Taking Hypoxia Research to New Heights

Throughout the history of high-altitude mountaineering in the Himalayan region, Sherpa have served as guides. And while the term ‘Sherpa’ has come to mean almost any guide or porter hired for a climbing expedition, the Sherpa are a distinct ethnic group that lives mainly in the country of Nepal. Among the international climbing community, Sherpa are famous for their climbing ability and hardiness, carrying heavy loads with apparently minimal effort. At very high altitudes, they demonstrate an exceptional degree of physical resilience to hypoxia. Xtreme Everest 2 (XE2) was part of an ongoing clinical research program designed to look into this resilience. Conducted by the Cauldwell Xtreme Everest Hypoxia Research Consortium, the study was unique in comparing participants drawn from two distinct populations: native ancestral high-altitude dwellers (Sherpa) and native lowlanders. The focus of the program is to characterize acclimatization to environmental hypoxia during a standardized ascent to high altitude in order to identify key biomarkers of adaptation. The results of the research could lead to development of novel diagnostic and treatment strategies for the pathophysiological hypoxemia and cellular hypoxia observed in critically ill patients, and help save hundreds of thousands of lives of people with a range of diseases including cancer, diabetes, heart and lung disease, cystic fibrosis and congenital heart disease. An earlier study, Cauldwell Extreme Everest (CXE), was the largest comprehensive prospective observational study to be performed at altitude. CXE was designed to explore inter-individual difference in response to hyperbaric hypoxia. The study hypothesized that (1) mechanisms distinct from those related to global oxygen transport play an important role in determining performance at high altitude and that (2) genotype differences would explain a substantial proportion of intra-individual variation in environmentally induced phenotypes (gene-environment interactions). Results from the study included novel findings related to microcirculatory blood flow, mitochondrial biology, and plasma nitrogen oxides. Following sustained exposure to hypoxia at high altitudes, the researchers found that several markers of insulin resistance were increased. The change in these biomarkers is related to increased blood levels of markers of inflammation and as well as oxidative stress. In XE2, these hypotheses were explored further. Sixty-four Sherpa and more than 100 lowlanders were studied over two months. Experiments focused on microcirculatory and mitochondrial function, nitrogen oxide metabolism and epigenetics (methylation and histone modification). The results of XE2, along with those from CXE, will become part a large-scale biobank of samples linked to a phenotype database. The database will be used to identify adaptive mechanisms, drive a translational research agenda and provide a unique bioresource for the study of human adaptation to hypoxia.