We’ve all felt isolated at times, but the so-called “invisible epidemic” that is loneliness is about much more than ephemeral feelings of sadness. Doctors have known for some time that loneliness is associated with not only chronic illness but death, too. Now, scientists are beginning to unravel why this is, with the discovery that social isolation puts our body in “fight or flight” mode, preparing for social threat. This triggers a cascade of events that ultimately alter the production of white blood cells, leaving us vulnerable to disease.
This study, conducted by researchers at the University of Chicago, actually builds on earlier work by the same group. Interestingly, they previously found that perceived social isolation, or loneliness, is associated with changes in gene expression that favor those involved in inflammation while dampening those concerned with antiviral responses. Although inflammation helps us heal, inappropriate inflammatory responses can actually cause more harm than good, damaging cells and leading to an array of conditions if left unabated.
For this latest investigation, the researchers began by further exploring this phenomenon, called CTRA (conserved transcriptional response to adversity), in humans. After looking at the “transriptomes,” or gene readouts, of white blood cells belonging to 141 lonely older adults, as anticipated CTRA was found to be up-regulated. In addition, heightened activity was observed in the sympathetic nervous system, a branch responsible for activating the body’s “fight or flight” response which helps us react to emergency situations.
Moreover, loneliness could be used to predict future CTRA gene expression patterns, and vice versa, indicating that a reciprocal mechanism is at play whereby these responses help propagate one another over time. Moving on, the team decided to examine primate models of loneliness to see if they could unpick the processes that lead to CTRA gene expression. Lonely rhesus macaques, like humans, displayed heightened CTRA activity, alongside a boost in the fight or flight chemical norepinephrine (noradrenaline).
Image credit: Rhesus macaque. Kurkul/Shutterstock
This is where the research ties together nicely: norepinephrine can trigger the production of a type of white blood cell, called an immature monocyte, that displays CTRA activity – less antiviral gene expression and more pro-inflammatory gene expression. And when the team looked at the pools of cells present in the blood of lonely humans and macaques, sure enough they found an abundance of monocytes, which are derived from the immature precursors.
The effects of this alteration in gene expression patterns were indeed felt by the lonely monkeys, which showed impaired antiviral responses to infection with simian immunodeficiency virus, the primate version of HIV. When compared with control animals, lonely macaques had higher levels of viral replication in both the blood and brain.
The researchers therefore propose a model wherein heightened CTRA activity can be explained, at least in part, by a loneliness-driven fight or flight response that boosts immature monocyte levels. The resulting gene expression patterns not only leave the lonely individual vulnerable to infection through a dampened antiviral response, but also susceptible to chronic disease due to inappropriate inflammation.
The findings of this study have been published in Proceedings of the National Academy of Sciences.