Socially isolated and sick

Loneliness kills, according to research dating back to the 1970s. In one classic study, published in the American Journal of Epidemiology (Vol. 109, No. 2, pages 186-204), socially isolated people in Alameda County, Calif., were between two and three times more likely to die during the nine-year study than those who had many friends.

"The increase in morbidity with social isolation is equal to that of cigarette smoking," notes Martha McClintock, PhD, a University of Chicago psychology professor who researches social isolation and stress.

But while the pathway from smoking to cancer is largely established, the path from loneliness and other forms of chronic stress to many health consequences--including increased risk for cancer, cardiovascular illness and Alzheimer's disease--is not, she says. In humans, some of the effect may be due to the practical benefits of having a social network, says Gretchen Hermes, a fourth-year MD-PhD student at the University of Chicago. For instance, people with many friends might be more likely to brush their teeth and exercise. And gregarious people may have more friends who bring them food or medicine when they get sick.

But new animal studies suggest that there are direct, physiological pathways from loneliness and other chronic stressors to illness. And those pathways may differ depending on gender and temperament, with male and behaviorally inhibited animals being particularly susceptible, researchers are finding.

Acute stress: an immune booster?

Hermes and her colleagues found that, overall, social isolation suppressed wound healing in male and female rats, according to a study published last year in the American Journal of Physiology-Regulatory, Comparative and Integrative Physiology (Vol. 290, No. 1, pages 273-282). However, when they also acutely stressed the rats by trapping them in a small tube, the socially isolated female rats surprised researchers with an enhanced immune response, while the socially isolated male rats showed a further suppression of the immune response.

The researchers housed 60 female and 60 male rats either in groups of five or in isolated cages for more than three months. Then they injected half of the animals with a few milligrams of seaweed, right under their skin. The substance is harmless, but the immune system identifies it as foreign and surrounds it with scar tissue before absorbing it back into the body.

Both male and female isolated rats took longer to heal the wound than their group-housed brothers and sisters, the researchers found. While rats don't often face seaweed injections in the wild, the procedure taps into an underlying defense against many common illnesses, McClintock says.

"The basic inflammatory response is involved in a whole variety of different diseases, ranging from heart disease to infectious diseases and some forms of cancer," she notes.

Though socially isolated male and female rats responded similarly to the seaweed test, differences emerged when they were also exposed to an acute stressor. Two weeks before the seaweed injection, the researchers placed half of the socially isolated animals in a restraint tube for 30 minutes, a procedure that mimics the experience of being trapped in a collapsing burrow, says Hermes.

For the female rats, the trial revved up their immune systems--and they healed faster than those who didn't spend time in the restraint tube. The acutely stressed males, conversely, showed a slowed immune response.

"The females were much more resilient," Hermes notes.

The results fit with research on humans, says McClintock.

"Men who are lonely, or bereaved, or who lose their partners are known to be more vulnerable to disease and death, whereas women are more resilient," she notes.

The differences in both rats and humans may stem from the evolutionary pressure, McClintock theorizes. To pass on their genes, male animals only need to live long enough to mate. Female animals have to make it for the long haul.

"They need to survive to deliver and to take care of their young," she notes. "You can imagine it would be beneficial for evolution to select for females who could respond to a brief stressor with augmenting their immune function."

The cost of inhibition

One strength of the study is that they were able to randomly assign animals to social or isolated groups, notes McClintock. "That doesn't happen in nature," she says. For instance, some rats and humans tend to seek out others, while behaviorally inhibited animals will more likely live in isolation.

Even discounting of the effect of isolation, behavioral inhibition does seem to carry a health cost, according to a study published in the July issue of Hormones and Behavior (Vol. 50, No. 1, pages 454-462). In fact, behaviorally inhibited rats--those that tend to explore less because they find novel environments more threatening--died of natural causes a full six months earlier than their easygoing sisters, researchers found.

Penn State biobehavioral health professor Sonia Cavigelli, PhD, and her colleagues tested the temperament of 81 female rats when they were 20 days old, by placing them in an unfamiliar room, which included opaque walls and novel objects. Some of the animals moved freely around the room and sniffed the objects, while others huddled in the corner.

The animals then were housed in groups of three and lived out their natural lifespan. The particular strain of rat used in the study tends to live about two years, and they usually die of cancerous tumors that begin in their mammary glands, says Cavigelli.

While all the animals tended to die of tumors over time, the gregarious animals developed them about six months later than the inhibited ones. This may be because the inhibited animals don't socialize as much as other animals, or they may just get startled more often.

"Individuals that go through the stress response more frequently go through faster wear and tear on the system," Cavigelli notes.

Both studies shed light on the intricate mechanisms through which chronic stress, due to either social isolation or hypervigilance, can kill, says McClintock.

"They really begin to get to the richness of the dynamic," she notes. "In the area of stress, immunity, social context and sex, one shouldn't expect simple main effects."