BackgroundChronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear.ResultsWe examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias.ConclusionsCumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0828-5) contains supplementary material, which is available to authorized users.

Theoretical models of persecutory delusions have emphasized the impact of reasoning biases and negative emotion at the early stages of symptom formation. However, the causal mechanisms remain unclear. This study tests the hypothesis that state anxiety will increase paranoid ideation and that this increase will be moderated by the level of individual vulnerability and mediated by the tendency to jump to conclusions. Healthy participants (n = 90) with varying levels of vulnerability (psychosis symptoms assessed by the Community Assessment of Psychic Experiences) were randomly assigned to either an anxiety or a nonanxiety condition. Anxiety was induced by pictures from the International Affective Picture System and by in sensu exposure to individual anxiety-provoking situations. During each condition, symptoms of paranoia were assessed by a state-adapted version of the Paranoia Checklist. Jumping to conclusions (JTC) was assessed using a modified version of the beads task. Overall, participants in the anxiety condition reported significantly more paranoid thoughts and showed more JTC than participants in the neutral condition. Participants with higher baseline vulnerability were more likely to show an increase in paranoia as reaction to the anxiety manipulation. Moreover, the association of anxiety and paranoia was mediated by the increased tendency to jump to conclusions in the beads task. The results are in line with a threat anticipation conceptualization of paranoia and provide evidence for an interaction of anxiety and reasoning biases in the development of paranoid beliefs. A combination of meta-cognitive training directed at reasoning biases and promoting emotion regulation skills might prove beneficial in preventing symptoms.

Recently, we used gene expression profiling of lung adenocarcinoma and paired normal tissue from smokers and nonsmokers to identify genes and molecular pathways associated with cigarette smoking and lung carcinogenesis. The gene encoding Glypican 3, a glycosylphosphatidylinositol-linked heparan sulfate proteoglycan, was decreased in lung adenocarcinoma. Within nonmalignant lung, GPC3 expression was decreased in smokers compared with nonsmokers; indicating that expression is associated with cigarette smoking. Microarray results were confirmed using an independent cohort of tumors and nonmalignant lung tissues. Immunohistochemical studies localized Glypican 3 protein expression to the apical surface of lung bronchiolar epithelial cells, potential cells of origin for adenocarcinoma. Northern blot analysis demonstrated expression was absent in all tested non-small cell lung carcinoma lines. Pharmacologic treatment of lung cell lines indicated that GPC3 expression was epigenetically silenced by promoter hypermethylation. Human lung carcinoma tumor cells ectopically expressing GPC3 demonstrated increased apoptosis response when exposed to etoposide and growth inhibition when implanted in nude mice. These findings suggest that GPC3 is a candidate lung tumor suppressor gene whose expression may be regulated by exposure to cigarette smoke and functions to modulate cellular response to exogenous damage.