Aerobic conditioning and ginsenoside modulation modify molecular resilience in middle-aged rats: Differential effects of individual and combined interventions

Hippocampal aging is characterized by early cognitive decline, disrupted redox homeostasis, and shifts in amyloid processing. This study evaluated the modulatory effects of aerobic exercise and ginseng supplementation, both individually and concurrently, against these alterations. Middle-aged Wistar rats (n = 30) were allocated into young control, middle-aged control, exercise, ginseng supplementation, and combined intervention groups, and assessed through T-maze and Morris Water Maze tasks. Hippocampal integrity was examined with Cresyl violet staining and Nrf2 protein immunohistochemistry. Gene expression of APP and BACE1 was quantified by quantitative PCR, and systems biology analyses identified the AMPK/SIRT1 signaling axis as a regulatory mechanism. Behavioral assessments revealed that while individual interventions ameliorated age-related deficits in spatial learning and memory, the combined treatment showed no significant benefit in the T-maze and performed worse than exercise monotherapy in the Morris Water Maze. Histological analysis demonstrated preserved CA1 pyramidal neuron density across treatment groups. Crucially, molecular analysis revealed a robust downregulation of the amyloidogenic pathway through the suppression of BACE1 transcription and the potentiation of Nrf2 nuclear translocation, indicative of enhanced antioxidant defense. Gene profiling supported the AMPK/SIRT1 signaling axis as a central molecular hub, suggesting that exercise and ginsenosides effectively modulate pathways to repress BACE1 transcription. These findings demonstrate that aerobic conditioning and ginseng supplementation promote molecular resilience and cellular homeostasis, providing a protective strategy against early age-related hippocampal vulnerability associated with upregulated Nrf2-positive cell counts and suppressed BACE1 transcription.