In our episode on the bends, you joined us as we explored how low we can go. Now we’re back with a similar invitation: come along to learn how high we can fly (and what happens to our bodies when we get up there). In this very special episode, we examine the short-term effects and potentially deadly consequences of life at great heights and ask how we came to understand the relationship between altitude, oxygen, and health. This journey begins earlier than you may have guessed, back to a time before oxygen was discovered, and winds through unexpected avenues, including misadventures in hot air balloons and early experiments demonstrating the vitality of air, as we trace how the pieces of high altitude physiology were put together. A big part of what makes this episode so very special is our guest, Dr. Jonathan Velotta, Assistant Professor of Evolutionary Biology at the University of Denver, who joins us to chat about some of the incredible ways that humans and other animals have adapted to live at high altitude. Tune in for a bird’s-eye view of what it’s like to have a high life.
| History | Biology |
| West, John Burnard. High Life: A History of High-altitude Physiology and Medicine. United Kingdom, American Physiological Society, 1998. | Luks, A.M., Swenson, E.R. and Bärtsch, P., 2017. Acute high-altitude sickness. European Respiratory Review, 26(143). |
| Reeves, John T., and Robert F. Grover, eds. Attitudes on altitude: Pioneers of medical research in Colorado’s high mountains. University Press of Colorado, 2001. | Murdoch, D., 2010. Altitude sickness. BMJ clinical evidence, 2010. |
| The history of the barometer (and how it works) – Asaf Bar-Yosef, TED-Ed.https://www.youtube.com/watch?v=EkDhlzA-lwI | Grocott, M., Montgomery, H. and Vercueil, A., 2007. High-altitude physiology and pathophysiology: implications and relevance for intensive care medicine. Critical Care, 11, pp.1-5. |
| Palmer, B.F., 2010. Physiology and pathophysiology with ascent to altitude. The American journal of the medical sciences, 340(1), pp.69-77. | |
| Villafuerte, F.C. and Corante, N., 2016. Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High altitude medicine & biology, 17(2), pp.61-69. | |
| Basnyat, B., Wu, T. and Gertsch, J.H., 2004. Neurological conditions at altitude that fall outside the usual definition of altitude sickness. High Altitude Medicine & Biology, 5(2), pp.171-179. | |
| Simonson, T.S., Yang, Y., Huff, C.D., Yun, H., Qin, G., Witherspoon, D.J., Bai, Z., Lorenzo, F.R., Xing, J., Jorde, L.B. and Prchal, J.T., 2010. Genetic evidence for high-altitude adaptation in Tibet. Science, 329(5987), pp.72-75. | |
| Scheinfeldt, L.B., Soi, S., Thompson, S., Ranciaro, A., Woldemeskel, D., Beggs, W., Lambert, C., Jarvis, J.P., Abate, D., Belay, G. and Tishkoff, S.A., 2012. Genetic adaptation to high altitude in the Ethiopian highlands. Genome biology, 13(1), pp.1-9. | |
| Millet, G.P., Chapman, R.F., Girard, O. and Brocherie, F., 2019. Is live high–train low altitude training relevant for elite athletes? Flawed analysis from inaccurate data. British Journal of Sports Medicine, 53(15), pp.923-925. | |
| Cobb, A.B., Levett, D.Z., Mitchell, K., Aveling, W., Hurlbut, D., Gilbert‐Kawai, E., Hennis, P.J., Mythen, M.G., Grocott, M.P., Martin, D.S. and Caudwell Xtreme Everest, Xtreme Everest 2009, Xtreme Everest 2 investigators, 2021. Physiological responses during ascent to high altitude and the incidence of acute mountain sickness. Physiological reports, 9(7), p.e14809. | |
| Mujika, I., Sharma, A.P. and Stellingwerff, T., 2019. Contemporary periodization of altitude training for elite endurance athletes: a narrative review. Sports medicine, 49, pp.1651-1669. |
| Evolutionary Biology |
| Beall, C.M., 2014. Adaptation to High Altitude: Phenotypes and Genotypes. Annual Review of Anthropology 43, 251–272. https://doi.org/10.1146/annurev-anthro-102313-030000 |
| Beall, C.M., 2007. Two routes to functional adaptation: Tibetan and Andean high-altitude natives. PNAS 104, 8655–8660. https://doi.org/10.1073/pnas.0701985104 |
| Beall, C.M., Cavalleri, G.L., Deng, L., Elston, R.C., Gao, Y., Knight, J., Li, C., Li, J.C., Liang, Y., McCormack, M., Montgomery, H.E., Pan, H., Robbins, P.A., Shianna, K.V., Tam, S.C., Tsering, N., Veeramah, K.R., Wang, W., Wangdui, P., Weale, M.E., Xu, Y., Xu, Z., Yang, L., Zaman, M.J., Zeng, C., Zhang, L., Zhang, X., Zhaxi, P., Zheng, Y.T., 2010. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. PNAS 107, 11459–11464. https://doi.org/10.1073/pnas.1002443107 |
| Beall, C.M., Decker, M.J., Brittenham, G.M., Kushner, I., Gebremedhin, A., Strohl, K.P., 2002. An Ethiopian Pattern of Human Adaptation to High-Altitude Hypoxia. Proceedings of the National Academy of Sciences of the United States of America 99, 17215–17218. |
| Beall, C.M., Laskowski, D., Erzurum, S.C., 2012. Nitric oxide in adaptation to altitude. Free Radical Biology and Medicine 52, 1123–1134. https://doi.org/10.1016/j.freeradbiomed.2011.12.028 |
| Beall, C.M., Laskowski, D., Strohl, K.P., Soria, R., Villena, M., Vargas, E., Alarcon, A.M., Gonzales, C., Erzurum, S.C., 2001. Pulmonary nitric oxide in mountain dwellers. Nature 414, 411–412. https://doi.org/10.1038/35106641 |
| Bishop, C.M., Spivey, R.J., Hawkes, L.A., Batbayar, N., Chua, B., Frappell, P.B., Milsom, W.K., Natsagdorj, T., Newman, S.H., Scott, G.R., Takekawa, J.Y., Wikelski, M., Butler, P.J., 2015. The roller coaster flight strategy of bar-headed geese conserves energy during Himalayan migrations. Science 347, 250–254. https://doi.org/10.1126/science.1258732 |
| Cheviron, Z.A., Bachman, G.C., Connaty, A.D., McClelland, G.B., Storz, J.F., 2012. Regulatory changes contribute to the adaptive enhancement of thermogenic capacity in high-altitude deer mice. PNAS 109, 8635–8640. https://doi.org/10.1073/pnas.1120523109 |
| Ivy, C.M., Scott, G.R., 2017. Control of breathing and ventilatory acclimatization to hypoxia in deer mice native to high altitudes. Acta Physiol 221, 266–282. https://doi.org/10.1111/apha.12912 |
| Ivy, C.M., Scott, G.R., 2015. Control of breathing and the circulation in high-altitude mammals and birds. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, Fueling the fire of life; a tribute to the career of William Kenneth Milsom 186, 66–74. https://doi.org/10.1016/j.cbpa.2014.10.009 |
| Moore, L.G., 2001. Human Genetic Adaptation to High Altitude. High Altitude Medicine & Biology 2, 257–279. https://doi.org/10.1089/152702901750265341 |
| Moore, L.G., Rounds, S.S., Jahnigen, D., Grover, R.F., Reeves, J.T., 1982. Infant birth weight is related to maternal arterial oxygenation at high altitude. Journal of Applied Physiology 52, 695–699. |
| Natarajan, C., Hoffmann, F.G., Weber, R.E., Fago, A., Witt, C.C., Storz, J.F., 2016. Predictable convergence in hemoglobin function has unpredictable molecular underpinnings. Science 354, 336–339. |
| Schweizer, R.M., Velotta, J.P., Ivy, C.M., Jones, M.R., Muir, S.M., Bradburd, G.S., Storz, J.F., Scott, G.R., Cheviron, Z.A., 2019. Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice. PLOS Genetics 15, e1008420–e1008420. https://doi.org/10.1371/journal.pgen.1008420 |
| Simonson, T.S., Wei, G., Wagner, H.E., Wuren, T., Qin, G., Yan, M., Wagner, P.D., Ge, R.L., 2015. Low haemoglobin concentration in Tibetan males is associated with greater high-altitude exercise capacity. J Physiol 593, 3207–3218. https://doi.org/10.1113/JP270518 |
| Storz, J.F., 2016. Hemoglobin–oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend? Journal of Experimental Biology 219, 3190–3203. https://doi.org/10.1242/jeb.127134 |
| Storz, J.F., 2007. Hemoglobin Function and Physiological Adaptation to Hypoxia in High-Altitude Mammals. J. Mammal. 88, 24–31. https://doi.org/10.1644/06-MAMM-S-199R1.1 |
| Storz, J.F., Quiroga-Carmona, M., Opazo, J.C., Bowen, T., Farson, M., Steppan, S.J., D’Elía, G., 2020. Discovery of the world’s highest-dwelling mammal. PNAS 117, 18169–18171. https://doi.org/10.1073/pnas.2005265117 |
| Velotta, J.P., Ivy, C.M., Wolf, C.J., Scott, G.R., Cheviron, Z.A., 2018. Maladaptive phenotypic plasticity in cardiac muscle growth is suppressed in high-altitude deer mice. Evolution 72, 2712–2727. https://doi.org/10.1111/evo.13626 |
| Villafuerte, F.C., Corante, N., 2016. Chronic Mountain Sickness: Clinical Aspects, Etiology, Management, and Treatment. High Alt Med Biol 17, 61–69. https://doi.org/10.1089/ham.2016.0031 |
| West, C.M., Wearing, O.H., Rhem, R.G., Scott, G.R., 2021. Pulmonary hypertension is attenuated and ventilation-perfusion matching is maintained during chronic hypoxia in deer mice native to high altitude. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. https://doi.org/10.1152/ajpregu.00282.2020 |
| Wilsterman, K., Moore, E.C., Schweizer, R.M., Cunningham, K., Good, J.M., Cheviron, Z.A., 2023. Adaptive structural and functional evolution of the placenta protects fetal growth in high elevation deer mice. https://doi.org/10.1101/2022.09.27.509814 |
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