Recent studies have identified genes involved in high-altitude adaptation in Tibetans. Three of these genes (EPAS1, EGLN1, and PPARA) are associated with relatively decreased hemoglobin (Hb) levels. Consistent with the phenotype, EGLN1 in Tibetans has a gain of function mutation that confers a higher affinity for oxygen, hence less sensitivity to hypoxia. Considering the strong metabolic demands imposed by hypoxia, we hypothesized that other selected genes might alter metabolism to allow adaptation to altitude despite the desensitization of the upstream hypoxia sensing caused by the EGLN1 mutation. A shift in fuel preference to glucose oxidation and glycolysis at the expense of fatty acid oxidation would provide adaptation to decreased oxygen availability. Measurements of serum metabolites from Tibetans living at high altitude are consistent with this hypothesis: The EPAS1 haplotype is significantly associated with increased lactate levels (suggesting increased anaerobic metabolism), and the PPARAhaplotype and serum free fatty acids are positively related (suggesting decreased fat oxidation). These data, combined with preliminary calorimetry data in a Tibetan population living at low altitude, suggest that the high altitude adaptations may offer protection from diabetes at high altitude but increase diabetes risk at lower elevations and/or with adoption of a nontraditional diet. We also hypothesize that because iron is a cofactor for EGLN1, there will be significant associations of phenotypes with the degrees of variation seen in tissue iron among human populations, many of which are iron deficient. We have begun to investigate the interactions of iron and hypoxia in animal models in order to allow us to make predictions that we can test in human populations. We have discovered that low iron is synergistic with hypoxia in triggering cellular autophagy, a process by which cellular organelles including mitochondria are digested to provide metabolites that can be used to provide energy, for example, providing amino acids for gluconeogenesis in the liver.