This study investigates the regional diversity and age-dependent changes in microglial transcriptomes across different brain regions in adult mice. The authors performed genome-wide transcriptional profiling of microglia from the cerebellum, cerebral cortex, and hippocampus at three ages: 4, 12, and 22 months. Key findings include: 1. **Regional Diversity**: Microglia exhibit distinct transcriptional identities across different brain regions, with the cerebellum and hippocampus showing more immune-vigilant states compared to the cerebral cortex and striatum. 2. **Age-Dependent Changes**: Microglial aging occurs non-uniformly across brain regions, with the cerebellum showing an accelerated and amplified aging trajectory, while the hippocampus shows a diminishing distinction from other forebrain regions. 3. **Gene Co-Expression Networks**: Networks of gene co-expression underpinning regional heterogeneity are differentially sensitive to aging, with immune regulation and bioenergetics being key contributors. 4. **Transcriptional Regulators**: Transcriptional regulators such as NR4A, ERR, ROR, EBF1, FOXL1, AP1, and c-Rel are involved in the regulation of genes encoding microglial cell surface proteins and immune and inflammatory functions. 5. **Core Microglial Signature**: A core signature distinguishing microglia from systemic macrophages is retained across regions, but its expression declines with age, particularly in the cerebellum. The study highlights the importance of regional microglial diversity in meeting the location-dependent demands of brain tissue and suggests that age-related changes in this diversity may contribute to region-specific sensitivities to neurodegenerative processes.This study investigates the regional diversity and age-dependent changes in microglial transcriptomes across different brain regions in adult mice. The authors performed genome-wide transcriptional profiling of microglia from the cerebellum, cerebral cortex, and hippocampus at three ages: 4, 12, and 22 months. Key findings include: 1. **Regional Diversity**: Microglia exhibit distinct transcriptional identities across different brain regions, with the cerebellum and hippocampus showing more immune-vigilant states compared to the cerebral cortex and striatum. 2. **Age-Dependent Changes**: Microglial aging occurs non-uniformly across brain regions, with the cerebellum showing an accelerated and amplified aging trajectory, while the hippocampus shows a diminishing distinction from other forebrain regions. 3. **Gene Co-Expression Networks**: Networks of gene co-expression underpinning regional heterogeneity are differentially sensitive to aging, with immune regulation and bioenergetics being key contributors. 4. **Transcriptional Regulators**: Transcriptional regulators such as NR4A, ERR, ROR, EBF1, FOXL1, AP1, and c-Rel are involved in the regulation of genes encoding microglial cell surface proteins and immune and inflammatory functions. 5. **Core Microglial Signature**: A core signature distinguishing microglia from systemic macrophages is retained across regions, but its expression declines with age, particularly in the cerebellum. The study highlights the importance of regional microglial diversity in meeting the location-dependent demands of brain tissue and suggests that age-related changes in this diversity may contribute to region-specific sensitivities to neurodegenerative processes.