Among the 22,283 genes assayed, 209 showed systematically different levels of expression in people who reported feeling lonely and distant from others consistently over the course of 4 years (see Figure). These effects did not involve a random smattering of all human genes, but focally affected three specific groups of genes. Genes supporting the early “accelerator” phase of the immune response—inflammation—were selectively up-regulated; and two groups of genes involved in the subsequent “steering” of immune responses—genes involved in responses to viral infections (particularly Type I interferons), and genes involved in the production of antibodies by B lymphocytes—were down-regulated. These results provided a molecular framework for understanding why socially isolated individuals show heightened vulnerability to inflammation-driven cardiovascular diseases (i.e., excessive nonspecific immune activity) and impaired responses to viral infections and vaccines (i.e., insufficient immune responses to specific pathogens). A major clue about the psychological pathways mediating these effects came from the observation that differential gene-expression profiles were most strongly linked to a person's subjective sense of isolation rather than to their objective number of social contacts.
Figure: Gene expression in human immune cells in lonely and socially integrated people. Expression of 22,283 human gene transcripts was assayed in 10 million blood leukocytes sampled from each of 14 older adults who showed consistent differences over 4 years in their level of subjective social isolation. Two hundred nine gene transcripts showed at least 30% difference in average expression level between six people experiencing chronic social isolation and eight experiencing consistent social integration. In the heat-plot above, each row represents data from one of the 14 study participants, each column contains expression values for one of the 209 differentially active genes, and the coloring of each cell represents the relative level of that gene's expression in a given participant's leukocyte sample: Red = high expression, Black = intermediate expression, Green = low expression.