One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition

Abstract

The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated: the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system. This review summarizes studies examining the relationship between isolation and mortality and the pathophysiological mechanisms underlying SI. Cardiovascular, cerebrovascular, and neurological diseases including atherosclerosis, myocardial infarction, ischemic stroke and Alzheimer's disease are given special emphasis in the context of SI. Sex differences are highlighted and studies are separated into clinical and basic science for clarity.

Fig. 1

Lower levels of daily social support correlated with increased neural activity in both the dorsal anterior cingulate cortex (dACC) and Brodmann’s area (BA) 8 of the dorsal superior frontal gyrus as well as increased cortisol reactivity to acute social stress tasks. Neurons of the dACC fire in animals experiencing distress associated social rejection, whereas BA 8 activity has been associated with maternal separation. By contrast, participants who interacted with more supportive individuals displayed attenuated neural activity and cortisol response to the acute stress task. Yellow indicate regions that correlate positively with social distress; green indicate regions that correlate negatively with social support; red indicates regions that correlate positively with cortisol responses. Reprinted from NeuroImage, Vol 35/Issue 4, Naomi I. Eisenberger, Shelley E. Taylor, Shelly L. Gable, Clayton J. Hilmert, Matthew D. Lieberman, Neural pathways link social support to attenuated neuroendocrine stress responses, pp. 1601–1612, Copyright (2007), with permission from Elsevier.

Fig. 2

Effect of chronic loneliness on neuroendocrine and peripheral leukocyte response. Loneliness stimulates the HPA axis by increasing ACTH and CRH secretion from the hypothalamus and pituitary, respectively. Consequently, the physiological concentrations of serum GC (cortisol in humans; corticosterone in rodents) will become chronically elevated. This contributes to excessive stimulation of the intracellular GR, particularly in peripheral leukocytes, leading to receptor desensitization and a reduction in GR expression. Leukocyte GR signaling normally regulates trafficking patterns as well as inflammatory gene expression. Alterations in these fundamental peripheral immune cell functions contribute to susceptibility to inflammatory diseases. This figure was generated using Servier Medical Arts

Fig. 3

SNS-mediated leukocyte dysregulation with stress. Chronic stressors (such as repeated social disruption) exacerbate the activity of the sympathetic branch of the autonomic nervous system. These motor projections innervate bone marrow throughout the body, releasing norepinephrine (NE) into the synaptic space. NE binds to G-protein coupled β-adrenergic receptors present on the hematopoietic stem cell membrane to drive it toward a monocytic/granulocytic progenitor cell (via cAMP-PKA signaling). Pharmacological antagonists (propranolol) rescue the non-stressed phenotype, reducing the percentage of circulating immature pro-inflammatory monocytes to control levels. This figure was generated using Servier Medical Arts

Fig. 4

Pre-stroke SI exacerbates histological damage in rodents. Comparison of tetrazolium chloride (TTC) staining of 2 mm coronal sections taken from young male and female mice assigned to their permanent housing conditions 7 days prior to surgery and analyzed at 72 hours post-reperfusion. With kind permission from Springer Science and Business Media and Acta Neuropathologica, Vol 124, 2012, pp. 425–438, NFκB contributes to the detrimental effects of social isolation after experimental stroke, Venugopal R. Venna, Gillian Weston, Sharon E. Benashski, Sami Tarabishy, Fudong Liu, Jun Li, Lisa H. Conti, and Louise D. McCullough, Figure 1a and 1c, Copyright (2012).

Fig. 5

Ipsilateral striatal brain sections in mouse 49 days after surgery showing increased BDNF immunohistochemical staining in PH animals. Green represents BDNF positive cells and blue represents cell nuclei. Animals were assigned to their permanent housing condition immediately following experimental stroke or sham (control) surgery. SH/SH displays a sham operated mouse brain that was PH with another healthy (sham) partner, ST/SH indicates a stroked mouse that was PH with a healthy (sham) partner, ST/ST shows a stroked mouse brain that was PH with an unhealthy (stroked) partner, and ST/ISO describes a stroked and isolated mouse. Post-stroke isolation was associated with significantly decreased BDNF signaling, suggesting that isolation decreased neuroplasticity and neurogenesis after ischemic injury. Reprinted from Behavioural Brain Research, Vol 260, Lena M. O’Keefe, Sarah J. Doran, Laetitia MwilambweTshilobo, Lisa H. Conti, Venugopal R. Venna, Louise D. McCullough, Social isolation after stroke leads to depressive-like behavior and decreased BDNF levels in mice, pp. 162–170, Copyright (2014), with permission from Elsevier.

Fig. 6

Social isolation and other stressors may accelerate AD pathology by increasing the activity of both the SNS and the HPA axis. Isolation-induced HPA axis dysfunction increases the likelihood of developing AD pathology. Accumulation of plaques and/or neurofibrillary tangles further dysregulates HPA axis functioning and increases glucocorticoid secretion, which in turn accelerates pathology. This results in a cycle of increasing HPA axis disruption and pathology buildup. Stimulation of the SNS by social isolation increases β-adrenergic receptor activation, resulting in the upregulation of tau pathology, amyloid beta accumulation, and pro-inflammatory myelopoiesis. This figure was generated using Servier Medical Arts