After over 70 years of research on the association between stressful life events and health, it is generally accepted that we have a good understanding of the role of stressors in disease risk. In this review, we highlight that knowledge but also emphasize misunderstandings and weaknesses in this literature with the hope of triggering further theoretical and empirical development. We organize this review in a somewhat provocative manner, with each section focusing on an important issue in the literature where we feel that there has been some misunderstanding of the evidence and its implications. Issues that we address include the definition of a stressful event, characteristics of diseases that are impacted by events, differences in the effects of chronic and acute events, the cumulative effects of events, differences in events across the life course, differences in events for men and women, resilience to events, and methodological challenges in the literature. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Summary Background Indices of cortisol activity, including the cortisol awakening response (CAR), diurnal slope, and cortisol output across the day (total daily output), are often studied as mechanistic indicators that could link stress with health. Yet there is a paucity of data speaking to their temporal features, particularly whether they behave in a more state- or trait-like manner across time. Methods To address this issue, data from 3 studies were used to assess CAR, diurnal slope and total daily output stability over different age groups and time spans: 130 healthy children and adolescents collected salivary cortisol samples 5 times/day (1, 4, 9 and 11 h after wake) over 2 days at 5 visits spaced 6 months apart (Study 1); 147 adolescent girls collected saliva 6 times/day (wake, 1, 4, 9 and 14 h after wake) for 2 days at 3 visits, each a year apart (Study 2); and 47 healthy, primarily middle age adults collected saliva 6 times/day (wake, 1, 4, 9 and 14 h after wake) for 3 days at 4 visits spaced 2–3 months apart (Study 3). Stability was estimated by multilevel model-derived intraclass correlation coefficients (ICCs). Results Across studies, approximately 50% of the variance in cortisol indices was attributable to day-to-day fluctuations, suggesting state-like properties. Of the indices, total daily output emerged as the most stable over time, followed by diurnal slope and CAR, but stability estimates were generally quite modest regardless of index and sample. Over time spans of >1 year, ICCs were ≤.13. Conclusions Most of the variance in CAR, diurnal slope and total daily output reflects day-to-day fluctuation; there was little evidence for more stable trait-like influences. These findings suggest that future research should focus on short-term fluctuations in stress, cortisol and health, as opposed to lengthy disease processes.

Chronic stress is associated with morbidity and mortality from numerous conditions, many of whose pathogenesis involves persistent inflammation. Here, we examine how chronic stress influences signaling pathways that regulate inflammation in monocytes. The sample consisted of 33 adults caring for a family member with glioblastoma and 47 controls whose lives were free of major stressors. The subjects were assessed four times over eight months. Relative to controls, caregivers’ monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys cortisol’s anti-inflammatory signals to monocytes. Transcript origin analyses revealed that CD14+/CD16− cells, a population of immature monocytes, were the predominate source of inflammatory gene expression among caregivers. We considered hormonal, molecular, and functional explanations for caregivers’ decreased glucocorticoid-mediated transcription. Across twelve days, the groups displayed similar diurnal cortisol profiles, suggesting that differential adrenocortical activity was not involved. Moreover, the groups’ monocytes expressed similar amounts of glucocorticoid receptor protein, suggesting that differential receptor availability was not involved. In ex vivo studies, subjects’ monocytes were stimulated with lipopolysaccharide, and caregivers showed greater production of the inflammatory cytokine interleukin-6 relative to controls. However, no group differences in functional glucocorticoid sensitivity were apparent; hydrocortisone was equally effective at inhibiting cytokine production in caregivers and controls. These findings may help shed light on the mechanisms through which caregiving increases vulnerability to inflammation-related diseases.

This research has important implications because it considers modifiable risk factors for dementia that, if unchecked, may compromise the lives of CGs and their ability to function. It is hoped that an understanding of such stress-mediator-cognitive processes will help clinicians, researchers, policy-makers, and stakeholders mitigate what may be characterized as an "ironic tragedy"-dementia in both members of the caregiving dyad-if left unchecked.

Social difficulties during adolescence influence life-span health. To elucidate underlying mechanisms, we examined whether a noxious social event, targeted rejection (TR), influences the signaling pathways that regulate inflammation, which is implicated in a number of health problems. For this study, 147 adolescent women at risk for developing a first episode of major depression were interviewed every 6 months for 2.5 years to assess recent TR exposure, and blood was drawn to quantify leukocyte messenger RNA (mRNA) for nuclear factor-κB (NF-κB) and inhibitor of κB (I-κB) and the inflammatory biomarkers C-reactive protein and interleukin-6. Participants had more NF-κB and I-κB mRNA at visits when TR had occurred. These shifts in inflammatory signaling were most pronounced for adolescents high in perceived social status. These findings demonstrate that social rejection upregulates inflammatory gene expression in youth at risk for depression, particularly for those high in status. If sustained, this heightened inflammatory signaling could have implications for life-span health.