Advanced Glycation End Products (AGEs) and Other Adducts in Aging-Related Diseases and Alcohol-Mediated Tissue Injury

Rungratanawanich et al.
Experimental & Molecular Medicine (2021) 53:168–188

https://doi.org/10.1038/s12276-021-00561-7 Experimental & Molecular Medicine
REVIEW ARTICLE Open Access
Advanced glycation end products (AGEs) and

other adducts in aging-related diseases and
alcohol-mediated tissue injury
Wiramon Rungratanawanich1, Ying Qu1, Xin Wang2, Musthafa Mohamed Essa3,4 and Byoung-Joon Song1
Abstract
Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from
nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress,
inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of
AGEs in the development and progression of various aging-related pathological conditions, such as diabetes,
cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer.
Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is
known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain
damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by
which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we
first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on
the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological
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connection of AGE–alcohol–adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential
translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders
according to the mechanistic insights presented.
Introduction are ascribed to their ability to produce reactive oxygen

Advanced glycation end products (AGEs) are potentially (ROS) and nitrogen (RNS) species, as well as oxidative
harmful heterogeneous molecules of irreversible products stress and inflammation, leading to structural and func-
derived from nonenzymatic glycation. Reactions involving tional protein alterations, cellular dysfunction and apop-
nonenzymatic glycation occur between the reactive car- tosis, and ultimately multitissue/organ injuries3. Cross-
bonyl group of a reducing sugar and nucleic acids, lipids, links formed by the interactions of AGEs with their cell
or proteins. AGEs can be formed endogenously or pro- surface receptors for advanced glycation end products
vided by exogenous sources under normal and patholo- (RAGEs) have been found during the development and
gical conditions1,2. The pathological implications of AGEs progression of various aging-related diseases, such as
diabetes, cardiovascular complications, kidney malfunc-
tions, osteoporosis, cancer, neurodegenerative diseases,
Correspondence: Wiramon Rungratanawanich (wiramon. and liver disorders4,5
[email protected]) or Byoung-Joon Song ([email protected])
1 Alcohol (ethanol), one of the most addictive substances
Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane
Biochemistry and Biophysics, National Institute on Alcohol Abuse and consumed by billions of people, has been found to cause
Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA
2
more than 200 diseases and injuries worldwide6,7. In the
Neuroapoptosis Drug Discovery Laboratory, Department of Neurosurgery,
United States alone, more than 250 billion dollars are lost
Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Road,
Boston, MA 02115, USA annually due to alcoholism-related disorders and their
Full list of author information is available at the end of the article
© The Author(s) 2021

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Official journal of the Korean Society for Biochemistry and Molecular Biology
Rungratanawanich et al. Experimental & Molecular Medicine (2021) 53:168–188 169
consequences8. In addition, multiple millions of global hyperglycemia, and oxidative stress2–4. For example,
deaths have been reported from excessive alcohol con- persistently high blood glucose, often observed in people
sumption due to acute and long-term consequences such with type 2 diabetes, increases the reservoir of substrate
as accidents, injuries, and a wide range of diseases7,9. for accelerating AGE formation and activates protein
Chronic misuse of alcohol promotes damage to multiple kinase C and NADPH oxidases, producing ROS13,18.
tissues and organs. It can lead to the development of Additionally, elevated oxidative stress can act as a catalyst
various pathological states, such as alcohol use disorder, to stimulate AGE accumulation, while activation of AGEs
alcoholic liver disease, and alcohol-related brain damage, can increase oxidative stress, creating a synergistic feed-
as well as increase the risk of cancer in the gastrointestinal forward loop to accelerate pathophysiological condi-
tract, respiratory tract, breast, and liver10,11. However, tions2–4.
despite the considerable amount of research in this area,
the underlying molecular mechanisms by which alcohol Exogenous AGEs
exerts its cellular toxicity and organ damage remain to be Exogenous AGEs include dietary AGEs (e.g., foods and
further characterized. beverages such as soft drinks containing high fructose
In this review, we first briefly describe the properties of corn sirup and/or sugar) and cigarette smoke. Addition-
AGEs: their formation, accumulation, and RAGE inter- ally, dietary AGEs can be produced during food pre-
actions. We then focus on the causative functions of paration. This formation of dietary AGEs depends on
AGEs that impact various aging-related diseases. In various factors, such as (1) temperature. e.g., the food
addition, we highlight the biological connections of browning process; (2) water content. e.g., dry-heat cook-
AGE–alcohol–adduct formations in alcohol-mediated ing; (3) pH status, e.g., food processing at high pH; and (4)
multiorgan damage. Finally, we briefly describe the cooking time and method, e.g., long-term cooking or
potential translational research opportunities for treating storage and frying or broiling. These variations activate
various AGE- and/or alcohol-related adduct-associated the nonenzymatic Maillard reaction, leading to the for-
disorders based on the mechanistic insights presented. mation of glycation products and AGEs5,19. For example,
high heat and prolonged cooking time enhance the rate
AGE formation and amount of AGE production in diets20. Foods with
Endogenous AGEs high pH values (up to 10) have elevated AGEs due to free
Endogenous AGEs represent adducts that are produced amino groups under alkaline conditions21. Putative
and slowly accumulated within the body during the nor- examples of dietary AGEs are modern Western diets such
mal aging process and under the oxidative stress, as bakery goods, breakfast cereals, cheese, and meat
inflammatory, and hyperglycemic (high blood sugar) cooked by a dry-heat method22. In addition to dietary
conditions often observed in diabetes and other metabolic AGEs, cigarette smoke is found to contain reactive gly-
syndromes1,4,12,13. AGEs are formed by a nonenzymatic cation products, which can increase AGE accumulation in
glycation reaction, also known as the Maillard reaction, the tissues and circulating blood of smokers23.
between the carbonyl group of a reducing sugar and a free The amounts of AGEs in exogenous sources are usually
amino group (N-terminus, lysine, or arginine residue) of much higher than those of endogenously produced
proteins or (adenine or guanine) of nucleic acids. This AGEs2–4,24. Thus, it is likely that the intake of foods and/
reaction is followed by a highly reversible nucleophilic or beverages with high levels of exogenous AGEs create
addition reaction to generate a reversible Schiff base more health problems than endogenously produced
adduct, which is rearranged to a more stable and cova- AGEs, although both exogenous and endogenous AGEs
lently bound Amadori product (e.g., hemoglobin A1c). are similar in their biological functions and potentially act
Then, the Amadori product undergoes rearrangement, synergistically to stimulate oxidative stress, inflammation,
dehydration, and oxidation reactions to form irreversible and cellular damage, contributing to detrimental patho-
products, AGEs, in the body. In addition to nonenzymatic physiology2–4,24.
glycation, AGEs can be formed through the polyol path-
way and lipid peroxidation in the presence and absence of AGE accumulation
hyperglycemia, depending on the substrate type, reactant Intracellular AGEs
concentration, exposure time, and host cellular context14– AGEs gradually accumulate during the aging process
17
. through normal metabolic and glycation activities. The
Various factors are involved in promoting AGE forma- aggregation of AGEs from endogenous and/or exogenous
tion. These factors include excessive and/or prolonged sources can negatively affect the functions of many
alcohol consumption, cigarette smoking, the intake cells in the entire body, resulting in diverse cellular
of high fat/caloric diets and/or extensively processed responses and ultimately cellular damage and degenera-
food, renal status, homeostatic imbalance, inflammation, tion. Intracellular AGE accumulation can stimulate
aberrant protein glycation, abnormal protein folding, and binds diverse ligands, such as members of the S100 protein
the aggregation of irregular or oligomeric proteins, as well family, amyloid-β peptides (Aβ), prions, and high-mobility
as elevated oxidative stress and inflammation and upre- group protein B1 (HMGB1), which alter cellular functions
gulated apoptotic signaling pathways. These changes can and contribute to various pathophysiologies42–44.
contribute to protein inactivation, endoplasmic reticulum In addition to RAGEs, AGEs can interact with other cell
(ER) stress, mitochondrial dysfunction, cell apoptosis, and surface receptors that possess the opposite function of
organ damage25,26. For instance, in neuronal tissues, the RAGEs. These AGE cell surface receptors include AGE-
accumulation of AGEs induces glycation of α-synuclein R1, AGE-R2, AGE-R3, and scavenger receptors such as
and tau proteins, leading to protein dysfunction accom- macrophage scavenger receptors, scavenger receptor class
panied by the aggregation of harmful protein oligomers B type I and II (SR-BI, SR-BII), and cluster of differ-
capable of initiating and developing neurodegenerative entiation 36 (CD36). The interaction of AGEs with these
diseases27,28. receptors can enhance their catabolism and clearance by
modulating endocytosis and degradation45,46, suggesting a
Extracellular AGEs potentially adaptive defensive mechanism in the body
AGEs are long-lived irreversibly formed molecules to reduce the detrimental effects of increased glycation
found in the circulatory system and tissues, particularly products.
those with long-lasting proteins such as lens crystallins,
cartilage, glomerular basement membrane, and extra- AGEs and aging-related diseases (see summary in
cellular matrix29,30. Cross-linking AGEs with extracellular Table 1)
matrix proteins, including laminin, elastin, and collagen, AGEs and diabetes
can alter the elasticity and function of tissues. In fact, Chronic hyperglycemia, frequently observed in experi-
higher levels of AGE cross-links are commonly detected mental models and human diabetes, exhibits elevated
in experimental animal models and autopsied tissue AGE formation, serum AGE levels, RAGE expression, and
samples from people who are aging or have cancer, obe- AGE-RAGE interactions. Consequently, these changes
sity, or diabetic complications31–33. In addition to long- lead to increased oxidative stress, insulin resistance,
lived proteins, AGEs can bind to proteins with short half- inflammation, pancreatic β-cell dysfunction with apop-
lives such as serum albumin, thereby activating RAGEs tosis, and eventually diabetic complications, including
and inducing inflammatory responses followed by protein retinopathy, neuropathy, cardiomyopathy, microvascular
dysfunction and cell damage34. complications, and nephropathy47–50.
Dietary AGEs have been found to disrupt and down-
RAGEs and other AGE receptors regulate sirtuin1 (SIRT1) expression, resulting in the
A RAGE is a multiligand cell surface receptor in the acetylation and inactivation of peroxisome proliferator-
immunoglobulin superfamily35. Generally, RAGEs are activated receptor γ coactivator-1α (PGC1α), a master
expressed widely in various cells, such as endothelial regulator of mitochondrial metabolism. AGEs also sti-
cells, macrophages/monocytes, neutrophils, lymphocytes, mulate mitochondrial ROS production and c-Jun N-
microglia, astrocytes, and neurons, and organs, such as terminal protein kinase (JNK) and NADPH oxidase
the brain, heart, lung, kidney, and liver36,37. However, activity to induce mitochondrial dysfunction and oxida-
under pathological conditions, RAGEs can be upregulated tive stress51–53. Furthermore, increased oxidative stress
and participate in various aging-related pathophysiologies, and JNK/MAPK expression can contribute to pancreatic
such as adult-onset type 2 diabetes mellitus (DM), car- β-cell dysfunction with apoptosis, glucose-induced insulin
diovascular disorders, myocardial infarction, chronic secretion impairment, and subsequent insulin resistance,
kidney failure, pancreatitis, cancer, Alzheimer’s disease which is a key hallmark of type 2 DM54. Restriction of
(AD), Parkinson’s disease (PD), hepatic fibrosis, and dietary AGEs can reduce and/or reverse these effects by
alcohol-mediated tissue injury37,38. enhancing insulin sensitivity and upregulating AGE-R1
The interaction of AGE-RAGE triggers intracellular and and SIRT1 expression while suppressing NF-κB, tumor
extracellular signaling pathways through the activation of necrosis factor-alpha (TNF-α), leptin, and serum AGEs in
extracellular signal-regulated kinases 1 and 2 (ERK1/2), type 2 DM55.
mitogen-activated protein kinases (MAPK), phosphoino- AGEs play important roles in diabetic microvascular
sitide 3-kinase (PI3K), protein kinase B (AKT), NADPH complications by cross-linking with extracellular matrix
oxidase, and nuclear factor-κB (NF-κB). Activation of proteins, thereby altering vascular elasticity, structure,
these proteins usually increases oxidative stress and and function56. In addition, the AGE-RAGE interaction
inflammation that, in turn, promotes RAGE expression in further instigates pericyte apoptosis, vascular inflamma-
a positive feed-forward loop, contributing to chronic dis- tion and permeability, and blood-tissue barrier break-
ease development39–41. In addition to an AGE, a RAGE down56. In contrast, the inhibition of RAGE by RAGE
Table 1 Summary of the AGEs and AGE-RAGE interaction in aging-related diseases.
Diseases Mechanisms Consequences
Diabetes ↓ SIRT1, active PGC1α ↑ oxidative stress, inflammation, mitochondrial dysfunction

↑ ROS, MAPK (JNK), NADPH oxidase ↑ pancreatic β-cell dysfunction and apoptosis, insulin resistance,
glucose -induced insulin secretion impairment= diabetic
complications51–55
• Diabetic microvascular ↑ extracellular matrix glycation ↓ vascular elasticity
complications ↑ vascular inflammation and permeability and blood-tissue barrier
breakdown
↑ pericyte apoptosis56,57
Cardiovascular diseases AGEs ≡ mononuclear, endothelial, and ↑ oxidative stress and inflammation
smooth muscle cells ↑ oxidation of LDLs
RAGE ≡ HMGB1 and S100 ↑ cardiomyocyte dysfunction, apoptosis, and tissue damage
↑ MAPK = severity of coronary atherosclerosis and coronary artery disease55–64
Kidney diseases RAGE ≡ HMGB1 ↑ oxidative stress and inflammation
↑ extracellular matrix glycation ↑ mesangial cell proliferation inhibition, hypertrophy, and apoptosis
↑ proximal tubular senesces ↑ podocyte damage, glomerular hypertrophy, and proteinuria
↑ NF-κB, MAPK, PKC, ERK1/2, MCP-1, TNF-α, IL- ↑ fibrosis
6, CTGF, TGF-β = renal failure and end-stage renal disease65–75
Obesity RAGE ≡ HMGB1 and S100 ↑ oxidative stress and inflammation
↑ HMGB1 and S100 ↑ body weight and energy intake
↑ JNK, IKK, NF-κB, TNF-α ↑ hypothalamic insulin and leptin resistance
↑ disruption of the hypothalamic function = hypothalamic dysfunction76–78
Osteoporosis RAGE ≡ HMGB1 and S100 ↓ mass and structural composition of bone
↑ ROS, NF-κB, MAPK, ERK1/2, TNF-α, IL-1β, ↓ osteoblast growth, differentiation, and apoptosis
caspase-3, Wnt, PI3K, VEGF, MMP-13 ↑ osteoclast generation79–85
Cancer RAGE ≡ HMGB1 and S100 ↑ oxidative stress and inflammation
↑ extracellular matrix glycation ↑ epithelial-mesenchymal cell transition and migration
↑ NF-κB, NADPH oxidase, VEGF, local hypoxia ↑ cancer microenvironment as well as tumoral angiogenesis and
↑ tumor-associated macrophages proliferation
↑ cancer initiation, progression, migration, invasion, and
metastasis31,32,86–94
Gut microbiome-associated ↑ particular microbiome growth ↑ loss of microbial diversity
diseases ↑ modulation of the composition and ↑ intestinal epithelial cell damage, gut barrier dysfunction, intestinal
amounts of intestinal microflora permeability, and bacterial translocation
↑ proinflammatory cytokines, toxic = systemic endotoxemia, inflammation and multiorgan injury95–101
metabolites, and bacterial products
Neurodegenerative diseases ↑ reactive gliosis ↑ oxidative stress and cellular stress
↑ NF-κB ↑ activated gliosis
= neuronal death and degeneration4,102–108
• Alzheimer’s disease RAGE ≡ Aβ and HMGB1, AGE- albumin ↑ oxidative stress
↓ SIRT1 ↑ Aβ aggregation
↑ Aβ, tau, and amyloid precursor ↑ activated gliosis
protein (APP) = neuronal apoptosis and neurodegeneration109–113
↑ phosphorylated tau
↑ cross-linked AGE-Aβ and their aggregates
↑ AGE-albumin adducts
↑ NF-κB, JNK, ERK1/2, caspase-3, PI3K, Bax,
iNOS, p38, JAK/STAT
Table 1 continued
Diseases Mechanisms Consequences
• Parkinson’s disease AGEs ≡ α-synuclein ↑ aggregation of α-synuclein toxic oligomers

RAGE ≡ S100 ↑ Lewy body formation
↑ NF-κB and TNF-α ↑ activated gliosis
↑ death of the dopaminergic neurons
= neurodegeneration114–119
Liver diseases ↓ GSH, SIRT1, and TIMP3 ↑ oxidative stress and inflammation
↑ ROS, NF-κB, NADPH oxidase, MAPK ↑ inflammatory cell death of parenchymal cells and tissue remodeling
↑ phosphorylation of IRS-1, JNK, c-JUN, IKK, process fibrosis/cirrhosis
UCP-2, ERK1/2 ↑ cell apoptosis, hepatocyte dysfunction, and steatosis
= induce initiation and progression of NAFLD
= Inflammatory liver injury [nonalcoholic steatohepatitis (NASH)],
hepatic fibrosis and cirrhosis55–57,120–131
↑ increase/activate, ↓ decrease/inactivate, = lead to/result in, ≡ interact/cross-link.
antiserum can prevent the toxicity induced by AGEs in and enhance collagen and laminin production in the
diabetic microvascular complications57. extracellular matrix together with proximal tubular
senescence, oxidative stress, and inflammatory pro-
AGEs and cardiovascular diseases cesses66. On the other hand, acute/chronic kidney disease
AGEs can stimulate cardiovascular complications in the and end-stage renal failure can reduce AGE clearance.
presence or absence of hyperglycemia58. The accumula- Consequently, glomerular and tubular cells are exposed to
tion and exposure to AGEs exacerbate oxidative stress potentially harmful AGEs for extended periods of time
and inflammation and initiate the oxidation of low- owing to the lower rates of glomerular filtration. These
density lipoproteins (LDLs), which are harmful to cardi- changes lead to accelerated progression and/or exacer-
ovascular function. In blood vessels, accumulated AGEs bation of kidney malfunction and nephropathy along with
also interact with mononuclear, endothelial, and smooth greater amounts of AGEs in the circulation68,69.
muscle cells, resulting in cellular dysfunction, tissue In addition, AGEs can be produced in renal mesangial
damage, and atherosclerosis development55–57,59. In acute cells and induce the expression of monocyte chemoat-
myocardial infarction, increased expression of RAGE and tractant protein-1 (MCP-1). AGEs also activate NF-κB,
its interaction with AGEs, HMGB1, and S100 induce MAPK, and protein kinase C (PKC) to promote mesangial
cardiomyocyte apoptosis by activating the MAPK path- proliferative inhibition, hypertrophy, and apoptosis70,71.
way60,61. Additionally, higher levels of circulating AGEs Similarly, the AGE-RAGE interaction in the kidney can
are positively correlated with the incidence of cardiovas- increase oxidative stress, inflammation, and fibrosis by
cular disorders and severity of coronary atherosclerosis stimulating connective tissue growth factor (CTGF),
and coronary artery disease independent of diabetic sta- transforming growth factor-β (TGF-β), MAPK, NF-κB
tus62–64, suggesting a causal role of AGEs in cardiovas- and PKC pathways to develop podocyte damage, glo-
cular diseases. merular hypertrophy, proteinuria, and ultimately end-
stage renal failure66,72,73. The RAGE ligand HMGB1 also
AGEs and kidney diseases plays a causal role in renal inflammation by enhancing
The kidney is a highly specialized organ that reabsorbs ERK1/2, TNF-α, interleukin (IL)-6, and MCP-1, leading to
many essential molecules, including water and salt, while nephropathy and chronic kidney disease74,75.
removing potentially toxic compounds to protect the
body. The accumulation of AGEs in the kidney can ele- AGEs and obesity
vate oxidative stress and inflammation, contributing to Dietary and endogenous AGEs and the AGE-RAGE
renal failure65. In humans, serum contains AGE peptides interaction can promote oxidative stress and inflamma-
and free AGE adducts. AGE peptides are generally filtered tion, contributing to the accelerated progression of
by renal glomeruli and further reabsorbed by proximal obesity-related complications such as elevated serum
convoluted tubules and eliminated from the body in the AGEs, insulin resistance, AGE accumulation, and
form of free AGE adducts in the urine66,67. Increased elevated proinflammatory cytokines in adipose tis-
circulating AGEs can accumulate in the renal glomeruli sues67,76, although consumption of dietary AGEs does not
necessarily increase obesity based on its marginal asso- oxidase activity, local hypoxia, VEGF expression, and NF-
ciation with increased body weight gain67,76. Adipose κB activation to produce oxidative stress and inflamma-
tissues also produce molecular RAGE ligands (such as tion, supporting the cancer microenvironment and pro-
HMGB-1) and RAGE-inducible molecules (e.g., MCP-1 moting tumoral angiogenesis and proliferation32,87.
and IL-6). Upon RAGE interaction, these bound mole- The overexpression of RAGE and its interaction with a
cules activate their own production in adipose tissues, ligand are associated with various types of cancer. RAGE
suggesting a causal role of RAGE signaling in the is highly upregulated in metastatic and aggressive breast,
inflammatory pathway49,67. In addition to dietary AGEs, ovarian, and pancreatic cancer, acting as a promotor of
endogenous AGEs can be trapped and accumulated in the progression of premalignant precursors to invasive
adipose tissues, and AGE accumulation can be prevented carcinoma88,89. In hepatocellular carcinoma (HCC),
by RAGE inhibition77. RAGE overexpression and interaction with HMGB1
AGEs are reported to modify energy balance by dis- induce tumor-associated macrophage activation and NF-
rupting hypothalamic function. Aggregated AGEs can κB expression to promote tumoral proliferation, invasion,
activate the JNK, Iκ-B kinase (IKK), NF-κB, and TNF-α and metastasis90,91. After binding with S100, RAGE also
pathways to trigger hypothalamic insulin and leptin contributes to the epithelial-mesenchymal cell transition
resistance, resulting in hypothalamic dysfunction, imbal- and cell migration, which is associated with tumor inva-
anced energy control, and subsequently elevated food sion and metastasis in cervical cancer and osteosarcomas,
consumption and body weight with obesity and metabolic suggesting a contributing role for RAGE in tumor
syndromes78. malignancy92. Furthermore, in cigarette smokers, elevated
levels of RAGE are positively correlated with the
AGEs and osteoporosis development of oral squamous cell, lung, and breast
Body bone mass is determined by the delicate balance carcinoma93,94.
between osteoclasts and osteoblasts involved in regulating
bone formation, differentiation, and apoptosis in response AGEs and gut microbiome-associated diseases
to various stimuli79. In bone, accumulated AGEs can The gut microbiota plays a critical role in regulating
increase osteoclast generation while decreasing osteoblast body function by producing diverse metabolites and
growth and differentiation. Initially, AGEs enhance the influencing the gut-liver-brain axis and other pathways,
levels of osterix, a transcription factor that promotes such as immune system pathways. The composition and
osteoblast differentiation and bone formation. However, function of gut flora can be affected by endogenous and
chronic AGE accumulation induces osteoblast apoptosis exogenous factors, particularly food consumption with
through activation of proapoptotic caspase-3, MAPK, and different levels of dietary AGEs95,96.
intracellular ROS generation80–82, indicating an intricate In the body, less than 30% of dietary AGEs are absorbed
role for AGEs in bone physiology and remodeling. in the intestine after ingestion, and less than 15% are
The interaction of AGE-RAGE augments the produc- excreted in urine and feces, leading to a hypothesis that
tion of proinflammatory cytokines and suppresses osteo- the remaining unabsorbed AGEs are degraded by gut
blast differentiation via the Wnt, PI3K, and ERK1/ microorganisms97. The intestinal microbiota produces
2 signaling pathways83. Moreover, RAGE binding to its deglycating enzymes to digest AGEs, which are utilized
ligands (such as HMGB1 and S100) also triggers the for energy production. As a result of this mechanism,
production or activation of TNF-α, IL-1β, caspase-3, unabsorbed AGEs may play a role in modulating the
MAPK, NF-κB, vascular endothelial growth factor composition and number of intestinal microflora98.
(VEGF), and matrix metalloproteinase 13 (MMP-13), AGEs can modify gut microbiota composition by trig-
negatively affecting the mass and structural composition gering the growth of particular microbiomes, resulting in
of bone84. Notably, several conditions, including aging, the loss of microbial diversity and an increased possibility
diabetes, renal failure, tobacco smoking, and excessive of intestinal leakiness98,99. Elevated accumulation of AGEs
alcohol consumption that induce AGE accumulation and can enhance gut barrier dysfunction, intestinal perme-
AGE-RAGE interaction, are risk factors for increased ability, and bacterial translocation by stimulating the
bone fracture and osteoporosis46,85. production and release of proinflammatory cytokines,
potentially toxic metabolites and bacterial products, as
AGEs and cancer well as causing intestinal epithelial cell damage, con-
Elevated amounts of AGEs are observed in tumor tis- tributing to systemic endotoxemia, inflammation, and
sues in cancer. Increased AGEs and AGE-RAGE inter- multiorgan injury98. AGE-modulated gut microflora is
actions provide a link to cancer initiation, progression, also associated with the pathogenesis of type 2 DM,
migration, and metastasis31,86. The binding of AGEs to obesity, neurodegenerative diseases such as AD, and end-
RAGE triggers extracellular matrix glycation, NADPH stage renal failure, where restriction of dietary AGEs can
improve the gut microbial composition and subsequently elevated oxidative stress and Aβ aggregation111. Aβ is also
attenuate disease conditions100,101. produced by the AGE-albumin-RAGE interaction, which
in turn supports AGE-albumin adduct formation in a
AGEs and neurodegenerative diseases positive feed-forward cycle. The binding of the AGE-
The brain is a highly specialized organ with tightly albumin adduct to RAGE provides a link to neuronal
regulated motor, behavior, neurocognitive, and executive apoptosis by activating the proapoptotic JNK and Bcl-2-
functions. However, it generally lacks defensive or pro- associated X protein (Bax) pathways111. In addition to
tective enzymes/proteins compared to peripheral tissues AGEs and AGE adducts, HMGB1 and Aβ can bind
such as the liver and kidney102. Thus, under normal RAGEs to activate the NF-κB, ERK1/2, p38, JNK, PI3K,
conditions, the brain is protected by a special functional Janus kinase/signal transducers and activators of tran-
system, the blood-brain barrier (BBB). In the brain, AGEs scription (JAK/STAT) pathways, leading to neuronal cell
can be produced as a result of elevated oxidative stress death and neurodegeneration112. Furthermore, AGEs
during aging or chronic exposure to toxic agents such as cross-linked with Aβ can also decrease the ability of
alcohol (ethanol), n-6 fatty acid-containing high-fat microglia to clear plaques113.
Western diets, and sugary soft drinks. Oxidative stress can
also be generated due to AGE formation in the brain. This AGEs and Parkinson’s disease
feed-forward process creates a vicious cycle that exacer- Dietary AGEs promote AGE formation in the substantia
bates oxidative damage with the subsequent initiation and nigra114. In PD brains, AGEs can accumulate early in
progression of neurodegenerative diseases4,103. However, newly formed Lewy bodies, suggesting that AGEs could
the amounts of plasma AGEs, which can stimulate the play a contributing role in Lewy body formation in
aggregation of specifically modified proteins, are different developing PD115. AGEs cross-linked with α-synuclein are
in Alzheimer’s and Parkinson’s disease patients in a sex- also present in PD brains, resulting in the aggregation of
dependent manner, thus requiring a careful interpretation α-synuclein toxic oligomers115,116. Moreover, RAGE can
of test results104. Similar to AGEs, RAGEs are significantly interact with S100 in PD brains, activating the NF-κB and
or markedly expressed in many areas of the brain, such as TNF-α signaling pathways to promote dopaminergic
the cortex, hippocampus, cerebellum, and substantia neuronal death and subsequent neurodegeneration in
nigra105–107 during the development of neurodegenerative PD117,118. AGE-albumin, the most abundant AGE product
diseases. Activated microglial cells produce and secrete in the human PD brain, is synthesized by activated
AGE-albumin to induce RAGE expression in neurons and microglial cells. Aggregated AGE-albumin upregulates
promote neuronal cell death, thereby contributing to RAGE, leading to the apoptosis of primary dopamine
neurodegenerative disorders4,108. Additionally, the accu- neurons in the brain119.
mulation of AGEs and the AGE-RAGE interaction greatly
induce reactive gliosis and the NF-κB proinflammatory AGEs and liver diseases
pathway, leading to cellular stress, activated gliosis, and The liver plays a vital role in the metabolism and
eventually neuronal degeneration105. synthesis of various essential molecules and proteins
needed for many other organs. It is involved in the cata-
AGEs and Alzheimer’s disease bolism and elimination of circulating AGEs using liver
Various forms of AGEs are markedly aggregated in sinusoidal endothelial cells and Kupffer cells. This func-
neuronal plaques in the brain as well as in the serum and tion of the liver declines during the aging process and in
cerebrospinal fluid (CSF) in experimental models and various liver diseases, resulting in the accumulation of
autopsied brains from AD patients compared with the AGEs or their aggregates120,121.
corresponding controls. Accumulated AGEs can accel- Intracellular AGE accumulation is observed in animal
erate the formation of Aβ, tau, and amyloid precursor models of hepatic steatosis and other advanced liver dis-
protein (APP) and induce the hyperphosphorylation of eases, such as hepatic inflammation (steatohepatitis) and
tau and the cross-linking of AGE-Aβ, leading to an fibrosis/cirrhosis. Accumulated AGEs in hepatocytes can
increase in these aggregates109. AGEs also suppress SIRT1 stimulate apoptosis and inflammation, leading to cellular
expression and stimulate inducible nitric oxide synthase dysfunction, steatosis, and ultimately nonalcoholic fatty
(iNOS) and caspase-3 to enhance neuronal apoptosis and/ liver disease (NAFLD)121–123.
or degeneration with elevated gliosis110. Endogenous and exogenous AGEs provoke the initia-
One of the most abundant AGE-protein adducts in the tion and progression of NAFLD. However, consumption
brain is the AGE-albumin adduct, which was confirmed of dietary AGEs from sources such as fructose- or
by mass spectral analysis, and causes RAGE over- sucrose-enriched diets and/or soft drinks can worsen liver
expression in primary neurons in human AD brains. The fibrosis faster than consumption of endogenous AGEs.
formation of the AGE-albumin adduct is intensified by The aggregation of AGEs decreases the levels of the most
important cellular antioxidant peptides, glutathione activation of CYP2E1, in turn, contribute to alcohol- and
(GSH), SIRT1, and tissue inhibitor of metalloproteinase 3 nonalcohol-induced pathophysiology136–144. In the sec-
(TIMP3), accompanied by increased oxidative stress and ond step, acetaldehyde is converted to acetate due to the
inflammation, promoting inflammatory liver injury and low km (for acetaldehyde) mitochondrial aldehyde dehy-
fibrosis in experimental animal models and NAFLD drogenase 2 isozyme (ALDH2) in humans145. Notably,
patients55–57,124–126. CYP2E1 also takes part in this step with NADPH acting as
Accumulated AGEs and AGE-RAGE interactions in a cofactor to convert acetaldehyde to acetate146. Finally,
these cells augment the generation of ROS and the acti- the acetate that is produced is further degraded to CO2
vation of MAPK and NF-κB pathways, leading to and H2O, ending the final step of ethanol oxidation in the
inflammatory cell death in the parenchyma and tissue liver132–134. Furthermore, the remaining unmetabolized
remodeling processes during fibrosis127,128. ethanol, acetaldehyde, and acetate can be distributed to
Increased amounts of RAGE are also observed in the many other organs, including the heart, lung, kidney,
liver of hepatocellular carcinoma (HCC), and its level is pancreas, and brain, causing damage in various peripheral
significantly greater than it is liver affected by hepatitis tissues and neurobehavioral effects caused by damage to
and healthy liver specimens. The amounts of serum AGEs the brain.
are also higher in HCC than in NASH and healthy liver
specimens. In HCC, the AGE-RAGE interaction is asso- Brain alcohol metabolism
ciated with angiogenesis and tumor proliferation and Similar to the liver, ethanol oxidizing enzymes are also
invasion, which are ameliorated by RAGE inhibition. functional in the brain and include ADH, catalase,
These results suggest an important role for AGEs and CYP2E1, and ALDH2, which make different contribu-
RAGE in promoting NAFLD, NASH, fibrosis/cirrhosis, tions. Cerebral ADH plays very little or virtually no role in
and HCC pathogenesis129–131. ethanol metabolism in the brain compared to its action by
its hepatic isoform. However, cerebral catalase acts as the
AGEs and alcohol-mediated tissue injury main oxidizing enzyme, accounting for more than 60% of
Alcohol metabolism (see summary in Fig. 1) ethanol oxidation in the brain under normal condi-
Hepatic alcohol metabolism tions147. However, catalase may have a limited role in
The major type of alcohol that is consumed is ethanol ethanol metabolism in certain brain regions, except for
(CH3CH2OH). Upon consumption, ethanol is absorbed aminergic neurons, where it is present in high con-
via simple diffusion in the small intestine into the blood centrations134,148–150. In contrast, CYP2E1 is widely
and rapidly circulates throughout the body6. Ethanol expressed throughout the brain, such as in the cerebral
metabolism primarily occurs in the liver in three major cortex, hippocampus, and cerebellum. Similar to that in
steps: (1) ethanol oxidation to acetaldehyde, (2) acet- the liver, brain CYP2E1 is also inducible by ethanol and
aldehyde metabolism to acetate, and (3) acetate catabo- may therefore play a key role in cerebral ethanol meta-
lism to H2O and CO2132–134. bolism, especially after chronic and/or binge alcohol
In step I of the hepatic oxidative metabolism of alcohol intake151–155. The role of CYP2E1 in brain ethanol
(ethanol), three distinct enzymes are involved: alcohol metabolism and its association with alcohol-mediated
dehydrogenase (ADH), catalase, and cytochrome P450- oxidative neuronal injury155–160 and aging-related AD and
2E1 (CYP2E1). Cytosolic ADH is a major enzyme that PD161 have also been suggested. Finally, mitochondrial
catalyzes the oxidative metabolism of ethanol to acet- ALDH2 is the final enzyme for converting acetaldehyde to
aldehyde by using the cofactor nicotinamide adenine acetate148, although acetaldehyde is locally produced in
dinucleotide (NAD+) converted to NADH132–134. Cata- the brain due to its very limited ability to cross the BBB162.
lase present in peroxisomes may participate in ethanol In contrast, ALDH1B and other isoforms may be involved
oxidation in the presence of H2O2132–134, although this in acetaldehyde metabolism in rodents145,147,163.
enzyme appears to play no major role in hepatic ethanol
metabolism under physiological conditions due to the AGE–alcohol–adduct formations (Fig. 1)
limited supply of H2O2135. After chronic and/or large Free amino acid residues of proteins, lipids, nucleic
amounts of ethanol intake, CYP2E1, the major compo- acids, and nucleophilic molecules are major targets of
nent of the microsomal ethanol oxidizing system (MEOS) adduct formation or covalent binding with reactive
with a higher km (~10 mM for ethanol) than that of ADH molecules such as acetaldehyde, acrolein, crotonaldehyde,
(km <1 mM for ethanol), is also involved in ethanol formaldehyde, malondialdehyde, 4-hydroxynonenal,
metabolism through an NADPH-dependent pathway. In 8-hydroxydeoxyguanosine, N2-((furan-2-yl)methyl)-2′-
contrast to those of ADH and catalase, CYP2E1 expres- deoxyguanosine, and N2-ethyl-2′-deoxyguanosine164–166.
sion and activity are usually induced by ethanol and other After alcohol consumption, CYP2E1 in step I of oxidative
substances, such as dietary fats. The induction and ethanol metabolism can generate a series of oxygen free
Polyol pathway
Glucose Sorbitol Fructose
Reactive dicarbonyls
Lipid peroxidation
AGEs
Maillard reaction
Reducing sugar
+ Schiff base Amadori product
Amino group
AA-AGE
CYP2E1 MDA, 4-HNE, MAA, HER

NADPH NADP+
Alcohol/ ALDH CO2

ADH Acetate
Acetaldehyde +
Ethanol
NAD+ NADH
NAD+ NADH H2O
Catalase
H2O2 H2O
Fig. 1 Overview of the biological connections in AGE–alcohol–adduct formations. Under conditions that increase lipid peroxidation, polyol
pathway, and Maillard reaction, such as exposure to alcohol and/or high n-6 fat diets or high fructose drinks, different AGEs are produced. Ethanol
and its reactive metabolites generated by CYP2E1 are also likely involved in the AGE synthesis pathways to produce the final acetaldehyde and AGE
(AA-AGE) adducts. The formation of AA-AGE adducts can be observed after chronic alcohol exposure. These AA-AGE adducts exhibit similar
properties (e.g., brown color and polymerization) as the AGE adducts cross-link with sugar molecules, and they are different from MAA adducts
formed by AA and MDA interactions. However, treatment with an antioxidant can halt AA-AGE adduct formation, supporting the idea that AA-AGE
adducts can be generated from a Schiff base product similar to AA adducts and AGEs.
radicals (e.g., ROS) to trigger lipid peroxidation, resulting Increased levels of MAA adducts from alcohol exposure
in the formation of various ethanol metabolites and stimulate protein dysfunction and immune-induced tissue
adducts, including (1) acetaldehyde (AA) from ethanol injury through interactions with Toll-like receptor-3
oxidation, (2) malondialdehyde (MDA) and (3) 4- (TLR-3), TLR-6, calpain, collagen alpha-1 (XII) chain,
hydroxynonenal (4-HNE) from lipid peroxidation, (4) procollagen type XIV alpha-1, protocadherin beta, or
malondialdehyde–acetaldehyde adduct (MAA) from the complement component proteins167,180.
acetaldehyde-MDA-protein hybrid adduct, and (5) Acetaldehyde adducts (AA adducts) are formed by the
hydroxyethyl radicals (HER) from the presence of iron interaction of acetaldehyde, a direct metabolite of ethanol
during ethanol metabolism167–171, although some of these oxidation and a human carcinogen, with certain amino
adducts may not be readily detected due to their low acids, including lysine, cysteine, and aromatic amino
levels under physiological conditions. acids. However, these amino acids in different proteins
MDA and 4-HNE are reactive lipid peroxides with short may exert an unequal preference for AA adduct forma-
half-lives that can form covalent adducts with various tion. The proteins commonly bound to acetaldehyde to
proteins and nucleic acids in the body. For instance, produce AA adducts include membrane proteins of the
ethanol intake can induce 4-HNE to interact with cyto- red blood cells (erythrocytes), hemoglobin (oxygen
chrome C oxidase (complex IV) and ALDH2 in the transport), tubulin (cellular structure), lipoproteins (lipid
mitochondria, GRP78 and disulfide isomerase in the ER, transport), albumin (blood), and collagen (connective
and ERK1/2, phosphatase and tensin homolog (PTEN), tissue)167,169,180. In addition, some of these AA adducts
AMP-activated protein kinase (AMPK), and gamma- are produced in a CYP2E1-dependent manner137,181.
glutamylcysteine synthetase (GCS) in the cytosol. These The formation of adduct proteins can prolong protein
adduct formations inactivate their target proteins and half-lives and accumulate as aggregated proteins. Since
result in the accumulation of lipid aldehydes, ER stress, mammalian ubiquitin-dependent proteasomal degrada-
mitochondrial dysfunction, cell signaling alteration, and tion is usually catalyzed after the conjugation of ubiquitin
potentially multitissue injury172–177. with lysine residues, it is expected that AA adduct for-
Interactions between acetaldehyde or MDA and cellular mation and ubiquitin conjugation may compete for
proteins lead to the formation of MAA adducts, which are common lysine residues. Therefore, when lysine residues
highly stable and resistant to rapid degradation178,179. are already occupied by reactive acetaldehyde, lipid
Table 2 Summary of the biological connections of AGE–alcohol–adducts with alcohol-mediated tissue injury.
Cells/organs AGE–alcohol–adducts Consequences
Brain AGE-albumin adducts ↑ RAGE overexpression

↑ MAPK (JNK and p38K), Bax, and microglial activation
↑ neuronal inflammation, apoptosis, and damage108,111,119,202
Ethanol ↑ RAGE expression
↑ ROS, Nrf2, GFAP, Iba1, lipid peroxidation, HMGB1,
TLR-4, neuroimmune markers,
↑ CYP2E1, oxidative stress, and inflammation
↑ neuroinflammation, neuronal apoptosis, and memory Impairment203,204
AA-protein adducts: ↓ microtubule formation
AA-tubulin adducts ↑ dysfunction of cytoskeletal components of nerve cells
AA-DA adducts (salsolinol) ↑ neurotoxin involved in the pathogenesis of AUD and PD
↑ neuronal damage and degeneration189–198
AA-DNA adducts ↓ DNA integrity and neuronal viability
↓ represses DNA repair enzymes/system
↑ genetic instability and DNA mutations
↑ correlated with AUD53,192,197,198
AA-AGE adducts ↑ ROS and oxidative stress
↑ neurotoxicity, neuronal apoptosis, and degeneration in a dose-dependent manner199
Liver AGE production ↓ decrease in albumin turnover in plasma
plasma AGEs ↑ aggregation of adduct proteins
AGE-protein adducts ↑ activation of Kupffer and HSCs
↑ death of hepatocytes232,233
AA adducts ↑ TNF-α, IL-12, IL-18, MIF, PDGF
MDA adducts ↑ stimulate the transformation of the HSCs
MAA adducts ↑ activate myofibroblasts
4-HNE adducts ↑ activates infiltration of neutrophils into the liver↓ ALDH2 function214–230
HER adducts ↑ CYP2E1, oxidative stress, AFLD, and advanced ALD203–213
Ethanol
AA-AGE adducts ↑ RAGE expression
↑ ROS and oxidative stress
↑ hepatic fatty degeneration and steatosis
↑ hepatocyte ballooning, apoptosis, and steatosis
↑ ALD and AFLD215,231
Lung soluble RAGE (+HMGB1) ↑ lung inflammation239,240
MDA adducts ↑ oxidative stress
4-HNE adducts ↑ pulmonary dysfunction
↑ lung epithelial barrier dysfunction
↑ acute respiratory distress syndrome (ARDS)164,234
MAA adducts ↓ impedes the wound healing process
↑ inflammatory processes, PKC-mediated release of IL-8
↑ correlated with AUD179,235–238
Heart MDA adducts ↓ ALDH2 function
4-HNE adducts ↑ oxidative stress
↑ cardiac dysfunction241–244
Gut AA-adducts ↑ oxidative stress
AA-MDA adducts ↑ leaky gut with increased intestinal cell permeability and endotoxemia137,181,245–250
Table 2 continued
Cells/organs AGE–alcohol–adducts Consequences
Pancreas 4-HNE adducts ↑ pancreatitis, β-cell apoptosis251–255

HER adducts
Erythrocytes AA adducts ↑ correlated with FASD257,258
Testis RAGE overexpression ↑ oxidative stress and inflammation↑ testis dysfunction and degeneration253,259–261
↑ increase/activate, ↓ decrease/inactivate.
aldehydes, AGEs, or AA, adducts persist for extended changes include the development of alcohol tolerance and
periods of time and may end up as aggregated proteins addiction, emotional dysregulation, and executive, neuro-
due to the lack of free lysine needed for ubiquitin cognitive, and motor dysfunctions with neuroinflammation
conjugation and subsequent proteolysis. In fact, the and/or neurodegeneration. Excessive alcohol exposure
hypothesis of extended half-lives and aggregations of increases oxidative stress and the levels of reactive acet-
these adduct proteins is exemplified by the stabilization aldehyde and lipid aldehydes with a simultaneous decrease
of CYP2E1 by ethanol and acetone through the in defensive molecules and detoxification enzymes, includ-
blockade of its rapid degradation via ubiquitin-dependent ing GSH and ALDH253,172,177. These changes subsequently
proteolysis182–186. lead to the accumulation of acetaldehyde adducts and pos-
AA adducts are produced in two separate pathways that sibly AGEs in the brain, which has a much lower detox-
yield two different types of adducts, depending on the ification capacity than the liver, as previously mentioned102.
existing conditions. The first pathway is the formation of Additionally, reactive electrophilic acetaldehyde can strongly
AA adducts with specific amino acids (lysine, cysteine, or induce covalent adduct formation with nucleophilic mole-
aromatic amino acids) and N-ethyl amino acid groups cules such as proteins and DNA, forming acetaldehyde-
under reducing conditions. The second is AA adduct protein (AA-protein) or acetaldehyde-DNA (AA-DNA)
synthesis under nonreducing conditions, that creates a adducts in the brain187–189.
wide range of adducts for which the complete mechan- AA-protein adducts are widely present in the brains of
isms remain to be further characterized. In the second alcohol-exposed rodents or people with alcohol use dis-
pathway, the initial step is the formation of a Schiff base order (AUD)189–192. After alcohol consumption, AA-
adduct followed by several rearrangements and reactions protein adducts are rapidly produced in the cerebral
to yield diverse AA adducts168. cortex primarily with mitochondrial proteins and loca-
Under conditions that include increased lipid perox- lized in the white matter, deep layers of the frontal cortex,
idation, such as exposure to alcohol and/or high n-6 fat and molecular layer of the cerebellum188,189,191. AA-
diets or intake of high fructose drinks, different AGEs are protein adducts are also formed with cytosolic proteins,
produced by Schiff base formation (Fig. 1). Thus, ethanol including tubulins, known as AA-tubulin adducts,
and its reactive metabolite, acetaldehyde, are likely resulting in microtubule malformation and the cytoske-
involved in the AGE synthesis pathways to produce the letal dysfunction of nerve cells193,194. Furthermore, acet-
final acetaldehyde and AGE (AA-AGE) adducts. The aldehyde can interact with dopamine (DA) to produce
formation of AA-AGE adducts can be observed after AA-DA adducts, including salsolinol, a neurotoxin and
chronic alcohol exposure. These AA-AGE adducts exhibit potent stimulant in alcohol, which is involved in the
similar properties (e.g., brown color and polymerization) pathogenesis of AUD and PD194,195. Additionally, the
as the AGE adducts cross-link with sugar molecules, and aggregation of these AA-protein adducts can enhance
they are distinguished from MAA adducts formed by AA neuronal damage and degeneration in different brain
and MDA interactions. Furthermore, treatment with regions190,196. These findings suggest a critical role for
an antioxidant can halt AA-AGE adduct formation, AA-protein adducts in promoting brain damage and
supporting the idea that AA-AGE adducts can be gener- pathophysiology associated with chronic alcohol
ated from a Schiff base product similar to AA adducts consumption.
and AGEs168. The presence of acetaldehyde in the brain also alters
DNA integrity and neuronal viability. Acetaldehyde can
Brain (see summary in Table 2) form AA-DNA adducts in the brain and in peripheral
Chronic and excessive alcohol consumption can alter blood leukocytes of people with AUD since ethanol,
brain structure and function, causing behavioral, emotional, acetaldehyde, and lipid aldehydes such as MDA and
and intellectual abnormalities. These neurobehavioral 4-HNE can inhibit DNA repair enzymes53. The dual
mechanisms of simultaneously elevated AA-DNA adducts adducts are produced rapidly in the hepatic centrilobular
and suppressed DNA repair systems following alcohol zone (zone III), sinusoids, and HSCs as well as on the
intake may contribute to genetic instability and DNA hepatocyte surface in the liver. The amounts of these
mutations, promoting neurological pathologies192,197,198. adducts are also markedly elevated in the early phase of
In addition to cerebral AA-protein adducts, ethanol alcoholic liver disease (ALD) in the presence or absence of
intake or exposure can induce and accelerate AGE pro- clinical or histological signs216–219, suggesting their role in
duction in the brain. Aggregation of cross-linked AGEs the initial development and progression of ALD. In
further upregulates RAGE expression and activation, addition to individual AA and MDA adducts, MAA
contributing to diverse outcomes with neurobehavioral adducts (AA-MDA-protein hybrid adducts) are found in
impairment, as observed in people with AUD190. HSCs, liver sinusoidal endothelial cells, and Kupffer cells
In neurons, direct exposure of AA-AGE adducts to in ALD models. They also stimulate the transformation of
cortical neurons triggers ROS generation, leading to oxi- HSCs into activated myofibroblasts, resulting in the ele-
dative stress and consequently neuronal apoptosis and vated production of potent profibrotic factors such as
degeneration in a dose-dependent manner. These effects platelet-derived growth factor (PDGF)220–222. The pre-
can be prevented by treatment with the antioxidant N- sence of MAA adducts in these cells can induce proin-
acetylcysteine (NAC) or a neutralizing anti-AA-AGE flammatory cytokines such as TNF-α, IL-12, IL-18, and
antibody, suggesting a direct role for AA-AGE adducts macrophage migration inhibitory factor (MIF)223–225. In
in generating oxidative stress-induced neurotoxicity199. hepatic Kupffer cells, 4-HNE adducts are also present and
Daily alcohol exposure for ten consecutive days also activate the infiltration of neutrophils into the liver,
instigated microglial activation to synthesize and secrete leading to the activation of HSCs and an inflammatory
AGE-albumin adducts in the hippocampus and entorhinal cytokine response226–228. These findings indicate a con-
cortex of the rat brain. Accumulated AGE-albumin tributing role of MAA and 4-HNE adducts in promoting
adducts increase the expression of RAGE and activate the hepatic immune response associated with ALD
the MAPK (JNK and p38K)-dependent cell death pathway development. In advanced ALD with cirrhosis, 4-HNE
to promote inflammation, apoptosis, and neuronal and MDA adducts are also found in greater amounts than
damage, which are significantly attenuated by treatment in nonalcoholic liver cirrhosis and normal liver139,228,
with soluble RAGE and chemical AGE inhibitors200. suggesting the involvement of 4-HNE and MDA adducts
Moreover, ethanol ingestion also upregulates RAGE in promoting advanced ALD. Finally, adducts derived
expression in the orbitofrontal cortex and increases the from HER are also detected in the liver and localized in
levels of oxidative stress, HMGB1, TLR-4, neuroimmune the microsomes and plasma membranes of hepatocytes
markers, and proinflammatory cytokines in the brain201. and are inducible by alcohol exposure229,230.
Additionally, chronic exposure to alcohol enhances RAGE Ethanol consumption stimulates the formation of AA-
expression, ROS generation, nuclear factor erythroid AGE in the liver. Increased AA-AGE adduct formation
2–related factor 2 (Nrf2), TLR-4, glial fibrillary acidic and accumulation were positively correlated with the
protein (GFAP), ionized calcium-binding adapter mole- progression of ALD, as indicated by hepatic fat accu-
cule 1 (Iba1), and lipid peroxidation, resulting in neu- mulation and steatohepatitis, which are reversibly
roinflammation, neuronal apoptosis, and memory ameliorated by alcohol abstinence215. HSCs directly
impairment202. These results strongly suggest a con- exposed to AA-AGE adducts can enhance RAGE
tributing role of the AGE-RAGE axis in alcohol-induced expression, ROS generation, and oxidative stress to
neuroinflammation and neurodegeneration through ele- promote hepatocyte ballooning, apoptosis, and stea-
vated oxidative stress and upregulated cell death pathways tosis231. These findings suggest a role for AA-AGE
in the brain. adducts in the pathogenesis of AFLD. Alcohol ingestion
also enhances AGE synthesis and plasma AGEs in the
Liver circulation, especially in the portal and hepatic veins of
Chronic and excessive alcohol intake is known to cause cirrhotic livers. Elevated AGE levels support AGE-
liver injury from mild steatosis (simple fat accumulation protein adduct formation accompanied by decreased
in so-called alcoholic fatty liver disease, AFLD) to more albumin turnover in plasma232. Additionally, AGE-
advanced liver disease such as inflammation (alcoholic protein adducts can accumulate as aggregated proteins
steatohepatitis, ASH), fibrosis/cirrhosis, hepatic cancer, in the cells, leading to the activation of Kupffer and
liver failure, and death203–213. Although many aberrant HSCs in the liver and microglial cells in the brain fol-
signaling pathways are found in the pathogenesis of liver lowed by parenchymal cell death (e.g., hepatocytes and
diseases, elevated levels of adducts with AA, MDA, MAA, neurons, respectively), suggesting the involvement of
4-HNE, and HER likely contribute to alcohol-induced cell AGEs in the progression of ALD and alcohol-mediated
injury214,215. After ethanol intake, AA, MDA, and 4-HNE multiorgan injury233.
Other organs Pancreas Consumption of alcohol enhances the expres-

Although more detailed studies need to be conducted, sion of 4-HNE and HER adducts as well as inflammation
the involvement of AGEs – alcohol –adducts in different in the pancreas251,252. The functional role of these adducts
cells/tissues is presented as follows: may be related to alcohol-mediated pancreatitis, although
this area needs to be evaluated in the future. Since
Lung Chronic and/or excessive alcohol intake can cause CYP2E1 and ALDH2 are also expressed in the pan-
acute respiratory distress syndrome (ARDS) and other creas253–255, future study of the opposite regulation of
types of pulmonary dysfunction characterized by reduced CYP2E1 (i.e., induction) and ALDH2 (i.e., inactivation)
air exchange rates with increased lung epithelial barrier during the production of MDA and/or 4-HNE adducts
dysfunction, possibly through increased oxidative stress and the subsequent damage may be important for
and MDA and 4-HNE adducts164,234. Ethanol intake understanding the pathogenesis mechanisms of alcohol-
stimulates MAA adduct formation in the lung. Elevated mediated pancreatitis and dysfunction.
levels of MAA adducts are found in the pulmonary
bronchoalveolar lavage fluids obtained from chronically Serum Ethanol intake is known to increase the amounts
alcohol-exposed animals and in people with AUD179,235. of MDA adducts and AGEs in the serum. The amounts of
MAA adducts bind scavenger receptor A (SR-A) on lung MDA adducts are more positively correlated with AGE
macrophages to activate inflammatory processes in airway concentrations than with blood glucose levels256. How-
epithelial cells236. The formation of MAA adducts also ever, the effect of elevated MDA adducts in serum on
impedes the wound healing process of bronchial epithelial alcohol-related multiorgan damage needs to be investi-
cells and activates PKC-mediated release of IL-8 in the gated in the future.
lung. However, these changes are attenuated by treatment
with PKC inhibitors237,238. In addition to adduct forma- Erythrocytes After alcohol consumption, AA adducts are
tion, ethanol exposure can increase soluble RAGE produced in blood erythrocytes and are also correlated
expression in bronchoalveolar lavage fluid together with with the incidence of fetal alcohol spectrum disorders
RAGE ligand (HMGB1) in the inflammatory lung239,240. (FASDs)257,258. The pathological mechanisms and impli-
cations of these findings need to be evaluated in future
Heart Excessive alcohol consumption is known to cause studies.
cardiac dysfunction with reduced blood ejection force and
volume, possibly by augmenting oxidative stress, increasing Testis Excessive alcohol consumption is known to cause
the levels of MDA and 4-HNE adducts and suppressing testis dysfunction and degeneration, possibly by increas-
ALDH2 activity241,242. Elevated oxidative stress caused by ing oxidative stress. Alcohol intake can induce RAGE
alcohol oxidation increases acetaldehyde and MDA adduct overexpression in the testis, whereby RAGE is localized in
synthesis in the heart243,244. However, the contributing the interstitial cells and the basal compartment of the
roles of AA-MDA adducts in alcohol-mediated myocardio- seminiferous tubules. Prolonged ethanol exposure stimu-
pathy need to be further characterized. Since CYP2E1 and lates RAGE activation to produce oxidative stress and
ALDH2 are expressed in the heart, future studies of the inflammatory mediators, leading to testicular dysfunction
opposite regulation of CYP2E1 (i.e., induction) and ALDH2 and degeneration259. CYP2E1 and ALDH2 are also
(i.e., suppression) during the alcohol-mediated production expressed in the testis253,260,261. Thus, it would be of
of MDA and/or 4-HNE adducts and the consequent interest to find the opposite regulations (i.e., induction of
cardiomyopathy would be of interest. CYP2E1 with suppression of ALDH2) and their implica-
tions in alcohol-mediated production of MDA and/or 4-
Gut Excessive alcohol intake is known to cause leaky gut HNE adducts and subsequent testis dysfunction.
with increased intestinal cell permeability and endotox-
emia, possibly via increased CYP2E1 and oxidative
stress245–248. Ethanol ingestion is likely to increase AA Translational applications
formation in the intestine as a consequence of gut We have thus far described the formation of various
bacteria-mediated alcohol metabolism and the low levels AGE adducts, interactions with many cellular compo-
of ALDH2 expression in the gut249, although additional nents, including RAGE, and their pathological implica-
studies are needed to extrapolate the roles of these factors tions in aging-related diseases and alcohol-mediated
in alcohol-mediated gut damage and inflammation. Since multiorgan damage. Considering the underlying molecular
CYP2E1 was shown to be involved in the production of mechanisms of these processes and functional implica-
hepatic AA- and AA-MDA adducts137,181,250, it would be tions, we can suggest a variety of different strategies for
of interest to study the direct role of CYP2E1 in alcohol- use in the effective prevention and therapy of AGE-
mediated AGE production and GI pathologies. associated tissue injury and/or RAGE-related diseases.
For instance, we can reduce the amounts of potentially (e.g., diallyl disulfide in garlic273,275; phenyl isothiocyanate
harmful AGEs by decreasing the production of endo- in cabbage and cruciferous vegetables276; ellagic acid in
genous AGEs to prevent many disease states, including pomegranate247; polyunsaturated fatty acids, including
aging-related diseases, and by lowering the dietary intake docosahexaenoic acid (22:6n-3)277 and indole-3-carbinol
of exogenous AGEs. In fact, decreased intake of n-6 fatty in vegetables and fruits278; berberine in fruits and vege-
acids in high-fat Western diets, dairy products, and soft tables279; walnut280; curcumin281,282; quercetin283; and
drinks with high fructose or sucrose contents in con- synthetic compounds (chlormethiazole and YH-
junction with increased consumption of n-3 fatty acid- 439137,284) can prevent alcohol-induced oxidative stress
enriched fish and plant-based foods such as legumes, and the formation of various adducts, including AA
vegetables, fruits, and whole grains are recommended to adducts137 and AA-MAA adducts53,285, although the
decrease AGE levels in the body. These healthy dietary preventive effects of all these dietary compounds on AGE-
choices are consistent with the food recommendations of associated adduct formation have not been specifically
the American Diabetes Association, the American Heart evaluated. In addition, dietary AGEs decreased the
Association, and the American Institute for Cancer amounts of SIRT1131 and other defensive proteins,
Research262–264. Many herbs and spices, such as cloves, including peroxisome proliferator -activated receptor-γ
rosemary, and curcumin, and natural antioxidants, such coactivator 1-α (PGC-1α)51–53 and ALDH2172. Sub-
rice (Oryza sativa L.), and blueberry, exhibit antiglycation chronic alcohol intake also decreased the levels of SIRT1
activities. These foods are rich in polyphenols such as and PGC-1α and other isoforms286,287. Thus, activation of
gallic acid, flavonoids, anthocyanin, and ferulic acid, SIRT1 by resveratrol and its synthetic structural deriva-
which attenuate protein glycation and prevent the bio- tives288,289 and melatonin290 may prevent adduct forma-
synthesis of AGEs265–270. As mentioned above, cooking tion and AGE-associated disease conditions. Furthermore,
methods can play a critical role in regulating the levels of consumption of anti-inflammatory antioxidants from
AGE formation, with effects ranging from those caused by natural dietary supplements279,281,282,290 and/or synthetic
oven-frying > frying > broiling > roasting > boiling/ origins199 can help reduce the incidence and severity of
poaching/stewing/steaming. For example, cooking meat AGE-associated inflammation and related disorders.
(e.g., chicken, pork, or beef) by boiling or stewing can Furthermore, soluble RAGE119,200, inhibitors of the RAGE
reduce the AGE contents to one-half of that prepared by signaling pathway130,131, neutralizing antibodies against
broiling1,271. In addition, the water content, cooking RAGE57 or AA-AGE adduct199, and other AGE-degrading
method, temperature and time, and food pH are crucial to compound(s), such as pyridoxamine and ALT-711200,
the final amount of AGEs. Marinating food or meat with lipoic acid291, synthetic compounds OPB-9195292, and
acidic ingredients such as lemon juice and vinegar can nitrothiadiazolo[3,2-α]pyrimidines293, have been reported
decrease the amounts of dietary AGEs produced during to decrease AGE adduct formation. Based on these find-
the high-heat cooking process by as much as 50%272. ings, lifestyle changes that include decreased alcohol
These culinary methods are commonly used for tradi- consumption, reduced tobacco smoking, and avoidance of
tional Asian, Mediterranean, and other cuisines world- potentially harmful diets along with increased physical
wide to create palatable and healthy dishes. In addition, exercise and daily intake of vegetables and fruits, should
changes in behavior or lifestyle, such as decreasing the be actively promoted and undertaken for proper man-
amount and frequency of alcohol intake and tobacco agement of the levels of AGE-related adducts to help
smoking, and engaging in physical exercise to reduce prevent aging-related diseases and alcohol-mediated
obesity and diabetes can lower the production organ damage.
of endogenous AGEs, subsequently preventing AGE-
associated disease conditions. Concluding remarks (see overview in Fig. 2)
We have also described the roles of increased oxidative AGEs can be produced endogenously and exogenously.
stress in promoting the production of AA, MDA, MAA, The accumulation of AGEs and the interaction of
and other AGE-related adducts and the consequences in AGE-RAGE play causative roles in various aging-related
aging-related diseases and alcohol-mediated multiorgan diseases and alcohol-mediated tissue injuries by interfer-
damage. In particular, CYP2E1 contributes to the pro- ing with cell signaling pathways and forming adducts
duction of AA and MAA adducts, as demonstrated in with cellular macromolecules, contributing to their inac-
experimental rodent and cell culture models137,180,216,273. tivation and pathophysiology in many tissues/organs.
Therefore, the inhibition of oxidative stress-producing These suggest biological connections between AGEs and
enzymes such as CYP2E1137,181 and NADPH oxidase274 is alcohol adduct formation in relation to alcohol-mediated
an option to prevent the formation of AGE adducts and inflammation, gut leakiness, and multiorgan damage. In
AGE-associated cellular and/or organ damage. For addition, the information described in this review can be
instance, taking naturally occurring CYP2E1 inhibitors useful to understand the underlying mechanisms of
Fig. 2 Overview of the causative functions of AGEs in aging-related diseases and alcohol-mediated multiorgan dysfunction or damage.
AGEs can be produced endogenously and exogenously. The accumulation of AGEs and the interaction of AGE-RAGE play causative roles in various
aging-related diseases and alcohol-mediated tissue injuries by interfering with cell signaling pathways and forming adducts with cellular
macromolecules, contributing to their inactivation and pathophysiology in many tissues/organs. These suggest biological connections between
AGEs and alcohol adduct formation in relation to alcohol-mediated inflammation, gut leakiness, and multiorgan damage.
various diseases caused by alcohol intake, nonalcoholic Author contributions

W.R. conceptualization and original draft preparation; Y.Q., X.W., and M.M.E.
substances, environmental risk factors, genetic mutations, manuscript review and editing; B.J.S. conceptualization, review and editing,
and aging. These mechanistic insights can serve as a and supervision.
springboard for future translational applications for both
the prevention and treatment of diverse disease states. Conflict of interest
The authors declare that they have no conflict of interest.
Funding Publisher’s note

This research was supported by the Intramural Program Research Fund of the Springer Nature remains neutral with regard to jurisdictional claims in
National Institute of Alcohol Abuse and Alcoholism, National Institutes of published maps and institutional affiliations.
Health. Y.Q. was supported by Shanghai General Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai, China. Received: 15 November 2020 Revised: 14 December 2020 Accepted: 15
December 2020.
Published online: 10 February 2021
Author details References

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Advanced Glycation End Products (AGEs) and Other Adducts in Aging-Related Diseases and Alcohol-Mediated Tissue Injury

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Rungratanawanich et al.

Experimental & Molecular Medicine (2021) 53:168–188

REVIEW ARTICLE Open Access

Advanced glycation end products (AGEs) and

Introduction are ascribed to their ability to produce reactive oxygen

© The Author(s) 2021

Table 1 Summary of the AGEs and AGE-RAGE interaction in aging-related diseases.

Diseases Mechanisms Consequences

Diabetes ↓ SIRT1, active PGC1α ↑ oxidative stress, inﬂammation, mitochondrial dysfunction

Diseases Mechanisms Consequences

• Parkinson’s disease AGEs ≡ α-synuclein ↑ aggregation of α-synuclein toxic oligomers

↑ increase/activate, ↓ decrease/inactivate, = lead to/result in, ≡ interact/cross-link.

CYP2E1 MDA, 4-HNE, MAA, HER

Alcohol/ ALDH CO2

Cells/organs AGE–alcohol–adducts Consequences

Brain AGE-albumin adducts ↑ RAGE overexpression

Cells/organs AGE–alcohol–adducts Consequences

Pancreas 4-HNE adducts ↑ pancreatitis, β-cell apoptosis251–255

Other organs Pancreas Consumption of alcohol enhances the expres-

various diseases caused by alcohol intake, nonalcoholic Author contributions

Funding Publisher’s note

Author details References

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