10.3389/fpsyg.2012.00132

Vollständiger Abstract

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High-fructose diet (HFD) has emerged as a critical dietary risk factor for metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease. This review delineates the molecular mechanisms underlying the pathological cascade linking high-fructose intake, gut dysbiosis, chronic inflammation, and accelerated aging. At the metabolic level, excess fructose is rapidly phosphorylated by ketohexokinase (KHK), depleting intracellular ATP while driving overproduction of uric acid and reactive oxygen species (ROS). These events activate the NLRP3 inflammasome and NF-κB signaling, promoting hepatic <i>de novo</i> lipogenesis. At the microbial level, chronic fructose loading selectively depletes butyrate-producing taxa (<i>Faecalibacterium prausnitzii</i>, <i>Roseburia</i> spp.) while enriching Gram-negative Proteobacteria pathobionts, elevating luminal lipopolysaccharide (LPS) concentrations. Butyrate deficiency downregulates tight junction proteins (ZO-1, occludin, claudin-1), compromising intestinal barrier integrity, enabling systemic LPS translocation and establishing metabolic endotoxemia. At the inflammatory level, circulating LPS sustains TLR4-MyD88-NF-κB axis activation, driving chronic overexpression of TNF-α, IL-6, and IL-1β, establishing a self-reinforcing "inflammaging" network centered on the dysbiosis → leaky gut → endotoxemia → NF-κB → NLRP3 loop. At the aging level, sustained inflammatory signaling accelerates biological aging through five interconnected pathways: (1) cellular senescence and paracrine propagation of the senescence-associated secretory phenotype (SASP); (2) ROS-mediated telomeric oxidative damage coupled with DNA damage response-NF-κB activation; (3) mitochondrial dysfunction driving SASP transcription via the mtROS-cGAS-STING axis; (4) inflammation-induced epigenetic clock acceleration through aberrant DNMT3A/B targeting and asymmetric H3K27ac/me3 remodeling; and (5) immunosenescence encompassing TEMRA accumulation, Treg dysfunction, and M1 macrophage polarization, closing a self-sustaining inflammatory loop. At the intervention level, five strategic categories are synthesized: dietary modification (fructose restriction, Mediterranean diet); probiotic and prebiotic microbial restoration; bile acid FXR/TGR5 modulation with exogenous SCFA supplementation; senolytic, NAD⁺ precursor, and mTOR/AMPK-targeted pharmacotherapy; and fecal microbiota transplantation for systemic reconstitution. Clinical evidence demonstrates measurable improvements in glycemic regulation, insulin sensitivity, and SASP attenuation, though individual responses are substantially modulated by baseline microbiota composition. This review provides an integrative framework for understanding HFD-driven accelerated aging and establishes an evidence base for multilevel, precision-guided anti-inflammaging interventions.

Abstract: PubMed · Datensatz