cells
Review

Effects of Toxic AGEs (TAGE) on Human Health
Masayoshi Takeuchi 1, * , Akiko Sakasai-Sakai 1 , Takanobu Takata 2 , Jun-ichi Takino 3
and Yoshiki Koriyama 4
1

2

3

4

*

Citation: Takeuchi, M.; Sakasai-Sakai,

Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku,
Uchinada-machi, Kahoku 920-0293, Ishikawa, Japan; asakasai@kanazawa-med.ac.jp
Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku,
Uchinada-machi, Kahoku 920-0293, Ishikawa, Japan; takajjjj@kanazawa-med.ac.jp
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University,
5-1-1 Hirokoshingai, Kure 737-0112, Hiroshima, Japan; j-takino@hirokoku-u.ac.jp
Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science,
3500-3 Minamitamagaki, Suzuka 513-8670, Mie, Japan; koriyama@suzuka-u.ac.jp
Correspondence: takeuchi@kanazawa-med.ac.jp; Tel.: +81-76-218-8456

Abstract: The habitual and excessive consumption of sugar (i.e., sucrose and high-fructose corn syrup,
HFCS) is associated with the onset and progression of lifestyle-related diseases (LSRD). Advanced
glycation end-products (AGEs) have recently been the focus of research on the factors contributing
to LSRD. Approaches that inhibit the effects of AGEs may be used to prevent and/or treat LSRD;
however, since the structures of AGEs vary depending on the type of reducing sugars or carbonylcompounds to which they respond, difficulties are associated with verifying that AGEs are an etiological factor. Cytotoxic AGEs derived from glyceraldehyde, a triose intermediate in the metabolism of
glucose and fructose, have been implicated in LSRD and are called toxic AGEs (TAGE). A dietaryimbalance (the habitual and excessive intake of sucrose, HFCS, or dietary AGEs) promotes the generation/accumulation of TAGE in vivo. Elevated circulating levels of TAGE have been detected in
non-diabetics and diabetics, indicating a strong relationship between the generation/accumulation of
TAGE in vivo and the onset and progression of LSRD. We herein outline current findings on “TAGE
as a new target” for human health.

A.; Takata, T.; Takino, J.-i.; Koriyama,Y. Effects of Toxic AGEs (TAGE) on
Human Health. Cells 2022, 11, 2178.

Keywords: advanced glycation end-products (AGEs); toxic AGEs (TAGE); lifestyle-related diseases(LSRD); healthy life expectancy; human healthhttps://doi.org/10.3390/cells11142178
Academic Editors: Eloy Bejarano andAllen Taylor

1. Introduction
Received: 13 June 2022
Accepted: 10 July 2022
Published: 12 July 2022
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The chronic consumption of sugar-sweetened beverages (SSB) and processed foods,
which have a very high sugar content (i.e., high-fructose corn syrup, HFCS, and sucrose),
has been implicated in the development of obesity and metabolic syndrome (MetS) as
well as in the onset and progression of diabetes mellitus (DM) and diabetic complications, cardiovascular disease (CVD), non-alcoholic steatohepatitis (NASH), cancer, andAlzheimer’s disease (AD); however, the underlying mechanisms have not yet been clarified
in detail [1–4]. The formation of advanced glycation end-products (AGEs) occurs under hyperglycemic conditions through the Maillard reaction (a non-enzymatic glycation reaction)
between proteins/amino acids and reducing sugars [5,6]. The sugars (i.e., glucose, fructose,
and glyceraldehyde (GA)) or carbonyl compounds (i.e., glycolaldehyde, glyoxal (GO),methylglyoxal (MGO), and 3-deoxyglucosone (3-DG)) involved in this reaction influence
the types of AGEs generated. Marked variations have been reported in the structuresof AGEs in vivo, and complex reactions are needed for their formation; therefore, thestructures of only a few AGEs have been elucidated [5–8].
Sugar metabolic pathways (i.e., glycolysis, the polyol pathway, and fructolysis) leadto the production of GA [9–11], which, in turn, contributes to the generation of a group ofcompounds called GA-derived AGEs (GA-AGEs). These AGEs are strongly cytotoxic, andCells 2022, 11, 2178. https://doi.org/10.3390/cells11142178

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2 of 22thus are referred to as toxic AGEs (TAGE) [12]. The accumulation of TAGE has been shown
to play a role in the pathogenesis of DM and diabetic complications [13–15], NASH [16–19],
CVD [20–22], AD [23–25], and cancer [26–29]. In a previous review, we summarized, in
detail, TAGE accumulation and cell damage in the brain, liver, and heart [11]. In this review,the content that overlaps with the previous paper has been simplified, and novel findings
have been added. In our recent study, the intracellular generation/accumulation of TAGE
was detected in many cell types [30–42]. Elevated levels of TAGE damage cells, which
results in the leakage of TAGE into the circulation and to the surrounding cells; the damage
induced promotes the onset and progression of lifestyle-related diseases (LSRD) [9–11].
Extracellular TAGE interact with the receptor for AGEs (RAGE), which affects intracellularsignaling, gene expression, and the release of pro-inflammatory molecules; they also
increase the generation of reactive oxygen species (ROS) by different cell types [15], all ofwhich have been implicated in the pathological changes associated with LSRD.
The accumulation of ROS under oxidative stress conditions results in the induction oflipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivatives, such as GO, MGO, malondialdehyde,
and 4-hydroxy-2-nonenal, giving rise to AGEs and advanced lipoxidation end-products(ALEs). AGEs and ALEs play key roles in the cellular response to oxidative stress stimuli
through the regulation of a variety of cell signaling pathways [43]. ROS are also important for aging and health promotion, but in this review, we focus on the importance of
intracellular TAGE accumulation from the perspective of glycation.
We herein describe the relationships between intracellular TAGE levels and damage
to various cell types. Circulating levels of TAGE have also been shown to contribute to
LSRD. The “TAGE theory” is a novel concept that will provide novel insights for researchon human health (Figure 1).

Figure 1. TAGE as a new target for human health. AD: Alzheimer’s disease; CRC: colorectal
cancer; CVD: cardiovascular disease; DM: diabetes mellitus; NASH: non-alcoholic steatohepatitis;
NBNC-HCC: non-B or non-C (NBNC)-hepatocellular carcinoma; TAGE: toxic advanced glycation
end-products.

2. Production of AGEs in the Human Body
The production and accumulation of AGEs occurs in tissues with aging, and is accelerated in patients with DM [5,15,44,45]. We previously identified seven distinct classes
of AGEs and Nε-(carboxymethyl)lysine (CML) (Figure 2) in the serum of hemodialysis(HD) patients with diabetic nephropathy (HD-DN) [5,46]. Figure 2 shows the produc-

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3 of 22tion of AGEs through a process involving metabolic pathways for sugar, including sugar
auto-oxidation and the Maillard reaction. CML, MGO-derived AGEs (MGO-AGEs), andglucose-derived AGEs (Glu-AGEs) have been the focus of research in the field of LSRD.
Serum AGE fractions from HD-DN patients were previously shown to exert neurotoxic
effects, which were only neutralized by the addition of the anti-TAGE antibody [23]. In
other words, cell damage appears to be induced by TAGE structures that are recognizedby the anti-TAGE antibody. TAGE have the strongest binding affinity for RAGE [47,48],
with binding inducing the production of ROS by NADPH oxidase, vascular endothelial
growth factor (VEGF) expression, and pro-inflammatory cytokine production in manycells [15,49,50], all of which may contribute to the onset and progression of LSRD.

Figure 2. Routes for the production of advanced glycation end-products (AGEs) in the humanbody. DHA-P: dihydroxyacetone-phosphate; HbA1c: hemoglobin A1c; GO-AGEs: glyoxal (GO)derived AGEs; Glycol-AGEs: glycolaldehyde-derived AGEs; CML: Nε-(carboxymethyl)lysine; GluAGEs: glucose-derived AGEs; MGO-AGEs: methylglyoxal (MGO)-derived AGEs; 3-DG-AGEs:
3-deoxyglucosone (3-DG)-derived AGEs; GA-AGEs: glyceraldehyde (GA)-derived AGEs; Fru-AGEs:
fructose-derived AGEs; GOLD: GO-lysine dimer; G-H1: GO-derived hydroimidazolone 1; GApyridine: glycolaldehyde-derived pyridine; DOLD: 3-DG-lysine dimer; CEL: Nε-(carboxyethyl)lysine;
MOLD: MGO-lysine dimer; MG-H1: MGO-derived hydroimidazolone 1; GLAP: glyceraldehydederived pyridinium; TAGE: toxic AGEs; P-NH2 : free amino residue of a protein.

We previously prepared a specific antibody to analyze the toxicity of GA-AGEs [51].
This antibody recognized different epitopes to GA-derived structures, such as 3-hydroxy5-hydroxymethyl-pyridinium (GLAP) [52] and triosidines [53], but not AGEs with wellcharacterized CML and Nε-(carboxyethyl)lysine (CEL) or various AGEs (i.e., pyrraline,
pentosidine, crossline, argpyrimidine, GO- or MGO-lysine dimers, and GO- or MGO-

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4 of 22

derived hydroimidazolone) produced from reducing sugars and carbonyl molecules [54,55].
It also did not recognize AGEs with unknown structures, such as GO-/glycolaldehyde/glucose-/3-DG-/MGO-/GA-/fructose-derived AGEs [51,54,55]. Therefore, unknown
GA-AGE structures that are recognized by the anti-TAGE antibody may be cytotoxic. Basedon these findings, AGEs that are recognized by the anti-TAGE antibody are hereinafterreferred to as TAGE.
3. Detection of Intracellular and Circulating TAGE
Different epitopes are recognized by the anti-TAGE antibody [51] and GA-derived
AGE structures with a pyridinium ring, such as GLAP [52] and triosidines [53]. Neither
structure has AGE-specific fluorescence or protein cross-links. We identified two compounds with a 1,4-dihydropyrazine ring that have fluorescence and cross-links to be TAGE
candidate structures [PCT/JP2019/34195].
3.1. Slot Blot (SB) Analysis of Intracellular TAGE Levels
Total TAGE levels in cell extracts treated with reagents were assessed using a SBanalysis with an anti-TAGE antibody. Cell extracts were prepared using lysis buffer (2 M
thiourea, 7 M urea, 30 mM Tris, 4% 3-[(3-cholamido-propyl)-dimethyl-ammonio]-1-propane
sulfonate, and protease inhibitor cocktail). Polyvinylidene difluoride membranes fixed withcell lysates using a SB apparatus were incubated with the anti-TAGE antibody and then witha horseradish peroxidase (HRP)-conjugated secondary antibody. A chemiluminescencereagent was used to detect immunoreactive proteins, and proteins were scanned using
a chemiluminescence imaging system. TAGE levels in cell extracts were then calculatedusing a calibration curve for TAGE-bovine serum albumin (BSA).
3.2. Enzyme-Linked Immunosorbent Assay (ELISA) for TAGE Levels in Serum/Vitreous Fluid
A competitive ELISA with an anti-TAGE antibody was used to measure serum levelsof TAGE, as previously described [51]. In brief, each well of a 96-well microtiter plate
was coated with TAGE and incubated in a cold room overnight. Wells were washed threetimes with phosphate-buffered saline (PBS)-Tween-20 (PBS-Tween-20). Wells were thenblocked by an incubation in a solution of PBS containing BSA. After washing with PBSTween-20, sera were added to each well as a competitor for the TAGE antibody, followedby an incubation. Wells were washed with PBS-Tween-20 and developed with an alkaline
phosphatase-linked anti-rabbit IgG utilizing p-nitrophenyl phosphate as the colorimetricsubstrate. The following values were obtained for sensitivity and the intra- and inter-assay
coefficients of variation: 0.01 U/mL, 6.2%, and 8.8%, respectively [55,56].
4. Cytotoxicity of TAGE
Many cell types that possess the pathways for the generation of GA from glucose
and/or fructose may produce intracellular TAGE [9–11], and subsequently induce cell death.
TAGE leak from cells and interact with RAGE to exert their effects on the surrounding
cells. The TAGE-RAGE axis alters intracellular signaling, which in turn up-regulates theexpression of RAGE that may contribute to LSRD.
4.1. TAGE Cytotoxicity in the Liver
The habitual and excessive consumption of SSB and processed foods that have ahigh content of sugar [57] and/or dietary AGEs (mainly Glu-/Fru-AGEs [58]) alters themetabolic system in hepatocytes, which leads to the excessive production of GA and,ultimately, the generation/accumulation of TAGE [9,10]. The strong cytotoxicity of TAGE
causes intra-/extracellular damage in hepatocytes and hepatic stellate cells (HSC). Nonalcoholic fatty liver diseases (NAFLD) are currently recognized as the most common
liver disorder. NAFLD is a spectrum of diseases that range from non-alcoholic fatty liver(NAFL) to NASH, which cause fibrosis, and may progress to cirrhosis, liver failure, andhepatocellular carcinoma (HCC).

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5 of 224.1.1. Intracellular TAGE and Hepatocyte Cell Death
A previous study reported the presence of detectable levels of TAGE in the hepatocytesof patients with NASH, and negligible levels in those of patients with NAFL [16]. The
cytotoxicity of TAGE has been implicated in NASH-mediated dysfunctions in hepatocytes.
i.

ii.

iii.

The accumulation of TAGE has been shown to induce damage in HCC cell lines(HepG2 and Hep3B) and primary cultured hepatocytes [30–32]. The intracellularaccumulation of TAGE induced by GA increased the mRNA expression levels of
C-reactive protein and decreased the chaperone activity of Hep3B cells [30]. The
intracellular TAGE accumulation also induced necrotic-type cell death associated with
TAGE-modified caspase-3 [31], and promoted the production of ROS in HepG2 cells
and primary cultured hepatocytes [32].
Heterogeneous nuclear ribonucleoprotein M (hnRNPM), an RNA-binding protein,
was identified as a target protein for TAGE in Hep3B cells incubated in GA- orhigh fructose-containing media [59,60]. Furthermore, following the knockdown of
hnRNPM, the up- or down-regulated expression of genes associated with extracellularexosome-containing extracellular spaces was observed [60].
HCC cell lines and primary cultured cells have been used as in vitro models of NASH.
However, they have several disadvantages, such as specialized characteristics byimmortalization or limited growth potential. A decrease was noted in the viability ofhepatocyte-like cells (HLCs), which differentiated from human induced pluripotent
stem cells (hiPSCs) (hiPSC-HLCs), as TAGE accumulated in cells, which was consistent
with previous findings on HCC cells and primary cultured hepatocytes [33]. In
addition, the accumulation of TAGE up-regulated the expression of inflammationrelated genes (i.e., interleukin (IL)-6, IL-8, and monocyte chemoattractant protein(MCP)-1) in hiPSC-HLCs. Experimental data from hiPSC-HLCs are considered tomore accurately reflect the pathology of humans.

These studies provide a novel strategy for examining the involvement of hepatocyte
toxicity due to the accumulation of TAGE in the pathogenesis of NASH.
4.1.2. Effects of Extracellular TAGE on HSC
The activation of HSC by cytokines, such as transforming growth factor (TGF)-β1, tumor
necrosis factor (TNF)-α, and platelet-derived growth factors, has been reported in patientswith chronic liver damage. This is followed by their differentiation into myofibroblast-likecells and the secretion of a large amount of extracellular matrix (ECM) material, including
collagen I [61]. In our previous study, we showed that TAGE induced the expression ofgenes and proteins related to fibrogenesis and inflammation, such as TGF-β1, α-smoothmuscle actin, collagen type Iα2, and MCP-1, in the cultured human HSC cell line, LI90, via
NADPH oxidase-derived ROS production [62]. Furthermore, apoptosis was detected in TGFβ1-treated LX-2 cells, a human HSC cell line, and this effect was significantly suppressed by
TAGE co-treatment. Therefore, TGF-β1-induced apoptosis was inhibited by TAGE. Althoughno significant changes were observed in the mRNA expression levels of collagen I in eachcell, the TGF-β1 and TAGE co-treatment significantly increased the secretion of the collagen
I protein into the culture medium [63]. Collectively, these findings suggest that the total
production of ECM molecules, such as collagen I, was promoted by TAGE through the
inhibition of apoptosis in HSC activated by the TGF-β1 treatment. Therefore, liver fibrosis inpatients with chronic hepatitis, such as NASH, may be aggravated by TAGE.
4.2. Cytotoxicity of TAGE in Skeletal Muscle
Patients with LSRD, including type 2 DM and NASH, are at an increased risk ofsarcopenia [64–66]. Sarcopenia is a progressive and generalized skeletal muscle disorderthat is characterized by the accelerated loss of muscle mass and function, which is associatedwith adverse outcomes, including the deterioration of activities of daily living and qualityof life in addition to an increased risk of falls and mortality [64]. Myoblasts are precursor

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6 of 22cells in skeletal muscle that differentiate to form myotubes and, ultimately, myofibers.
Previous studies demonstrated that the death of or dysfunctions in myoblasts resulted in
the loss of skeletal muscle [64,67,68]. Although patients with LSRD are at risk of sarcopenia,
the mechanisms by which cell death is induced in myoblasts have not yet been elucidated indetail. We recently reported that the intracellular production of TAGE with a physiologicalconcentration of GA strongly induced cell death in the mouse myoblast cell line C2C12 [34].
In contrast, we also reported that circulating TAGE levels increased in STAM mice, aNASH mouse model, which had steatohepatitis and fibrosis. Based on these findings,
we investigated whether extracellular TAGE induced cell death in C2C12. The findings
obtained showed that extracellular TAGE, at a level that was five-fold higher than thephysiological concentration, did not induce cell death. Since extracellular TAGE were
not cytotoxic at a physiological concentration, cell death in myoblasts only appears to be
induced by intracellular TAGE.
4.3. Cytotoxicity of TAGE in Pancreatic Islet β-Cells (β-Cells)
A decrease in the number of β-cells, which produce and secrete insulin, contributes
to the pathophysiology of DM [69]. The death of and dysfunctions in β-cells have been
implicated in the development of glucotoxicity, lipotoxicity, and oxidative stress [70,71].
Autophagy protects β-cells against dysfunction and death in DM [70]. TAGE are cytotoxic
and play a role in the pathogenesis of DM. Elevated serum TAGE levels have been reported
in DM patients, and are cytotoxic. Intracellular TAGE have been shown to induce β-celldeath, and may inhibit autophagy by reducing microtubule-associated protein 1 light chain
3 (LC3)-I, LC3-II, and p62, thereby suppressing their degradation. Although autophagy is
generally associated with increases in the protein levels of LC3-II and decreases in thoseof LC3-I and p62, the levels of all of these proteins were reduced in DM. This pattern ofreduced protein levels of LC3-I, LC3-II, and p62 is rare, and suggests the inhibition of
autophagy by intracellular TAGE. However, a previous study demonstrated that physiological concentrations of extracellular TAGE were not cytotoxic [35]. Collectively, thesefindings will contribute to a more detailed understanding of the involvement of TAGE in
the pathogenesis of DM.
4.4. Cytotoxicity of TAGE in Bone
Bone is remodeled through continuous resorption by osteoclasts and the replacementof old bone with new bone formed by osteoblasts. The differentiation and maturation of
osteoblasts are essential for the formation of new bone, with the depletion of osteoblasts
inducing osteoporosis. DM has been identified as one of the risk factors for osteoporotic
fractures. Previous studies demonstrated that the risk of fractures was higher for DM patients [72,73]. Fractures significantly reduce quality of life and worsen life expectancy [74].
We recently reported GA-induced mouse osteoblastic cell death and detected TAGE modifications in several intracellular proteins. Moreover, a correlation was observed between
decreases in the expression levels of both Runx2, an essential transcription factor for the differentiation of osteoblasts, and collagen and the accumulation of TAGE. The GA treatment
also decreased normal protein levels of collagen in cells, suggesting that TAGE-induced
modifications in collagen resulted in the formation of an abnormal structure. These findings
revealed for the first time the cytotoxic effects of GA and TAGE against osteoblasts, theirsuppression of osteoblastic differentiation, and their reduction of normal collagen levels [36]. These findings provide evidence for the involvement of TAGE in the pathogenesisof osteoporotic fractures associated with DM.
4.5. Cytotoxicity of TAGE in the HeartCVD is induced by the death of and dysfunctions in cardiomyocytes. TAGE havebeen suggested to play a role in the increased risk of CVD in patients with DM. Cardiac
fibroblasts are activated and differentiate by specific signals from cardiomyocytes, and playa critical role in the induction of injury responses.

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7 of 224.5.1. Intracellular TAGE and Cardiomyocyte DeathWe recently revealed that intracellular TAGE decreased beating rates and induced cell
death in cardiomyocytes without myocardial ischemia as well as diabetic adverse cardiac
remodeling [37], and also reported elevated serum TAGE levels in patients with myocardialischemia [9,10]. Furthermore, we indicated the inhibition of autophagy by intracellular
TAGE [37]. Although previous studies demonstrated that intracellular TAGE were cytotoxic in cell lines of various organs [30,31,33–39,42], our findings showed time-dependent
decreases in the expression levels of LC3-II/LC3-I in cardiomyocytes treated with GA [37].
TAGE-modified proteins in cardiomyocytes have yet to be identified; however, TAGE havebeen suggested to alter the proteins involved in the regulation of autophagy-related pathways, such as those contributing to the generation of LC3-II. The intracellular productionof TAGE may occur in human and rat cardiomyocytes and directly induce cell damage,thereby contributing to CVD.
4.5.2. Intracellular TAGE and Human Cardiac Fibroblast (HCF) Cell Death
Cardiac fibroblasts are activated and differentiate into cardiac myofibroblasts by
specific signals, such as TGF-β from cardiomyocytes; they produce and secrete proteinsassociated with the ECM, such as collagen, to protect cardiac tissues; they also play a criticalrole in the induction of injury responses. We treated HCF with GA, which resulted in the
production of intracellular TAGE and, ultimately, cell death [38]. In contrast, extracellularlevels of TAGE that were approximately 10- to 30-fold higher than physiological concentrations did not induce cell death in HCF [38]. Only intracellular TAGE induced cell death in
HCF under physiological conditions, and may directly suppress heart repair or injury. The
activation of cardiac fibroblasts is essential for repair and remodeling after the inductionof cell death in cardiomyocytes by intracellular TAGE; however, intracellular TAGE inthese cells may impair their functions, which suppresses the fibrotic healing response andpotentially results in heart dysfunction.
4.5.3. Extracellular TAGE and Cardiomyocytes and HCF
Extracellular TAGE in the vascular system have been implicated in the developmentof CVD, and relationships have been reported between serum TAGE levels and the risk
factors for CVD [20–22,55,75]. We previously reported that the activation of the extracellular
TAGE-RAGE axis led to the intracellular production of ROS and activation of nuclear factor(NF)-κB in vascular wall cells, which have been suggested to up-regulate the expressionof various genes related to atherosclerosis and inflammation, and promote the onset andprogression of CVD in DM [15]. Cardiomyocytes and cardiac fibroblasts both express
RAGE, and hence a cytotoxic response may be induced in these cells by the TAGE-RAGE
axis. However, extracellular TAGE did not directly inhibit the pulsation of cardiomyocytes
nor induce cell death in cardiomyocytes or cardiac fibroblasts [38].
4.6. Cytotoxicity of TAGE in the Brain
DM has recently been proposed as a risk factor for the onset and progression ofAD [76,77]. AD is characterized by the accumulation of senile plaques and neurofibrillarytangles (NFT), which mainly comprise amyloid β (Aβ) protein and tau protein, respectively [76,78]. A previous study reported that TAGE mainly localized in the cytosol ofneurons in the hippocampus and parahippocampal gyrus in AD brains [24]. We also
demonstrated that TAGE were stronger neurotoxins than AGEs, such as Glu-AGEs and
CML, in neurons [23,79].
4.6.1. Intracellular TAGE and Neuronal Cells
In our previous study, we showed the following:i.

The accumulation of intracellular TAGE in GA-treated human neuroblastoma SHSY5Y cells, which resulted in cell death [39];Cells 2022, 11, 2178

8 of 22ii.
iii.

A reduction in the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
and the inhibition of glycolysis in GA-treated neuronal cells [39];A reduction in the activity of GAPDH in AD patients [80]. We also demonstrated the
involvement of GAPDH in apoptosis in neurodegenerative disorders [81].

We found that TAGE induced similar alterations to those observed in AD. GA induced
dysfunctional neurite outgrowth via TAGE-β-tubulin aggregation, which resulted in the
TAGE-dependent abnormal aggregation of β-tubulin and tau phosphorylation in SH-SY5Y
cells [40]. These findings indicated that the formation of TAGE-β-tubulin contributed tothe production of paired helical filaments, one of the components of NFT. More recently,
we showed that AGE inhibitors (i.e., aminoguanidine and pyridoxamine) suppressed theformation of TAGE-β-tubulin, mitigated the GA-induced inhibition of neurite outgrowth,and reduced GA-mediated increases in tau phosphorylation levels [41]. Glial intracellular
TAGE accumulation may induce cell death in primary cultured astrocytes and contributeto the disruption of the blood-brain barrier (unpublished data). Therefore, intracellular
TAGE may be causative agents for the onset and progression of AD.
4.6.2. Extracellular TAGE on Neuronal Cells
We previously demonstrated the stronger neurotoxicity of TAGE in a neuronal primaryculture system than Glu-AGEs, MGO-AGEs, and CML, which are AGEs that have been
examined in detail [23,79]. Moreover, the addition of an anti-TAGE antibody completely
mitigated the neurotoxicity of serum AGEs in HD-DN patients, whereas antibodies of othertypes of AGEs or CML did not [23,79].
4.6.3. Extracellular TAGE on Brain Vascular Endothelial Cells (EC)The vascular endothelium, a monolayer of vascular EC, functions as a barrier that
regulates the permeation of blood components through vessel walls. We previously demonstrated that TAGE increased tissue factor (TF), a major regulator of normal hemostasis andpathological thrombosis, the expression of which is associated with the overproduction of
ROS [82]. We also demonstrated that brain microvascular EC were more susceptible thanaortic vascular EC to TAGE-enhanced permeability, which was dependent on VEGF expression induced by the TAGE-RAGE-ROS axis [83]. We recently reported that TAGE induced
enhancements in vascular permeability through the disruption of adherens junctions andtight junctions via complex signaling, including ROS and non-ROS pathways. Ras guanyl
nucleotide releasing protein 2 (RasGRP2), which activates small G proteins, prevented
the disruption of adherens junctions, which inhibited vascular hyperpermeability. Thesefindings suggest that the essential role of RasGRP2 is as a protective factor against vascularpermeability, and will contribute to the development of novel therapeutic strategies for
TAGE-induced LSRD [84]. Therefore, vascular permeability is increased in the brain of DM
patients and the transfer of serum TAGE into the brain is promoted.
4.7. Cytotoxicity of TAGE in Cancer
TAGE appear to bind to RAGE, leading to the release of pro-inflammatory cytokines,
increased cellular damage, and the higher expression of VEGF in cancer cells [15,49].
Despite promising experimental evidence [26,27], there were no previous observational
studies on circulating TAGE and the risk of death among cancer survivors. Two cell culture
studies suggested that TAGE enhanced the migration and invasion of melanoma [26] andlung cancer cells [27], and thus may contribute to the progression of cancer.
4.7.1. Melanoma
In our previous study, we showed that the growth and migration of human melanoma
G361 cells were stimulated by TAGE [26]. Furthermore, neutralizing antibodies raised
against RAGE prevented the formation of tumors by melanoma cell xenografts in athymic
mice. Survival rates were higher in tumor-bearing mice, and the anti-RAGE antibody
suppressed spontaneous pulmonary metastases of melanoma. An examination of the beds

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9 of 22of human melanoma tumors and normal skin revealed the presence of detectable andnegligible levels of TAGE, respectively.
4.7.2. Lung Cancer
We also investigated the mechanisms by which TAGE increase the malignancy ofcancer using the lung cancer cell line A549. The findings obtained showed that (i) cellproliferation was suppressed by the addition of TAGE, (ii) TAGE significantly increased cell
migration and infiltration ability, and (iii) extracellular TAGE induced the production of
ROS via RAGE. Rac1 was activated by the production of ROS, which enhance cell migration
ability, while the activation of matrix metalloproteinase 2 promoted infiltration ability [27].
4.7.3. Pancreatic Cancer
PANC-1 cells were treated with GA, which induced the production of intracellular
TAGE and cell death. The high-molecular-weight complexes of heat shock proteins (i.e.,heat shock protein (HSP)90β, HSP70, and HSP27) were produced after the GA treatment
in a dose-dependent manner. We considered high-molecular-weight complexes to be
dimers and trimers with TAGE-mediated aggregation. Extracellular TAGE promoted
the proliferation of PANC-1 cells [42]. Therefore, although intracellular TAGE induce
pancreatic cancer cell death, their secretion and release may promote the proliferation ofother pancreatic cancer cells.
4.7.4. Colorectal Cancer (CRC)
TAGE possess pro-inflammatory and pro-oxidative properties, which may contributeto the progression of CRC and poor survival. The TAGE-RAGE axis has been suggested totrigger multiple signaling pathways (e.g., NF-κB and phosphatidylinositol 3 kinase/protein
kinase B), resulting in increases in the hyperproliferation and/or metastatic potential of
CRC cells and CRC progression. Furthermore, chronic hyperglycemia may facilitate thegeneration of AGEs, and has been associated with CRC progression via various metabolic
pathways, including the insulin growth factor pathway. These findings suggest thatinvestigations on TAGE in CRC survivors will provide novel insights into the preventionof CRC progression and improvements in CRC survival-related outcomes [29].
In other words, the TAGE-RAGE axis may increase malignancy from the growth stage
to the metastasis/infiltration stage of cancer cells by enhancing the production of ROS incancer cells.
4.8. Limitation
The TAGE stress and oxidative stress have been clarified in the research using hepatocytes [32], but the progress of the research involving the target molecule is still forthcoming.
The relationship between DM and oxidative stress is important in other cells, including
erythrocytes, and findings on various AGEs and active oxygen have been reported [43,85].
This review focuses on the findings related to TAGE, in order to distinguish it from thefindings of other AGEs and ALEs.
4.9. Brief Summary and Perspectives
The effects of AGEs have been attributed to their extracellular binding to RAGE or
their accumulation in numerous tissues; however, further studies are warranted to elucidate
the impact of intracellular TAGE. In vitro intracellular TAGE molecules have been shown toexert cytotoxic effects in hepatocytes [30,31,33], myoblasts [34], β-cells [35], osteoblasts [36],cardiomyocytes [37], cardiac fibroblasts [38], neuroblastoma cells [39], and pancreatic ductal
cells [42]. These molecules are intermediates of the abnormal metabolism of glucose andfructose in the presence of excess GA. The involvement of TAGE in apoptotic and/or
necrotic events, and hence cell death and tissue damage, has been suggested.

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5. Clinical Relevance of Circulating TAGE Levels and LSRD
The accumulation of intracellular TAGE contributes to a number of cellular disorders,
and their leakage into the extracellular space increases circulating TAGE levels. Therefore,
circulating TAGE levels have potential as novel biomarkers for predicting the onset andprogression of LSRD (Tables 1 and 2).
Table 1. Clinical relevance of circulating TAGE levels.
Subjects

Main Findings

Ref.

Apparently Healthy

Serum TAGE levels independently correlated with decreases in the number and migratory
activity of circulating EPC in apparently healthy subjects.

[86]

Serum TAGE levels were independent determinants of PAI-1 in the general population.

[87]

A positive relationship was observed between fibrinogen levels and serum TAGE levels.
TAGE-associated thrombogenic abnormalities may be involved in atherogenesis.

[75]

Flow-mediated vasodilation correlated with serum levels of TAGE and sRAGE, and the ratio of
TAGE to sRAGE.

[88]

Serum sRAGE levels were positively associated with serum TAGE levels.

[89]

LDL-C levels were independent determinants of serum TAGE levels.

[90]

Serum TAGE levels independently correlated with serum PEDF levels. PEDF levels may beelevated in response to TAGE levels as a counter system against TAGE-elicited tissue damage.

[91]

Serum TAGE levels independently correlated with the HOMA-IR index, suggesting that TAGE
play a pathological role in insulin resistance.

[92]

Adiponectin was inversely associated with the ratio of serum levels of TAGE to sRAGE andvascular inflammation.

[93]

Serum levels of apoB48 were correlated with TAGE, PEDF, and adiponectin (inversely).

[94]

Serum DPP-4 levels were independently associated with various metabolic parameters. TAGE
may up-regulate cellular DPP-4 expression and subsequently increase circulating levels of DPP-4.

[95]

Non-Diabetic Men

HOMA-IR was independently associated with high serum levels of TAGE and low testosterone.

[96]

Non-Diabetic Chronic
Kidney Disease (CKD)

Serum TAGE and sRAGE levels correlated with each other, and TAGE and HMGB-1 wereindependently associated with ADMA.

[97]

Serum sRAGE levels were positively associated with serum TAGE levels.

[98]

Serum sRAGE levels were positively associated with serum TAGE and sVCAM-1 levels.

[99]

Serum levels of TAGE and sRAGE were independent determinants of serum MCP-1 levels.

[13]

Serum TAGE levels were independently associated with vascular inflammation evaluated by
FDG-PET, suggesting that serum TAGE levels are a biomarker that reflects vascular inflammation
within an area of atherosclerosis.

[55]

Diurnal glycemic fluctuations (GF) were associated with the severity of CAD, even in prediabetic
patients. GF and TAGE levels may play a pathological role in the progression of CAD.

[21]

TAGE and medication for hypertension were independently associated with area of visceraladipose tissues, whereas medication for TAGE, DM, IMT, and PEDF were independent correlatesof subcutaneous adipose tissue areas.

[100]

Serum TAGE levels were independently associated with log TMA. The TAGE to sRAGE ratio
correlated with log TMAO, a marker of cardiometabolic disorders.

[101]

Serum TAGE and TNF-α levels were associated with LVEF and BNP values in patients withdiabetic adverse cardiac remodeling.

[102]

Serum TAGE levels correlated with poor follicular and embryonic development and a lower
likelihood of ongoing pregnancy.

[56]

Health Examination(General Population)

Non-Diabetic General
Population(Outpatients)

Type 2 DM

Cardiovascular
Disease (CVD)/Heart
FailureInfertile WomenCells 2022, 11, 2178

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Table 1. Cont.
Subjects

Main Findings

Ref.

Non-Alcoholic
Steatohepatitis(NASH)

Serum TAGE levels were significantly higher in NASH patients than in NAFL or healthy controls.
Moreover, TAGE inversely correlated with adiponectin.

[16]

Non-B or
Non-C-Hepatocellular
Carcinoma

Serum TAGE levels were significantly higher in NBNC-HCC patients than in NASH andcontrol subjects.

[18]

Colorectal Cancer

Serum TAGE levels were not associated with the risk of colon cancer, but showed a positive
association with the risk of rectal cancer.

[29]

Schizophrenia

Serum TAGE levels were significantly higher, and sRAGE levels were significantly lower inpatients with acute schizophrenia than in healthy controls.

[103]

Septic Shock Patients

Serum ADMA levels were significantly elevated in patients with septic shock, and serum TAGE
levels were independent determinants of ADMA.

[104]

Autoimmune
Uveoretinitis

Serum TAGE levels were significantly higher for each etiology of uveitis (HLA-B27, VKH disease,
Bechet’s disease, and sarcoidosis) than in healthy controls.

[105]

Diabetic Retinopathy/Nephropathy

In diabetic patients, serum TAGE levels increased as the stages of retinopathy andnephropathy developed.

[106]

Diabetic Retinopathy

A positive correlation was observed between vitreous levels of TAGE and VEGF in patients withdiabetic retinopathy.

[107]

TAGE, toxic AGEs; EPC, endothelial progenitor cells; PAI-1, plasminogen activator inhibitor-1; sRAGE, soluble
form of receptor for AGEs; LDL-c, low-density lipoprotein cholesterol; PEDF, pigment epithelium-derived
factor; HOME-IR, homeostatic model assessment of insulin resistance; DPP-4, dipeptidyl peptidase-4; HMGB1, high mobility group box 1; ADMA, asymmetric dimethylarginine; sVCAM-1, soluble form of vascular celladhesion molecule 1; MCP-1, monocyte chemoattractant protein 1; FDG-PET, fluorodeoxyglucose-positronemission tomography; IMT, intima-media thickness; TMA, trimethylamine; TMAO, trimethylamine N-oxide;
CAD, coronary artery disease; TNF-α, tumor necrosis factor-α; LVEF, left ventricular ejection fraction; BNP, brain
natriuretic peptide; NAFL, non-alcoholic fatty liver; NBNC-HCC, non-B or non-C-hepatocellular carcinoma; HLA,
leukocyte antigen; VKH, Vogt–Koyanagi–Harada; VEGF, vascular endothelial growth factor.

Table 2. Changes in circulating TAGE levels with treatment.
Subjects

Therapeutic Agents

Correlation Factor

Ref.

Healthy Humans

Collagen tripeptide(CTP)

A significant reduction in serum TAGE levels was observed in all
subjects and in the high-risk group after the CTP treatment.

[22]

Non-Diabetic CKD

Statin (Atorvastatin)

Atorvastatin may attenuate proteinuria in non-diabetic CKD withdyslipidemia partly by reducing serum TAGE levels.

[108]

Non-Diabetic
Hypertensive CKD

Calcium channel blocker(Azelnidipine)

A treatment with azelnidipine decreased serum levels of TAGE,
sRAGE, and proteinuria.

[109]

α-Glucosidase inhibitor(Acarbose)

A treatment with acarbose significantly decreased serum TAGE andfree fatty acid levels.

[14]

DPP-4 inhibitor(Alogliptin)

Serum TAGE levels were only reduced in patients with baseline
TAGE >7 U/mL after a treatment with alogliptin.

[110]

Sulfonyl urea
(Glimepiride)

Glimepiride may repair tissue damage by decreasing serum TAGE
levels.

[111]

Insulin (Glulisine)

Switching to multiple daily injection therapy with glulisine
decreased serum levels of TAGE and sRAGE.

[112]

Statin (Atorvastatin)

Atorvastatin decreased serum TAGE levels in
hypercholesterolaemic T2DM patients.

[113]

Statin(Pitavastatin/Atorvastatin)

Serum TAGE levels significantly decreased with statin therapy,
whereas sRAGE levels did not change.

[20]

Type 2 DM

JAPAN-ACSSub-Study

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Table 2. Cont.
Subjects

Therapeutic Agents

Correlation Factor

Ref.

SAMIT (Statin for Acute
Myocardial
Infarction Trial)

Statin (Atorvastatin)

Statin therapy initiated early after the onset reduced serum TAGE
levels, and may exert cardioprotective effects in patients with AMI.

[114]

DPP-4 inhibitor(Sitagliptin)

Ovarian dysfunction was attenuated, and ongoing pregnancy rates
were significantly increased in the group treated with sitagliptin,
which decreased serum TAGE levels.

[115]

Hishi (Trapa bispinosaRoxb.) extract

Hishi lowered serum TAGE levels and increased live births in older
patients with ART.

[116]

NASH with
Dyslipidemia

Statin (Atorvastatin)

Atorvastatin decreased serum TAGE levels in NASH patients withdyslipidemia.

[17]

Non-Diabetic
CRF Patients

Oral adsorbent(AST-120/Kremedin)

The administration of AST-120 significantly decreased serum TAGE
levels in non-diabetic CRF patients.

[117]

Hemodialysis(HD) Patients

L-Carnitine

The vasculoprotective properties of L-carnitine in HD patients may
be partly attributed to its inhibitory effects on TAGE.

[118]

Diabetic Retinopathy

Photocoagulation

A positive correlation was observed between vitreous levels of
TAGE and VEGF in patients with diabetic retinopathy sufficiently
treated with photocoagulation.

[119]

Infertile WomenCKD, chronic kidney disease; T2DM, type 2 diabetes mellitus; JAPAN-ACS, Japan assessment of pitavastatin
and atorvastatin in acute coronary syndrome; AMI, acute myocardial infarction; ART, assisted reproductive
technologies; CRF, chronic renal failure; VEGF, vascular endothelial growth factor.

5.1. Healthy Population (Apparently Healthy/General Population)
Endothelial progenitor cells (EPC) maintain the structure and function of the endothelium, and thus facilitate angiogenesis and vascular repair. High serum levels of TAGE
independently correlated with decreases in the number and migratory activity of circulating
EPC in healthy volunteers with normal blood test values [86], suggesting TAGE-induced
impairments in the repair of EC. We previously demonstrated that serum levels of TAGE,
but not HbA1c, Glu-AGEs, or CML, were associated with thrombogenic markers, including plasminogen activator inhibitor-1 and fibrinogen [75,87], in the general population.
Furthermore, correlations were reported between flow-mediated vasodilation and serum
levels of TAGE and the soluble form of RAGE (sRAGE), as well as the ratio of TAGE tosRAGE in health examinations [88]. In healthy volunteers administered collagen tripeptide,
an inhibitor of the generation of TAGE, the cardiac-ankle vascular index, an index of bloodvessel stiffness, was shown to decrease with reductions in serum levels of TAGE [22].
5.2. Non-Diabetic General Population (Outpatients)
We previously revealed that serum TAGE levels independently correlated with serum
levels of sRAGE [89], low-density lipoprotein cholesterol [90], serum pigment epitheliumderived factor, markers of insulin resistance (IR) [91], the homeostatic model assessmentof IR (HOMA-IR) index [92], adiponectin (inversely) [93,94], and dipeptidyl peptidase-4(DPP-4) [95] in a non-diabetic general population. We also found that HOMA-IR was
independently associated with high serum levels of TAGE and low testosterone [96]. Furthermore, TAGE and sRAGE levels correlated with each other, while TAGE and highmobility group box 1 were independently associated with asymmetric dimethylarginine(ADMA) in non-diabetic chronic kidney disease (CKD) patients [97]. Atorvastatin, a3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, may decrease proteinuria in nondiabetic CKD with dyslipidemia partly by reducing serum levels of TAGE [108]. The
calcium channel blocker, azelnidipine, but not amlodipine, decreased serum levels ofTAGE, sRAGE, and proteinuria [109]. Azelnidipine may exert renoprotective effects in
non-diabetic hypertensive CKD patients via its unique inhibition of the TAGE-RAGE axis.

Cells 2022, 11, 2178

13 of 225.3. Diabetic Outpatients
Serum TAGE levels were previously reported to be higher in diabetic patients than in
healthy controls [13]. A correlation was observed between serum TAGE levels and sRAGE,
which may reflect tissue RAGE expression, in non-diabetic and diabetic subjects [89,98,99],
indicating their potential as a biomarker for activation of the TAGE-RAGE axis. Correlations were also detected between serum TAGE levels and inflammatory biomarkers, suchas MCP-1 [13], and the soluble form of vascular cell adhesion molecule-1 [99] in type 2 DM.
We demonstrated significant reductions in serum TAGE levels in DM patients treated withacarbose for 12 weeks [14]. We also found that serum TAGE levels were significantly reduced by a DPP-4 inhibitor [110], sulfonyl urea [111], and insulin [112], and these decreases
were associated with reductions in the levels of biomarkers of organ damage in DM andCKD patients. Furthermore, we showed decreases in serum TAGE levels in T2DM patientstreated with atorvastatin [113]. Collectively, these findings indicate the potential of serum
TAGE levels as a new biomarker for the early diagnosis of LSRD or in assessments of theeffectiveness of therapeutic strategies to prevent/treat the onset and progression of LSRD
regardless of the presence/absence of DM.
5.4. CVD/Heart Failure
We previously reported the following:i.

ii.

Serum levels of TAGE, but not HbA1c or CML, independently correlated with vascular inflammation in outpatients using [18 F] fluorodeoxyglucose-positron emission
tomography [55];Among pre-DM patients, circulating levels of TAGE were significantly higher inthe high mean amplitude of the glycemic excursions (MAGE) group than in the
low MAGE group [21]. TAGE and medication for hypertension were independently
associated with area of visceral adipose tissues, whereas medication for TAGE, DM,
intima-media thickness, and PEDF were independent correlates of subcutaneous
adipose tissue areas [100].

TAGE were also independently associated with log trimethylamine. The TAGE tosRAGE ratio correlated with log trimethylamine N-oxide, a marker of cardiometabolic
disorders [101]. More recently, the levels of TAGE and TNF-α showed close associations
with left ventricular ejection fraction and brain natriuretic peptide values in patients withdiabetic adverse cardiac remodeling [102]. TAGE and TNF-α may play a pathologicalrole in the development of diabetic adverse cardiac remodeling. We previously reported
that elevated baseline TAGE levels were associated with the progression of plaques inan assessment of pitavastatin and atorvastatin in an acute coronary syndrome trial (TheJAPAN-ACS Sub-study) [20]. High baseline TAGE levels were associated with the progression of plaques in the JAPAN-ACS trial. Statin therapy was initiated early after the onset
reduced TAGE levels and appeared to exert cardioprotective effects in patients with acute
myocardial infarction [114].
5.5. Infertility
We previously reported age-related decreases in the number of oocytes collected
and pregnancy rates; ongoing pregnancy rates were also reduced in younger womenwith elevated serum TAGE levels [56]. Furthermore, correlations were observed between
serum TAGE levels and follicle development, fertilization, embryo development, andpregnancy in assisted reproductive technologies (ART), indicating the novelty and utility of
the accumulation of TAGE as an indicator of poor responders that is independent of age andday-3 follicle-stimulating hormone levels [56]. Among non-pregnant poor responders who
were administered the DPP-4 inhibitor, sitagliptin, and underwent ART, the ameliorationof ovarian dysfunction and significant increases in ongoing pregnancy rates were observedin those whose serum TAGE levels were decreased by sitagliptin [115]. A prospective
randomized open-label controlled trial was conducted on women undergoing ART withor without Hishi (a safe herbal medicine that markedly inhibits the formation of AGEs

Cells 2022, 11, 2178

14 of 22in vitro) extract. The cumulative live birth rate was significantly higher in Hishi patients
than in controls (47% vs. 16%). The live birth rate per embryo transfer, including freshand cryopreserved, was significantly higher with Hishi (28% vs. 10%). Hishi significantly
enhanced oocyte developmental potential, improved endometrial receptivity in natural
cycles, and decreased serum and follicular fluid levels of TAGE [116]. Collectively, thesefindings indicate the potential of serum TAGE levels as a biomarker in evaluations of theprevention, early diagnosis, and treatment of ovarian dysfunction.
5.6. NASH
NAFLD is a spectrum of diseases that ranges from NAFL to NASH, and is one of themost common causes of hepatic disease. We examined serum levels of AGEs (TAGE, GluAGEs, and CML) in NASH patients with no evidence of liver cirrhosis, in NAFL patients,
and in healthy controls [16]. The accumulation of TAGE in both tissue and serum washigher in NASH patients than in NAFL patients and healthy controls. A positive correlation
was observed between serum TAGE levels and HOMA-IR, while an inverse association
was noted between serum levels of TAGE and adiponectin levels. TAGE were present at
detectable levels in the hepatocytes of NASH patients, but at negligible levels in those of
NAFL patients, and Glu-AGE or CML levels did not significantly differ between thesegroups [16]. We previously reported that serum levels of TAGE in NASH patients withdyslipidemia were reduced by a treatment with atorvastatin [17]. A 6-month treatment
with atorvastatin significantly decreased the activities of liver alanine aminotransferaseand γ-glutamyl transpeptidase (γ-GTP) in all patients. Moreover, increases were observedin plasma adiponectin levels and decreases in plasma TNF-α levels in NASH and NAFL
patients, while serum levels of TAGE significantly decreased. Collectively, these findings
suggest the potential of serum levels of TAGE, but not Glu-AGEs or CML, as a biomarker
for predicting the progression of NASH.
5.7. Cancer (Non-B or Non-C (NBNC)-HCC and CRC)
5.7.1. NBNC-HCC
We previously reported that serum levels of TAGE were significantly higher in NBNCHCC patients than in NASH patients without HCC and in control subjects [18]. A multiple
regression analysis revealed that age and the levels of γ-GTP and high-density lipoproteincholesterol (inversely) independently correlated with TAGE levels. Therefore, TAGE appear
to play a role in the pathogenesis of NBNC-HCC, and thus have potential as biomarkers
for discriminating NBNC-HCC from NASH.
5.7.2. CRC
We conducted a large nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, in order to investigate the relationshipbetween TAGE and the risk of CRC [29]. A correlation was not observed between TAGE
concentrations and the risk of CRC. However, in a sub-group analysis, a positive correlation
was noted between TAGE and the risk of rectal cancer [29]. Additionally, the risk of rectal
cancer was higher in individuals who consumed alcohol. Substantial clinical evidence
supports a role for TAGE in the pathophysiology of DM and other LSRD [9,10]; however,observational studies have not yet been conducted among cancer survivors. During amean follow-up of 48 months, TAGE positively correlated with all-cause and CRC-specificmortality among patients with CRC. A stronger positive association between TAGE andmortality was observed among distal colon cancer cases (unpublished data). Therefore,
our findings support the direct association between serum TAGE and CRC-specific andall-cause mortality among CRC patients.
5.8. Schizophrenia and AD
We previously reported significant increases and decreases in TAGE and sRAGE
levels, respectively, in patients with acute schizophrenia, which remained stable over theCells 2022, 11, 2178

15 of 22clinical course [103]. Furthermore, patients with schizophrenia had a higher TAGE tosRAGE ratio than healthy control subjects. These findings confirmed the utility of TAGE in
addition to the TAGE to sRAGE ratio as diagnostic markers of schizophrenia. However,in neuropathological studies on schizophrenia without prominent neurodegeneration,schizophrenia is considered to be a functional disease, indicating the different roles ofincreases in TAGE levels in schizophrenia and neurodegenerative diseases. Previous studies
demonstrated that AD patients had significantly lower Aβ42 levels and significantly higher
total tau and p-tauT181 levels in cerebrospinal fluid (CSF) than age-matched healthy elderly
controls [120,121]. Furthermore, other AD biomarkers in the CSF, such as VEGF [122]and TGF-β1 [123], were elevated in AD patients. In our recent study, we showed thefollowing effects of the intracellular production of TAGE: reductions in the level of Aβ42
and increases in the levels of total tau and p-tauT181 in culture media, as well as increases in
the intracellular levels of total tau, p-tauT181, VEGF, and TGF-β in human neuroblastoma
SH-SY5Y cells [39]. Therefore, CSF and/or serum levels of TAGE have potential as a usefulbiomarker for the early detection of AD [124].
5.9. Other Diseases
ADMA levels were significantly elevated in patients with septic shock, and serum
TAGE levels were identified as independent determinants of ADMA [104]. Serum TAGE
levels were significantly higher for each etiology of uveitis (leukocyte antigen (HLA)B27, Vogt–Koyanagi–Harada (VKH) disease, Bechet’s disease, and sarcoidosis) than in
healthy controls [105]. In DM patients, serum levels of TAGE increased as the stages ofretinopathy and nephropathy developed [106]. The administration of AST-120 significantly
decreased serum levels of TAGE in non-diabetic chronic renal failure patients [117]. The
vasculoprotective properties of L-carnitine in HD patients may be partly attributed to its
inhibitory effects on TAGE [118]. We previously reported a positive correlation between
vitreous levels of TAGE and VEGF in patients with diabetic retinopathy [107] and in thosewith diabetic retinopathy treated with photocoagulation [119].
5.10. Brief Summary and Perspectives
High serum levels of TAGE predict the onset and progression of various LSRD, evenin healthy subjects with normal blood test values. Therefore, the findings of our seriesof studies indicate the potential of serum levels of TAGE as a useful biomarker for theprevention/early diagnosis of LSRD and in evaluations of the efficacy of treatments for
LSRD. The measurement of TAGE levels via specific competitive ELISA [9] may facilitate
the identification of high-risk patients and provide important information for treatment
decision-making in the future.
6. Conclusions and Perspectives
The habitual and excessive consumption of SSB, processed foods, and/or rice/bread/
noodles, which are characteristic of the modern daily diet, have been shown to elevate
cellular levels of GA, which, in turn, promotes the production of TAGE from intracellular
proteins [9–11]. Elevated levels of TAGE damage cells, which results in the leakage ofTAGE into the circulation, thereby elevating circulating TAGE levels. Moreover, the habitual and excessive consumption of dietary AGEs (mainly Glu-/Fru-AGEs) promotes theaccumulation of TAGE and up-regulates the expression of RAGE, resulting in TAGE-RAGE
interactions. Activation of the TAGE-RAGE axis leads to the production of ROS, which
up-regulate the expression of RAGE and promote the generation of TAGE, which havebeen implicated in the onset and progression of LSRD (Figure 3). Collectively, our findings
indicate that pre-diagnostic circulating TAGE levels are positively associated with LSRD.
The novel concept of the “TAGE theory” is expected to open new perspectives for research
into numerous diseases.

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Figure 3. The onset and progression of lifestyle-related diseases (LSRD) are associated with thehabitual excessive intake of sugars and/or dietary AGEs. TAGE are produced from the metabolite of
glucose, the main component of rice, bread, and noodles, as well as the metabolites of sugars (sucroseand HFCS) added to beverages and processed foods. Fluctuations in TAGE levels in the human bodyare closely associated with dietary habits. The chronic intake of excessive amounts of SSB, processed
foods, and/or rice/bread/noodles, which is characteristic of the modern daily diet, increases thecellular levels of the sugar metabolite glyceraldehyde (GA), which promotes the production of TAGE
from intracellular proteins. Elevated levels of TAGE damage cells, which results in the leakage ofTAGE into the circulation, thereby increasing circulating TAGE levels. Moreover, the habitual andexcessive consumption of excessive dietary AGEs (mainly Glu-/Fru-AGEs) promotes the accumulationof TAGE and up-regulates the expression of RAGE, resulting in TAGE-RAGE interactions. Activationof the TAGE-RAGE axis leads to the production of ROS, which up-regulate the expression of RAGE
and promote the generation of TAGE, which have been implicated in the onset and progression of
LSRD. SSB: sugar-sweetened beverages; HFCS: high-fructose corn syrup; AGEs: advanced glycation
end-products; GA: glyceraldehyde; TAGE: toxic AGEs; RAGE: receptor for AGEs; ROS: reactive
oxygen species; LSRD: lifestyle-related diseases; P-NH2 : free amino residue of protein.
Author Contributions: All authors contributed substantially to the preparation of this review (M.T.:
designed the review, original and revised draft preparation, review, and editing; A.S.-S., T.T., J.-i.T. andY.K.: review, and editing). All authors have read and agreed to the published version of the manuscript.
Funding: This research was supported by JSPS KAKENHI Grant Numbers 16H01811 & 21H04865(M.T.), 21K11583 (A.S.-S.), 21K11607 (T.T.), 19K11781 (Y.K.), and by a KAKEN Grant for Assistancefrom Kanazawa Medical University (K2019-24 & K2020-26 for M.T.).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are contained within the article.
Conflicts of Interest: The authors declare that no conflict of interest exist.

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