Stress is an underlying cause of multiple diseases and according to the American Psychological Association (APA), 9 in 10 adults believe that stress contributes to the development of major illness. In addition, stress is a key driver of chronic disease, that according to the Centers for Disease Control and Prevention (CDC), contributed to 86% of all healthcare spending in the USA in 2012. Thus, stress has a monumental impact on human health and the economy, and requires a multidisciplinary solution involving a paradigm shift away from the current status quo.

From an evolutionary perspective, the main purpose of the acute stress response orchestrated by the central nervous system (CNS) was to counter imminent dangers. Accelerated heart rate, elevated blood pressure, suppression of both digestive and immune functions are all consequences of the natural “fight-or-flight” self-preservation mechanisms. Unfortunately, degraded health issues emerge when this heightened state of stress and inflammation remain engaged for extended periods. Today’s modern lifestyles often create these unhealthy chronic stress conditions, subverting this historic survival mechanism and causing unintended, detrimental health consequences. Indeed, chronic stress is an underlying cause of multiple diseases. Corticotropin releasing factor (CRF) is the peptide hormone that initiates and directs the stress response, and is a crucial mediator of the autonomic, behavioral, endocrine, visceral, immune and reproductive responses to stress. The classical stress response starts with the release of CRF from the hypothalamus in the brain. This in turn stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH), which then stimulates cortisol production from the adrenal glands. In humans, the CRF peptide family of stress hormones includes CRF itself and the urocortins 1, 2 and 3 (“the keys”). Peptides are important signaling molecules built from amino acids. These “keys” engage two receptors, CRF1 and CRF2, representing “the locks” and transmit the hormonal signals to cells that determines the body’s response to stress. In addition, there is a binding protein (CRF-BP) that can modulate the activity of the CRF family of hormones by regulating the accessibility of the “keys” to the “locks”. Altogether CRF, urocortins 1, 2 and 3, CRF receptors 1 and 2 and CRF binding protein constitute the main factors mediating the body’s response to acute and chronic stress.