Chronological age as a major determinant of systemic metabolic remodeling in women

: Chronological aging is a major source of interindividual biological variability, yet the metabolic background that accompanies aging in women remains incompletely defined. Using large-scale plasma metabolomic and lipidomic profiling across the adult female lifespan, this study identifies coordinated metabolic signatures that progressively emerge with aging and dominate systemic metabolic variability independently of body mass index and estradiol status. Aging was associated with consistent remodeling of amino acid and organic acid metabolism, including enrichment of phenylalanine and tryptophan pathways and accumulation of kynurenine-related metabolites. In parallel, lipidomic signatures revealed selective remodeling of polyunsaturated phospholipids, diacylglycerols, triacylglycerols, cholesteryl esters, and ether-linked lipid species, indicating age-related changes in membrane organization and redox-associated lipid processes. After accounting for chronological age, these metabolic signatures were not independently associated with cognitive impairment or age-related comorbidities, suggesting that age accounts for a substantial component of the observed metabolic variation. Together, these findings define age-associated metabolic signatures that contribute to female aging biology and provide a framework for interpreting age-related changes in systemic metabolic states, with implications for metabolism-informed stratification approaches across the aging process.