Loneliness has been linked to everything from heart disease to Alzheimer’s disease. Depression is common among the lonely. Cancers tear through their bodies more rapidly, and viruses hit them harder and more frequently. In the short term, it feels like the loneliness will kill you. A study suggests that’s because the pain of loneliness activates the immune pattern of a primordial response commonly known as fight or flight.

For decades, researchers have been seeing signs that the immune systems of lonely people are working differently. Lonely people’s white blood cells seem to be more active in a way that increases inflammation, a natural immune response to wounding and bacterial infection. On top of that, they seem to have lower levels of antiviral compounds known as interferons.

That seemed to provide a link to a lot of the poor health outcomes associated with loneliness, since chronic inflammation has been linked to everything from cancer to depression. The human body isn’t built to hold a high level of inflammation for years. “That explains very clearly why lonely people fall at increased risk for cancer, neurodegenerative disease and viral infections as well,” says Steve Cole, a genomics researcher at the University of California, Los Angeles, and lead author on the study published in the Proceedings of the National Academy of Sciences on Monday.

But it still doesn’t explain how or why loneliness could change our bodies. To find that out, Cole and his collaborators tracked 141 people over five years. Every year, the researchers measured how lonely the participants felt and took blood samples to track the activity of genes involved with immunity and inflammation. They also tracked concentrations of the hormone norepinephrine, one of the two main signals during the flight-or-fight response.

Cole noticed that when people felt lonesome, they had significantly higher levels of norepinephrine coursing through their blood. That could explain all the other immune changes that happen when people suffer from social isolation.

In a life-threatening situation, norepinephrine cascades through the body and starts shutting down immune functions like viral defense, while ramping up the production of white blood cells called monocytes. “It’s this surge in these pro-inflammatory white blood cells that are highly adapted to defend against wounds, but at the expense of our defenses against viral diseases that come from close social contact with other people,” Cole says.

At the same time, lonely people seem to be shutting down genes that would make their bodies sensitive to cortisol, which lowers inflammation. That ramps up the defensive inflammation response, Cole says.

Loneliness would hit the switch on a defense plan our bodies initiate in the face of mortal danger, Cole thinks, if isolation is somehow truly lethal. “At this point, my best guess was that loneliness really is one of the most threatening experiences we can have,” he says. “Though I didn’t think of loneliness as being that awful. It’s not pleasant, but not something my body should be getting all up in arms about.”

In the world of cubicles and studio apartments, loneliness is everywhere. We find it in both crowds and empty rooms. We change cities and lose friends. Even in marriage, people can be strangers to one another. But things were very different for our ancestors. When humans were evolving in a prehistoric environment, they banded together for food and for protection.

To be ostracized from your tribe was a death sentence, says Charles Raison, a psychiatrist at the University of Wisconsin, Madison who did not work on the study. “Literally they would die. There was no human way to live in isolation,” he says.

Being alone in the wild meant you could be mauled by animals or even other human beings. Then your body would need extra defenses against wounds and infection, but less protection against viruses you get from other people, like the flu. In that case, the stressful response to loneliness would simply be the body’s way of trying to survive exile.

But this fight-or-flight immune response is really nonspecific, says Turhan Canli, a neuroscientist at Stony Brook University in New York who was not involved with the study. Loneliness might not necessarily have to do with ancient survival, he says. Our bodies basically have one panic button, and any kind of adverse condition can trigger this response. “I think loneliness is a kind of psychological stress,” he says. “The change in the immune response is part of biological changes that come with a stress condition.”

What Canli finds really interesting about Cole’s results is that people who felt lonely one year had increased gene activity around inflammation and norepinephrine later on. And people who had increased inflammation felt lonelier the next year. “It’s a two-way street,” he said. “Loneliness predicted biological changes, and biological changes predicted changes in loneliness.”

So the shock of social isolation could fuel inflammation in the body. And the immune system may affect a region of the brain processing fear and anxiety. “Inflammation can change people’s experiences of the social world and what they’re thinking,” says Naomi Eisenberger, a neuroscientist at the University of California, Los Angeles, who was not involved with the study. That could make us more apprehensive about social interaction and lead to more isolation.

If the cycle continues, that could explain chronic isolation and the subsequent depression and illnesses plaguing the lonely. “There are things we can do to get out of a depressed or lonely state, but they’re not easy,” Cole says. “Part of the reason is because these negative psychological states develop some kind of molecular momentum.”

But that doesn’t mean the loop is permanent. “Inflammatory biology is one thing, but it’s not the only thing,” he says. All it does is push our proclivity for social activity one way or another. But loneliness is deep. It’s encoded in our genetics, and it’s not easy to shake.

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