Age-related increase in LDL-cholesterol is associated with enhanced oxidative stress and disturbed sphingolipid metabolism

We investigated alterations in plasma metabolites associated with the age-related increase in circulating concentration of low-density lipoprotein (LDL)-cholesterol. The study included 602 healthy, nondiabetic subjects (aged 30–65 years). Among 393 individuals with LDL-cholesterol within the normal limit at baseline, 56 (14.2 %) developed high fasting LDL-cholesterol levels after 3 years. The 337 subjects that retained normal LDL-cholesterol were matched for age, gender, BMI, and fasting LDL-cholesterol to form the control group (n = 78). At the 3-year follow-up, the high-LDL group showed greater increases in serum total-cholesterol and LDL-cholesterol, plasma oxidized LDL, lipoprotein-associated phospholipase A₂ activity, and urinary 8-epi-prostaglandin F_2α than the control group after adjusting for baseline levels. The high-LDL group also showed significant decreases in sphingomyelin (SM) (d18:0/16:1) and phosphatidylcholine (PC) (18:0/20:4), which were associated with an increases on LDL-cholesterol, and significant increases in palmitic amide and lactosylceramide. Mean changes in the levels of SM (d18:0/16:1), C17 sphinganine, PC (18:0/20:4), and eight lysoPCs containing C16:1, C16:0, C17:0, C18:1, C18:0, C20:4, C20:3, and C22:6 were statistically different between control and high-LDL groups. Overall, the change in ox-LDL positively correlated with changes in LDL-cholesterol, Lp-PLA₂ activity, palmitic amide, oleamide, lysoPCs, and C17 sphinganine, and negatively correlated with changes in SM (d18:0/16:1) (r = −0.501, P < 0.001). An age-related increase in LDL-cholesterol is associated with enhanced oxidative stress and disturbed sphingolipid metabolism.