leads to ischemic heart attacks that can severely damage the heart and often lead to heart failure.
AGE cross-links slowly form in the heart muscle, causing a gradual loss of pumping capacity . This occurs even in the absence of heart disease. Animal studies using anti-AGE drugs have demonstrated remarkable improvements in arterial elasticity and the contractile function of the heart.
In a study using monkeys, the effects of the AGE-breaking drug Alagebrium on arterial and heart stiffness were evaluated. The monkeys’ arteries became 25-60% more pliable, and their hearts were able to fill with 16% more blood .
Advanced glycation end products and neurodegenerative disease
The human brain has low antioxidant reserves and consumes copious amounts of oxygen and glucose. Therefore, it is very susceptible to oxidative damage . AGEs exacerbate oxidative damage in the brain through RAGE stimulation of the NOX and NFkB pathways [19,22].
In neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, the formation of protein aggregates is a defining characteristic. Beta-amyloid, tau, and alpha-synuclein are just a few examples. These proteins become glycated in tandem with the severity of disease  .
AGE crosslinks are present in the plaques and tangles of Alzheimer’s, the predominant cause of dementia [14,38]. Further, studies show that the growth of ß-amyloid plaques in Alzheimer’s is accelerated by AGE crosslinking . However, it may be possible to short-circuit this process. The development of amyloid precursor proteins, hastened by AGEs, can be blocked with a ROS inhibitor .
Glycation of tau protein also induces oxidative stress. This establishes a role for AGEs in the formation of Alzheimer’s toxic neurofibrillary tangles .
MG has been shown to contribute to the development of Alzheimer’s disease. Recent research indicates that AGE precursors such as MG may be promising targets for treatment .
Alpha-synuclein protein, a factor in Parkinson’s disease, is known to undergo glycation. This transformation is thought to promote the aggregation process . This has not been clearly demonstrated in human beings, but it is known that alpha-synuclein is very rich in lysine, a prime amino acid target for AGE formation. Furthermore, laboratory studies show that AGEs induce the aggregation of alpha-synuclein [44,45].
Tissue samples show that AGE and RAGE levels are increased in the brains of Parkinson’s disease patients , which is consistent with other findings. It has been shown that AGEs and oxidative stress worsen diseases that involve alpha-synuclein protein aggregates (Lewy bodies) .
Advanced glycation end products and aging
AGEs are not among the hallmarks of aging described by Carlos Lopez-Otin in 2013 . In 2020, Alexander Fedinstev and Alexy Moskalev made the case for including AGEs as “a missing hallmark of aging” . They argued that AGEs cause direct damage to long-lived proteins throughout the body and, as a consequence, drive other hallmarks of aging. AGEs do affect all of the accepted hallmarks of aging, often in multiple ways.
AGEs drive cellular senescence by provoking inflammation and oxidative damage . Senescent cells, in turn, can induce senescence in neighboring cells, including stem cells .
AGEs contribute to the stiffening of the extracellular matrix, which alters intracellular communication [52,53]. AGEs also glycate DNA and change patterns of DNA expression by persistently driving inflammation and causing oxidative stress. Therefore, AGEs promote genomic instability and alter the epigenetic landscape in DNA [45,54,55].
AGEs promote oxidative stress, causing telomere attrition and mitochondrial dysfunction [56,59]. They also alter proteostasis  and change nutrient sensing in cells through RAGE signaling . Therefore, AGEs accelerate every hallmark of aging.
This has implications across the spectrum of longevity research. For example, cellular reprogramming aims to reset patterns of gene expression to a youthful state. However, this begs the question: why did the cell deviate from its youthful state in the first place?
AGEs are part of the answer. When the environment of the cell changes, the cell matches gene expression to those changes. Therefore, partial reprogramming may not persist because it does not match gene expression to the environment within which the cells operate.
Possible solutions to advanced glycation end products
Diet and exercise
Contemporary eating practices often make use of dry heat. This promotes the formation of dietary AGEs by 10 to 100-fold compared to alternate cooking methods . Dietary AGEs are known to increase oxidative stress and sterile inflammation . Furthermore, consumption of dietary AGEs is linked to the development of diabetic complications, cardiovascular disease and kidney disease .
As a rule, high-fat animal-derived foods are rich in AGEs and form additional AGEs during cooking. In contrast, foods high in carbohydrates, such as vegetables, fruits, whole grains, and milk, harbor relatively few AGEs .
Dietary AGEs can be minimized by eating food raw, boiled, poached, or steamed. Shorter cooking times and lower temperatures are also helpful. Finally, lowering pH through acidic ingredients, such as lemon juice and vinegar, inhibits the formation of AGEs. The Vlassara Lab, at Mount Sinai School of Medicine, has produced a dietary AGE database as a tool for choosing and preparing food .
Caloric restriction studies indicate that eating less also lowers AGE burden. In one study, rats were allowed to eat as much as they liked or only 60% of that amount. The rats that ate less had lower AGE levels: a 25% reduction in CML and a 50% reduction in pentosidine .
Numerous studies show that lactic acid bacteria can reduce blood sugar, oxidative stress, and early glycation (HbA1c) [64,65]. This suggests that these probiotics could reduce AGE accumulation over the long haul. However, no studies to date have shown this.
Studies have demonstrated that exercise is linked to a significant decrease in serum AGE levels in both healthy and diabetic individuals [66-68].
The FDA has not approved any AGE breakers nor drugs that prevent their formation. Notable attempts include PTB, aminoguanidine, and alagebrium, which worked well in non-human studies. However, human studies produced results too poor to gain FDA approval.
One reason for this failure is that we were chasing the wrong AGEs. Our understanding of AGEs at the time was based on harsh AGE detection methods. Methods such as acid hydrolysis  destroyed prevalent AGEs like glucosepane, which was only discovered after the development of enzyme-based methods of detecting AGEs .
Efforts to target glucosepane with AGE breakers is still underway. In 2015, the Spiegel Lab at Yale developed a method for synthesizing glucosepane. This made glucosepane research much easier.
In 2020, the Spiegel lab and its colleagues developed anti-glucosepane antibodies. These antibodies were used to directly detect the presence of glucosepane in retinal tissue . This is not a new method of cleaving AGEs, but there is speculation that future developments in this area might involve anti-glucosepane antibodies.
Another promising approach to curtailing the formation of AGEs involves manipulation of the glyoxalase defense system. Glyoxalase enzymes, in concert with other detoxification enzymes, can remove compounds such as MG and 3-DG .
 J. S. Sjöberg and S. Bulterijs, “Characteristics, formation, and pathophysiology of glucosepane: A major protein cross-link,” Rejuvenation Res., vol. 12, no. 2, pp. 137–148, 2009
 Q. Zhang, J. M. Ames, R. D. Smith, J. W. Baynes, and T. O. Metz, “A perspective on the Maillard reaction and the analysis of protein glycation by mass spectrometry: probing the pathogenesis of chronic disease,” J. Proteome Res., vol. 8, no. 2, pp. 754–769, 2009
 J. Uribarri et al., “AGE’s in Foods and practical ways to reduce them,” J Am Diet Assoc., vol. 110, no. 6, pp. 911–16, 2010
 J. E. Hodge, “Dehydrated Foods, Chemistry of Browning Reactions in Model Systems,” J. Agric. Food Chem., vol. 1, no. 15, pp. 928–943, 1953
 S. Rahbar, “An abnormal hemoglobin in red cells of diabetics,” Clin. Chim. Acta, vol. 22, no. 2, pp. 296–298, 1968
 R. J. Koenig, C. M. Peterson, R. L. Jones, C. Saudek, M. Lehrman, and A. Cerami, “Correlation of Glucose Regulation and Hemoglobin AIc in Diabetes Mellitus,” N. Engl. J. Med., vol. 295, no. 8, pp. 417–420, 1976
 A. Cerami, “The unexpected pathway to the creation of the HbA1c test and the discovery of AGE’s,” J. Intern. Med., vol. 271, no. 3, pp. 219–226, 2012
 S. Zhao, L. Zhijie, and J. Liu, “Screening and identification of proteins that interact with receptor for advanced glycation end products (RAGE) via T7 select phage display sys,” Med. J. Chinese People’s Lib. Army, vol. 12, 1982
 C. Sharma, A. Kaur, S. S. Thind, B. Singh, and S. Raina, “Advanced glycation End-products (AGEs): an emerging concern for processed food industries,” J. Food Sci. Technol., vol. 52, no. 12, pp. 7561–7576, 2015
 A. Fedintsev, A. Moskalev, and Y. A. P. Taz, “Stochastic non-enzymatic modification of long-lived macromolecules – A missing hallmark of aging,” Ageing Res. Rev., vol. 62, no.3, p. 101097, 2020
 A. Fedintsev and A. Moskalev, “Stochastic non-enzymatic modification of long-lived macromolecules – A missing hallmark of aging,” Ageing Res. Rev., vol. 62, p. 101097, 2020
 N. Verzijl et al., “Effect of collagen turnover on the accumulation of advanced glycation end products,” J. Biol. Chem., vol. 275, no. 50, pp. 39027–39031, 2000
 P. J. Thornalley, “Glutathione-dependent detoxification of a-oxoaldehydes by the glyoxalase system: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors,” Chem. Biol. Interact., vol. 111–112, pp. 137–151, 1998
 J. J. Li, D. Voisin, A.-L. Quiquerez, and C. Bouras, “Differential expression of advanced glycosylation end-products in neurons of different species,” Brain Res., vol. 641, no. 2, pp. 285–288, 1994
 R. Jaramillo et al., “DNA Advanced Glycation End Products (DNA-AGEs) Are Elevated in Urine and Tissue in an Animal Model of Type 2 Diabetes,” Chem. Res. Toxicol., vol. 30, no. 2, pp. 689–698, 2017
 S. J. Zieman and D. A. Kass, “Advanced Glycation End Product Cross-Linking: Pathophysiologic Role and Therapeutic Target in Cardiovascular Disease,” Congest. Hear. Fail., vol. 10, no. 3, pp. 144–151, 2004
 C. Prasad, K. E. Davis, V. Imrhan, S. Juma, and P. Vijayagopal, “Advanced Glycation End Products and Risks for Chronic Diseases: Intervening Through Lifestyle Modification,” Am. J. Lifestyle Med., vol. 13, no. 4, pp. 384–404 2017
 L. J. Sparvero et al., “RAGE (Receptor for Advanced Glycation Endproducts), RAGE Ligands, and their role in Cancer and Inflammation,” J. Transl. Med., vol. 7, no. 1, p. 17, 2009
 M. Sedeek, R. Nasrallah, R. M. Touyz, and R. L. Hébert, “NADPH Oxidases, Reactive Oxygen Species, and the Kidney: Friend and Foe,” J. Am. Soc. Nephrol., vol. 24, no. 10, pp. 1512 LP – 1518, 2013
 J. A. Leopold and J. Loscalzo, “Oxidative mechanisms and atherothrombotic cardiovascular disease,” Drug Discov. Today. Ther. Strateg., vol. 5, no. 1, pp. 5–13, 2008
 J. Chaudhuri et al., “The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality,” Cell Metab., vol. 28, no. 3, pp. 337–352, 2018
 B. Sido, V. Hack, A. Hochlehnert, H. Lipps, C. Herfarth, and W. Dröge, “Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease,” Gut, vol. 42, no. 4, pp. 485–492, 1998
 P. J. Thornalley, “Dicarbonyl Intermediates in the Maillard Reaction,” Ann. N. Y. Acad. Sci., vol. 1043, no. 1, pp. 111–117, 2005
 L.-J. Yan, “Redox imbalance stress in diabetes mellitus: Role of the polyol pathway,” Anim. Model. Exp. Med., vol. 1, no. 1, pp. 7–13, 2018
 R. Harvey, Biochemistry (Lippincott’s Illustrated Review), 5th ed. Baltimore, MD: Lippincott, Williams, & Watkins, 2011.
 M. T. Murray, “165 – Diabetes Mellitus Types I and II,” J. E. Pizzorno and M. T. B. T.-T. of N. M. (Fifth E. Murray, Eds. St. Louis (MO): Churchill Livingstone, 2020, pp. 1262-1286
 M. Busch, S. Franke, C. Rüster, and G. Wolf, “Advanced glycation end-products and the kidney,” Eur. J. Clin. Invest., vol. 40, no. 8, pp. 742–755, 2010
 M. Hasanuzzaman et al., “Coordinated Actions of Glyoxalase and Antioxidant Defense Systems in Conferring Abiotic Stress Tolerance in Plants,” International Journal of Molecular Sciences , vol. 18, no. 1. 2017
 C. Ott, K. Jacobs, E. Haucke, A. Navarrete Santos, T. Grune, and A. Simm, “Role of advanced glycation end products in cellular signaling,” Redox Biol., vol. 2, no. 1, pp. 411–429, 2014
 D. Schröter and A. Höhn, “Role of Advanced Glycation End Products in Carcinogenesis and their Therapeutic Implications,” Curr. Pharm. Des., vol. 24, no. 44, pp. 5245–5251, 2019
 C. M. Pfeffer and A. T. K. Singh, “Apoptosis: A Target for Anticancer Therapy,” Int. J. Mol. Sci., vol. 19, no. 2, p. 448, 2018
 S. Vasdev, V. Gill, and P. Singal, “Role of Advanced Glycation End Products in Hypertension and Atherosclerosis: Therapeutic Implications,” Cell Biochem. Biophys., vol. 49, no. 1, pp. 48–63, 2007
 Y. Wallez and P. Huber, “Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis,” Biochim. Biophys. Acta – Biomembr., vol. 1778, no. 3, pp. 794–809, 2008
 A. V Poznyak et al., “Overview of OxLDL and Its Impact on Cardiovascular Health: Focus on Atherosclerosis ,” Frontiers in Pharmacology , vol. 11. 2021
 S. F. Yan, R. Ramasamy, and A. M. Schmidt, “The receptor for advanced glycation endproducts (RAGE) and cardiovascular disease,” Expert Rev. Mol. Med., vol. 11, pp. e9–e9, 2009
 V. P. V. et al., “A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys,” Proc. Natl. Acad. Sci., vol. 98, no. 3, pp. 1171–1175, 2001
 J. Li, D. Liu, L. Sun, Y. Lu, and Z. Zhang, “Advanced glycation end products and neurodegenerative diseases: Mechanisms and perspective,” J. Neurol. Sci., vol. 317, no. 1–2, pp. 1–5, 2012
 R. E. Tanzi, “A genetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders,” J. Clin. Invest., vol. 104, no. 9, pp. 1175–1179,1999
 G. Münch et al., “Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of ß-amyloid peptide,” Biochim. Biophys. Acta – Mol. Basis Dis., vol. 1360, no. 1, pp. 17–29, 1997
 S.-Y. Ko, Y.-P. Lin, Y.-S. Lin, and S.-S. Chang, “Advanced glycation end products enhance amyloid precursor protein expression by inducing reactive oxygen species,” Free Radic. Biol. Med., vol. 49, no. 3, pp. 474–480, 2010
 M. D. Ledesma, P. Bonay, and J. Avila, “t Protein from Alzheimer’s Disease Patients Is Glycated at Its Tubulin-Binding Domain,” J. Neurochem., vol. 65, no. 4, pp. 1658–1664, 1995.
 M. Haddad et al., “Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles,” Int. J. Mol. Sci., vol. 20, no. 19, p. 4906, Oct. 2019
 O. T. Fleming et al., “Sirtuin 2 Inhibitors Rescue a-Synuclein-Mediated Toxicity in Models of Parkinson’s Disease,” Science (80-. )., vol. 317, no. 5837, pp. 516–519, 2007.
 D. Lee, C. W. Park, S. R. Paik, and K. Y. Choi, “The modification of a-synuclein by dicarbonyl compounds inhibits its fibril-forming process,” Biochim. Biophys. Acta – Proteins Proteomics, vol. 1794, no. 3, pp. 421–430, 2009
 V. Padmaraju, J. J. Bhaskar, U. J. S. Prasada Rao, P. V Salimath, and K. S. Rao, “Role of Advanced Glycation on Aggregation and DNA Binding Properties of a-Synuclein,” J. Alzheimer’s Dis., vol. 24, pp. 211–221, 2011
 E. Dalfó, M. Portero-Otín, V. Ayala, A. Martínez, R. Pamplona, and I. Ferrer, “Evidence of Oxidative Stress in the Neocortex in Incidental Lewy Body Disease,” J. Neuropathol. Exp. Neurol., vol. 64, no. 9, pp. 816–830, 2005
 R. Castellani, M. A. Smith, G. L. Richey, and G. Perry, “Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease,” Brain Res., vol. 737, no. 1, pp. 195–200, 1996
 M. A. Blasco, L. Partridge, M. Serrano, G. Kroemer, and C. Lo, “Review The Hallmarks of Aging,” Cell no. 5 pp.1194-1217 2013
 A. Fedintsev and A. Moskalev, “Stochastic non-enzymatic modification of long-lived macromolecules – a missing hallmark of aging” Aging Research Reviews” 2020
 C. Correia-Melo, G. Hewitt, and J. F. Passos, “Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence?,” Longev. Heal., vol. 3, no. 1, p. 1, 2014
 G. Nelson, O. Kucheryavenko, J. Wordsworth, and T. von Zglinicki, “The senescent bystander effect is caused by ROS-activated NF-kB signaling,” Mech. Aging Dev., vol. 170, 2017, pp. 30–36, 2018
 J. Zhao, “Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart,” World J. Diabetes, vol. 5, no. 6, p. 860, 2014
 A. Liedert, D. Kaspar, R. Blakytny, L. Claes, and A. Ignatius, “Signal transduction pathways involved in mechanotransduction in bone cells,” vol. 349, pp. 1–5, 2006
 A. Perrone, A. Giovino, J. Benny, and F. Martinelli, “Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects,” Oxid. Med. Cell. Longev., vol. 2020, p. 3818196, 2020
 C. Ott, K. Jacobs, E. Haucke, A. Navarrete Santos, T. Grune, and A. Simm, “Role of advanced glycation end products in cellular signaling,” Redox Biol., vol. 2, pp. 411–429, 2014
 P. Deo et al., “Advanced glycation end-products accelerate telomere attrition and increase pro-inflammatory mediators in human WIL2-NS cells,” Mutagenesis, vol. 35, no. 3, pp. 291–297, Jul. 2020
 E. S. Cannizzo et al., “Age-Related Oxidative Stress Compromises Endosomal Proteostasis,” Cell Rep., vol. 2, no. 1, pp. 136–149, 2012
 X. Hou et al., “Advanced glycation endproducts trigger autophagy in cadiomyocyte Via RAGE/PI3K/AKT/mTOR pathway,” Cardiovasc. Diabetol., vol. 13, no. 1, pp. 1–8, 2014
 X. Wang et al., “Advanced glycation end products induce oxidative stress and mitochondrial dysfunction in SH-SY5Y cells,” Vitr. Cell. Dev. Biol. – Anim., vol. 51, no. 2, pp. 204–209, 2015
 J. Uribarri et al., “Advanced glycation end products in foods and a practical guide to their reduction in the diet,” J. Am. Diet. Assoc., vol. 110, no. 6, pp. 911–16.e12, 2010
 J. Uribarri et al., “Circulating Glycotoxins and Dietary Advanced Glycation Endproducts: Two Links to Inflammatory Response, Oxidative Stress, and Aging,” Journals Gerontol. Ser. A, vol. 62, no. 4, pp. 427–433, 2007
 J. O’Brien, P. A. Morrissey, and J. M. Ames, “Nutritional and toxicological aspects of the Maillard browning reaction in foods,” Crit. Rev. Food Sci. Nutr., vol. 28, no. 3, pp. 211–248, 1989
 W. T. Cefalu et al., “Caloric Restriction Decreases Age-Dependent Accumulation of the Glycoxidation Products, N?-(Carboxymethyl)lysine and Pentosidine, in Rat Skin Collagen,” Journals Gerontol. Ser. A, vol. 50A, no. 6, pp. B337–B341, 1995
 H. S. Ejtahed, J. Mohtadi-Nia, A. Homayouni-Rad, M. Niafar, M. Asghari-Jafarabadi, and V. Mofid, “Probiotic yogurt improves antioxidant status in type 2 diabetic patients,” Nutrition, vol. 28, no. 5, pp. 539–543, 2012
 M. Snelson and M. T. Coughlan, “Dietary advanced glycation end products: Digestion, metabolism and modulation of gut microbial ecology,” Nutrients, vol. 11, no. 2, 2019
 K. L. Rodrigues et al., “Influence of Physical Exercise on Advanced Glycation End Products Levels in Patients Living With the Human Immunodeficiency Virus,” Front. Physiol., vol. 9, p. 1641, 2018
 M. H. Macías-Cervantes, J. M. D. Rodríguez-Soto, J. Uribarri, F. J. Díaz-Cisneros, W. Cai, and M. E. Garay-Sevilla, “Effect of an advanced glycation end product-restricted diet and exercise on metabolic parameters in adult overweight men,” Nutrition, vol. 31, no. 3, pp. 446–451, 2015
 P. M. Magalhães, H. J. Appell, and J. A. Duarte, “Involvement of advanced glycation end products in the pathogenesis of diabetic complications: the protective role of regular physical activity,” Eur. Rev. Aging Phys. Act., vol. 5, no. 1, pp. 17–29, 2008
 P. Odetti, J. Fogarty, D. R. Sell, and V. M. Monnier, “Chromatographic Quantitation of Plasma and Erythrocyte Pentosidine in Diabetic and Uremic Subjects,” Diabetes, vol. 41, no. 2, pp. 153–159, 1992
 K. M. Bieme, D. Alexander Fried, and M. O. Lederer, “Identification and quantification of major maillard cross-links in human serum albumin and lens protein: Evidence for glucosepane as the dominant compound,” J. Biol. Chem., vol. 277, no. 28, pp. 24907–24915, 2002
 M. D. Streeter et al., “Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue,” ACS Chem. Biol., vol. 15, no. 10, pp. 2655–2661, 2020
 G. Aragonès et al., “Glyoxalase system as a therapeutic target against diabetic retinopathy,” Antioxidants, vol. 9, no. 11, pp. 1–25, 2020