Frailty and slowed gait become more prevalent with advanced age and predict major health outcomes. These complex phenotypes are influenced by multiple aspects of aging and multimorbidity, and may be manifestations of dysregulation in physiologic systems. Metabolomics, the large-scale study of small molecules that are intermediates or end-products of metabolism, can help us better understand aging-related metabolic changes that contribute to frailty and walking ability by capturing global metabolic profiles occurring most closely to the phenotypes. Here, I aimed to 1) identify metabolites and pathways associated with high versus low walking ability using a nested case-control study of 120 older adults matched on age, gender, race, and fasting time, 2) determine metabolites and pathways associated with frailty to vigor among 287 older black men, and 3) develop and validate a metabolite composite score to determine whether it explains the frailty-associated higher mortality. Regarding aim 1, I found 96 metabolites, mostly lipids/lipid-like molecules, especially triacylglycerols, associated with walking ability. Body composition partly explained associations between select metabolites and walking ability, though many remained independently associated. Triaclyglycerols containing mostly polyunsaturated fatty acids were higher, whereas triaclyglycerols containing mostly saturated or monounsaturated fatty acids were lower among those with high walking ability. Arginine and proline metabolism was a top pathway associated with walking ability. In aims 2 and 3, I found 37 metabolites associated with frailty to vigor and used those metabolites to develop a novel composite score. The metabolite composite score significantly predicted mortality and explained 56% of the higher mortality associated with frailty, where organic acids/derivatives (mostly amino acids) and lipids/lipid-like molecules accounted for almost all of the attenuation. The metabolite composite score also predicted mortality in a validation cohort. Differences in patterns of plasma lipids and amino acids were common classes of metabolites associated with these aging-related phenotypes. Knowledge on differences in these metabolites and metabolic pathways associated with frailty to vigor and walking ability is of public health interest because it provides a better characterization of these complex aging-related phenotypes that can inform points in their pathophysiology to intervene on to promote healthy aging and preserve independence throughout late-life
