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Review
. 2018 Mar 20;28(9):837-851.
doi: 10.1089/ars.2017.7312. Epub 2017 Oct 23.

Loneliness, Social Isolation, and Cardiovascular Health

Ning Xia  1 , Huige Li  1   2   3
Affiliations
Review

Loneliness, Social Isolation, and Cardiovascular Health

Ning Xia et al. Antioxid Redox Signal. .

Abstract

Significance: Social and demographic changes have led to an increased prevalence of loneliness and social isolation in modern society. Recent Advances: Population-based studies have demonstrated that both objective social isolation and the perception of social isolation (loneliness) are correlated with a higher risk of mortality and that both are clearly risk factors for cardiovascular disease (CVD). Lonely individuals have increased peripheral vascular resistance and elevated blood pressure. Socially isolated animals develop more atherosclerosis than those housed in groups.

Critical issues: Molecular mechanisms responsible for the increased cardiovascular risk are poorly understood. In recent reports, loneliness and social stress were associated with activation of the hypothalamic-pituitary-adrenocortical axis and the sympathetic nervous system. Repeated and chronic social stress leads to glucocorticoid resistance, enhanced myelopoiesis, upregulated proinflammatory gene expression, and oxidative stress. However, the causal role of these mechanisms in the development of loneliness-associated CVD remains unclear.

Future directions: Elucidation of the molecular mechanisms of how CVD is induced by loneliness and social isolation requires additional studies. Understanding of the pathomechanisms is essential for the development of therapeutic strategies to prevent the detrimental effects of social stress on health. Antioxid. Redox Signal. 28, 837-851.

Keywords: cardiovascular disease; loneliness; oxidative stress; social isolation.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Prevalence of loneliness. The reported prevalence of loneliness in Europe (148) and China (149), respectively. The overall prevalence of loneliness among adults older than 65 in the United States (135) is shown for comparison. There are significant differences in the prevalence among European countries with a higher prevalence in group EU1 (Bulgaria, Hungary, Latvia, Poland, Romania, Russia, Slovakia, and Ukraine) than group EU2 (Austria, Cyprus, Estonia, France, Portugal, Slovenia, and Spain), and group EU3 (Belgium, Denmark, Finland, Germany, Ireland, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom) (148). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 2.</b>
FIG. 2.
Impact of social support on mortality. The odds of mortality due to social isolation and loneliness are similar to light smoking (15 cigarettes/day) and alcohol consumption (6 drinks/day), and exceed the risks conferred by physical inactivity and obesity. Note: Effect size of zero indicates no effect. Complex measures of social integration are single measures that assess multiple components of social integration such as marital status, network size, and participation (59). Reproduced and modified from Holt-Lunstad et al. (59), which is an open-access article distributed under the terms of the Creative Commons Attribution License. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 3.</b>
FIG. 3.
Proposed mechanisms of loneliness-associated cardiovascular disease (CVD). Loneliness and social isolation lead to activation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), and to behavioral alteration, including physical inactivity, smoking, and sleep disruption. SNS activation enhances monocytopoiesis in the bone marrow resulting in expansion of immature proinflammatory monocytes. In addition, SNS also stimulates monocyte egress from the spleen. Chronic social stress leads to glucocorticoid (GC) resistance, upregulation of proinflammatory gene expression, as well as enhanced cytokine production by immune cells. Cytokines, in turn, can potentiate GC resistance. The resulting enhanced inflammation and oxidative stress may be involved in atherosclerosis development and blood pressure elevation. Both proinflammatory monocytes and cytokines can traffic to the brain and amplify loneliness by inducing “sickness behaviors.” Epinephrine (Epi) and norepinephrine (NE) induce vasoconstriction, an effect that is enhanced by GC. Moreover, GC reduces endothelial nitric oxide synthase (eNOS) gene expression and serine 1177 phosphorylation in endothelial cells resulting in decreased nitric oxide (NO) production and impaired vasodilation. However, the causal role of these mechanisms in the development of loneliness-associated CVDs has not been demonstrated so far, although their involvement is likely. ACTH denotes adrenocorticotropic hormone. The images of brain, bone, spleen, and monocytes used in this figure are from Servier Medical Art licensed under the Creative Commons Attribution 3.0 Unported License (111). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 4.</b>
FIG. 4.
Mechanisms of glucocorticoid resistance. Reduction in glucocorticoid sensitivity can be ascribed to alteration of factors that regulate glucocorticoid bioavailability and activity such as [1] increased corticosteroid-binding globulin (G); [2] increased expression of the multidrug resistance transporter (MDR pump); [3] increased expression of cortisol-inactivating enzyme 11β-HSD-2; [4] reduced glucocorticoid binding to the glucocorticoid receptor (GRα); [5] inflammasome-mediated degradation of GRα; [6] reduced GR nuclear translocation due to phosphorylation by p38 and JNK classes of mitogen-activated protein kinase (MAPK); [7] increased GR interaction with inflammatory-related transcription factors, such as NF-κB or AP-1; and [8] increased expression of the inhibitory glucocorticoid receptor GRβ. HSP, heat shock protein. X indicates inhibition of gene expression. Partly adapted from Refs. , , , . To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
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