Perspective

Molecular Psychiatry (2017) 22, 640–646; doi:10.1038/mp.2017.35 published online 14 March 2017

Epigenetic programming by stress and glucocorticoids along the human lifespan

A S Zannas1,2 and G P Chrousos3

  1. 1Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
  2. 2Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
  3. 3First Department of Pediatrics and Division of Endocrinology, Metabolism and Diabetes, National and Kapodistrian University of Athens Medical School, Athens, Greece

Correspondence: Dr AS Zannas, Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany. E-mail: aszannas@gmail.com

Received 10 December 2016; Revised 8 January 2017; Accepted 17 January 2017
Advance online publication 14 March 2017

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Abstract

Psychosocial stress triggers a set of behavioral, neural, hormonal, and molecular responses that can be a driving force for survival when adaptive and time-limited, but may also contribute to a host of disease states if dysregulated or chronic. The beneficial or detrimental effects of stress are largely mediated by the hypothalamic-pituitary axis, a highly conserved neurohormonal cascade that culminates in systemic secretion of glucocorticoids. Glucocorticoids activate the glucocorticoid receptor, a ubiquitous nuclear receptor that not only causes widespread changes in transcriptional programs, but also induces lasting epigenetic modifications in many target tissues. While the epigenome remains sensitive to stressors throughout life, we propose two key principles that may govern the epigenetics of stress and glucocorticoids along the lifespan: first, the presence of distinct life periods, during which the epigenome shows heightened plasticity to stress exposure, such as in early development and at advanced age; and, second, the potential of stress-induced epigenetic changes to accumulate throughout life both in select chromatin regions and at the genome-wide level. These principles have important clinical and translational implications, and they show striking parallels with the existence of sensitive developmental periods and the cumulative impact of stressful experiences on the development of stress-related phenotypes. We hope that this conceptual mechanistic framework will stimulate fruitful research that aims at unraveling the molecular pathways through which our life stories sculpt genomic function to contribute to complex behavioral and somatic phenotypes.