This article is part of Nature Outlook: Vision, an editorially independent supplement produced with financial support from Astellas Pharma. About this content.

In the next 15 years, NASA hopes to launch a mission to Mars. But the long journey poses a challenge — not least from a mysterious ailment that alters astronauts’ eyesight. Spending long periods in the microgravity of space can lead to changes in the eye, including swelling in the region where the optic nerve extends to the brain; flattening of the rear of the normally round organ; wrinkles that emerge at the back of the retina; and shifts in the refractive index that change how the eye focuses. Together, these changes have been dubbed spaceflight-associated neuro-ocular syndrome (SANS). Despite more than a decade of study, researchers still don’t know exactly what causes it, who’s at highest risk or how to prevent or treat it.

Tyson Brunstetter, an aerospace optometrist at the Johnson Space Center in Houston, Texas, was serving in the US Navy when he read the first report on the syndrome, in 2011. He found the condition fascinating, but did not consider it a major obstacle to spaceflight. “I said, ‘It’s NASA. They’ll figure it out in six months’. And yet here I am, part of the team trying to figure out what exactly is going on.”

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NASA considers SANS one of its ‘red risks’ for a Mars mission, owing to its potential severity and the number of astronauts that could be exposed. Other high-priority risks include radiation exposure, changes in mental health and difficulty maintaining adequate nutrition.

Although some changes have been detected in astronauts’ eyes after as few as ten days in space, physicians think that the risk increases as more time is spent in microgravity. So far, SANS has been an issue mostly for people doing six-month stints on the International Space Station (ISS). A much longer trip to Mars — roughly nine months in each direction — could cause damage that interferes with astronauts’ ability to see what they’re doing, perhaps permanently.

Not everyone who goes into space develops SANS. Around two-thirds of astronauts on long missions to the ISS experience changes in visual acuity, particularly for close-up vision. Only about one-fifth of such cases are considered serious enough to earn the designation of SANS. Changes that can be detected during an examination, such as an enlarged blind spot and thickened retina owing to swelling where the optic nerve joins the retina (known as optic-disc oedema), are unlikely to be noticed by the affected person.

Most of the changes associated with the syndrome seem to resolve after returning to Earth. Even the most severe cases of swelling resolve after about 12 months back in normal gravity, Brunstetter says. And although eyeball flattening and refractive-index shifts might be permanent, these alterations can be offset with prescription lenses. In fact, NASA supplies astronauts with what it calls space-anticipation glasses of varying powers in case their vision shifts during a mission. “No one has had permanent vision loss due to SANS,” Brunstetter says.

The concern, however, is that longer missions might exacerbate problems. If optic-disc oedema continues long enough, the enlarged blind spot might start to interfere with vision, Brunstetter says. The wrinkles, known as choroidal folds, could also become more of an issue. These tend to stick around after astronauts come home. So far, Brunstetter says, the folds haven’t affected anyone’s vision, perhaps because they haven’t occurred in a part of the eye where they could cause problems. But longer stays in space can increase the number of folds, and therefore potentially distort vision in the same way as crumpled camera film warps the resulting photograph. “The problem with that is you can’t just fix those by putting on a different pair of glasses,” he says.

Coming to a head

The main suspect for the cause of SANS is the fluid shift that occurs in microgravity. On Earth, gravity pulls blood and cerebrospinal fluid towards the ground, while the heart and other muscles push them throughout the body. Without gravity, more fluid than usual collects in the head.

When they first described the syndrome in 2011, NASA scientists thought that it might have been caused by increased pressure in the head from excess fluid. But this wouldn’t explain why the problems become clinically significant only in some astronauts. “If this was as simple as you go into flight and fluid goes in your head, that would happen to everybody,” says Scott Smith, a nutritionist at the Johnson Space Center who studies SANS. It also seems that the pressure in the head does not get high enough to bring about these changes — at least, not by itself.

“If we’re wrong, all you’ve done is give people vitamins and made their pee yellow.” —Scott Smith, nutritionist

Brunstetter thinks it’s possible that a mild increase in pressure could cause problems if sustained over a long enough time. The fluid shift does cause blood vessels in the head to swell, which might affect the blood supply to the back of the eye, he says. Another possibility is that it changes metabolic activity in the cells, such as by interfering with the exchange of sodium, suggests Joshua Ong, an ophthalmologist at the University of Michigan in Ann Arbor who specializes in space medicine. Ann Tsung, a NASA flight surgeon, is currently seeking approval to test whether GLP-1 agonists — drugs that have gained widespread attention under names such as Ozempic and Mounjaro as treatments for diabetes and obesity — can treat SANS by lowering intracranial pressure.

Another potential culprit is carbon dioxide, high levels of which increase blood flow in the brain and could further increase pressure. The level of CO2 is generally higher in the ISS than back on Earth, and it could be higher still in sleeping compartments. Studies on Earth in which volunteers lie with their head tilted down for a month or more to simulate microgravity have indicated that high CO2 levels increase signs of SANS. However, the rate of SANS has not dropped as engineers have got better at scrubbing CO2 from the ISS’s air.

Smith suspects that SANS involves an interplay of CO2, vitamin deficiency and genetics. He and his team found that astronauts who develop SANS have higher levels of an amino acid known as homocysteine than do those who avoid the syndrome. High levels of this amino acid are known to increase the risk of coronary artery disease and blood clots, and can result from a diet deficient in folic acid or vitamin B12. Homocysteine is also involved in a function of living cells known as the one-carbon pathway, and further study revealed differences in genes related to this metabolic function between the two groups of astronauts. Four ‘risk alleles’ were identified; astronauts with at least three of them saw the thickness of their retinas change more than did those with only one or two alleles. “What we think is happening is that their genetics are causing them to have higher requirements for these vitamins, making them what we would call functionally deficient,” Smith says.

Further evidence for this idea came courtesy of some old notes. Smith and his team discovered that several years ago, an astronaut who had developed some of the most substantial signs of SANS ever reported had been treated by NASA flight surgeons with vitamins — an idea they got from Smith’s team’s work. The astronaut’s retinal thickening decreased after treatment. When Smith later examined her genes, he found she had all four risk alleles.

That isn’t conclusive evidence, Smith says. “It’s a case study. You can’t prove anything. But it sure is intriguing.” Coincidentally, CO2 levels in the station also decreased during the astronaut’s time there. These events have, however, led to a prospective study in which 16 astronauts over several missions will be given vitamins to see whether it affects their likelihood of developing SANS. “If we’re wrong, all you’ve done is give people vitamins and made their pee yellow,” Smith says. But if they’re right, he says, they will have gone some way to mitigating one of NASA’s red risks.

Defying microgravity

Measures to prevent SANS might take a more mechanical form, with researchers trying to counteract the effects of microgravity on the body. The Russian space agency has a device aboard the ISS called a chibis suit, which surrounds the lower body and uses a vacuum to draw some fluid back down to the legs. But the equipment is bulky, and the time people spend inside has to be tailored to their physiology. Astronauts might also wear venoconstrictive thigh cuffs, which act like loose tourniquets, preventing blood in the veins from flowing out of the legs too quickly without interfering with arterial blood flow. All of these countermeasures require further testing.

Microgravity can cause other problems for astronauts besides SANS, including a loss of muscle mass and bone density. A more comprehensive approach that could protect against these issues as well might be to provide artificial gravity, says Ethan Waisberg, a physician at the University of Cambridge, UK. The concept is familiar in science fiction, notably in the 1968 film 2001: A Space Odyssey, in which astronauts on a ship bound for Jupiter jog inside a centrifuge created by their spinning living quarters to keep their muscles in shape. “By simulating Earth’s gravitational force,” Waisberg says, “we can restore a normal fluid distribution in our astronauts.”

Building a centrifuge into a spaceship, or spinning the entire craft, presents engineering challenges. The smaller the circumference of the centrifuge, the faster it would have to spin to mimic Earth’s gravity, and rapid spinning could cause vertigo in the astronauts. However, a large centrifuge would add to the weight, cost and complexity of the spaceship. Waisberg says that a smaller, less complicated alternative might be a human-powered centrifuge, in which an astronaut peddles a bicycle around a wheel, like a hamster exercising in a cage.

Despite the difficulties in finding the cause and the treatment for SANS, Smith says that researchers will keep hunting for answers. “There’s a lot of people out there with ideas,” he says. “If this was simple, somebody would have figured it out by now.”