Physical Fitness Dynamics Shape Immune Remodeling in Healthy Aging: A 3-Year Longitudinal Study

Aging is accompanied by functional decline and immune remodeling, yet the dynamics and early modifiability of these processes remain incompletely understood. Research suggests that lifestyle factors, particularly physical activity and fitness, influence immune aging. This study investigated longitudinal changes in physical performance and immune parameters in a well-characterized cohort of clinically healthy elderly. In this study, 49 clinically healthy elderly underwent repeated assessments of cardiorespiratory fitness, muscular strength, body composition, immune cell phenotypes, and serum cytokines at baseline, 1-year, and 3-year follow-up. We observed a shift toward an aged T cell profile, characterized by reductions in naïve and regulatory T cells (Tregs), alongside increases in differentiated and senescence-associated subsets. Treg subsets followed divergent trajectories, with resting Tregs (rTregs) declining and memory-like Tregs (mTregs) increasing. Serum levels of classical pro-inflammatory cytokines remained largely stable over the study period. Despite stable self-reported physical activity, participants showed declines in cardiorespiratory fitness and strength. Immune remodeling was primarily associated with declines in physical fitness, alongside an increase in highly differentiated CD4⁺ and senescent CD8⁺ T cell subsets, lower rTregs, higher mTregs, and increased CD4^-CD8^- lymphocyte frequencies, while habitual physical activity was independently related to effector T cell dynamics. Together, these findings indicate that subtle functional decline in clinically healthy older adults is paralleled by immune changes characteristic of early immunosenescence, occurring largely in the absence of overt systemic inflammation. These results highlight physical fitness as a potentially modifiable determinant of immune trajectories and immune resilience in healthy aging.