Bioactive compounds and exercise in aging and neurodegeneration: mechanistic insights from the gut–brain–metabolic axis

Aging and neurodegenerative disorders are associated with impaired hippocampal plasticity, yet existing literature largely examines exercise, nutrition, or metabolic regulation in isolation. This review synthesizes emerging evidence supporting an integrative neuro-nutritional-metabolic framework in which bioactive compounds and physical exercise converge to modulate hippocampal neurogenesis, synaptic plasticity, and cognitive resilience. Recent investigative efforts elucidate the neuro-nutritional-metabolic axis as a pivotal interface that integrates bioactive compounds derived from diet, systemic metabolic processes, and neuronal functionality. In this review, the term 'neuro-nutritional-metabolic axis' refers to an integrative framework describing the bidirectional interactions among dietary bioactive compounds, systemic metabolic regulation, and central nervous system plasticity. This concept extends established models such as the microbiota-gut-brain axis and muscle-brain communication by emphasizing their convergence on metabolic and neurotrophic signaling pathways relevant to hippocampal function. Simultaneously, physical exercise is acknowledged as a significant modulator of neurotrophic signaling pathways, mitochondrial performance, and neuroinflammatory responses. This review synthesizes mechanistic evidence derived predominantly from preclinical studies alongside emerging but comparatively limited clinical findings to evaluate how bioactive compounds and physical exercise interact to influence hippocampal plasticity and cognitive function. We examine the convergence of these interventions on essential molecular pathways, as well as antioxidant and anti-inflammatory cascades, to facilitate neuronal survival, synaptic reorganization, and cognitive resilience. Moreover, we investigate their potential to mitigate metabolic dysfunction, oxidative stress, and chronic inflammation, which are pivotal factors contributing to cognitive deterioration in the context of aging and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. Comprehending these synergistic interactions lays the groundwork for formulating tailored, multimodal interventions that specifically address the neuro-nutritional-metabolic axis to enhance memory retention, optimize learning processes, and support cognitive resilience and may contribute to the modulation of risk factors associated with neurodegenerative conditions.