A large body of epidemiological research has linked characteristics of the social environment to human physical health [1,2], but the genomic mechanisms of these effects remain largely unexplored. One of the most robust social risk factors involves the number and quality of an individual's close personal relationships. People who are socially isolated have increased risk of all-cause mortality [1,2], and several specific infectious, neoplastic, and cardiovascular diseases [3-6]. The biological basis for these epidemiological findings is poorly understood, in part because it is unclear whether the effects of social isolation stem predominantly from the objective deprivation of instrumental social support (for example, physical, cognitive, or economic assistance), or from the biological consequences of the experienced threat and dysphoria associated with subjective social isolation (that is, loneliness). Few epidemiological studies have clearly distinguished between objective and subjective social isolation, but among those that have, some evidence supports a significant contribution from each aspect [1,5,7-10]. However, the physiological signaling pathways by which these dynamics impact the pathobiology of disease remain poorly understood.
