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Physical exercise and nutritional strategies have become powerful tools for improving brain health, boosting cognitive performance, slowing cognitive decline, and reducing the risk of neurodegenerative diseases, primarily by influencing neurotrophic factors such as brain-derived neurotrophic factor (BDNF). This review examines the impact of various exercise types (endurance, high-intensity interval training, and resistance) along with dietary approaches (ketogenic diet and intermittent fasting) on BDNF, with a focus on their potential to promote cognition and neuroprotective benefits, particularly in the middle-aged and older population. Several molecular and physiological pathways may be involved, including activation of the PGC-1α-FNDC5-BDNF pathway, lactate signaling, increased blood flow to the brain and body, splenic platelet release, and stimulation of TrkB, IGF-1, irisin, and cathepsin B. Nutritional interventions may also boost BDNF through mechanisms involving β-HB and Notch 1 signaling. Research from both animal and human studies highlights the potential benefits of exercise and dietary modifications in supporting brain health and cognitive function. However, differences in study design and methodological limitations make it difficult to draw firm conclusions. These effects appear to be influenced by factors such as exercise characteristics (intensity, modality, and duration), the timing of blood collection, and the type of cognitive assessments. Future studies should focus on identifying the most effective intervention protocols and mechanisms, as well as understanding the individual factors that influence responsiveness to neurotrophic changes. Overall, targeted exercise and dietary strategies offer a promising approach to maintain brain health and reduce cognitive decline associated with aging and disease. Show less

High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK-ERK-CREB-BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline. Show less