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The Nobel Assembly at Karolinska Institutet

has today decided to award the 2019 Nobel Prize in Physiology or Medicine jointly to William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza for their discoveries of how cells sense and adapt to oxygen availability


Animals need oxygen for the conversion of food into useful energy. The fundamental importance of oxygen has been understood for centuries, but how cells adapt to changes in levels of oxygen has long been unknown.

William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza discovered how cells can sense and adapt to changing oxygen availability. They identified molecular machinery that regulates the activity of genes in response to varying levels of oxygen.

The seminal discoveries by this year’s Nobel Laureates revealed the mechanism for one of life’s most essential adaptive processes. They established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function. Their discoveries have also paved the way for promising new strategies to fight anemia, cancer and many other diseases.

Oxygen at center stage

Oxygen, with the formula O2, makes up about one fifth of Earth’s atmosphere. Oxygen is essential for animal life: it is used by the mitochondria present in virtually all animal cells in order to convert food into useful energy. Otto Warburg, the recipient of the 1931 Nobel Prize in Physiology or Medicine, revealed that this conversion is an enzymatic process.

During evolution, mechanisms developed to ensure a sufficient supply of oxygen to tissues and cells. The carotid body, adjacent to large blood vessels on both sides of the neck, contains specialized cells that sense the blood’s oxygen levels. The 1938 Nobel Prize in Physiology or Medicine to Corneille Heymans awarded discoveries showing how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain.

HIF enters the scene

In addition to the carotid body-controlled rapid adaptation to low oxygen levels (hypoxia), there are other fundamental physiological adaptations. A key physiological response to hypoxia is the rise in levels of the hormone erythropoietin (EPO), which leads to increased production of red blood cells (erythropoiesis). The importance of hormonal control of erythropoiesis was already known at the beginning of the 20th century, but how this process was itself controlled by O2 remained a mystery.

Gregg Semenza studied the EPO gene and how it is regulated by varying oxygen levels. By using gene-modified mice, specific DNA segments located next to the EPO gene were shown to mediate the response to hypoxia. Sir Peter Ratcliffe also studied O2-dependent regulation of the EPO gene, and both research groups found that the oxygen sensing mechanism was present in virtually all tissues, not only in the kidney cells where EPO is normally produced. These were important findings showing that the mechanism was general and functional in many different cell types.

Semenza wished to identify the cellular components mediating this response. In cultured liver cells he discovered a protein complex that binds to the identified DNA segment in an oxygen-dependent manner. He called this complex the hypoxia-inducible factor (HIF) . Extensive efforts to purify the HIF complex began, and in 1995, Semenza was able to publish some of his key findings, including identification of the genes encoding HIF. HIF was found to consist of two different DNA-binding proteins, so called transcription factors, now named HIF-1α and ARNT. Now the researchers could begin solving the puzzle, allowing them to understand which additional components were involved and how the machinery works.

VHL: an unexpected partner

When oxygen levels are high, cells contain very little HIF-1α. However, when oxygen levels are low, the amount of HIF-1α increases so that it can bind to and thus regulate the EPO gene as well as other genes with HIF-binding DNA segments (Figure 1). Several research groups showed that HIF-1α, which is normally rapidly degraded, is protected from degradation in hypoxia. At normal oxygen levels, a cellular machine called the proteasome, recognized by the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose, degrades HIF-1α. Under such conditions a small peptide, ubiquitin, is added to the HIF-1α protein. Ubiquitin functions as a tag for proteins destined for degradation in the proteasome. How ubiquitin binds to HIF-1α in an oxygen-dependent manner remained a central question.

The answer came from an unexpected direction. At about the same time as Semenza and Ratcliffe were exploring the regulation of the EPO gene, cancer researcher William Kaelin, Jr. was researching an inherited syndrome, von Hippel-Lindau’s disease (VHL disease). This genetic disease leads to dramatically increased risk of certain cancers in families with inherited VHL mutations. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer. Kaelin also showed that cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes; but that when the VHL gene was reintroduced into cancer cells, normal levels were restored. This was an important clue showing that VHL was somehow involved in controlling responses to hypoxia. Additional clues came from several research groups showing that VHL is part of a complex that labels proteins with ubiquitin, marking them for degradation in the proteasome. Ratcliffe and his research group then made a key discovery: demonstrating that VHL can physically interact with HIF-1α and is required for its degradation at normal oxygen levels. This conclusively linked VHL to HIF-1α.

Oxygen sHIFts the balance

Many pieces had fallen into place, but what was still lacking was an understanding of how O2 levels regulate the interaction between VHL and HIF-1α. The search focused on a specific portion of the HIF-1α protein known to be important for VHL-dependent degradation, and both Kaelin and Ratcliffe suspected that the key to O2-sensing resided somewhere in this protein domain. In 2001, in two simultaneously published articles they showed that under normal oxygen levels, hydroxyl groups are added at two specific positions in HIF-1α (Figure 1). This protein modification, called prolyl hydroxylation, allows VHL to recognize and bind to HIF-1α and thus explained how normal oxygen levels control rapid HIF-1α degradation with the help of oxygen-sensitive enzymes (so-called prolyl hydroxylases). Further research by Ratcliffe and others identified the responsible prolyl hydroxylases. It was also shown that the gene activating function of HIF-1α was regulated by oxygen-dependent hydroxylation. The Nobel Laureates had now elucidated the oxygen sensing mechanism and had shown how it works.

Oxygen shapes physiology and pathology

Thanks to the groundbreaking work of these Nobel Laureates, we know much more about how different oxygen levels regulate fundamental physiological processes. Oxygen sensing allows cells to adapt their metabolism to low oxygen levels: for example, in our muscles during intense exercise. Other examples of adaptive processes controlled by oxygen sensing include the generation of new blood vessels and the production of red blood cells. Our immune system and many other physiological functions are also fine-tuned by the O2-sensing machinery. Oxygen sensing has even been shown to be essential during fetal development for controlling normal blood vessel formation and placenta development.

Oxygen sensing is central to a large number of diseases (Figure 2). For example, patients with chronic renal failure often suffer from severe anemia due to decreased EPO expression. EPO is produced by cells in the kidney and is essential for controlling the formation of red blood cells, as explained above. Moreover, the oxygen-regulated machinery has an important role in cancer. In tumors, the oxygen-regulated machinery is utilized to stimulate blood vessel formation and reshape metabolism for effective proliferation of cancer cells. Intense ongoing efforts in academic laboratories and pharmaceutical companies are now focused on developing drugs that can interfere with different disease states by either activating, or blocking, the oxygen-sensing machinery.

Figure 2. The awarded mechanism for oxygen sensing has fundamental importance in physiology, for example for our metabolism, immune response and ability to adapt to exercise. Many pathological processes are also affected. Intensive efforts are ongoing to develop new drugs that can either inhibit or activate the oxygen-regulated machinery for treatment of anemia, cancer and other diseases.

Key publications

Semenza, G.L, Nejfelt, M.K., Chi, S.M. & Antonarakis, S.E. (1991). Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci USA88, 5680-5684

Wang, G.L., Jiang, B.-H., Rue, E.A. & Semenza, G.L. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.  Proc Natl Acad Sci USA, 92, 5510-5514

Maxwell, P.H., Wiesener, M.S., Chang, G.-W., Clifford, S.C., Vaux, E.C., Cockman, M.E., Wykoff, C.C., Pugh, C.W., Maher, E.R. & Ratcliffe, P.J. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399, 271-275

Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J.M., Lane, W.S. & Kaelin Jr., W.G. (2001) HIFa targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science, 292, 464-468

Jaakkola, P., Mole, D.R., Tian, Y.-M., Wilson, M.I., Gielbert, J., Gaskell, S.J., von Kriegsheim, A., Heberstreit, H.F., Mukherji, M., Schofield, C.J., Maxwell, P.H., Pugh, C.W. & Ratcliffe, P.J. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292, 468-472

William G. Kaelin, Jr. was born in 1957 in New York. He obtained an M.D. from Duke University, Durham. He did his specialist training in internal medicine and oncology at Johns Hopkins University, Baltimore, and at the Dana-Farber Cancer Institute, Boston. He established his own research lab at the Dana-Farber Cancer Institute and became a full professor at Harvard Medical School in 2002. He is an Investigator of the Howard Hughes Medical Institute since 1998.

Sir Peter J. Ratcliffe was born in 1954 in Lancashire, United Kingdom. He studied medicine at Gonville and Caius College at Cambridge University and did his specialist training in nephrology at Oxford. He established an independent research group at Oxford University and became a full professor in 1996. He is the Director of Clinical Research at Francis Crick Institute, London, Director for Target Discovery Institute in Oxford and Member of the Ludwig Institute for Cancer Research.

Gregg L. Semenza was born in 1956 in New York. He obtained his B.A. in Biology from Harvard University, Boston. He received an MD/PhD degree from the University of Pennsylvania, School of Medicine, Philadelphia in 1984 and trained as a specialist in pediatrics at Duke University, Durham. He did postdoctoral training at Johns Hopkins University, Baltimore where he also established an independent research group. He became a full professor at the Johns Hopkins University in 1999 and since 2003 is the Director of the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering.


Want to breathe with unconstrained lungs, cruise over hills as if they were pesky speed bumps, and shave down your PR? Then you’ll need to spend some time huffing and puffing in thin mountain air. Although there’s no conclusive sweet spot for optimal elevation training, USA Track & Field has recommended that athletes live between 7,000 and 8,000 feet above sea level. Sparse oxygen at such altitude forces your body to increase its number of red blood cells, thus increasing the amount of oxygen delivered to muscles during exercise and improving performance.

Lately, some of the best runners in the country have been traveling abroad for their stints at altitude. Nick Symmonds said he trained for a month at around 6,000 feet in San Luis Potosi, Mexico, leading up to the 2014 indoor track national championships. Ryan Hall and his wife, Sara, flew to Addis Ababa, Ethiopia, to run at 7,000 feet in preparation for this year’s Boston Marathon. Desi Linden trained in Iten, Kenya(elevation 7,900), for the same race.

But there are plenty of high altitude destinations stateside. Flatlanders ought to be cautious when traveling any of these places—and not just because of the lack of oxygen. Visitors often become residents. Marathoner Frank Shorter moved to Boulder, Colorado, in 1970 to prepare for the 1972 Munich Olympics, and Boulderites still see him on area trails.

Here are ten of our favorite places to run at altitude, from high to higher:

  1. Bozeman, Montana

  2. Albuquerque, New Mexico

  3. Boulder, Colorado

  4. Mount Laguna, California

  5. Colorado Springs, Colorado

  6. Santa Fe, New Mexico

  7. Flagstaff, Arizona

  8. Mancos, Colorado

  9. Park City, Utah

  10. Mammoth Lakes, California


To prepare for last month’s World Cup, the American and English squads took two different paths toward acclimating to South Africa’s higher altitude. The English players spent two weeks training in the Austrian Alps, but the Americans chose to not sacrifice the practice time needed to adjust their bodies to the elevation of the tournament.

Because both teams lost and were sent home at the same point in the tournament, it’s hard to say which approach was better. But now, new research from Oxford University suggests that an approach somewhere in the middle may be best.

Why altitude training works

Athletes from many sports have used altitude training to prepare for a big match or event, and not just when the event will be at a high altitude. They do this because the air is “thinner” at high altitudes meaning there are fewer oxygen molecules per volume of air. Every breath taken at a high altitude delivers less of what working muscles require.

While the effect is most dramatic at altitudes greater than 8,000 feet (2,438 meters) above sea level, it is noticeable even at 5,000 feet (1,524 meters) above sea level.

To compensate for the decrease in oxygen, one of the body’s hormones, erythropoietin (EPO), triggers the production of more red blood cells to aid in oxygen delivery to the muscles.

You might have heard of EPO in news stories about performance-enhancing drugs. A synthetic version of EPO has been used by endurance athletes to mimic the body’s natural process of red blood cell creation. So far, most sports organizations are more concerned with this artificial version rather than triggering it naturally up in the mountains.

By training at high altitudes, athletes aim to allow their bodies to produce extra red blood cells. Then, they head to a competition at lower elevations to take advantage of their changed physiology, which should last for 10 to 20 days.

While the benefits of altitude training have been demonstrated, specifics on how to best undertake it have remained elusive.

New findings

“It is the higher capacity to deliver fuel to muscles that athletes are interested in,” said Dr. Federico Formenti, a physiology researcher at the University of Oxford and lead author of the new study. “However, it’s not clear how long they should train at altitude or how high up they need to be to get the optimal benefits.”

Formenti’s team studied the effects of altitude training in patients with a rare genetic disorder, called Chuvash polycythemia or CP, and a group of equally fit people without CP. In people without the disorder, the body’s reaction to high altitudes starts with a protein called hypoxia-inducible factor (HIF), which triggers a series of physiological changes. But in those with the disorder, a person’s level of HIF remains elevated even when they are at sea level. This condition offered the researchers an opportunity to study the metabolic effects of permanently being in the “high-altitude” state.

The researchers asked volunteers to pedal a bike at a constant rate while the resistance was slowly increased. The results showed those with CP had to quit the test early and achieved a work rate that was 70 percent that of those without CP.

“We found that the metabolism of CP patients is different and leads to poorer physical performance and endurance,” Formenti said. “Although this is a small study necessarily so because of there are so few people with the condition the results are striking. The differences seen in those with Chuvash polycythemia were large, and five patients were more than enough to see this effect.”

Because the people with CP did more poorly than those without it, the researchers concluded that there are limits to the benefits of training at high altitudes, which also increases levels of HIF in the body.

So, optimizing the altitude training formula of how high to go and how long to stay there could be the difference between raising the Cup or going home early.

The research was published in the journal Proceedings of the National Academy of Sciences and was funded by the British Heart Foundation and the Wellcome Trust.

Text by Live Science


Employed by elite athletes and professional sporting teams for over 40 years, altitude training offers its users a degree of success – which is all it might take. Professor Chris McLellan PhD looks at the history behind altitude training.

Adaptation to high altitude was first acknowledged by balloonists and alpinists in the early 1800’s who discovered the physical limits of going above 13,000ft (3,960m), the so-called “death zone”.

It wasn’t until small animals were taken along for the aeronauts to examine in flight that they realised the key to survival at high altitudes was in fact oxygen, the “active” gas component of air.

The first high altitude simulator for human testing was built at The Sorbonne in Paris in 1877. The machine was a giant, double-cylinder vacuum chamber large enough for a man to fit in it. Scientists were able to create a vacuum equal to 20,000ft (6,100m) of altitude. The man inside the chamber was able to survive by bringing along a rubber bag containing pure oxygen that he could breathe from.

Sir Edmund Hillary used native Sherpa living at 15,000ft (4,570m) as guides to help him reach the summit of Mt Everest. The familiar dark red cheeks of a Sherpa is caused by an increase in capillary blood vessels to their skin and an increase in myoglobin, the red pigment of muscles responsible for storing oxygen in the muscle cells. As myoglobin increases it leads to a dark red colour in muscles enhancing oxygen storage capacity.

High myoglobin is why whales can hold their breath underwater for hours at a time and how some birds can fly for days at 30,000ft without stopping. High myoglobin and high capillaries help circulate and retain oxygen in the muscle.

At sea level, air is denser and there are more molecules of gas per litre of air.

Regardless of altitude, air is composed of 20.9% oxygen and 79% nitrogen. As the altitude increases, the pressure exerted by these gases decreases, therefore there are fewer molecules per unit volume: this causes a decrease in partial pressures of gases in the body, which elicits a variety of physiological changes in the body that occur at whilst high altitude.

Athletes or individuals who wish to gain a competitive edge for endurance events can take advantage of exercising at high altitude, which is typically defined as any elevation above 5,000ft (1500 m).

One suggestion for optimising adaptations and maintaining performance is the live-high, train-low principle.

This training idea involves living at higher altitudes in order to experience the physiological adaptations that occur, such as increased red blood cell levels and higher VO2 max, while maintaining the same exercise intensity during training at sea level.

At high altitudes, there is a decrease in oxygen hemoglobin saturation. This hypoxic condition stimulates the production of erythropoietin (EPO), a hormone secreted by the kidneys. EPO stimulates red blood cell production from bone marrow in order to increase hemoglobin saturation and oxygen delivery. While EPO occurs naturally in the body, it is also made synthetically to help treat patients suffering from kidney failure and to treat patients during chemotherapy.

The study of altitude training was heavily delved into during and after the 1968 Mexico Olympics at an elevation of 7,349ft (2240m). During these Olympic Games, ‘endurance’ events saw significant below-record finishes while anaerobic sprint events, broke all types of records. The conclusions drawn, were equivalent to those hypothesized: that endurance events would suffer and that short events would not see significant negative changes. This was attributed not only to less resistance during movement — due to the less dense air, but also to the anaerobic nature of the sprint events.

Ultimately, these games inspired investigations into altitude training from which unique training principles were developed with the aim of avoiding underperformance.

Altitude training continues to be a hot topic amongst the research community as they continue to identify ways in which training at altitude can improve professional sports and athletic performance.

Thinking about altitude training for your gym or studio? Talk to the guys who can make it happen and get in before your competition does – click here.

Simulated Altitude Training (SAT) Instructor courses are available through Fitness Science Australia. This foundations course includes an overview of the history of SAT, terminology, physiological adaptations to SAT in response to a variety of training conditions, client screening and assessment, SAT progression, integration and periodisation and workout structure and session planning.

The horse racing industry is steeped in tradition and folklore dating back 100 years.In many instances the lessons learned over time have proven to be most effective means of training race horses – both thoroughbred and standardbred. However, to gain that competitive edge, trainers and veterinarians are turning to the lessons learned in human exercise science to apply to training the elite athletic horse.

In recent years, heart rate monitoring and blood lactate analysis have gained wide spread acceptance within the horse training community. Since the 1968 Mexico Olympics, elite human athletes have focused on the benefits of altitude training. It is significant that most world records for long distance events are held by athletes who were born, and/or who train at, altitude. These athletes are physiologically more efficient at uptake, delivery and utilization of oxygen. Clearly the exposure to altitude does improve an individuals overall vitality that has consistently translated to improved performances in certain individuals.

Until recent times the ability to train horses at “altitude“ in the same way as human athletes (with scientifically documented research to support the practice) was impractical. That was, of course, until the advent of Intermittent Hypoxic Training (IHT)

IHT provides a number of immediate and simple strategies that can be applied to the racing and breeding of horses, based on independently conducted scientific research reviews, observation, practical experience and direct extrapolation from the human model experience.

It has been proven that IHT significantly improves the efficiency of oxygen metabolism in the body, allowing the horse to maximize its genetic potential. IHT is a very potent means of endurance improvement and stimulation of the anti-oxidant health preservation system. Enhanced blood oxygen carrying capacity and efficiency of oxygen consumption by tissues and cells, along with increased capacity of the anti-oxidant (free radical scavenging) system in the body are major attributes of Intermittent Hypoxic Training.

After a course of IHT the following physiological changes are apparent:

  • Improved blood biochemical indices
  • Improved immunological status
  • Increased VO2 max
  • Reduced muscle damage following exercise (lower muscle enzymes)
  • Smooth muscle stimulation
  • Enhanced sympatho-adrenal system
  • Cardiovascular system adaptation resulting in: 
    vasodilation, increased microvessel density and reduced peripheral resistance 
    decreased mean arterial blood pressure and heart rate
  • Respiratory system adaptation resulting in: 
    improved lung tissue where damaged 
    increased Hypoxic Ventilatory Response 
    increased minute ventilation, total and vital lung capacity

There is no evidence that IHT enhances performance beyond the horse’s genetic potential. IHT does not appear to cause statistically significant changes on red blood cell parameters but may help normalise anaemic horses. There is evidence, that IHT may have a therapeutic role in reducing the muscle damage associated with strenuous exercise.

In summary IHT can help “re-vitalize” a horse. It does this by stimulating the horse’s own immune system to overcome the stresses of training and racing. With the use of IHT, the horse is more likely to reach his or her individual physiological potential for performance. There is no evidence that IHT will enhance the performance in an un-natural way.

Nature Vet High Performance Technologies Pty Ltd believe that IHT will facilitate each horse to compete at its full potential without the negative impact of the stresses associated with racing, such as musculoskeletal, respiratory, cardiovascular, immune system suppression and neurological problems.


Acclimatization of Horses for Air Travel:

When horses are flown in aircraft they are subjected to a lower oxygen pressure than that experienced at sea level. The cargo hold is routinely pressurized to between 2000 and 3000 metres above sea level. Thus, horses are experiencing the effects of altitude. For unacclimatized horses this is physiologically demanding and all horses arrive at their destination physiologically depleted. By the use of IHT, horses can be conditioned to higher altitudes and thus significantly reduce the detrimental effects of long haul flights. Your horse will arrive physiologically fitter and ready to race or perform much sooner than otherwise.

Enhanced Effects on Fertility:

A theoretical application of IHT is to stimulate and train the developing foetus in utero. In humans born at high altitude, this effect appears to persist as permanently enhanced oxygen metabolism.
Also IHT in humans has shown to enhance fertility by increasing the density of capillaries in the endometrium and placenta. Similarly it would be expected that IHT could enhance the pregnancy carrying capacity of older valuable mares showing signs of fibrosis of the endometrium. This is only one of the many mechanisms that we feel could help the reproductive potential in geriatric mares.

Vascular Endothelial Growth Factor (VEGF):

Perhaps the most exciting application of IHT is in the management of the lung damage associated with Exercise Induced Pulmonary Haemorrhage (EIPH) in horses. Human studies have shown that IHT promotes release of Vascular Endothelial Growth Factor. Increases in VEGF may play a significant therapeutic role in the treatment and management of this serious affliction endemic in racehorses. Until now there has not been a potential therapeutic treatment for the horse with EIPH. If the human studies prove to translate to the horse this serious problem in racing could be diminished significantly.

GO2Altitude® equine hypoxicators are supplied with

Worlds – best equine ERA® Mask for hypoxic training and medications delivery 
MDI and nebulizer for treatment of horses and camels.


PREHISTORIC AND CONTEMPORARY human populations living at altitudes of at least 8,000 feet (2,500 meters) above sea level may provide unique insights into human evolution, reports an interdisciplinary group of scientists.

Indigenous highlanders living in the Andean Altiplano in South America, in the Tibetan Plateau in Asia, and at the highest elevations of the Ethiopian Highlands in east Africa have evolved three distinctly different biological adaptations for surviving in the oxygen-thin air found at high altitude.

“To have examples of three geographically dispersed populations adapting in different ways to the same stress is very unusual,” said Cynthia Beall, a physical anthropologist at Case Western Reserve University in Cleveland, Ohio. “From an evolutionary standpoint the question becomes, Why do these differences exist? We need to figure out when, how, and why that happened.”

To begin to answer some of these questions, a multidisciplinary group of scientists, including Beall, met earlier this month at the annual meeting of the American Association for the Advancement of Science in Seattle, Washington.

“High-altitude populations offer a unique natural lab that allows us to follow [many] lines of evidence – archaeological, biological, climatological – to answer intriguing questions about social, cultural, and biological adaptations,” said Mark Aldenderfer, an archaeologist at the University of California, Santa Barbara, who organized the AAAS symposium with Beall.

(Aldenderfer and Beall are both past recipients of research grants from the National Geographic Society Committee for Research and Exploration.)

Adapting to High Altitudes

The Andean and Tibetan plateaus rise some 13,000 feet (4 kilometers) above sea level. As prehistoric hunter-gatherers moved into these environments, they encountered desolate landscapes, sparse vegetation, little water, and a cold, arid climate.

In addition, early settlers to the high plateaus likely suffered acute hypoxia, a condition created by a diminished supply of oxygen to body tissues. At high altitudes the air is much thinner than at sea level. As a result, a person inhales fewer oxygen molecules with each breath.

Symptoms of hypoxia, sometimes known as mountain sickness, include headaches, vomiting, sleeplessness, impaired thinking, and an inability to sustain long periods of physical activity. At elevations above 25,000 feet (7,600 meters), hypoxia can kill.

The Andeans adapted to the thin air by developing an ability to carry more oxygen in each red blood cell. That is: They breathe at the same rate as people who live at sea level, but the Andeans have the ability to deliver oxygen throughout their bodies more effectively than people at sea level do.

“Andeans counter having less oxygen in every breath by having higher hemoglobin concentrations in their blood,” Beall said. Hemoglobin is the protein in red blood cells that carries oxygen through the blood system. Having more hemoglobin to carry oxygen through the blood system than people at sea level counterbalances the effects of hypoxia.

Tibetans compensate for low oxygen content much differently. They increase their oxygen intake by taking more breaths per minute than people who live at sea level.

“Andeans go the hematological route, Tibetans the respiratory route,” Beall said.

In addition, Tibetans may have a second biological adaptation, which expands their blood vessels, allowing them to deliver oxygen throughout their bodies more effectively than sea-level people do.

Tibetans’ lungs synthesize larger amounts of a gas called nitric oxide from the air they breathe. “One effect of nitric oxide is to increase the diameter of blood vessels, which suggests that Tibetans may offset low oxygen content in their blood with increased blood flow,” Beall said.

A pilot study Beall conducted of Ethiopian highlanders living at 3,530 meters (11,580 feet) suggests that—unlike the Tibetans— they don’t breathe more rapidly than people at sea level and aren’t able to more effectively synthesize nitric oxide. Nor do the Ethiopians have higher hemoglobin counts than sea-level people, as the Andeans do.

Yet despite living at elevations with low oxygen content, “the Ethiopian highlanders were hardly hypoxic at all,” Beall said. “I was genuinely surprised.”

So what adaptation have the Ethiopian highlanders’ bodies evolved to survive at high altitude? “Right now we have no clue how they do it,” Beall said.

Tracking Prehistoric Migrations

Knowing how long the populations have been living at the top of the world is crucial to answering the evolutionary question of whether these adaptations are the result of differences in the founding populations, random genetic mutations, or the passage of time.

Archaeologists, paleontologists, and climatologists are pooling their knowledge to pinpoint when some of these early migrations to the high plateaus occurred.

Aldenderfer, the University of California, Santa Barbara, archaeologist, says cultural adaptations would have to occur first.

“The ability to survive in such harsh environments required control of fire, an expanded tool kit that included bone needles to make complicated clothing that protected the body in a significant way, and the cultural flexibility to change subsistence practices,” he said.

Climatologists’ changing understanding of the nature of the last ice age is contributing to archaeological efforts.

Ice-core and other evidence show that, rather than being a monolithic period lasting 100,000 years with frigid temperatures and glacial landscapes, the Ice Age included long periods of relatively mild weather.

“Through most of the 20th century it was thought that the Tibetan Plateau was covered by a monstrous ice sheet during the last glacial maximum, about 21,000 years ago,” Aldenderfer said. “People couldn’t live on an ice sheet. So archaeologists wouldn’t even bother to look for sites from that time period.”

Knowing the Tibetan Plateau more closely resembled Arctic tundra has lead to the discovery of new sites. Archaeological evidence suggests hunter-gatherers occupied the Tibetan plateau some 25,000 to 20,000 years ago. People began moving into the Andean Altiplano around 11,500 to 11,000 years ago.

What motivated prehistoric people to move into the harsh and challenging conditions presented by high altitude?

“The highlands offered an attractive option with a landscape that was open and pristine,” Aldenderfer said. “People probably started out moving up and down for short terms, and then gradually settled at the higher elevations.”

Changing environmental conditions also created “new opportunities and new constraints,” he said.

In South America, for example, the maritime environment began transforming as temperatures warmed, glaciers retreated, and sea levels rose. Large mammals such as mammoths and mastodons gradually went extinct, as did other herbivores. Warmer temperatures allowed plants and animals to move to higher elevations, creating resource-rich patches of habitat in highland areas. Familiar coastal resources also changed as fish and shellfish habitats shifted.

Similar processes likely occurred in Tibet. Prehistoric people occupied the landscape during the interglacial process, when conditions were relatively benign and hunting was plentiful, Aldenderfer said.

“Suddenly it gets really cold. Biomass declined precipitously. It becomes very arid because of wind-flow patterns. The landscape becomes one of very patchy vegetation, rocky. And the huge herds of gazelle, antelope, and sheep wax and wane,” Aldenderfer said. “What happens? Do the people adapt and tough it out? Did they abandon the highlands? Or do these early populations more or less go extinct? There’s no evidence yet. But finding biological differences suggests they toughed it out and adapted.”


Text from The National Geographic


IHT has been found to have positive effects on coronary heart disease (CHD) patients

For decades, athletes have been using hypoxic training or the practice of limiting oxygen availability while training, to improve their performance. Training in an environment with low oxygen is known to boost the production of red blood cells, aid stamina and even improve lung and heart function. This is why in the West and many parts of Asia, many endurance athletes such as marathon runners continue to live and/or train at high altitudes.

While intermittent hypoxia may have its roots dating back to the middle ages, the modern scientific study of intermittent hypoxia therapy (IHT) — also known as periodic hypoxia, interval hypoxia and hypoxic preconditioning, among others — took off in 1930’s in the Soviet Union, driven mainly by military requirements. Today IHT is widely prescribed in the former Soviet Union and Russia as a drug-free treatment option with very few contraindications. Of the two million patients undergoing IHT, 75 to 95 percent reported good or satisfactory results.

IHT and its possible applications has also become the subject of a considerable amount of research in the last 30 years. The number of publications indexed in PUBMED under the key word “intermittent hypoxia” has increased from a mere 15 in 1983 to 385 by 2013. The results of this research has extended the use of IHT beyond its established roles in altitude acclimatisation and sports performance enhancement to treatments for a variety of conditions such as coronary heart disease (CHD). It is now gaining a reputation among healthcare professionals and growing in popularity in Europe and the United States.

Recently, two clinical trials were published which showed CHD patients benefiting from IHT.

In one of the clinical trials which enrolled 40 coronary heart disease patients suffering from exertional angina, the significant increases in exercise tolerance was accompanied by normalising lipids profiles, lowered blood pressure and reduced incidence of angina attacks.  Another study which enrolled 46 male and female smoking and non-smoking patients showed that exercise tolerance was increased with peak oxygen consumption increasing 14.25 to 14.55 ml/kg/min and remained significantly elevated at 14.84ml/kg/min for the next month.

The good news is that coronary heart patients don’t need to climb mountains to enjoy the benefits of IHT. Doctors and trained therapists can offer IHT in the comfort and convenience of their clinics with the ReOxy, a new medical non-invasive modality of treatment for cardiovascular diseases.

According to the inventor of ReOxy, Dr. Alexey Platonenko, ReOxy is very different from its Soviet predecessors. Trying to compare the two is like comparing an old model T Ford to the latest Tesla; they are both cars but they run on very different technologies. Dr.Platenenko elaborates, “The ReOxy is the first device of its kind that allows precise calculation and dosing of hypoxic load tailored individually for each patient. ReOxy uses Self-Regulated Treatment (SRT) technology that relies upon the principle of biological feedback, where the patient’s bodily reactions define and control the therapeutic parameters throughout the whole treatment session.”

He adds that it is crucially important to correctly calculate the individual dose to be used for every hypoxia treatment and not to over or under-dose. “Overdosing hypoxia can result in negative effects similar to those caused by obstructive sleep apnea syndrome. On the other hand, under-dosing can reduce the procedure’s efficacy. In ReOxy’s case, the hypoxic load dose is calculated in a similar way to doses for pharmacological substances. It can subsequently be repeated, increased or decreased as required.”

Being a non-invasive, non-pharmacological treatment, IHT can be safely prescribed and used concurrently with other therapies and prescription drugs. For added safety, the SRT reads and analyses information from a built-in pulse oximeter to adjust the supplied air mixture and timing for each patient in response to changes in vital indicators, i.e. blood oxygen saturation and heart rate.

Dr.Platonenko adds, “It took us three years of non-stop research and liaising with leading industry suppliers from all over the world to develop the individual breathing set we currently use and which we believe offers the best user experience.”


Text by Health Care Asia


Living and training at altitude has long been used as a way to increase the oxygen carrying capacity of the human body. If you live at high altitude, your body responds by increasing your number red blood cells.  These red blood cells carry oxygen from the lungs to the muscles during exercise.

Sensors in your kidneys detect a lower than normal oxygen level and then release a hormone called erythropoietin (EPO).  This hormone stimulates an increase in red blood cell formation.

Elite athletes sometimes use synthetic EPO for this purpose. This drug can increase your red blood cell production and expand your blood’s capacity to carry oxygen to your muscles.

But EPO is banned in competitive sports and potentially harmful as it can make your blood too thick and put undue stress on your heart. And moving to the mountains is not always an option.

What about “elevation” masks as a method of hypoxic training for running?

These masks provide resistance to your breathing and have been shown to increase your ability to breathe more air. It’s basically like strength training for your breathing muscles. So they are effective in that regard.

And while exercising with one of these masks has been shown to reduce the oxygen level in the blood, the reduction was not as much as would be expected with actual training at altitude. And  they don’t reduce the oxygen level to the degree shown to increase EPO. (See the study reviewed below.)

Also, there is not much scientific support for the idea that breathing increased volumes of air will improve your performance. “Elevation” masks  do increase the strength of respiratory muscles, but do not improve performance in exercise. (See reference below.) This is probably because breathing volume is not the rate limiting factor in performance for most people.

Getting more air in and out of your lungs is not the problem, getting the oxygen from that air into the blood and from the blood into the muscle cells is the issue. And to do that, you need to increase your number of red blood cells.

So “elevation” masks have not been shown to increase EPO production and therefore increase red blood cell count. But there is a way to naturally stimulate production of EPO by your own body, so you don’t have to move to the mountains, or take performance enhancing drugs.

Reducing Blood Oxygen During Exercise Increases EPO

Some researchers in Canada were curious about the decrease in oxygen concentration in the blood that happens during exercise at elevation. They wanted to know if it would cause an increase in the hormone erythropoietin (EPO).

Previous researchers had shown that it takes a minimum of two hours of breathing the low-oxygen air present at high altitudes to stimulate EPO production. So these researches set out to answer a question.

Would EPO increase be stimulated in less time than 2 hours, if exercise is added to the mix? If so, it would be a great method of hypoxic training for running.

They tested 5 athletes by having them exercise for 3 minutes at two separate levels of elevation, 1000 meters and 2100 meters. The researchers measured their EPO levels before the exercise and after. They took blood samples 4, 7, 24, and 48 hours after the exercise intervention.

At the 1000-meter level, the athletes had an average time of 24 seconds below 91% oxygen saturation measured with a pulse oximeter, and 24% higher EPO levels 24 hours after the exercise.

At the 2100-meter level the athletes had an average time of 136 seconds below 91% oxygen saturation, with this measurement dipping to an average of 82%. 24 hours later their EPO levels were 36% higher. Spending 136 seconds below 91% stimulated an increase in EPO.

A study using “elevation” masks did not find this degree of hypoxemia (low oxygen) during exercise, even when the mask was set on what the manufacturer claimed was equivalent to 4572 meters of elevation.

The researchers also measured EPO in a group of people who were exposed to 13 minutes of breathing low-oxygen air and a placebo group who had no intervention. Both of these groups had no elevation in EPO during the 48 hours they were monitored.

So exercise that reduces your oxygen saturation in your blood to under 91% for roughly 136 seconds is likely to give you a bump in EPO production.

And here is the best way I’ve found to accomplish this without moving to the mountains. (I’m not opposed to moving to the mountains. It’s just not always convenient for many people.)

Breath Holding During Exercise: A method of hypoxic training for running.

This comes from the Buteyko Method. Avoid doing this in a swimming pool or body of water. You can use this method with any land based exercise. It creates a low oxygen and high carbon dioxide environment in your body. This is the most convenient way to implement hypoxic training for running.

  1. Inhale and exhale through your nose.
  2. Hold your nose.
  3. Proceed with your chosen exercise (walking, running, hopping, squatting) until you feel a strong urge to breathe.
  4. Let go of your nose and breathe through it until your breathing has relaxed. Keep exercising as before.
  5. Repeat for 10 rounds or more.
  6. You can perform this exercise several times a day. We currently don’t have research to confirm or deny if more than once per day increases your EPO level more than doing it just once per day.

You can use a pulse oximeter to monitor this exercise. It is a small device that fits on the tip of your finger and reads your pulse rate and the amount of oxygen saturation of your blood as a percentage.

Many of the available  monitors have a time delay of 10 seconds or so. Keep that in mind if you don’t see the number decrease immediately.

There is no need to lower your oxygen saturation below 80 percent. According to the study described above, getting your oxygen saturation to less than 91 percent for approximately 24 seconds can result in an increase of EPO of up to 24 percent, while maintaining this saturation around 136 seconds can increase your EPO about 36 percent.


Text from Run Better Now


In one of the most comprehensive studies of its kind, researchers at the University of Colorado School of Medicine in partnership with the Harvard School of Global Health have found that people living at higher altitudes have a lower chance of dying from ischemic heart disease and tend to live longer than others.

“If living in a lower oxygen environment such as in our Colorado mountains helps reduce the risk of dying from heart disease it could help us develop new clinical treatments for those conditions,” said Benjamin Honigman, MD, professor of Emergency Medicine at the CU School of Medicine and director of the Altitude Medicine Clinic. “Lower oxygen levels turn on certain genes and we think those genes may change the way heart muscles function. They may also produce new blood vessels that create new highways for blood flow into the heart.”

Another explanation, he said, could be that increased solar radiation at altitude helps the body better synthesize vitamin D which has also been shown to have beneficial effects on the heart and some kinds of cancer.

The study was recently published in the Journal of Epidemiology and Community Health.

At the same time, the research showed that altitudes above 4,900 feet were detrimental to those suffering from chronic obstructive pulmonary disease.

“Even modestly lower oxygen levels in people with already impaired breathing and gas exchange may exacerbate hypoxia and pulmonary hypertension [leading to death],” the study said.

Honigman, senior author of the study, along with researchers that included Robert Roach, PhD, director of the School of Medicine’s Altitude Research Center, Deborah Thomas, PhD, a geographer at the University of Colorado Denver and Majid Ezzati of the Harvard School of Global Health, spent four years analyzing death certificates from every county in the U.S. They examined cause-of-death, socio-economic factors and other issues in their research.

They found that of the top 20 counties with the highest life expectancy, eleven for men and five for women were located in Colorado and Utah. And each county was at a mean elevation of 5,967 feet above sea level. The men lived between 75.8 and 78.2 years, while women ranged from 80.5 to 82.5 years.

Compared to those living near sea-level, the men lived 1.2 to 3.6 years longer and women 0.5 to 2.5 years more.

Despite these numbers, the study showed that when socio-economic factors, solar radiation, smoking and pulmonary disease were taken into account, the net effect of altitude on overall life expectancy was negligible.

Still, Honigman said, altitude seems to offer protection against heart disease deaths and may also play a role in cancer development.

Colorado, the highest state in the nation, is also the leanest state, the fittest state, has the fewest deaths from heart disease and a lower incidence of colon and lung cancer compared to others.

“We want to now look at these diseases in a more focused way so we can see the mechanisms behind hypoxia and why they affect the body the way they do,” Honigman said. “This is a public health issue in Colorado and the mountain West. We have more than 700,000 people living at over 7,000 feet above sea level. Does living at altitude change the way a disease progresses? Does it have health effects that we should be investigating? Ultimately, we hope this research will help people lead healthier lives.”


Text from Science Daily


In general, IHT contributes to improved immunological status. The occurrence of allergies and inflammatory diseases decreases. This has been observed in continuous exposure to altitude, as well as with IHT. Studies have been able to show improvements to conditions of an inflammatory nature, such as arthritis, asthma, allergic rhinitis, autoimmune thyroiditis and inflammatory skin diseases.

Even the difficult-to-treat and disabling disease rheumatoid arthritis showed a positive response, with seven out of 10 patients receiving IHT showing less inflamed joints, reduced pain and morning stiffness and reduced need for medication. All patients reported improved mood, sleep and appetite and increased . physical activity.

Asthma has received particular attention, with several studies showing significant improvement. Observations made in the Netherlands have shown that asthmatics treated in climatic chambers that simulated altitudes of 1500 to 2550 metres improved rapidly, and with 60 to 100 treatments were ‘cured’. This certainly fits with the common observation that asthmatics, despite their obvious fears about altitude, usually have less asthma and do much better at altitude. I have taught the Buteyko method for the past nine years. This highly successful method (also originating in Russia) teaches that hyperventilation and loss of carbon dioxide (which is anti- inflammatory and bronchodilator) worsen the asthmatic condition.Inflammation in the lungs is one reason asthmatics hyperventilate.

Another perpetuating factor to hyperventilation could be inefficient oxygen metabolism. Until this is improved, the asthmatic will continue to hyperventilate. The improved oxygen capacity observed after adaptation to hypoxia results in the oxygen required by the body being supplied with less volume of air needing to be taken in and less hyperventilation taking place.

Recent experiences with patients on artificial ventilation indicate that the stress of breathing itself might adversely affect susceptible airways. Lower ventilation levels are associated with a 30 per cent lower mortality rate in patients with severe lung disease.


Text by Rosalba Courtney

More than 350 athletes, climbers and teams throughout the world are using the Hypoxia Training and are seeing excellent gains in performance – quite phenomenal in many cases.

This is because Intermittent Hypoxia Training (IHT) increases the effeciency of exercise and training.

The maximum use of oxygen has not changed for 40 years even in the world’s greatest runners.

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