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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

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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, Gavrilović, Filipović, & Radojčić, 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)

4 Level of Social Integration and Age-Adjusted Mortality in Five Prospective Studies House, Landis, & Umberson, 1988

5 For humans, simply feeling isolated is detrimental to health and well-being. This distressing feeling is called LONELINESS

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7 Defining loneliness Discrepancy between actual and desired quantity and/or quality of social relationships. Aversive feeling

8 Loneliness intensity: Age differences? year-olds year-olds Few Many Not lonelyLonely

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 Alzheimer’s 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)

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).

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, ). --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, ).

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, HR = 1.14 ( ) Those with highest loneliness levels were 2.21X as likely to die as those with lowest levels Luo, Hawkley, Waite, & Cacioppo, under review

13 Model IModel IIModel IIIModel IV Variables Hazard ratio CI Hazard ratio CI Hazard ratio CI Hazard Ratio CI Loneliness in ***[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

14 Model IModel IIModel IIIModel IV Variables Hazard ratio CI Hazard ratio CI Hazard ratio CI Hazard Ratio CI Loneliness in ***[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 [.89, 1.07] Self-rated health in ***[.57,.75] Functional limitations in **[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

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

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

17 Consequences of Loneliness Neurobiological Cardiovascular Hypothalamic-pituitary-adrenocortical axis Gene transcription Behavioral Physical activity Functional limitations Sleep quality

18 Total Peripheral Resistance in 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

19 * Systolic Blood Pressure in yr-olds Hawkley, Berry, Masi, & Cacioppo, Psychology & Aging, 2006 Loneliness is associated with elevated SBP in older adults in CHASRS (50-68 years old)

20 BP5BP5 L1 L2 L3 L4 L5 BP1BP1BP2BP2BP3BP3BP4BP4.773**.768**.498**.503** * Time-varying covariates: Social network size, Drinking, smoking, BMI, exercise, Chronic conditions, CV & anti-lipid meds …5.190* …1…2…3…4… *-.078 Hawkley, Thisted, Masi, & Cacioppo, Psychology & Aging, 2010 Loneliness predicts greater increases in SBP Demographic Covariates: Age Gender Race/ethnicity Education …4…3…2

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?

22 Adam, Hawkley, Kudielka, & Cacioppo, PNAS, 2006 Loneliness predicts altered HPA regulation In year-olds, the cortisol “stress” reaction ramps up more quickly and peaks higher in lonely than in nonlonely adults. Salivary cortisol (ng/ml)

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 * Higher morning cortisol, less fatigue later that day.09** n.s n.s. Higher day before loneliness, higher next day awakening response Morning Cortisol Level Day Before Fatigue Loneliness predicts altered HPA regulation

24 Lonely Non-lonely Difference: p =.0001 Up-regulated Loneliness-related transcripts Down-regulated 150 Loneliness is associated with altered gene transcription Cole, Hawkley, Arevalo, Sung, Rose, & Cacioppo, 2007

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 Integrated NF-  B p =.011 Isolated promoter sites / gene Integrated Difference p = 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

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

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 Monocytes Dendritic cells NK cells CD4+ T cells CD8+ T cells B cells A. Discovery sample B. Confirmation sample Diagnosticity p-value Cole, Hawkley, Arevalo, & Cacioppo, PNAS, 2010

28 63% reported spending <30 min/day (range = 1 – 107 min/day) 11% did not report any vigorous activity during the past 2 weeks Physical activity in year-old CHASRS participants

29 Loneliness predicts decreases in physical activity * * * 100% 75% Year  132 Hawkley, Thisted, & Cacioppo, Health Psychology, 2009 In year-olds, loneliness was associated with an increased rate of discontinuation of physical activity over a two-year period.

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 * * * *

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

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).

33 Loneliness predicts daytime dysfunction, not sleep duration (50-68 yr-olds) Hawkley, Preacher, & Cacioppo, 2010

34 Loneliness & Behavioral Confirmation Rotenberg, 1994

35 Loneliness is contagious Cacioppo, Fowler, & Christakis, 2009 Lonely people are isolated (“quarantined”)

36 Negativity fosters even more negativity, in mood and social interaction quality (Hawkley, Preacher, & Cacioppo, 2008)

37 Loneliness Interventions Meta-analytic review Keywords: loneliness, intervention, treatment, prospective, medication, and/or pharmacology Published between 1970 and September 2009

38 Loneliness interventions ( ) meta-analysis Masi, Chen, Hawkley, & Cacioppo, Personality & Social Psychology Review,

39 Loneliness interventions meta-analysis: Randomized group comparison (N = 20) Mean effect size = (95% CI: -0.32, -0.08) Masi, Chen, Hawkley, & Cacioppo, Personality & Social Psychology Review, 2010 Intervention type Social cognitive training (4 studies) = ** ○ Reframing of negative social experiences; modifying attributional styles (e.g., McWhirter & Horan, 1996) Social support (12 studies) = * ○ Group meetings to share stressful experiences and coping strategies (e.g., Samarel et al., 2002) Social skills training (2 studies) = ○ How to initiate and maintain positive friendships (e.g., Kremers et al., 2006) Social access (2 studies) = ○ Internet access & training: chat room, exchange (e.g., White et al., 2002)

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

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<0.0001). VanderWeele, Hawkley, Thisted, & Cacioppo, JCCP, 2011

42 Summary Loneliness is not equivalent to being alone. Loneliness is not inevitable with age. Loneliness is painful. Loneliness feels unsafe and elicits implicit vigilance for threat. Negative social Positive social Green Blue Red Yellow Blue Yellow Green Red Loved Belong Rejected Isolated

43 Summary Feeling lonely/isolated has neurobiological and behavioral consequences. Cardiovascular health: acceleration of age-related increases in SBP HPA regulation: elevated cortisol Gene transcription: pro-inflammatory profile Functional limitations Impaired sleep quality Depressive symptoms Effects are not explained by social support, perceived stress, hostility Effects are not explained by health behaviors

44 Summary Effects of loneliness accumulate (Caspi et al., 2006; Hawkley et al., 2010), and interventions to reduce loneliness may also accumulate to benefit health outcomes (e.g., depressive symptoms). Optimal age/time of intervention(s) may differ depending on outcome Loneliness and well-being ? /learn_2.jpg

45 With thanks to collaborators and contributors: John T. Cacioppo, Ph.D., University of Chicago Steve Cole, Ph.D., UCLA Emma Adam, Ph.D., Northwestern University Ron Thisted, Ph.D. University of Chicago Linda Waite, Ph.D. University of Chicago Ye Luo, Ph.D., Clemson University Catherine Norris, Ph.D., Dartmouth University Chris Masi, M.D., Ph.D., University of Chicago Kristopher Preacher, Ph.D., University of Kansas And the staff of the University of Chicago Social Neuroscience Laboratory Jessica Bell, M. A. Hsi-Yuan Chen, M.A. Laura Finch, B.A. Danielle Lerner, B.A. Sara Polis, M.A. Josh Rooks, B.A. Ashley Smith, M.A. This research was supported by grants from the National Institute on Aging to J. T. Cacioppo (PI), PO1 AG & RO1 AG , and to L. C. Hawkley (PI), RO1 AG


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