Mammals at High Altitude, With Notes on High-Flying Birds

The environment at high montane altitudes is challenging in many respects. It can be cold, windy, dehydrating, and high in ultraviolet radiation. The most immediate challenge for a mammal or bird at high altitude, however, is to meet the O₂ demands of its cells, because the source of O₂—the atmosphere—is rarefied. This low level of O₂ cannot be escaped. People can escape cold temperatures by building dwellings, and animals can do so by building nests, but the low level of O₂ in the ambient air at high altitude exists everywhere, including in a dwelling or nest. Here we discuss several dimensions of this challenge; other aspects are discussed in Boxes 8.3 (V̇_O2max) and 24.5 (blood and circulation).

Permanent human settlements occur at 3500–4500 m (11,500–15,000 ft) on the Andean and Tibetan Plateaus. The people in these settlements have ordinary resting and maximum rates of O₂ consumption compared with members of the general population at sea level, and they lead active lives—despite the fact that the atmospheric O₂ partial pressure is only 60%–65% as high as at sea level.

Evolutionary adaptation, based on natural selection and gene-frequency changes, has probably occurred in the high-altitude populations in the Andes and Tibet. These populations, which began independently, have existed now for 10,000–20,000 years—representing hundreds of generations. Recent research has established beyond doubt that the Andean and Tibetan populations differ in striking ways in their physiological attributes at high altitude.

When a person born and reared at low altitude moves to the high mountains, his or her functional traits change over time as acclimatization occurs. However, such a person may never acquire a close physiological resemblance to people born and reared at high altitude.

From what we have said thus far, you can see that for analyzing people at high altitude, we need to distinguish three groups: newly arrived lowlanders, acclimatized lowlanders, and native highlanders. Moreover, we need to recognize distinct populations of native highlanders. Among other mammals, many species resemble humans in being predominantly of lowland distribution, and they therefore—at least in principle—present the same complexities. By contrast, some species, such as llamas, are endemic to high altitudes (found only there in a wild state).

In the study of mammals that have principally lowland distributions—including humans—a major theme is that exposure to high altitudes may sometimes trigger responses that evolved for reasons other than adaptation to high altitude. Consider a population living at low altitude. Tissue hypoxia—a state of too little O₂ in the tissues—will arise inevitably in individuals of such a population from time to time. Tissue hypoxia will occur, for example, in people with anemic diseases or in individuals who suffer severe blood loss in accidents or wars. Accordingly, defenses against tissue hypoxia will evolve. Such defenses are well known in modern lowland populations, as we discuss later in this box and in Box 24.5. If individuals from such a lowland population go to high altitude, their whole body will be subjected to hypoxia because of the new environment. This hypoxia caused by high altitude may then trigger responses that evolved to defend against hypoxia occurring at low altitudes (caused, for example, by anemia or blood loss). Such responses may be detrimental (maladaptive) at high altitude. In brief, we must be alert to the possibility that some of the responses seen at high altitude may be misplaced responses!

Let’s now look at some of the information available on high-altitude physiology. The Figure A depicts the oxygen cascades of native lowland Peruvians living at sea level and of native Peruvian highlanders at 4500 m in the Andes. You’ll notice that despite the large drop in ambient O₂ partial pressure at 4500 m, the venous partial pressure of the highlanders is reduced only a little. Comparing the two populations, the venous O₂ partial pressure is kept similar: It is conserved. To understand why this occurs, physiologists study all the steps in the oxygen cascade (see page 594). From inspection of Figure A, you can see that the conservation of venous O₂ partial pressure in the Andean highlanders results from significant reductions in two of the partial pressure drops (steps) of the oxygen cascade. The drop in partial pressure between ambient air and alveolar gas is about 4.3 kPa (32 mm Hg) at high altitude and therefore is much smaller than the drop at sea level, 5.7 kPa (43 mm Hg); and the drop between arterial blood and mixed venous blood is about 1.5 kPa (11 mm Hg) at high altitude, versus 7.3 kPa (55 mm Hg) at sea level. The arterial-to-venous drop is a topic in blood gas transport and is discussed in Box 24.5. Here we examine lung function and systemic tissue physiology.

Figure A Oxygen cascades of people at sea level and high altitude Two groups of native male Peruvians were studied at their altitudes of residence. (Data from Torrance et al. 1970.)

One of the most important defenses that lowland people marshal at high altitude is hyperventilation, defined to be an increase in the rate of lung ventilation associated with any given rate of O₂ consumption. When lowlanders first move to high altitude, a prompt (acute) increase in their rate of ventilation occurs; this increase is probably activated principally by the reduction in their arterial O₂ partial pressure, sensed by the carotid bodies. As lowlanders pass their first days at high altitude, their rate of ventilation becomes even higher, evidently because of an increasing physiological sensitivity of the breathing control mechanisms to hypoxic stimulation. The hyperventilation of newly arrived lowlanders accelerates the flux of fresh air to their lungs and clearly helps them maintain a relatively high O₂ partial pressure in their alveolar gas despite the fact that they are breathing rarefied air. Nonetheless, based on the information available, hyperventilation gradually subsides if lowlanders spend extended lengths of time at altitude. Among native highlanders, Tibetans and Andeans differ strikingly. Tibetan highlanders exhibit marked chronic hyperventilation; at a given O₂ demand, their ventilation rate is roughly twice that of people residing at sea level. For them, hyperventilation is permanent! Andean highlanders exhibit less of a hyperventilation response. Most species of nonhuman mammals at high altitude display some degree of hyperventilation.

Although processes such as hyperventilation (and others discussed in Box 24.5) help keep O₂ partial pressures in the systemic blood capillaries from falling excessively at high altitude, capillary O₂ partial pressures do in fact decline. In the people at sea level in the figure, blood enters the systemic capillaries at an arterial O₂ partial pressure of about 12.5 kPa (94 mm Hg) and exits at a mixed venous O₂ partial pressure of about 5.2 kPa (39 mm Hg). In the people at 4500 m, blood enters at a much lower partial pressure, 5.9 kPa (44 mm Hg), and exits at a modestly lower one, 4.4 kPa (33 mm Hg). Thus the O₂ partial pressure in the capillaries—which drives O₂ diffusion to the mitochondria in cells—is, on average, reduced at high altitude, a common circumstance in mammals. Great interest is focused at present on how the tissues of mammals accommodate to this condition. Investigations of various species indicate that tissue-level adjustments that offset the effects of chronic tissue hypoxia are common, either as a consequence of acclimatization or as a result of adaptive evolution.

Genomic scientists are trying to identify genes that have been subject to natural selection in native highland populations. These studies have recently hit pay dirt in finding that genes in the HIF-2 signaling pathway (see page 604) have been subject to strong positive natural selection in Tibetan highlanders during the approximately 20,000 years since the Tibetan Plateau was colonized with permanent human settlements. These genes may prove to affect HIF-2 signaling in ways that aid life at high altitude, such as by controlling red blood cell production in advantageous ways (see Box 24.5). This Box Extension discusses elevated pulmonary blood pressure in humans at high altitude, specific tissue-level adjustments, HIF involvement, and llamas as examples of native highland mammals. It also addresses high-flying birds, especially the bar-headed goose (see page 22). 

In addition to hyperventilation, another organ-level response that typically occurs when lowland humans go to high altitude is elevated blood pressure in the blood vessels of their lungs. Although this phenomenon is not immediately relevant to the oxygen cascade, it is noteworthy because—if uncorrected for extended periods—it can lead to chronic disease. The phenomenon seems clearly to be an example of a misplaced response. A normal property of humans is that the pulmonary blood vessels constrict in response to tissue hypoxia. When people are living at low altitudes, this response occurs regionally in the lungs and helps distribute blood flow to the parts of the lungs in which oxygenation of the blood is occurring most effectively; if a certain region of the lungs is O₂-poor (hypoxic), constriction of the blood vessels there diverts blood flow to other regions that are O₂-rich. The constriction response is believed to have evolved to redistribute blood flow in the lungs in this wayn. At high altitude, however, the response may occur everywhere at once because the lungs may experience hypoxia everywhere! This misplaced activation of the response leads to elevated pulmonary blood pressure and sometimes to outright pulmonary hypertension. Native Andean highlanders exhibit the misplaced response. Tibetan highlanders do not, however, and by losing the response have freed themselves from being susceptible to pulmonary hypertension. Native highland species of mammals and birds typically exhibit either no vasoconstriction in response to whole-body hypoxia or a blunted response.

As mentioned earlier, great interest is focused at present on how the tissues of mammals accommodate to reduced O₂ partial pressures in their systemic blood capillaries at high altitude. Investigations of various species have suggested that several types of tissue-level adjustments sometimes occur, either as a consequence of acclimatization or as a result of adaptive evolution. There is evidence, some of it controversial, for the following sorts of tissue changes in mammals at high altitudes:

• A decrease in average muscle fiber diameter, leading to a shorter average diffusion distance between blood capillaries and muscle fiber mitochondria
• An increase in the concentration of myoglobin, a compound that facilitates diffusion of O₂ through cells (see Figure 3.11 and Chapter 24)
• Suppression of metabolism (hypometabolism) in some tissues, reducing O₂ demand
• A switch of the heart muscle toward greater use of glucose, which increases the ATP yield per O₂ molecule by about 13%
• A switch of skeletal muscle away from use of anaerobic glycolysis (because the ultimate O₂ cost per ATP is greater if lactic acid is synthesized and later metabolized than if the ATP is simply made aerobically; see Chapter 8)
• Other tissue-level changes that emphasize the use of metabolic fuels and catabolic pathways that increase the yield of ATP per O₂ molecule

The hypoxia-inducible factors HIF-1 and HIF-2 (see page 604) are known to help mediate some of these responses—adding increased interest to the recent genomic discovery, mentioned above, that genes in the HIF-2 signaling pathway have been subject to strong natural selection in Tibetan highlanders.

For comparison with the human oxygen cascades in Figure A, Figure B shows oxygen cascades at three altitudes in llamas (Lama glama), which have a long evolutionary history of life in mountains.

Figure B Oxygen cascades of llamas at three altitudes To obtain the data, a set of llamas (Lama glama) reared at sea level was studied at sea level, at 3400 m after 10 weeks of acclimatization, and during an acute exposure to the atmospheric pressure at 6000 m. (Data from Banchero et al. 1971.)

Although llamas hyperventilate at high altitude, they are less reliant on this defense than humans, perhaps because their hemoglobin has a higher affinity for O₂ than ours and thus does not require as high an alveolar O₂ partial pressure to become loaded with O₂ (see Box 24.4). At 3400 m, llamas (unlike humans) do not hyperventilate at all; at 6000 m, they hyperventilate less than humans do at the same altitude. At all altitudes, llamas have a lower mixed venous partial pressure of O₂ than humans (compare Figures A and B). This suggests that they place greater reliance than humans on tissue-level adaptations that aid tissue function under conditions of tissue hypoxia. It seems logical to hypothesize that mammals with lengthy evolutionary histories at high altitudes are more likely to have evolved extensive tissue-level adaptations than human populations with just 10,000–20,000 years of existence at high altitude.

About 20 species of birds have been observed flying at altitudes of 5000 m (16,400 ft) or higher, as exemplified in Figure C. Rueppell’s griffon (Gyps rueppellii) and the bar-headed goose (Anser indicus) have been reported in flight at altitudes higher than the peak of Mt. Everest.

Figure C Highest altitudes at which various species of birds have been observed in flight  (After Scott 2011.)

Such observations inspire wonder in terms of how the O₂ requirements of the flight muscles are met. Rarefied air increases the cost of lift generation during flapping flight. Thus flight is expected to be even more metabolically demanding at high altitude than at sea level. Recall from Box 8.3 that although humans can reach the peak of Mt. Everest without supplemental O₂, only extraordinary individuals can do so, and even they are walking at a speed of about 100 m/h near the top. The achievement of the high-flying birds is in an entirely different category.

The only high-flying bird for which we have truly extensive information is the bar-headed goose. It migrates twice a year over the Himalayas between Central Asia and places such as India in South Asia. Although bar-headed geese have been reported flying at altitudes higher than Mt. Everest (see Figure C), recent studies have shown that they typically choose flight paths over mountain passes rather than flying over the highest peaks during their migrations. Their typical flight altitudes as they cross the Himalayas are 4000–6000 m (13,000–20,000 ft). The geese make their trips over the Himalayas quickly—in just 7–8 h—and they power their upward flight to high altitudes by means of sustained muscular effort rather than using upslope winds to propel them.

The many physiological specializations seen in bar-headed geese can be analyzed to reveal which are the most important for achieving high-altitude flight. For flight at very high altitudes near 9000 m, aspects of breathing physiology are most critical. Bar-headed geese hyperventilate, have enlarged lungs, breathe with especially deep breaths, and in other ways exhibit particularly high facilitation of O₂ uptake by their lungs. These features have their greatest effect in permitting the birds to fly in the vicinity of 9000 m.

Bar-headed geese also exhibit many other specializations, including blood hemoglobin with a particularly high affinity for O₂ and numerous tissue-level specializations such as (1) enhanced numbers of blood capillaries (relative to tissue volume) in the myocardium and flight muscles and (2) aggregation of mitochondria near capillaries where the O₂ diffusion path is shortest. These other specializations are calculated to have their greatest importance at altitudes near 5000 m.

References

Banchero, N., R. F. Grover, and J. A. Will. 1971. Oxygen transport in the llama (Llama glama). Respir. Physiol. 13: 102–115.

Hawkes, L. A., and 12 other authors. 2011. The trans-Himalayan flights of bar-headed geese (Anser indicus). Proc. Natl. Acad. Sci. U.S.A. 108: 9516–9519.

Scott, G. R. 2011. Elevated performance: the unique physiology of birds that fly at high altitudes. J. Exp. Biol. 214: 2455–2462.

Scott, G. R., and W. K. Milsom. 2007. Control of breathing and adaptation to high altitude in the bar-headed goose. Am. J. Physiol. 293: R379–R391.

Torrance, J. D., C. Lenfant, J. Cruz, and E. Marticorena. 1970. Oxygen transport mechanisms in residents at high altitude. Respir. Physiol. 11: 1–15. 

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