Abstract
Background: Minor and major neurocognitive disorders, depression, and anxiety are common in older adults. The brain, and specifically the aging brain, relies heavily on oxygen and is highly sensitive to reductions in oxygen availability. Hypoxia occurs during both acute and prolonged exposure to altitude. While the negative effects of very low oxygen levels at high altitudes (above 3,500 m) on cognition and symptoms of depression as well as anxiety are well documented, we propose that moderate altitudes (1,000–2,500 m) may have potential benefits for brain health by promoting stress tolerance and adaptability. Summary: This narrative review summarizes the impact of environmental oxygen availability on cognitive function and symptoms of depression and anxiety, considering the hypoxic dose (severity and duration of hypoxia). Given the limited data on moderate altitude and older adults, we also included results from studies involving younger populations and higher altitudes for comparison, alongside theoretical perspectives that still require experimental validation. We propose that mild hypoxia at moderate altitudes may enhance the brain’s stress tolerance and adaptability, potentially through mechanisms involving metabolic and redox homeostasis as well as neurotransmitter regulation. However, the evidence remains inconclusive due to the influence of multiple confounding factors in most studies, complicating the ability to reach firm conclusions. Key Messages: Severe hypoxia at very high or extreme altitudes has detrimental effects on brain health, particularly in the aging brain, resulting in cognitive impairment and triggering or aggravating symptoms of depression and anxiety. In contrast, the potential benefits of prolonged exposure to moderate altitudes on brain and mental health, especially in aging populations, remain a topic of debate. The limited number of studies, coupled with the presence of multiple confounding factors, makes it difficult to draw definitive conclusions.