Search Results (969)

Background: Temporomandibular disorders constitute multifaced systemic impairments capable of compromising overall physiological homeostasis. This study compares oxidative and nitrosative stress biomarkers between patients with temporomandibular myofascial pain with referral and healthy controls. Methods: We enrolled 44 individuals with temporomandibular myofascial pain with referrals and 44 controls. The procedure involved clinical examination based on the Diagnostic Criteria for Temporomandibular Disorders and saliva collection. Biochemical determination involved advanced glycation end products (AGEs), advanced oxidation protein products (AOPPs), thiobarbituric-acid-reactive substances (TBARS), and total nitric oxide (NO). Results: Median concentrations of TBARS and total NO were significantly elevated in the study group relative to the controls (TBARS: 6.078 vs. 1.486; total NO: 138.6 vs. 23.82), whereas the concentration of AOPPs was significantly lower (151.1 vs. 505.3). Multiple regression revealed that myofascial pain was an independent predictor of the observed differences, even after we adjusted for age and salivary flow rate (TBARS: β = 4.78 [95% CI: 2.020, 7.541], _adjp = 0.0018; total NO β = 128.4 [95% CI: 82.70, 174.1] _adjp = 0.0004; AOPP β = −755.7 [95% CI: −1228, −283.5] _adjp-value = 0.0028. Conclusions: Myofascial pain with referral is independently associated with oxidative imbalance, highlighting the relevance of TBARS and total NO as promising severity biomarkers. The unexpected decrease in AGE and AOPP levels requires standardized studies to confirm diagnostic utility. Full article

Background/Objectives: Protein supplementation may elevate advanced glycation end products (AGEs) through higher dietary AGE (dAGE) content and increase amino acid-driven endogenous formation. Protein supplementation from different sources may differentially affect AGE levels, possibly through differences in amino acid composition, digestion and metabolism, but evidence from randomized controlled trials (RCTs) remains limited. This study aimed to examine the effect of protein supplementation from either casein (animal-based) or soy (plant-based) protein isolates on circulating, skin, and dAGE levels in older adults following a healthy dietary pattern (HDP). Methods: In this 16-week RCT, 55 older adults (mean age: 66 years old) in Singapore were assigned either to control (no supplementation), casein protein isolate supplementation, or soy protein isolate supplementation. This study was registered at clinicaltrials.gov as NCT05400005. Results and Discussion: Overall, there were no alterations in dietary, skin and total circulating AGE levels after protein supplementation when adhering to an HDP such as My Healthy Plate (MHP). However, different sources of protein supplementation resulted in differential changes in specific plasma AGE markers. Two-way ANOVA analysis showed that soy protein supplementation led to a significant increase in plasma N(6)-(1-carboxymethyl)-L-lysine (CML) compared to the other groups (week 0: 0.72 ± 0.10, week 16: 0.80 ± 0.10, p_int = 0.040), while a paired t-test showed that casein protein supplementation led to a significant within-group increase in plasma pentosidine (week 0: 0.77 ± 0.06, week 16: 0.80 ± 0.05, p-value = 0.045). Other AGEs showed no significant changes. Conclusions: Protein supplementation while adhering to MHP did not significantly influence overall circulating and skin AGEs in older adults in Singapore. A differential response was observed only for plasma CML levels with soy protein supplementation, whereas the within-group increase in plasma pentosidine following casein supplementation should be interpreted with caution and requires further investigation. Full article

The “unexplained failure” of rotator cuff repair is multifactorial, but its structural endpoint is anatomically consistent, i.e., the failure of the tendon-to-bone interface (enthesis) to heal. The native enthesis is a four-zone fibrocartilaginous gradient that does not regenerate but heals as a mechanically inferior fibrovascular scar, so the outcome of repair hinges on the interface’s healing capacity—which chronological age predicts poorly. This review organizes the aging biology governing bone-to-tendon healing capacity into eight domains: progenitor competence, cellular senescence and the SASP, immune aging, extracellular-matrix and collagen aging via advanced glycation end-product cross-linking, footprint angiogenesis, morphogen signaling, mechanotransduction, and bone quality. We then precisely define the DNA-methylation epigenetic clock—a continuous value produced by weighted CpG methylation, with defined units, reproducibility, and effect sizes—and propose it as a candidate quantitative readout of these domains; whether or not it truly integrates them into a single biologically meaningful measure at the enthesis is a hypothesis of this review, not an established mechanism. In 1087 twins, epigenetic age acceleration predicted fracture and osteoporosis risk, with hazard ratios of 1.29–3.17 per standard deviation; moreover, aging is tissue-specific, so the enthesis may run ahead of blood. Critically, the clock provides a single axis on which current regenerative-medicine strategies—stem cells, exosomes, immunomodulation, biomimetic gradient scaffolds, growth factors, senolytics, and epigenetic reprogramming—can be systematically categorized by how far each shifts biological age toward a healing-competent state; partial reprogramming, which rewinds the clock directly, shows that the clock is simultaneously the readout and the therapeutic target. We integrate this into a “hidden biological age of bone-to-tendon healing”, explicitly stating that this remains an unvalidated hypothesis requiring prospective validation. Full article

Introduction: Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus (DM). Among the established risk factors for DR, “metabolic memory” plays a key role. Its development is mainly driven by advanced glycation end-products (AGEs), some of which possess characteristic fluorescent properties. Aims: To examine the relationship between skin AGEs, noninvasively assessed through skin autofluorescence (SAF), and the presence and severity of DR in subjects with long-standing type 1 DM (T1DM) and no history of atherosclerotic cardiovascular disease. Methods: 81 subjects with T1DM and 45 healthy controls were included. All individuals underwent SAF measurements and fundus photographs were taken in subjects with T1DM. Associations between SAF, its change over time and the presence and severity of DR were analyzed. Results: A significant positive correlation was found between SAF and the severity of DR. Only SAF and renal parameters showed a significant positive association with the presence of sight-threatening DR (STDR). There was a statistically significant increase in SAF levels over 3 years in STDR. Conclusions: SAF, but not HbA1c or diabetes duration, was associated with the severity of DR. SAF may therefore represent a promising, rapid, and non-invasive biomarker for identifying individuals at increased risk of STDR. Full article

Advanced glycation end products arise during thermal processing and endogenous metabolism, contributing to oxidative stress, inflammation, and the progression of chronic diseases. Dietary polyphenols have emerged as promising advanced glycation end product (AGE) inhibitors through antioxidant activity, carbonyl trapping, metal chelation, and modulation of inflammatory pathways. This review summarizes current evidence on the effects of polyphenols in food systems and highlights how different polyphenol subclasses vary in their antiglycation potential depending on chemical structure, food matrix, and cooking conditions. Although experimental studies consistently demonstrate inhibitory effects, the translation to humans remains limited by low bioavailability, metabolic transformation, and heterogeneous analytical methods. Standardized AGE measurements are needed to improve mechanistic insight, and evaluations of dose–response relationships are needed to clarify their relevance in real-world diets. Future research should prioritize long-term human studies and practical culinary strategies to determine whether polyphenol-rich foods can meaningfully reduce dietary AGE exposure and support chronic disease prevention. Full article

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, pancreatic β-cell dysfunction, and dysregulated glucose and lipid metabolism. Sustained hyperglycemia and hyperlipidemia promote excessive reactive oxygen species (ROS) production, antioxidant defense depletion, and chronic low-grade inflammation, thereby aggravating insulin signaling impairment, β-cell injury, and diabetes-related complications. Although current glucose-lowering therapies have improved glycemic control, weight management, and cardiorenal outcomes, oxidative stress and inflammation remain incompletely addressed in many individuals with T2DM. Curcumin, a natural polyphenol derived from Curcuma longa L., exhibits antioxidant, anti-inflammatory, lipid-regulating, insulin-sensitizing, and tissue-protective activities. Evidence suggests that curcumin may alleviate T2DM-associated oxidative stress by suppressing ROS generation, reducing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, modulating the advanced glycation end-product/receptor for advanced glycation end-product (AGE/RAGE) axis, activating nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling, preserving mitochondrial homeostasis, and protecting β-cells. It may also inhibit nuclear factor-κB (NF-κB) and mitogen-activated protein kinase/c-Jun N-terminal kinase (MAPK/JNK) signaling, decrease pro-inflammatory cytokines and C-reactive protein (CRP), improve metabolic tissue inflammation, and attenuate gut-derived inflammation by regulating gut microbiota and intestinal barrier function. However, current clinical evidence mainly supports modest improvements in metabolic, inflammatory, oxidative stress-related, and selected complication-related biomarkers rather than definitive disease-modifying outcomes. Moreover, formulation heterogeneity, low bioavailability, limited pharmacokinetic reporting, and insufficient long-term endpoint data remain major translational barriers. This review summarizes the molecular mechanisms, clinical evidence, formulation-dependent interpretation, safety considerations, and translational limitations of curcumin as a candidate adjunctive intervention for T2DM, rather than as a replacement for evidence-based antidiabetic therapy. Full article

Background/Objectives: Methylglyoxal-derived hydroimidazolone-1 (MG-H1), an advanced glycation end product, has implications in the pathogenesis of diabetic kidney disease (DKD). Although liquid chromatography–mass spectrometry is the current gold standard for quantifying MG-H1, its overall complexity limits its utility. We developed an ELISA to measure MG-H1 using a specific monoclonal antibody. Methods: Competitive ELISA was used to quantify total, high-molecular-weight (HMW), and low-molecular-weight (LMW) MG-H1 in serum. The assay’s specificity was validated against structurally related compounds. Spike-and-recovery experiments were conducted to assess accuracy and precision. Serum samples from healthy controls, diabetic patients without kidney disease, and patients with DKD were analyzed (n = 10, 23, and 19, respectively). MG-H1’s correlation with renal biomarkers and diagnostic performance was assessed using receiver operating characteristic analyses. Results: The ELISA exhibited preferential reactivity toward MG-H1 compared with structurally related compounds. Spike-and-recovery experiments resulted in recovery rates ranging 108–119%. MG-H1 levels were increased in patients with DKD, although the magnitude of the changes varied among the MG-H1 forms. All MG-H1 forms correlated positively with serum creatinine and blood urea nitrogen, and negatively with estimated glomerular filtration rate. No significant correlations were observed with glycoalbumin, and only a modest association was observed between LMW MG-H1 and HbA1c. Exploratory ROC analyses suggested that all MG-H1 forms could discriminate DKD from DM, with total and HMW MG-H1 showing performance comparable to that of conventional renal function markers. Conclusions: This competitive ELISA enables high-throughput quantification of MG-H1 in serum and demonstrates analytical feasibility; further multicenter validation is required before clinical implementation. Full article

Background/Objective: Cinnamaldehyde (CA) is a naturally occurring bioactive compound derived from the leaves, bark, roots, and flowers of the Chinese medicinal plant Cinnamomum cassia. It exhibits a broad spectrum of pharmacological properties, encompassing antioxidant, antibacterial, anti-diabetic, antifungal, and anticancer activities. Notably, it has shown potential therapeutic benefits in the management of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Ochratoxin A (OTA), a common contaminant found in foods such as cereals, coffee, and raisins, is also present in traditional Chinese medicinal materials, including Astragalus and liquorice. T2DM and NAFLD share intertwined pathophysiological pathways, including insulin resistance, dyslipidaemia, chronic low-grade inflammation and oxidative stress, with insulin resistance serving as the common pathological hub for both conditions. Consequently, they frequently co-occur and exacerbate each other. OTA exerts dual-targeted toxicity to the pancreas and liver, which may synergistically drive the development of the comorbidity of T2DM and NAFLD. These two processes are mutually causal and together constitute the pathological basis of metabolic comorbidity. Methods: Network toxicology employs toxicological data, gene expression, and protein–protein interaction (PPI) networks to predict the targets of toxins, while network pharmacology, based on systems biology principles, reveals how drugs exert regulatory effects through multiple targets and pathways. In this study, we employed an integrated network toxicology and network pharmacology approach to jointly decipher the potential mechanisms by which CA intervenes in OTA-induced comorbid T2DM-NAFLD. First, a network toxicology approach was employed to preliminarily screen for core toxicological targets responsible for OTA’s pathogenicity. Subsequently, network pharmacology was used to identify potential targets of CA-mediated intervention in the disease. Finally, the common overlap among the CA intervention targets, OTA toxicity targets, and disease targets was defined as the final set of potential targets for CA-mediated intervention in OTA-induced T2DM-NAFLD comorbidity. A PPI network was constructed using the STRING database, and topological analysis was performed with Cytoscape. Core targets were selected using the median values of six parameters—betweenness centrality, closeness centrality, degree centrality, eigenvector centrality, LAC (local average connectivity) score, and network centrality—as cut-off thresholds, and the top 10 key genes were further identified using the cytoHubba plugin. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database, and the results were visualized on the CNSknowall platform. Lastly, molecular docking of the core targets was performed using the CB-DOCK2 platform to validate binding affinity. Results: Based on an integrated analysis of network toxicology, network pharmacology, and molecular docking, 10 key targets were systematically identified. These may serve as potential mediators of cinnamaldehyde in the treatment of OTA-induced T2DM-NAFLD comorbidity. Among these, six targets—albumin (ALB), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), interleukin-6 (IL-6), tumor necrosis factor (TNF), actin beta (ACTB), and estrogen receptor 1 (ESR1)—possess crystal structures amenable to molecular docking. KEGG enrichment analysis revealed that CA and OTA jointly participate in key pathological processes such as the cancer pathway, the lipid and atherosclerosis pathway, the advanced glycation end-products–receptor for advanced glycation end-products (AGE-RAGE) signaling pathway, the phosphatidylinositol 3-kinase–protein kinase B (PI3K-Akt) signaling pathway, the TNF signaling pathway, and the interleukin-17 (IL-17) signaling pathway. OTA exacerbates inflammatory responses, impairs insulin signaling, promotes hepatic steatosis, and disrupts systemic metabolic homeostasis, ultimately contributing to T2DM-NAFLD comorbidity. Conversely, cinnamaldehyde counteracts these pathological processes through multiple mechanisms, including antioxidant and anti-inflammatory effects as well as regulation of glucose and lipid metabolism, thereby restoring metabolic homeostasis. Conclusions: This study has preliminarily identified the toxicological targets of OTA and the potential intervention targets of CA, offering new avenues for preventing and intervening in OTA-induced metabolic toxicity. Furthermore, it provides a theoretical basis for CA as a potential multi-target therapeutic agent and presents novel insights worthy of further investigation into the prevention of T2DM-NAFLD comorbidity. Full article

While Alzheimer’s disease (AD) is primarily considered a disorder of protein aggregation, converging evidence from clinical, neuropathological, and mechanistic studies strongly supports the notion that brain endothelial dysfunction is a primary and early event in AD pathogenesis. Brain endothelial pathways are among the most differentially expressed in human AD brains. Brain endothelial alterations precede amyloid deposition and cognitive deficits in experimental AD models and closely parallel the degree of neuronal loss in human AD brains. Despite growing evidence to support brain endothelial contributions to neurodegeneration, studies examining the potential of the brain endothelium as a druggable target in AD have been scarce. Further, there has been a relative paucity of validated fluid biomarkers that can reliably measure brain endothelial injury in AD, independently of overt vascular disease or disruption to other cerebrovascular constituents. In this perspective, we propose a brain endothelial glycocalyx-centric model of AD in which brain endothelial dysfunction, driven predominantly by non-enzymatic glycation and carbonyl stress, acts as a key upstream regulator of aberrant protein trafficking, blood–brain barrier instability, and dysregulated neuro-immune cascades. Further, recent evidence suggests the presence of direct interactions of the brain endothelium with key pathways involved in neuronal survival and synaptic signaling, highlighting potential direct contributions of brain endothelial disturbances to cognitive impairment. Within this framework, we identify several brain endothelial axes, including reduction in carbonyl stress, improved glycation-dependent signaling, attenuation of advanced glycation end-product (AGE)-mediated toxicity, and enhanced endothelial glycocalyx stability and resilience as potential therapeutic approaches in AD. Modulating brain endothelial glycation has potential as a novel therapeutic strategy in AD which may complement other disease-modifying treatments, particularly in the earliest preclinical stages. In conclusion, this framework positions the brain endothelium as a mechanistic hub linking metabolic stress to aberrant protein aggregation and neurodegeneration in AD with potential therapeutic implications in AD and other neurodegenerative disorders. Full article

The geropsychosis hypothesis proposes that anxiety, mood, psychotic, and neurocognitive disorders may share a common biophysical origin with aging itself, rather than arising from wholly disparate pathological routes in many instances. Specifically, we postulate that these conditions may emerge from the bioaccumulation of metals, advanced glycation end products (AGEs), advanced lipoxidation end products (ALEs), and their hybrid complexes in post-pubescent individuals. Such inputs may drive self-reinforcing molecular feedback loops underlying clinically meaningful insults against the nervous system, extending emerging conceptualizations of aging to mental health. Through comprehensive analysis of upstream molecular damage and neural function, this framework offers a mechanistic foundation for conceptualizing several mental disorders as emerging from a unified source. In doing so, the geropsychosis hypothesis may help identify new therapeutic targets and intervention strategies to address underlying contributors to psychiatric pathology. Full article

High fructose intake rapidly induces protein glycation, oxidative stress, inflammation, and disturbances in the cultivable fraction of gut bacteria, contributing to early metabolic impairment. This study examined whether selected plant-derived bioactives and a prebiotic–probiotic formulation could mitigate fructose-induced biochemical and microbial alterations. Male Wistar rats were fed fructose for 45 days, and advanced glycation end product (AGE)-associated fluorescence, oxidative stress markers, and lipid peroxidation were measured to assess metabolic changes. Culture-dependent enumeration of intestinal and fecal bacteria was performed to evaluate shifts in cultivable aerobic and facultative bacterial counts, while limonene, eugenol, and emodin were tested for antibacterial activity against aerobic and facultative bacterial isolates obtained from fructose-fed rats during our previous study. The prebiotic–probiotic formulation was assessed alone and in combination with these bioactives. Fructose feeding increased protein glycation, oxidative stress, lipid peroxidation, and reduced counts of cultivable gut bacteria. Treatment with the bioactives and the formulation lowered glycation-related fluorescence, reduced oxidative stress, and decreased lipid peroxidation. The bioactives exhibited antioxidant and antiglycation activity and inhibited growth of selected cultivable bacterial isolates, including Corynebacterium stationis. While emodin contributed primarily through its known α-glucosidase inhibitory and antiglycation properties rather than antibacterial activity. Combined treatment partially restored cultivable bacterial counts and improved metabolic parameters. Overall, the interventions attenuated fructose-induced biochemical disturbances and modulated the cultivable gut bacterial counts, suggesting a complementary approach to managing early metabolic changes in rats associated with high fructose intake. Full article

Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression. Full article

Background/Objectives: Chronic complications of diabetes mellitus are closely associated with increased oxidative stress and the formation of advanced glycation end products (AGEs). This study aimed to investigate the antioxidant and antiglycation potential of hesperetin-7-O-glucoside (HCD) and diosmetin-7-O-glucoside (DCD) formulations complexed with cyclodextrins, using in vitro and in silico experimental models to evaluate their efficacy in mitigating hyperglycemia-induced molecular damage. Methods: Antioxidant activity was assessed using chemical and erythrocyte-based oxidative stress models, whereas antiglycation activity was evaluated in BSA–fructose, BSA–methylglyoxal, and arginine–methylglyoxal models. Results: Both formulations showed measurable antioxidant effects, with concentration-dependent behavior observed in some of the evaluated assays. In the DPPH assay, HCD and DCD achieved maximum inhibition values of 30.71% and 26.61%, respectively. Furthermore, DCD exhibited higher total antioxidant capacity (102.80 µg vitamin C equivalents/mL) and nitric oxide scavenging activity (37.89%) than HCD. In a cellular model, both formulations (200 µg/mL) significantly reduced AAPH-induced hemolysis, with DCD providing superior protection (7.05% vs. 16.63% for HCD). Under oxidative stress induced by high glucose concentration in erythrocytes, HCD and DCD reduced non-protein thiol levels, and HCD significantly increased catalase enzyme activity. Regarding antiglycation activity, DCD demonstrated superior efficacy relative to HCD in the BSA-fructose system, achieving 43.23% inhibition. DCD also displayed concentration-dependent inhibition of fructosamine formation (up to 47.99%) and BSA glycation by methylglyoxal (up to 45.20%). Both formulations significantly reduced carbonylated protein levels and preserved free thiol groups. In the arginine–methylglyoxal model, DCD and HCD reached 44.03% and 48.82% inhibition, respectively. Molecular docking revealed high binding affinity of both flavonoids to the protein active site (−9.00 kcal/mol for hesperetin-7-O-glucoside and −9.04 kcal/mol for diosmetin-7-O-glucoside), suggesting a structural protective role. Conclusions: The HCD and DCD formulations demonstrated antioxidant and antiglycation activities that may contribute to attenuating molecular alterations associated with chronic hyperglycemia through complementary mechanisms, including antioxidant effects, protection against protein carbonylation, and inhibition of glycation. While these findings highlight the potential of the evaluated formulations, additional mechanistic and in vivo studies are required to establish their pharmacological applicability. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) not only improve glycemic control but also possess anti-inflammatory and antioxidant properties. In this study, the effects of semaglutide and liraglutide on oxidative stress and wound healing were examined in human dermal fibroblasts (NHDFs) and keratinocytes (NHEKs) under diabetes-mimicking conditions. Cells were exposed to high glucose and hydrogen peroxide, followed by treatment with semaglutide or liraglutide at concentrations of 22.5 and 45 pg/mL for 48 h. We assessed cell viability, apoptosis, intracellular reactive oxygen species (ROS), Ki-67, and Pax-7. Advanced glycation end-products (AGEs) and their receptor (RAGE) were quantified via ELISA. Wound healing was evaluated by scratch assay, and the gene expression of antioxidants, cytokines, and matrix components was measured by real-time PCR. Semaglutide significantly improved NHDF viability and proliferation under diabetic conditions, reducing ROS production more effectively than liraglutide. Apoptosis decreased, evidenced by increased Bcl-2 alongside decreased Bax and cleaved caspase-3, particularly with semaglutide. Furthermore, semaglutide uniquely activated Pax-7 expression. While both agents upregulated antioxidants, semaglutide more effectively suppressed AGEs/RAGE and inflammatory cytokines. Both drugs enhanced collagen expression and accelerated wound closure; however, semaglutide achieved near-complete healing within 48 h. Neither drug induced observable changes in NHEKs. Semaglutide exhibits strong antioxidative, cytoprotective, and pro-regenerative effects in diabetic NHDFs, outperforming liraglutide across multiple parameters. These findings highlight semaglutide’s therapeutic potential for diabetic wound healing, warranting further in vivo investigation. Full article

Ageing is characterized by progressive metabolic and inflammatory dysregulation, in which methylglyoxal (MGO), a highly reactive dicarbonyl by-product of glycolysis, is involved in the formation of advanced glycation end products (AGEs). This review provides an integrated overview of the bidirectional relationship between MGO-derived carbonyl stress and the gut microbiota, focusing on its implications for ageing and age-related diseases. We summarize current evidence on MGO production, clearance, tissue distribution, and reactivity, with particular attention to the intestinal lumen as a site where dietary compounds, host metabolism, and microbial activity converge. Age-related dysbiosis may impair intestinal barrier integrity, alter microbial metabolite production, and promote chronic low-grade inflammation, thereby reinforcing metabolic dysfunction and favoring free MGO accumulation. Conversely, MGO and AGEs can reshape microbial communities, compromise epithelial tight junctions, and amplify inflammatory signalling through receptor-dependent and independent mechanisms. Evidence from in vitro, animal, and clinical studies supports a role for the MGO–microbiota axis in metabolic, cardiovascular, gastrointestinal, neurodegenerative, and frailty-related conditions. Targeting microbiota composition, intestinal barrier function, and MGO scavenging pathways may therefore represent a promising strategy to mitigate carbonyl stress and preserve health during ageing. Full article