Temporal associations between T-cell senescence and apoptosis with arterial stiffness in middle-aged/older adults: the VEGGIE trial

Background: Age-related structural arterial remodeling (S) and load-dependent (LD) arterial stiffening can be calculated using arterial pulse-wave velocity (PWV) and blood pressure. Senescence-associated T-cells are cross-sectionally associated with both S-PWV and LD-PWV; however, the temporality is not known. The purpose of this analysis was to determine whether higher T-cell senescence may precede or follow higher S-PWV and LD-PWV, leveraging data from the VEGGIE trial. Methods: The VEGGIE trial was an 18-week randomized, controlled, caloric restriction weight-loss trial in middle-aged and older adults (age:57.6 ± 5.8 years, n=58, systolic blood pressure=129±17mmHg at baseline). PWV was estimated (ePWV) using mean arterial pressure and age at each timepoint with previously established reference values. S-ePWV and LD-ePWV were calculated from total ePWV (T-ePWV) using participant-specific exponential models. CD3+ T-cell senescence (p16INK4a and p21CIP1/WAF1) and apoptosis (BCL2 anti-apoptotic and BAK1 pro-apoptotic) gene expression was measured using real-time TaqMan quantitative reverse-transcription polymerase chain reaction and normalized to housekeeping genes. Plasma concentrations of 25 senescence associated secretory phenotype (SASP) biomarkers were also measured using multiplex assay. Multivariable linear regressions tested associations between baseline T-cell senescence and arterial stiffness with 18-week change in PWV or T-cell senescence. Models were adjusted for biologic sex, BMI, race, and treatment-group. Interaction effects of sex, BMI, race, and treatment-group were explored. Pearson correlation matrixes were used to assess associations between plasma SASP biomarkers, T-cell senescence and apoptosis genes, and PWV measures. Results: Higher baseline BAK1 was nominally associated with increases in T-ePWV (β=0.16, P=0.059) and significantly associated with increases in S-ePWV (β=0.099, P=0.037) over 18-weeks. No interaction effects of treatment group were observed. Race by baseline BCL2 and gender by baseline P21 interaction effects, for T-ePWV and S-ePWV, respectively, were observed (p< 0.05). Associations between BCL2 and T-ePWV stratified for race were not significant (p< 0.05); however, higher baseline P16 expression was negatively associated with delta S-ePWV in males, but not females (p=0.047 vs. p=0.16). Several SASP biomarkers were positively associated with both baseline BAK1 and delta T-ePWV or S-ePWV. Interestingly, higher baseline T-ePWV was nominally associated with decreases in delta P21 and (β=-0.33, P=0.056) and S-ePWV was significantly associated with decreases in delta P21 (β=-0.38, P=0.048). Conclusions: Temporal associations between CD3+ senescence and arterial stiffness may be bi-directional. Apoptosis of regulatory, anti-inflammatory T-cells may allow for a pro-inflammatory environment that promotes structural arterial remodeling. The stiff extracellular matrix associated with structural arterial remodeling may drive T-cell senescence, furthering pro-inflammatory production and structural remodeling. Future research is needed directly measuring PWV and T-cell senescence over longer periods. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.