Lipidomic profiling reveals age-dependent changes in complex plasma membrane lipids that regulate neural stem cell aging

The aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs), which may underlie age-associated defects in sensory and cognitive functions1-6. While mechanisms that restore old NSC function have started to be identified7-23, the role of lipids - especially complex lipids - in NSC aging remains largely unclear. Using lipidomic profiling by mass spectrometry, we identify age-related lipidomic signatures in young and old quiescent NSCs in vitro and in vivo. These analyses reveal drastic changes in several complex membrane lipid classes, including phospholipids and sphingolipids in old NSCs. Moreover, poly-unsaturated fatty acids (PUFAs) strikingly increase across complex lipid classes in quiescent NSCs during aging. Age-related changes in complex lipid levels and side chain composition are largely occurring in plasma membrane lipids, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we find that aging is accompanied by modifications in plasma membrane biophysical properties, with a decrease in plasma membrane order in old quiescent NSCs in vitro and in vivo. To determine the functional role of plasma membrane lipids in aging NSCs, we performed genetic and supplementation studies. Knockout of Mboat2, which encodes a phospholipid acyltransferase, exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. As Mboat2 expression declines with age, Mboat2 deficiency may drive NSC decline during aging. Interestingly, supplementation of plasma membrane lipids derived from young NSCs boosts the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs in old individuals, which has important implications for countering brain decline during aging.