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

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 H2O2 exposure, with VA (5 µM) and the MIX (6.1 µM) exacerbating H2O2-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.