Ether lipids and sphingolipids drive sex-specific human aging dynamics.

Aging is a dynamic process characterized by complex molecular changes, including shifts in lipid metabolism. To systematically define lipidome dynamics with age and identify sex-specific lipidomic signatures, we performed targeted lipidomic profiling of plasma samples from 1030 adults aged 50-98 years, analyzing 543 lipid species across all lipid classes using high-throughput mass spectrometry and assessing the circulating fatty acid composition by gas chromatography. Our results reveal age-related lipidomic shifts, with ceramides and ether-linked phospholipids most affected. We identified three aging crests (55-60, 65-70, 75-80 years), with the 65-70 years crest dominant in men and the 75-80 years crest in women. Lipid enrichment analyses highlight acylcarnitines, sphingolipids and ether-linked phospholipids as key contributors, with functional indices indicating compositional shifts in lipid species. These findings suggest an impairment of lipid functional categories, including loss of dynamic properties, alterations in bioenergetics, antioxidant defense, cellular identity, and signaling platforms. This study underscores the non-linear nature of lipid metabolism in aging and provides a foundation for identifying biomarkers and interventions to promote healthy aging.