In recent years, an increasing level of attention has been given to microglia as an important contribution to neurodegeneration in the aging brain. Microglia are innate immune cells resident in the central nervous system, analogous to the macrophages found elsewhere in the body. They are deeply involved in the complex processes of normal tissue function and maintenance, not just a defense against pathogens and malfunctioning cells. With age, microglia become more inflammatory at the expense of tissue function. Here, researchers look at this harmful change in the behavior of microglia through the lens of cellular metabolism: what are the alterations in metabolism that accompany and perhaps cause unwanted inflammatory activities in this cell population? Finding ways to adjust the behavior of microglia is becoming a priority in the development of therapies to treat neurodegenerative conditions, and a greater understanding of how these cells change with age is a first step on that path.
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.
Link: https://doi.org/10.1111/acel.70660
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