Exaggerated neurobiological sensitivity to threat as a mechanism linking anxiety with increased risk for diseases of aging

Abstract

Anxiety disorders increase risk for the early development of several diseases of aging. Elevated inflammation, a common risk factor across diseases of aging, may play a key role in the relationship between anxiety and physical disease. However, the neurobiological mechanisms linking anxiety with elevated inflammation remain unclear. In this review, we present a neurobiological model of the mechanisms by which anxiety promotes inflammation. Specifically we propose that exaggerated neurobiological sensitivity to threat in anxious individuals may lead to sustained threat perception, which is accompanied by prolonged activation of threat-related neural circuitry and threat-responsive biological systems including the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system (ANS), and inflammatory response. Over time, this pattern of responding can promote chronic inflammation through structural and functional brain changes, altered sensitivity of immune cell receptors, dysregulation of the HPA axis and ANS, and accelerated cellular aging. Chronic inflammation, in turn, increases risk for diseases of aging. Exaggerated neurobiological sensitivity to threat may thus be a treatment target for reducing disease risk in anxious individuals.

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

“…Over time and with continuous exposure to stressors, both HPA and immune function become dysregulated. Although extensive work has been done to characterize the role of endocrine dysfunction in the pathophysiology and maintenance of PTSD (Daskalakis et al, 2013;Hauger et al, 2012;O'Donovan et al, 2013;Yehuda and LeDoux, 2007), our understanding of the role of inflammation in the etiology and maintenance of fear-and anxiety-based disorders remains limited. Thus, in the current review, we will summarize significant findings that indicate that PTSD, and other fear-and anxiety-based disorders, are characterized by increased inflammatory processes associated with greater symptom severity.…”

Associations of Trauma and Posttraumatic Stress Disorder With Inflammation and Endothelial Function: On Timing, Specificity, and Mechanisms

“…However, few studies have examined if interventions targeting health behaviors reduce inflammation and improve endothelial function in trauma-exposed individuals. Another potential mechanism of trauma’s effects on inflammation and endothelial function is exaggerated threat sensitivity, which can drive activation of biological stress systems that promote inflammation, underlie symptoms of PTSD, and increase risk for poor health behaviors (8). One previous study indicated that individuals with PTSD and higher levels of threat sensitivity had the highest levels of inflammation (9).…”

Signaling Pathways Relevant to Cognition-Enhancing Drug Targets

“…Stress exposure over a life span may accelerate cellular aging and promote cognitive dysfunction (Lupien et al 2009). Furthermore, exacerbated neurobiological sensitivity to threat may even increase the risk of developing age-related diseases (for a review, see O'Donovan et al 2013). The first association between the dynorphinergic system and anxious behaviors was observed with naloxone, an opioid partial agonist, reversing the effect of benzodiazepines (Billingsley and Kubena 1978).…”