ANTIOXIDANTS & REDOX SIGNALING

Volume 28, Number 9, 2018

Mary Ann Liebert, Inc.
DOI: 10.1089/ars.2017.7312

FORUM REVIEW ARTICLE

Loneliness, Social Isolation, and Cardiovascular Health

Ning Xia1 and Huige Li1–3

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 per-
ception 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. How-
ever, 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: loneliness, social isolation, cardiovascular disease, oxidative stress

Introduction The perception of social isolation is not restricted to humans;

behaviors related to social isolation have been also documented

L oneliness, defined as the discrepancy between a

person’s desired and actual social relationships, is an
emotional response to social isolation, while social isolation
in animals (12, 14). Perceived social isolation (PSI) has dam-
aging effects on the physical health of humans and animals
manifested by activation of the hypothalamic–pituitary–
is an objective measure of the lack of social connections or adrenal (HPA) axis and increased depressive behavior (14).
interactions. Consequently, loneliness is thought to be more Experiments with animals housed individually are important
related to relationship quality than quantity (57, 78). for investigating the molecular mechanisms and the causal
In addition to physical presence, humans need relationships effects of social deprivation in disease development (11, 119).
that provide mutual value and trust, and promote communi- Social isolation and loneliness are common sources of
cation and collaboration toward common goals (15, 57, 78). chronic stress in adults (82, 124). Moreover, a growing
Although it is commonly thought that social isolation leads to number of individuals are at risk for loneliness in modern
loneliness, loneliness can be experienced within a marriage, society because of social and demographic changes (78).
family, friendship, or larger social group. In contrast, one can People are living longer and the number of people aged 60
feel socially contented while being alone (11, 12, 57, 78). years and older has tripled since 1950. Older age is associated

1
Department of Pharmacology, Johannes Gutenberg University Medical Center, Mainz, Germany.
2
Center for Translational Vascular Biology (CTVB), Johannes Gutenberg University Medical Center, Mainz, Germany.
3
German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.
ª Ning Xia and Huige Li 2018; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the
Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits any non-
commercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.

837
838 XIA AND LI

with reduced social interactions, longer periods of time living

alone, and higher prevalence of loneliness (49, 104). How-
ever, loneliness is more than simply the result of age-related
losses but can be experienced at all stages of life (7, 74).
The prevalence of loneliness has increased commensurate
with deferred marriage, increased two-income households,
and increased residence in single-family homes (78). In ad-
dition, the Internet has completely changed the way people
live and interact (15). Despite increased digital connectivity,
more people are experiencing social isolation (15). Rather
than enhancing well-being, recent studies suggest that social
media may undermine it (68). The prevalence in modern
society (Fig. 1) is high enough to justify intervention (92).

Loneliness as a Mortality Risk Factor

Chronic social isolation has been shown to increase the FIG. 2. Impact of social support on mortality. The odds
risks of morbidity and mortality similar to known factors, of mortality due to social isolation and loneliness are similar
including high blood pressure, smoking, and obesity (60). A to light smoking (15 cigarettes/day) and alcohol consump-
meta-analysis involving 148 studies and 308,849 individuals tion (6 drinks/day), and exceed the risks conferred by
followed for an average of 7.5 years showed that this effect of physical inactivity and obesity. Note: Effect size of zero
social isolation was independent of other risk factors (Fig. 2). indicates no effect. Complex measures of social integration
are single measures that assess multiple components of social
The quantity and quality of relationships have been inversely integration such as marital status, network size, and partici-
correlated with health risks (58, 59). Strong social relation- pation (59). Reproduced and modified from Holt-Lunstad
ships can increase the likelihood of survival by as much as et al. (59), which is an open-access article distributed under
50% relative to individuals whose relationships are weaker the terms of the Creative Commons Attribution License. To
(59). An increase in mortality has been correlated with both see this illustration in color, the reader is referred to the web
loneliness and social isolation (58, 125). The overall odds version of this article at www.liebertpub.com/ars
of mortality due to loneliness and social isolation are 1.50,
which was comparable to light smoking and greater than the Loneliness as a Cardiovascular Risk Factor
risks due to obesity and hypertension (59). A recent meta-
analysis indicated that social isolation, loneliness, and living An early study published in 1992 showed that coronary
alone increased the possibility of death by *29%, 26%, and heart disease (CHD) patients who were not married and did
32%, respectively (58). not have a confidant had a significantly higher 5-year inci-
dence of mortality (50%) than that (18%) observed in patients
with a spouse or partner (146). Two reviews about social
relationships and CHD associated the degree of loneliness
with the incidence and prognosis of CHD, although the evi-
dence was relatively weak (3, 124)
A recent systematic review followed by a meta-analysis of
16 prospective longitudinal studies showed that loneliness
and social isolation were correlated with increased risks of
CHD (29%) and stroke (32%) (138). The association was
comparable to anxiety and job stress, which are recognized
risk factors for CHD (138). This finding reinforces existing
evidence demonstrating that poor social connections robustly
predict morbidity and mortality, and that loneliness and so-
cial isolation are additional risk factors of cardiovascular
disease (CVD) (57).
FIG. 1. Prevalence of loneliness. The reported preva- Hypertension
lence of loneliness in Europe (148) and China (149), re-
spectively. The overall prevalence of loneliness among Results from longitudinal (54) and cross-sectional (13)
adults older than 65 in the United States (135) is shown for studies have shown the association between increased blood
comparison. There are significant differences in the preva- pressure and loneliness in older and middle-aged individuals;
lence among European countries with a higher prevalence in this association strengthens with increasing age of individuals
group EU1 (Bulgaria, Hungary, Latvia, Poland, Romania, (52). Moreover, individuals who were lonelier by one standard
Russia, Slovakia, and Ukraine) than group EU2 (Austria,
deviation had systolic blood pressure (SBP) that was 3.7 mmHg
Cyprus, Estonia, France, Portugal, Slovenia, and Spain), and
group EU3 (Belgium, Denmark, Finland, Germany, Ireland, greater at study initiation and was predicted to increase by
the Netherlands, Norway, Sweden, Switzerland, and the 2.3 mmHg over the next 4 years (52). Thus, these findings
United Kingdom) (148). To see this illustration in color, the would predict that over 4 years, the most lonely individuals
reader is referred to the web version of this article at www would exhibit an increase in SBP that was 14.4 mmHg
.liebertpub.com/ars (3.6 mmHg/year) higher than the least lonely individuals (54).
LONELINESS AND SOCIAL ISOLATION 839

Increase in total peripheral resistance (TPR) is the main in these stressed monkeys was independent of serum lipid
cause of elevated SBP in individuals up to 40 years of age, when levels (63). In female cynomolgus monkeys that consumed a
arterial stiffness assumes a growing role (43). TPR levels are moderately atherogenic diet, social deprivation by individual
chronically increased in young adults who are lonely relative to housing significantly increased coronary artery atheroscle-
nonlonely individuals of the same age (13, 50). The more rapid rosis without a change in plasma lipid concentrations (115).
increase in TPR leads to premature arterial stiffening and Similarly, Watanabe heritable hyperlipidemic rabbits (79,
increase of SBP (43). Consequently, lonely individuals may 96) and apolipoprotein E-knockout mice (6) housed in social
develop earlier or more severe structural abnormalities in re- isolation showed greater atherosclerotic lesion areas than
sistance arteries that promote deposition of collagen and de- those in an affiliative social environment.
crease elastic fiber content (54). Molecular mechanisms underlying the enhanced athero-
sclerosis in socially isolated animals may involve sympa-
thetic nervous system (SNS) overactivation and physical
Atherosclerosis inactivity, as well as enhanced vascular inflammation and
There is a large body of evidence from animal studies oxidative stress (79, 86, 87).
showing that social isolation and social stress accelerate
Pathways Affected by Loneliness—The Molecular Link
atherogenesis. Male cynomolgus monkeys exposed to social
stress (e.g., via periodic reorganizing of groups with different In a review article published in this Forum, Meyer and
conspecifics) and fed a diet low in fat and cholesterol de- Wirtz addressed the molecular mechanisms linking cytokine
veloped more severe atherosclerosis of the coronary artery function and HPA axis components to mitochondrial redox
compared with control monkeys under nonstress conditions signaling under psychosocial stress (83). In the present arti-
(maintained in stable groups) (63). The lack of significant cle, we discuss how loneliness and social isolation affect
effects of social stress on blood pressure, serum lipid, and health by activating behavioral and psychological mecha-
glucose levels, or ponderosity indicated that atherogenesis nisms as well as pathophysiological pathways (Fig. 3).

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 proin-
flammatory 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
840 XIA AND LI

Behavioral and psychological changes release in response to acute stress) (140), and depressed in-
Social species create organizations (ranging from dyads dividuals with CHD have increased inflammatory marker
and families to societies) beyond the individual, which have expression and decreased GR expression and GR sensitivity
benefits such as mutual protection and assistance (12). compared with nondepressed CHD patients (89).
Therefore, social isolation represents a dangerous situation, A variety of molecular mechanisms have been implicated in
through which a socially isolated individual may react with glucocorticoid resistance (Fig. 4), including GR degradation,
implicit vigilance for social threats, fragmented sleep to disruption of GR translocation, and/or GR-DNA binding, as
evade predation, and increased cardiovascular activity to deal well as changes in GR phosphorylation status (94, 105, 117).
with potential assaults (12). Although these responses may be Importantly, inflammatory cytokines potentiate glucocorticoid
protective for short-term survival, when isolation becomes resistance (94). As glucocorticoid resistance exacerbates in-
chronic, they have long-term detrimental effects on mental flammation and production of proinflammatory cytokines,
and physical health (12). there may exist a positive feedback mechanism in the devel-
Social isolation and loneliness are associated with health opment of glucocorticoid resistance. In addition, glucocorti-
risk behaviors such as reduced physical activity, reduced coid resistance can be attenuated by b-adrenoceptor blockade
sleep quality, and smoking (7, 53, 57, 113, 138). Loneliness in socially isolated mice, which indicates a contribution of the
also has been associated with depression, anxiety, dysphoria, SNS to glucocorticoid resistance (48, 101).
and social withdrawal (12). Similar observations have been In endothelial cells, glucocorticoids reduce nitric oxide
made in animal studies. Male adult rodents subjected to social (NO) production via endothelial NO synthase (eNOS). NO
isolation exhibit a significant decrease in physical activity derived from eNOS is a crucial antihypertensive and anti-
and sleep quality (11, 13). Mice subjected to social isolation atherosclerotic factor (42, 70). Both the expression level (142)
exhibited disrupted sleep and reduced slow-wave sleep (65). and serine 1177 phosphorylation (136) of eNOS are decreased
by glucocorticoid treatment. Reduced endothelial NO pro-
duction represents a crucial mechanism in the development of
The HPA axis
glucocorticoid therapy-induced hypertension (107, 141, 142).
The major neuroendocrine systems involved in the stress Moreover, glucocorticoids also potentiate the vasoconstricting
response are the HPA axis and sympathetic adrenomedullary effect of catecholamines (150). However, the contribution of
axis (11). Activation of the HPA axis is a consistent finding in these mechanisms to blood pressure elevation and athero-
lonely individuals (51), whereas the association between sclerosis in lonely and socially isolated individuals remains to
loneliness and increased circulating levels of catecholamines be determined. It is not clear whether the loneliness-associated
is less consistent (11). glucocorticoid resistance also occurs in endothelial cells or
The HPA axis plays an important role in regulating the is restricted to immune cells. Nevertheless, acetylcholine-
response to stress (12). The HPA axis is the main producer of induced, endothelium-dependent vasodilation is impaired in
glucocorticoids, including cortisol (humans) and corticoste- the aorta of socially isolated prairie voles (97), which suggests
rone (rodents). Glucocorticoid release follows the circadian reduced endothelial NO production from eNOS.
rhythm, where highest levels occur in the morning and lowest
levels occur in the evening. Loneliness in humans is associ-
The SNS
ated with larger morning cortisol rises (1), higher circulating
cortisol levels (23, 33), and decreased glucocorticoid receptor The SNS projects from the central nervous system through
(GR) sensitivity (21, 25), indicating higher levels of HPA the splanchnic nerve directly to the adrenal medulla. This
activation in lonely individuals (12). direct innervation enables a rapid response to acute stress via
Similar HPA axis activation has been observed in animal secretion of epinephrine (and smaller amounts of norepi-
models of PSI. Chronic separation of pair-bonded prairie nephrine and dopamine) into the circulation (11). In addition,
voles was associated with increased levels of corticosterone the SNS innervates the entire body, including the lymphoid
(10, 81, 126), whereas chronic separation from a low- system (48), and SNS nerve fibers release norepinephrine
preference partner (e.g., same-sex sibling) resulted in no in- directly into the thymus, spleen, and lymph nodes (11).
crease in levels of corticosterone (10). Evidence for the association between loneliness and ele-
Glucocorticoids govern physiological functions, including vated catecholamine levels (44) has not been as consistently
immunity, metabolism, cardiovascular activity, reproductive shown as the effect of loneliness on the HPA axis (11, 52). In
processes, neurodegeneration, and apoptosis (11). Gluco- humans and macaques, chronic PSI has been associated with
corticoids mediate these physiological functions via rapid- elevated urinary levels of norepinephrine metabolites but not
acting, nongenomic effects and slow-acting genomic effects. epinephrine (23).
For example, stimulation of GRs in leukocytes by cortisol Interestingly, social stress appears to be much more
results in suppression of proinflammatory gene networks. strongly related to local catecholamine levels in SNS-
However, chronic social stress induces glucocorticoid resis- innervated tissues (e.g., thymus, spleen, lymph nodes, and
tance (Fig. 4) in which the GR becomes less efficient in tumors) than systemic catecholamine levels. For instance,
transducing glucocorticoid signals (27). Glucocorticoid re- poor social support and high prevalence of depression in
sistance, in turn, leads to excessive inflammation as well as ovarian cancer patients were associated with significantly
hyperactivity of corticotropin-releasing hormone and SNS higher norepinephrine levels in tumor tissues compared with
pathways (94), which may contribute to development of patients with strong social networks and lower prevalence of
diseases, including atherosclerosis, diabetes, neurodegen- depression. In contrast, no effect of social support on plasma
eration and tumor metastasis (11). Interestingly, CHD pa- norepinephrine was found in the same patient population (75,
tients show a blunted cortisol stress response (less cortisol 76). Moreover, the high tumor norepinephrine levels were
LONELINESS AND SOCIAL ISOLATION 841

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 11b-HSD-2; [4] reduced glucocorticoid binding to the glucocorticoid receptor (GRa); [5] inflammasome-mediated
degradation of GRa; [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-
jB or AP-1; and [8] increased expression of the inhibitory glucocorticoid receptor GRb. HSP, heat shock protein. X
indicates inhibition of gene expression. Partly adapted from Refs. 94, 105, 117, 139. To see this illustration in color, the
reader is referred to the web version of this article at www.liebertpub.com/ars

paralleled by stronger norepinephrine effects mediated by b- These immature monocytes are proinflammatory, while the
receptors, for example, transcription pathways that mediate more mature Ly6clo monocytes are immunoregulatory (127).
inflammation, metastatic capacity, and cell proliferation (19, Peripheral blood mononuclear cells (PBMCs) from young
28, 75, 76). adults subjected to chronic socioeconomic stress showed total
The social regulation of tissue norepinephrine levels is not monocyte transcriptome expansion and immature proin-
only a result of functional but also structural changes. Studies flammatory CD16- monocyte transcriptome expansion (101).
in nonhuman primates have found a substantial amount of Moreover, this proinflammatory gene expression profile was
socially regulated plasticity in the innervation of lymph mediated by upregulation of myelopoiesis induced by the SNS
nodes (120, 122). Animals housed under unstable conditions (101). The bone marrow microenvironment, where hemato-
showed catecholaminergic innervation of lymph nodes that poiesis and differentiation of monocytes take place, is inner-
was more than twice as dense as animals socialized under vated by the SNS (35), which implies that mobilization of
stable social conditions. These animals had an impaired an- hematopoietic stem cells is regulated by the SNS (4, 64).
tiviral immune response, normally mediated by type I inter- Repeated social defeat (RSD) in mice is used as a model
feron, which resulted in increased simian immunodeficiency for social disruption stress (SDR). Like SDR, RSD results in
virus (SIV) load (122). Given lymphoid organs’ fundamental activation of the HPA axis and the SNS. RSD in mice results
immunoregulatory role, social stress-induced innervation of in increased bone marrow monocytopoiesis and Ly6chi
lymph nodes may have a range of effects on immunity and monocyte accumulation in blood, spleen, bone marrow, and
inflammation (120, 121). brain (80, 101). Pretreatment of mice with propranolol (b-
The SNS is also involved in upregulated production of im- adrenergic receptor blocker) before RSD prevented periph-
mature and proinflammatory monocytes by the bone marrow eral Ly6chi monocyte expansion and proinflammatory gene
in response to social stress, an effect that is mediated by upregulation in monocytes from peripheral blood (101).
b-adrenergic receptors (101). Social stress leads to a proin- Interestingly, SNS activation in the spleen results in the
flammatory state characterized by increased monocytopoiesis release of primed monocytes (80). Splenomegaly and glu-
and selective expansion of an immature monocyte subset cocorticoid resistance in CD11b+ and CD11c+ myeloid
(Ly6chi and CD16- in mice and humans, respectively) (55, 101). populations of the spleen were observed in mice subjected to
842 XIA AND LI

RSD (48). Pretreatment of mice with propranolol before RSD the parasympathetic nervous system mitigates the potentially
led to decreased RSD-induced plasma IL-6 and splenomeg- deleterious effects of heightened sympathetic output (91, 133),
aly, and attenuated anxiety-like behavior (48). loneliness may cause a potentially healthy response (auto-
The re-establishment of anxiety-like behavior in RSD nomic coactivation) to become harmful (selective activation of
mice in response to subthreshold stress was correlated with the SNS).
Ly6chi monocyte release from the spleen and accumulation in Hence, one mechanism by which social isolation may
the brain. Moreover, trafficking of monocytes to the brain and negatively impact health outcomes is via altered autonomic
anxiety-like behavior induced by subthreshold stress were nervous system function (45). Indeed, a lower HF-HRV has
prevented by splenectomy before RSD in these mice. Thus, been correlated with adverse health outcomes (45), including
trafficking of monocytes to the brain was associated with the reduced cognitive function, depression, CVD, and all-cause
recurrence of anxiety-like behavior in these RSD mice (80, mortality (73, 132, 134, 137).
128, 147).
The immune system
The vagal system
Social isolation and socioeconomic stress have been as-
An important function of the vagal system is to prevent the sociated with the conserved transcriptional response to ad-
detrimental effects of SNS overactivation (18, 67). Heart rate versity (CTRA) in leukocytes, characterized by upregulation
variability (HRV) is measured by the variation in the beat-to- of proinflammatory gene expression and downregulation of
beat interval (112, 133), which is partly modulated by the au- antibody- and antiviral immunity-related genes (25, 26, 101).
tonomic nervous system at the sinoatrial node of the heart (45, Human myeloid-derived antigen-presenting cells such den-
69). High-frequency heart rate variability (HF-HRV) denotes dritic cells, monocytes, and B cells have been identified by
heart rate variations associated with respiration. Respiratory transcript origin analyses as the major cellular contributors of
sinus arrhythmia occurs when the heart rate accelerates and the transcriptional response of the immune system to lone-
decelerates on inspiration and expiration, respectively (112). liness (24).
HF-HRV is determined by vagally mediated parasympathetic In lonely individuals, SNS activation (101), rather than
activity (112). The cardiovascular center inhibits vagal outflow circulating levels of cortisol, causes the shift between pro-
during inhalation and restores vagal outflow during exhalation and anti-inflammatory signaling (25, 101). Loneliness also
(112). Although the heart is dually innervated, the influence of has been correlated with elevated levels of norepinephrine
the SNS on the heart occurs too slowly to affect beat-to-beat metabolites (but not epinephrine) in urine (23). SNS activa-
changes quickly (133). Therefore, HF-HRV directly measures tion enhanced myelopoiesis (55, 101) and concurrently reg-
parasympathetic control of the heart (45, 91). ulated CTRA-related gene expression (23).
Recent studies have suggested that positive social inter- Reciprocal regulation of the leukocyte transcriptome may
actions have an effect on HF-HRV (45). Marriage was as- result in two distinct functional consequences: enhanced in-
sociated with greater HF-HRV (102), and happy marriages flammation and an impaired antiviral response.
were associated with even greater HF-HRV (123). One study Monocytes are the main source of the proinflammatory
of 2066 male civil servants in the United Kingdom (the function of the CTRA (101), which results from immature
Whitehall cohort) found a correlation between smaller HF- CD14++/CD16- monocyte subset expansion (23) and upregu-
HRV and low social integration (56). Similarly, the effect of lated proinflammatory gene expression (24). While the num-
social integration on autonomic nervous system function was ber of total circulating leukocytes (24) was not significantly
demonstrated in a recent study of students who had moved to changed in lonely individuals, the percentage of circulating
a foreign country. The lack of social integration within the monocytes was increased and CTRA-associated gene expres-
initial 5 months in the host country was correlated with a sion was upregulated (23). Upregulation of CTRA-related
higher heart rate and lower HF-HRV (45). The results sug- gene expression in human resulted likely from selective ex-
gested that changes in autonomic nervous system function, pansion of the immature CD14++/CD16- classical monocyte
measured by HF-HRV, may be an important link between subset rather than the total CD14++ monocyte population (23).
social integration and health (45). Similarly, macaques with high PSI also showed upregulated
Studies in animal models of social isolation have sug- circulating monocyte frequencies and percentages. Within the
gested that HRV may be regulated by the social environment. monocyte population, classical CD14++/CD16- monocytes
Socially isolated prairie voles had lower HF-HRV compared were expanded, and nonclassical CD14++/CD16+ monocytes
with socially paired voles at baseline and during exposure to were unchanged (23). Analogous to high-PSI humans, high-
stress (46, 47). Exogenous oxytocin administration increased PSI macaques showed upregulated CTRA-related gene ex-
the HF-HRV of socially isolated voles to a level similar to pression in the classical CD14++/CD16- monocytes from the
socially paired voles (47). PBMC population (23). Moreover, circulating lymphocytes
Similarly, oxytocin administration to healthy young adults from high-PSI humans (24, 25) and macaques (23) showed
significantly increased both sympathetic (indexed by pre- glucocorticoid resistance, including downregulated GR ex-
ejection period) and parasympathetic (indexed by HF-HRV) pression and upregulated NF-jB expression (23).
autonomic cardiac control (91). Importantly, the level of Based on these data, Cole et al. proposed a mechanistic
loneliness negatively predicted alterations in autonomic con- model in which loneliness results in an SNS-mediated expan-
trol of cardiac function induced by oxytocin treatment, which sion of myeloid-lineage cells characterized as immature,
was independent of anxiety, depression, and serum markers. proinflammatory, and glucocorticoid resistant (23). Upregula-
Lonelier individuals had lower response to oxytocin-induced tion of proinflammatory gene expression in lonely people
effects on HF-HRV (91). Because simultaneous activation of may be explained by glucocorticoid resistance even with
LONELINESS AND SOCIAL ISOLATION 843

concurrently elevated cortisol levels, as the anti-inflammatory hypothalamus after 2 weeks was an early pathological event
effects of endogenous glucocorticoids are diminished be- that preceded the increase of corticotropin-releasing factor
cause of impaired GR signaling (23). The resulting long-term levels in the hypothalamus and adrenocorticotropic hor-
inflammation may represent a key mechanism in the de- mone levels in the plasma at 4 weeks, and increased corti-
velopment of loneliness-associated chronic diseases such as costerone levels in plasma and saliva after 7 weeks (20).
atherosclerosis, cancer, and neurodegeneration (23). Thus, the early increase of oxidative stress likely triggered
The other part of the leukocyte CTRA, namely, reduced the stress response and HPA-axis activation (20).
type I interferon activity and reduced antibody-related gene NADPH oxidase (NOX) enzymes comprise a family of
expression, likely comes from dendritic cells, which produce membrane proteins that generate reactive oxygen species (ROS)
interferon, and B lymphocytes, respectively (23, 24). This (108). Among the NOX enzymes found in the brain (NOX1,
may lead to impaired immunity as the functional conse- NOX2, NOX3, and NOX4), NOX2 has a critical role in social
quence. At baseline, high-PSI macaques showed down- isolation (20, 108). Social isolation in rats led to upregulation of
regulated PBMC mRNA levels of interferon genes compared NOX2 and its components (p22phox, p67phox, p47phox, and
to controls. After infection with SIV, interferon gene ex- p40phox) in the brain (109). Treatment of rats with the anti-
pression was significantly upregulated in controls but not in oxidant/NOX inhibitor apocynin (starting after 4 weeks of so-
high-PSI animals. High-PSI macaques also showed weaker cial isolation) stopped the progression of HPA-axis activation
suppression of SIV gene expression in PBMCs, increased induced by social isolation (20). Rats that had a loss-of-function
viral load in plasma and cerebrospinal fluid, and decreased mutation in the NOX2 subunit p47phox were completely pro-
titers of anti-SIV IgG antibodies (23). tected from changes in the neuroendocrine profile and behavior
Importantly, CTRA gene expression may reciprocally affect induced by social isolation (20). These results suggested that
loneliness. In lonely individuals, the immature proinflammatory NOX2-derived oxidative stress in the hypothalamus was a
monocytes can traffic into the brain, leading to anxiety and causal factor in social isolation-induced HPA activation and in
altered social behavior. Moreover, release of proinflammatory the development of anxiety-like symptoms.
cytokines in the brain may promote ‘‘sickness behaviors,’’ The relationship between oxidative stress and the HPA
which include affective, perceptual, and motivational processes axis in social isolation seems to be bidirectional. As men-
that could augment loneliness and decrease the desire for social tioned above, NOX2-mediated oxidative stress in the hip-
interaction, creating a vicious cycle (22, 23). As mentioned pocampus lies upstream of social isolation-induced changes
above, this positive feedback loop involves trafficking of in the HPA axis. On the contrary, glucocorticoids derived
monocytes to the brain (80, 143, 147). from the HPA axis also have an impact on NOX expression
and activity (108). In hippocampal neurons, glucocorticoids
have been shown to upregulate the expression (151) and
Oxidative stress
activity (66) of NOX. There is also evidence that social iso-
Disturbed redox homeostasis in oxidative distress may lation may induce oxidative stress in the prefrontal cortex and
represent a key molecular link from chronic psychosocial hippocampus by inhibiting antioxidant enzymes (39, 108).
stress to CHD (116). Social isolation induces oxidative stress However, these results are inconsistent (Table 1).
in the brain and in peripheral tissues. In the brain, oxidative Social isolation-induced oxidative stress also has been ob-
stress was shown to be a crucial mechanism triggering HPA served in the vasculature. For example, individually caged
activation. In the periphery, oxidative stress may be the result Watanabe heritable hyperlipidemic rabbits have a higher NOX
of social isolation-induced changes in the HPA, SNS, and the activity in the aortic arch (86). As NOXs are the main pro-
immune system as detailed above. Indeed, a large-scale study ducers of ROS in the vasculature (42, 71, 72), the increased
involving 2858 subjects showed that markers of the HPA vascular activity of NOX may promote atherosclerosis de-
axis, SNS, and inflammation were associated with oxidative velopment by inducing oxidative stress. Mechanistically, so-
damage in a dose-response manner (9). cial isolation-induced HPA activation, GR resistance, SNS
Social isolation rearing of rats (individual housing starting activation, and inflammation, as described above, may all
at the age of 21 days) led to an increase in oxidative stress in contribute to vascular oxidative stress. Although a short in-
the hypothalamus and the prefrontal cortex (20, 109). Im- cubation for 24 h with glucocorticoids was reported to reduce
portantly, the elevation in oxidative stress markers in the p22phox expression in human smooth muscle cells, chronic

Table 1. Reported Changes in Antioxidant Enzymes in the Hippocampus of Socially Isolated Rats
Age at Duration of
Animals isolation isolation (weeks) Antioxidant systems Reference
Male rats 3 weeks 8 SODY; catalaseY; GPxY (114)
Male rats 2–3 months 3 SOD14; SOD24 (38, 40)
Male rats 2.5 months 3 GSHY; MDA4; SOD4 (152)
Male rats 3 months 3 SOD[; catalase[ (95)
Male rats 3 months 3 SOD4; catalase4; GPx expression4; (32)
GPx activityY; GLR expression[; GLR activity4
Male rats 3 months 3 GCLM[; GSTA34; GLR4 (31)
GCLM, glutamate cysteine ligase modifier subunit; GLR, glutathione reductase; GPx, glutathione peroxidase; GSTA3, glutathione S-
transferase A3; MDA, malondialdehyde; SOD, superoxide dismutase; Y, reduction; [, increase; 4, no significant changes.
844 XIA AND LI

dexamethasone treatment has been shown to upregulate NOX1 detrimental effects of loneliness on health, because current
expression in rat smooth muscle cells (77, 118). loneliness reduction interventions are not always successful
Exogenous administration of the sympathetic neurotrans- and are not equally effective for every individual. The fol-
mitter norepinephrine in rats was shown to increase systemic lowing potential strategies are proposed based on the path-
ROS production by stimulating circulating leukocytes (110). ogenic mechanisms summarized above.
Conversely, ROS stimulated central and peripheral SNS ac-
tivity (16). Treatment of freshly isolated human PBMC with Allopregnanolone. Given the important role of the HPA
norepinephrine increased the gene expression of NOX com- axis activation in chronic loneliness, modulation of the HPA
ponents and intracellular superoxide production, effects that axis may represent a rational strategy to treat loneliness-
are preferentially mediated by a2-receptors (30). Moreover, associated disorders. Animal studies have demonstrated that
norepinephrine treatment also enhances adhesion of CD14+ 3a, 5a-tetrahydroprogesterone (allopregnanolone [ALLO])
monocytes to endothelial cells (30). These results are con- decreased stress-induced activation of the HPA axis and fa-
sistent with the observation in humans that loneliness results cilitated recovery from stressful events (14).
in an SNS-mediated increase of proinflammatory immature ALLO is a progesterone-derived, endogenous neuroactive
monocytes (23). Indeed, proinflammatory monocytes may steroid in the brain (14, 15). It is a potent modulator of the c-
have a crucial role in CVD pathogenesis by infiltrating into aminobutyric acid (GABAA) receptor complex and has
the vascular wall, causing local inflammation and oxidative powerful antianxiety, anesthetic, and anticonvulsant proper-
stress, as shown in the mouse model of angiotensin II- ties (14). Whereas acute stress increases ALLO levels, re-
induced hypertension (144). peated stress results in decreased serum levels of ALLO,
Thus, it is possible that environmental stressor-stimulated which suggests that the chronic stress-induced hyperactiva-
pathways, triggered by social isolation, traffic noise, or air tion of the HPA axis is partly attributable to a downregulation
pollution (84, 85, 145), may converge into a common of ALLO synthesis (14). Indeed, ALLO specifically regulates
mechanism, that is, inducing vascular dysfunction and CVD the functions of the HPA axis (8).
by causing vascular oxidative stress and inflammation. Recent reports in animal models demonstrated that
ALLO has an important role in social isolation. Individual
Interventional and Therapeutic Strategies housing of adult male mice reduced ALLO levels, which
was attributable to downregulation of the rate-limiting en-
Because of the detrimental effects of loneliness on physi- zyme 5a-reductase type I in ALLO biosynthesis. Down-
cal and mental health and the growing prevalence, there is an regulation occurred specifically in selected neurons of the
urgent need for the development of interventional and ther- basolateral amygdala, hippocampus, and medial prefrontal
apeutic strategies. Currently, there is no pharmacological cortex (2, 34, 98). Importantly, administration of exogenous
treatment for loneliness (14). There are, however, approaches ALLO can normalize social isolation-induced HPA dys-
that can mitigate loneliness or alleviate the damaging effects function (8, 103) and behavioral effects (37, 88, 98, 99).
of loneliness on health. Similar results have been obtained with ganaxolone, a
synthetic analog of ALLO (100).
Interventions to reduce loneliness Interestingly, the social isolation-induced behavioral ef-
When Engel proposed the biopsychosocial model of dis- fects can also be normalized with some selective serotonin
ease 40 years ago, the dominant model of disease at that time reuptake inhibitors at doses far below those required to block
was biomedical, leaving no room within its framework for the serotonin reuptake (37, 88, 90, 98, 99). These results indicate
social, psychological, and behavioral dimensions of illness that such drugs may lead to improvement in behaviors not by
(36). Nowadays, the contribution of such factors to disease is inhibiting serotonin reuptake, but rather by elevating corti-
well accepted in the scientific community. Moreover, corre- colimbic levels of ALLO.
sponding intervention strategies have been developed in the Based on the animal studies, Cacioppo et al. hypothesized
past decades. As early as in 1983, Ornish et al. showed that that ALLO has an important role in loneliness in humans (14,
a short-term intervention consisting of stress management 15). The potential of ALLO, ALLO precursors, and ALLO
training and dietary changes could improve cardiovascular analogs as novel treatments for loneliness needs to be tested
status in CHD patients (93). in clinical studies (14).
In particular, interventions aimed to mitigate loneliness
include strategies to improve social skills, enhance social b-Blockers. Direct SNS innervation of the spleen and
support, increase opportunities for social contact, and address primary and secondary lymphoid organs links behavioral
maladaptive social cognition (15). A recent meta-analysis processes to regulation of the immune system (120). Epi-
demonstrated that the use of cognitive behavioral therapy to nephrine and norepinephrine stimulate receptors belonging
address maladaptive social cognition was most effective for to two major subclasses: the a- and the b-adrenergic re-
reducing loneliness (78). Other approaches such as medita- ceptors (48). Most immune cells have a1 and b2 receptors,
tion, qigong, tai chi, yoga, and promoting purpose and which typically exert opposite effects (Table 2). Under
meaning in life may reduce the detrimental effects of lone- homeostatic conditions, the signals mediated by b2 recep-
liness on health (22, 26, 29, 41). tors usually predominate (5). Activation of b-adrenergic
receptors by catecholamines increases the production of
proinflammatory cytokines in several cell types (48). b2
Interventions to reduce the health effects of loneliness
receptor activation in mouse macrophages has been shown
Besides interventions to reduce loneliness, it also is im- to upregulate IL-1b and IL-6 expression, which promotes a
portant to develop therapeutic strategies to prevent the proinflammatory immune response (131).
LONELINESS AND SOCIAL ISOLATION 845

Table 2. Expression and Function of Adrenergic Receptors in Immune Cells

Cell type b2 a1 Reference
Neutrophils Yneutrophil interaction with endothelial cells; [neutrophils release into the (5, 106)
Yphagocytosis; Ylysosomal enzyme release; circulation
Yrespiratory burst
Monocytes/ Both pro- and anti-inflammatory effects reported Proinflammatory effects (monocytes (5, 106)
macrophages acquire a1 receptor after homing)
NK cells NK cell in blood ([acutely, Ychronically); both [NK cytotoxicity (5, 106)
increased and decreased NK activities have been
reported
DC YAg protein cross-presentation; YIL-12; shift from Stimulation of DC migration (5, 106)
Th1 to Th2-type immune response
Th0 cells [IFN-c and Th1-cell differentiation (in the — (5)
presence of TNF-a and IL-12); [Th2-cell
differentiation (in the presence of IL-4 and IL-
10)
Th1 cells YIFN-c (negative feedback) — (5)
Th2 cells — (epigenetic loss of b2 receptors) — (5, 17)
B cells Dependent on activation state of B cell ([IgG1/IgE — (5)
production during Ag processing; [IgG2 after
Ag processing; YAb production by plasma cells)
DC, dendritic cells; NK, natural killer.

The SNS upregulates production of immature, proinflam- nomic cardiac control (15, 91). However, findings have been
matory monocytes in the bone marrow, which is mediated via inconsistent and negative effects have been reported (15).
b-adrenergic receptors (48, 101). Moreover, b-adrenergic Thus, additional research is required to examine the thera-
receptor-mediated mechanism is involved in social stress- peutic potential of oxytocin in the treatment of chronic
induced glucocorticoid resistance (48, 101) and monocyte loneliness (15).
trafficking from the spleen (48, 80, 147).
When fed a cholesterol-containing diet and housed in pe-
riodically reorganized social groupings (i.e., social disrup- NOX inhibitors. As discussed above, oxidative stress is
tion), highly aggressive and competitive (dominant) male involved in different steps of social isolation-induced pa-
cynomolgus monkeys developed exacerbated coronary artery thology. Oxidative stress triggers HPA activation (20), po-
atherosclerosis (62). Pharmacological treatment with the b- tentiates SNS activity (16), and promotes vascular damage.
blocker propranolol prevented the exacerbation of athero- The role of antioxidant enzymes in this scenario is uncertain
sclerosis caused by the unstable social environment (62). (Table 1). In contrast, NOX seems to play a key role.
Importantly, the antiatherogenic effects of propranolol on Therefore, NOX inhibitors may be of therapeutic interest.
dominant male monkeys were independent of resting heart Moreover, NOX inhibition may be a potential strategy to
rate, blood pressure, and serum lipid concentrations (62). improve resilience. In this context, resilience explains how
Given the complex effects of b2 receptors in different and why some individuals live in a state of chronic loneliness
immune cells and in other cell types, the therapeutic potential and yet do not develop mental illness (108). A loss-of-
of b blockers for loneliness-associated diseases cannot be function polymorphism in the p47phox subunit of NOX
predicted at this stage, which warrants additional studies, completely prevented behavioral and neuroendocrine chan-
especially in animal models of social isolation. ges typically associated with social isolation in rats (20).
Thus, NOX may be a crucial candidate target molecule for
Oxytocin. Oxytocin is a neuropeptide produced in the developing approaches to improve positive adaptation, and to
hypothalamus, which promotes a strong desire for social af- maintain or regain mental health despite experiencing
filiation (15). Besides the traditionally known role in uterine chronic loneliness or social isolation.
contraction, oxytocin is suggested to be a stress-responsive
hormone that exerts a regulatory influence on the HPA axis
Summary and Future Directions
(96). Moreover, the oxytocin receptor is expressed on major
vascular cells, including endothelial cells, vascular smooth Robust evidence supports the concept that loneliness and
muscle cells and also macrophages (61, 129). In vitro ex- social isolation increase morbidity and mortality, and should
periments showed that oxytocin reduced NADPH-oxidase be included as a risk factor for CVD. Chronic social stress is
activity and inflammatory cytokine secretion by macro- associated with activation of the SNS and the HPA axis re-
phages and endothelial cells (129). Chronic oxytocin ad- sulting in selective expansion of proinflammatory mono-
ministration attenuated atherosclerosis in Watanabe heritable cytes, enhanced expression of cytokines, and glucocorticoid
hyperlipidemic rabbits (129, 130) and in socially isolated resistance. These mechanisms likely contribute to the in-
apolipoprotein E-knockout mice (87). creased risk of lonely individuals developing CVD. Their
In humans, oxytocin administration promoted prosocial involvement, however, has not been proven so far and needs
behaviors such as affiliation and trust, and influenced auto- to be verified in future studies.
846 XIA AND LI

Acknowledgments 15. Cacioppo S, Grippo AJ, London S, Goossens L, and Ca-

cioppo JT. Loneliness: clinical import and interventions.
Grants from the Deutsche Forschungsgemeinschaft (DFG;
Perspect Psychol Sci 10: 238–249, 2015.
LI-1042/1-1 and LI-1042/3-1) and the intramural fund (Stufe 16. Campese VM, Ye S, Zhong H, Yanamadala V, Ye Z, and
I) of the Johannes Gutenberg University Medical Center Chiu J. Reactive oxygen species stimulate central and
Mainz supported the original work from the authors’ labo- peripheral sympathetic nervous system activity. Am J
ratory included in this review. Physiol Heart Circ Physiol 287: H695–H703, 2004.
17. Case AJ and Zimmerman MC. Sympathetic-mediated
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LONELINESS AND SOCIAL ISOLATION 851

Abbreviations Used NO ¼ nitric oxide

ALLO ¼ allopregnanolone NOX ¼ NADPH oxidase
CHD ¼ coronary heart disease PBMC ¼ peripheral blood mononuclear cell
CTRA ¼ conserved transcriptional response to adversity PSI ¼ perceived social isolation
CVD ¼ cardiovascular disease ROS ¼ reactive oxygen species
eNOS ¼ endothelial nitric oxide synthase RSD ¼ repeated social defeat
GABA ¼ c-aminobutyric acid SBP ¼ systolic blood pressure
GR ¼ glucocorticoid receptor SDR ¼ social disruption stress
HF-HRV ¼ high-frequency heart rate variability SIV ¼ simian immunodeficiency virus
HPA ¼ hypothalamic–pituitary–adrenal SNS ¼ sympathetic nervous system
HRV ¼ heart rate variability TPR ¼ total peripheral resistance