Abstract
BACKGROUND: The inflammatory pathophysiology of hypertension involves interactions between innate and adaptive immune pathways. While interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have established roles, the contributions of specific T cell-derived cytokines, especially interferon-γ (IFN-γ), interleukin-17A (IL-17A), and interleukin-1 (IL-1), remain less defined in age-stratified human populations. The aging immune system undergoes characteristic shifts that may differentially engage these pathways in regulating blood pressure, with this immune senescence being notably accelerated in people living with HIV (PLWH). Therefore, this study aimed to investigate age-stratified associations between key cytokines and systolic blood pressure (SBP) and to determine how these relationships interact with metabolic factors in both PLWH and non-PLWH. METHODS: We conducted a cross-sectional analysis of 332 adults, stratified into two age groups: < 45 years (n = 121) and ≥ 45 years (n = 211). Of the participants, 241 were living with HIV (PLWH) and 91 were HIV-negative. Multiple linear regression models, adjusted for demographics, HIV status, LDL cholesterol, and smoking, assessed associations between SBP and plasma levels of IFN-γ, IL-17A, IL-6, IL-1, and TNF-α. Analyses were performed separately for each age group. In secondary analysis, we evaluated the cytokine-SBP associations using multilinear regression within the HIV + subgroup and in a pooled model including both PLWH and HIV-negative participants to assess consistency across HIV serostatus. RESULTS: The older cohort had significantly higher median SBP, BMI, and LDL cholesterol (all p < 0.001). Regression models revealed distinct, age-dependent drivers of SBP. In adults < 45 years, only IFN-γ (β = 0.00107, p = 0.018) and chronological age (β = 0.487, p = 0.047) showed significant positive associations with SBP. In contrast, for adults ≥ 45 years, body mass index (BMI) was the dominant and consistent predictor across all models (β range: 1.95-2.08, all p < 0.001). In this older group, IL-17A was additionally significant in its specific model (β = 0.00322, p = 0.0448). Systemic levels of IL-6, IL-1, and TNF-α were not significantly associated with SBP in either cohort. Secondary analysis showed consistent cytokine-SBP relationships by HIV status, with a slight reduction in effect size seen in IL-17A after adding HIV-negative participants: HIV+ (β = 0.0029, p = 0.035) to the combined cohort (β = 0.0027, p = 0.048). IFN-γ remained stable with near-identical effect sizes (HIV+: β = 0.0010, p = 0.011; combined: β = 0.0010, p = 0.010). CONCLUSION: The regulation of blood pressure appears to undergo a fundamental pathophysiological transition with advancing age. In younger adults (< 45 years), SBP is associated with adaptive immune activity, mainly the Th1-associated IFN-γ. After midlife (≥ 45 years), this relationship is superseded by a model dominated by adiposity, within which the Th17-associated IL-17A acts as a contributing inflammatory mediator. These age-stratified cytokine-blood pressure relationships were consistent across PLWH and HIV-negative individuals, suggesting that this pathophysiological succession operates independently of HIV serostatus. Collectively, these findings advocate for age-tailored, mechanism-based approaches to the understanding and managing blood pressure-related risk.