New Directions in Geroscience: Integrating Social and Behavioral Drivers of Biological Aging.

ABSTRACT: The "geroscience hypothesis" posits that slowing the physiological processes of aging would lead to delayed disease onset and longer healthspan and lifespan. This shift from a focus on solely treating existing disease to slowing the aging process is a shift toward prevention, including a focus on risk factors found in the social environment. Although geroscience traditionally has focused on the molecular and cellular drivers of biological aging, more fundamental causes of aging may be found in the social exposome-the complex array of human social environmental exposures that shape health and disease. The social exposome may interact with physiological processes to accelerate aging biology. In this commentary, we review the potential of these insights to shape the emerging field of translational geroscience. The articles in this special issue highlight how social stress and social determinants of health are associated with biomarkers of aging such as inflammation, epigenetic clocks, and telomeres, and spotlight promising interventions to mitigate stress-related inflammation. For geroscience to incorporate the social exposome into its translational agenda, studies are needed that elucidate and quantify the effects of social exposures on aging and that consider social exposures as intervention targets. The life course perspective allows us to measure both exposures and aging biology over time including sensitive periods of development and major social transitions. In addition, given rapid changes in the measurement of aging biology, which include machine learning techniques, multisystem phenotypes of aging are being developed to better reflect whole body aging, replacing reliance on single system biomarkers. In this expanded and more integrated field of translational geroscience, strategies targeting factors in the social exposome hold promise for achieving aging health equity and extending healthy longevity.

Glucocorticoid and Adrenergic Receptor Distribution Across Human Organs and Tissues: A Map for Stress Transduction.

OBJECTIVE: Psychosocial stress is transduced into disease risk through energy-dependent release of hormones from the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes. The levels of glucocorticoid and adrenergic hormones, together with the sensitivity of tissues to their signaling, define stress responses. To understand existing pathways responsible for the psychobiological transduction of stressful experiences, we provide a quantitative whole-body map of glucocorticoid and adrenergic receptor (AR) expression. METHODS: We systematically examined gene expression levels for the glucocorticoid receptor (GR), α- and ß-ARs (AR-α1B, AR-α2B AR-ß2, and AR-ß3), across 55 different organs using the Human Protein Atlas and Human Proteome Map datasets. Given that mitochondria produce the energy required to respond to stress, we leveraged the Human Protein Atlas and MitoCarta3.0 data to examine the link between stress hormone receptor density and mitochondrial gene expression. Finally, we tested the functional interplay between GR activation and AR expression in human fibroblast cells. RESULTS: The GR was expressed ubiquitously across all investigated organ systems, whereas AR subtypes showed lower and more localized expression patterns. Receptor co-regulation, meaning the correlated gene expression of multiple stress hormone receptors, was found between GR and AR-α1B, as well as between AR-α1B and AR-α2B. In cultured human fibroblasts, activating the GR selectively increased AR-ß2 and AR-α1B expression. Consistent with the known energetic cost of stress responses, GR and AR expressions were positively associated with the expression of specific mitochondrial pathways. CONCLUSIONS: Our results provide a cartography of GR and AR expression across the human body. Because stress-induced GR and AR signaling triggers energetically expensive cellular pathways involving energy-transforming mitochondria, the tissue-specific expression and co-expression patterns of hormone receptor subtypes may in part determine the resilience or vulnerability of different organ systems.

Effects of aerobic exercise on neurocognitive function in postmenopausal women receiving endocrine therapy for breast cancer: The Exercise Program in Cancer and Cognition randomized controlled trial.

Objective: The Exercise Program in Cancer and Cognition (EPICC) Study was a randomized controlled trial (RCT) designed to determine whether six months of moderate-intensity aerobic exercise improves neurocognitive function in women with breast cancer (BC) receiving endocrine therapy (ET). Methods: Postmenopausal women with hormone receptor+, early-stage BC, within two years post-primary therapy were randomized to the exercise intervention (six months, ≥150 minutes of moderate-intensity aerobic exercise/week) or usual care control condition. Outcomes were assessed at pre-randomization and after intervention completion. Groups were compared using linear mixed-effects modeling. Results: Participants (N=153) were X ¯ = 62.09 ± 8.27 years old, with stage I BC (64.1%) and a median of 4.7 months post-diagnosis. We found a group-by-time interaction (p=0.041) and a trend for the main effect of time (p=0.11) for processing speed with improved performance in the exercise group and no change in the controls. Similar main effects of time were observed for learning and memory (p=0.024) and working memory (p=0.01). Better intervention adherence was associated with improved processing speed (p=0.017). Conclusions: Six months of moderate-intensity aerobic exercise improves processing speed in postmenopausal women with BC receiving ET who initiate exercise within two years of completing primary therapy (surgery +/- chemotherapy). This is the first large-scale study to examine the effects of aerobic exercise on neurocognitive function in women with BC. Additional research is needed to address the long-term effects of aerobic exercise on cognitive function.

Historical Structural Racism in the Built Environment and Physical Health among Residents of Allegheny County, Pennsylvania.

Historical structural racism in the built environment contributes to health inequities, yet to date, research has almost exclusively focused on racist policy of redlining. We expand upon this conceptualization of historical structural racism by examining the potential associations of probable blockbusting, urban renewal, and proximity to displacement from freeway construction, along with redlining, to multiple contemporary health measures. Analyses linked historical structural racism, measured continuously at the census-tract level using archival data sources, to present-day residents' physical health measures drawn from publicly accessible records for Allegheny County, Pennsylvania. Outcome measures included average life expectancy and the percentage of residents reporting hypertension, stroke, coronary heart disease, smoking, insufficient sleep, sedentary behavior, and no health insurance coverage. Multiple regression analyses were conducted to examine separate and additive associations between structural racism and physical health measures. Redlining, probable blockbusting, and urban renewal were associated with shorter life expectancy and a higher prevalence of cardiovascular conditions, risky health behaviors, and residents lacking health insurance coverage. Probable blockbusting and urban renewal had the most consistent correlations with all 8 health measures, while freeway displacement was not reliably associated with health. Additive models explained a greater proportion of variance in health than any individual structural racism measure alone. Moreover, probable blockbusting and urban renewal accounted for relatively more variance in health compared to redlining, suggesting that research should consider these other measures in addition to redlining. These preliminary correlational findings underscore the importance of considering multiple aspects of historical structural racism in relation to current health inequities and serve as a starting point for additional research.

I'm still me, I'm still a person: war metaphor use and meaning making in women with metastatic breast cancer.

PURPOSE: The war metaphor is one strategy used frequently in breast cancer to inspire individuals in a "fight" against cancer and assist patients in navigating their illness experience. Despite prominent use, the emotional impact of this language has not been examined in the context of meaning making among women with metastatic breast cancer (MBC). METHODS: This study involved a semi-structured interview considering the war metaphor's impact on women's illness experience with MBC. Participants (n = 22) had been diagnosed with MBC for at least 6 months or following 1 disease progression and were undergoing treatment at an NCI-designated cancer center in Western Pennsylvania at the time of interview. Each participant underwent an individual interview exploring the war metaphor's impact on illness experience. Qualitative thematic analysis was performed to assess feelings about the war metaphor and emotional response to the lived experience of cancer. RESULTS: Two themes were identified surrounding metaphor use and participants' experiences with meaning making in cancer. First, women with MBC perceive the diagnosis as an "unfair fight" due to its incurable nature. Second, patients use alternative language of "living life" and communicate resistance to being defined by their cancer diagnosis. CONCLUSION: War metaphors are one collection of terminology people use to understand their diagnosis. However, their use may apply pressure to prioritize positivity in the face of diagnosis and treatment, in a unique clinical context where this may not be adaptive. These findings affirm a need to consider patients' lived experiences to best facilitate psychological adjustment to illness.

Beyond Neighborhood Disadvantage: Local Resources, Green Space, Pollution, and Crime as Residential Community Correlates of Cardiovascular Risk and Brain Morphology in Midlife Adults.

OBJECTIVE: Residing in communities characterized by socioeconomic disadvantage confers risk of cardiometabolic diseases. Residing in disadvantaged communities may also confer the risk of neurodegenerative brain changes via cardiometabolic pathways. This study tested whether features of communities-apart from conventional socioeconomic characteristics-relate not only to cardiometabolic risk but also to relative tissue reductions in the cerebral cortex and hippocampus. METHODS: Participants were 699 adults aged 30 to 54 years (340 women; 22.5% non-White) whose addresses were geocoded to compute community indicators of socioeconomic disadvantage, as well as air and toxic chemical pollutant exposures, homicide rates, concentration of employment opportunities, land use (green space), and availability of supermarkets and local resources. Participants also underwent assessments of cortical and hippocampal volumes and cardiometabolic risk factors (adiposity, blood pressure, fasting glucose, and lipids). RESULTS: Multilevel structural equation modeling demonstrated that cardiometabolic risk was associated with community disadvantage ( ß = 0.10, 95% confidence interval [CI] = 0.01 to 0.18), as well as chemical pollution ( ß = 0.11, 95% CI = 0.02 to 0.19), homicide rates ( ß = 0.10, 95% CI = 0.01 to 0.18), employment opportunities ( ß = -0.16, 95% CI = -0.27 to -0.04), and green space ( ß = -0.12, 95% CI = -0.20 to -0.04). Moreover, cardiometabolic risk indirectly mediated the associations of several of these community features and brain tissue volumes. Some associations were nonlinear, and none were explained by participants' individual-level socioeconomic characteristics. CONCLUSIONS: Features of communities other than conventional indicators of socioeconomic disadvantage may represent nonredundant correlates of cardiometabolic risk and brain tissue morphology in midlife.

Mindfulness-Based Stress Reduction reduces pro-inflammatory gene regulation but not systemic inflammation among older adults: A randomized controlled trial.

OBJECTIVE: Aging is associated with increased pro-inflammatory gene expression and systemic inflammation, and psychosocial stress may accelerate these changes. Mindfulness interventions show promise for reducing psychosocial stress and extending healthspan. Inflammatory pathways may play a role. In a sample of lonely older adults, we tested whether mindfulness training reduces proinflammatory gene expression and protein markers of systemic inflammation. METHODS: Lonely older adults (65-85 years; N = 190) were randomly assigned to an 8-week Mindfulness-Based Stress Reduction (MBSR) or matched Health Enhancement Program (HEP). Blood was drawn pre- and post-intervention and at 3-month follow-up. In peripheral blood mononuclear cells (PBMCs), RNA profiling was used to assess transcriptional regulation by pro-inflammatory NF-kB as well as ß-adrenergic CREB, antiviral IRF, and glucocorticoid receptor (GR) transcription factors. Plasma was assayed for proinflammatory markers IL-6 and CRP. Analyses tested time (pre, post, follow-up) by condition (MBSR versus HEP) effects. RESULTS: MBSR reduced NF-kB (d = .17, p = .028) but did not alter CREB (d = .10, p = .20), IRF (d = .13, p = .086), or GR activity (d = .14, p = .063) relative to HEP over time. Contrary to predictions, there were no time × condition effects of MBSR compared to HEP on reducing circulating IL-6 or CRP. CONCLUSIONS: In lonely older adults, MBSR reduced cellular pro-inflammatory gene regulation in ways that would predict reduced disease risk. However, no similar effect was observed for circulating protein markers of inflammation. These results provide specificity about how mindfulness interventions may impact distinct inflammatory markers among aging adults in ways that may have important implications for healthspan. TRIAL REGISTRATION: Clinical Trials identifier NCT02888600.

A systematic review and meta-analysis of the stability of peripheral immune markers in healthy adults.

Peripheral immune markers are widely used to predict risk for inflammatory disease. However, whether single assessments of inflammatory biomarkers represent stable individual differences remains unclear. We reviewed 50 studies (N = 48,674; 57 % male; mean age 54 (range 13-79) years) that assessed markers of inflammation on >1 occasion, with time between measures ranging from 24 h to 7+ years. Separate random effects meta-analyses were conducted for each inflammatory marker and time interval. Markers that had broad coverage across most time intervals included C-reactive protein (CRP; k = 37), interleukin (IL)-6 (k = 22), TNF-α (k = 10), and fibrinogen (Fg; k = 9). For CRP, IL-6, and TNF-α, stability estimates generally decreased with time, with strong to moderate stability over intervals <6 months (r's = 0.80-0.61), modest to moderate stability over 6 months - 3 years (r's = 0.60-0.51), and low stability for >3 years (r's = 0.39-0.30). Estimates were less reliable for Fg for time intervals ≤ 3 years although they generally followed the same pattern; more reliable findings suggested greater stability for Fg than other markers for intervals >3 years (r = 0.53). These findings suggest that single measures of inflammatory biomarkers may be an adequate index of stable individual differences in the short term (<6 months), with repeated measures of inflammatory biomarkers recommended over intervals ≥ 6 months to 3 years, and absolutely necessary over intervals >3 years to reliably identify stable individual differences in health risk. These findings are consistent with stability estimates and clinical recommendations for repeated measurement of other cardiovascular measures of risk (e.g., blood lipids, blood pressure).

Subjective Social Status and Longitudinal Changes in Systemic Inflammation.

BACKGROUND: Subjective social status (SSS) refers to a person's perception of their social rank relative to others and is cross-sectionally linked to systemic inflammation independently of objective socioeconomic status. PURPOSE: We test the extent to which SSS relates to multiyear changes in inflammation, or if associations differ by race or sex. METHODS: Healthy adults (N = 331; 30-51 years) completed a baseline visit and 278 participants returned for a second visit 2.85 years later. At both visits, participants underwent a fasting blood draw and completed community (SSSC) and US (SSSUS) versions of the MacArthur Scale. Multiple linear regression analyses examined change in interleukin-6 (IL-6) and C-reactive protein (CRP) predicted by each type of SSS, adjusting for time between visits, sex, race, age, body mass index, smoking, baseline inflammation, and objective socioeconomic status. Additional analyses further adjusted for hopelessness and depressive symptoms. Interactions examined moderations by sex and race. RESULTS: Lower SSSC was longitudinally associated with greater IL-6 independently of all covariates, including education and income (ß = -0.06), hopelessness (ß = -0.06), and depressive symptoms (ß = -0.06). Lower SSSUS was longitudinally associated with greater IL-6 independently of demographic covariates including education and income (ß = -0.06), but was slightly attenuated after adjusting for hopelessness (ß = -0.06) and depressive symptoms (ß = -0.06). There were no associations for CRP or moderation by race or sex. CONCLUSIONS: Lower SSS may be associated with greater circulating markers of inflammation over time as suggested by increases in IL-6.

Subjective social status (SSS) refers to how people perceive their social rank compared with others and has been linked to meaningful differences in physical health. Increases in inflammation may contribute to associations between lower SSS and poorer physical health. In a sample of healthy adults, we examined whether SSS was associated with prospective, multiyear changes in markers of systemic inflammation and if this differed by sex or race. We found that adults who perceived their social status as lower than peers in their community exhibited an accelerated increase in interleukin-6, a marker of systemic inflammation, over a 3-year period. When participants were asked to compare themselves to people in the broader USA, the pattern was similar but less robust. Results were independent of individual differences in sociodemographic characteristics including family-adjusted income and education. Findings did not differ by sex or race and were not explained by differences in adiposity and symptoms of depression and hopelessness. Effects for C-reactive protein, a second marker of inflammation, were generally nonsignificant. Although preliminary, findings suggest an immune pathway by which perceived social status may relate to chronic diseases of aging.

Systemic Inflammation Contributes to the Association Between Childhood Socioeconomic Disadvantage and Midlife Cardiometabolic Risk.

BACKGROUND: Childhood socioeconomic disadvantage is associated with increased risk for chronic inflammation and cardiometabolic disease at midlife. PURPOSE: As it is presently unknown whether inflammation mediates the relationship between childhood socioeconomic status (SES) and adulthood cardiometabolic risk, we investigated associations between retrospectively reported childhood SES, circulating levels of inflammatory markers, and a latent construct of cardiometabolic risk in midlife adults. METHODS: Participants were 1,359 healthy adults aged 30-54 (Adult Health and Behavior I&II; 52% women, 17% Black) who retrospectively reported childhood SES (parental education, occupational grade). Measures included plasma interleukin (IL)-6, C-reactive protein (CRP), and cardiometabolic risk factors. Structural equation modeling was conducted, with cardiometabolic risk modeled as a second-order latent variable with adiposity, blood lipids, glucose control, and blood pressure as first-order components. RESULTS: Lower childhood SES was associated with greater risk for cardiometabolic disease at midlife (ß = -0.08, CI[-0.04, -0.01], p = .01) in models adjusted for demographics, but this association was attenuated in models that adjusted for adulthood SES and health behaviors. In fully-adjusted models, the relationship between lower childhood SES and adult cardiometabolic risk was partially explained by higher circulating levels of CRP (ß = -0.05, CI[-0.02, -0.01], p = .001), but not by IL-6. In an exploratory model, lower adulthood SES was also found to independently contribute to the association between childhood SES and adult cardiometabolic risk (ß = -0.02, CI[-0.01, -0.001], p = .02). CONCLUSIONS: The current study provides initial evidence that systemic inflammation may contribute to childhood socioeconomic disparities in cardiometabolic risk in midlife. Future work would benefit from prospective investigation of these relationships.

The personality meta-trait of stability and carotid artery atherosclerosis.

BACKGROUND: Several personality traits increase the risk for atherosclerotic cardiovascular disease. Because many of these traits are correlated, their associations with disease risk could reflect shared variance, rather than unique contributions of each trait. We examined a higher-order personality trait of Stability as related to preclinical atherosclerosis and tested whether any such relationship might be explained by correlated variation in cardiometabolic risk factors. METHOD: Among 798 community volunteers, lower-order traits of Neuroticism, Agreeableness, and Conscientiousness were modeled as latent variables (from self- and informant ratings) and used to estimate the second-order factor, Stability. Cardiometabolic risk was similarly modeled from indicators of glycemic control, blood pressure, adiposity, and lipids. Carotid artery atherosclerosis was measured as intima-media thickness (IMT) by duplex ultrasonography. RESULT: A structural equation model incorporating direct and indirect effects showed lower Stability associated with greater IMT, and this relationship was accounted for by the indirect pathway via cardiometabolic risk. Secondary analyses showed that: (1) Neuroticism, Agreeableness, and Conscientiousness were unrelated to IMT independent of Stability; and (2) Stability predicted variation in IMT when estimated from informant-, but not self-rated, traits. CONCLUSION: Personality traits may associate with atherosclerotic burden through their shared, rather than unique, variance, as reflected in Stability.

Stress-Related Inflammation and Social Withdrawal in Mothers of a Child With Cancer: A 1-Year Follow-Up Study.

OBJECTIVE: Acute inflammation-induced sickness behavior involves changes in social behavior that are believed to promote recovery. Whether chronic inflammation can influence social behaviors in ways that promote recovery is unknown. In a sample of mothers of a child with cancer, this report explores the relationship between inflammation that accompanies the stress of diagnosis and changes in social network, cancer-related stress, and inflammation across 1 year. Three hypotheses tested whether a) initial levels of stress associate with initial levels of inflammation, b) initial levels of inflammation predict social network changes over time, and c) social network changes over time buffer changes in stress and inflammation over time. METHODS: Cancer-related stress (Impact of Events Scale), social network (social roles and contacts from the Social Network Inventory), and systemic inflammation (circulating interleukin [IL]-6) were assessed in 120 mothers three times after their child's cancer diagnosis: after diagnosis (T1), 6-month follow-up (T2), and 12-month follow-up (T3). RESULTS: Consistent with predictions, greater cancer-related stress after diagnosis (T1) was associated with higher IL-6 after diagnosis (T1; b = 0.014, standard error [SE] = 0.01, p = .008). In turn, higher IL-6 after diagnosis (T1) was associated with a decrease in social roles over time (T1 ➔ T3; B = -0.030, SE = 0.01, p = .041). Finally, dropping social roles over time (T1 ➔ T3) was associated with decreases in cancer-related stress (B = 25.44, SE = 12.31, p = .039) and slower increases in IL-6 (B = 1.06, SE = 0.52, p = .040) over time. CONCLUSIONS: This study provides a first indication that chronic stress-related systemic inflammation may predict changes in social behavior that associate with stress recovery and slower increases in inflammation in the year after a major life stressor.

Increased burden of cardiovascular risk among youth suicide attempters.

BACKGROUND: Suicide and cardiovascular disease rank among the leading causes of disability and premature mortality worldwide. Young adult suicide attempters are at increased risk of mortality from cardiovascular disease even compared to those with major depressive disorder suggesting an increased burden of cardiovascular risk factors. We compared the cardiovascular risk burden between youth attempters and other high-risk individuals. METHODS: Participants were from the Collaborative Psychiatric Epidemiology Surveys (CPES), a U.S. population-based study, aged 18-30 years [suicide attempt (SA): n = 303; suicidal ideation (SI): n = 451; controls: n = 3671]; and psychiatric inpatients admitted for a SA (n = 38) or SI (n = 40) and healthy controls (n = 37) aged 15-30 years. We computed a cardiovascular risk score and high- and low-risk latent classes based on risk factors of high blood pressure, obesity, and smoking. RESULTS: Suicide attempters showed an increased cardiovascular risk score (CPES: B = 0.43, 95% confidence interval (CI) 0.31-0.54, p < 0.001; inpatient sample: B = 1.61, 95% CI 0.53-2.68, p = 0.004) compared to controls. They were also more likely to be classified in the high cardiovascular risk group (CPES: odds ratio (OR) 3.36, 95% CI 1.67-6.78, p = 0.001; inpatient sample: OR 9.89, 95% CI 1.38-85.39, p = 0.03) compared to those with SI (CPES: OR 1.15, 95% CI 0.55-2.39, p = 0.71; inpatient sample: OR 1.91, 95% CI 0.25-15.00, p = 0.53). CONCLUSIONS: Youth attempters show an increased burden for cardiovascular risk compared to other high-risk individuals in inpatient and population-based samples. Clinicians should pay particular attention to cardiovascular risk factors among suicide attempters in order to reduce their risk for cardiovascular events.

The association of physical illness and low-grade inflammatory markers with depressive symptoms in a large NHANES community sample: Dissecting mediating and moderating effects.

BACKGROUND: Both low-grade elevation in peripheral inflammatory markers (e.g., white blood count (WBC) and C-reactive protein (CRP)) and physical illness (both chronic and acute) have been associated with depressive symptomology. However, it is unclear if low-grade elevation in inflammatory markers mediates relationships between physical illness and depression or if physical illness positively moderates relationships between inflammatory markers and depression. METHODS: In a well-powered, racially diverse cohort (n = 21,525) from NHANES datasets, we examined if inflammatory markers (CRP and WBC) and physical illnesses (acute and chronic) were independently associated with depression severity. We also examined if associations between physical illness and depression severity were mediated by inflammatory markers and if physical illness moderated associations between inflammatory markers and depression. RESULTS: We found that both inflammatory markers and physical illness were associated with depression severity, even after considering a wide range of potential confounders (e.g., age, gender, body mass index). Inflammatory markers mediated a marginal portion (<5%; p < 0.001) of potential effects of physical illness on depression severity. In moderation analyses, associations between inflammatory markers and depression severity were significantly stronger in participants with chronic physical illness than those without. This moderating effect was not present for acute physical illness. CONCLUSIONS: Inflammatory markers and physical illness appear independently linked to depression severity and, in individuals with chronic physical illness, inflammatory markers are more tightly connected to depressive symptomology. Such findings could help guide future individualized treatment research for depression based on both inflammatory marker level and physical illness burden.

Mindfulness-based stress reduction increases stimulated IL-6 production among lonely older adults: A randomized controlled trial.

Loneliness is a potent psychosocial stressor that predicts poor health and mortality among older adults, possibly in part by accelerating age-related declines in immunocompetence. Mindfulness interventions have shown promise for reducing loneliness and improving markers of physical health. In a sample of lonely older adults, this two-arm parallel trial tested whether mindfulness training enhances stimulated interleukin-6 (IL-6) production, a measure of innate immune responsivity. Lonely older adults (65-85 years; N = 190) were randomized to an 8-week Mindfulness-Based Stress Reduction (MBSR) or control Health Enhancement Program (HEP) intervention. Lipopolysaccharide (LPS)-stimulated production of IL-6 was measured in vitro by blinded outcome assessors at pre-intervention, post-intervention, and 3-month follow-up. Mixed-effects linear models tested time (pre, post, follow-up) by condition (MBSR vs. HEP) effects. As predicted, a significant time × condition effect on stimulated IL-6 production was observed across pre, post, and follow-up timepoints. Significant MBSR vs. HEP differences emerged from pre- to post-intervention (p =.009, d = 0.38) and from pre-intervention to 3-month follow-up (p =.017, d = 0.35), with larger increases in IL-6 production following MBSR compared to HEP. No study-related adverse events were reported. Results show that mindfulness training may be effective for boosting innate immunocompetence among lonely older adults. Given that immunocompetence tends to decline with age, mindfulness training may help to counteract the effects of aging and psychosocial stress on infection risk and recovery from injury.

The effects of SmartCare© on neuro-oncology family caregivers' distress: a randomized controlled trial.

PURPOSE: Patients with primary malignant brain tumors have high symptom burden and commonly rely on family caregivers for practical and emotional support. This can lead to negative mental and physical consequences for caregivers. We investigated effectiveness of an 8-week nurse-led online needs-based support program (SmartCare©) with and without online self-guided cognitive behavioral therapy (CBT) for depression compared to enhanced care as usual (ECAU) on depressive symptoms, caregiving-specific distress, anxiety, mastery, and burden. METHODS: Family caregivers scoring ≥ 6 on a depressive symptoms inventory were randomized to three groups: ECAU plus self-guided CBT and SmartCare©; ECAU plus SmartCare©; ECAU only. Primary outcomes (depressive symptoms; caregiving-specific distress) and secondary outcomes (anxiety, caregiver mastery, and caregiver burden) were assessed online. Intention to treat (ITT) and per protocol (PP) analyses of covariance corrected for baseline scores were performed for outcomes at 4 months. RESULTS: In total, 120 family caregivers participated. Accrual and CBT engagement were lower than expected, therefore intervention groups were combined (n = 80) and compared to ECAU (n = 40). For depressive symptoms, no statistically significant group differences were found. Caregiving-specific distress decreased in the intervention group compared with ECAU (ITT: p = 0.01, partial ɳ2 = 0.08; PP: p = 0.02, partial ɳ2 = 0.08). A trend towards improvement in mastery for the intervention group compared with ECAU was identified (ITT: p = 0.08, partial ɳ2 = 0.04; PP: p = 0.07, partial ɳ2 = 0.05). CONCLUSIONS: SmartCare©, with or without self-guided CBT, reduced caregiving-specific distress with a trend towards improving mastery. SmartCare© has the potential to improve the lives of families coping with a brain tumor diagnosis. TRIAL REGISTRATION NUMBER: NCT02058745; 10 February 2014.

Mindfulness-Based Stress Reduction Buffers Glucocorticoid Resistance Among Older Adults: A Randomized Controlled Trial.

OBJECTIVE: Mindfulness interventions have been effective for improving a range of health outcomes; however, pathways underlying these effects remain unclear. Inflammatory processes may play a role, possibly through increased resistance of immune cells to the anti-inflammatory effects of glucocorticoids (i.e., glucocorticoid resistance, or GCR). Here, we conducted an initial examination of whether mindfulness training mitigates GCR among lonely older adults. METHODS: Lonely older adults (65-85 years; n = 190) were randomly assigned to an 8-week Mindfulness-Based Stress Reduction (MBSR) or a matched Health Enhancement Program (HEP). Whole blood drawn before and after the intervention and at 3-month follow-up was incubated with endotoxin and varying concentrations of dexamethasone, and interleukin-6 production was assessed using enzyme-linked immunosorbent assay. GCR was assessed as the concentration of dexamethasone required to decrease the stimulated interleukin-6 response by 50% (half maximal inhibitory concentration), with higher concentrations indicating greater GCR. Mixed-effects linear models tested time (pre, post, follow-up) by condition (MBSR versus HEP) effects. RESULTS: There was no overall time by condition effect on GCR across all time points. However, a significant time by condition effect was observed from preintervention to postintervention (d = 0.29), such that MBSR buffered increases in GCR observed in the HEP group. Although MBSR showed small, nonsignificant reductions in GCR from preintervention to 3-month follow-up, group differences were not maintained at the 3-month follow-up (d = 0.10). CONCLUSIONS: Results suggest that MBSR may protect against declines in the sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids among at-risk lonely older adults and show value in studying this biological mechanism in future trials.Trial Registration: Clinical Trials identifier NCT02888600.

Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents.

BACKGROUND: Depression has been associated with low-grade elevation of plasma cytokines (e.g. interleukin-6, IL-6; tumor necrosis factor alpha, TNFα) in both cross-sectional and longitudinal studies in adults. Preclinical and clinical studies also suggest that IL-6 and TNFα elevation are associated with anhedonia. However, few studies have examined longitudinal relationships between cytokines and depression/anhedonia in clinically depressed samples, particularly adolescents. METHODS: Thirty-six adolescents with a depressive disorder receiving standard-of-care community treatment were assessed at a baseline and a follow-up timepoint. Self-report and clinical measures of depression and anhedonia, along with plasma IL-6 and TNFα levels, were obtained at both timepoints. Baseline cytokine measures were examined in association with baseline and follow-up clinical measures. On an exploratory basis, change in clinical measures over time was examined in relation to change in cytokine levels over time. RESULTS: Higher baseline TNFα levels predicted higher follow-up depression severity after approximately four months (controlling for baseline depression). Higher baseline TNFα levels also associated positively with baseline anhedonia and predicted higher anhedonia at follow-up (controlling for baseline anhedonia). No association was found between change in clinical measures and change in cytokine levels over time. CONCLUSIONS: Among adolescents receiving standard-of-care community treatment for depression, higher levels of TNFα predicted greater depressive symptoms at 4-month follow-up, suggesting this cytokine may be used to help identify patients in need of more intensive treatment. Elevated TNFα levels were also associated with concurrent and future anhedonia symptoms, suggesting a specific mechanism in which TNFα affects depression trajectories. Future studies should examine the relationships between cytokine levels and depression/anhedonia symptoms at multiple timepoints in larger cohorts of depressed adolescents.

Physical activity, cardiorespiratory fitness, and cognitive function in postmenopausal women with breast cancer.

Physical activity may improve cognitive function in women with breast cancer. In a cross-sectional study, we explored the relationship between cognitive function and physical activity (actigraph) and cardiorespiratory fitness (sub-maximal graded exercise test) in 73 postmenopausal women with early stage breast cancer prior to the initiation of systemic adjuvant therapy. Cognitive function was assessed with a standardized battery of neurocognitive measures assessing eight domains. Data were analyzed using partial correlations, controlling for age and total hours of actigraph wear-time. Women were, on average, 63.71 (± 5.3) years of age with 15.47 (± 2.48) years of education. For physical activity, greater average number of steps per day were associated with better attention (r = .262, p = .032) and psychomotor speed (r = .301, p = .011); greater average hours of moderate and moderate/vigorous intensity physical activity were associated with better visual memory (r = .241, p = .049; r = .241, p = .049, respectively); and greater average daily energy expenditure was associated with better visual memory (r = .270, p = .027) and psychomotor speed (r = .292, p = .017). For fitness, higher peak maximum VO2 was associated with better concentration (r = .330, p = .006), verbal memory (r = .241, p = .048), and working memory (r = .281, p = .019). These results suggest that higher levels of physical activity and cardiorespiratory fitness are associated with better cognitive function in postmenopausal women with breast cancer. Randomized controlled trials (RCT) to examine whether physical activity improves cognitive function in women with breast cancer are warranted. These RCTs should also determine the mechanisms of the influence of physical activity on cognitive function. CLINICAL TRIALS REGISTRATION NUMBER: NCT02793921; Date: May 20, 2016.

Efficacy of a Stress Management Intervention for Mothers of Children with Cancer.

OBJECTIVE: Mothers of children with cancer confront life stress that can impact their psychological and physical health and, in turn, the health of the family. Recommendations advocate preemptive stress-management interventions; however, few studies have investigated their efficacy. Here, we report results of a parallel randomized pilot trial examining health benefits of a stress management intervention designed to teach coping skills. METHODS: One hundred twenty mothers (age 36 ± 8 years) of children newly diagnosed with cancer were randomized to a 12-session stress management intervention (n = 60) or usual care (n = 60). Sessions took place in the inpatient or outpatient setting of a children's hospital. Primary outcome variables included psychological function and physical health assessed preintervention and postintervention and at 6-month follow-up (∼12 months postdiagnosis). RESULTS: Enrollment, retention, and satisfaction data supported feasibility and acceptability. Latent change score models showed the intervention reduced perceived stress (d = -0.37, p = 0.03), anxiety symptoms (ds = -0.38 and -0.56, ps < .03) and, a nonsignificant effect for depressive symptoms (d = -0.29, p = .11) across the 6 months following diagnosis. Intervention participants also endorsed fewer depressive symptoms than controls ∼12 months after diagnosis. The intervention improved stress management skills, which associated with the psychological benefits of participation. There were no intervention-related changes in perceived health or markers of inflammation. CONCLUSION: Intervention-related improvements in stress management skills may result in better psychological health in the face of caring for a child with cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02022449.