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The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality
Open accessAbstract
Accumulation of advanced glycation end products (AGEs) on nucleotides, lipids, and peptides/proteins are an inevitable component of the aging process in all eukaryotic organisms, including humans. To date, a substantial body of evidence shows that AGEs and their functionally compromised adducts are linked to and perhaps responsible for changes seen during aging and for the development of many age-related morbidities. However, much remains to be learned about the biology of AGE formation, causal nature of these associations, and whether new interventions might be developed that will prevent or reduce the negative impact of AGEs-related damage. To facilitate achieving these latter ends, we show how invertebrate models, notably Drosophila melanogaster and Caenorhabditis elegans, can be used to explore AGE-related pathways in depth and to identify and assess drugs that will mitigate against the detrimental effects of AGE-adduct development.
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“The fundamental role of AGEs, including glycoxidation products, in human aging, but also in aging of vertebrate and invertebrate model organism has been reviewed in 2018 by Chaudhuri and colleagues [153]”
From Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases (2021) · cites this paper as [153]
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“a growing body of evidence reveals that levels of glycoxidation products increase as a function of age in several tissues, dependent on the dietary intake and the presence of hyperglycemic conditions [152,153]”
From Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases (2021) · cites this paper as [153]
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“together indicating the relevance of AGEs as biomarkers of aging and age-related diseases”
From Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases (2021) · cites this paper as [153]
In the citing paper
“However, under pathological conditions, RAGEs can be upregulated and participate in various aging-related pathophysiologies, such as adult-onset type 2 diabetes mellitus (DM), cardiovascular disorders, myocardial infarction, chronic kidney failure, pancreatitis, cancer, Alzheimer’s disease (AD), Parkinson’s disease (PD), hepatic fibrosis, and alcohol-mediated tissue injury37,38.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [37]
In the citing paper
“Generally, RAGEs are expressed widely in various cells, such as endothelial cells, macrophages/monocytes, neutrophils, lymphocytes, microglia, astrocytes, and neurons, and organs, such as the brain, heart, lung, kidney, and liver36,37.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [37]
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“Briefly, protein glycation is a series of non-enzymatic reactions collectively termed the Maillard reaction [58] (Figure 1).”
BackgroundYuan, X., Nie, C., Liu, H., Ma, Q., Peng, B., Zhang, M., Chen, Z., & Li, J. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1991265 · Cited by 52
“…pathogenesis of other chronic diseases, such as nonalcoholic fatty liver disease (Fernando et al. 2019), cancer (Ahmad et al. 2018), diabetes and diabetic complications (Parveen et al. 2021), Alzheimer’s disease (Prasad 2019), atherosclerosis (Wang et al. 2018) and obesity (Chaudhuri et al. 2018).”
BackgroundProteomic architecture of valvular extracellular matrix
Bouchareb, R., Guauque-Olarte, S., Snider, J., Zaminski, D., Anyanwu, A., Stelzer, P., & Lebeche, D. (2021) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2020.11.008 · Cited by 52
“MetS may affect aortic valve ECM through the overaccumulation of advanced glycation end-products (11).”
BackgroundEndocrine Regulation of Lifespan in Insect Diapause
Hutfilz, C. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.825057 · Cited by 56
“…for hydrolyzation of advanced glycation end products (AGEs), which are associated with diseases of old age in various Frontiers in Physiology | www.frontiersin.org 8 February 2022 | Volume 13 | Article 825057 model organisms (Oudes et al., 1998; Semba et al., 2010; Chaudhuri et al., 2018).”
BackgroundGranic, A., Hurst, C., Dismore, L. L., Dodds, R. M., Witham, M. D., Robinson, S. M., & Sayer, A. A. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111744 · Cited by 58
“…inconclusive (Ebert et al., 2019; Dalal et al., 2009; Kim et al., 2018; Moriwaki eta l, 2021), these may act as scavengers of circulating AGEs, thus inhibiting the AGE-RAGE binding and the activation of pro-inflammatory pathway (Chaudhuri et al., 2018; Daussin et al., 2021; Riuzzi et al., 2018).”
BackgroundInfluentialHuang, W., Zhang, Z., Colucci, M., Deng, L., Yang, M., Huang, X., Zhou, X. J., Jin, Y., Lazzarini, E., Balbi, C., et al. (2024) · Environment International · doi:10.1016/j.envint.2024.108447 · Cited by 57
Xue, C., Quan, W., Li, Y., He, Z., Qin, F., Wang, Z., Chen, J., & Zeng, M. (2022) · Food Chemistry · doi:10.1016/j.foodchem.2022.132660 · Cited by 51
Polyphenols: A Comprehensive Review of their Nutritional Properties
Ebrahimi, P., & Lante, A. (2021) · The Open Biotechnology Journal · doi:10.2174/1874070702115010164 · Cited by 50
Luo, Y., Zhang, J., Ho, C., & Li, S. (2022) · Food Science and Human Wellness · doi:10.1016/j.fshw.2021.12.012 · Cited by 50
Dong, L., Li, Y., Chen, Q., Liu, Y., Wu, Z., Pan, D., Yan, N., & Liu, L. (2023) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2023.2213768 · Cited by 49
“Besides, the accumulation of AGEs was also a propulsive factor for oxidative stress and inflammation (Chaudhuri et al. 2018).”
The association between dietary and skin advanced glycation end products: the Rotterdam Study
Chen, J., Waqas, K., Tan, R. C., Voortman, T., Ikram, M. A., Nijsten, T. E. C., de Groot, C. P. G. M., Uitterlinden, A. G., & Zillikens, M. C. (2020) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqaa117 · Cited by 48
“Several human, animal, and in vitro studies have suggested the involvement of dietary AGEs (dAGEs) in, for example, metabolic diseases (8, 9), cardiovascular diseases (9, 10), diabetes (11), Alzheimer’s disease (12), food allergy (13), and hampered skeletal muscle growth and muscle contractile function (14).”
BackgroundDiverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain
Kepchia, D., Huang, L., Dargusch, R., Rissman, R. A., Shokhirev, M. N., Fischer, W. H., & Schubert, D. A. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00641-2 · Cited by 48
Subedi, L., Lee, J. H., Gaire, B. P., & Kim, S. Y. (2020) · Antioxidants · doi:10.3390/antiox9090792 · Cited by 47
“Hyperglycemia-mediated autoxidation normally results from the production of major AGE precursors, namely, methylglyoxal (MGO) and glyoxal (GO) [4].”
BackgroundChin, A. F., Han, J., Clement, C. C., Choi, Y., Zhang, H., Browne, M., Jeon, O. H., & Elisseeff, J. H. (2023) · Aging Cell · doi:10.1111/acel.13979 · Cited by 52
“Our proteomic survey included a battery of PTMs de - scribed as advanced glycation and lipoxidation end products (AGEs and ALEs, respectively), whose accumulation are known to robustly track with age and age-associated diseases (Chaudhuri et al., 2018).”
MethodSerum AGE/RAGEs as potential biomarker in idiopathic pulmonary fibrosis
Machahua, C., Montes‐Worboys, A., Planas‐Cerezales, L., Buendia-Flores, R., Molina‐Molina, M., & Vicens‐Zygmunt, V. (2018) · Respiratory Research · doi:10.1186/s12931-018-0924-7 · Cited by 47
Dietary Advanced Glycation End Products: Their Role in the Insulin Resistance of Aging
Portero‐Otín, M., de la Maza, M. P., & Uribarri, J. (2023) · Cells · doi:10.3390/cells12131684 · Cited by 46
“In summary, enteral AGES, orally absorbed AGEs, or AGE precursors may contribute to the pathogenesis of IR by different underlying mechanisms: (1) direct modification of signaling molecules, such as insulin itself, which reduces its biological activity and affinity for the insulin receptor and therefore impairs insuli…”
BackgroundNagayach, A., Bhaskar, R., Ghosh, S., Singh, D. K. K., Han, S. S., & Sinha, J. K. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102450 · Cited by 51
Overview of Metformin and Neurodegeneration: A Comprehensive Review
Kruczkowska, W., Gałęziewska, J., Buczek, P., Płuciennik, E., Kciuk, M., & Śliwińska, A. (2025) · Pharmaceuticals · doi:10.3390/ph18040486 · Cited by 52
Metagenomic analysis characterizes stage-specific gut microbiota in Alzheimer’s disease
Jia, L., Ke, Y., Zhao, S., Liu, J., Luo, X., Cao, J., Liu, Y., Guo, Q., Chen, W., Chen, F., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-02973-7 · Cited by 52
“We observed signi fi cant differences in cognitive behavior between the groups through behavioral tests.”
SARS‐CoV‐2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors
Stilhano, R. S., Costa, A. J., Nishino, M. S., Shams, S., Bartolomeo, C. S., Breithaupt‐Faloppa, A. C., Silva, E. A., Ramirez, A. L., Prado, C. M., & Ureshino, R. P. (2020) · The FASEB Journal · doi:10.1096/fj.202001394rr · Cited by 48
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Carbonyl Stress in Red Blood Cells and Hemoglobin
Kosmachevskaya, O. V., Novikova, N. N., & Topunov, A. F. (2021) · Antioxidants · doi:10.3390/antiox10020253 · Cited by 46
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Lyu, L., Yu, J., Liu, Y., He, S., Zhao, Y., Qi, M., Ping, F., Xu, L., Li, W., Zhang, H., et al. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab703 · Cited by 45
Pivotal role of AGE-RAGE axis in brain aging with current interventions
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Eye on the horizon: The metabolic landscape of the RPE in aging and disease
Hansman, D., Du, J., Casson, R. J., & Peet, D. J. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101306 · Cited by 50
Public Health Risks Associated with Food Process Contaminants – A Review
Zahir, A., Ge, Z., & Khan, I. A. (2024) · Journal of Food Protection · doi:10.1016/j.jfp.2024.100426 · Cited by 44
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“AGEs activate RAGE (the receptors for AGEs) signaling and cause carbonyl stress, leading to activation of NF-kB, inflammatory response, ROS production, and endothelial dysfunction [162,163].”
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“Introduction 17 Glycation of circulating, cellular, and matrix proteins by glucose are thought to be a major factor in 18 pathogenesis of diabetes and related cardiovascular diseases.(1) This process is known as the Maillard 19 reaction and begins with the nucleophilic addition between an amino group of a protein and…”
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Metadata
- Authors
- Chaudhuri, J., Bains, Y., Guha, S., Kahn, A., Hall, D., Bose, N., Gugliucci, A., & Kapahi, P.
- Affiliations
- Buck Institute for Research on Aging (US)
- Touro University California (US)
- Corresponding author
- Chaudhuri, Jyotiska
- Gugliucci, Alejandro
- Kapahi, Pankaj
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 28
- Issue
- 3
- Pages
- 337-352
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6355252
- OpenAlex
- W2892213316
- Cited by
- 669
- References
- 179
- Citations by year
- 2026: 70 · 2025: 118 · 2024: 91 · 2023: 107 · 2022: 83 · 2021: 116 · 2020: 48 · 2019: 34 · 2018: 1
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Funders
- American Federation for Aging Research
- Larry L. Hillblom Foundation
- impact circle award
- NIH (R21 AG053066, RO1 AG045835, RO1 5RO1HL113887)
- Touro University California
- NIH/NIA (T32 AG000266)
- Hillblom Foundation Postdoctoral Fellowship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Agricultural and Biological Sciences › Food Science › Potato Plant Research
- Keywords
- advanced glycation end products, aging, metabolic disorders, AGE formation, age-related diseases, Drosophila melanogaster, Caenorhabditis elegans, invertebrate models, drug screening
- MeSH terms
- Aging, Animals, Drosophila melanogaster, Humans, Metabolic Diseases, Yeasts, Signal Transduction, Glycation End Products, Advanced, Caenorhabditis elegans, Oxidative Stress, Neurodegenerative Diseases, Models, Animal, Mice, Rats
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