Synergy of exercise and hypoxia for brain health and aging – A narrative review
Authors: Burtscher Johannes , Kopp Martin 
Published: September 2024

Regular exercise is a well-established means to improve brain health and prevent age-related neurological diseases, including dementia (Marques-Aleixo et al., 2020). The precise mechanisms how direct exercise effects are transmitted to the brain remain incompletely understood. However, the increased oxygen demand and associated metabolic stress in the primarily affected tissues – the working skeletal muscle, the cardiovascular and the respiratory system – likely play crucial roles in exercise-signalling to the brain (Severinsen & Pedersen, 2020). Besides the mobilization of beneficial circulating factors, the modulation of blood properties and blood-flow, the immune system and the autonomous system are involved. Intriguingly, physiological stress induced by low environmental oxygen availability (hypoxia) can induce the activation of similar processes like exercise. The aim of this contribution is to evaluate the role of hypoxia in the benefits of exercise on the brain.
Accumulating evidence demonstrates the potential of direct modulation of inspired oxygen levels to improve neurological diseases (Burtscher et al., 2021). Reduced all-cause mortality in people living at moderate altitudes (and therefore in chronic, mild hypobaric hypoxia) may also be associated with reduced risk of neurological diseases, including of stroke (Faeh et al., 2009). This is surprising, because the hypoxic stress at moderate altitudes (usually defined as altitudes between 1,500 and 2,500 m) is generally considered too low to induce substantial hypoxia adaptations. It is thus possible that the combination of moderate environmental hypoxia at moderate altitude with the increased oxygen demand during exercise is required to promote protective adaptations, such as of the brain. Considering this possibility, synergistic and complementary molecular and systemic responses and adaptations to exercise and hypoxia may benefit the brain. Among the involved molecular processes are mitochondrial changes following cellular stress that are also linked to the regulation of adaptations by the transcription factor hypoxia inducible factor, which is activated by both hypoxia and exercise. Mitochondria are the main molecular oxygen consumers, respond sensitively to stress and dispose of a wide array of intra- and intercellular communication modes (Memme et al., 2021). Moreover, exerkines, blood-borne factors released in response to exercise, have emerged as important mediators of inter-organ exercise-signalling (Severinsen & Pedersen, 2020) and modulate the autonomic and immune system in response to hypoxic and metabolic stress.
In conclusion, the activation of endogenous responses to hypoxic and metabolic stress are powerful means to improve brain health and healthy aging. Based on the overlapping and distinct physiological responses to hypoxia and exercise, brain benefits of exercising at higher altitudes and advances in the development of customized strategies to improve brain resilience are promising approaches to target neurological diseases. While the safe performance of exercise in moderate altitudes is already considered an impactful way to improve brain health, the optimization of combined exercise and (artificially induced) hypoxia for specific target groups requires further in-depth investigation.
References
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