Human adaptation to high‐altitude: A contemporary comparison of the oxygen cascade in Andean, Tibetan and Ethiopian highlanders

Human populations native to high altitude have evolved distinct physiological adaptations to chronic hypoxia. This adaptation is evident in the O₂ transport cascade. In this review, with brief inclusion of the related genetic adaptations, we compare the O₂ cascade across three well-characterized high-altitude populations: Andeans (Aymara and Quechua), Tibetans/Sherpa and Ethiopians (Amhara and Oromo). We contrast the steps of the O₂ cascade: (1) ventilation; (2) pulmonary O₂ diffusion; (3) cardiac output and circulation; (4) haematological traits; and (5) tissue O₂ utilization. Tibetans exhibit a robust hypoxic ventilatory response and efficient pulmonary diffusion capacity. They maintain preserved cardiac function with optimized muscle energetics. These adaptations are supported by enhanced tissue blood flow and greater muscle capillary density. Andeans demonstrate a blunted ventilatory response and marked remodelling of the pulmonary circulation, resulting in elevated pulmonary arterial pressure and mild but persistent right ventricular hypertrophy along with lifelong sympathetic overactivity. They also show strong haematological adaptations, with increased haemoglobin concentration. Ethiopians, particularly Amhara highlanders, show ventilatory status close to sea-level values, with limited pulmonary and cerebral vasoreactivity to hypoxia. Although data remain limited, the Amhara highlanders exhibit higher oxygen saturation and enhanced tissue blood flow in comparison to Oromo counterparts. In conclusion, these physiological (i.e., O₂ cascade) differences provide evidence of the diverse patterns of evolutionarily adaptive responses to the stresses of high-altitude hypoxia. Further research comparing the O₂ cascade across these Indigenous populations will enhance our understanding of the genetic and physiological adaptations to life at high altitude.