Living at high altitude leads to longer life by changing metabolism

An estimated two million people worldwide reside above 4,500 meters (14,764 feet) in elevation, comparable to the heights of Mount Rainier, Mount Whitney, and numerous peaks in Colorado and Alaska. Intriguingly, these individuals have been observed to have lower rates of metabolic diseases, such as diabetes, coronary artery disease, hypercholesterolemia, and obesity. Researchers supported by the U.S. National Science Foundation at Gladstone Institutes have recently made strides in understanding this phenomenon.

The scientists discovered that chronic exposure to low oxygen levels, as experienced at high altitudes, altered the way mice metabolized sugars and fats. The study, published in the journal Cell Metabolism, offers insights into the metabolic differences in people living at high altitudes and suggests potential new treatments for metabolic diseases.

“When an organism is exposed to chronically low levels of oxygen, different organs reshuffle their fuel sources and their energy-producing pathways,” explained Isha Jain, senior author of the study. “We hope these findings will help us identify metabolic switches that might be beneficial for metabolism even outside of low-oxygen environments.”

At sea level, where a third of the global population resides, oxygen accounts for approximately 21% of the air we breathe. However, at elevations above 4,500 meters, oxygen makes up a mere 11% of the air. Despite these lower oxygen levels, known as hypoxia, people can adapt and thrive in these conditions.

High altitude, hypoxia, and how they impact the body

Previous research on hypoxia’s impact has often been limited to isolated cells or cancerous tumors, which are commonly oxygen-deficient. Jain’s group aimed to investigate the long-term effects of hypoxia on organs throughout the body. They collaborated with colleagues at Gladstone and the University of California, San Francisco, to house adult mice in pressure chambers containing 21%, 11%, or 8% oxygen levels – all of which are survivable by humans and mice.

Over three weeks, the researchers monitored the mice’s behavior, temperature, carbon dioxide levels, blood glucose levels, and used positron emission tomography (PET) scans to study nutrient consumption by different organs. In the initial days of hypoxia, mice in 11% or 8% oxygen environments exhibited reduced mobility and periods of complete stillness. 

However, by the end of the third week, their movement patterns normalized. Likewise, their blood carbon dioxide levels, which typically decrease when mice or humans breathe faster to compensate for low oxygen, initially dropped but returned to normal levels by the end of the study.

The animals’ metabolism, on the other hand, appeared to be more permanently affected by hypoxia. Mice in hypoxic cages experienced decreases in blood glucose levels and body weight, with neither returning to pre-hypoxic levels.

These metabolic changes parallel those observed in humans living at high altitudes and are associated with a reduced risk of diseases, including cardiovascular disease. This understanding of hypoxia’s contribution could pave the way for developing new drugs that replicate these beneficial effects, offering hope for those suffering from metabolic diseases.

Extending the human lifespan

There is a growing body of research focused on understanding the biological processes of aging and developing strategies to extend human lifespan. Some of the prominent areas of research include:

1. Telomeres and Telomerase: Telomeres are protective caps at the ends of chromosomes that shorten as cells divide. When telomeres become too short, cells can no longer divide, leading to cellular senescence and aging. Researchers are investigating ways to activate or introduce telomerase, an enzyme that can lengthen telomeres, to extend the lifespan of cells and, potentially, humans.
2. Senescence and Senolytics: Cellular senescence is a state where cells stop dividing and accumulate in tissues, contributing to aging and age-related diseases. Senolytics are a class of drugs that selectively eliminate senescent cells, reducing inflammation and improving tissue function. Studies on senolytics in animal models have shown promising results in extending healthspan, and human clinical trials are underway.
3. Caloric Restriction and Intermittent Fasting: Caloric restriction and intermittent fasting have been shown to extend the lifespan and improve overall health in various organisms, including yeast, worms, flies, and mice. Researchers are studying the underlying molecular mechanisms and the potential benefits of these dietary interventions in humans.
4. Targeting mTOR Signaling Pathway: The mTOR (mechanistic target of rapamycin) signaling pathway plays a crucial role in cell growth, metabolism, and aging. Inhibition of mTOR has been shown to extend lifespan in multiple species, and drugs like rapamycin are being investigated for their potential to increase human lifespan and healthspan.
5. Sirtuins and NAD+ Boosters: Sirtuins are a family of proteins that regulate cellular processes, including metabolism, DNA repair, and inflammation. NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that declines with age and is essential for sirtuin function. Researchers are studying ways to increase NAD+ levels, such as with precursors like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), to promote healthy aging and extend lifespan.
6. Gene Editing and Gene Therapy: Advances in gene editing technologies, such as CRISPR-Cas9, have opened new possibilities for manipulating genes associated with aging and age-related diseases. Researchers are working on developing gene therapies to target these genes and potentially extend human lifespan.
7. Stem Cell Therapy and Regenerative Medicine: As we age, our stem cells lose their regenerative capacity, leading to tissue dysfunction and aging. Researchers are exploring ways to rejuvenate stem cells and develop stem cell therapies to treat age-related diseases, promote tissue regeneration, and extend human lifespan.

These research areas, along with many others, represent the ongoing efforts to unravel the complex biology of aging and develop interventions that can promote healthy aging and extend human lifespan.

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