Can loneliness make you sick?

Loneliness is more than just a socio-emotional condition; it can be a significant cause of poor health, and is of special concern in the elderly.

Also known as perceived social isolation, loneliness reflects a discrepancy between desired and actual social relationships, and has been known to be a major risk factor for chronic illness and mortality in humans for more than a quarter century. Loneliness is not a uniquely human phenomenon, however; in most socially living species, there is likely to be a subset of individuals that are dissatisfied with the quantity and quality of their social relationships. A study published in 2014 demonstrated this phenomenon in rhesus macaques.

Although the risk factors have been well understood, the molecular mechanisms by which loneliness can affect health have not been well defined.

A new report, involving both humans and rhesus monkeys as subjects, significantly expands our understanding of these health-related mechanisms by focusing on gene expression in leukocytes — cells of the immune system that are involved in protecting the body against bacteria and viruses.

The study team included researchers from UCLA, the California National Primate Research Center (CNPRC) at UC Davis, and the University of Chicago.

Lead authors Steven Cole, PhD, UCLA School of Medicine, John Capitanio, PhD, Core Scientist in the Brain, Mind, and Behavior Unit at the CNPRC, UC Davis, and John Cacioppo, PhD, University of Chicago published their important findings today in the high impact journal Proceedings of the National Academy of Sciences (“Myeloid differentiation architecture of leukocyte transcriptome dynamics in perceived social isolation”, Cole et al, PNAS Nov 23, 2015).

The human study examined gene expression in leukocytes collected annually in a study that lasted more than five years. In humans, loneliness at one time point was associated at a later time point with increased expression of genes that lead to inflammation, a decreased expression of genes related to protection from viruses, and an increased percentage in blood of monocytes, a specific type of leukocyte that is involved in many immune responses, including inflammation. Loneliness was also associated with increased concentrations of norepinephrine, a marker of the sympathetic nervous system, which is responsible for the flight or fight response. Together these results suggested that the effect of loneliness on health may be mediated by the impact loneliness has on the sympathetic nervous system, which in turn affects monocyte numbers and leukocyte gene expression.

At the CNPRC, the monkey study was performed to see if similar changes were evident, to provide more detail about these mechanisms, and to understand how loneliness can affect disease. The parallels were striking – lonely monkeys showed a similar pattern of gene expression for increased inflammation and reduced anti-viral responses, higher levels of norepinephrine, and elevated monocyte numbers.

Rhesus monkeys are a highly social nonhuman primate species, and the animals in this study lived outdoors in large, half-acre field corrals, in a rich social environment consisting of 80–150 animals. Animals were identified as lonely, when just like in humans, there was a discrepancy in the desired and actual social relationships.

“Importantly, our study describes a naturally occurring model of loneliness. Animal models of loneliness are usually induced models – for example an animal is physically separated from its companions. Our research suggests loneliness in monkeys can occur even in the presence of others – just like in humans” emphasizes Dr. Capitanio.

The monkey studies extended the human studies by showing that it is a specific subset of monocytes that was increased in the lonely animals. Moreover, there were indications in the monkey studies that the machinery that controls gene transcription was also compromised.

A second sample of monkeys that had been infected with the simian immunodeficiency virus, which causes an AIDS-like disease in rhesus monkeys, confirmed these findings: in the presence of this virus, monocyte subsets were elevated, and the expression of anti-viral genes was reduced. Because these animals were infected with a virus, the authors predicted the ability of the lonely animals to control replication of the virus would be compromised, and a poorer antibody response would be seen. This is exactly what was found.

Together, the human and monkey studies show a consistent picture: lonely individuals’ chronic perceptions of social threat stimulate the sympathetic nervous system, which affects the type and number of leukocytes that are produced in the bone marrow. These leukocytes are primed to create an inflammatory response, even under conditions that might not normally elicit such a response. Moreover, these cells seem to be insensitive to the hormones that would normally dampen the inflammatory response. The leukocytes of lonely individuals are also less effective in fighting off viruses, and in the presence of a viral infection, the ability of lonely individuals to return quickly to health is compromised.

The researchers plan future research to confirm the specific neuro-immune interactions that mediate these physiologic dynamics. The current study’s molecular, cellular, behavioral, and immunologic validation of a macaque model of human perceived social isolation provides a useful experimental system for mapping the causal interactions among social perception, neural activity, immunologic function, and health in the human population.

This study was supported by National Institutes of Health Grants R37-AG033590, P01-AG18911, R01-AG034052, R01-AG043404, P30-AG017265, P30-AG028748, R01-DA024441, and P51-OD011107.

The University of Chicago news release can be found here.

Cacioppo JT, Cacioppo S, Cole SW, Capitanio JP, Goossens L, Boomsma DI. Loneliness across phylogeny and a call for comparative studies and animal models. Perspect Psychol Sci. 2015 Mar;10(2):202-12. doi: 10.1177/1745691614564876. Review. PMID: 25910390

Capitanio JP, Cole SW. Social instability and immunity in rhesus monkeys: the role of the sympathetic nervous system. Philos Trans R Soc Lond B Biol Sci. 2015 May 26;370(1669). pii: 20140104. doi: 10.1098/rstb.2014.0104. PMID: 25870391

Capitanio JP, Hawkley LC, Cole SW, Cacioppo JT. A behavioral taxonomy of loneliness in humans and rhesus monkeys (Macaca mulatta). PLoS One. 2014 Oct 29;9(10):e110307. doi: 10.1371/journal.pone.0110307. eCollection 2014. PMID: 25354040

Cacioppo JT, Cacioppo S, Capitanio JP, Cole SW. The neuroendocrinology of social isolation. Annu Rev Psychol. 2015 Jan 3;66:733-67. doi: 10.1146/annurev-psych-010814-015240. Epub 2014 Aug 22. Review. PMID: 25148851

Hawkley LC, Cole SW, Capitanio JP, Norman GJ, Cacioppo JT. Effects of social isolation on glucocorticoid regulation in social mammals. Horm Behav. 2012 Aug;62(3):314-23. doi:10.1016/j.yhbeh.2012.05.011. Epub 2012 Jun 1. Review. PMID: 22663934