Statistical mediation of the relationships between chronological age and lipoproteins by nonessential amino acids in healthy men

Aging is a major risk factor for metabolic impairment that may lead to age-related diseases such as cardiovascular disease. Different mechanisms that may explain the interplay between aging and lipoproteins, and between aging and low-molecular-weight metabolites (LMWMs), in the metabolic dysregulation associated with age-related diseases have been described separately. Here, we statistically evaluated the possible mediation effects of LMWMs on the relationships between chronological age and lipoprotein concentrations in healthy men ranging from 19 to 75 years of age. Relative and absolute concentrations of LMWMs and lipoproteins, respectively, were assessed by nuclear magnetic resonance (NMR) spectroscopy. Multivariate linear regression and mediation analysis were conducted to explore the associations between age, lipoproteins and LMWMs. The statistical significance of the identified mediation effects was evaluated using the bootstrapping technique, and the identified mediation effects were validated on a publicly available dataset. Chronological age was statistically associated with five lipoprotein classes and subclasses. The mediation analysis showed that serine mediated 24.1% (95% CI: 22.9 - 24.7) of the effect of age on LDL-P, and glutamate mediated 17.9% (95% CI: 17.6 - 18.5) of the effect of age on large LDL-P. In the publicly available data, glutamate mediated the relationship between age and an NMR-derived surrogate of cholesterol. Our results suggest that the age-related increase in LDL particles may be mediated by a decrease in the nonessential amino acid glutamate. Future studies may contribute to a better understanding of the potential biological role of glutamate and LDL particles in aging mechanisms and age-related diseases.