It torments the young and terrorises the old. It carved "caverns" in Emily Dickinson's soul and left William Blake "bereaved of light."
Loneliness, long a bane of humanity, is increasingly seen today as a serious public health hazard. Scientists who have identified significant links between loneliness and illness are pursuing the precise biological mechanisms that make it such a menace, digging down to the molecular level and finding that social isolation changes the human genome in profound, long-lasting ways.
Not only that, but the potential for damage caused by these genetic changes appears comparable to the injuries to health from smoking and, even worse, from diabetes and obesity. The scientists' conclusion: Loneliness can be a lethal risk. And the United States - which so prizes individuality - is doing far too little to alleviate it.
"In public health, we talk all the time about obesity and smoking and have all these interventions, but not about people who are lonely and socially isolated," said Kerstin Gerst Emerson, an assistant professor at the University of Georgia's Institute of Gerontology. "There are really tangible, terrible outcomes. Lonely people are dying, they're less healthy, and they are costing our society more."
Psychologist Steve Cole, who studies how social environments affect gene expression, says researchers have known for years that lonely people are at greater risk for heart attacks, metastatic cancer, Alzheimer's and other ills. "But we haven't understood why," he said.
Then last year, Cole and his colleagues at the UCLA School of Medicine, along with collaborators at the University of California at Davis and the University of Chicago, uncovered complex immune system responses at work in lonely people. They found that social isolation turned up the activity of genes responsible for inflammation and turned down the activity of genes that produce antibodies to fight infection.
The abnormalities were discovered in monocytes, a type of white blood cell, produced in the bone marrow, that is dramatically changed in people who are socially isolated. Monocytes play a special immunological role and are one of the body's first lines of defence against infection. However, immature monocytes cause inflammation and reduce antibody protection. And they are what proliferates in the blood of lonely people.
Such cellular changes, says University of Chicago social neuroscientist John Cacioppo, are a byproduct of human evolution.
Early on, when survival depended crucially on cooperation and communication, social isolation was a huge risk. So evolution shaped the primitive human brain to desire and need social interaction in the same way it shaped the brain to desire and need food.
The pain of loneliness is like the pain of hunger - it's a biological signal that something is wrong.
"When you get hungry you may not be aware your blood sugar level is dropping, but if you're driving and you see the golden arches (of McDonald's)," you'll pull in for food, Cacioppo said.
Today, social isolation is often an unavoidable lifestyle. But it puts the body, on the cellular level, on constant alert for a threat. That helps explain why lonely people are more likely to act negatively toward others, which makes it that much harder for them to forge relationships.
"I do see these patients all the time," said psychiatrist Jacqueline Olds, who has a private practice in Cambridge, Massachusetts, and has co-written two books on the subject. "Many of the people who end up lonely give off signals they want to be alone out of anxiety. . . . Feeling left out has a huge effect on our psyche from our evolutionary worries that everyone else will survive and we won't."
The most broadly accepted definition of loneliness is the distress people feel when reality fails to meet their ideal of social relationships. Loneliness is not synonymous with being alone. Many people live solitary lives but are not lonely. Conversely, being surrounded by others is no guarantee against loneliness.
Loneliness is also not the same as depression, though the two often go hand in hand. The first,related to the drive to belong, is motivational. The other, a more general feeling of sadness or hopelessness, is not.
At the University of Georgia, Gerst and health economist Jayani Jayawardhana wanted to see how widespread the distress from loneliness actually is. They analysed longitudinal data from two national health and retirement studies conducted in 2008 and 2012. Through the answers provided by 7060 individuals 60 and older, the researchers concluded that chronic loneliness was "a significant public health issue," one that "contributes to a cycle of illness and health-care utilisation."
Among their more unusual findings: Even when controlling for an increase in physician visits because of illness, loneliness appeared to be an important predictor of those visits. The doctor-patient relationship, it seemed, provided one of the few social outlets for isolated people.
Psychotherapist Matt Lundquist, director of TriBeCa Therapy in New York City, has become something of an expert on loneliness. Hardly a week goes by, he says, without one of his patients expressing "agony" over something seen on Facebook. "It's a reinforcement that everybody has these connections and (they) don't," he said Friday.
Lundquist is "shocked that there isn't more conversation" about social isolation within public-health circles. "Loneliness is a brutal issue."
A study published online last month in the Proceedings of the National Academy of Sciences, suggests there is also a parallel effect with health and loneliness. With every positive increase in social relationships, researchers in North Carolina and China saw improvement in specific physiological biomarkers such as blood pressure and body mass index.
The largest positive effect was associated with those who had a variety of relationships, such as with friends, romantic partners and co-workers.
"Each one of these may provide different pathways . . . (that) can potentially impact health," said Julianne Holt-Lunstad, a psychologist at Brigham Young University who recently analysed 70 different loneliness studies from around the world. They covered more than 3.4 million participants over a period of 35 years.
Many researchers believe the United States is not doing enough to address loneliness as a public health issue. For inspiration, they point to the United Kingdom. Begun in 2011, its national Campaign to End Loneliness involves five social-service agencies and about 2500 smaller organisations, all working to raise people's awareness of loneliness.
"Much of our time is spent campaigning: communicating with, convincing and persuading those who make choices about health and healthcare spending to tackle and prevent loneliness," Kellie Payne, the campaign's learning and research manager, wrote in an email.
German psychoanalyst Frieda Fromm-Reichmann could have predicted the science more than a half-century ago. One of the first to examine social isolation from an empirical perspective, she wrote that the "naked horror" of loneliness shadows our lives because the longing for intimacy is always with us.
"There is no human being who is not threatened by its loss."