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

The aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs). 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 changes in complex lipids in quiescent NSCs in vitro and in vivo. Moreover, several polyunsaturated fatty acids increase across lipid classes in quiescent NSCs during aging. Using spatial lipidomics, we find that some of the changes in complex lipids are also observed in situ. Several age-related changes in complex lipids and side chain composition are occurring at the plasma membrane, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we show that aging is accompanied by a decrease in plasma membrane order, a key membrane biophysical property, 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. Knocking out the phospholipid acyltransferase MBOAT2 exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. Mboat2 overexpression reverses age-related lipidomic changes in old quiescent NSCs and boosts their ability to activate in vitro and in vivo. Moreover, supplementation of plasma membrane lipids from young NSCs improves the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs, which has important implications for countering brain decline during aging.