Exogenous ketone monoester supplementation: a potential alternative strategy to mitigate altitude sickness?

Exposure to high-altitude reduces oxygen availability, leading to hypoxemia. To combat this physiological stressor, the body initiates a cascade of short- and long-term compensatory responses (i.e., high-altitude acclimatization). Some notable adaptations include rapid increases in ventilation, heightened sympathetic neural activity, and reductions in plasma volume during early acclimatization, followed by increases in hemoglobin mass and concentration. Despite these physiological responses, many of the ~ 40 million people who travel to high altitude regions (i.e., > 2500 m) each year, suffer from acute mountain sickness (AMS), which is often paired with reductions in overall sleep quality. Acetazolamide (ACZ), the most prescribed high-altitude pharmacological intervention, alleviates AMS symptoms by inducing a renal metabolic acidosis, which increases basal ventilation and improves oxygenation. However, the unpleasant side effects of ACZ for some individuals and the lack of 100% efficacy underscores the need for alternative and potentially more effective treatments for AMS. Exogenous ketone monoester (KME) supplementation raises circulating ketone body levels and has been demonstrated to increase resting ventilation at both sea-level and high-altitude. Similar to ACZ, the mechanism(s) responsible for KME-stimulated hyperventilation are thought to be primarily linked to a hallmark acidosis response, leading to increases in blood oxygen saturation similar to ACZ at high altitude. Additionally, there is preliminary evidence that KME may improve sleep architecture and efficiency at high altitude, which are known to exacerbate the development of AMS. This perspective outlines key physiological mechanisms, identifies current knowledge gaps, and proposes future directions for exploring the potential impact of KME in mitigating AMS.