Thin air: altitude training, blood doping and the people who were born to live high

Part 1: The body under load

1Many of the world’s best distance runners were born and raised more than 2,000 metres above sea level, in the highlands of Kenya and Ethiopia. Athletes from other countries have tried to copy their advantage by spending weeks at high-altitude training camps, or by sleeping in tents in which the air contains less oxygen than normal. To understand why altitude matters, we first need to look at how the body responds to exercise. Runners from these two countries have won a large share of the major marathons in recent decades.

2During exercise, muscle cells use ATP much faster than at rest. Most of this ATP is made by aerobic respiration in the mitochondria, where oxidative phosphorylation produces far more ATP from each glucose molecule than glycolysis alone. When the supply of oxygen to the muscles cannot keep up, more pyruvate is converted to lactate. This allows glycolysis to continue, but it produces only a small amount of ATP, and the build-up of lactate and hydrogen ions contributes to fatigue.

3Faster respiration in the muscles releases more carbon dioxide into the blood. Carbon dioxide reacts with water to form carbonic acid, which releases hydrogen ions, so the pH of the blood falls slightly. This change is detected by chemoreceptors in the medulla oblongata of the brain and in the walls of the aorta and the carotid arteries. Receptors in the muscles and joints also detect movement and send impulses to the brain as soon as exercise begins.

4Impulses from these receptors reach the ventilation centre in the medulla oblongata. The ventilation centre sends more impulses along the nerves to the diaphragm and the intercostal muscles, which contract more strongly and more often. Breathing becomes deeper and faster. In a trained endurance athlete, the volume of air breathed in each minute can rise from about 6 dm³ at rest to more than 150 dm³ during a race, which removes carbon dioxide and supplies oxygen.

5The heart responds too. The cardiovascular control centre, also in the medulla oblongata, increases the frequency of impulses in sympathetic neurones to the sinoatrial node, the heart’s natural pacemaker. The neurotransmitter noradrenaline released at the sinoatrial node makes it produce waves of excitation more frequently, so the heart rate rises. At the same time, adrenaline from the adrenal glands increases both the rate and the force of contraction.

6The volume of blood pumped by each ventricle every minute is called the cardiac output. It is calculated by multiplying the heart rate by the stroke volume, the volume of blood pumped out of the ventricle in each beat. In an illustrative trained runner, the heart rate was 70 beats per minute and the stroke volume was 75 cm³ at rest. During maximum exercise, the heart rate rose to 180 beats per minute and the stroke volume to 120 cm³.

7Endurance training changes the body in several ways. The wall of the left ventricle becomes thicker and the chamber becomes larger, so the stroke volume increases and the resting heart rate falls, sometimes to below 40 beats per minute. In the muscles, the number of capillaries around each fibre increases, and so does the number of mitochondria inside the slow twitch fibres. These fibres also contain more myoglobin, a red protein that stores oxygen.

Part 2: Living high

8At an altitude of 2,500 metres, the air pressure is about one quarter lower than at sea level. The air still contains 21 per cent oxygen, but the partial pressure of oxygen in the alveoli is lower. As a result, haemoglobin in the blood leaving the lungs is less saturated with oxygen, and less oxygen is delivered to the tissues. Visitors to high altitude feel breathless, sleep badly and find that exercise is much harder than usual.

9Within hours, breathing becomes deeper. Over the following days, cells in the kidneys detect the low concentration of oxygen in the blood and release more of the hormone erythropoietin, known as EPO. EPO is a glycoprotein. It travels in the blood to the bone marrow, where it binds to receptors on the cell surface membranes of stem cells that give rise to red blood cells. Binding activates signalling pathways inside the cells, and over several weeks more red blood cells are produced.

10Coaches use this response in a method called "live high, train low". Athletes sleep and rest at altitude, so their EPO concentration rises, but they travel down to lower ground to train, so they can still run at high speeds. In an illustrative study, 16 runners who slept at a simulated altitude of 2,500 metres for four weeks increased their total haemoglobin mass by a mean of 4.1 per cent, while a control group showed no change.

11Some athletes now use tents or rooms in which some of the oxygen has been removed from the air. These are legal in most sports, although some people argue that they are against the spirit of fair competition. The gains are small and vary greatly between individuals. A few athletes produce a large increase in red blood cells, while others hardly respond at all. Part of this variation seems to be inherited, which suggests that differences in genes affect how strongly the kidneys respond to low oxygen.

12"Altitude is a real stimulus, but it is not magic," says Dr Lena Fischer, an exercise physiologist who works with national distance-running teams. "Living high makes it harder to recover from hard sessions, and if you train high you simply cannot run as fast. The athletes who benefit most are the ones who already respond strongly to low oxygen, and we still cannot reliably predict who they will be." For that reason, many teams now measure each athlete’s response with blood tests before deciding whether altitude training is worthwhile.

Short cuts and their dangers

13In the 1990s, some professional cyclists began injecting recombinant EPO, a form of the hormone made by genetically modified cells grown in culture. Injected EPO can raise the proportion of the blood made up of red cells far higher than altitude does. This increases the oxygen-carrying capacity of the blood, but it also makes the blood more viscous, so it flows more slowly and is more likely to clot. Several young cyclists died suddenly during this period.

14Recombinant EPO has a slightly different pattern of sugar groups from the EPO made in the kidneys, and this difference can be detected in urine. Because some athletes learned to take small doses that were difficult to detect, sports authorities also introduced the athlete biological passport. Blood samples are taken from each athlete many times a year, and an unexpected change in the values for that athlete can be used as evidence of doping.

15Anabolic steroids such as testosterone are misused for a different reason. Testosterone is a lipid-soluble steroid hormone, so it can diffuse through the cell surface membrane of muscle cells. Inside the cell it binds to a receptor protein in the cytoplasm, and the hormone–receptor complex moves into the nucleus. There it binds to specific sequences of DNA close to certain genes, and acts as a transcription factor, increasing the synthesis of muscle proteins.

16Misusing anabolic steroids can damage the liver and heart, raise blood pressure and reduce fertility, because the high concentration of steroid inhibits the release of hormones from the pituitary gland that control the testes and ovaries. Steroids are banned in almost all sports, both in and out of competition. Because the body’s own testosterone concentration varies between people, testers compare the ratio of testosterone to a related steroid in the urine, and can identify synthetic testosterone from the slightly different proportions of carbon isotopes it contains.

Born to live high

17People have lived on the Tibetan plateau, more than 3,500 metres above sea level, for thousands of years. Surprisingly, most Tibetans do not have unusually high concentrations of haemoglobin. Instead, many carry an allele of a gene called EPAS1, which is involved in the response of cells to low oxygen. This allele reduces the increase in red blood cell production that would otherwise occur at altitude, so their blood does not become too viscous. Tibetans also breathe faster and have a greater blood flow to their tissues.

18The EPAS1 allele is found in nearly 90 per cent of Tibetans, but in fewer than 10 per cent of Han Chinese people living at low altitude, even though the two populations separated only a few thousand years ago. Studies of DNA suggest that the allele came originally from the Denisovans, an extinct group of humans whose ancestors interbred with the ancestors of Tibetans. Studies suggest that Tibetan women whose haemoglobin concentration stays close to the sea-level average tend to have more surviving children, which is exactly the kind of difference that natural selection acts on.

19The Quechua and Aymara people of the Andes have also lived at high altitude for thousands of years, but they adapted in a different way. Many of them do have higher haemoglobin concentrations than people at sea level, along with a larger chest and lung volume. Some older Andean highlanders develop chronic mountain sickness, in which the blood becomes so thick that the heart struggles to pump it. Studies of Ethiopian highlanders suggest that they have evolved yet another set of adaptations, involving different genes again.

20"The Tibetan story is a beautiful example of evolution in our own species," says Dr Fischer. "It also tells athletes something important. More red blood cells is not always better. Evolution found a balance between carrying more oxygen and keeping the blood flowing, and anyone who tries to push past that balance with a syringe is taking a serious risk." "Natural selection had thousands of years and many generations to get that balance right."