Serum metabolic signatures of cognitive resilience in a longitudinal aging cohort

Abstract Aging is typically accompanied by a progressive decline in cognitive function, yet some individuals maintain exceptional cognitive performance, even across the transition from middle to older age, defining exceptional cognitive resilience. While existing measures of resilience primarily rely on clinical assessments, its molecular determinants and early predictive markers remain poorly understood. Here, we performed untargeted LC-MS/MS profiling of longitudinal serum samples to identify metabolic signatures associated with cognitive resilience, which was established based on cognitive tests conducted over 28 years in a cohort of 237 participants. We observed associations across multiple chemical classes, including carnitines, glutamine conjugates, phosphocholines, as well as diet-and drug-derived metabolites. Chemical class-specific analyses revealed distinct metabolic profiles, including predominantly negative associations of medium-chain acylcarnitines with cognitive resilience, increased accumulation of glucuronide conjugates in individuals with low cognitive resilience, altered metabolism of the antihypertensive drug, metoprolol, and elevated levels of dietary compounds such as piperine and lutein in individuals with high cognitive resilience. By leveraging public metabolomics data, we further contextualized the metabolic signatures with respect to their organ specificity, microbial origin, and disease associations. Collectively, these metabolic features, including several previously underexplored compounds, represent promising candidates for functional characterization in mechanisms of aging biology and provide mechanistic insights into the molecular basis of cognitive resilience. Highlights Serum metabolite MS/MS features, including acyl carnitines, phosphocholines, and hippuric acid conjugates, are associated with cognitive resilience in 237 individuals transitioning from middle to older age. Diet-derived piperine is positively associated with cognitive resilience. Differences in β-blocker drug metabolism, rather than parent drug levels, are associated with cognitive resilience. Repository-scale searches for the resilience-associated metabolites reveal organ specificity, microbial contributions, and their presence across multiple disease contexts. Competing Interest Statement P.C.D. is an advisor and holds equity in Cybele, Sirenas, and BileOmix, and he is a scientific co-founder, advisor, and holds equity and/or receives income from Ometa, Enveda, and Arome with prior approval by UC San Diego. P.C.D. consulted for DSM Animal Health in 2023.