Blueberry Anthocyanins Alleviate Testicular Aging in Middle-Aged Mice by Targeting Inflammaging and Reprogramming the cAMP-Wnt and Methionine-NAD+ Metabolic Axes.

Abstract

Emerging evidence suggests that inflammaging contributes significantly to male reproductive senescence and oxidative stress, yet safe, non-invasive interventions that act on the upstream regulatory circuitry of the spermatogonial niche remain elusive. Here we investigated the restorative potential of a high-anthocyanin Blueberry Anthocyanin Extract (BAE) in a middle-aged murine model, integrating physiological monitoring, histopathology, and paired testicular transcriptomics and metabolomics to resolve the molecular logic of BAE-mediated rejuvenation. BAE prevented age-associated physiological deterioration without detectable toxicity, reversed seminiferous tubule degeneration, and restored sperm kinematics. Mechanistically, multi-omics integration converged on three coordinated regulatory modules rather than a single pathway. First, BAE engaged adenylyl cyclase-cAMP-PKA signaling to license canonical Wnt/β-catenin activity, driving spermatogonial proliferation (PLZF, PCNA, c-Myc, Ccnd1). Second, BAE suppressed ROS-dependent IKK/NF-κBNF (p65) activation, lowering testicular and systemic TNF-α and IL-6 and resolving the pro-inflammatory niche. Third, BAE reprogrammed the methionine cycle and elevated NAD+, activating the AMPK-SIRT1-PGC1α axis while restraining leucine- and methionine-driven mTORC1 signaling, thereby coupling redox balance to cell-cycle re-entry. Collectively, these data identify BAE as a dual-action, immunometabolic modulator that simultaneously reactivates the spermatogonial proliferative program and dismantles the inflammaging circuit. By concurrently targeting the cAMP-Wnt, ROS-NF-κB, and methionine-NAD+ axes, high-anthocyanin BAE offers a mechanism-based functional-food strategy to delay male reproductive aging and preserve fertility.

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