The adorable-looking Andean leaf-eared mouse. Credit: Marcial Quiroga-Carmona

Mammals shouldn’t permanently live much above 5,500 meters (18,000 feet). Above this altitude, the combination of oxygen-starved air, freezing temperatures, scarce food, and relentless winds was thought to make long-term life nearly impossible. 

Then, in 1912, British zoologist Oldfield Thomas discovered tiny Andean leaf-eared mice (Phyllotis vaccarum) living more than a kilometer higher than this assumed limit, on volcanic summits above 6,700 meters (22,000 feet), close to the death zone where even experienced climbers struggle to survive. 

“It was completely unexpected. People did not think mammals could survive at these altitudes, but they’re there,” Graham Scott, a professor and expert in animal physiology at McMaster University, said.

The 100 years following the discovery kept many biologists thinking: how could a small rodent survive year-round in an environment so hostile that humans and other mammals struggle to endure it even briefly?

Now, a new study has revealed the answer. It suggests that these remarkable animals evolved a suite of adaptations that help them cope with several extreme challenges at once, including one scientists never expected—the ability to detoxify toxic plant compounds. 

Scientists compared mice living from sea level to nearly 7,000 meters

Unlike most high-altitude specialists, the Andean leaf-eared mouse occupies an astonishing range of habitats, ranging from Chile’s Pacific coast at sea level to the summits of Andean volcanoes exceeding 6,700 meters. This unusual distribution allowed researchers to compare animals living under dramatically different environmental conditions while studying the same species.

The study took years of mountaineering expeditions across the Andes. Researchers collected and analyzed more than 160 mice from multiple elevations, including the summit of Volcán Llullaillaco, where the atmospheric oxygen is only about 44 percent of what it is at sea level, and temperatures remain below freezing for much of the year. 

View of Volcan Llullaillaco, one of the 31 peaks of the Central Andes. At 6,739 m above sea level, it is the highest volcano known to have been active. It is the site where a live Andean leaf-eared mouse was captured at the highest altitude ever recorded. Provided by Naim Bautista

They then combined whole-genome sequencing, physiological experiments, muscle analyses, metabolic measurements, and population genetics to identify the biological changes that distinguish high-altitude mice from their lowland relatives.

One of the biggest surprises was that high-altitude and low-altitude mice still interbreed. Despite this constant exchange of genes, the adaptations needed for life at extreme elevations have persisted, indicating that natural selection continues to favor them.

The researchers also found little evidence that large structural changes in the genome drove these adaptations, suggesting evolution fine-tuned existing genes rather than dramatically rewriting the genome.

The mice turned themselves into efficient biological furnaces

Physiological tests revealed that the mountain mice are exceptionally good at generating heat while using very little oxygen.

Their skeletal muscles contain unusually high numbers of mitochondria—the tiny structures often described as the cell’s powerhouses. These mitochondria allow the animals to sustain higher rates of aerobic metabolism despite the thin air.

An Andean leaf-eared mouse. Provided by Marcial Quiroga-Carmona

“They’re more like a marathon runner than a sprinter. Their muscle cells are packed with mitochondria that allow them to sustain heat-producing activity for longer periods,” Scott added.

Instead of relying mainly on carbohydrates, the mice also shifted toward burning fats, which provide a steady fuel source for both shivering muscles and specialized brown fat tissue that produces heat without muscle contractions. Together, these adaptations help them maintain body temperature in an environment where freezing conditions are almost constant.

The researchers also identified genetic changes linked to energy production, blood vessel regulation, and long-term tolerance of low oxygen. Interestingly, unlike some other high-altitude animals and human populations that evolved hemoglobin with enhanced oxygen-binding properties, these mice showed little evidence of relying on that strategy. 

Instead, they appear to have improved multiple physiological systems that work together to keep tissues functioning under chronic hypoxia.

“Evolution is a complex process. When animals encounter really challenging environments, there are a lot of different things they need to cope with, not just the obvious ones,” Grant McClelland, a professor of biology at McMaster University, said.

The biggest surprise wasn’t oxygen—it was food

At first glance, the barren volcanic landscape seems almost devoid of vegetation. Yet the mice appear to survive on whatever food they can find, including sparse alpine vegetation, lichens, and other material growing on the volcanic slopes. 

However, many of these plants available to the mice produce defensive chemicals that are toxic to animals. This is where the researchers became more intrigued by the animal’s genome. They analyzed it in depth and found something truly strange.

They came across evidence of natural selection in genes involved in breaking down plant toxins. These detoxification pathways likely allow the mice to process toxic compounds that would be difficult for many other mammals to handle.

This result was particularly surprising because “we were initially focused on the most obvious environmental challenges, things like low oxygen and cold, but there were important factors we didn’t expect, including how these animals deal with what they’re eating,” Scott added.

This tiny mouse could matter far beyond the Andes

The study builds on years of research into life at high altitude. Previous work has shown that animals such as the bar-headed goose, yak, and Tibetan antelope possess specialized adaptations for surviving in oxygen-poor environments. 

However, those studies largely focused on oxygen transport and respiration. This new research suggests that adaptation to extreme environments may depend just as much on metabolism, nutrition, and detoxification as on breathing itself. 

The findings could eventually help scientists better understand how cells respond to prolonged oxygen deprivation—a condition that also occurs in diseases such as cancer.  Understanding how these adaptations evolved may ultimately provide clues for future biomedical research.

However, the current study also has its limitations. For instance, the researchers still do not know exactly what the mice eat throughout the year or precisely how each detoxification gene contributes to survival. Future field studies will investigate the animals’ diet in greater detail and determine whether these genetic changes directly enable them to exploit toxin-containing food sources. 

The study is published in the journal Science.