Abstract Aging is associated with systemic inflammation and cellular apoptosis accelerating physiological dysfunctions. Whether physically active way of life affects these associations is unclear. This study measured the levels of serum inflammatory and apoptotic molecules, their change over 10 years, and their associations with physical performance in sprint-trained male athletes. HsCRP, cell counts, HGB, FasL, miR-21, and miR-146a were measured cross-sectionally (𝑛 = 67, 18–90 yrs) and serum FasL, miR-21, and miR-146a and their aging-related associations with physical performance were assessed over a 10-year follow-up (𝑛 = 49, 50–90yrs). The cross-sectional study showed positive age correlations for neutrophils and negative for lymphocytes, red blood cells, HGB, FasL, and miR-146a. During the 10-year follow-up, FasL decreased (𝑃 = 0.017) and miR-21 (𝑃 < 0.001) and miR-146a (𝑃 = 0.005) levels increased. When combining the molecule levels, aging, and physical performance, FasL associated with counter movement jump and bench press (𝑃 < 0.001), miR-21 and miR-146a with knee flexion (𝑃 = 0.023; 𝑃 < 0.001), and bench press (𝑃 = 0.004; 𝑃 < 0.001) and miR-146a with sprint performance (𝑃 < 0.001). The studied serum molecules changed in an age-dependent manner and were associated with declining physical performance. They have potential as biomarkers of aging-related processes influencing the development of physiological dysfunctions. Further research is needed focusing on the origins and targets of circulating microRNAs to clarify their function in various tissues with aging.