Multiple exercise modalities—endurance, high-intensity intervals, and resistance training—alongside ketogenic diets and intermittent fasting all elevate brain-derived neurotrophic factor (BDNF) through distinct molecular mechanisms. Key pathways include PGC-1α-FNDC5-BDNF activation, lactate signaling, enhanced cerebral blood flow, and stimulation of TrkB, IGF-1, irisin, and cathepsin B. Nutritional interventions appear to work through β-hydroxybutyrate and Notch 1 signaling pathways.
This convergent evidence strengthens the case for lifestyle medicine targeting neurodegeneration, particularly as populations age. The mechanistic diversity suggests multiple therapeutic entry points rather than reliance on single interventions. However, the field remains fragmented by methodological inconsistencies—varying exercise protocols, blood collection timing, and cognitive assessments make cross-study comparisons problematic. The focus on middle-aged and older adults is strategically sound given BDNF's established role in synaptic plasticity and neuronal survival. While promising for cognitive preservation, the research landscape needs standardized protocols to identify optimal intervention timing, intensity, and individual responsiveness factors. This represents incremental but important progress in understanding how modifiable lifestyle factors can mechanistically protect against age-related cognitive decline.
