High altitude presents a formidable physiological challenge: reduced oxygen availability (hypoxia) challenges cellular energy metabolism and redox homeostasis. Despite adaptive responses at the whole-body level that enhance convective oxygen delivery, tissue hypoxia persists, necessitating metabolic responses that alter oxygen utilisation. Notably, populations with a long history of residence at altitude have evolved distinctive physiological strategies that enable them to thrive in this environment. Understanding these adaptations can reveal fundamental principles governing human metabolism under conditions of limited oxygen availability.

This talk will explore how studies conducted during the Caudwell Xtreme Everest and Xtreme Everest 2 expeditions have shaped our understanding of metabolic responses to hypoxia. In lowlanders, exposure to high altitude induces extensive remodelling of skeletal-muscle metabolism and mitochondrial function. These responses may help preserve cellular energy homeostasis, but they are accompanied by reduced capacity for lipid oxidation and may contribute to the decline in physical performance seen during prolonged hypoxic exposure.

The Sherpa people provide an illuminating contrast. Their skeletal muscle exhibits a metabolic phenotype characterised by reduced reliance on fatty-acid oxidation, greater use of carbohydrate-derived substrates and efficient production of ATP relative to oxygen consumption. These characteristics are associated with genetic variation in pathways regulating cellular oxygen sensing and fuel selection, suggesting that natural selection has acted not simply on oxygen delivery, but also on the way oxygen is used.

I will also present recent work integrating metabolomic and genetic data across ascent to examine how ancestry, altitude and sex influence lipid metabolism and transport in Sherpas and lowlanders. Together, these studies highlight that metabolic adaptation—matching fuel selection and mitochondrial function to oxygen availability—is a central component of human adaptation to high altitude.