| Rank |
Pathway / Axis |
Cancer Cells |
Normal Cells |
Label |
Primary Interpretation |
Notes |
| 1 |
Insulin / IGF-1 signaling |
↓ IGF-1 signaling (tumor context) |
↑ or ↓ IGF-1 (age- and baseline-dependent normalization) |
Driver |
Growth-signal reprogramming |
Exercise normalizes IGF-1 toward age-appropriate levels while reducing tumor-promoting signaling |
| 2 |
AMPK → mTOR nutrient sensing |
↑ AMPK; ↓ mTOR (growth restraint) |
↑ AMPK; ↓ mTOR (metabolic optimization) |
Driver |
Energy-sensing reprogramming |
Repeated AMPK activation enforces catabolic signaling incompatible with tumor anabolism |
| 3 |
Immune surveillance (NK cells, T cells) |
↑ immune-mediated tumor pressure |
↑ immune competence |
Driver |
Enhanced antitumor immunity |
Exercise mobilizes NK cells and improves immune trafficking into tumors |
| 4 |
Mitochondrial metabolism / metabolic flexibility |
↓ metabolic advantage |
↑ mitochondrial capacity and flexibility |
Secondary |
Energy efficiency divergence |
Normal cells adapt metabolically; cancer cells lose relative advantage |
| 5 |
Reactive oxygen species (ROS) |
↑ ROS (secondary, transient) |
↑ transient ROS → adaptive signaling |
Secondary |
Hormetic redox signaling |
Exercise induces transient ROS that act as signals rather than toxins |
| 6 |
Glutathione (GSH) and antioxidant capacity |
↔ or insufficient upregulation |
↑ GSH and antioxidant enzymes |
Adaptive |
Redox resilience in normal tissue |
Normal cells adaptively increase antioxidant defenses; tumors adapt poorly |
| 7 |
NRF2 antioxidant response |
↔ modest activation |
↑ NRF2 (adaptive) |
Adaptive |
Stress adaptation |
NRF2 supports recovery and resilience rather than cytotoxicity |
| 8 |
Inflammatory signaling (NF-κB / cytokines) |
↓ pro-tumor inflammation |
↓ chronic inflammation |
Secondary |
Anti-inflammatory milieu |
Exercise reduces chronic low-grade inflammation that supports tumor progression |
| 9 |
Cell cycle / proliferation |
↓ proliferation (indirect) |
↔ normal turnover |
Phenotypic |
Growth restraint |
Proliferation effects arise from upstream hormonal and metabolic changes |
| Rank |
Pathway / Axis |
Direction |
Label |
Primary Interpretation |
Key Cognitive / AD Relevance |
Notes |
| 1 |
BDNF / TrkB neurotrophic signaling |
↑ BDNF |
Driver |
Synaptic plasticity and neuronal survival |
Improves learning, memory consolidation, and hippocampal resilience |
BDNF induction is the single most robust and reproducible neurocognitive effect of exercise |
| 2 |
Neurogenesis (hippocampal dentate gyrus) |
↑ neurogenesis |
Driver |
Structural cognitive reserve |
Supports memory formation and delays cognitive decline |
Adult hippocampal neurogenesis is exercise-responsive and BDNF-dependent |
| 3 |
Cerebral blood flow / angiogenesis (VEGF) |
↑ perfusion |
Driver |
Improved nutrient and oxygen delivery |
Enhances executive function and processing speed |
Vascular health strongly predicts AD progression |
| 4 |
Mitochondrial biogenesis (PGC-1α) |
↑ mitochondrial capacity |
Driver |
Energy resilience in neurons |
Preserves synaptic function and neuronal firing reliability |
Mitochondrial dysfunction is an early AD feature |
| 5 |
Neuroinflammation (microglia, cytokines) |
↓ chronic inflammation |
Driver |
Microglial normalization |
Reduces neurotoxic inflammatory signaling linked to cognitive decline |
Exercise shifts microglia toward a neuroprotective phenotype |
| 6 |
Insulin signaling / brain glucose utilization |
↑ insulin sensitivity |
Secondary |
Improved neuronal fuel utilization |
Supports memory and executive function |
“Type 3 diabetes” concept in AD makes this pathway central |
| 7 |
Amyloid-β production & clearance |
↓ Aβ burden (modest) |
Secondary |
Reduced proteotoxic stress |
Slows pathological cascade rather than reversing plaques |
Exercise improves clearance more than production suppression |
| 8 |
Tau phosphorylation / aggregation |
↓ tau pathology (indirect) |
Secondary |
Axonal stability preservation |
Supports memory retention and neuronal transport |
Effect mediated via inflammation and insulin signaling |
| 9 |
Oxidative stress / ROS |
↓ chronic ROS |
Adaptive |
Redox stabilization |
Protects synapses and mitochondria |
Transient exercise ROS induces long-term antioxidant adaptation |
| 10 |
Cognitive performance (memory, executive function) |
↑ performance |
Phenotypic |
Functional outcome |
Improved memory, attention, processing speed |
Emergent result of upstream neurotrophic, vascular, and metabolic effects |