King of the Mountains: Tibetan and Sherpa Physiological Adaptations for Life at High Altitude

Anecdotal evidence surrounding Tibetans' and Sherpas' exceptional tolerance to hypobaric hypoxia has been recorded since the beginning of high-altitude exploration. These populations have successfully lived and reproduced at high altitude for hundreds of generations with hypoxia as a constant evolutionary pressure. Consequently, they are likely to have undergone natural selection toward a genotype (and phenotype) tending to offer beneficial adaptation to sustained hypoxia. With the advent of translational human hypoxic research, in which genotype/phenotype studies of healthy individuals at high altitude may be of benefit to hypoxemic critically ill patients in a hospital setting, high-altitude natives may provide a valuable and intriguing model. The aim of this review is to provide a comprehensive summary of the scientific literature encompassing Tibetan and Sherpa physiological adaptations to a high-altitude residence. The review demonstrates the extent to which evolutionary pressure has refined the physiology of this high-altitude population. Furthermore, although many physiological differences between highlanders and lowlanders have been found, it also suggests many more potential avenues of investigation.

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Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high-altitude natives

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.01.086 ◽

2006 ◽

Vol 341 (4) ◽

pp. 1218-1224 ◽

Cited By ~ 23

Author(s):

Charu Rajput ◽

Shehla Najib ◽

Tsering Norboo ◽

Farhat Afrin ◽

M.A. Qadar Pasha

Keyword(s):

High Altitude ◽

Hypobaric Hypoxia ◽

Gene Variants ◽

Endothelin 1 ◽

High Altitude Natives

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Selected Contribution: Acute and sustained ventilatory responses to hypoxia in high-altitude natives living at sea level

Journal of Applied Physiology ◽

10.1152/japplphysiol.00856.2002 ◽

2003 ◽

Vol 94 (3) ◽

pp. 1255-1262 ◽

Cited By ~ 26

Author(s):

Alfredo Gamboa ◽

Fabiola León-Velarde ◽

Maria Rivera-Ch ◽

Jose-Antonio Palacios ◽

Timothy R. Pragnell ◽

...

Keyword(s):

Confidence Interval ◽

High Altitude ◽

Sea Level ◽

Hypoxic Exposure ◽

Ventilatory Responses ◽

High Altitude Natives ◽

Ventilatory Depression ◽

End Tidal ◽

Sustained Hypoxia

High-altitude (HA) natives have blunted ventilatory responses to hypoxia (HVR), but studies differ as to whether this blunting is lost when HA natives migrate to live at sea level (SL), possibly because HVR has been assessed with different durations of hypoxic exposure (acute vs. sustained). To investigate this, 50 HA natives (>3,500 m, for >20 yr) now resident at SL were compared with 50 SL natives as controls. Isocapnic HVR was assessed by using two protocols: protocol 1, progressive stepwise induction of hypoxia over 5–6 min; and protocol 2, sustained (20-min) hypoxia (end-tidal Po 2 = 50 Torr). Acute HVR was assessed from both protocols, and sustained HVR from protocol 2. For HA natives, acute HVR was 79% [95% confidence interval (CI): 52–106%, P = not significant] of SL controls for protocol 1 and 74% (95% CI: 52–96%, P < 0.05) for protocol 2. By contrast, sustained HVR after 20-min hypoxia was only 30% (95% CI: −7–67%, P < 0.001) of SL control values. The persistent blunting of HVR of HA natives resident at SL is substantially less to acute than to sustained hypoxia, when hypoxic ventilatory depression can develop.

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Regulation of catecholamine release from the adrenal medulla is altered in deer mice (Peromyscus maniculatus) native to high altitudes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00005.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. R407-R417 ◽

Cited By ~ 2

Author(s):

Angela L. Scott ◽

Nicole A. Pranckevicius ◽

Colin A. Nurse ◽

Graham R. Scott

Keyword(s):

High Altitude ◽

Adrenal Medulla ◽

Hypobaric Hypoxia ◽

Chronic Hypoxia ◽

Acute Hypoxia ◽

Catecholamine Secretion ◽

Deer Mice ◽

Dopa Decarboxylase ◽

Plasma Epinephrine ◽

High Altitude Natives

High-altitude natives have evolved to overcome environmental hypoxia and provide a compelling system to understand physiological function during reductions in oxygen availability. The sympathoadrenal system plays a key role in responses to acute hypoxia, but prolonged activation of this system in chronic hypoxia may be maladaptive. Here, we examined how chronic hypoxia exposure alters adrenal catecholamine secretion and how adrenal function is altered further in high-altitude natives. Populations of deer mice ( Peromyscus maniculatus) native to low and high altitudes were each born and raised in captivity at sea level, and adults from each population were exposed to normoxia or hypobaric hypoxia for 5 mo. Using carbon fiber amperometry on adrenal slices, catecholamine secretion evoked by low doses of nicotine (10 µM) or acute hypoxia (Po2∼15–20 mmHg) was reduced in lowlanders exposed to hypobaric hypoxia, which was attributable mainly to a decrease in quantal charge rather than event frequency. However, secretion evoked by high doses of nicotine (50 µM) was unaffected. Hypobaric hypoxia also reduced plasma epinephrine and protein expression of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase in the adrenal medulla of lowlanders. In contrast, highlanders were unresponsive to hypobaric hypoxia, exhibiting typically low adrenal catecholamine secretion, plasma epinephrine, and DOPA decarboxylase. Highlanders also had consistently lower catecholamine secretion evoked by high nicotine, smaller adrenal medullae with fewer chromaffin cells, and a larger adrenal cortex compared with lowlanders across both acclimation environments. Our results suggest that plastic responses to chronic hypoxia along with evolved changes in adrenal function attenuate catecholamine release in deer mice at high altitude.

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