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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG033590-04
Application #
8423751
Study Section
Social Psychology, Personality and Interpersonal Processes Study Section (SPIP)
Program Officer
Gerald, Melissa S
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2013-04-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$342,826
Indirect Cost
$42,052
Name
University of Chicago
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Cole, Steven W; Capitanio, John P; Chun, Katie et al. (2015) Myeloid differentiation architecture of leukocyte transcriptome dynamics in perceived social isolation. Proc Natl Acad Sci U S A 112:15142-7
Moieni, Mona; Irwin, Michael R; Jevtic, Ivana et al. (2015) Trait sensitivity to social disconnection enhances pro-inflammatory responses to a randomized controlled trial of endotoxin. Psychoneuroendocrinology 62:336-42
Cole, Steven W; Nagaraja, Archana S; Lutgendorf, Susan K et al. (2015) Sympathetic nervous system regulation of the tumour microenvironment. Nat Rev Cancer 15:563-72
Cacioppo, Stephanie; Grippo, Angela J; London, Sarah et al. (2015) Loneliness: clinical import and interventions. Perspect Psychol Sci 10:238-49
Cacioppo, John T; Cacioppo, Stephanie; Capitanio, John P et al. (2015) The neuroendocrinology of social isolation. Annu Rev Psychol 66:733-67
Cacioppo, S; Cacioppo, J T (2015) Why may allopregnanolone help alleviate loneliness? Med Hypotheses 85:947-52
Cole, Steven W; Levine, Morgan E; Arevalo, Jesusa M G et al. (2015) Loneliness, eudaimonia, and the human conserved transcriptional response to adversity. Psychoneuroendocrinology 62:11-7
Cacioppo, John T; Cacioppo, Stephanie; Cole, Steven W et al. (2015) Loneliness across phylogeny and a call for comparative studies and animal models. Perspect Psychol Sci 10:202-12
Cole, Steven W (2014) Human social genomics. PLoS Genet 10:e1004601

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