Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biologic mechanisms contributing to this health ...disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves upregulation of proinflammatory genes and downregulation of genes involved in type I IFN response and antibody synthesis.
We compared pretransplant leukocyte CTRA gene expression between a group of 78 high versus low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes.
Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA upregulation compared with matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity, including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival.
Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT.
Inflammation plays a significant role in the pathophysiology of depression. However, not all individuals exposed to inflammatory challenge develop depression, and identifying those at risk is ...necessary to develop targeted monitoring, prevention, and treatment strategies. Within a randomized double-blind placebo-controlled study (n = 115), we examined whether leukocyte transcriptome profiles predicted inflammation-induced depressed mood in volunteers who received low-dose intravenous endotoxin (n = 58; aged 18-50). At baseline, transcription factor (TF) activities were assessed using genome-wide transcriptional profiling of peripheral blood mononuclear cells and promoter-based bioinformatic analyses. Then, participants were administered endotoxin. Self-reported depressed mood was assessed using the Profile of Mood States. Based on extant studies linking transcriptional profiles to depressive disorder, we examined whether post-endotoxin depressed mood is predicted by baseline activity of TFs related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR). Twenty-one participants (36%) experienced an increase in depressed mood from baseline to 2 h post endotoxin, when depressive response peaks. Bioinformatics analyses controlling for age, sex, ethnicity, body mass index, and physical sickness response revealed that post-endotoxin depressed mood was predicted by increased baseline activity of TFs related to inflammation (NF-kB) and beta-adrenergic signaling (CREB) and by decreased activity of GR-related TFs (P's < 0.001). Inflammation-induced depressed mood is predicted by peripheral transcriptome profiles related to immune activation, sympathetic activation, and glucocorticoid insensitivity. With further replication, these stress-related molecular profiles could be used for a novel genomic approach for identifying individuals at high-risk for the inflammatory subtype of depression.
Exposure to stress is a risk factor for poor health and accelerated aging. Immune aging, including declines in naïve and increases in terminally differentiated T cells, plays a role in immune health ...and tissue specific aging, and may contribute to elevated risk for poor health among those who experience high psychosocial stress. Past data have been limited in estimating the contribution of life stress to the development of accelerated immune aging and investigating mediators such as lifestyle and cytomegalovirus (CMV) infection. This study utilizes a national sample of 5,744 US adults over age 50 to assess the relationship of social stress (viz., everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress) with flow cytometric estimates of immune aging, including naïve and terminally differentiated T cell percentages and the ratio of CD4
to CD8
cells. Experiencing life trauma and chronic stress was related to a lower percentage of CD4
naïve cells. Discrimination and chronic stress were each associated with a greater percentage of terminally differentiated CD4
cells. Stressful life events, high lifetime discrimination, and life trauma were related to a lower percentage of CD8
naïve cells. Stressful life events, high lifetime discrimination, and chronic stress were associated with a higher percentage of terminally differentiated CD8
cells. High lifetime discrimination and chronic stress were related to a lower CD4
:CD8
ratio. Lifestyle factors and CMV seropositivity partially reduced these effects. Results identify psychosocial stress as a contributor to accelerating immune aging by decreasing naïve and increasing terminally differentiated T cells.
This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors.
Leukocyte subsets, plasma inflammatory markers, and ex ...vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited > or = 2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk.
Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-alpha following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P < 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69+ T lymphocytes, as highly diagnostic of fatigue (P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83).
These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.
•Greater chronic stress exposure was associated with elevated p16INK4a gene expression.•Greater perceived stress associated with increased p16INK4a gene expression.•Greater accumulated daily stress ...appraisals associated with elevated p16INK4a mRNA.•Psychosocial stress measures were not associated with leukocyte telomere length.
Previous research has linked exposure to adverse social conditions with DNA damage and accelerated telomere shortening, raising the possibility that chronic stress may impact biological aging pathways, ultimately increasing risk for age-related diseases. Less clear, however, is whether these stress-related effects extend to additional hallmarks of biological aging, including cellular senescence, a stable state of cell cycle arrest. The present study aimed to investigate associations between psychosocial stress and two markers of cellular aging—leukocyte telomere length (LTL) and cellular senescence signal p16INK4a. Seventy-three adults (Mage = 43.0, SD = 7.2; 55% female) with children between 8–13 years of age completed interview-based and questionnaire measures of their exposures to and experiences of stress, as well as daily reports of stress appraisals over an 8-week diary period. Blood samples were used to assess markers of cellular aging: LTL and gene expression of senescent cell signal p16INK4a (CDKN2A). Random effects models covarying for age, sex, ethnicity/race, and BMI revealed that participants with greater chronic stress exposure over the previous 6 months (b = 0.011, p = .04), perceived stress (b = 0.020, p < .001), and accumulated daily stress appraisals over the 8-week period (b = 0.013, p = .02) showed increased p16INK4a. No significant associations with LTL were found. These findings extend previous work on the impact of stress on biological aging by linking chronic stress exposure and daily stressful experiences to an accumulation of senescent cells. Findings also support the hypothesis that chronic stress is associated with accelerated aging by inducing cellular senescence, a common correlate of age-related diseases.
Having associations with a range of adverse physical health outcomes including mortality, loneliness is increasingly recognized as a pressing public health concern, but the mechanisms studied to date ...do not yet explain all loneliness-related health risk. We sought to evaluate whether epigenetic influences on DNA methylation could help explain the relationship between loneliness and health. To do so, we first estimated associations between loneliness and epigenetic age acceleration (EAA) in a subsample of participants in the study of midlife in the United States (n = 1,310), before testing whether EAA mediated and/or moderated the association between loneliness and the onset of chronic health conditions in older adulthood (n = 445 completing longitudinal follow-ups). Greater loneliness was weakly associated with greater EAA in the Horvath, DunedinPACE, and GrimAge measures after accounting for demographic (0.08 ≤ β ≤ 0.11) and behavioral (0.06 ≤ β ≤ 0.08) covariates. Loneliness also predicted increases in chronic condition counts and these effects were more pronounced for individuals with higher DunedinPACE EAA values (interaction term β = 0.09, p = .009), suggesting possible synergistic impacts. EAA measures appear to be promising in helping to understand individual variations in the health impacts of loneliness, but the specific mechanisms involved require further research.
Public Significance Statement
Lonely individuals face poorer health outcomes than nonlonely individuals. These data support the notion that loneliness is associated with accelerated epigenetic aging which may amplify the impact of loneliness on physical health in older adulthood.
•Studies of marital quality and health have targeted conflict as the key mechanism.•As conflict declines over time, partner distress may grow more central.•Recent work has linked partner distress to ...proinflammatory reactivity.•This study was the first to compare reactivity to partner distress and conflict.•Proinflammatory gene expression rose further with partner distress than conflict.
Marital quality shares ties to inflammatory conditions like cardiovascular disease and diabetes. For decades, research has focused on marital conflict as a primary mechanism given its potential to trigger inflammatory responses. However, longitudinal evidence suggests that marital conflict declines over time, and little attention has been paid to the inflammatory aftermath of other types of marital exchanges. A spouse’s emotional distress is an important but overlooked marital context, as partners are exposed to each other’s upsetting emotions throughout adulthood. To directly compare reactivity in proinflammatory gene expression to these two marital stressors and to examine differences by age and marital satisfaction, 203 community adults ages 25–90 (N = 102 couples) provided blood samples and rated their negative mood before and after they 1) watched their partner relive an upsetting personal memory and, in a separate visit 1–2 weeks later, 2) discussed a conflictual topic in their relationship. Controlling for age, sex, race/ethnicity, BMI, alcohol use, smoking, and comorbidities, increases in proinflammatory gene expression were significantly larger after the partner’s upsetting disclosure than after marital conflict (B = 0.073, SE = 0.031, p = .018). This pattern paralleled emotional reactivity to the tasks, wherein negative mood rose more in response to the partner’s disclosure than to marital conflict (B = 4.305, SE = 1.468, p = .004). In sum, proinflammatory and mood reactivity to spousal distress exceeded reactivity to marital conflict, a well-established marital stressor. Findings reveal spousal distress as a novel mechanism that may link marriage to inflammation-related diseases, and even pose risks for both happy and unhappy couples across adulthood.
•Sexual and gender minorities (SGM) are a growing proportion of the population.•Marked health disparities are observed among SGM individuals.•Biobehavioral pathways underlying SGM health disparities ...warrant attention.•A Biopsychosocial Minority Stress Framework for SGM health is proposed.•Existing research in this area and opportunities for knowledge acquisition are reviewed.
The number of US adults identifying as lesbian, gay, bisexual, transgender, or a different sexual identity has doubled since 2008, and about 40 % of the sexual and gender minority population identify as people of color. Minority stress theory posits that sexual and gender minorities are at particular risk for stress via stigma and discrimination at the structural, interpersonal, and individual levels. This stress, in turn, elevates the risk of adverse health outcomes across several domains. However, there remains a conspicuously limited amount of research on the psychoneuroimmunology of stress among sexual and gender minorities. We developed the Biopsychosocial Minority Stress Framework which posits that sexual minority status leads to unique experiences of minority stress which results in adverse health behavioral factors, elevated psychological distress and sleep disturbance, and immune dysregulation. Moderators in the model include both individual differences and intersectional identities. There is a crucial need to understand the biological-psychological axis of stress among the increasingly visible sexual and gender minority population to increase their health, longevity, and quality of life.
•Individuals exposed to neighborhood violence have a higher risk of lifecourse health problems.•Signs of this risk are evident in childhood, but the underlying mechanisms are unknown.•This paper ...suggests a mechanistic role for monocyte-driven inflammatory activity.•It also suggests a role for glucocorticoid and adrenergic signaling in this inflammatory activity.
Individuals exposed to persistent neighborhood violence are at increased risk for developing mental and physical health problems across the lifespan. The biological mechanisms underlying this phenomenon are not well understood. Thus, we examined the relationship between children’s exposure to neighborhood violence and inflammatory activity, a process involved in the pathogenesis of multiple health problems. 236 children from the Chicago area participated in a two-year longitudinal study (mean age at baseline, 13.9 years; 67% female; 39% White, 34% Black, 33% Hispanic). Neighborhood violence was measured as the homicide frequency in a child’s Census block group in the five years before study entry. Fasting blood was drawn at study entry and two years later (in eighth and tenth grade). The blood was used to quantify protein biomarkers of systemic inflammatory activity and perform genome-wide expression profiling of isolated monocytes. Neighborhood violence was associated with higher systemic inflammatory activity at both assessments. It also was associated with a monocyte transcriptional profile indicative of increased signaling along the nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1) control pathways, which are key orchestrators of pro-inflammatory effector functions. Neighborhood violence also was associated with transcriptional indications of higher beta-adrenergic and lower glucocorticoid signaling, which could function as neuroendocrine conduits linking threatening experiences with inflammatory activity. Neighborhood violence was not associated with two-year changes in protein biomarkers, although it did presage a transcriptional profile indicative of increasing AP-1 and declining glucocorticoid signaling over follow-up. Collectively, these observations highlight cellular and molecular pathways that could underlie health risks associated with neighborhood violence.
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