SEX-SPECIFIC ALTERATIONS IN CIRCULATING LIPIDOME DURING MOUSE AGING

Abstract Lipids serve as pivotal elements in biological systems, fulfilling diverse roles ranging from cellular structure components to signaling molecules and energy reserves. They encompass a variety of classes including structural membrane lipids (e.g., cholesterol, phosphatidylcholine, phosphatidylethanolamine), energy-storing lipids (e.g., triglycerides, fatty acids), and bioactive lipids (e.g., lyso-phospholipids, ceramides). Increasing evidence shows associations between lipids and age-related diseases (e.g., atherosclerosis, cancer, diabetes, and neurodegenerative diseases), indicating lipid metabolism is involved with health and longevity. In this study, we applied multi-dimensional mass spectrometry-based shotgun lipidomics to quantitatively measure the plasma lipidome alterations across different ages in C57BL/6 mice. We systematically collected plasma samples from both sexes across 7 adult-to-old-age timepoints (8 to 32 months, in 4-month increments, with 8-10 mice per sex at each age). Our data revealed a sex-dependent regulation within the circulating lipidome in which males demonstrated higher concentrations across nearly all lipid classes at each timepoint compared to females. Notably, with advanced ages, males exhibited a decline in major phospholipids and an accumulation of cholesteryl ester—suggestive of an age-related shift in lipoprotein composition. An age-associated increase in phosphatidylserine, previously linked to apoptotic signaling, was exclusive to males. Conversely, females showed a consistent plasma lipid profile throughout their lifespan. The only shared change between sexes is plasmalogen decreasing with age, which could imply increasing oxidative stress. Our findings illuminate sex-specific regulatory mechanisms in lipid metabolism during aging in mice, with potential implications for understanding sex differences in the aging process.