[Hopeful]

“This study provides the first systematic analysis of genome-wide transcriptional alterations as a potential mechanism of social-epidemiological influences on human health. Individuals who experience themselves as chronically isolated from others have an increased risk of several inflammation-related diseases, and the broad pattern of leukocyte transcriptional alterations identified in this study provides a framework for understanding that risk at the molecular level. . . . This study has identified a clear genomic fingerprint of social isolation, and defined candidate transcription control pathways that may shape its expression, but several limitations must be considered when interpreting these results. First, the present findings are based on a relatively small number of individuals sampled from the low and high extremes of a social-epidemiological risk dimension, and thus require replication in larger samples that are more broadly representative of the total variation in human social phenotypes. However, it is remarkable that the size and inter-individual consistency of transcriptional alterations associated with subjective social isolation is sufficiently pronounced to reach high levels of statistical significance in a relatively small sample. It is unclear whether alterations in inflammatory signaling and gene transcriptional alteration might be observed in other tissues. It is also unclear whether the strong quantitative relationship between subjective social isolation and leukocyte transcriptional profiles observed here stems from a causal effect of social processes on gene expression (for example, via the neuroendocrine system), or whether differential gene expression in the immune system might instead drive variations in social behavior (for example, via effects of pro-inflammatory cytokines and prostaglandins on the central nervous system function.) The effects of acute “sickness behavior” are unlikely to explain the present results because this study analyzed long-term individual differences in experienced loneliness (that is, consistently expressed over at least three years). However, longitudinal studies will be required to rule out the possibility that variations in chronic inflammation might potentially influence long-term individual differences in social behavior. This study’s identification of a plausible neuroendocrine mediator or transcriptional alteration (GR signaling), which is known to relate to social phenotype in humans and is causally impacted by experimental social isolation in animal models, is consistent with social influences on gene expression. Experimental manipulations of long-term social behavior may ultimately be required to definitively establish causation in the human clinical setting. What is clear from this study’s ancillary analyses is that relationships between gene expression and social isolation cannot be attributed to correlated differences in other known demographic, psychological, social or medical risk factors (including perceived stress, depression, hostility, socio-economic status, and altered subset distributions within the circulating leukocyte pool). Ancillary analyses controlling for transient variations in loneliness suggest that the transcriptional correlates of chronic subjective social isolation (trait loneliness) do not stem solely from transient variations in state loneliness. A persistent sense of social isolation appears to represent a distinct epidemiological risk factor that is associated with broad alterations in immune cell gene expression linked to reciprocal shifts in the activity of pro- and anti- inflammatory transcription control pathways."

Hopeful