Louise C. Hawkley & John T. Cacioppo University of Chicago
Prepared for The New York Academy of Medicine/Royal Society of
Medicine New York, NY September 27, 2011 Slide 2 Slide 3
Experimental Effects of Social Isolation in Non-Humans Decreases
lifespan of the fruit fly, Drosophila melanogaster (Ruan & Wu,
PNAS, 2008) Promotes the development of obesity and Type 2 diabetes
in mice (Nonogaki, Nozue, & Oka, Endocrinology, 2007) Delays
the positive effects of running on neurogenesis in adult rats
(Stranahan, Khalil, & Gould, Nature Neuroscience, 2006)
Increases activation of the sympatho-adrenomedullary response to an
acute immobilization or cold stressor in rats (Dronjak, Gavrilovi,
Filipovi, & Radoji, Physiology & Behavior, 2004) Decreases
the expression of genes regulating glucocorticoid response
[glucocorticoid receptor (GR), mineralocorticoid receptor (MR),
11b-hydroxysteroid dehydrogenases 1 & 2 (11b-HSD1 &
11b-HSD2)] in the frontal cortex of piglets (Poletto, Steibel,
Siegford, & Zanella, Brain Research, 2006) Decreases open field
activity, increases basal cortisol concentrations, and decreases
lymphocyte proliferation to mitogens in pigs (Kanitz, Tuchscherer,
Puppe, Tuchscherer, & Stabenow, Brain, Behavior, and Immunity,
2004) Larger morning rises in cortisol in squirrel monkeys (Lyons,
Ha, & Levine, Hormones and Behavior, 1995) Higher 24 hr urinary
catecholamines and evidence of oxidative stress in the aortic arch
of the Watanabe Heritable Hyperlipidemic rabbit (Nation, et al.,
Psychosomatic Medicine, 2008) Slide 4 Level of Social Integration
and Age-Adjusted Mortality in Five Prospective Studies House,
Landis, & Umberson, 1988 Slide 5 For humans, simply feeling
isolated is detrimental to health and well-being. This distressing
feeling is called LONELINESS Slide 6 Slide 7 Defining loneliness
Discrepancy between actual and desired quantity and/or quality of
social relationships. Aversive feeling Slide 8 Loneliness
intensity: Age differences? 50-68 year-olds 18-25 year-olds Few
Many Not lonelyLonely Slide 9 Perceived Social Isolation in Humans
Diminished immunity (Kiecolt-Glaser et al., Psychosomatic Medicine,
1984; Pressman et al., Health Psychology, 2005) Less salubrious
sleep (Hawkley et al., 2010; Jacobs et al., Journal of the American
Geriatric Society, 2006; Pressman et al., Health Psychology, 2005)
Progression of Alzheimers Disease (Wilson et al., Archives of
General Psychiatry, 2007) Reduction in independent living (Russell
et al., Psychology & Aging, 1997) Obesity (Lauder et al.,
Psychology, Health, & Medicine, 2006) Alcoholism (Akerlind
& Hornquist, Social Science & Medicine, 1992) Reduced
physical activity (Hawkley, Thisted, & Cacioppo, 2009) Slide 10
Perceived Social Isolation in Humans Altered gene transcription
favoring pro-inflammatory status (Cole et al., 2007, 2010).
Increased hypothalamic pituitary adrenocortical activity (Steptoe
et al., 2004) Depression (Heikkinen & Kauppinen, Archives of
Gerontology and Geriatrics, 2004; ) and suicidal ideation and
behavior (Rudatsikira, Muula, Siziya, & Twa-twa, BMC
Psychiatry, 2007) Poorer health (Caspi et al., Archives of
Pediatric Adolescent Medicine, 2006; Seeman, American Journal of
Health Promotion, 2000; Thurston & Kubzansky, 2009) Mortality
(Olsen et al., 1991; Patterson & Veenstra, 2010; Penninx et
al., 1999; Shiovitz-Ezra & Ayalon, 2009). Slide 11 Socially
Isolated Children 20 Years Later Risk of Cardiovascular Disease
Caspi, Harrington, Moffitt, Milne, & Poulton (ARCH PEDIATR
ADOLESC MED, 2006) Socially isolated children were at significant
risk of poor adult health compared with non-isolated children (risk
ratio, 1.37; 95% confidence interval, 1.17-1.61). --this
association was independent of other well established childhood
risk factors for poor adult health (low childhood socioeconomic
status, low childhood IQ, childhood overweight), was not accounted
for by health damaging behaviors (lack of exercise, smoking,
alcohol misuse), and was not attributable to greater exposure to
stressful life events. In addition, longitudinal findings showed
that chronic social isolation across multiple developmental periods
had a cumulative, dose-response relationship to poor adult health
(risk ratio, 2.58; 95% confidence interval, 1.46-4.56). Slide 12
Health & Retirement Study (HRS) Nationally representative,
longitudinal study of older Americans (born before 1953)
re-interviewed every two years. Data from 2002, 2004, 2006, 2008 N
= 2,101 in Year 2002 Effect of loneliness on mortality risk over a
six-year period, 2002-2008 HR = 1.14 (1.06-1.23) Those with highest
loneliness levels were 2.21X as likely to die as those with lowest
levels Luo, Hawkley, Waite, & Cacioppo, under review Slide 13
Model IModel IIModel IIIModel IV Variables Hazard ratio CI Hazard
ratio CI Hazard ratio CI Hazard Ratio CI Loneliness in
20021.14***[1.06, 1.23] Married Relatives living nearby Friends
living nearby Sleep quality poor Physical exercise Past smoker a
Current smoker a Depressive symptoms in 2002 Self-rated health in
2002 Functional limitations in 2002 Age1.09***[1.08, 1.10]
Female.49***[.39,.62] Black a.90[.62, 1.30] Hispanic a 1.09[.69,
1.73] Education1.02[.98, 1.06] Household income
(log).81***[.73,.89] Household assets (log).95**[.91,.99] Hazard
ratios of the Weibull models of mortality from 2002 to 2008 Slide
14 Model IModel IIModel IIIModel IV Variables Hazard ratio CI
Hazard ratio CI Hazard ratio CI Hazard Ratio CI Loneliness in
20021.14***[1.06, 1.23]1.13**[1.05, 1.22]1.12**[1.03,
1.21]1.07+[.99, 1.17] Married.91[.69, 1.21].93[.70, 1.23].87[.65,
1.15] Relatives living nearby.92[.72, 1.17].92[.72, 1.17].93[.72,
1.19] Friends living nearby.86[.66, 1.11].95[.73, 1.24].91[.70,
1.19] Sleep quality poor1.02[.96, 1.08].94+[.89, 1.00] Physical
exercise.60***[.47,.78].79+[.61, 1.04] Past smoker a 1.37*[1.06,
1.78]1.30+[1.00, 1.69] Current smoker a 1.57*[1.06, 2.32]1.46+[.98,
2.17] Depressive symptoms in 2002.98[.89, 1.07] Self-rated health
in 2002.65***[.57,.75] Functional limitations in 2002 1.08**[1.02,
1.13] Age1.09***[1.08, 1.10]1.09***[1.07, 1.10]1.09***[1.07,
1.10]1.08***[1.07, 1.10]
Female.49***[.39,.62].48***[.38,.61].50***[.39,.65].50***[.38,.64]
Black a.90[.62, 1.30].90[.62, 1.32].90[.62, 1.31].78[.54, 1.13]
Hispanic a 1.09[.69, 1.73]1.09[.69, 1.74]1.06[.67, 1.69]1.02[.64,
1.61] Education1.02[.98, 1.06]1.02[.98, 1.06]1.02[.98,
1.07]1.05*[1.01, 1.09] Household income
(log).81***[.73,.89].82***[.74,.91].83***[.74,.92].86**[.77,.96]
Household assets (log).95**[.91,.99].95*[.92,.99].96*[.92,
1.00].97[.93, 1.01] Hazard ratios of the Weibull models of
mortality from 2002 to 2008 3 2 1 Slide 15 Loneliness: Conceptual
Background Aversive: Social equivalent to physical pain
(Eisenberger & Lieberman, 2004) Social rejection activates
affective and sensory components of physical pain (Kross et al.,
2011) Cacioppo & Hawkley, TICS, 2009 Slide 16 Loneliness:
Conceptual Background Appetitive: Functions like hunger and thirst
to motivate & reward formation and maintenance of social
connections crucial for the survival of the genes (Cacioppo &
Hawkley, TICS, 2009) Pleasant social - Pleasant nonsocial Ventral
striatum + - Cacioppo et al., 2009 Slide 17 Consequences of
Loneliness Neurobiological Cardiovascular
Hypothalamic-pituitary-adrenocortical axis Gene transcription
Behavioral Physical activity Functional limitations Sleep quality
Slide 18 Total Peripheral Resistance in 18-25 yr-olds Cacioppo,
Hawkley, Crawford, et al., 2002; Hawkley, Burleson, Berntson, &
Cacioppo, 2003 Altered blood pressure regulation in lonely young
adults Until about age 55, the primary determinant of increased SBP
is TPR (Franklin et al., 1997). SBP = TPR * CO Slide 19 * Systolic
Blood Pressure in 50-68 yr-olds Hawkley, Berry, Masi, &
Cacioppo, Psychology & Aging, 2006 Loneliness is associated
with elevated SBP in older adults in CHASRS (50-68 years old) Slide
20 BP5BP5 L1 L2 L3 L4 L5
BP1BP1BP2BP2BP3BP3BP4BP4.773**.768**.498**.503** -.004.011.152.15*
-.080 Time-varying covariates: Social network size, Drinking,
smoking, BMI, exercise, Chronic conditions, CV & anti-lipid
meds 5.190* 12345 -.053-.021-.184*-.078 Hawkley, Thisted, Masi,
& Cacioppo, Psychology & Aging, 2010 Loneliness predicts
greater increases in SBP Demographic Covariates: Age Gender
Race/ethnicity Education 432 Slide 21 Total Peripheral Resistance
Endothelial function SNS Pathway HPA Pathway Oxidative stress
Psychosocial Factors: LONELINESS + Personality CV Risk Demographics
SES RISK FACTORS Physiological mechanisms What mechanisms
contribute to loneliness differences in TPR in younger adults? What
mechanisms contribute to increased risk for chronic disease and
disability? Slide 22 Adam, Hawkley, Kudielka, & Cacioppo, PNAS,
2006 Loneliness predicts altered HPA regulation In 50-68 year-olds,
the cortisol stress reaction ramps up more quickly and peaks higher
in lonely than in nonlonely adults. Salivary cortisol (ng/ml) Slide
23 Adam, Hawkley, Kudielka, & Cacioppo, PNAS, 2006 Day Before
Perceived Isolation Cortisol Awakening Response Same Day Perceived
Isolation Same Day Fatigue Day Before Reports Day-Specific Morning
Cortisol Parameters Same Day Reports -.03 -.07* Higher morning
cortisol, less fatigue later that day.09** n.s. -.05 n.s. Higher
day before loneliness, higher next day awakening response Morning
Cortisol Level Day Before Fatigue Loneliness predicts altered HPA
regulation Slide 24 Lonely Non-lonely Difference: p =.0001
Up-regulated Loneliness-related transcripts 25 50 75 100 125 0
Down-regulated 150 Loneliness is associated with altered gene
transcription Cole, Hawkley, Arevalo, Sung, Rose, & Cacioppo,
2007 Slide 25 Down-regulated genes Type 1 interferon; innate
antiviral responses; innate antimicrobial responses Up-regulated
genes leukocyte activation and inflammation; pro-inflammatory
cytokines; cellular responses to oxidative stress Differences in
gene expression were replicated in a confirmation sample (N = 93)
Differences in gene expression were linked to perceived social
isolation, not objective social isolation, indicating the
instrumental role of the CNS Glucocorticoid p =.033 Isolated
promoter sites / gene.10.20.30.40.00 Integrated NF- B p =.011
Isolated promoter sites / gene.10.20.30.40.50.00 Integrated
Difference.1.3110 0.2.4.6.8.10.12 p =.007 3 Genome cis-structural
NF- B / GRE ratio Observed ratio = 5.08 (chance: 35/10,000) Gene
expression: Pro-inflammatory profile Cole, Hawkley, Arevalo, Sung,
Rose, & Cacioppo, 2007; Cole, Hawkley, Arevalo, & Cacioppo,
2010 Slide 26 Socially affine conditions (safe, accepting) increase
threat of viral infection via increased physical & intimate
contact love = viruses Socially hostile conditions (social
conflict, rejection) increase threat of bacterial infection via
increased likelihood of injury. war = bacteria Cole, Hawkley,
Arevalo, & Cacioppo, PNAS, 2010 Types of social environments
differ in the types of immune challenge they present Slide 27
Transcript origin diagnosticity score (Z-score units relative to
genome-wide average) Monocytes Dendritic cells NK cells CD4+ T
cells CD8+ T cells B cells Leukocyte subset contribution to
differential gene expression in lonely
individuals.0070.0069.9868.9988.9999.0096 Monocytes Dendritic cells
NK cells CD4+ T cells CD8+ T cells B cells.0001.9245.9999.2482 A.
Discovery sample B. Confirmation sample Diagnosticity p-value Cole,
Hawkley, Arevalo, & Cacioppo, PNAS, 2010 Slide 28 63% reported
spendingSlide 29 Loneliness predicts decreases in physical activity
* * * 100% 75% Year 132 Hawkley, Thisted, & Cacioppo, Health
Psychology, 2009 In 50-68 year-olds, loneliness was associated with
an increased rate of discontinuation of physical activity over a
two-year period. Slide 30 L2 L4 L6 FL2 FL4 FL6 Loneliness predicts
increases in functional limitations Estimates hold constant
sociodemographic variables plus social integration health behaviors
Luo, Hawkley, Waite, & Cacioppo, under review * * * * Slide 31
Loneliness & Implicit Vigilance for Social Threat Egidi,
Shintel, Nusbaum, & Cacioppo, unpublished Social Emotional
Stroop Negative social Positive social Green Blue Red Yellow Blue
Yellow Green Red Loved Belong Rejected Isolated Slide 32
Loneliness, vulnerability and poor sleep quality Undergraduates at
OSU: loneliness was associated with daytime dysfunction (Cacioppo,
Hawkley, et al., 2002) Sleep cap study of undergraduates showed
that loneliness was associated with greater sleep disruption
(micro-awakenings), but not with less sleep duration (Cacioppo,
Berntson, Hawkley, et al., 2002) Hutterites: lower levels of
loneliness than general population, but individual differences were
associated with poorer sleep quality as measured by an index of
sleep fragmentation (Kurina et al., in press). Slide 33 Loneliness
predicts daytime dysfunction, not sleep duration (50-68 yr-olds)
Hawkley, Preacher, & Cacioppo, 2010 Slide 34 Loneliness &
Behavioral Confirmation Rotenberg, 1994 Slide 35 Loneliness is
contagious Cacioppo, Fowler, & Christakis, 2009 Lonely people
are isolated (quarantined) Slide 36 Negativity fosters even more
negativity, in mood and social interaction quality (Hawkley,
Preacher, & Cacioppo, 2008) Slide 37 Loneliness Interventions
Meta-analytic review Keywords: loneliness, intervention, treatment,
prospective, medication, and/or pharmacology Published between 1970
and September 2009 Slide 38 Loneliness interventions (1970-2009)
meta-analysis Masi, Chen, Hawkley, & Cacioppo, Personality
& Social Psychology Review, 2010 50 27 0 20 Slide 39 Loneliness
interventions meta-analysis: Randomized group comparison (N = 20)
Mean effect size = -0.198 (95% CI: -0.32, -0.08) Masi, Chen,
Hawkley, & Cacioppo, Personality & Social Psychology
Review, 2010 Intervention type Social cognitive training (4
studies) = -0.598** Reframing of negative social experiences;
modifying attributional styles (e.g., McWhirter & Horan, 1996)
Social support (12 studies) = -0.162* Group meetings to share
stressful experiences and coping strategies (e.g., Samarel et al.,
2002) Social skills training (2 studies) = -0.062 How to initiate
and maintain positive friendships (e.g., Kremers et al., 2006)
Social access (2 studies) = 0.017 Internet access & training:
chat room, email exchange (e.g., White et al., 2002) Slide 40 L1 L2
L3 L4 L5 D1 D2 D3 D4D4 D4D4 D5 Age Female Black Hispanic Education
Married/live-in partner Psych1 Antidepress1 PhysFx1 Age Female
Black Hispanic Education Married/live-in partner Psych1
Antidepress1 PhysFx1 Age Female Black Hispanic Education
Married/live-in partner Psych2 Antidepress2 PhysFx2 Age Female
Black Hispanic Education Married/live-in partner Psych3
Antidepress3 PhysFx3 Age Female Black Hispanic Education
Married/live-in partner Psych4 Antidepress4 PhysFx4 Age Female
Black Hispanic Education Married/live-in partner Psych5
Antidepress5 PhysFx5 Age Female Black Hispanic Education
Married/live-in partner Psych2 Antidepress2 PhysFx2 Age Female
Black Hispanic Education Married/live-in partner Psych3
Antidepress3 PhysFx3 Age Female Black Hispanic Education
Married/live-in partner Psych4 Antidepress4 PhysFx4 Age Female
Black Hispanic Education Married/live-in partner Psych5
Antidepress5 PhysFx5.79**.57**.10.18*.58**.45**.43*.33*.30*
Loneliness predicts increases in depressive symptoms Cacioppo,
Hawkley, & Thisted, Psychology & Aging, 2010 Slide 41
Loneliness reduction effects accumulate If interventions to reduce
loneliness by one standard deviation were made one and two years
prior to assessing depressive symptoms, both would have an effect
and would together result in an average reduction in depressive
symptoms of 0.34 standard deviations (95% CI: 0.21, 0.46, P
