Help us reach more people
Help us reach more people

Like most scientists, Steve Cole didn’t believe in things that happen without reason. But no matter what variable he tested — and he tried all the usual suspects, from sleep to sex — nothing seemed to explain what made the gay men die.

It was the late 1980s, the age that gave us the personal computer, the disposable contact lens and The Simpsons, but also: the Challenger explosion, the global stock market crash and New Coke. AIDS was raging in the US. Steve Cole was a young psychology researcher who had landed on a study of 800 HIV-positive, AIDS-free gay men and who was trying to crack the workings of the lethal virus. Over nine years Cole tracked 80 of these men. Every six months they gave blood, sat for interviews and filled in questionnaires, and every time there were fewer and fewer of them. A significant number fell sick, many perished. And as they did, Cole wondered why some subjects succumbed to HIV while others resisted it. He looked at the obvious — age, socioeconomic status, overall health, sleep quality, exercise habits, sex life, anxiety levels, depression history — but none of these predicted who would get AIDS or how soon they’d die.

At one point Cole thought to compare the openly gay men to those who hid their identity. It turned out, surprisingly, that closeted men got AIDS faster and died sooner than out men. Why? What about being in the closet made those men more vulnerable to HIV? A strand of research at the time implicated repressed emotions as a possible factor — closeted men bottled up their feelings and that made them sick — but the evidence was thin and the biological mechanism unknown. After all, how do you convert emotion into disease? How do feelings turn into something real?

In a follow-up study, Cole decided to test yet another variable: the subjects’ sensitivity to rejection. He found that on average closeted men were more sensitive to being rejected than openly gay men. Which made sense: if you cared too much about other people’s judgement, you’d want to hide those parts of you likely to be stigmatised, such as your sexual identity.

More importantly, Cole also found that sensitivity to social rejection predicted AIDS diagnosis and early mortality even better than whether or not one was openly gay. In other words, the mysterious deaths of the HIV-infected men appeared to stem not from their failure to express themselves but from a fear of being rejected if they did. Indeed, sensitive men who hid their identity did not suffer more than those in the open: the closet, Cole theorised, probably protected them from social rejection and its dire health effects. Suppressing their emotions saved perhaps their relationships, and their relationships, in turn, saved their lives.

At the time, the impact of social connections on health wasn’t entirely new. For a long time researchers had observed a curious link between social isolation and a number of diseases — from heart disease to cancer to some neurodegenerative disorders. But no studies had been conducted to test this link directly and no one could really explain it. According to one theory, social relationships exert a positive influence on health because of peer pressure. If, the theory went, there are people around you whose opinions you care about, you’d be more likely to swing by the gym, slug kale juice every morning and skip the second and the third glass of wine at the end of a tough workday.

But Cole’s research showed that it wasn’t actually bad habits that wrecked his subjects’ health. The gay men who contracted AIDS were just as physically fit and mentally well as those who resisted the disease. There seemed to be something else, something more direct, that was stripping off some participants’ immune defences, leaving them fatally exposed to the virus.

For a long time, however, Cole couldn’t find out what was actually going on inside the men’s bodies. The technology that now allows scientists to zoom into our cells and read our genetic code was still new and prohibitively expensive. Then, in the early 2000s, Cole got his hands on a gene sequencing machine. He also met John Cacioppo from the University of Chicago, who had pioneered the idea that social relationships shape our brains, impacting our thoughts, behaviours and physical health on the very level of biology

Cacioppo never bought the peer pressure theory of social relationships. “What I knew was that no matter what social species you’re talking about, all the way down to fruit flies, if you isolate them, they die earlier”. And since fruit flies are hardly the type to sink into debauchery unless other fruit flies keep an eye on them, there had to be another route for social isolation to get so deeply under the skin of humans and animals.

To find out what this route might be, Cole and Cacioppo analysed data from 14 elderly Chicagoans across a diversity of ethnic and economic backgrounds. The data, collected over four years, included the subjects’ demographics, habits, behaviours, medical conditions and self-reported feelings of loneliness. In addition, Cole and Cacioppo scraped the inside of each participant’s cheek with a swab, then gene sequenced and analysed the DNA samples.

For more stories that stay with you, subscribe to our newsletter.

The results were remarkable: it turned out that the immune systems of the lonely behaved differently from those of the non-lonely — and dramatically so. For instance, the lonely subjects’ anti-viral defences were partially shut down, which suggested a possible reason why the socially sensitive gay men were so vulnerable to HIV. But that wasn’t where the damage ended. In addition to suppressing the body’s innate defences against viruses, loneliness also seemed to crank up its inflammation to dangerous levels, raising the risk of myriad diseases.

Inflammation, in normal doses, is not a foe. In fact, it’s part of the body’s defense mechanism against malicious microbes as well as a marvelous demonstration of nature’s flair in designing human beings. Circulating your bloodstream are thousands of immune cells. These cells come equipped with receptors that can not only detect invading pathogens but also tell them apart and mount a defense tailored to each type of bug.

The immune system’s default mode is anti-viral. That’s because as a social species we are constantly exposed to viruses, which spread from one person to another. Bacteria, on the other hand, can infiltrate through open wounds. During injury the immune cells squeeze out of the blood vessels and go to fight the bacteria at its location, triggering a cascade of healing processes. One of these processes is inflammation. It’s the redness, the swelling and the heat you experience when you injure yourself and it’s what keeps infection from spreading throughout your body.

Once the intruder is dealt with, inflammation subsides. If it doesn’t, it can become extremely dangerous. Prolonged inflammation had long been known as a risk factor for infectious diseases but around the time that Cole and Cacioppo began their collaboration, other researchers started to link inflammation to a host of other, non-infectious illnesses — from asthma to arthritis, diabetes, cancer, Alzheimer’s and depression. A 2012 review of the clinical literature suggested that chronic inflammation may, in fact, lie at the root of many more diseases than we’d initially thought. “Perhaps”, the researchers concluded, “even all of them”.

In their own study, Cole and Cacioppo showed that loneliness might trigger inflammation the same way that a physical injury would — but without activating the built-in break that normally keeps inflammation in check. The lonely subjects’ immune systems had switched from their default anti-viral mode to a chronic injury-fighting mode, leaving them exposed to both viral infections and inflammation-related diseases. This switch provided a clue to how our social world interacts with our biology, how loneliness can wreak havoc on our brains and bodies.

It could also explain why both the closeted and the rejection-sensitive gay men fell prey to HIV more easily: the former were more likely to be socially isolated while the latter felt social isolation more strongly. And isolation, it appeared, could fool the body into thinking it’s in mortal danger, tinkering with one of its most fundamental survival mechanisms — the immune system — and even turning it against us.

Though astonishing, the link between loneliness and immune activity hinged on just one study of only 14 people. In science correlations like that constantly come up, yet many fail to replicate in later research. Genetics at the time had a particularly embarrassing replication rate: alleged “breakthroughs”, hot off the press one day, often wound up demolished and discredited the next.

Naturally, Cole was cautious about drawing conclusions early on. But as more studies followed soon, a growing body of evidence emerged to support his initial findings. In 2011 he and Cacioppo extended their original sample from 14 to 93 people and got the same results: reduced viral defenses and elevated inflammation in the lonely subjects. This pattern cropped up in various other studies: of people suffering from PTSD and breast cancer, people grieving or caring for dying spouses, people dealing with relationship difficulties, even people being evaluated while performing a task.

So far, the research suggests that the situations that most reliably predict a dangerous surge of inflammation involve social rejection and loss. The health impact of divorce, for example, depends largely on who initiates it: if it’s your spouse, you not only lose an important relationship but feel rejected, too, which will derail your immune system more than if the decision to end the marriage came from you.

A 2010 meta-analysis of 148 studies concluded that being lonely is not only bad for your health; it’s, in fact, significantly worse than drinking or not exercising. Loneliness emerged as a risk factor for early death with an impact as big as smoking and three times bigger than obesity. Yet according to Cacioppo, even this may be an understatement since, he says, obesity “does not make you as miserable as loneliness”. Not even stress can measure up. “We think of stress as a risk factor for disease,” says Cole. “And it is, somewhat. But if you actually measure stress using our best available instruments, it can’t hold a candle to social isolation. Social isolation is the best-established, most robust social or psychological risk factor for disease out there. Nothing can compare.”

John Cacioppo didn’t set out to study loneliness because of a harrowing personal experience. “People are disappointed when they hear that.” He was a social psychologist at a time when social psychology tried to explain human behaviour through the social and cultural experiences we are aware of and can verbalise. But most of human behaviour is unconscious and so it went largely unaccounted for by the existing theories. The solution, for Cacioppo, was not a return to the digging of repressed desires from dreams and fantasies — by that time psychoanalysis was seen as little more than quackery — but a better understanding of the brain, the grand originator of all thought, emotion and motivation. There was no way, he thought, “to comprehend the full scope and processes of mental existence without delving into biological reality”.

But neuroscientists at that time paid no attention to the social world that Cacioppo wanted to marry with “biological reality”. They saw human behaviour as little more than electrical currents zipping inside our heads. This made no sense to Cacioppo. He knew that the brain evolved in an intensely social context. Throughout history, relationships with other humans were far too important for our survival to have left no mark on our biology and evolutionary development.

In 1992 Cacioppo and his colleague Gary Bernston founded social neuroscience, which aims to study the neural, hormonal, genetic and molecular mechanisms underlying social behaviour. In one of the field’s founding documents — a hefty 1357-page tome published by MIT Press in 2002 — Cacioppo includes a quote by David Spiegel at Stanford University that marvellously sums up the main tenets of social neuroscience:

We are fundamentally social organisms, our mythic rugged individualism notwithstanding. We are born to the most prolonged period of abject dependency of any mammal. For the species to survive, human infants must instantly engage their parents in protective behaviour, and the parents must care enough about their offspring to nurture and protect them. Even once grown we are not particularly splendid physical specimens. Other animals can run faster, see and smell better, and fight more effectively than we can. Our major evolutionary advantage is our brain and ability to communicate, remember, plan, and work together. Our survival depends on our collective abilities, not our individual might. Thus, it makes sense that our health may also depend on our interactions with one another.

The breakdown of these interactions seemed like a good starting point for studying their health impact; hence Cacioppo’s focus on loneliness. To be sure, he never expected that his research would fill over two decades, but the more he learned about social isolation, the more there was still to learn. “This just continues to change how I think about us as a species”.

From an evolutionary point of view, loneliness appears to serve a purpose, which Cacioppo likens to that of hunger. Hunger prods you to go look for food before you run out of fuel and starve to death. It signals a survival risk. And to make sure you do heed that signal, hunger feels unpleasant and it bothers you until you feed yourself. Loneliness acts in a similar way. Historically, we depended on others for protection and nurturing, and social isolation could literally cost us our lives. Loneliness left us vulnerable to lurking predators and conniving tribes. Feeling lonely, just like feeling hungry, is a danger signal. When you stray too far from the tribe, the pang of loneliness drives you back to repair alliances, invest in new relationships and thus avoid dying.

The fact that during our evolution loneliness cued physical threat can help explain the unusual immune activity of people facing loss and social rejection. For a long time researchers saw inflammation as an automatic physiological response to bacterial invasion: immune cell receptors sniff out a foreign agent and off goes a built-in sequence of defense reactions and healing processes. But now we know that the same mechanisms can kick in pre-emptively, before bugs have infiltrated the body, before an injury has actually occurred.

Here’s how it works: Contrary to what we’ve long thought, it turns out that immune cells do not just passively execute pre-wired defense mechanisms. Instead, they actively listen to outside signals — especially those coming from the brain — and act on them. When your brain sends a message that you are lonely, the immune cells hear danger! and turn off some of your antiviral defenses: you need those now, after all, since viruses spread among people. Being lonely, you run a higher risk of injury and infection by bacteria, which is why your immune system diverts resources from antiviral to antibacterial defenses. In other words, it starts pumping out inflammation.

Remember, this switch happens not when you get injured but when you feel lonely. The brain interprets loneliness as a threat and tells the body to switch into defense mode. Throughout evolution, this was an adaptive response since it allowed the immune system to prepare in advance and avoid a surprise microbial attack. Today, though, this same pre-emptive mechanism can do us more harm than good.

In the modern world, loneliness seldom equals mortal danger. You get lonely and feel rejected for all kinds of non-life-threatening reasons: you break up with your boyfriend, get passed up for promotion, give a talk and it tanks, call a friend to have a good cry about it and she’s distracted. Clearly, you begin to think, your friendship doesn’t mean a whole lot to her. Perhaps she used to envy you and now she gloats internally at your spectacular fall. Before you know it, you’ve spun a drama of epic proportions out of the tiniest smidgeons of evidence.

Meanwhile, your immune system hasn’t caught up to Modern Man’s Maladies. It’s still stuck in caveman times. It still equates social rejection, no matter how trivial, with getting mortally wounded or becoming lion’s dinner. It still links loneliness with physical danger. That’s why, says Cole, “purely symbolic or imagined stimuli — that is, situations that have not yet happened and may never actually occur — can engage the same ancestral programs that are triggered by actual social or physical threats.”

But unlike actual threats, which come and swiftly go (you kill or die, eat or get eaten), imagined — or perceived — threats can linger a long while, fed off by our deepest fears, looming ever larger in our imaginations. When these threats take up residence in our minds, inflammation can turn from an acute emergency response into a chronic assault on the body and make us vulnerable to a battery of mental disorders and physical illnesses.

Health-wise, the perception of being rejected or alone actually inflicts more damage than the underlying reality. In one study, for example, the negative impact of feeling lonely on the immune system was twice as large as that of the subjects’ marriage status or their frequency of social contact — the more objective measures of social integration and connectedness.

This is not to say that objective circumstances don’t matter; of course they do. Losing a valued relationship, a job prospect, your self-esteem — these are not trivial matters; the hurt is not simply in your head. Only a psychopath could pass unscarred by the dramas and indignities that life offers up left and right. Still, as far as loneliness goes, the research suggests that the factual reality of it impacts our immune system in a different way — and to a smaller extent — than the subjective experience of it.

Indeed when he speaks of loneliness, Cacioppo defines it as perceived, rather than objective, social isolation. And if you think about it, that makes sense. Intuitively we know that being lonely is not a simple equation of the number of other people present in or absent from our lives. Who hasn’t felt alone in a crowd or been a stranger at a glitzy cocktail party? There’s a reason we make movies about angst-ridden Thanksgiving dinners and dreaded family gatherings at Christmas: we often feel loneliest surrounded by our closest.

Looked at this way, loneliness can be profoundly unsettling. It makes the old Milton quote assume a new and rather unnerving tangibility: “The mind is its own place, and in itself can make a heaven of hell, a hell of heaven.” Cole would say, slightly less poetically but no less forebodingly, that our cells have their own psychology, which makes “the world of the mind convert into the biochemistry of the body”.

Despite the fact that technology has connected us to a degree never before seen in history, the prevalence of loneliness hasn’t changed much from decade to decade. Most researchers estimate that between 20% and 30% of people are chronically lonely. One study finds that among Londoners that number is closer to 50%. Loneliness is also universal. It can equally affect both introverts and extroverts, says Cacioppo, and the only difference between the two types is the number of close relationships each needs to feel connected (one for introverts versus three for extroverts).

What makes loneliness so pervasive? And why has technology done little to reduce it? Evolution, again, provides a clue.

“It is not the case that historically other human beings were always necessarily a good thing to have around,” explains Cole. “There were occasions in which other human beings were raiding your camp or stealing your food and your spouse, or infecting you with diseases. So, human beings are great assets to other human beings but they can also be great threats.” According to Cacioppo, this has hardwired into us a negative bias against other people that acts in tandem with our attraction to them. Our social existence emerges from this constant tug of war between a desperate need to connect with others and the very real threat that they posed to our survival.

Sensitivity to social threat may, in fact, be even more deeply etched into our biology than a desire for connection. Consider the evolution of our sense of taste. We are far more sensitive to bitter than we are to sweet, says Cacioppo, because throughout history bitter tastes often meant poison. A strong visceral reaction against bitter ensured that we stay away from foods which could kill us.

Similarly, a built-in negative bias against other humans would have protected us from miscalculated friendliness. “If I make an error and detect a person as a foe who turns out to be a friend, that’s okay, I don’t make a friend as fast, but I survive”, says Cacioppo. “But if I mistakenly detect someone as a friend when they’re a foe, that can cost me my life”.

So there are two conflicting forces that shape our social existence, amounting to what Cole refers to as the “paradox of loneliness”. Social motivation pulls us towards other people, social threat drives us away from them. This paradox can help explain why being alone is not the same as being lonely. People low on social motivation, for example, tend to feel quite happy on their own or with just a few close friends. We call them introverts and theirs is not so much loneliness as solitude.

For people high on social motivation the reverse is true: they need a bigger number of social ties in order to feel connected and the absence of such ties can plunge them into deep loneliness. Then there are those people who desperately crave connection yet just as desperately want to be left alone. This is, in fact, one of the particularly cruel twists of depression: the more you need others to help you out of your hole, the more you withdraw into it, burying yourself deeper and deeper still.

Why do some people feel more threatened by others, thus risking social isolation? According to Cole, there are two main factors. The first one is innate: you may have been born with a particularly sensitive nervous system that picks up the subtlest cues of social threats in your environment. A negative bias against other people can also be acquired through life experiences — especially those occurring during the early years. Childhood, after all, is a critical developmental window and a sort of dress rehearsal for later life. Growing evidence suggests that early adversity can reprogram vital biological systems in a way adapted to hostile conditions in the future. The nervous system, for example, can become more vigilant for signs of danger, the immune system more responsive to those signs, and inflammation more easily triggered.

No matter how it arises, negative social bias can ultimately take on a life of its own and warp reality in an invisible yet dramatic way. Suppose you are wired (whether by nature or experience) to see the world as a dangerous place. In your day-to-day interactions, you’ll treat others with suspicion or at least a mild reserve, and in response, they’ll be more ambivalent and reserved towards you. Their new attitude will reinforce your initial suspicions, which will make you more mistrustful of their motives and perhaps even hostile, which will make them even more ambivalent and reserved. And on and on.

“It becomes this vicious cycle or loop,” says Cole, “where the behaviour creates another loop from the social world outside me so then the social world really is kind of, in a self-fulfilling prophecy sense, proving my theory.” Which means that threats without any basis in reality can actually become real. In other words, not only do your objective circumstances influence your perception, but your perception can also alter your objective circumstances. As perception and reality feed off each other, they begin to close in on you and, loop after loop after loop, cut you off from others.

Hard to break, this self-perpetuating cycle can ultimately lead to chronic loneliness — and riding shotgun, of course, is chronic inflammation. But it gets worse. Every loop between social threat and immune response further sensitises the nervous system to danger signals while also grooving in the pathways that these signals use to travel from brain to body. Every burst of inflammation releases molecules that stimulate the same neuro-immune pipeline which produced it in the first place. This sets in motion yet another vicious cycle that continually reinforces inflammation in a process that scientists call “biological embedding”.

The health effects of biologically embedded inflammation are varied and insidious. In the short term, it can lead to hypervigilance, social anxiety and heightened sensitivity to pain. As the brain becomes increasingly sensitised to threat signals and the immune system more responsive to them, symptoms turn more severe, with disrupted sleep, chronic pain and depressed mood now common. Over time, the whole mechanism can become so sensitive that lower and lower stress levels are needed to trigger it. At this point, things once considered mere trivialities or else a normal part of life can dramatically crank up your inflammation and make you sick.

Most harrowing of all, it can get to a point where no external trigger is needed at all: inflammation becomes so deeply embedded that it just keeps raging on even if your life seems nothing short of miraculous. In the long term, this can lead to inflammation-related diseases such as rheumatoid arthritis, cardiovascular disease, diabetes, Alzheimer’s, some cancers, as well as treatment-resistant depression, premature ageing and early mortality.

To call this bleak would be an understatement. It’s chilling, morbid even. But a number of researchers think there is reason for hope: the better we understand inflammation, the more we can do about it. Steve Cole, for one, doesn’t believe that the human genome evolved to make us miserable. Quite the opposite, in fact: our genes, he says, want us to be happy, to thrive. Just like he once set out to demystify the gay men’s disease and early death, Cole is now trying to pin down the biology of health, happiness and connection

But that demands a post of its own.

To learn what works and what doesn’t in coping with loneliness and reducing inflammation, sign up below to receive the next research report.