Worldwide, over 2 million people live at an altitude of 4,500 meters or higher. Interestingly, these high-altitude residents have a lower incidence of metabolic diseases such as diabetes, coronary artery disease, hypercholesterolemia, and obesity when compared to individuals living at sea level. Researchers have long been intrigued by this phenomenon and have made groundbreaking discoveries that shed light on how the human body adapts its metabolism under chronically low oxygen levels or hypoxia, like those experienced at high altitudes.
A recent study conducted by researchers at the Gladstone Institutes revealed that sustained exposure to low levels of oxygen, similar to those found at an altitude of 4,500 meters, caused a significant change in the metabolism of mice. The findings provide valuable insights into the metabolic differences of individuals living at high altitudes and offer new avenues for developing novel treatments for metabolic diseases. When exposed to chronically low oxygen levels, different organs in the body reshuffle their fuel sources and energy-producing pathways in various ways. This adaptation process enables people who live above 4,500 meters, where oxygen makes up just 11% of the air, to survive and thrive despite the shortage of oxygen, known as hypoxia. The researchers conducted their study on adult mice housed in pressure chambers containing 21%, 11%, or 8% oxygen—levels at which both humans and mice can survive. Over three weeks, the scientists observed the animals' behaviour, monitoring their temperature, carbon dioxide levels, and blood glucose. They used positron emission tomography (PET) scans to study how different organs consumed nutrients.
In the first few days of hypoxia, the mice moved less and spent hours entirely still. However, their movement patterns returned to normal by the end of the third week. Similarly, carbon dioxide levels in the blood, which decrease when mice or humans breathe faster to get more oxygen, initially decreased but returned to normal levels by the end of the three weeks. The animals' metabolism, however, seemed more permanently altered by the hypoxia. Blood glucose levels and body weight dropped for animals housed within the hypoxic cages, and neither returned to pre-hypoxic levels. These lasting changes generally mirror what has been seen in humans who live at high altitudes.
The PET scans of each organ revealed lasting changes as well. The body needs high oxygen levels to metabolize fatty acids (the building blocks of fats) and amino acids (the building blocks of proteins). In contrast, less oxygen is required to metabolize the sugar glucose. In most organs, hypoxia led to an increase in glucose metabolism—an expected response to the shortage of oxygen. However, the researchers found that in brown fat and skeletal muscle—two organs already known for their high glucose metabolism—glucose consumption levels decreased. The study showed that while some organs consume more glucose, others become "glucose savers" instead. This observation contrasts with the previous assumption that the entire body's metabolism becomes more efficient in using oxygen under hypoxic conditions, burning more glucose and fewer fatty acids and amino acids.
The findings of this study have significant implications for treating and preventing metabolic diseases. The lasting effects of long-term hypoxia observed in the mice, such as lower body weight and glucose levels, are associated with a lower risk of human diseases, including cardiovascular disease. Understanding how hypoxia contributes to these changes could lead to developing new drugs that mimic the beneficial effects of high-altitude living. Researchers hope to follow up on this work with studies that examine how individual cell types and levels of signalling molecules change in different ways with hypoxia. Such research could point toward ways to mimic the protective metabolic effects of hypoxia with drugs—or even high-altitude trips. By unravelling the metabolic changes as the body adapts to hypoxia, researchers can better understand how these adaptations protect against metabolic disease. This knowledge could pave the way for innovative drug development, offering new therapeutic options to individuals with diabetes, coronary artery disease, hypercholesterolemia, and obesity. In the future, we might even see recommendations for people to spend time at high altitudes for health reasons, similar to how athletes train at altitudes to improve their performance.
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