Mitochondrial Bioenergetic Profiling in T Cell Subsets Associates With Functional Health in Older Adults: A Cross-sectional Analysis From the INSPIRE-T Cohort

Aging varies across individuals, highlighting the need for better markers of functional decline. This study investigates the hypothesis that T cell energy metabolism is correlated with functional health in older adults. We used flow cytometry-based profiling to examine energy metabolism, focusing on mitochondrial OXPHOS activity (Mitochondrial dependence [MitoDep], expressed as percentage), in peripheral CD4 and CD8 T cell subsets from 187 participants aged 70-89 years (mean age 78.7 [SD 5.3], 57.7% [n = 108] women) within the Inspire-T cohort. Associations with Fried frailty phenotype were evaluated, using logistic regression. Relationships with intrinsic capacity score were assessed using partial least square regression and piecewise linear regression models, adjusting for age, sex, and comorbidities. Mitochondrial dependence was significantly lower in prefrail/frail individuals (47% of the study population) across several T cells subsets. In CD4 regulatory T cell (CD4Treg) subsets, higher MitoDep was significantly associated with reduced odds of prefrailty/frailty. Piecewise regression identified a breakpoint in memory CD4Treg MitoDep at 58.5% (95% CI, 50.7-67.5). Below this threshold, reduced MitoDep was significantly associated with lower intrinsic capacity (β = 0.40, p = .0104). This study establishes a novel link between T cell mitochondrial OXPHOS activity and functional health in older adults, offering insights for improved patient stratification and personalized lifestyle or therapeutic interventions.