#	Pagina
attuale pagina	/open-h2020/projects/194839/results.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - STRESSAGED (Molecular Mechanisms Linking Psychological Stress and Ageing-Related Disease)

Teaser

Summary

Aging-related diseases are currently the leading causes of morbidity and mortality, having enormous impact on individuals and societies. A ubiquitous and potentially preventable factor predisposing to their development is psychological stress, but the molecular mechanisms underlying this relation are largely unknown. This project has addressed this knowledge gap by examining epigenetic modifications and, in particular, DNA methylation changes as molecular signatures that are induced by lifetime stressors and act in concert with advancing age to shape genomic function and disease risk.

Work performed

The overarching aim of this project has been to elucidate the molecular mechanisms through which psychological stress can contribute to aging-related diseases. To achieve this aim, the project has pursued three complementary objectives: 1) to identify genomic sites where stressors alter the effects of age on DNA methylation; 2) to identify age- and stressor-regulated DNA methylation sites that have functional consequences and examine their relation to negative health outcomes; and 3) to mechanistically dissect the relevance of these epigenetic changes using relevant cellular models.

One of the primary findings of the project is that cumulative lifetime stress can accelerate epigenetic aging, a marker of biological aging, which is measured with DNA methylation-based predictors of chronological age, in peripheral blood of highly traumatized African American individuals. Notably, the effect of stress on epigenetic aging was not seen with only childhood or recent stress and the effects were most pronounced in older individuals, so it appears that stress exposure accumulates to eventually affect the epigenome as one grows older. Furthermore, the effect of stress on epigenetic aging was more evident for personal stressors â€“ stressors that affect the individual directly, for example divorce, unemployment, and financial stressors, whereas it was much weaker for network stressors â€“ stressors affecting the individualâ€™s social network, such as knowing someone who was robbed. Moreover, this work found that many of the age-related DNA methylation sites used to calculate epigenetic aging are located at glucocorticoid binding sites and undergo changes in methylation when individuals are exposed to a synthetic glucocorticoid, called dexamethasone. These findings are informative because glucocorticoids, such as cortisol, increase in our circulation when we are exposed to stress. Thus high levels or dysregulated cortisol secretion in individuals exposed to more stress could be driving these effects on epigenetic aging. Lastly, we found that genes near these age-related sites also undergo changes in expression following dexamethasone and many of these genes are implicated in aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Thus the effects of stress on epigenetic aging may be one way through which stress contributes to these and other aging-related diseases. These findings were published in the journal Genome Biology (Zannas et al. 2015).

In addition, work in progress shows that specific genetic loci may be particularly influenced by stress as one grows older, and these effects may contribute to aging-related processes. This ongoing work combines data generated from human cohorts with experiments in cellular models.

Final results

The findings of the project have contributed to the identification of epigenetic regulation as a novel mechanism linking psychosocial stress with aging-related disease. Overall, these findings enhance our understanding and may eventually contribute to the development of biomarkers, targeted prevention strategies, and novel treatments for aging-related diseases. For a detailed review on how this work complements other studies and promotes state of the art see: Gassen et al., Neuroscience and Biobehavioral Reviews, 2016.