PR002588 (Project)

Description: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 functions. While mechanisms that restore old NSC function have started to be identified, 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, polyunsaturated fatty acids (PUFAs) strikingly increase across complex lipid classes in quiescent NSCs during aging. Lipidomic profiling of isolated plasma membrane vesicles shows that agerelated differences in complex lipid levels and side chain composition are largely occurring in plasma membrane lipids. Experimentally, we find that aging is accompanied by modifications in 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 perform genetic and supplementations 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 to counter brain decline during aging.