Research has repeatedly shown that a lack of social ties increases risk for poor health. Recent research has demonstrated that poor mental and physical health outcomes are distally associated with social isolation, are more proximally associated with perceived social isolation, and are not explicable in terms of differences in health behaviors. Recent studies have identified alterations in hypothalamic-pituitary-adrenal (HPA) axis regulation of inflammatory biology in leukocytes as a potential mechanism of isolation-related health risks. Individuals reporting chronically high levels of subjective social isolation have shown a heightened rise in morning cortisol levels (Adams et al. 2006), and alterations in genome-wide transcription of glucocorticoid target genes and NF-:B target genes (Cole et al. 2007). These isolation-related alterations in leukocyte biology might stem from a functional desensitization of the glucocorticoid receptor (GR) in isolated people (Cole 2008), which in turn, is reciprocally related to NF-:B expression, a key factor in regulation of cellular responses to infection, cancer, and inflammation. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of perceived social isolation. Initial genomics analyses tested a relatively small sample and provided preliminary support for this hypothesis. This revised application seeks to extend those initial findings by (1) expanding the range of genomic analyses, (2) identifying the specific aspect of glucocorticoid-mediated transcriptional control driving those effects, (3) determining the plausibility of a causal role for subjective social isolation in predicting transcriptional control in longitudinal studies, and (4) establishing an animal model of subjective social isolation that can provide a platform for experimental studies. Utilizing participants from the Chicago Health, Aging and Social Relations longitudinal study, a population-based sample of middle-aged and older adults, we investigate whether transcriptional alterations occur only in those who show chronically high levels of subjective isolation, or whether similar effects occur even at minimal or variable levels of subjective isolation. Differential expression of GR and/or NF-:B proteins, and/or post-translational modifications of the GR (e.g., GR phosphorylation) will be examined as potential molecular mechanisms of altered glucocorticoid transcriptional control. The plausibility of a causal role for social isolation will be evaluated by examining the extent to which naturally occurring changes in subjective isolation over a two-year period predict changes in transcriptional control. Finally, a non-human primate model will be evaluated by conducting social behavioral assays to distinguish among and determine stability of """"""""sociability"""""""" phenotypes in adult male rhesus monkeys, and biological assays will be done to determine relationships between social phenotypes and measures of HPA activity, GR- mediated signal transduction, and genome-wide transcriptional profiles.

Public Health Relevance

Research has repeatedly shown that social isolation increases risk for poor health. We previously found functional genomic differences between individuals high and low in social isolation which could contribute to differences in risk of disease. The proposed research therefore is designed to identify the specific biological mechanisms mediating these genomic effects.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Social Psychology, Personality and Interpersonal Processes Study Section (SPIP)
Program Officer
Gerald, Melissa S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Arts and Sciences
United States
Zip Code
Abdellaoui, Abdel; Chen, Hsi-Yuan; Willemsen, Gonneke et al. (2018) Associations between loneliness and personality are mostly driven by a genetic association with Neuroticism. J Pers :
Abdellaoui, A; Nivard, M G; Hottenga, J-J et al. (2018) Predicting loneliness with polygenic scores of social, psychological and psychiatric traits. Genes Brain Behav 17:e12472
Cacioppo, John T; Cacioppo, Stephanie (2018) The Population-Based Longitudinal Chicago Health, Aging, and Social Relations Study (CHASRS): Study Description and Predictors of Attrition in Older Adults. Arch Sci Psychol 6:21-31
Mies, Gabry W; Verweij, Karin J H; Treur, Jorien L et al. (2018) Polygenic risk for alcohol consumption and its association with alcohol-related phenotypes: Do stress and life satisfaction moderate these relationships? Drug Alcohol Depend 183:7-12
Capitanio, John P (2017) Naturally Occurring Nonhuman Primate Models of Psychosocial Processes. ILAR J 58:226-234
Mehl, Matthias R; Raison, Charles L; Pace, Thaddeus W W et al. (2017) Natural language indicators of differential gene regulation in the human immune system. Proc Natl Acad Sci U S A 114:12554-12559
Nagaraja, Archana S; Dood, Robert L; Armaiz-Pena, Guillermo et al. (2017) Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight 2:
Chun, K; Capitanio, J P; Lamkin, D M et al. (2017) Social regulation of the lymph node transcriptome in rhesus macaques (Macaca mulatta). Psychoneuroendocrinology 76:107-113
Gao, Jianjun; Davis, Lea K; Hart, Amy B et al. (2017) Genome-Wide Association Study of Loneliness Demonstrates a Role for Common Variation. Neuropsychopharmacology 42:811-821
Nagaraja, A S; Dorniak, P L; Sadaoui, N C et al. (2016) Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. Oncogene 35:2390-7

Showing the most recent 10 out of 43 publications