Social stressors associated with age-related T lymphocyte percentages in older US adults: Evidence from the US Health and Retirement Study

Background

This study focuses on social stressors, that is, difficult or challenging circumstances¹ that arise from social position and experience that are expected to be stressful, that occur in adulthood. Past research has categorized stressors in various ways, often depending on discipline; however, stressors are typically distinguished by timescale (e.g., acute, daily hassles, life events, chronic stressors) ². It distinguishes discrimination-related stressors from other stressors because past research suggests these stressors have distinct, independent effects on health ^{3, 4, 5}. It also distinguishes traumatic life events from other stressors, as is common in past research ^{2, 6, 7}. Thus, it assesses five stress variables that have been well established past research and are available in a large number of studies of health and aging (viz., stressful life events, chronic stress, everyday discrimination, lifetime discrimination, and life trauma).

Social stress can modify the immune system in several ways, including increased inflammatory signaling and reduced antiviral responses ^{1, 8-10}, suggesting that social stress may accelerate immune aging ^11-21. However, past research has utilized small clinical and specialized samples, potentially limiting power to detect effects, power to assess mediators, and generalizability of results. In this study, a nationwide sample of 5,641 US adults over the age of 50 is utilized to assess associations between five categories of social stress that have well established effects on heath and enumerative measures of immunological aging, including naïve CD4+ T cell percentages (CD4+/CD3+/CD19−/CD45RA+/CCR7+/CD28+) naïve CD8+ T cell percentages (CD8+/CD3+/CD19−/CD45RA+/CCR7+/CD28+), terminally differentiated effector memory CD4+ T cell percentages (TemRA; CD4+/CD3+/CD19−/CD45RA+/CCR7−/CD28−), terminally differentiated effector memory CD8+ T cell percentages (CD8+/CD3+/CD19−/CD45RA+/CCR7−/CD28−), and the ratio of CD4+ to CD8+ T cells. Analyses also assessed potential mediation of these associations by socioeconomic and lifestyle factors and cytomegalovirus (CMV) seropositivity.

Study Design

This study utilizes data from the US Health and Retirement Study (HRS) 2016 Venous Blood Study (n = 9,934). Multiparameter flow cytometry was used to assess counts and percentages of 24 different types of immune cells using the standardized protocol by the Human Immunology Project ²² with minor modifications performed on an LSRII or a Fortessa ×20 flow cytometer (BD Biosciences).

It utilizes five well-established health-relevant measures of social stress: stressful life events ²³, chronic stress ²⁴, everyday discrimination ²⁴, lifetime discrimination ²⁵, and life trauma ²⁶. Because everyday discrimination, stressful life events, lifetime discrimination, and life trauma assess life course or ongoing exposure to stress, it uses the first available data from the years these measures were assessed (2006 to 2016 for everyday discrimination, 2008 to 2012 for stressful life events, and 2006 to 2012 for lifetime discrimination and life trauma). Because this study has interest in assessing ongoing chronic stress, it only uses data from the 2014 and 2016 leave behind questionnaire.

Socioeconomic and lifestyle factors were assessed using self-reports of education (categorized: 0 to 11 y, 12 y, 13 to 15 y, and 16+ years as the reference), self-reported smoking (categorized: current smoker, past smoker, and nonsmoker as the reference), BMI (categorized: ≥ 25 and < 30 overweight, ≥ 30 and < 35 obese 1, ≥ 35 obese 2, and < 25 normal and underweight as the reference), and alcohol use (categorized: 1 to 4 drinks per day drinking, 5+ drinks per day drinking, and nondrinker as the reference).

CMV seropositivity was assessed using IgG antibodies in serum with the Roche e411 immunoassay analyzer (Roche Diagnostics Corporation) (categorized: borderline, reactive, or nonreactive as the reference) ²⁷.

In all models the study controls for chronological age, race/ethnicity (non-Hispanic Black, Hispanic, bon-Hispanic other race, and non-Hispanic White as reference), and sex (male as reference).

Results

The weighted sample is 55.2% female and has a median age of 68 y. Of the sample, 84.9% is non-Hispanic White, 6.9% is non-Hispanic Black, 5.8% is Hispanic, and 2.5% is non-Hispanic other race; 10.1% has less than 12 y of education, 30.7% has 12 y of education, 26.1% has 13 to 15 y of education, and 33.1% has 16 or more years of education. Of the sample, 9.4% are current smokers and 45.4% are former smokers, more than one-third of the sample is obese (36.1%), and 53.6% were nondrinkers. On average, participants reported relatively low everyday discrimination, 0.50 stressful life events, 0.65 incidents of lifetime discrimination, 1.09 life traumas, and a moderate level of chronic stress. There was substantial variance on all of these scales.

Results from nested analyses regressing T cell subset percentage/ratio on each stressor while controlling for age, sex, race/ethnicity, and various potential mediators, are shown below.

The association between terminally differentiated CD8+ T cells and more stressful life events was reduced to nonsignificance after controlling for education, BMI, smoking, drinking and CMV seropositivity. The association between stressful life events and CD8+ naïve T cell percentage remained statistically significant after controlling for all covariates. Experiencing greater chronic stress was related to a greater percentage of terminally differentiated CD4+ and terminally differentiated CD8+ T cells, a lower percentage of CD4+ naïve T cells, and a lower ratio of CD4+ to CD8+ T cells.

The association between chronic stress and CD4+ naïve T cells became nonsignificant after controlling for socioeconomic and lifestyle factors and CMV seropositivity. The association between chronic stress and terminally differentiated CD4+ T cells remained significant even after adjusting for education, BMI, smoking, drinking, and CMV seropositivity. The association between terminally differentiated CD8+ T cells and greater lifetime discrimination was reduced to nonsignificance after controlling for education, BMI, smoking, drinking, and CMV seropositivity. The associations between lifetime discrimination and terminally differentiated CD4+ and CD8+ naïve T cell percentages were both substantially reduced by these mediators but remained statistically significant.

Experiencing more everyday discrimination was related to having a higher percentage of terminally differentiated effector memory CD4+ T cells. This association was reduced after accounting for CMV seropositivity. Finally, experiencing a greater number of life traumas was related to a smaller percentage of CD4+ naïve T cells and CD8+ naïve T cells. The association between CD4+ naïve T cells and trauma was reduced to nonsignificance after controlling for education, BMI, smoking, and drinking, suggesting that these socioeconomic and lifestyle factors may mediate this association.

Associations between life trauma and CD8+ naïve T cells remained significant after including all covariates. There was only one statistically significant interaction. The effect of experiencing more lifetime discrimination on naïve CD8+ T cell percentage was amplified for Hispanic respondents compared to non-Hispanic White respondents.

Conclusions

Despite its limitations, this study provides important insights on the role of social stress in immune aging, highlighting a key role for health behaviors and social-environmental conditions as correlates of naïve T cell decline as well as a distinctive association of stressors with higher terminally differentiated CD4+ T cell percentages (i.e., independent of variables controlled for here). These results raise the possibility that interventions such as CMV vaccination and senolytic therapies might potentially help reduce social disparities in T cell immunologic aging ²⁸. Interventions aimed at reducing stress or increasing resilience may be needed to address these inequalities.

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