Wild blueberry-derived polyphenol metabolites attenuate telomere shortening in an in vitro model of metabolic syndrome

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Abstract Purpose Metabolic syndrome (MetS) is a multifactorial disorder characterized by metabolic alterations that increase cardiovascular risk and may accelerate telomere attrition, potentially contributing to age-related diseases. Dietary (poly)phenols (PPs), including those derived from blueberries (BB), may counteract telomere shortening through their multitarget biological effects; however, additional mechanistic studies are required. This study investigated the effects of BB-derived PP metabolites, ferulic acid (FA), isoferulic acid (IA), vanillic acid (VA), and hippuric acid (HA), on telomere length (TL) in an in vitro MetS model. Methods The MetS model was established using THP-1 monocytes exposed to free fatty acids and TNF-α. Metabolites were tested individually and in combination (MIX) at physiologically relevant concentrations (0.1–50 µM). Cytotoxicity, telomere length, and intracellular reactive oxygen species (ROS) were assessed. Results The MetS stimulus significantly reduced TL (mean difference − 0.61; 95% CI − 0.80 to − 0.41; p < 0.001). Pre-treatment with FA (1 µM), VA (0.5–5 µM), and MIX (6.1 µM) significantly attenuated telomere attrition, restoring TL compared to the control (mean differences 0.30–0.37; p < 0.05), whereas lower concentrations of FA, IA, and HA were ineffective. ROS modulation was context-dependent: PP metabolites did not directly affect basal ROS levels but modified the response to H 2 O 2 exposure, with VA (5 µM) and the MIX (6.1 µM) exacerbating H 2 O 2 -induced ROS generation under MetS conditions. Conclusion These findings indicate that selected BB-derived PP metabolites could mitigate telomere shortening under metabolic stress independently of acute ROS modulation, supporting a potential role of dietary PPs in preserving genomic integrity under MetS-like conditions.