Background and Aims.

Altitude hypoxia-related reduction in systemic oxygen availability provokes significant stress and induces a variety of adaptive physiological responses. Although altitude adaptation has been a focus of extensive research for a century and a half there remains an ongoing search for novel interventions to mitigate the acute and prolonged hypoxia-related decrement in human performance, functional capacity and maladaptation. This is not only of high interest for mountaineers or athletes competing at altitude but is also potentially relevant for clinical states associated with local or systemic hypoxia such as severe pulmonary disease, cerebrovascular or cardiovascular events, or intensive care pathophysiology. Based on the early work on rodents and joint (both partners) preliminary work it seems that one such novel, but to date not scrutinized, strategy could be exogenous ketosis induced by intermittent oral ketone supplementation (IEK). Indeed, there is convincing preliminary evidence to indicate that ketone bodies may augment hypoxic tolerance and also serve as fuel for muscular and neuronal cellular activity. Accordingly, the present project aims to comprehensively investigate the effects of exogenous ketosis on physiological, cognitive and functional adaptation to acute and prolonged hypoxic exposure hypoxia during rest and exercise. Specifically, we aim to elucidate:

1) The effects of acute exogenous ketosis during prolonged exercise in hypoxia.

2) The effects of exercise with exogenous ketosis on sleep architecture and quality in hypoxia.

3) The effects of exogenous ketosis on hypoxic tolerance and prolonged high-altitude adaptation.

Project methodology.

For this purpose, three blinded randomized, placebo-controlled studies will be performed in healthy individuals. The state-of-the-art methodology will be employed by both participating research groups to investigate the functional effects of the tested interventions and elucidate the exact physiological, cellular, and molecular mechanisms involved in acute and chronic adaptation to hypoxia during IEK. In study I, 14 participants will undergo four acute exercise sessions under the following nutritional and environmental conditions (cross-over design): normoxic exercise + placebo; hypoxic exercise + placebo, normoxic exercise + KE; hypoxic exercise + KE. In study II 24 participants will undergo four different nutritional and environmental conditions experimental sessions (crossover design): KE intake immediately after exercise and 30 min before sleep in normoxia; KE intake immediately after exercise and 30 min before sleep in hypoxia; placebo intake and sleep in normoxia, iv) placebo, and sleeping in hypoxia. In study III, 30 participants (15 control (placebo) group; 15 KE supplementation) will undergo 10 days of chronic normobaric hypoxia (~4000m) in a hypoxic facility. As mentioned, a comprehensive assessment of physiological (cardiovascular, tissue oxygenation status, hormonal), cognitive, and performance adaptation will be performed during all three studies with additional measures conducted before and after the chronic (prolonged) altitude adaptation (Study III). All of the above work will be performed with constant collaboration and exchanges/travelling of the involved researchers between Slovenia and Belgium to gain the best possible synergies.

Applied value and scientific novelty.