This review integrates animal and human research to examine the neurobiological mechanisms through which exercise protects and restores brain function. It highlights the impact of physical activity on hippocampal structure and function, including spatial memory, pattern separation, neurotrophic factors, and vasculature. Key findings include: 1. **Hippocampal Structure and Function**: Exercise enhances hippocampal-dependent spatial memory and relational memory, particularly in tasks requiring pattern separation. Studies in both animals and humans show that exercise improves hippocampal volume and function, which correlate with better cognitive performance. 2. **Neurotrophic Factors**: Exercise increases levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF), which support neural survival, growth, and synaptic plasticity. These factors are crucial for cognitive function and may mediate the benefits of exercise on the brain. 3. **Synaptic Plasticity**: Exercise induces long-term potentiation (LTP) in the dentate gyrus (DG) of the hippocampus, enhancing synaptic plasticity and neurogenesis. This is associated with increased spine density and improved learning and memory. 4. **Neurogenesis**: Exercise more than doubles new neuron production in the young and aged brain, particularly in the DG. This neurogenesis is regulated by neurotrophins and immune cells, and it correlates with improved synaptic plasticity and memory. 5. **Angiogenesis**: Exercise increases brain endothelial cell proliferation and angiogenesis, particularly in the hippocampus. This may enhance blood flow and protect against cognitive decline. 6. **Genetics and Epigenetics**: Genetic background and (epi)genetic modifications influence the neurogenic response to exercise. For example, the APOE gene, which has three alleles (e2, e3, e4), affects cognitive function and the response to physical activity. The e4 allele is associated with an increased risk of cognitive decline, but physically active individuals with this allele show reduced cognitive decline compared to sedentary carriers. Overall, the evidence suggests that exercise benefits brain function and cognition across the mammalian lifespan, potentially reducing the risk of Alzheimer's disease in humans. The review emphasizes the importance of cross-species, multi-method research to bridge the gap between animal and human studies and to better understand the mechanisms underlying the benefits of physical activity on the brain.This review integrates animal and human research to examine the neurobiological mechanisms through which exercise protects and restores brain function. It highlights the impact of physical activity on hippocampal structure and function, including spatial memory, pattern separation, neurotrophic factors, and vasculature. Key findings include: 1. **Hippocampal Structure and Function**: Exercise enhances hippocampal-dependent spatial memory and relational memory, particularly in tasks requiring pattern separation. Studies in both animals and humans show that exercise improves hippocampal volume and function, which correlate with better cognitive performance. 2. **Neurotrophic Factors**: Exercise increases levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF), which support neural survival, growth, and synaptic plasticity. These factors are crucial for cognitive function and may mediate the benefits of exercise on the brain. 3. **Synaptic Plasticity**: Exercise induces long-term potentiation (LTP) in the dentate gyrus (DG) of the hippocampus, enhancing synaptic plasticity and neurogenesis. This is associated with increased spine density and improved learning and memory. 4. **Neurogenesis**: Exercise more than doubles new neuron production in the young and aged brain, particularly in the DG. This neurogenesis is regulated by neurotrophins and immune cells, and it correlates with improved synaptic plasticity and memory. 5. **Angiogenesis**: Exercise increases brain endothelial cell proliferation and angiogenesis, particularly in the hippocampus. This may enhance blood flow and protect against cognitive decline. 6. **Genetics and Epigenetics**: Genetic background and (epi)genetic modifications influence the neurogenic response to exercise. For example, the APOE gene, which has three alleles (e2, e3, e4), affects cognitive function and the response to physical activity. The e4 allele is associated with an increased risk of cognitive decline, but physically active individuals with this allele show reduced cognitive decline compared to sedentary carriers. Overall, the evidence suggests that exercise benefits brain function and cognition across the mammalian lifespan, potentially reducing the risk of Alzheimer's disease in humans. The review emphasizes the importance of cross-species, multi-method research to bridge the gap between animal and human studies and to better understand the mechanisms underlying the benefits of physical activity on the brain.