Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study

Background: Cellular changes in adaptive immune system accompany the process of aging and contribute to an aging-related immune phenotype (ARIP) characterized by decrease in naïve T-cells (T_N) and increase in memory T-cells (T_M). A population-representative marker of ARIP and its associations with biological aging and age-related chronic conditions have not been studied previously. Methods: We developed two ARIP indicators based on well understood age-related changes in T cell distribution: T_N/(T_CM (Central Memory) + T_EM (Effector Memory) + T_EFF (Effector)) (referred as T_N/T_M) in CD4 + and CD8 + T-cells. We compared them with existing ARIP measures including CD4/CD8 ratio and CD8 + TN cells by evaluating associations with chronological age and the Klemera Doubal measure of biological age (measured in years) using linear regression, multimorbidity using multinomial logistic regression and two-year mortality using logistic regression. Results: CD8 + T_N and CD8 + T_N/T_M had the strongest inverse association with chronological age (beta estimates: -3.41 and -3.61 respectively; p-value < 0.0001) after adjustment for sex, race/ethnicity and CMV status. CD4 + T_N/T_M and CD4 + T_N had the strongest inverse association with biological age (β = -0.23; p = 0.003 and β = -0.24; p = 0.004 respectively) after adjustment for age, sex, race/ethnicity and CMV serostatus. CD4/CD8 ratio was not associated with chronological age or biological age. CD4 + T_N/T_M and CD4 + T_N was inversely associated with multimorbidity. For CD4 + T_N/T_M, people with 2 chronic conditions had an odds ratio of for 0.74 (95%CI: 0.63–0.86 p = 0.0003) compared to those without any chronic conditions while those with 3 chronic conditions had an odds ratio of 0.75 (95% CI: 0.63–0.90; p = 0.003) after adjustment for age, sex, race/ethnicity, CMV serostatus, smoking, and BMI. The results for the CD4 + T_N subset were very similar to the associations seen with the CD4 + T_N/T_M. CD4 + T_N/T_M and CD4 + T_N were both associated with two-year mortality (OR = 0.80 (95% CI: 0.67–0.95; p = 0.01) and 0.81 (0.70–0.94; p = 0.01), respectively). Conclusion: CD4 + T_N/T_M and CD4 + T_N had a stronger association with biological age, age-related morbidity and mortality compared to other ARIP measures. Future longitudinal studies are needed to evaluate the utility of the CD4 + subsets in predicting the risk of aging-related outcomes.