Psychosocial and behavioral determinants of immune aging

This thesis explored the hypothesis that cytomegalovirus (CMV) infection and its reactivation may be a shared mechanism linking psychosocial and behavioral factors with the age-associated decline in immunity, known as immunosenescence. The first empirical chapter (Chapter 3) showed that psychological stress factors were positively associated with CMV reactivation, as measured by increased CMV-specific IgG antibodies (CMV-IgG) among those infected, while socioeconomic and lifestyle factors were associated with CMV infection rates. Chapter 4 investigated personality traits and revealed that increased neuroticism predicted elevated odds of CMV infection and higher conscientiousness was associated with lower CMV-IgG levels. Chapter 5 demonstrated that more frequent physical activity was associated with lower levels of highly-differentiated T-cells, but this association was reduced to non-significance by adjustment for CMV infection. Chapter 6 showed that dysregulated glucose metabolism, measured as higher glycated hemoglobin levels, was associated with increased highly-differentiated T-cells in CMV-infected individuals. Furthermore, hyperglycemia interacted with CMV infection for a further increased accumulation of these cells. In sum, these results suggest that CMV and psychosocial and behavioral factors co-determine the progression of immunosenescence, and that CMV reactivation may reflect imbalance among these factors. Thus, CMV reactivation is proposed as a common pathway in psychobiological relationships with immunosenescence

The impact of latent CMV infection on NK-cell mobilization and expression of KLRG1 and CD57 in response to acute exercise.

Natural killer (NK) cells are cytotoxic effectors of the innate immune system that are able to distinguish healthy autologous cells from tumors and virally infected cells. NK-cells kill the targeted cells by releasing cytotoxic proteins, a process that is governed by inhibitory surface receptors, such as KLRG1. Additionally, activated NK-cells are able to proliferate in response to immunological stimuli, a process that is inhibited in NK-cells expressing the senescence marker CD57. Acute bouts of exercise are known to mobilize NK cells into the blood compartment, which could alter immunity; however, whether or not exercise alters NK-cell KLRG1 and CD57 expression has not been fully elucidated. Furthermore, as latent CMV infection is associated with an increased frequency of inhibitory NK cells, it is not known if CMV status influences NK-cell mobilization in response to acute exercise. PURPOSE: To examine the impact of latent CMV infection on the mobilization of NK-cells and their expression of KLRG1 and CD57 in response to acute exercise. METHODS: Otherwise healthy CMV seropositive (CMV+) and CMV seronegative (CMV-) males (age 23-35 years) completed a 30-min cycling protocol at 85% of maximum power. Lymphocytes isolated from whole blood before, immediately after, and one hour after exercise were surface-stained with monoclonal antibodies against CD3, CD56, KLRG1 and CD57 and analyzed by 4-color flow cytometry. RESULTS: Preliminary analysis of the data show a prodigious increase in the number of CD56 dim (mature, highly cytotoxic subset) NK-cells immediately after exercise in all subjects, which subsequently fell below pre-exercise values 1 hour later. In CMV- subjects, the proportion of CD56 bright (immature, mildly cytotoxic) NK cells was considerably higher 1 hour post-exercise than before exercise, but the number of cells changed very little suggesting that the increased proportion was due merely to the egress of CD56 dim NK cells. Interestingly, CMV seropositivity was associated with a near complete absence of CD56 bright NK cells that was unaffected by exercise. Neither exercise nor CMV status influenced the proportion of NK-cells expressing KLRG1 or CD57. CONCLUSION: Preliminary analysis of this data indicates that acute exercise preferentially mobilizes CD56 dim NK cells without altering KLRG1 and CD57 expression. Latent CMV infection is associated with a lowered proportion of CD56 bright NK-cells; however, the NK-cell response to exercise was not influenced by CMV status. Future work will examine the role of aging on NK-cell response to exercise and CMV status

The Impact of Latent Herpesvirus Infections on the Mobilization of Recent Thymic Emigrants and Extrathymic T-cells in Response to Acute Aerobic Exercise in Man

T-cells typically mature in the thymus gland, which eventually succumbs to age-related atrophy, resulting in a decreased naïve T-cell repertoire in middle to later years. Aged individuals and those with persistently reactivating herpesvirus infections have an increased reliance on the extrathymic maturation of T-cells due to the shrinking effects that age and latent viral infection has on the naïve T-cell repertoire. Acute bouts of aerobic exercise are known to mobilize T-cells that exhibit both a naïve and late-stage differentiation phenotype into the blood compartment; however, it is not known if recent thymic emigrants (RTE) or extrathymic T-cells contribute to the lymphocytosis associated with exercise. PURPOSE: To examine the impact of latent cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection on the mobilization of RTE and extrathymic T-cells in response to acute exercise. METHODS: Otherwise healthy CMV or EBV seropositive (CMV+ or EBV+) and CMV or EBV seronegative (CMV- or EBV-) males (age 23-35y) completed a 30-min cycling protocol at 85% of maximum power. Lymphocytes isolated from whole blood before, immediately after, and one hour after exercise were surface stained with monoclonal antibodies to identify phenotypes of RTE (CD103+/CD62L-) and extrathymic T-cells believed to mature in the liver (CD3+/CD25-/CD122+) and the epithelium of the small intestine (CD3+/CD4-/CD8-; TCRγδ+/ CD8αα+; CD3-/CD2+/CD7+). Cell populations were analyzed by flow cytometry and antibodies against CMV and EBV were determined in serum by ELISA. RESULTS: Preliminary analyses show that the proportion of RTE among the total CD3+/CD4+ or CD3+/CD8+ T-cell subsets did not change immediately after exercise, but was elevated above baseline 1h later due to the preferential egress of late stage differentiated T-cells. Neither CMV nor EBV status influenced the proportions of RTE in blood in response to exercise. T-cells mainly found in intestinal mucosa (i.e. CD3+/CD4-/CD8- and CD3-/CD2+/CD7+) were found to increase in blood immediately after exercise; an effect that appeared to be more pronounced in EBV but not CMV-infected subjects. CONCLUSION: An acute bout of aerobic exercise elicits the mobilization of T-cells exhibiting phenotype characteristics of extrathymically matured T-cells, suggesting that extrathymic T-cell mobilization contributes to the lymphocytosis associated with acute exercise. This effect appears to be amplified in subjects carrying a latent EBV but not CMV infection. Future research should attempt to establish the impact of long-term exercise and latent herpesvirus infections on the frequency of RTE and extrathymic T-cells in the aged, as this could have significant implications for age-associated immune dysfunction

Effect of HSV-1 Infection on the Exercise-induced Mobilization of T-cell Subsets

Acute exercise mobilizes highly-differentiated memory and senescent T-cells into the blood compartment, which could have important implications for post-exercise immune surveillance. This response differs in individuals with latent cytomegalovirus (CMV) infection (a herpesvirus), but it is unknown if other latent herpesviruses, such as herpes simplex virus type 1 (HSV-1), also influence this exercise-induced immune response. As HSV-1 infects 50% of the US population, this could have implications for many athletes. PURPOSE: To examine the effects of an acute bout of exercise on the frequency and relative proportion of naïve, memory, and senescent T-cells in the peripheral blood in HSV-1 infected and non-infected participants. METHODS: Eleven HSV-1-infected and twelve non-infected men (mean±SD: Age: 28±5 yrs; VO2max: 40.64±10.15 ml/kg/min) cycled at 85% of their estimated maximum power for 30 min. Blood samples were collected before and immediately after exercise, and mononuclear cells were isolated using density gradient centrifugation. Cells were labeled with monoclonal antibodies to identify naïve (CD28+CD57-KLRG1- or CD45RA+CCR7+), memory (CD28+CD57-KLRG1+, CD45RA+CCR7-, CD45RA-CCR7+, or CD45RA-CCR7-), and senescent (CD28-CD57+KLRG1+) subsets of CD3+CD4+ and CD3+CD8+ T-cells using four-color flow cytometry. HSV-1 serostatus was determined by an ELISA test. Main effects for exercise and serostatus, and exercise x serostatus interaction effects, were detected using maximum likelihood linear mixed models. RESULTS: A main effect for exercise was found on proportions of naïve (-8.82±8.49%), memory (+35.04±26.48%), and senescent (+64.12±56.12%) CD4+ T-cells, as well as on naïve (-21.02±11.56%) and senescent (+53.89±53.26%) CD8+ T-cells (p\u3c0.05). There were main effects for serostatus on proportions of memory CD4+ and CD8+ T-cells, with decreased levels in HSV-1+ subjects in all memory phenotypes examined (p\u3c0.05). Interaction effects between HSV-1 serostatus and exercise were found. HSV-1+ subjects had lower naïve cell counts, and a greater increase in the proportion of senescent cells, post-exercise (p\u3c0.05) than HSV-1-non-infected subjects. CONCLUSIONS: HSV-1 infection led to a decrease of memory T-cell subsets found in peripheral blood. It also influenced the relative response of naïve and senescent T-cells to acute exercise, although this effect was not nearly as great as that seen with other herpesviruses (i.e. CMV). This indicates that individuals with and without latent HSV-1 infection may have a different lymphocyte mobilization in response to exercise

Elevated HbA1c 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 HbA1c 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 HbA1c was associated with increased numbers of EM (B = 2.75, p \u3c 0.01) and EMRA (B = 2.90, p \u3c 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 \u3c 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. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3731-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users

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

ObjectiveRegulation 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.MethodsData 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.ResultsInter-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%).ConclusionsPositive 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

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 (β = −0.28, p = .004 and β = −0.37, p < .001, respectively) and better ADL function (β = 0.23, p = .022 and β = 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.</p