Association of Plasma Small-Molecule Intermediate Metabolites With Age and Body Mass Index Across Six Diverse Study Populations

Older age and obesity are associated with metabolic dysregulation; the mechanism by which these factors impact metabolism across the lifespan is important, but relatively unknown. We evaluated a panel of amino acids (AAs) and acylcarnitines (ACs) to identify effects of age and adiposity (body mass index) on circulating small-molecule metabolites in a meta-analysis of six diverse study populations. Targeted metabolic profiling was performed in six independent studies, representing 739 subjects with a broad range of age, body mass index, health states, and ethnic origin. Principal components analysis was performed on log-normalized values for AAs and ACs separately, generating one AC factor and two AA factors for each study. A common AC factor consisted primarily of acetylcarnitine, medium-chain AC, and several long-chain AC. AA Factor 1 consisted primarily of large neutral AAs. Glycine was its own factor. Metabolic profiling and factor analysis identified clusters of related metabolites of lipid and AA metabolism that were consistently associated with age and body mass in a series of studies with a broad range of age, body mass index, and health status. An inverse association of glycine with body mass index and male gender supports its role as a marker of favorable metabolic health. An important focus of future investigations should be to determine whether these clusters of metabolic intermediates are possible early predictors of health outcomes associated with body mass; are involved with accelerated aging; are involved in the causative pathway of aging; and how modification of these metabolic pathways impact the biology of aging.