Ketone Supplementation: Novel Strategy for Augmenting Altitude Exercise Performance?

Abstract

An insightful Perspective for Progress by Salgado and colleagues (1) outlines some interesting novel approaches to augment exercise performance at terrestrial altitude in unacclimatized low-landers. These approaches could be utilized instead of, or supplementary to, the classical approach of hypoxic preacclimatization (2). The outlined strategies, particularly respiratory muscle training and combined approaches, show some promise for provoking relevant physiological changes and thereby facilitating altitude performance. Nevertheless, we feel that the landscape of novel "nonconventional" strategies remains incomplete without discussing the potential of exogenous ketones. Indeed, pre, per, and post exercise ingestion of ketone supplements represents a novel nutritional strategy aiming to improve exercise performance and recovery. Ketone supplements, particularly the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate and the ketone precursor (R)-1,3-butanediol, induce a transient elevation of the circulating ketone bodies acetoacetate and D-β-hydroxybutyrate, irrespective of the availability of other macronutrients. Although the acute effect of exogenous ketosis on normoxic exercise performance remains equivocal (3), accumulating evidence suggests potential ergogenic effects resulting from improved recovery and potentially improved hypoxic tolerance (4). Regarding the latter, early work in rodents indicated that increasing blood ketone bodies enhanced survival time in severe hypoxia (5). Additionally, recent work from our laboratories showed that the physiological changes induced by ketone inges-tion in normoxia generally replicate the mechanisms that underly improvements in altitude performance upon preacclimatization or the nonconventional strategies highlighted by Salgado and colleagues. This includes (i) increased ventilation, (ii) higher energetic efficiency, (iii) elevated circulating erythropoietin, and (iv) increased skeletal muscle VEGF and capillarization (3). Therefore, we recently started to investigate the potential of ketone ingestion to improve performance and adaptation in/to hypoxia in humans. These studies indicated that ketone ingestion attenuated hypoxia-induced blood (and skeletal muscle) oxygen desaturation both at rest and during exercise, especially when oxygen saturation levels drop below approximately 85% (4,6). This was mostly underlined by acidosis-induced hyperventila-tion, thereby improving arterial pO 2. Most recently, we also observed that ketone ingestion alleviated the development of acute mountain sickness, which may further compromise exercise capacity upon acute altitude exposure (6). Despite the lack of direct evidence for enhanced endurance performance in (se-vere) hypoxic conditions upon ketosis, the observed effects on oxygenation and acute mountain sickness are promising for improving (submaximal) exercise performance during high-altitude sojourns. While the authors refer to studies wherein other potential strategies such as dietary nitrate are discussed, another and one of the most "nontraditional" and very topical approaches includes carbon monoxide supplementation (7). While its applicability for augmenting blood oxygen-carrying capacity (via simulated erythropoiesis and hemoglobin mass augmentation) is well established, the ethical and medical issues regarding its usage should probably override its physiological benefits (8). Taken together, the available data suggests that exogenous ketone supplementation could prove beneficial for augmenting high-altitude tolerance and/or exercise performance and thereby complement the strategies proposed by Salgado et al. (1). Nonetheless, future work is warranted to identify the optimal ketone supplementation strategies (e.g., dose and timing) and targeted applications (e.g., exercise, rest, and/or sleep) to develop effective individualized and targeted approaches.