Lisa M. Jaremka

Loneliness predicts pain, depression, and fatigue: understanding the role of immune dysregulation.

OBJECTIVE The pain, depression, and fatigue symptom cluster is an important health concern. Loneliness is a common risk factor for these symptoms. Little is known about the physiological mechanisms linking loneliness to the symptom cluster; immune dysregulation is a promising candidate. Latent herpesvirus reactivation, which is reflected by elevated herpesvirus antibody titers, provides a window into immune dysregulation. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are two common herpesviruses. METHODS Participants were 200 breast cancer survivors who were 2 months to 3 years post-treatment at the time of the study. They completed questionnaires and provided a blood sample that was assayed for CMV and EBV antibody titers. RESULTS Lonelier participants experienced more pain, depression, and fatigue than those who felt more socially connected. Lonelier participants also had higher CMV antibody titers which, in turn, were associated with higher levels of the pain, depression, and fatigue symptom cluster. Contrary to expectations, EBV antibody titers were not associated with either loneliness or the symptom cluster. CONCLUSIONS The pain, depression, and fatigue symptom cluster is a notable clinical problem, especially among cancer survivors. Accordingly, understanding the risk factors for these symptoms is important. The current study suggests that loneliness enhances risk for immune dysregulation and the pain, depression, and fatigue symptom cluster. The present data also provide a glimpse into the pathways through which loneliness may impact health.

Loneliness Promotes Inflammation During Acute Stress

Although evidence suggests that loneliness may increase risk for health problems, the mechanisms responsible are not well understood. Immune dysregulation is one potential pathway: Elevated proinflammatory cytokines such as interleukin-6 (IL-6) increase risk for health problems. In our first study (N = 134), lonelier healthy adults exposed to acute stress exhibited greater synthesis of tumor necrosis factor-alpha (TNF-α) and IL-6 by peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) than their less lonely counterparts. Similarly, in the second study (N = 144), lonelier posttreatment breast-cancer survivors exposed to acute stress exhibited greater synthesis of IL-6 and interleukin-1 beta (IL-1β) by LPS-stimulated PBMCs than their counterparts who felt more socially connected. However, loneliness was unrelated to TNF-α in Study 2, although the result was in the expected direction. Thus, two different populations demonstrated that lonelier participants had more stimulated cytokine production in response to stress than less lonely participants, which reflects a proinflammatory phenotype. These data provide a glimpse into the pathways through which loneliness may affect health.

Pain, Depression, and Fatigue: Loneliness as a Longitudinal Risk Factor

OBJECTIVE Pain, depression, and fatigue function as a symptom cluster and thus may share common risk factors. Interpersonal relationships clearly influence health, suggesting that loneliness may promote the development of the pain, depression, and fatigue symptom cluster. We hypothesized that loneliness would be related to concurrent symptom cluster levels and increases in symptom cluster levels over time. METHOD We utilized two observational studies with distinct longitudinal samples. Study 1 was a sample of cancer survivors and benign controls (N = 115) assessed annually for 2 years. Study 2 was a sample of older adults caring for a spouse with dementia (caregivers) and non-caregiver controls (N = 229) assessed annually for 4 years. Participants completed annual measures assessing loneliness, pain, depression, and fatigue. RESULTS Across both samples, lonelier participants experienced more concurrent pain, depression, and fatigue and larger increases in symptom cluster levels from one year to the next than less lonely participants. Sleep quality did not mediate the results in either study. All analyses were adjusted for relevant demographic and health variables. CONCLUSIONS Two longitudinal studies with different populations demonstrated that loneliness was a risk factor for the development of the pain, depression, and fatigue symptom cluster over time. The current research helps identify people most at risk for pain, depression, and fatigue, and lays the groundwork for research about their diagnosis and treatment. These data also highlight the health risks of loneliness; pain, depression, and fatigue often accompany serious illness and place people at risk for poor health and mortality.

Attachment Anxiety Is Linked to Alterations in Cortisol Production and Cellular Immunity

Although evidence suggests that attachment anxiety may increase risk for health problems, the mechanisms underlying these effects are not well understood. In the current study, married couples (N = 85) provided saliva samples over 3 days and blood samples on two occasions. Participants with higher attachment anxiety produced more cortisol and had fewer numbers of CD3+ T cells, CD45+ T cells, CD3+CD4+ helper T cells, and CD3+CD8+ cytotoxic T cells than participants with lower attachment anxiety. Higher cortisol levels were also related to fewer numbers of CD3+, CD45+, CD3+CD4+, and CD3+CD8+ cells, which is consistent with research showing that cortisol alters the cellular immune response. These data suggest that attachment anxiety may have physiological costs, and they provide a glimpse into the pathways through which social relationships affect health. The current study also extends attachment theory in an important new direction by demonstrating the utility of a psychoneuroimmunological approach to the study of attachment anxiety, stress, and health.

Synergistic Relationships Among Stress, Depression, and Troubled Relationships: Insights from Psychoneuroimmunology

Stress and depression consistently elevate inflammation and are often experienced simultaneously, which is exemplified by people in troubled relationships. Troubled relationships also elevate inflammation, which may be partially explained by their ability to engender high levels of stress and depression. People who are stressed, depressed, or in troubled relationships are also at greater risk for health problems than their less distressed counterparts. Inflammation, a risk factor for a variety of age‐related diseases including cardiovascular disease, Type II diabetes, metabolic syndrome, and frailty, may be one key mechanistic pathway linking distress to poor health. Obesity may further broaden the health implications of stress and depression; people who are stressed or depressed are often overweight, and adipose tissue is a major source of proinflammatory cytokines. Stress, depression, and troubled relationships may have synergistic inflammatory effects: loneliness, subclinical depression, and major depression enhance inflammatory responses to an acute stressful event. The relationship between distress and inflammation is bidirectional; depression enhances inflammation and inflammation promotes depression. Interesting questions emerge from this literature. For instance, some stressors may be more potent than others and thus may be more strongly linked to inflammation. In addition, it is possible that psychological and interpersonal resources may buffer the negative inflammatory effects of stress. Understanding the links among stress, depression, troubled relationships, and inflammation is an exciting area of research that may provide mechanistic insight into the links between distress and poor health.

Yoga and self-reported cognitive problems in breast cancer survivors: a randomized controlled trial

Cancer survivors often report cognitive problems. Furthermore, decreases in physical activity typically occur over the course of cancer treatment. Although physical activity benefits cognitive function in noncancer populations, evidence linking physical activity to cognitive function in cancer survivors is limited. In our recent randomized controlled trial, breast cancer survivors who received a yoga intervention had lower fatigue and inflammation following the trial compared with a wait list control group. This secondary analysis of the parent trial addressed yogas impact on cognitive complaints.

Marital distress prospectively predicts poorer cellular immune function

OBJECTIVE Distressed marriages enhance risk for a variety of health problems. Immune dysregulation is one potential mechanism; cross-sectional studies have demonstrated that marital distress is linked to maladaptive immune alterations. The current study filled an important gap in the literature by examining the ability of marital distress to prospectively predict immune alterations over a two-year period. METHOD Participants were 90 couples (N=180 individuals; Mage=25.67) married less than a year at the time of their first study visit. Both members of a couple completed a baseline assessment of marital quality and provided blood samples at baseline and two years later. 63 couples (N=123 individuals) completed the follow-up assessment. RESULTS Spouses in more distressed marriages had larger declines in cellular immune function over time than spouses in less distressed marriages. Furthermore, the results were highly consistent across two different indices, proliferative responses to two mitogens, concanavalin A (Con A) and phytohemagglutinin (PHA). CONCLUSIONS Marital distress has a variety of negative health consequences. The current study provided important evidence that marital distress has longer-term immune consequences. Accordingly, the present results provide a glimpse into the pathways through which marital distress may impact health over time.

Interpersonal stressors predict ghrelin and leptin levels in women

OBJECTIVE Stressful events enhance risk for weight gain and adiposity. Ghrelin and leptin, two hormones that are implicated in appetite regulation, may link stressful events to weight gain; a number of rodent studies suggest that stressors increase ghrelin production. The present study investigated the links among daily stressors, ghrelin and leptin, and dietary intake in humans. METHOD Women (n=50) completed three study appointments that were scheduled at least 2 weeks apart. At each visit, women arrived fasting and ate a standardized breakfast and lunch. Blood samples were collected 45min after each meal. Women completed a self-report version of the Daily Inventory of Stressful Events (DISE) at each appointment. Two composites were created from the DISE data, reflecting the number of stressors that did and did not involve interpersonal tension. RESULTS Women who experienced more stressors involving interpersonal tension had higher ghrelin and lower leptin levels than those who experienced fewer interpersonal stressors. Furthermore, women who experienced more interpersonal stressors had a diet that was higher in calories, fat, carbohydrates, protein, sugar, sodium, and fiber, and marginally higher in cholesterol, vegetables (but not fruits), vitamin A, and vitamin C. Stressors that did not involve interpersonal tension were unrelated to ghrelin and leptin levels or any of the dietary components examined. CONCLUSIONS These data suggest that ghrelin and leptin may link daily interpersonal stressors to weight gain and obesity.

Attachment anxiety is related to Epstein-Barr virus latency

Attachment theory provides a framework for understanding individual differences in chronic interpersonal stress. Attachment anxiety, a type of relationship insecurity characterized by worry about rejection and abandonment, is a chronic interpersonal stressor. Stress impacts cellular immunity, including herpesvirus reactivation. We investigated whether attachment anxiety was related to the expression of a latent herpesvirus, Epstein-Barr virus (EBV), when individuals were being tested for breast or colon cancer and approximately 1 year later. Participants (N=183) completed a standard attachment questionnaire and provided blood to assess EBV viral capsid antigen (VCA) IgG antibody titers. Individuals with more attachment anxiety had higher EBV VCA IgG antibody titers than those with less attachment anxiety. The strength of the association between attachment anxiety and antibody titers was the same at both assessments. This study is the first to show an association between latent herpesvirus reactivation and attachment anxiety. Because elevated herpesvirus antibody titers reflect poorer cellular immune system control over the latent virus, these data suggest that high attachment anxiety is associated with cellular immune dysregulation.

Marital discord, past depression, and metabolic responses to high-fat meals: Interpersonal pathways to obesity

BACKGROUND Longitudinal studies have implicated both marital distress and depression in the development of the metabolic syndrome, a risk factor for diabetes and cardiovascular disease. This study addressed the impact of hostile marital interactions and a mood disorder history on obesity-related metabolic responses to high-fat meals. METHODS This double-blind, randomized crossover study included serial assessments of resting energy expenditure (REE), fat and carbohydrate oxidation, triglycerides, insulin, glucose, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) before and after two high-fat meals. During two separate 9.5h visits, 43 healthy married couples, ages 24-61 (mean=38.22), received either a high saturated fat meal or a high oleic sunflower oil meal, both 930kcal and 60g fat. The Structured Diagnostic Interview for DSM-IV assessed mood disorder history. Couples discussed a marital disagreement during both visits; behavioral coding of these interactions provided data on hostile marital behaviors. RESULTS Men and women who displayed more hostile behaviors and who also had a mood disorder history had significantly lower post-meal REE, higher insulin, and higher peak triglyceride responses than other participants, with nonsignificant effects for fat and carbohydrate oxidation. Participants with a mood disorder history had a steeper rise in postprandial IL-6 and glucose than those without a past history. Higher levels of hostile behaviors were associated with higher post-meal TNF-α. The two meals did not differ on any outcome assessed. CONCLUSIONS People spend about 18 of every 24h in a postprandial state, and dining with ones partner is a common daily event. Among subjects with a mood disorder history, the cumulative 6.75-h difference between high and low hostile behaviors translates into 128kcal, a difference that could add 7.6pounds/year. Our findings illustrate novel pathways through which chronic marital stress and a mood disorder history synergistically heighten the risk for obesity, metabolic syndrome, and cardiovascular disease.