Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration

Shao, Wei; Wang, Kai; Liu, Yongchao; Zhang, Haojia; Sun, Zijin; Zhou, Rui

doi:10.3390/ijms27125580

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Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration

by

Wei Shao

^†,

Kai Wang

^†,

Yongchao Liu

,

Haojia Zhang

,

Zijin Sun

^* and

Rui Zhou

^*

School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(12), 5580; https://doi.org/10.3390/ijms27125580 (registering DOI)

Submission received: 15 April 2026 / Revised: 5 June 2026 / Accepted: 8 June 2026 / Published: 20 June 2026

(This article belongs to the Special Issue Molecular Mechanisms and Translational Insights in Neurological Disorders)

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Abstract

The mammalian brain fundamentally relies on precise lipid homeostasis to maintain structural integrity and complex neural signaling. Emerging evidence positions lipid metabolism reprogramming not merely as a secondary pathological byproduct but as a core initiating driver of age-related neurodegenerative diseases. This review systematically evaluates the mechanisms of cerebral lipid dyshomeostasis during brain aging, highlighting glial cells as the central mediators of this pathological cascade. We comprehensively dissect the age-associated “lipid drift”, emphasizing apolipoprotein E (APOE)-induced cholesterol transport defects and lipid raft pathology, the accumulation of lipid droplets that triggers microglial metabolic stress (LDAMs), and ceramide-driven neuronal apoptosis coupled with the exosome-mediated propagation of pathogenic proteins. Furthermore, we map these aberrant lipid networks to specific pathological signatures in Alzheimer's, Parkinson's, and demyelinating diseases. Finally, we critically evaluate promising therapeutic interventions, including nutritional strategies, LXR/RXR agonists, and nanotechnology-enabled delivery systems designed to bypass the blood–brain barrier. By integrating high-throughput lipidomics for early diagnostic biomarker discovery, we underscore the translational imperative of restoring cerebral lipid homeostasis as a disease-modifying strategy for neurodegeneration.

Keywords: cerebral lipid homeostasis; lipid metabolism reprogramming; neurodegenerative diseases; brain aging; apolipoprotein E (APOE)

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MDPI and ACS Style

Shao, W.; Wang, K.; Liu, Y.; Zhang, H.; Sun, Z.; Zhou, R. Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration. Int. J. Mol. Sci. 2026, 27, 5580. https://doi.org/10.3390/ijms27125580

AMA Style

Shao W, Wang K, Liu Y, Zhang H, Sun Z, Zhou R. Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration. International Journal of Molecular Sciences. 2026; 27(12):5580. https://doi.org/10.3390/ijms27125580

Chicago/Turabian Style

Shao, Wei, Kai Wang, Yongchao Liu, Haojia Zhang, Zijin Sun, and Rui Zhou. 2026. "Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration" International Journal of Molecular Sciences 27, no. 12: 5580. https://doi.org/10.3390/ijms27125580

APA Style

Shao, W., Wang, K., Liu, Y., Zhang, H., Sun, Z., & Zhou, R. (2026). Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration. International Journal of Molecular Sciences, 27(12), 5580. https://doi.org/10.3390/ijms27125580

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Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration

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