The relationships between age-related changes in circulating endogenous metabolites, inflammatory and oxidative stress markers, and arterial stiffness in 57 middle-aged (34-55 years), nonobese men were studied over the course of 3 years. Arterial stiffness was measured using brachial-ankle pulse wave velocities (ba-PWV). Plasma metabolomic profiling was performed using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry. After 3 years, decreased HDL cholesterol and increased malondialdehyde (MDA) and ox-LDL levels were observed. Among 15 identified lipids, lysoPCs (C16:0, C18:0, C18:2, C20:4, and C20:5) and linoleyl carnitine were the major plasma metabolites that contributed to the age-related differences. LysoPC16:0 (variable importance in the projection value, 6.2029) was found as the most important plasma metabolite for evaluating these changes. Changes in lysoPC16:0 levels positively correlated with the changes in 8-epi-PGF2α (r = 0.608), MDA (r = 0.413), high-sensitivity C-reactive protein (r = 0.509), IL-6 (r = 0.497), and ba-PWV (r = 0.283) levels. ba-PWV levels positively correlated with the changes in waist-to-hip ratios (WHR), inflammatory and oxidative stress markers. In a subgroup analysis of subjects with decreased ba-PWVs vs. increased ba-PWVs, changes in WHR and levels of lysoPC16:0, ba-PWV, IL-6, 8-epi-PGF2α, MDA, and P-selectin were significantly different. Our results suggest that age-related increases in lysoPC16:0 may contribute to lipid peroxidation, thereby activating proinflammatory phenotypes and arterial stiffness.