Anybody who has ever experienced altitude sickness, even the mildest form known as acute mountain sickness, knows how debilitating it can be. Symptoms, which include lightheadedness, nausea, fatigue, and headache, most often occur at altitudes above 8,000 feet.
The molecular processes behind those feelings are the subject of new research by Colleen Julian, PhD, associate professor in the University of Colorado Department of Biomedical Informatics, who received a $500,000 U.S. Department of Defense (DOD) grant to study metabolomic adaptation to high altitude.
“To minimize risk to servicemen and women, we need to have a detailed understanding of the molecular and physiological adaptations that humans undergo at high altitudes,” Julian says. “The goal is to enhance our ability to predict altitude readiness, identify factors that drive tolerance to high altitude, and gather the information needed to develop novel strategies to prevent altitude sickness.”
Helping the military understand the body’s responses to high altitude may just be the beginning.
Understanding hypoxia, which happens when there isn’t enough oxygen being delivered throughout the body, its relation to altitude, and how the body acclimates to having less oxygen could help researchers understand other diseases where a lack of oxygen is relevant.
Hypoxia and altitude
"With ascending altitude, the barometric pressure falls, and along with it, the partial pressure of oxygen decreases," Julian explains. "This means there are fewer oxygen molecules in every breath a person takes and therefore less oxygen is available to support cellular metabolism.”
“To put it into perspective, the partial pressure of oxygen is about 35% lower in Leadville, Colorado, at an altitude of 10,000 feet than it is at sea level,” she continues. “Given the importance of oxygen for human survival, we are highly sensitive to even minor changes in oxygen status. So, our bodies attempt to compensate."
In healthy individuals, the environmental hypoxia of high altitude invokes physiological responses to offset oxygen limitations, improve oxygen delivery, and enhance physical and cognitive performance at high altitudes. If these responses are adequate, they also prevent high-altitude illness.
“Through these processes, we become more tolerant to high altitude. This is what we call high-altitude acclimatization,” Julian says. “But when acclimatization fails, people can develop high-altitude illnesses, such as acute mountain sickness or high altitude pulmonary or cerebral edema. These conditions have negative impacts on physical and cognitive performance at high altitudes that can range in severity from mild to life-threatening.”
While acute mountain sickness can be incapacitating, it generally resolves naturally after about two to three days. In some cases, however, it can progress to high-altitude cerebral and pulmonary edema – both of which can be fatal.
Julian and fellow researchers hypothesize that metabolic adaptations to hypoxia are a critical piece of acclimatization, responsible for coordinating acclimatization to high altitude and preventing high-altitude illness.
Oregon to Bolivia
Diving into this research required healthy study participants from Eugene, Oregon, which sits at sea level, to travel to a high-altitude site at 17,000 feet in the mountains above El Alto, Bolivia.
The research participants underwent detailed assessments of physical performance, cognitive function, control of breathing, altitude sickness symptoms, and various measures of hypoxia, prior to ascent and over the course of 16 days at high altitude. This allowed the research team to determine the physiological responses and adaptations to sustained hypoxia.
“In this study, we are profiling metabolomic responses of each participant across acclimatization and looking at the data in the context of physiological changes occurring across the same period,” Julian explains.
A scene from high up in the mountains of Bolivia, where DBMI researcher Colleen Julian, PhD, and a team conducted detailed assessments of participants and their reactions to altitude.
Researchers already know that there’s a lot going on in the body when it’s acclimating to higher altitude. For example, Julian says, ventilation and red blood cell production increase, which results in higher oxygen saturation and increased oxygen delivery to the rest of the body.
There’s much less known about the molecular process behind those adaptations.
“One of the unique aspects of this project is that we’re looking beyond oxygen delivery,” Julian says. “Our metabolomic studies will allow us to map how sustained hypoxia and acclimatization affect the ways in which oxygen is utilized to generate the energy required to sustain physiological and cognitive performance in the high-altitude environment.”
The military and beyond
While the grant funding Julian’s work comes from the DOD with hopes that the research could help protect members of the military, the work could also play an important role in medicine.
"Hypoxia is a central component — either a cause or consequence — of almost every major disease, including cancer, heart disease, diabetes, respiratory illnesses, and even major pregnancy complications,” Julian explains, “Understanding how we adapt to and tolerate hypoxia not only has relevance for the safety of our servicemen and women but also extensive clinical importance.”
Julian will begin work on the project this fall and plans to deliver results by 2025.