Abstract: Aerobic (endurance) exercise training protects from age-related neurological and psychiatric diseases. The bidirectional signaling between tissues directly involved in aerobic exercise, such as skeletal muscle and the brain, is well established; however, the precise mechanisms by which exercise benefits the brain remain elusive. We summarize the role of hypoxia (reduced oxygen availability) signaling as a potential mediator of exercise outcomes on the brain. The increased oxygen demand in organs such as skeletal muscle and heart during aerobic exercise induces hypoxia responses, including the activation of hypoxia-inducible factor pathways. These responses promote adaptations leading to improved oxygen transport, mitochondrial functions, and oxidative stress management in the brain and thereby counteract central pathological developments associated with neuropsychiatric and neurodegenerative diseases. Passive hypoxia exposures can similarly improve brain functions; we provide an extensive overview of the existent literature on that topic. We conclude that the combination of aerobic exercise and ambient hypoxia can result in synergistic and/or additive positive outcomes in the brain. However, the dose of either stimulus and individual resilience/vulnerabilities determines if the induced stress responses are successful and safe. If the stress management capacities are insufficient, the different stimuli may have antagonistic effects or inhibit beneficial adaptations. The selection of combinations for optimal adaptation is an important challenge for future research.

Key words: cardiorespiratory fitness, exercise, hypoxia inducible factor, mental health, mitochondria, neurodegeneration, neurological disorders, neuroprotection, oxygen, physical activity