Environmental Enrichment Attenuates Aging-Induced BBB Disruption and Cognitive Impairment with Activation of FNDC5/Irisin Signaling

Aging disrupts the neurovascular unit (NVU) and blood–brain barrier (BBB), elevates glial inflammatory tone, and compromises hippocampal memory. Environmental enrichment (EE)—a multimodal, lifestyle-based intervention—improves cognition, but its association with BBB/NVU and FNDC5/irisin-related signaling in aging remains incompletely understood. Aged male C57BL/6J mice (21 months old) were housed under EE or standard conditions for 11 weeks. Hippocampal-dependent spatial working memory was assessed using the radial eight-arm maze, and neuronal (NeuN), glial (Iba1, GFAP), and BBB/NVU markers (AQP4 endfoot polarity, occludin, ZO-1, PECAM-1, microvessel length/density) were quantified. FNDC5/irisin-related signaling was evaluated by measuring PGC-1α, FNDC5/irisin, IGF-1, BDNF, pAKT, and serum irisin. EE improved spatial working memory in aged mice, reducing working-memory errors, increasing correct choices before the first error, and enhancing path efficiency. EE attenuated the age-related decline of NeuN(+) neurons in the hippocampal CA1 and CA3 regions and suppressed microglial and astrocytic activation. EE strengthened BBB/NVU integrity by restoring AQP4 endfoot polarity, increasing occludin, ZO-1, and PECAM-1, and increasing cortical microvessel length and density. At the molecular level, EE upregulated the PGC-1α–FNDC5/irisin–IGF-1 axis and was accompanied by increased cortical BDNF and pAKT levels, as well as elevated circulating irisin, changes that occurred in parallel with NVU stabilization and reduced glial activation. EE mitigates age-related cognitive decline in association with coordinated neuronal, glial, vascular, and FNDC5/irisin-related signaling changes, supporting BBB/NVU preservation and cognitive resilience during aging.