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Peer-reviewedCC BYScience Advances

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

  • Xiaoai Zhao1,2,3
  • Ryan M. Feitzinger2
  • Jeeyoon Na2,4
  • Xin Yan5
  • Andrew Erickson1,3
  • Kévin Contrepois2
  • Olivia Y. Zhou2,6,7
  • Francesco Vallania8,9
  • Mathew Ellenberger2
  • Chloe M. Kashiwagi2
  • Stephanie D. Gagnon2
  • Cynthia J. Siebrand2
8 more authors
  • Matías Cabruja2
  • Gavin McAllister Traber2
  • Andrew S. McKay2
  • Daniel Hornburg2
  • Purvesh Khatri8,9
  • Michael P. Snyder2
  • Richard N. Zare5
  • Anne Brunet2,10,11
11 affiliations
  1. 1Department of Comparative Medicine, Yale University, New Haven, CT, USA
  2. 2Department of Genetics, Stanford University, Stanford, CA, USA
  3. 3Yale Center for Molecular and Systems Metabolism, Yale University, New Haven, CT, USA
  4. 4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
  5. 5Department of Chemistry, Stanford University, Stanford, CA, USA
  6. 6Stanford Biophysics Program, Stanford University, Stanford, CA, USA
  7. 7Stanford Medical Scientist Training Program, Stanford University, Stanford, CA, USA
  8. 8Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA
  9. 9Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, CA, USA
  10. 10Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA, USA
  11. 11Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
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Abstract

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 1–6 . While mechanisms that restore old NSC function have started to be identified 7–23 , 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.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026lipidomic,
  title = {{Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging}},
  author = {Xiaoai Zhao and Ryan M. Feitzinger and Jeeyoon Na and Xin Yan and Andrew Erickson and Kévin Contrepois and Olivia Y. Zhou and Francesco Vallania and Mathew Ellenberger and Chloe M. Kashiwagi and Stephanie D. Gagnon and Cynthia J. Siebrand and Matías Cabruja and Gavin McAllister Traber and Andrew S. McKay and Daniel Hornburg and Purvesh Khatri and Michael P. Snyder and Richard N. Zare and Anne Brunet},
  journal = {Science Advances},
  year = {2026},
  month = jul,
  doi = {10.1126/sciadv.aeh9771},
  url = {https://doi.org/10.1126/sciadv.aeh9771},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging
AU  - Xiaoai Zhao
AU  - Ryan M. Feitzinger
AU  - Jeeyoon Na
AU  - Xin Yan
AU  - Andrew Erickson
AU  - Kévin Contrepois
AU  - Olivia Y. Zhou
AU  - Francesco Vallania
AU  - Mathew Ellenberger
AU  - Chloe M. Kashiwagi
AU  - Stephanie D. Gagnon
AU  - Cynthia J. Siebrand
AU  - Matías Cabruja
AU  - Gavin McAllister Traber
AU  - Andrew S. McKay
AU  - Daniel Hornburg
AU  - Purvesh Khatri
AU  - Michael P. Snyder
AU  - Richard N. Zare
AU  - Anne Brunet
PY  - 2026
DA  - 2026/07/29
JO  - Science Advances
DO  - 10.1126/sciadv.aeh9771
UR  - https://doi.org/10.1126/sciadv.aeh9771
AB  - 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 1–6 . While mechanisms that restore old NSC function have started to be identified 7–23 , 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.
SN  - 2375-2548
ER  -