Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging.
Publication Year:
2024
PubMed ID:
38840206
Funding Grants:
Public Summary:
Microglia are immune cells that live in the brain and help keep it healthy, as well as respond to injury or disease. As we age, these cells change, but it’s not fully understood how or whether those changes help protect the brain or contribute to damage.
In this study, researchers compared how microglia age in male and female mice. They found that aging caused more changes in microglia from females than from males, and that the differences between males and females became bigger with age.
They discovered that older female microglia were more likely to switch how they produce energy—relying more on a fast, sugar-based process. They also produced higher levels of a signaling molecule called C3a, especially in females. This molecule appears to trigger changes that make microglia more active in clearing debris and responding to problems.
Further analysis showed that older female mice had more of a specific type of microglia linked to disease responses. In a mouse model of Alzheimer’s disease, these same changes were seen and were strongest in a subtype of microglia thought to help protect the brain.
Overall, the findings suggest that a signaling loop involving C3a helps reprogram aging microglia—especially in females—into a form that may protect the brain, both during normal aging and in diseases like Alzheimer’s.
Scientific Abstract:
Microglia, the brain's resident macrophages, maintain brain homeostasis and respond to injury and infection. During aging they undergo functional changes, but the underlying mechanisms and their contributions to neuroprotection versus neurodegeneration are unclear. Previous studies suggested that microglia are sex dimorphic, so we compared microglial aging in mice of both sexes. RNA-sequencing of hippocampal microglia revealed more aging-associated changes in female microglia than male microglia, and more sex differences in old microglia than young microglia. Pathway analyses and subsequent validation assays revealed a stronger AKT-mTOR-HIF1alpha-driven shift to glycolysis among old female microglia and indicated that C3a production and detection was elevated in old microglia, especially in females. Recombinant C3a induced AKT-mTOR-HIF1alpha signaling and increased the glycolytic and phagocytic activity of young microglia. Single cell analyses attributed the aging-associated sex dimorphism to more abundant disease-associated microglia (DAM) in old female mice than old male mice, and evaluation of an Alzheimer's Disease mouse model revealed that the metabolic and complement changes are also apparent in the context of neurodegenerative disease and are strongest in the neuroprotective DAM2 subset. Collectively, our data implicate autocrine C3a-C3aR signaling in metabolic reprogramming of microglia to neuroprotective DAM during aging, especially in females, and also in Alzheimer's Disease.