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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

To compare two 16-week high-load, velocity-intentional resistance training programs-elastic bands (HL-VIRT-EB) vs. water-based (HL-VIRT-AQ)-combined with creatine or placebo supplementation on neuroplasticity, oxidative stress, inflammation, strength, physical function, cognition, and quality of life in older adults. In a randomized controlled trial, 103 community-dwelling older adults (57 women, 46 men; 68.2 ± 4.6 y) were assigned to HL-VIRT-EB + Creatine, HL-VIRT-EB + Placebo, HL-VIRT-AQ + Creatine, HL-VIRT-AQ + Placebo, Control+Creatine, or Control+Placebo. Training was performed 3×/week (60 min). Creatine was consumed daily (3 g). Outcomes included brain-derived neurotrophic factor, F2-isoprostanes (F2-iso), glutathione peroxidase (GPx), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), isokinetic strength (knee/elbow, 60°·s Both training modalities produced significant improvements in neurocognitive biomarkers, oxidative/inflammatory profiles, strength, functional performance and quality of life (p < 0.05). HL-VIRT-AQ yielded greater reductions in F2-iso and TNF-α and larger gains in functional tests compared to HL-VIRT-EB (d = 0.12-1.18), which elicited superior upper-limb strength gains. Creatine provided additional benefits, increasing GPx, reducing IL-6/TNF-α and improving strength and function when combined with exercise modalities. Creatine alone reduced F2-iso and TNF-α and improved perceived health versus placebo. High-load, velocity-intentional resistance training-on land or in water-effectively improves neurocognition, oxidative balance, inflammation, strength, function, and quality of life in older adults. Aquatic training is particularly effective for attenuating oxidative stress and inflammation. Creatine supplementation confers complementary, modality-specific benefits and supports their use in combination to high-speed resistance exercise to promote healthy aging. NCT06620666 (ClinicalTrials.gov). Show less

The accumulation of Aβ plaques and hyperphosphorylation of Tau neuropathologically characterize Alzheimer's disease (AD). Synaptic dysfunction and endoplasmic reticulum (ER) stress precede overt neuropathology. ER stress is characterized by the accumulation of unfolded/misfolded proteins, which leads to activation of the adaptive signaling pathway, the unfolded protein response (UPR). Chronic or unresolved ER stress, as in disease, is maladaptive and triggers the integrated stress response (ISR). We hypothesize that targeted attenuation of ISR activation would mitigate the early cognitive deficits and molecular pathology in the triple transgenic (3xTg) mouse model of AD. To test this hypothesis, we used an adeno-associated viral (AAV) vector to overexpress BiP, the key ER chaperone and UPR regulator, in the hippocampi of young 3xTg mice. BiP overexpression reduced phosphorylated PERK (pPERK), a marker of ISR activation, and increased synaptic proteins BDNF, PSD95, and choline acetyltransferase marker (ChAT). Hippocampal-dependent working memory, social memory, long-term spatial memory, and REM theta power were improved without changes in locomotion. BiP overexpression reduced neuroinflammation, as evidenced by a decrease in the astrocyte marker GFAP. Additionally, Aβ and Aβ42 levels were reduced in the hippocampus and cortex. Collectively, these findings indicate that modulation of ER stress via BiP overexpression ameliorates early cognitive and molecular alterations associated with AD. Show less

Nutrition is crucial for mental well-being and enhancing cognitive performance. Food restriction (FR), a moderate reduction in food intake, results in multiple effects on brain function. Most studies of FR have been conducted on adult animals rather than young ones. This study examines the acute effect of early-onset FR, starting at four-week age, on behavioral performance, molecular changes, and histological changes. Young mice were randomly assigned to four experimental groups: Control-1, Control-2, FR1, and FR2 groups. The control groups had free access to food, while the FR1 and FR2 groups experienced food deprivation for 12 h each day (7 pm to 7 am) over periods of 30 and 60 days, respectively. The average body weight of the mice was measured at the start and end of the study. The exploratory action, anxiety-like behaviors, and passive avoidance memory were evaluated using open field, elevated plus maze, and shuttle box devices. Histologic changes were assessed using H&E staining. The antioxidant capacity and alterations in gene expressions (BDNF and Inflammatory markers) were estimated in the hippocampus using FRAP methods and qRT-PCR, respectively. In young mice, 12-hour daily restricted feeding negatively affects cognitive, psychological, and exploratory behaviors. FR leads to a drop in antioxidant capacity, histological changes in the CA1 and CA3 regions, increased expression of inflammatory genes, and reduced BDNF expression. In summary, our outcome indicates that FR worsens brain oxidative stress, promotes inflammation in the brain, and eventually damages hippocampal neurons in young mice. Show less

Docosahexaenoic acid (DHA), one of the most critical polyunsaturated fatty acids, is vital for the neurological growth and cognitive function of infants and children. Approximately 98% of DHA in breast milk exists as triglycerides, with 60% esterified at the sn-2 position. To demonstrate the necessity of mimicking the form of DHA present in breast milk in nutritional food for young children, this study administered diets with varying sn-2 DHA contents (10%, 30%, and 50%) to four groups of mice and analyzed their behavioral performance, brain DHA concentration, expression of brain fatty acid transport proteins, histopathology, and expression of synaptic-related proteins in the hippocampus after 4 weeks. The results showed that compared with the control group, mice in the 50% sn-2 DHA group exhibited superior learning and memory capabilities in behavioral tests, with the most pronounced behavioral improvements in mice, which correlated with higher brain DHA accumulation (from 0.870 ± 0.055 mg/g brain to 1.809 ± 0.132 mg/g brain, p < 0.05), increased levels of MFSD2A (1.40-fold, p > 0.05), FABP5 (2.36-fold, p < 0.05), FATP1 (1.47-fold, p < 0.05), and ACSL6 (1.48-fold, p < 0.05), improved hippocampal neuron morphology, and enhanced the level of BDNF (1.55-fold, p < 0.05), SYN (1.45-fold, p < 0.05), and PSD-95 (1.57-fold, p < 0.05). These findings establish a foundation for developing DHA nutritional supplements. Show less