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Peer-reviewedCC BY-NC 4.0Redox Biology

Glial lipid reprogramming in brain aging: Lipid identity, organelle stress, and redox vulnerability

  • Mandeep Rana1
  • Wen-Chin Ko2
  • Kunal Nepali3
  • Chiung-Yuan Ko4
  • Ting-Lin Yen5
  • Jing-Shiun Jan6
  • Rajeev Taliyan7
  • Ching-Hao Li8
  • Chih-Hao Yang9
9 affiliations
  1. 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan
  2. 2Division of Cardiac Electrophysiology, Department of Cardiovascular Center, Cathay General Hospital, Taipei City, 106, Taiwan; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan
  3. 3School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan
  4. 4School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
  5. 5Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Department of Medical Research, Cathay General Hospital, Taipei, 106, Taiwan
  6. 6Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Research Center for Neuroscience, Taipei Medical University, Taipei, 110, Taiwan
  7. 7Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
  8. 8Research Center for Neuroscience, Taipei Medical University, Taipei, 110, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Corresponding author. Department of Physiology, College of Medicine, Taipei Medical University, Taiwan.
  9. 9Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Research Center for Neuroscience, Taipei Medical University, Taipei, 110, Taiwan; Corresponding author. Department of Pharmacology, College of Medicine, Taipei Medical University, Taiwan.
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Abstract

Brain aging is accompanied by progressive glial dysfunction, impaired metabolic adaptation, oxidative stress, and increased susceptibility to neurodegenerative disease. Although many studies of lipid metabolism in aging and neurodegeneration emphasize lipid abundance, lipid amount alone cannot explain why glia become redox-vulnerable. This review advances a chemistry-resolved integrative framework in which glial lipid reprogramming is understood through aging- and disease-associated changes in lipid identity, composition, oxidation state, storage form, subcellular localization, and lipid-mediated signaling. We discuss evidence from aged brain tissue, human neurodegenerative disease, iPSC-derived glial systems, and mouse models showing that altered lipid handling in microglia, astrocytes, and oligodendrocyte-lineage cells reshapes phagocytosis, inflammatory signaling, myelin processing, astrocytic metabolic support, and neuronal injury. We emphasize that acyl-chain saturation, head-group structure, oxidized lipid species, neutral lipid storage, plasmalogen-dependent redox buffering, peroxisomal lipid metabolism, and compartmental distribution determine how lipids regulate receptor engagement, lipid-droplet dynamics, lysosomal stress, mitochondrial function, ferroptotic susceptibility, and inflammatory redox signaling. Importantly, glial lipid reprogramming is further shaped by extracellular vesicle-mediated neuron-glia communication, regional lipid heterogeneity, and sex-dependent modifiers of glial metabolism. Oxidative stress therefore reflects the convergence of polyunsaturated fatty acid (PUFA)-enriched membranes, oxidized phospholipids, oxysterols, ceramide accumulation, plasmalogen loss, mitochondrial reactive oxygen species (ROS) production, lysosomal iron release, peroxisomal dysfunction, and declining glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), GTP cyclohydrolase 1-tetrahydrobiopterin (GCH1-BH4), and nuclear factor erythroid 2-related factor 2 (NRF2)-dependent protective systems. Finally, we discuss lipid-centered therapeutic opportunities targeting cholesterol efflux, apolipoprotein E (APOE) lipidation, lipid-droplet metabolism, sphingolipid pathways, lipid peroxide defense, plasmalogen support, extracellular vesicle biology, and lipid-based delivery systems. By shifting the focus from lipid accumulation to lipid identity, compartmental handling, and biological context, this review synthesizes glial lipid reprogramming as an integrative framework linking brain aging to redox-sensitive neurodegeneration.

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Cite

BibTeXRIS
BibTeX
@article{rana2026glial,
  title = {{Glial lipid reprogramming in brain aging: Lipid identity, organelle stress, and redox vulnerability}},
  author = {Mandeep Rana and Wen-Chin Ko and Kunal Nepali and Chiung-Yuan Ko and Ting-Lin Yen and Jing-Shiun Jan and Rajeev Taliyan and Ching-Hao Li and Chih-Hao Yang},
  journal = {Redox Biology},
  year = {2026},
  month = oct,
  doi = {10.1016/j.redox.2026.104453},
  url = {https://doi.org/10.1016/j.redox.2026.104453},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Glial lipid reprogramming in brain aging: Lipid identity, organelle stress, and redox vulnerability
AU  - Mandeep Rana
AU  - Wen-Chin Ko
AU  - Kunal Nepali
AU  - Chiung-Yuan Ko
AU  - Ting-Lin Yen
AU  - Jing-Shiun Jan
AU  - Rajeev Taliyan
AU  - Ching-Hao Li
AU  - Chih-Hao Yang
PY  - 2026
DA  - 2026/10/23
JO  - Redox Biology
DO  - 10.1016/j.redox.2026.104453
UR  - https://doi.org/10.1016/j.redox.2026.104453
AB  - Brain aging is accompanied by progressive glial dysfunction, impaired metabolic adaptation, oxidative stress, and increased susceptibility to neurodegenerative disease. Although many studies of lipid metabolism in aging and neurodegeneration emphasize lipid abundance, lipid amount alone cannot explain why glia become redox-vulnerable. This review advances a chemistry-resolved integrative framework in which glial lipid reprogramming is understood through aging- and disease-associated changes in lipid identity, composition, oxidation state, storage form, subcellular localization, and lipid-mediated signaling. We discuss evidence from aged brain tissue, human neurodegenerative disease, iPSC-derived glial systems, and mouse models showing that altered lipid handling in microglia, astrocytes, and oligodendrocyte-lineage cells reshapes phagocytosis, inflammatory signaling, myelin processing, astrocytic metabolic support, and neuronal injury. We emphasize that acyl-chain saturation, head-group structure, oxidized lipid species, neutral lipid storage, plasmalogen-dependent redox buffering, peroxisomal lipid metabolism, and compartmental distribution determine how lipids regulate receptor engagement, lipid-droplet dynamics, lysosomal stress, mitochondrial function, ferroptotic susceptibility, and inflammatory redox signaling. Importantly, glial lipid reprogramming is further shaped by extracellular vesicle-mediated neuron-glia communication, regional lipid heterogeneity, and sex-dependent modifiers of glial metabolism. Oxidative stress therefore reflects the convergence of polyunsaturated fatty acid (PUFA)-enriched membranes, oxidized phospholipids, oxysterols, ceramide accumulation, plasmalogen loss, mitochondrial reactive oxygen species (ROS) production, lysosomal iron release, peroxisomal dysfunction, and declining glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), GTP cyclohydrolase 1-tetrahydrobiopterin (GCH1-BH4), and nuclear factor erythroid 2-related factor 2 (NRF2)-dependent protective systems. Finally, we discuss lipid-centered therapeutic opportunities targeting cholesterol efflux, apolipoprotein E (APOE) lipidation, lipid-droplet metabolism, sphingolipid pathways, lipid peroxide defense, plasmalogen support, extracellular vesicle biology, and lipid-based delivery systems. By shifting the focus from lipid accumulation to lipid identity, compartmental handling, and biological context, this review synthesizes glial lipid reprogramming as an integrative framework linking brain aging to redox-sensitive neurodegeneration.
SN  - 2213-2317
ER  -