Harnessing Hypoxia

In the early 1960s, a long-running border dispute between India and China erupted into conflict in a stark, barren landscape of high-altitude plains. The Indian army decided to deploy 20,000 soldiers to its mountainous border — but soon after relocating above 3,600 meters in altitude, where there was less oxygen in the air to breathe, some soldiers got altitude sickness. Some even died.

Within a few years, however, a surprising pattern started to emerge.

The soldiers stationed in the mountains showed signs of being healthier than their counterparts at sea level. They experienced lower rates of heart disease, hypertension, diabetes, asthma, rheumatoid arthritis, and gastric disorders. They had fewer infections, psychiatric illnesses, and skin diseases. Military officials didn’t know what was causing those differences, but they felt compelled to share their observations in a 1977 journal article.

That article flew under the radar for nearly four decades, until 2016, when Vamsi Mootha, MD ’98, an HMS professor of systems biology at Massachusetts General Hospital, started scouring the literature based on a hunch. Mootha had recently found something else that seemed counterintuitive: Chronic hypoxia — that is, continuously breathing air with a lower concentration of oxygen, akin to living at a very high altitude — could alleviate rare forms of mitochondrial disease in mice. The findings flew in the face of the conventional understanding that chronic oxygen deprivation is unhealthy. When Mootha came across the study of the Indian military, he felt a serendipitous sense of validation.

“It really resonated with me,” says Mootha, who is also an institute member and co-director of the metabolism program at the Broad Institute of MIT and Harvard. “What they reported was fascinating.” It encouraged him to pursue a question that would kick-start a blossoming area of scientific inquiry: Could chronic oxygen restriction be harnessed as a medicine?

Into thin air

The notion that hypoxia could be useful wasn’t entirely new. Since the mid-20th century, elite athletes have trained at high altitudes so that their bodies produce more red blood cells, enhancing performance upon their return to sea level. For decades, cardiologists have exposed patients to brief periods of hypoxia to trigger protective pathways that prime heart cells to better survive procedures or heart attacks.

But unlike those temporary periods of oxygen restriction that are carefully managed to avoid prolonged strain, Mootha was looking to understand the effects of chronic, continuous hypoxia: an around-the-clock form of oxygen restriction. Since low oxygen levels can constrict blood vessels in the lungs, raise blood pressure, and even cause organ damage, chronic hypoxia had generally been considered dangerous.

As far as he could tell, no randomized trials had tested the effects of chronic hypoxia in humans. That’s what made the Indian army study so interesting. With tens of thousands of people breathing air with drastically different oxygen levels over a long period, it was the closest thing Mootha could find. It wasn’t perfect, and “you shouldn’t overinterpret it,” he cautions, as variables like UV radiation, food, or temperature could have influenced the results. “But when you combine it with our mouse studies, it really does create something provocative.”

A matter of mitochondria

Since well before he became interested in hypoxia, Mootha has been fascinated with mitochondria: tiny structures within cells that act like power plants, using oxygen to make the energy our bodies need to function. When mitochondria don’t function well, cells can’t use oxygen efficiently, starving organs like the brain, muscles, and heart of a key fuel they need to operate. There are hundreds of rare genetic diseases that cause mitochondrial dysfunction. Those diseases can lead to neurological issues, organ failure, and death; no effective treatments exist to reverse their progression.

In 2016, Mootha and colleagues were systematically disabling thousands of different genes in cells exposed to a toxin that mimics mitochondrial dysfunction to see which of these gene “knockouts” helped the cells survive. They found that they could unleash cells’ response to hypoxia even under normal oxygen levels by disabling a gene that normally serves as a brake on that response — and that helped the cells better cope with mitochondrial damage.

“We discovered that low oxygen might actually be better,” Mootha says.

That gave them the idea to put mice with a mitochondrial disease in a low-oxygen environment. They teamed up with the lab run by the late Warren Zapol, an HMS professor and anesthesiologist at Mass General, on a study of mice with a model of Leigh syndrome, a disease that causes progressive neurological illness. They divided the mice into two groups: One group lived in a chamber with air diluted down to around 11 percent oxygen, similar to Mount Everest Base Camp. Another group lived in air with about 21 percent oxygen, like that at sea level.

Zapol, who had spent much of his career studying how to mitigate the harmful effects of hypoxia, was skeptical. “At the beginning, he said, ‘This is impossible, we’re going to kill all these mice.’” recalls Lorenzo Berra, the HMS Reginald Jenney Associate Professor of Anaesthesia at Mass General, who worked in Zapol’s lab at the time. “But they survived.”

Not only did the mice breathing less oxygen survive, but within a few weeks, they showed a dramatic reduction in disease symptoms. They ended up living nearly three times longer than the mice breathing sea-level oxygen.

This was a surprise, because at the time, many people thought that the key to tackling mitochondrial dysfunction was to give the body more oxygen. Some human patients with mitochondrial diseases had even spent time in hyperbaric chambers, breathing increased oxygen in an attempt to treat their symptoms. But after he published the findings, Mootha started hearing from doctors whose patients had declined or even died after those treatments. Those doctors had wondered whether the excess oxygen caused harm; Mootha’s work supported their suspicions.

“It initially seemed paradoxical,” Mootha says, “but when we thought about it, there was a logic to it.” He reasoned that when mitochondria are fundamentally broken, the problem is not a lack of oxygen; rather, if anything, there is an excess of unused oxygen. Perhaps, he thought, adding oxygen to the body when mitochondria can’t consume it can overwhelm the system and cause damage.

He suspected that his findings would have wider implications. Mitochondrial dysfunction isn’t just involved in rare genetic diseases; it’s also thought to play a role in more common conditions, from Parkinson’s to cardiovascular disease. Mitochondrial damage is even implicated in the process of aging itself. Suddenly, so much anecdotal data — from reports of successful treatments at 19th-century Alpine tuberculosis clinics, to Michael J. Fox reporting a decrease in Parkinson’s symptoms while traveling in Bhutan, to studies finding longer lifespans in high-altitude cities — seemed like potential clues.

From anecdotes to evidence

Over the next few years, other researchers used similar methods to reveal more benefits of chronic, continuous hypoxia. Scientists at the University of Texas showed that mice living with reduced oxygen recovered more quickly from heart damage. Australian scientists observed improved motor function in mice recovering from strokes. Scripps Research Institute scientists found speedier resolution of limb paralysis in a mouse model of multiple sclerosis. And researchers at Duke University found reduced degeneration of retinal ganglion cells in mice with optic neuropathy. 

Meanwhile, Mootha and his colleagues discovered that hypoxia improved motor function in a mouse model of Friedreich’s ataxia, the most common mitochondrial disease caused by a single gene mutation. In 2023, they also found that restricted oxygen could slow down aging, increasing lifespan by 50 percent in mice with a genetic predisposition to accelerated aging.

Most recently, in an article published in August, they showed that hypoxia can slow or even reverse the progression of a mouse model of Parkinson’s — a disease that is associated with secondary mitochondrial dysfunction, and the second most common neurodegenerative disease.

“We found that oxygen accumulated to a toxic level in the brains of the mice, probably due to mitochondrial dysfunction,” says Fumito Ichinose, the HMS William Thomas Green Morton Professor of Anaesthesia at Mass General and a co-senior author of the study. “That made me think a lot about the amount of oxygen we are giving to patients in the operating room. Traditionally we’ve given a lot of oxygen, but now we’re being more careful.”

Looking under the hood

Mootha admits he doesn’t know the full mechanisms that are at play in the links between hypoxia and health; the connection with aging in particular remains a mystery. But he has a few ideas about what could be going on.

“I’m a car guy,” Mootha says, setting up an analogy. Think of each mitochondrion like a shiny, new vehicle. Just as exposure to oxygen causes metal car components to rust, oxygen can “rust” the many biomolecules, notably metals and iron-sulfur clusters, that act like essential wires for the electricity in mitochondria. Healthy mitochondria can shield themselves from the corrosive effects of oxygen, but in mutated or damaged mitochondria those mechanisms may be faulty.

When oxygen reacts with an iron molecule, it plucks off one of the molecule’s electrons, leaving behind a damaged form of the iron and producing a reactive oxygen molecule called a free radical. Scientists have known for a while that, elsewhere in the body, these damaging free radicals can typically be combated with antioxidants — but researchers have already tried using antioxidants to treat mitochondrial diseases in both mice and humans with no luck.

Perhaps that’s because antioxidants only address one half of the equation, says Mootha; they tackle the byproducts but not the original damage. To use his metaphor, it may be that antioxidants are like trying to scrub rust off the car, while chronic, continuous hypoxia is like preventing the car from rusting in the first place.

Why might that be? Life on Earth began in an environment without oxygen, Mootha explains, and the precursor to mitochondria were free-living anaerobic bacteria. Back then, the iron-sulfur clusters making up the bacteria’s wiring didn’t need to worry about rusting. Over time, photosynthesis developed and the atmosphere filled with oxygen. This powerful gas ultimately helped living cells generate more energy from fuels like glucose. But first, the bacteria needed to evolve mechanisms to shield themselves from its harmful rusting effects — mechanisms that persisted after the development of mitochondria.

“We think that when these adaptive mechanisms are broken, they are still compatible with life,” Mootha says, “but they set you up for oxygen sensitivity.” In other words, rusting can still happen and cause damage to mitochondria when those oxygen shields are faulty.

If Mootha is on the right track, the next challenge is clear: finding safe and practical ways to harness hypoxia’s protective effects in people.

How low can you go?

Whenever his team publishes new evidence of hypoxia’s benefits, Mootha’s phone starts ringing. Patients ask if they should move to high-altitude cities. Parents ask if he can try out chronic hypoxia with their kids. “Each time we learn something new, we’re tempted to think about the translation,” he says. “But we have to remember that extreme hypoxia can be dangerous, and we have to think about how we can translate it in a responsible way.”

That responsibility includes figuring out dosage and regimen, as well as pinpointing exactly which diseases can benefit from the approach. The mouse findings will also need to be replicated in clinical trials with humans.

Human trials are trickier to conduct, but researchers are working on it. Mootha and Berra recently teamed up on a phase 1 clinical trial recruiting healthy volunteers to live for a few days in tents in the hospital where the air was diluted down to 11 percent oxygen, showing that it could be done safely with no adverse outcomes.

If studies confirm that hypoxia can help humans with certain health conditions, the simplest treatment would be a move to the mountains. Millions of people live in high-altitude cities like La Paz, Bolivia, where oxygen concentrations are comparable to those used in Mootha’s studies. But if uprooting one’s life isn’t an option, Mootha imagines other ways to deliver hypoxia.

Maybe future air conditioners could scrub oxygen from ambient air, he says, controlling hypoxia levels like they control temperature.

Or perhaps hypoxia could be swallowed in the form of a pill. In a 2024 mouse study, Mootha’s team tried combining two FDA approved medicines — one for sickle cell disease, which binds to hemoglobin and prevents it from releasing oxygen, and one for kidney cancer, which prevents the body from making extra red blood cells to deliver oxygen to tissues — and found that the combination of the two medicines extended the mice’s lifespan.

They’ve also been using hypoxia as a tool to search for new drug targets. For an ongoing research project, former postdoctoral fellow Joshua Meisel worked under Mootha and worm geneticist Gary Ruvkun, PhD ’82, an HMS professor of genetics at Mass General, a 2024 Nobel Prize winner, and Mootha’s lab neighbor at Mass General, to raise worms with a model of mitochondrial ataxia in low-oxygen conditions.

Meisel confirmed that, like the mice, the worms with mitochondrial disease benefited from a low-oxygen environment. He then mutagenized the worms, subjecting them to a chemical treatment that induces many random gene mutations, before returning them to normal oxygen. Most of the worms died upon return. But by studying the survivors’ mutations, the researchers identified genes that might protect against oxygen sensitivity — genes encoding proteins that could one day be targeted with pills.

“You just mutagenize and ask for something to crawl out,” says Ruvkun, who was surprised to see mutations related to hypoxia that he’d never encountered before. “That’s the joy of genetics. It takes you for a ride.”

Of mice and worms

Aside from offering pathways for a hypoxia pill, that most recent study encourages Mootha that his team has found something important.

“When we did the study in 2016, I was concerned that it was some type of fluke, something weird about this specific mouse,” he says. “But the benefits of hypoxia and the exact same mutations are evolutionarily conserved in worms, too. It feels like we’ve uncovered a very, very profound relationship.”

Ever since Berra began collaborating with Mootha, he’s been noticing instances of beneficial hypoxia throughout nature. Human fetuses “survive beautifully with one-fifth of the oxygenation that we have in our blood right now,” he says, and seals empty their lungs of air and slow their heart rates as they dive to catch fish hundreds of feet into the ocean, reducing blood flow to their organs.

To Mootha, what once felt like a paradox has started making sense. And it’s led to findings that offer much-needed hope to patients with diseases that as of yet have no effective treatments.

“There’s been so much luck and serendipity in this entire discovery,” he says. “But sometimes you need that in science.”

Molly McDonough is the associate editor of Harvard Medicine.