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A specific transcriptional program, induced by a decrease in oxygen (O<jats:sub>2<\/jats:sub>) availability, for example, inspiratory hypoxia at high altitude, allows cells to adapt to lower O<jats:sub>2<\/jats:sub> and limited energy metabolism. This transcriptional program is partly controlled by and partly independent of hypoxia\u2010inducible factors. Remarkably, this same transcriptional program is stimulated in the brain by extensive motor\u2010cognitive exercise, leading to a relative decrease in O<jats:sub>2<\/jats:sub> supply, compared to the acutely augmented O<jats:sub>2<\/jats:sub> requirement. We have coined the term \u201cfunctional hypoxia\u201d\u00a0for this important demand\u2010responsive, relative reduction in O<jats:sub>2<\/jats:sub> availability. Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial \u201cbrain hardware upgrade,\u201d underlying advanced performance. Hypoxia\u2010induced erythropoietin expression in the brain likely plays a decisive role in these processes, which can be imitated by recombinant human erythropoietin treatment. This article review\u00a0presents hints of how inspiratory O<jats:sub>2<\/jats:sub> manipulations can potentially contribute to enhanced brain function. It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease. Finally, it sketches a planned multistep pilot study in healthy volunteers and first patients, about to start, aiming at improved performance upon motor\u2010cognitive training under inspiratory hypoxia.<\/jats:p>","DOI":"10.1002\/nep3.15","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T07:23:30Z","timestamp":1677050610000},"page":"55-65","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress"],"prefix":"10.1002","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8371-5711","authenticated-orcid":false,"given":"Hannelore","family":"Ehrenreich","sequence":"first","affiliation":[{"name":"Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences G\u00f6ttingen 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