Well-being and Long-term Physical Activity Participation in Midlife Adults: A Latent Class Analysis.

Background: Despite the benefits of physical activity, a large majority of adults fail to get the recommended amount of regular exercise, and interventions to increase physical activity typically achieve only temporary improvements. The potential contribution of positive psychological functioning to the maintenance of physical activity has not been widely examined. Purpose: To test the hypothesis that psychological well-being would increase the likelihood of sustained physical activity in adults using a person-centered approach with longitudinal data. Methods: Participants (N = 2,214) were from the longitudinal Survey of Midlife Development in the United States (MIDUS). Continuous latent variables representing physical activity at three waves of MIDUS were used to partition respondents into distinct (categorical) classes based on longitudinal activity profiles. Results: Latent class analyses identified three distinct physical activity profiles: sustained, consistently low, and declining activity (the normative class). Multinomial logistic regression analyses showed that the odds of membership in the sustained activity class were significantly higher for those with higher eudaimonic well-being (OR = 1.08 [1.03-1.13], p = .001), after adjustment for diverse covariates. Supplemental analyses revealed similar associations for specific subdomains of eudaimonic well-being. Conclusion: This study provides evidence that greater well-being may help sustain physical activity in the long term. These results suggest that improving well-being may be a useful addition to interventions aimed at increasing long-term physical activity participation.

Elevated HbA(1c) levels and the accumulation of differentiated T cells in CMV(+) individuals.

AIMS/HYPOTHESIS: Biological ageing of the immune system, or immunosenescence, predicts poor health and increased mortality. A hallmark of immunosenescence is the accumulation of differentiated cytotoxic T cells (CD27(-)CD45RA(+/-); or dCTLs), partially driven by infection with the cytomegalovirus (CMV). Immune impairments reminiscent of immunosenescence are also observed in hyperglycaemia, and in vitro studies have illustrated mechanisms by which elevated glucose can lead to increased dCTLs. This study explored associations between glucose dysregulation and markers of immunosenescence in CMV(+) and CMV(-) individuals. METHODS: A cross-sectional sample of participants from an occupational cohort study (n = 1,103, mean age 40 years, 88% male) were assessed for HbA(1c) and fasting glucose levels, diabetes, cardiovascular risk factors (e.g. lipids), numbers of circulating effector memory (EM; CD27(-)CD45RA(-)) and CD45RA re-expressing effector memory (EMRA; CD27(-)CD45RA(+)) T cells, and CMV infection status. Self-report and physical examination assessed anthropometric, sociodemographic and lifestyle factors. RESULTS: Among CMV(+) individuals (n = 400), elevated HbA(1c) was associated with increased numbers of EM (B = 2.75, p < 0.01) and EMRA (B = 2.90, p < 0.01) T cells, which was robust to adjustment for age, sex, sociodemographic variables and lifestyle factors. Elevated EM T cells were also positively associated with total cholesterol (B = 0.04, p < 0.05) after applying similar adjustments. No associations were observed in CMV(-) individuals. CONCLUSIONS/INTERPRETATION: The present study identified consistent associations of unfavourable glucose and lipid profiles with accumulation of dCTLs in CMV(+) individuals. These results provide evidence that the impact of metabolic risk factors on immunity and health can be co-determined by infectious factors, and provide a novel pathway linking metabolic risk factors with accelerated immunosenescence.

Consistent associations between measures of psychological stress and CMV antibody levels in a large occupational sample.

Cytomegalovirus (CMV) is a herpes virus that has been implicated in biological aging and impaired health. Evidence, largely accrued from small-scale studies involving select populations, suggests that stress may promote non-clinical reactivation of this virus. However, absent is evidence from larger studies, which allow better statistical adjustment for confounding and mediating factors, in more representative samples. The present study involved a large occupational cohort (N=887, mean age=44, 88% male). Questionnaires assessed psychological (i.e., depression, anxiety, vital exhaustion, SF-12 mental health), demographic, socioeconomic (SES), and lifestyle variables. Plasma samples were analyzed for both the presence and level of CMV-specific IgG antibodies (CMV-IgG), used as markers for infection status and viral reactivation, respectively. Also assessed were potential biological mediators of stress-induced reactivation, such as inflammation (C-reactive protein) and HPA function (awakening and diurnal cortisol). Predictors of CMV infection and CMV-IgG among the infected individuals were analyzed using logistic and linear regression analyses, respectively. Confirming prior reports, lower SES (education and job status) was positively associated with infection status. Among those infected (N=329), higher CMV-IgG were associated with increased anxiety (ß=.14, p<.05), depression (ß=.11, p=.06), vital exhaustion (ß=.14, p<.05), and decreased SF-12 mental health (ß=-.14, p<.05), adjusting for a range of potential confounders. Exploratory analyses showed that these associations were generally stronger in low SES individuals. We found no evidence that elevated inflammation or HPA-function mediated any of the associations. In the largest study to date, we established associations between CMV-IgG levels and multiple indicators of psychological stress. These results demonstrate the robustness of prior findings, and extend these to a general working population. We propose that stress-induced CMV replication warrants further research as a psychobiological mechanism linking stress, aging and health.

NK-cells have an impaired response to acute exercise and a lower expression of the inhibitory receptors KLRG1 and CD158a in humans with latent cytomegalovirus infection.

NK-cells and γδ T-cells are cytotoxic effectors of the immune system that are preferentially mobilized into the blood compartment in response to acute stress and exercise. While infection history is known to alter the phenotype and exercise-responsiveness of CD8+ T-cells, the influence of latent cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections on the phenotypes and exercise-responsiveness of NK-cells and γδ T-cells are unknown. Twenty healthy males (age: 28.4±5.4 years) cycled for 30 min at 85% peak power. Blood lymphocytes isolated before, immediately after, and 1 h after exercise were surface stained for CD3, CD4, CD8, CD56, CD57, CD158a, KLRG1, and γδ-TCR antigens by four-color flow cytometry. CMV and EBV serostatus (pos/neg) was determined by ELISA. CMVpos had lower proportions of NK-cells expressing inhibitory receptors (KLRG1+ and CD158a+) and higher proportions of terminally differentiated NK-cells (KLRG1-/CD57+) compared to CMVneg. CMVpos mobilized far fewer (132 cells/µL vs. 245 cells/µL) NK-cells in response to exercise despite having similar baseline NK-cell counts and physiological responses to exercise as CMVneg, although terminally differentiated NK-cells were equally responsive to exercise regardless of CMV serostatus (p=0.658). EBVpos had higher proportions of CD8+ NK-cells, but cellular responses to exercise were not influenced by EBV. The frequency and exercise-responsiveness of γδ T-cells was not affected by CMV or EBV serostatus (p>0.05). In conclusion, latent CMV infection is associated with lowered numbers of NK-cells expressing inhibitory receptors and a blunted mobilization of NK-cells in response to acute exercise. This may indicate a compromised immune response to "fight-or-flight" situations in those infected with CMV.

CMV and Immunosenescence: from basics to clinics.

Alone among herpesviruses, persistent Cytomegalovirus (CMV) markedly alters the numbers and proportions of peripheral immune cells in infected-vs-uninfected people. Because the rate of CMV infection increases with age in most countries, it has been suggested that it drives or at least exacerbates "immunosenescence". This contention remains controversial and was the primary subject of the Third International Workshop on CMV & Immunosenescence which was held in Cordoba, Spain, 15-16th March, 2012. Discussions focused on several main themes including the effects of CMV on adaptive immunity and immunosenescence, characterization of CMV-specific T cells, impact of CMV infection and ageing on innate immunity, and finally, most important, the clinical implications of immunosenescence and CMV infection. Here we summarize the major findings of this workshop.

Dynamical indicators of resilience from physiological time series in geriatric inpatients: Lessons learned.

The concept of physical resilience may help geriatric medicine objectively assess patients' ability to 'bounce back' from future health challenges. Indicators putatively forecasting resilience have been developed under two paradigms with different perspectives: Critical Slowing Down and Loss of Complexity. This study explored whether these indicators validly reflect the construct of resilience in geriatric inpatients. Geriatric patients (n = 121, 60% female) had their heart rate and physical activity continuously monitored using a chest-worn sensor. Indicators from both paradigms were extracted from both physiological signals. Measures of health functioning, concomitant with low resilience, were obtained by questionnaire at admission. The relationships among indicators and their associations with health functioning were assessed by correlation and linear regression analyses, respectively. Greater complexity and higher variance in physical activity were associated with lower frailty (ß = -0.28, p = .004 and ß = -0.37, p < .001, respectively) and better ADL function (ß = 0.23, p = .022 and ß = 0.38, p < .001). The associations of physical activity variance with health functioning were not in the expected direction based on Critical Slowing Down. In retrospect, these observations stress the importance of matching the resilience paradigm's assumptions to the homeostatic role of the variable monitored. We present several lessons learned.

Moderation of the Association Between Chronic Medical Conditions and Functional Limitations Over Time by Physical Activity: Effects of Age.

BACKGROUND: Age-related accumulation of chronic medical conditions increases disability in older adults. Physical activity potently combats chronic conditions and disability. However, it is unclear whether activity maintenance alleviates the effects of chronic conditions on disability and if this buffering effect differs with age. This study examined whether long-term physical activity can forestall functional limitations in the face of accumulating chronic conditions among middle-aged and older adults. METHODS: Participants (n = 2,119; 54.7% female) were from the Survey of Midlife Development in the United States. Self-reported physical activity, number of chronic conditions, and functional limitations were obtained across 18-20 years. Functional limitations were regressed against the change in chronic conditions, physical activity, and their interaction over time in a multilevel model of change. Baseline age was added as an additional moderator. RESULTS: Faster accumulation of chronic conditions [B(SE) = 2.08(0.32), p < .001] and steeper declines in activity [B(SE) = -2.29(0.41), p < .001] were associated with greater increases in functional limitations over time. Among those with faster-than-average increases in conditions, those who maintained activity had a slower progression of functional limitations, compared to those whose activity declined more rapidly [B(SE) = -11.18(3.96), p = .005]. Baseline age moderated the buffering effect of activity maintenance; older adults were protected against functional limitations only when conditions accumulated slowly [B(SE) = 0.23(0.08), p = .005]. CONCLUSION: This study provides evidence for an age-dependent buffering effect of activity maintenance on the longitudinal relationship between chronic conditions and functional limitations. Intervention strategies using physical activity to forestall disability should target midlife adults and consider the rate of condition accumulation.

Relative sensitivity of cortisol indices to psychosocial and physical health factors.

OBJECTIVE: Regulation of cortisol under resting conditions is widely used to assess physical and psychological status, but due to the diversity of possible assessments (e.g., cumulative levels; diurnal patterns), considering one or a few at a time hampers understanding and interpretation. Moreover, most studies of cortisol regulation focus on negatively-valanced experiences. This study examined the inter-correlations among cortisol indices and their relative contribution to the explained variance in diverse psychosocial and health factors, including positive functioning. METHODS: Data are from midlife and older adults (N = 513; 47.2% male). Cortisol was assessed in urine (overnight) and saliva (at rest and over 4 consecutive days). Positive and negative psychosocial and health factors were assessed by self-report. In addition to examining associations among cortisol indices, relative weight analysis was used to determine which indices were most robustly linked to specific psychosocial factors. RESULTS: Inter-correlations among indices were weak-to-moderate, suggesting that they measure different aspects of hypothalamic-pituitary-axis activity. Overall variance in psychosocial and health factors (R2) explained by the cortisol indices ranged from 0.01 to 0.07. Of this explained variance, relative weight analysis showed that waking cortisol contributed most to the variance in hedonic well-being (32.1%-38.2%), bedtime cortisol to depression-related factors (32.1%-46.9%), the cortisol awakening response to eudaimonic well-being (35.8%-50.5%), cortisol slope to perceived stress (29.2%), and urinary cortisol to physical factors (38.5% and 62.7%). CONCLUSIONS: Positive and negative factors were related to largely non-overlapping cortisol indices. This study illuminates nuanced associations among cortisol indices and diverse aspects of mental and physical health, facilitating thoughtful examination of the complex role of hypothalamic-pituitary-axis activity in health.

The Role of Affect on Physical Health Over Time: A Cross-Lagged Panel Analysis Over 20 Years.

BACKGROUND: While previous studies have investigated the interplay between affect and health (1) over an extended period of time, (2) in a representative population, and (3) while modelling positive and negative affect simultaneously, no single study has done all three at once. METHODS: The present study accomplishes this by sampling adults from the Midlife Development in the US study who completed affect (Mroczek & Kolarz, 1998) and health measures (chronic conditions, Charlson, Szatrowski, Peterson, & Gold, 1994; functional limitations, McHorney, Ware, Lu, & Sherbourne, 1994; self-reported health) measured three times over 20 years. We ran three (one per health metric) random-intercept cross-lagged panel models, where positive and negative affect were modelled simultaneously. RESULTS: Results indicated that positive and negative affect significantly predicted future heath (functional limitations/self-reported health) and that this relationship was reciprocal (i.e. health measures predicted future affect). However, there were no significant cross-lagged relations between affect and chronic conditions. CONCLUSION: Our results suggest that both positive and negative affect play an equal role in predicting future health for functional limitations and self-reported health as well as highlight the bi-directionality of this relationship. Additionally, the degree to which affect predicts future health may be moderated by the type of health outcome.

Resilience in Clinical Care: Getting a Grip on the Recovery Potential of Older Adults.

BACKGROUND: Geriatricians are often confronted with unexpected health outcomes in older adults with complex multimorbidity. Aging researchers have recently called for a focus on physical resilience as a new approach to explaining such outcomes. Physical resilience, defined as the ability to resist functional decline or recover health following a stressor, is an emerging construct. METHODS: Based on an outline of the state-of-the-art in research on the measurement of physical resilience, this article describes what tests to predict resilience can already be used in clinical practice and which innovations are to be expected soon. RESULTS: An older adult's recovery potential is currently predicted by static tests of physiological reserves. Although geriatric medicine typically adopts a multidisciplinary view of the patient and implicitly performs resilience management to a certain extent, clinical management of older adults can benefit from explicitly applying the dynamical concept of resilience. Two crucial leads for advancing our capacity to measure and manage the resilience of individual patients are advocated: first, performing multiple repeated measurements around a stressor can provide insight about the patient's dynamic responses to stressors; and, second, linking psychological and physiological subsystems, as proposed by network studies on resilience, can provide insight into dynamic interactions involved in a resilient response. CONCLUSION: A big challenge still lies ahead in translating the dynamical concept of resilience into clinical tools and guidelines. As a first step in bridging this gap, this article outlines what opportunities clinicians and researchers can already exploit to improve prediction, understanding, and management of resilience of older adults. J Am Geriatr Soc 67:2650-2657, 2019.

Normal Hematopoietic Progenitor Subsets Have Distinct Reactive Oxygen Species, BCL2 and Cell-Cycle Profiles That Are Decoupled from Maturation in Acute Myeloid Leukemia.

In acute myeloid leukemia (AML) quiescence and low oxidative state, linked to BCL2 mitochondrial regulation, endow leukemic stem cells (LSC) with treatment-resistance. LSC in CD34+ and more mature CD34- AML have heterogeneous immunophenotypes overlapping with normal stem/progenitor cells (SPC) but may be differentiated by functional markers. We therefore investigated the oxidative/reactive oxygen species (ROS) profile, its relationship with cell-cycle/BCL2 for normal SPC, and whether altered in AML and myelodysplasia (MDS). In control BM (n = 24), ROS levels were highest in granulocyte-macrophage progenitors (GMP) and CD34- myeloid precursors but megakaryocyte-erythroid progenitors had equivalent levels to CD34+CD38low immature-SPC although they were ki67high. BCL2 upregulation was specific to GMPs. This profile was also observed for CD34+SPC in MDS-without-excess-blasts (MDS-noEB, n = 12). Erythroid CD34- precursors were, however, abnormally ROS-high in MDS-noEB, potentially linking oxidative stress to cell loss. In pre-treatment AML (n = 93) and MDS-with-excess-blasts (MDS-RAEB) (n = 14), immunophenotypic mature-SPC had similar ROS levels to co-existing immature-SPC. However ROS levels varied between AMLs; Flt3ITD+/NPM1wild-type CD34+SPC had higher ROS than NPM1mutated CD34+ or CD34- SPC. An aberrant ki67lowBCL2high immunophenotype was observed in CD34+AML (most prominent in Flt3ITD AMLs) but also in CD34- AMLs and MDS-RAEB, suggesting a shared redox/pro-survival adaptation. Some patients had BCL2 overexpression in CD34+ ROS-high as well as ROS-low fractions which may be indicative of poor early response to standard chemotherapy. Thus normal SPC subsets have distinct ROS, cell-cycle, BCL2 profiles that in AML /MDS-RAEB are decoupled from maturation. The combined profile of these functional properties in AML subpopulations may be relevant to differential treatment resistance.

CMV amplifies T-cell redeployment to acute exercise independently of HSV-1 serostatus.

PURPOSE: Latent cytomegalovirus (CMV) infection has been shown to alter the lymphocyte response to acute aerobic exercise, likely due to the corresponding increase in exercise-responsive memory CD8(+) T cells. It is unknown if latent infection with another herpesvirus, herpes simplex virus 1 (HSV-1), also plays a role in shaping the lymphocyte response to exercise. METHODS: Thirty-two men (ages 39.3 ± 14.7 yr) counterbalanced by CMV and HSV-1 serostatus (positive/negative) cycled for 30 min at ∼80% peak power. Blood sampled before, immediately after, and 1 h after exercise was analyzed by flow cytometry for T-cell subset enumeration. RESULTS: In resting blood, HSV-1(+) had fewer lymphocytes, CD4(+) T cells, KLRG1(-) CD28(+) CD4(+) T cells, and CD45RA(-)CCR7(+)CD4(+) T cells than HSV-1(-), whereas CMV(+) had increased numbers of lymphocytes, CD8(+) T cells, KLRG1(+)CD28(-)CD4(+) and CD8(+) T cells, and CD45RA(+)CCR7(-)CD8(+) T cells and a lower CD4:CD8 T-cell ratio than CMV(-). After exercise, CMV(+) had a greater mobilization of CD8(+) T cells, KLRG1+CD28(-)CD4+ and CD8(+) T cells, and CD45RA+CCR7(-)CD8+ T cells independently of HSV-1 serostatus, as well as a greater egress of these subsets 1 h after exercise. HSV serostatus did not influence total CD8(+) T-cell response to exercise. CONCLUSIONS: The impact of latent CMV infection on the redeployment of T-cell subsets with exercise is independent of HSV-1 infection. This is most likely due to the unique ability of CMV to alter the composition of the memory T-cell pool in favor of exercise-responsive T-cell subsets.