Hypoxia as a medicine

Abstract

Oxygen is essential for human life, yet a growing body of preclinical research is demonstrating that chronic continuous hypoxia can be beneficial in models of mitochondrial disease, autoimmunity, ischemia, and aging. This research is revealing exciting new and unexpected facets of oxygen biology, but translating these findings to patients poses major challenges, because hypoxia can be dangerous. Overcoming these barriers will require integrating insights from basic science, high-altitude physiology, clinical medicine, and sports technology. Here, we explore the foundations of this nascent field and outline a path to determine how chronic continuous hypoxia can be safely, effectively, and practically delivered to patients.

Figure 1.. New facets of oxygen biology.

(A) When arterial oxygen delivery exceeds tissue oxygen consumption, the resulting “unused oxygen” can manifest as venous hyperoxia. (B) Oxygen toxicity is classically attributed to partially reduced oxygen species (for example, O₂⁻, H₂O₂) or ROS that are targeted by traditional antioxidants. Hypoxia therapy, however, acts upstream to prevent ROS formation and to prevent damage that emerges from excess oxidation of biomolecules (denoted as “X”) that have reduced the O₂. (C) In healthy states, there is a “basal tone” of hypoxia-sensing programs which can be suppressed in the setting of hyperoxia. “HIF” = hypoxia inducible factor, “HPV” = hypoxic pulmonary vasoconstriction. (D) For both wildtype genotypes and essential gene mutants, the phenotypes are independent of oxygen tension (solid circle is healthy phenotype, dotted circle is disease phenotype). By contrast, for OxyS mutants, the disease phenotype is suppressed at low oxygen tension but becomes clinically apparent as oxygen tension increases. (E) The developmental fates of wildtype, OxyS, and essential gene mutants are overlaid on a plot of arterial oxygen (PaO₂) (y-axis) versus life-stage (x-axis). Birth leads to an abrupt transition in PaO2. CREDIT: A. FISHER/SCIENCE TRANSLATIONAL MEDICINE

Figure 2.. Physiological responses to and pathological consequences of hypoxia for different organ systems.

Quantitative estimates are based on studies of healthy adult volunteers in the first 48 hours after moving from sea level to a 13% normobaric hypoxia chamber or the altitude equivalent to this oxygen concentration (hypobaric hypoxia). “CMRO₂” = cerebral metabolic rate of oxygen consumption (–110). CREDIT: A. FISHER/SCIENCE TRANSLATIONAL MEDICINE