Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging‐Associated Neurodegenerative Diseases

Abstract

Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes—including chronic low‐grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases—all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini‐review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex‐specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.