Cited by 983Stress Responses and CortisolNeuroendocrine regulation and behaviorHealth disparities and outcomes

The DOI matches its Crossref record; 129 of the 129 references it cites were found in a registry or an index; none of the 148 sources its claims cite is checked for support yet.

The Neuroendocrinology of Social Isolation

Open access
Cacioppo, John T., Cacioppo, Stephanie, Capitanio, John P., Cole, Steven W.·2015·Annual Review of Psychology

Abstract

Social isolation has been recognized as a major risk factor for morbidity and mortality in humans for more than a quarter of a century. Although the focus of research has been on objective social roles and health behavior, the brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others. Accordingly, population-based longitudinal research indicates that perceived social isolation (loneliness) is a risk factor for morbidity and mortality independent of objective social isolation and health behavior. Human and animal investigations of neuroendocrine stress mechanisms that may be involved suggest that (a) chronic social isolation increases the activation of the hypothalamic pituitary adrenocortical axis, and (b) these effects are more dependent on the disruption of a social bond between a significant pair than objective isolation per se. The relational factors and neuroendocrine, neurobiological, and genetic mechanisms that may contribute to the association between perceived isolation and mortality are reviewed.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that perceived social isolation (loneliness), more than objective isolation, is linked to morbidity and mortality through neuroendocrine stress mechanisms, especially increased HPA-axis activity. It synthesizes human and animal evidence indicating that chronic isolation from a meaningful social bond elevates glucocorticoids and may promote glucocorticoid resistance and inflammation, whereas SAM catecholamine findings are less consistent.

Key findings

  • Human studies generally link loneliness to higher HPA activity: chronic loneliness was positively correlated with salivary cortisol, and loneliness predicted a larger cortisol awakening response the following day independent of demographic factors, nervousness, or perceived stress, whereas the cortisol awakening response did not predict later loneliness; this was replicated in high school students. The paper notes the cortisol awakening response typically increases 50% to 60% in the first 30 to 45 minutes after awakening.
  • Loneliness has been associated with glucocorticoid resistance and proinflammatory gene expression: in a nationally representative sample of adults ages 54 and older from Taiwan, loneliness was associated with smaller neutrophil:lymphocyte and neutrophil:monocyte ratios, consistent with leukocyte glucocorticoid resistance; genome-wide microarray analyses showed reduced expression of glucocorticoid receptor–response genes, upregulated proinflammatory transcripts, and downregulated anti-inflammatory markers in middle- and older-age lonely adults.
  • Animal experiments suggest chronic social isolation increases HPA activity more when it disrupts a significant pair bond than from isolation per se: titi monkeys isolated from a pair mate showed a significant increase in plasma cortisol, whereas polygynous squirrel monkeys did not; prairie voles chronically isolated from a pair-bonded partner showed increased corticosterone, but those isolated from a same-sex sibling did not.
  • Across human and animal work, chronic social isolation is associated with relatively consistent increases in HPA-axis activity but little alteration in SAM catecholamine activity, and effects appear more dependent on disruption of a social bond between a significant pair than on objective isolation alone.

Methods

  • Narrative review of human and animal literature on the SAM and HPA neuroendocrine stress axes and social isolation/loneliness, focusing on adult mammals and adults.
  • Human evidence includes population-based longitudinal, cross-sectional, experience-sampling, fMRI, eye-tracking, immune, and gene-expression studies; animal evidence includes experimental assignment to normal versus socially isolated housing, acute and chronic isolation, and pair-bond disruption.
  • Main analysis is qualitative synthesis; no new data or formal meta-analysis are reported.

Limitations

  • Stated: the causal role of loneliness on neural and neuroendocrine mechanisms is difficult to test conclusively in humans; animal studies often use small sample sizes due to cost and animal-welfare concerns, reducing statistical power and producing inconsistent results; SAM findings are less numerous and consistent and may reflect perceived stress rather than perceived isolation per se; the oxytocinergic system is beyond the article’s scope.
  • Evident: as a narrative review, it does not report a systematic search, quality appraisal, or meta-analysis; heterogeneity in species, sex, isolation duration, relationship type, assayed tissue, measurement timing, and HPA parameters limits comparability across studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1146/annurev-psych-010814-015240

Cites

129 of 129 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 148 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Loneliness is associated with greater activation of the visual cortex in response to negative social images in contrast to negative nonsocial images.

    “Functional magnetic resonance imaging research also indicates that loneliness is associated with greater activation of the visual cortex in response to negative social images in contrast to negative nonsocial images (Cacioppo et al. 2009)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cacioppo et al. 2009
  • Premisecitation

    Perceived social isolation (loneliness) is a risk factor for morbidity and mortality independent of objective social isolation and health behavior.

    “population-based longitudinal research indicates that perceived social isolation (loneliness) is a risk factor for morbidity and mortality independent of objective social isolation and health behavior.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Luo et al. 2012
    • cites Luo & Waite 2014
    • cites Hawkley et al. 2009
  • Premisecitation

    Loneliness is associated with elevated tonic vascular resistance.

    “whether measured in a hospital laboratory (Cacioppo et al. 2002b) or over the course of a normal day using ambulatory procedures (Hawkley et al. 2003), loneliness is associated with elevated tonic vascular resistance—a marker of threat surveillance (Mendes et al. 2002).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cacioppo et al. 2002b
    • cites Hawkley et al. 2003
    • cites Mendes et al. 2002
  • Premisecitation

    Loneliness increases attention to negative social stimuli (e.g., social threats, rejection, exclusion).

    “growing evidence indicates that loneliness increases attention to negative social stimuli (e.g., social threats, rejection, exclusion).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cacioppo & Hawkley 2009
    • cites Jones et al. 1981
    • cites Cacioppo et al. 2006
  • Interpretationreasoning

    The association between indices of perceived and objective social isolation is mediated by the perceived quality of social relationships.

    “Accordingly, the association between indices of perceived and objective social isolation is mediated by the perceived quality of social relationships”
    Quote in the paperNot a substantial claim
  • It may state two separate claims as one. 49
  • Probably not a substantial claim. 7
  • The quote only partly states this claim. 2
  • It may state two separate claims as one.

    Premisecitation

    The brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others as well as regulating physiological processes relevant to morbidity and mortality.

    “the brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others”
    • Also stated in: § SOCIAL ISOLATION: A SOCIAL NEUROSCIENCE PERSPECTIVE · plain
      “the brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others as well as regulating physiological processes relevant to morbidity and mortality (Cacioppo & Berntson 1992).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cacioppo & Berntson 1992
  • It may state two separate claims as one.

    Premisecitation

    The HPA axis is sensitive to the interpretation by the brain of threats and stressors, and it influences a wide range of physiological, behavioral, and health outcomes.

    “The HPA axis is sensitive to the interpretation by the brain of threats and stressors, and it influences a wide range of physiological, behavioral, and health outcomes (e.g., Charmandari et al. 2005, Hostinar et al. 2014, McEwen & Gianaros 2011, Sapolsky et al. 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Charmandari et al. 2005
    • cites Hostinar et al. 2014
    • cites McEwen & Gianaros 2011
  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The prefrontal cortex modulates attention, working memory, conflicting inputs, and emotion regulation as well as integrates information from plans, prior knowledge, peripheral afferents, and the environment to coordinate neural, hormonal, and behavioral responses.

    “The prefrontal cortex modulates attention, working memory, conflicting inputs, and emotion regulation as well as integrates information from plans (e.g., goals) and prior knowledge, information from peripheral afferents, and information from the environment—including the social environment—to coordinate neural, hormonal, and behavioral responses (Hostinar et al. 2014, McEwen & Gianaros 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hostinar et al. 2014
    • cites McEwen & Gianaros 2011
  • It may state two separate claims as one.

    Premisecitation

    Loneliness is related to salivary cortisol levels, but this association reached statistical significance only for salivary cortisol levels measured an hour after awakening and at night.

    “Using a similar methodology at four points in time across the day, Pressman et al. (2005) similarly found loneliness to be related to salivary cortisol levels, although this association reached statistical significance only for salivary cortisol levels measured an hour after awakening and at night.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pressman et al. 2005
  • It may state two separate claims as one.

    Premisecitation

    The amygdala is especially important for rapid-onset, short-duration behaviors that occur in response to specific threats, whereas the BNST mediates slower-onset, longer-lasting responses that frequently accompany sustained threats and may persist even after threat termination.

    “The amygdala appears to be especially important for rapid-onset, short-duration behaviors that occur in response to specific threats, whereas the BNST appears to mediate slower-onset, longer-lasting responses that frequently accompany sustained threats (or the surveillance for threats) and that may persist even after threat termination (Walker et al. 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Walker et al. 2003
  • It may state two separate claims as one.

    Interpretationcitation

    Loneliness is typically associated with higher levels of HPA activation, although the strength of the association may vary depending on the chronicity of loneliness, the specific tissue assayed, the parameter used to gauge HPA activity, the time of day of the measurements, and the reliability of the measurements.

    “Subsequent investigations suggest that loneliness is typically associated with higher levels of HPA activation, although the strength of the association may vary depending on the chronicity of loneliness, the specific tissue assayed, the parameter used to gauge HPA activity, the time of day of the measurements, and the reliability (e.g., number) of the measurements.”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim.

    Premisecitation

    Trait loneliness was associated with a flattening of the diurnal cortisol rhythm in high school students.

    “trait loneliness was associated with a flattening of the diurnal cortisol rhythm”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Doane & Adam 2010
  • It may state two separate claims as one.

    Premisecitation

    Genome-wide microarray analyses revealed a reduction in expression of genes bearing glucocorticoid receptor response elements, an upregulation of proinflammatory gene transcripts, and a downregulation of anti-inflammatory markers in middle- and older-age adults high in loneliness compared with those low in loneliness.

    “Genome-wide microarray analyses revealed a reduction in the expression of genes bearing glucocorticoid receptor response elements, an upregulation of proinflammatory gene transcripts”
    • Also stated in: § NEUROENDOCRINE ACTIVITY AND PERCEIVED SOCIAL ISOLATION (LONELINESS) · plain
      “in middle- and older-age adults who are high in loneliness compared with those low in loneliness (Cole et al. 2007, 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cole et al. 2007
    • cites Cole et al. 2011
  • It may state two separate claims as one.

    Premisecitation

    Loneliness is positively correlated with salivary cortisol levels, but this association reached statistical significance only for chronic loneliness.

    “Results indicated that loneliness was positively correlated with salivary cortisol levels, but this association reached statistical significance only for chronic loneliness.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cacioppo et al. 2000
  • It may state two separate claims as one.

    Premisecitation

    Some data suggest an association between perceived social isolation and increased circulating levels of catecholamines, although the SAM findings are less numerous and consistent.

    “Some data also suggest an association between perceived social isolation and increased circulating levels of catecholamines, although the SAM findings are less numerous and consistent (e.g., Edwards et al. 2010, Hawkley et al. 2006) and may be attributable at least in part to differences in perceived stress rather than perceived isolation per se (Hawkley et al. 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Edwards et al. 2010
    • cites Hawkley et al. 2006
  • It may state two separate claims as one.

    Interpretationnone given

    Social threat in general, and loneliness in particular, is associated with glucocorticoid resistance and a complementary increase in proinflammatory gene expression that may contribute to some of the adverse health outcomes associated with perceived social isolation.

    “Several studies now suggest that social threat in general, and loneliness in particular, is associated with glucocorticoid resistance and a complementary increase in proinflammatory gene expression that may contribute to some of the adverse health outcomes associated with perceived social isolation.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Glucocorticoids influence a wide range of physiological functions including glucose regulation, metabolism, inflammatory control, cardiovascular activity, immunity, reproductive processes, neurodegeneration, and apoptosis.

    “Glucocorticoids (e.g., cortisol) influence a wide range of physiological functions that include glucose regulation, metabolism, inflammatory control, cardiovascular activity (e.g., endothelial function, atherosclerosis), cellular and humoral immunity, reproductive processes, and neurodegeneration and apoptosis.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Borski 2000
    • cites Chrousos 2009
    • cites Hawkley et al. 2012
  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Most effects of glucocorticoids are mediated by slower-acting genomic effects, with up to 20% of the expressed genome in a tissue susceptible to direct and indirect influences of glucocorticoids, estrogens, and androgens.

    “most are mediated by slower-acting genomic effects, where up to 20% of the expressed genome in a tissue is susceptible to the direct and indirect influences of glucocorticoids, estrogens, and androgens (Chrousos 2009, Hawkley et al. 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chrousos 2009
    • cites Hawkley et al. 2012
  • It may state two separate claims as one.

    Premisecitation

    In newly admitted nonpsychotic psychiatric inpatients, the high lonely group had significantly higher urinary cortisol than the low lonely group, whereas groups based on high or low recent stressful life events did not differ in urinary cortisol levels.

    “Analyses indicated that inpatients in the high lonely group had significantly higher levels of urinary cortisol than inpatients in the low lonely group, whereas the inpatients grouped in terms of high or low levels of recent stressful life events did not differ in urinary cortisol levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kiecolt-Glaser et al. 1984b
  • It may state two separate claims as one.

    Premisecitation

    Animal models of social disruption suggest that social factors can lead to glucocorticoid resistance, in which the glucocorticoid receptor becomes less efficient in transducing endogenous glucocorticoid signals, thereby increasing inflammatory biology that can contribute to diseases ranging from type II diabetes and atherosclerosis to neurodegeneration and tumor metastasis.

    “animal models of social disruption suggest that social factors can lead to glucocorticoid resistance in which the glucocorticoid receptor becomes less efficient in transducing endogenous glucocorticoid signals (e.g., Cole et al. 2009, Hanke et al. 2012, Pace et al. 2007, Powell et al. 2013), thereby increasing an inflammatory biology that can contribute to the development of diseases ranging from”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cole et al. 2009
    • cites Hanke et al. 2012
    • cites Pace et al. 2007
  • It may state two separate claims as one. The quote only partly states this claim.

    Interpretationreasoning

    Experimentally imposed social isolation can have different effects in various animal models; this may be due to species- and sex-related differences in natural social conditions and resulting differences in the contrast condition, and small sample sizes.

    “Experimentally imposed social isolation thus can have different effects in various animal models; this may be due to species- and sex-related differences in the natural social conditions of the animal populations studied and resulting differences in the contrast condition created by experimental social isolation”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one.

    Premisecitation

    Chronic social isolation from same-sex peers in rats elevates nuclear glucocorticoid protein in prefrontal cortex, downregulates glucocorticoid receptor expression in the prefrontal cortex, and decreases cytosolic glucocorticoid receptors in the hippocampus.

    “chronic social isolation from same-sex peers in rats elevates nuclear glucocorticoid protein in prefrontal cortex (Djordjevic et al. 2010), downregulates glucocorticoid receptor expression in the prefrontal cortex (Djordjevic et al. 2010), and decreases cytosolic glucocorticoid receptors in the hippocampus (Dronjak et al. 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Djordjevic et al. 2010 source
    • cites Dronjak et al. 2004
  • It may state two separate claims as one.

    Premisecitation

    A single acute or repeated acute social isolation from a group or from a same-sex sibling increases corticosterone levels in monogamous prairie voles.

    “Studies in monogamous prairie voles, for instance, show that a single acute (e.g., one hour) or repeated acute (e.g., one hour per day for four weeks) social isolation from a group or from a same-sex sibling increases corticosterone levels (e.g., Pournajafi-Nazarloo & Partoo 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pournajafi-Nazarloo & Partoo 2011
  • It may state two separate claims as one.

    Premisecitation

    Following one hour of social isolation from their pair mates, normally monogamous titi monkeys showed a significant increase in plasma cortisol, whereas normally polygynous squirrel monkeys did not.

    “Following one hour of social isolation from their pair mates, the normally monogamous titi monkeys (for whom partner preference is high) showed a significant increase in plasma cortisol, whereas the normally polygynous squirrel monkeys (for whom partner preference is relatively low) did not (Mendoza & Mason 1986a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mendoza & Mason 1986a
  • It may state two separate claims as one.

    Premisecitation

    The HPA axis in squirrel monkeys is unresponsive to isolation from polygamous partners or adult peers, but separation of squirrel monkey mothers from their infant produces significant increases in plasma cortisol levels in both the mother and the infant.

    “In contrast, the HPA axis in the squirrel monkeys is unresponsive to isolation from polygamous partners or adult peers (Hennessy 1986, Mendoza et al. 1992), but the separation of squirrel monkey mothers from their infant produces significant increases in plasma cortisol levels in both the mother and the infant (Coe et al. 1978, Mendoza et al. 1978, Vogt & Levine 1980).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hennessy 1986
    • cites Mendoza et al. 1992 source
    • cites Coe et al. 1978
  • It may state two separate claims as one.

    Premisecitation

    In male Siberian dwarf hamsters, four weeks of social isolation from a female partner versus pair housing with the female partner resulted in elevated plasma cortisol levels but similar levels of epinephrine and testosterone, and lower levels of norepinephrine.

    “The isolated males showed elevated plasma cortisol levels but similar levels of epinephrine and testosterone (and lower levels of norepinephrine) compared to pair-housed males.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castro & Matt 1997
  • It may state two separate claims as one.

    Premisecitation

    Chronic social isolation increases corticosterone levels in rats when experimental animals are socially isolated from a group of same-sex rats, but inconsistencies have also been observed.

    “Studies in rats similarly suggest that chronic social isolation increases corticosterone levels when experimental animals are socially isolated from a group of same-sex rats (Djordjevic et al. 2010; Dronjak et al. 2004; Garrido et al. 2012; Zlatković & Filipović 2012, 2013), but inconsistencies have also been observed (cf. Pournajafi-Nazarloo & Partoo 2011).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Djordjevic et al. 2010 source
    • cites Dronjak et al. 2004
    • cites Garrido et al. 2012
  • It may state two separate claims as one.

    Premisecitation

    Titi monkeys show elevated HPA activity when isolated from their monogamous partner, but they do not show HPA activation when separated from their infant.

    “The titi monkeys show elevated HPA activity when isolated from their monogamous partner, but they do not show HPA activation when separated from their infant (Mendoza & Mason 1986b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mendoza & Mason 1986b
  • It may state two separate claims as one.

    Premisecitation

    A small sample size reduces the likelihood of detecting a true effect, increases the likelihood that the effect size of a true effect is overestimated, and increases the likelihood that a statistically significant effect is not truly different from zero.

    “As Button et al. (2013) detail, a small sample size reduces the likelihood of detecting a true effect (due to low statistical power), increases the likelihood that the effect size of a true effect is overestimated”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Button et al. 2013
  • It may state two separate claims as one.

    Interpretationreasoning

    The nature of the relationship that is disrupted by isolating an animal and the duration of isolation are important influences on the neuroendocrine response to social isolation.

    “the nature of the relationship that is disrupted by isolating an animal and the duration of isolation are important influences on the neuroendocrine response to social isolation.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim.

    Interpretationnone given

    A major advantage of using animal models is the ability to experimentally manipulate social isolation from conspecifics, controlling for other aspects of the environment, to investigate its effects on the SAM and HPA axes.

    “A major advantage of using animal models is the ability to experimentally manipulate social isolation from conspecifics, controlling for other aspects of the environment (e.g., amount of space available, complexity of the environment, thermoregulation), to investigate its effects on the SAM and HPA axes.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one.

    Premisecitation

    In Wistar rats, chronic social isolation increased basal levels of ACTH and corticosterone, whereas no effect of social isolation or social crowding was found for basal catecholamine levels.

    “Chronic social isolation increased basal levels of ACTH and corticosterone, whereas no effect of social isolation (or social crowding) was found for basal catecholamine levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dronjak et al. 2004
  • It may state two separate claims as one.

    Premisecitation

    Prairie voles chronically isolated from their pair-bonded partner show increased corticosterone levels and higher corticosterone levels after a resident-intruder test, whereas prairie voles chronically isolated from a conspecific for whom partner preference is low show no such increase.

    “studies in monogamous prairie voles show that animals that are chronically isolated from their pair-bonded partner show increased corticosterone levels (e.g., Bosch et al. 2009, McNeal et al. 2014) and higher corticosterone levels after a resident-intruder test (Grippo et al. 2007a), whereas prairie voles that are chronically isolated from a conspecific for whom partner preference is low (e.g.,”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bosch et al. 2009
    • cites McNeal et al. 2014
    • cites Grippo et al. 2007a
  • It may state two separate claims as one.

    Premisecitation

    In adult female dairy goats, acute isolation increased norepinephrine levels but produced no change in epinephrine or cortisol levels.

    “A study of neuroendocrine responses to acute isolation in adult female dairy goats also documented increased norepinephrine levels but no change in epinephrine or cortisol levels (Carbonaro et al. 1992).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carbonaro et al. 1992
  • It may state two separate claims as one.

    Premisecitation

    In Wistar rats, repeated acute social isolation produces corticosterone levels that peak at 5 and 15 minutes, plateau through 30 minutes, and return to baseline after 90 minutes.

    “Studies in Wistar rats provide information about the temporal dynamics of the effect of repeated acute social isolation on levels of corticosterone: Levels peak at the 5- and 15-minute intervals, then plateau through the 30-minute interval, and finally return to baseline after 90 minutes of social isolation (Ferland & Schrader 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ferland & Schrader 2011
  • It may state two separate claims as one.

    Premisenone given

    There is not an animal literature on loneliness per se, but there is a large literature in which social animals are randomly assigned either to normal social living conditions or to socially isolated living conditions.

    “There is not an animal literature on loneliness per se, but there is a large literature in which social animals are randomly assigned either to normal social living conditions or to socially isolated living conditions.”
    Quote in the paperNot a substantial claim
  • It may state two separate claims as one.

    Premisecitation

    A functional magnetic resonance imaging study found that perceived isolation was associated with stronger activity in the visual cortex in response to unpleasant social relative to unpleasant nonsocial visual stimuli and weaker activity in the ventral striatal area in response to pleasant social compared to pleasant nonsocial visual stimuli.

    “a functional magnetic resonance imaging study found that perceived isolation was associated with (a) stronger activity in the visual cortex in response to unpleasant social relative to unpleasant nonsocial visual stimuli and (b) weaker activity in the ventral striatal area in response to pleasant social compared to pleasant nonsocial visual stimuli (Cacioppo et al. 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cacioppo et al. 2009
  • It may state two separate claims as one.

    Premisecitation

    Once reintroduced into social settings, isolated male rodents often display a greater propensity for dominant/aggressive behavior, which has parallels in the increased negativity/hostility profile observed in lonely individuals but possibly less so in the socially withdrawn/anxious/depressed profile observed in lonely humans.

    “Once reintroduced into social settings, isolated male rodents often display a greater propensity for dominant/aggressive behavior (Blanchard et al. 2001), which has parallels in the increased negativity/hostility profile observed in lonely individuals but possibly less so in the socially withdrawn/anxious/depressed profile observed in lonely humans (Cacioppo et al. 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Blanchard et al. 2001
    • cites Cacioppo et al. 2006
  • It may state two separate claims as one.

    Interpretationcitation

    The animal research suggests that chronic social isolation between meaningful pairs not only elevates basal levels of glucocorticoids but also tends to enhance the neuroendocrine response to an acute stressor (stress reactivity)-an effect not typically observed in the human literature.

    “The animal research, for instance, suggests that chronic social isolation between meaningful pairs not only elevates basal levels of glucocorticoids (see Table 1) but also tends to enhance the neuroendocrine response to an acute stressor (i.e., stress reactivity)—an effect not typically observed in the human literature.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1
  • It may state two separate claims as one.

    Premisecitation

    The presence of others did not differentially affect the ratings of the severity of stressors for individuals who did and did not feel socially isolated; instead, social interactions were experienced less positively by individuals who felt socially isolated.

    “the presence of others did not differentially affect the ratings of the severity of stressors for individuals who did and did not feel socially isolated; instead, social interactions, which themselves are a potential uplift and a source of pleasure for most individuals, were experienced less positively by individuals who felt socially isolated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hawkley et al. 2003
  • It may state two separate claims as one.

    Premisecitation

    CRH is produced not only by neurons in the medial parvocellular region of the paraventricular nucleus of the hypothalamus but also by cells in the lateral central amygdala that release CRH into the lateral BNST.

    “CRH is produced not only by neurons in the medial parvocellular region of the paraventricular nucleus of the hypothalamus but also by cells in the lateral central amygdala that release CRH into the lateral BNST (Walker & Davis 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Walker & Davis 2008
  • It may state two separate claims as one.

    Interpretationreasoning

    This pattern is similar to the immunologic effects observed in lonely humans, but it is not observed in rodents subject to objective social isolation.

    “This pattern is similar to the immunologic effects observed in lonely humans (Cole et al. 2007, 2011), but it is not observed in rodents subject to objective social isolation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cole et al. 2007
    • cites Cole et al. 2011
  • It may state two separate claims as one.

    Premisecitation

    Several studies in rhesus macaques have shown that unstable social conditions confer risk for greater mortality due to viral infection and induce both socially anxious behavior and immunoregulatory alterations that resemble those observed in lonely humans.

    “Several studies in rhesus macaques have shown that unstable social conditions (experimentally preventing the development of a stable social hierarchy) confer risk for greater mortality due to viral infection (Capitanio et al. 1998, Capitanio & Lerche 1998) and induce both socially anxious behavior and immunoregulatory alterations that resemble those observed in lonely humans (Sloan et al. 2007).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Capitanio et al. 1998
    • cites Capitanio & Lerche 1998
    • cites Sloan et al. 2007
  • It may state two separate claims as one.

    Premisecitation

    In an early test of the buffering hypothesis, lonely participants had higher vascular resistance than nonlonely participants, and vascular resistance was higher during stressors than during baseline, but the interaction did not approach significance.

    “Analyses revealed two main effects—higher vascular resistance in lonely than nonlonely participants and higher vascular resistance during the stressors than during the baseline—whereas the interaction did not approach significance (Cacioppo et al. 2002b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cacioppo et al. 2002b
  • It may state two separate claims as one.

    Premisecitation

    There is now a sizable literature in humans and animals for social buffering, including an attenuation of the sympathetic and HPA response to a stressor.

    “There is now a sizable literature in humans and animals for social buffering, including an attenuation of the sympathetic and HPA response to a stressor (Cacioppo et al. 1998, Hostinar et al. 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cacioppo et al. 1998
    • cites Hostinar et al. 2014
  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    These differences raise the possibility that the BNST plays a key role in the effects of perceived social isolation from a significant conspecific on basal HPA functioning.

    “These differences raise the possibility that the BNST plays a key role in the effects of perceived social isolation from a significant conspecific on basal HPA functioning.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    The distinction between the effects of the amygdala versus the BNST on HPA activity may also be relevant to understanding how social isolation affects neuroendocrine activity and mortality in contemporary society.

    “The distinction between the effects of the amygdala versus the BNST on HPA activity may also be relevant to understanding how social isolation affects neuroendocrine activity and mortality in contemporary society.”
    Quote in the paperNot a substantial claim
  • It may state two separate claims as one.

    Premisecitation

    Perceived social isolation has typically been associated with changes in tonic functioning such as basal differences in sympathetic vascular tonus, cortisol awakening responses, elevated evening cortisol levels, circulating glucocorticoid levels, and decreased glucocorticoid receptor sensitivity.

    “perceived social isolation has typically been associated with changes in tonic functioning such as basal differences in sympathetic vascular tonus (as gauged by vascular resistance), cortisol awakening responses, elevated evening cortisol levels, circulating glucocorticoid levels, and decreased glucocorticoid receptor sensitivity (e.g., Cacioppo et al. 2003, Hawkley et al. 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cacioppo et al. 2003
    • cites Hawkley et al. 2012
  • It may state two separate claims as one.

    Interpretationreasoning

    These behavioral findings suggest that perceived social isolation may both increase surveillance for social threats and decrease the rewards that one derives from interpersonal relationships.

    “These behavioral findings suggest that perceived social isolation may both increase surveillance for social threats and decrease the rewards that one derives from interpersonal relationships.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one.

    Premisecitation

    In an experience sampling study, undergraduate students were just as likely to interact with other people whether or not they felt socially isolated; for those who felt isolated, the interactions were rated as being of poorer quality and as providing less support and comfort.

    “In an experience sampling study, undergraduate students were just as likely to interact with other people whether or not they felt socially isolated. For those who felt isolated, the interactions were rated as being of poorer quality and as providing less support and comfort (Hawkley et al. 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hawkley et al. 2003
  • It may state two separate claims as one.

    Premisecitation

    The animal model for repeated social threat activates neuroendocrine responses in both the HPA and SAM axes, and it also induces proinflammatory/glucocorticoid-resistant immune dynamics analogous to those observed in lonely humans.

    “The animal model for repeated social threat activates neuroendocrine responses in both the HPA and SAM axes, and it also induces proinflammatory/glucocorticoid-resistant immune dynamics (Hanke et al. 2012, Powell et al. 2013) analogous to those observed in lonely humans (Cole 2008; Cole et al. 2007, 2011).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hanke et al. 2012
    • cites Powell et al. 2013
    • cites Cole 2008
  • It may state two separate claims as one.

    Premisecitation

    The HPA axis is under the influence of oxytocin and vasopressin, which exert opposite effects: oxytocin decreases and vasopressin increases HPA axis activity.

    “The HPA axis is also under the influence of oxytocin and vasopressin, and these hormones exert opposite effects on the HPA axis, with oxytocin decreasing and vasopressin increasing HPA axis activity (De Boer et al. 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites De Boer et al. 2012
  • It may state two separate claims as one.

    Premisecitation

    In a similar study, Steptoe et al. (2004) reported the interaction to be significant, but it held only for women and only for diastolic blood pressure, not systolic blood pressure or heart rate.

    “In a similar study, Steptoe et al. (2004) reported the interaction to be significant, but it held only for women and only for diastolic blood pressure, not systolic blood pressure or heart rate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Steptoe et al. 2004
  • It may state two separate claims as one.

    Premisereasoning

    Acute stressors used commonly in human studies are relatively mild models of the stressors encountered in modern societies, whereas acute stressors used in animal studies are relatively severe.

    “the acute stressors used commonly in human studies are relatively mild (e.g., public speaking, serial subtraction) models of the stressors encountered in modern societies. In contrast, the acute stressors used in animal studies are relatively severe (e.g., two hours of immobilization simulating the collapse of a burrow, two hours in a 4°C chamber).”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one.

    Premisecitation

    The amygdala is especially important for rapid-onset, short-duration behaviors that occur in response to specific threats, whereas the BNST appears to mediate slower-onset, longer-lasting responses that frequently accompany sustained threats and that may persist even after threat termination.

    “The amygdala is especially important for rapid-onset, short-duration behaviors that occur in response to specific threats, whereas the BNST appears to mediate slower-onset, longer-lasting responses that frequently accompany sustained threats and that may persist even after threat termination (Walker & Davis 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Walker & Davis 2008
  • It may state two separate claims as one.

    Premisenone given

    Social isolation of male adult rodents is generally associated with a substantial reduction in physical activity and a notable decrease in fighting and other overtly aggressive behavior.

    “social isolation of male adult rodents is generally associated with a substantial reduction in physical activity (and attending decreases in activity-related SNS activity) and a notable decrease in fighting and other overtly aggressive behavior.”
    Quote in the paperNot a substantial claim
  • It may state two separate claims as one.

    Premisecitation

    Experimentally imposed social instability induces SNS innervation of the lymph node tissues in which immune cells coordinate responses to tissue injury and infection, even though social instability does not appear to alter circulating SAM catecholamine levels.

    “Experimentally imposed social instability also induces SNS innervation of the lymph node tissues in which immune cells coordinate responses to tissue injury and infection (Sloan et al. 2007, 2008) even though social instability does not appear to alter circulating SAM catecholamine levels.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sloan et al. 2007
    • cites Sloan et al. 2008
  • It may state two separate claims as one.

    Interpretationreasoning

    Such observations suggest that nonhuman primate models may provide an ethologically valid context for analyzing the effects of perceived social isolation and may play an important role in identifying the most appropriate small rodent models for mechanistic investigations.

    “Such observations suggest that nonhuman primate models may provide an ethologically valid context for analyzing the effects of perceived social isolation and may play an important role in identifying the most appropriate small rodent models for mechanistic investigations.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    A full understanding of the core psychological and biological features of human loneliness requires a consideration of the brain's interpretation of the social environment.

    “To date it is clear that a full understanding of the core psychological and biological features of human loneliness requires a consideration of the brain’s interpretation of the social environment.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The brain is the key organ of social connections and processes.
  • It may state two separate claims as one.

    Interpretationnone given

    Chronic social isolation is associated with relatively consistent increases in HPA axis activity but little alteration in SAM catecholamine activity.

    “(a) chronic social isolation is associated with relatively consistent increases in HPA axis activity but little alteration in SAM catecholamine activity”
    Quote in the paperSubstantial claim
55 of 55
  • The paper relies on this without support.

    In many contexts across human history, a chief threat to a person’s reproductive success and survival has come from other humans.

    “In many contexts across human history, a chief threat to a person’s reproductive success and survival has come from other humans.”
  • The paper relies on this without support.

    The human brain categorizes, abstracts, interprets, and evaluates incoming stimuli in light of current states and goals as well as prior knowledge and predispositions.

    “The human brain does not simply respond to stimuli (including people) in an invariant fashion, but rather it categorizes, abstracts, interprets, and evaluates incoming stimuli in light of current states and goals as well as prior knowledge and predispositions.”
  • The paper relies on this without support.

    The HPA axis includes a negative feedback mechanism to limit its circulating hormonal outputs.

    “Unlike the adrenal medulla of the SAM axis, the adrenal cortex of the HPA axis is necessary for survival, and the HPA axis includes a negative feedback mechanism to limit its circulating hormonal outputs.”
  • The paper relies on this without support.

    The brain is the key organ of social connections and processes, and this should be true for other species for which sociality has been a central feature of life for millions of years.

    “The idea that the brain is the key organ of social connections and processes should be true for other species for which sociality has been a central feature of life for millions of years.”
  • The paper relies on this without support.

    The extent to which glucocorticoid receptors become insensitive to glucocorticoid signals is reflected in an attenuation of the established positive correlation between cortisol levels and the circulating neutrophil:lymphocyte and neutrophil:monocyte ratios.

    “The rationale is that the extent to which the glucocorticoid receptors become insensitive (resistant) to glucocorticoid signals should be reflected in an attenuation of the established positive correlation between cortisol levels and the circulating neutrophil:lymphocyte and neutrophil:monocyte ratios.”
  • The paper relies on this without support.

    Cortisol acts on glucocorticoid receptors in leukocytes, leading to a suppression of proinflammatory gene networks.

    “cortisol acts on the glucocorticoid receptors in leukocytes, leading to a suppression of proinflammatory gene networks”
  • The paper relies on this without support.

    The brain is the key organ of social connections and processes.

    “The brain is the key organ of social connections and processes”
  • The paper relies on this without support.

    The same objective social relationship can be experienced as caring and protective or as exploitive and isolating.

    “the same objective social relationship can be experienced as caring and protective or as exploitive and isolating”
  • The paper relies on this without support.

    Social isolation has been a recognized major risk factor for morbidity and mortality in humans for more than a quarter of a century.

    “Social isolation has been recognized as a major risk factor for morbidity and mortality in humans for more than a quarter of a century.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Metadata

Authors
Cacioppo, J. T., Cacioppo, S., Capitanio, J. P., & Cole, S. W.
Affiliations
  • University of Chicago (US)
  • University of California, Davis (US)
  • David Geffen School of Medicine, University of California, Los Angeles, California 90095;
Venue
Annual Review of Psychology
Published
2015-01-03
Volume
66
Issue
1
Pages
733-767
ISSN
  • 0066-4308 (ISSN-L)
  • 1545-2085
OpenAlex
W2133556218
Cited by
977
References
126
Citations by year
2026: 103 · 2025: 117 · 2024: 99 · 2023: 106 · 2022: 125 · 2021: 107 · 2020: 86 · 2019: 89 · 2018: 59 · 2017: 35 · 2016: 31 · 2015: 19
FWCI
2.36
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Psychology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (P51OD011107)
  • National Institute on Aging (R37AG033590)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
  • Social Sciences › Health › Health disparities and outcomes
Keywords
social isolation, loneliness, neuroendocrinology, hypothalamic-pituitary-adrenal axis, chronic stress, mortality risk, social bonds, perceived social isolation, genetic mechanisms, neurobiological mechanisms
MeSH terms
Animals, Brain, Humans, Loneliness, Social Isolation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review