Beyond Nutrient Composition: AGEs and Food Neo-Contaminants in Ultra-Processed Food Toxicity

1. Introduction

The incidence of diabetes and its cardiovascular, kidney, and metabolic complications—collectively recognized as cardiovascular-kidney-metabolic (CKM) syndrome—has risen markedly in recent years, paralleling a substantial increase in ultra-processed food (UPF) consumption [1,2,3]. Current data indicate that the United States and the United Kingdom have the highest levels of UPF intake, with such foods accounting for more than half of daily caloric intake; by contrast, countries with more traditional dietary patterns, such as Romania and Colombia, show some of the lowest levels of UPF consumption [4]. Despite strong epidemiological associations between UPF intake and adverse health outcomes, the specific factor or factors responsible for these harmful effects remain incompletely characterized.

A defining feature of many UPFs is the large-scale industrial use of thermal processing to enhance flavor, texture, microbiological safety, and shelf life. Although heat processing improves palatability, UPFs are also associated with increased appetite, excess energy intake, and the development of obesity [5]. Moreover, high-temperature processing creates conditions that favor the formation of AGEs and other neo-contaminants, including acrylamide, furan, 5-hydroxymethylfurfural, lipid oxidation products, and heterocyclic amines [6].

This review advances the hypothesis that AGEs and other thermally generated neo-contaminants are major contributors to the metabolic toxicity of UPFs, acting through pathways that promote oxidative stress, inflammation, insulin resistance, and tissue dysfunction. We synthesize current evidence on the formation, dietary exposure, and biological effects of these compounds and evaluate their relevance to metabolic disease risk in support of this hypothesis.

2. Dietary AGEs

2.1. Formation of AGEs in Food

AGEs arise mainly through the Maillard reaction, a non-enzymatic reaction between free amino groups and the carbonyl groups of reducing sugars; they also form through oxidative reactions involving sugars, lipids, and amino acids. Commonly measured and well-characterized AGEs include pentosidine, Nε-carboxymethyllysine (CML), Nε-carboxyethyllysine (CEL), and the methylglyoxal-derived MG-H1 [Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine] [6]

CML is a prototypical AGE and one of the earliest identified glycoxidation products. It forms primarily when lysine residues react with glyoxal (GO), a highly reactive α-dicarbonyl generated during oxidative degradation of reducing sugars, advanced Maillard reactions, and autoxidation of Amadori products. Under high-temperature, low-moisture conditions, the ε-amino group of lysine reacts with glyoxal to produce stable CML adducts [7]. CML is also considered an advanced lipoxidation end product (ALE), reflecting its formation through lipid-derived pathways: peroxidation of polyunsaturated fatty acids generates reactive aldehydes, including glyoxal, which can produce CML independently of sugar availability. This pathway is especially relevant in fat-rich and ultra-processed foods, where lipid oxidation and Maillard chemistry often occur together [8]. Under glycoxidative conditions, Amadori products undergo metal-catalyzed oxidation, generating reactive dicarbonyls that further accelerate CML formation; this process links oxidative stress to AGE accumulation and helps explain why oxygen exposure during food processing and storage promotes CML generation [9].

CEL, another well-characterized AGE, is structurally related to CML but differs in precursor chemistry: it forms through the reaction of methylglyoxal (MGO) with the ε-amino group of lysine. Because MGO is more reactive than glyoxal, CEL formation is particularly relevant in carbohydrate-rich, thermally processed foods [10]. Methylglyoxal promotes post-translational modification of peptides and proteins, ultimately leading to AGEs including the arginine-derived hydroimidazolone MG-H1 and CEL [11]. CEL forms both in biological systems (in vivo) and during food processing (ex vivo). In the body, CEL generation is closely linked to intermediary metabolism, particularly under hyperglycemia or increased glycolytic flux, where MGO production is elevated—a process especially relevant in metabolic diseases such as diabetes mellitus, in which AGE accumulation contributes to tissue damage and chronic inflammation [12]. In processed foods, CEL formation also results from advanced Maillard reactions favored by high temperature and low moisture; during heating, degradation of sugars and lipids generates dicarbonyl compounds, including MGO, which react with food proteins to yield CEL and other AGEs [13]. Oxidative degradation of unsaturated fatty acids likewise generates MGO and related carbonyl species, reinforcing the interplay between Maillard chemistry and lipid oxidation in complex food systems; in experimental model systems, oxidized lipids markedly enhance CEL formation in protein-rich matrices [8].

2.2. Dietary Exposure to AGEs

Quantifying human exposure to dietary AGEs has advanced substantially over the past few decades, driven by the development of food composition databases and improvements in analytical chemistry. A foundational resource is the Uribarri et al. database [14], which catalogued AGE content in more than 500 foods prepared using diverse cooking methods. This database has enabled estimation of dietary AGE intake in both clinical and epidemiological studies and has been widely used to link high AGE intake to oxidative stress, inflammation, diabetes, and cardiovascular disease.

Despite its influence, the Uribarri database has important methodological constraints. AGE quantification relied primarily on immunochemical assays—particularly ELISA targeting CML—which capture only a narrow subset of the chemically diverse AGE family. Because AGEs encompass dozens of structurally distinct compounds formed through Maillard chemistry, lipid oxidation, and sugar degradation, reliance on a single marker likely underestimates total dietary exposure. Additional variability arises from differences in food preparation, moisture content, and thermal conditions, which can dramatically alter AGE formation yet are difficult to standardize across studies. The lack of standardization across analytical techniques, variability in preparation conditions, and the inherent difficulty of translating experimental measurements into real-world exposure estimates remain major challenges.

Recent advances have begun to address these limitations. The Glycation Database developed at Abertay University compiles thousands of analytically measured glycation compounds—including early Maillard intermediates, reactive dicarbonyls, and advanced AGEs—across a wide range of foods [15]. Parallel improvements in LC–MS/MS have markedly increased sensitivity and molecular specificity, enabling quantification of individual AGEs such as CML, CEL, and MG-H1, as well as their precursors. These technologies also allow examination of how processing variables—temperature, duration, pH, water activity, and oxygen exposure—influence AGE formation in real food systems [16].

Together, these developments highlight both progress and persistent uncertainty in estimating dietary AGE exposure. Although modern databases and mass spectrometry–based methods offer improved resolution, substantial challenges remain because of the complexity of food matrices and the dynamic nature of industrial processing. Consequently, dietary AGE estimates should be interpreted cautiously, particularly in epidemiological studies where exposure misclassification may obscure true associations with metabolic disease.

2.3. Transit of Food AGEs Through the Gastrointestinal Tract

Only a small fraction of food-derived AGEs is absorbed in the small intestine and reaches the circulation. Unabsorbed AGEs pass into the colon, where they may still exert systemic effects—either directly, by acting on the colonic wall to induce local inflammation, or indirectly, by interacting with the colonic microbiota to yield degradation products with or without harmful effects [6]. The influence of dietary AGEs on the colonic microbiota is an area of increasing interest [17].

2.4. Mechanisms of AGE-Induced Toxicity

AGEs exert pathogenic effects through two major mechanisms: direct biochemical modification of proteins, and activation of cellular signaling pathways via receptors such as RAGE (Figure 1). These complementary processes generate a self-amplifying cycle of oxidative stress, inflammation, and tissue dysfunction that is highly relevant to CKM syndrome [18].

1. Structural modification of proteins. AGEs irreversibly modify extracellular matrix proteins such as collagen and elastin, promoting cross-linking, stiffening, and loss of elasticity. These alterations impair vascular compliance, increase pulse-wave velocity, and contribute to hypertension and microvascular injury. AGE-mediated cross-linking also disrupts matrix turnover by reducing proteolytic susceptibility, accelerating the accumulation of dysfunctional matrix proteins in vascular, renal, and cardiac tissues. These changes are particularly pronounced for AGEs such as CML, CEL, and pentosidine, which accumulate under chronic hyperglycemia, oxidative stress, and high dietary AGE intake [19].

2. Activation of RAGE signaling. The second major mechanism involves binding of AGEs to RAGE, a multiligand pattern-recognition receptor expressed on endothelial cells, smooth muscle cells, immune cells, and adipocytes. Engagement of RAGE initiates a broad inflammatory and oxidative signaling program: AGE–RAGE interaction activates NADPH oxidase, driving reactive oxygen species (ROS) production, and stimulates transcription factors including NF-κB, MAPKs, and JAK/STAT [19,20]. Key downstream consequences include:

• Amplification of oxidative stress through NADPH oxidase activation and mitochondrial dysfunction
• NF-κB–driven inflammation, with increased expression of TNF-α, IL-6, IL-1β, VCAM-1, and ICAM-1
• Endothelial dysfunction via reduced nitric oxide bioavailability and eNOS uncoupling
• Enhanced leukocyte adhesion and vascular infiltration, promoting atherosclerotic plaque formation
• Positive-feedback upregulation of RAGE, sustaining chronic inflammatory activation

This self-reinforcing loop is central to the progression of vascular injury, insulin resistance, and metabolic dysfunction.

3. Metabolic consequences: insulin resistance and adipose dysfunction. AGE–RAGE signaling interferes with insulin receptor signaling by activating stress kinases (e.g., JNK, p38 MAPK) that inhibit IRS-1 phosphorylation and downstream PI3K–Akt signaling, leading to impaired glucose uptake, increased insulin resistance, and adipose tissue dysfunction. In adipose tissue, AGEs promote macrophage infiltration, reduce adiponectin secretion, and impair lipid handling, contributing to systemic insulin resistance and dyslipidemia [20].

4. An integrated toxicity model. Together, structural protein modification and RAGE-mediated signaling create a biochemical environment characterized by oxidative stress, chronic inflammation, endothelial dysfunction, and impaired metabolic regulation. These mechanisms provide a coherent framework linking high dietary AGE intake—particularly from UPFs—to the development and progression of diabetes, cardiovascular disease, kidney injury, and the broader CKM syndrome.

3. Food Neo-Contaminants Beyond AGEs

In addition to AGEs, thermal processing generates a diverse group of chemical contaminants—collectively termed neo-contaminants—that arise from Maillard chemistry, sugar dehydration, amino acid pyrolysis, and lipid oxidation. Neo-contaminants formed during cooking and industrial thermal processing include acrylamide, furan, 5-hydroxymethylfurfural (HMF), heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs), and chloropropanols such as 3-MCPD and glycidol. These compounds have traditionally been studied for carcinogenic potential, but accumulating evidence indicates that several also exert metabolic, endocrine, and inflammatory effects highly relevant to the toxicity profile of UPFs [21].

A unifying feature of these contaminants is their co-generation with Maillard-derived flavor compounds. Highly browned foods—fried snacks, roasted coffee, grilled meats—produce attractive aromas that activate reward pathways and may help explain the potentially addictive appeal of high-AGE, highly processed foods. This sensory reinforcement may amplify exposure to neo-contaminants while simultaneously driving excess caloric intake [22]. Figure 2 shows the chemical structures of several neo-contaminants of interest.

1. Acrylamide. Acrylamide forms predominantly through the Maillard reaction between asparagine and reducing sugars during high-temperature, low-moisture processing (>120 °C) [23]. It is classified as a probable human carcinogen, but its toxicological profile extends beyond carcinogenicity [24]. Acrylamide and its metabolite glycidamide induce oxidative stress, neurotoxicity, reproductive toxicity, and DNA adduct formation. Importantly, emerging evidence identifies acrylamide as a metabolic disruptor that promotes adipogenesis, dysregulates lipid and glucose metabolism, and exacerbates insulin resistance—effects that are particularly pronounced in individuals with diabetes [25]. These findings position acrylamide as a plausible obesogenic, linking UPF consumption to metabolic disease through endocrine-disrupting pathways [26].

2. Furan. Furan is a highly volatile compound generated from the thermal degradation of carbohydrates, amino acids, polyunsaturated lipids, carotenoids, and ascorbic acid. It is abundant in roasted coffee, jarred baby foods, canned products, and cereal-based snacks [27,28,29,30,31]. Classified as a possible human carcinogen, furan undergoes metabolic activation by CYP2E1 to form cis-2-butene-1,4-dial (BDA), a reactive electrophile that forms adduct with proteins and nucleic acids. Furan exposure induces hepatotoxicity, nephrotoxicity, oxidative stress, inflammation, and epigenetic alterations [32]. Margin-of-exposure analyses consistently indicate potential public health concern, especially for infants consuming thermally processed baby foods.

3. 5-Hydroxymethylfurfural (HMF). HMF arises from sugar dehydration and Maillard reactions in carbohydrate-rich foods such as baked goods, coffee, honey, fruit juices, and dairy products [33,34,35]. Although less acutely toxic than acrylamide or furan, HMF can convert to reactive derivatives—including chloromethylfurfural and sulfoxymethylfurfural—that exhibit mutagenic and cytotoxic properties. High HMF concentrations have been associated with mucosal irritation, oxidative stress, and potential contributions to neurodegenerative, cardiovascular, and metabolic disorders [33,34,35]. Notably, correlations between HMF and acrylamide levels in fried and baked foods suggest that HMF may serve as a practical indicator of acrylamide formation in industrial processing [36,37].

4. Heterocyclic amines (HCAs). HCAs form during high-temperature cooking of protein-rich foods, particularly meats and seafood, through reactions involving amino acids, creatine/creatinine, and sugars. They fall into two major categories [38]:

• Pyrolytic aminocarbolines (ACs), generated at >300 °C (grilling, roasting, frying)
• Amino-imidazo-azaarenes (AIAs), formed at 100–300 °C (pan-frying, baking)

Several HCAs—including MeIQx, PhIP, Glu-P-1, and IQ—are classified as Group 2A/2B carcinogens. Beyond mutagenicity, HCAs promote oxidative stress, inflammation, and endocrine disruption. Chronic exposure has been linked to colorectal, breast, and prostate cancer risk, and emerging evidence suggests that HCAs may impair metabolic homeostasis through mitochondrial stress and inflammatory signaling.

5. Polycyclic aromatic hydrocarbons (PAHs). PAHs form during incomplete combustion of organic matter, particularly in charred or smoked foods. Several PAHs (e.g., benzo[a]pyrene) are potent carcinogens and endocrine disruptors. Their lipophilicity facilitates bioaccumulation in adipose tissue, where they may contribute to chronic inflammation and metabolic dysfunction [39].

6. 3-MCPD and glycidol. Chloropropanols such as 3-monochloropropane-1,2-diol (3-MCPD) and glycidol form during high-temperature refining of vegetable oils and in baked or fried foods containing fats. Glycidol is highly genotoxic, forming DNA adducts and inducing heritable mutations. Both compounds impair reproductive function, disrupt steroidogenesis, and induce oxidative stress. Given the widespread use of refined oils in UPFs, chloropropanol exposure represents a significant and underappreciated metabolic risk [40].

Integrated Perspective

Although historically studied in isolation, these neo-contaminants share several mechanistic features with one another and with AGEs:

• Generation under industrial thermal conditions typical of UPFs
• Promotion of oxidative stress and inflammation
• Endocrine disruption and metabolic impairment
• Synergistic toxicity when multiple contaminants co-occur
• Coupling with reward-enhancing Maillard aromas that drive overconsumption

Collectively, these compounds form a chemical signature of UPFs that extends far beyond macronutrient composition. Their combined biological effects provide a compelling mechanistic framework linking UPF consumption to obesity, insulin resistance, diabetes, cardiovascular disease, and CKM syndrome [21].

4. Dietary AGEs and Food Neo-Contaminants as Determinants of UPF Toxicity

Food composition and processing are complex, and multiple mechanisms—acting independently or together—may explain the adverse effects of UPFs. AGE generation during industrial processing and home cooking satisfies several criteria implicating AGEs as major contributors to UPF toxicity [18]:

1. AGEs are generated in food during thermal treatment, whether industrial or domestic.

2. Specific food-derived AGEs, such as CML, are structurally and physiologically indistinguishable from their endogenous counterparts.

3. Specific AGEs, including CML, whether endogenous or exogenous, have been shown to injure multiple cell systems and tissues.

4. Oral administration of labeled AGE loads in humans demonstrates absorption into the circulation, with most eliminated in urine and some retained in the circulation and tissues.

5. AGE-enriched diets induce insulin resistance or type 2 diabetes in mouse models, whereas low-AGE diets prevent these outcomes [41,42].

6. Healthy human subjects consuming AGE-enriched diets show increased inflammatory and insulin-resistance markers [43].

7. Individuals with insulin resistance or type 2 diabetes who consume AGE-enriched diets show increased inflammatory and insulin-resistance markers, whereas low-AGE diets exert the opposite effect [44,45].

Taken together, the temporal relationship between AGE exposure and insulin resistance, along with their covariation, supports a plausible causal relationship.

Substantial evidence links AGEs with insulin resistance and diabetes. The food neo-contaminants discussed here have been most strongly associated with carcinogenicity and hepatotoxicity, whereas evidence for their metabolic effects is less consistent. Nevertheless, several of these compounds may contribute to insulin resistance, β-cell dysfunction, obesity, and ultimately type 2 diabetes. Because the strength of evidence varies considerably across compounds, compound-specific mechanistic and translational studies are needed.

In Table 1 we show Advanced glycation end product and neo-contaminants content in common UPF considering CML column from highest to lowest. Additionally heat map show harmonized concentrations (μg/kg ) of advanced glycation end products (CML and CEL) and neo-contaminants (acrylamide, furan, and 5-HMF). (Figure 3).

5. Strategies to Reduce Formation of AGEs and Other Neo-Contaminants During Processing and Cooking

5.1. Cooking Methods That Reduce AGE Formation

A substantial body of evidence indicates that dietary AGE exposure is influenced more strongly by cooking method than by the intrinsic composition of raw foods. This largely reflects activation of the Maillard reaction, a non-enzymatic process involving reducing sugars and proteins or lipids that depends strongly on heat, time, and moisture [14,46].

Dry-heat methods—grilling, baking, roasting, and frying—are consistently associated with markedly increased AGE formation. These techniques can raise AGE levels several-fold relative to raw foods, primarily because they involve high temperatures (>140 °C), low water activity, and enhanced lipid oxidation [14,47]. Under these conditions, well-characterized AGE compounds such as CML and MG-H1 form in substantial amounts, as elevated temperature and reduced moisture promote advanced stages of the Maillard reaction and accelerate protein modification and oxidative processes [16,47]. Frying is among the most potent promoters of AGE accumulation because high temperatures, lipid-rich environments, and prolonged cooking times enhance both glycation reactions and the formation of additional harmful compounds, including acrylamide [48]. Protein- and fat-rich foods, such as meats and cheeses, are especially susceptible to AGE formation during dry-heat cooking because of their high content of reactive amino groups and lipid-oxidation products [14].

Moist-heat methods—boiling, steaming, poaching, and low-temperature water-based cooking—are associated with substantially lower AGE formation, primarily because of lower temperatures (typically around 100 °C), higher moisture content, and reduced oxidative conditions (49). Water limits the Maillard reaction by diluting reactants and reducing thermal degradation, thereby inhibiting AGE formation; as a result, moist-heat methods generally produce substantially lower AGE concentrations than dry-heat techniques [46,49].

5.2. Emerging Technologies to Reduce AGEs in UPFs

Several emerging technologies for mitigating AGE formation in UPFs have been reported [21], including optimized thermal approaches such as low-temperature vacuum heating [50], vacuum microwave and infrared heating, and non-thermal technologies such as high-pressure processing [51], pulsed electric fields [52], ultrasound [53], and cold plasma [54]. These technologies reduce AGE formation by limiting thermal exposure, decreasing the accumulation of reactive carbonyl compounds, and reducing protein and lipid oxidation. Nanomaterials have also shown potential to reduce and control AGE generation [55]. Early work focused on metallic nanomaterials—including gold, silver, selenium, palladium, platinum, zinc oxide, and cadmium nanoparticles—which demonstrated effective AGE inhibition owing to their unique electronic structures and surface properties [56].

5.3. Exogenous Additives

Functional additives such as food gels are gaining attention for their ability to enhance the stability of bioactive compounds like polyphenols during processing, which may help reduce AGE formation [57,58]. Natural antioxidants have also shown potential to inhibit glycation pathways and scavenge reactive intermediates involved in AGE generation [59]. A recent review highlights encapsulated polyphenols and other bioactive-compound protection systems as promising strategies for reducing AGE formation during thermal processing [60]. However, few studies simulate AGE formation during thermal processing, and fewer still use real food systems. Wang et al. therefore suggested that future research incorporate high-temperature models—such as lysine–reducing sugar and arginine–reducing sugar systems—focusing on the stability of these additives and their inhibitory effects on AGEs [21].

5.4. Reversal of Glycation: Is It Possible?

AGEs have long been regarded as irreversible products of protein aging, but recent findings challenge this paradigm. Trabosh et al. demonstrated that CML can be enzymatically removed from proteins and aged human tissues using an engineered enzyme (CMLase), suggesting that at least some forms of glycation-derived protein damage may be reversible. Further studies are required to determine whether such molecular repair is feasible and whether it translates into functional recovery in vivo [61].

6. Conclusions

The available evidence supports the view that thermal processing contributes significantly to the adverse health profile of UPFs by promoting the formation of AGEs and multiple food neo-contaminants with inflammatory, oxidative, metabolic, and toxicological effects. Although the strength of evidence differs across compounds, the convergence of mechanistic, experimental, and human data suggests that reducing exposure to these processing-derived products may represent an important strategy for lowering cardiometabolic risk.

Future Directions. Future research should refine exposure assessment, identify the most biologically relevant compounds and food sources, clarify dose–response relationships, and evaluate whether practical changes in food processing, product formulation, and cooking practices can reduce AGE and neo-contaminant burden without compromising food safety, nutrition, or acceptability.