The study reveals the "sensome," a unique set of genes in microglia responsible for sensing the brain environment. Using direct RNA sequencing, the researchers identified a distinct transcriptome for microglia in healthy and aged mice, showing that aging leads to downregulation of endogenous ligand recognition genes and upregulation of microbial recognition and host defense genes. Microglia also express genes involved in neuroprotection, which increase with age. The sensome includes receptors and proteins for sensing endogenous ligands and microbes, with 1299 candidate genes identified. The study also compares microglia and macrophages, finding that microglia have unique genes for sensing and interacting with their environment. Validation through dual fluorescent in situ hybridization confirmed that sensome genes are exclusively expressed in microglia. Proteomic analysis showed that mRNA and protein levels correlate, supporting the DRS findings. Quantitative PCR confirmed the DRS results. Aging shifts microglial priming states toward a neuroprotective phenotype, with significant changes in the sensome, including downregulation of endogenous ligand sensing genes and upregulation of microbial sensing genes. The study provides a comprehensive understanding of microglial gene expression and function, highlighting the importance of the sensome in maintaining brain homeostasis and responding to injury or infection. The findings suggest that microglia play a crucial role in neurodegenerative diseases and that targeting microglial functions could be a therapeutic approach. The study also identifies new microglial markers and highlights the importance of the sensome in brain health and disease.The study reveals the "sensome," a unique set of genes in microglia responsible for sensing the brain environment. Using direct RNA sequencing, the researchers identified a distinct transcriptome for microglia in healthy and aged mice, showing that aging leads to downregulation of endogenous ligand recognition genes and upregulation of microbial recognition and host defense genes. Microglia also express genes involved in neuroprotection, which increase with age. The sensome includes receptors and proteins for sensing endogenous ligands and microbes, with 1299 candidate genes identified. The study also compares microglia and macrophages, finding that microglia have unique genes for sensing and interacting with their environment. Validation through dual fluorescent in situ hybridization confirmed that sensome genes are exclusively expressed in microglia. Proteomic analysis showed that mRNA and protein levels correlate, supporting the DRS findings. Quantitative PCR confirmed the DRS results. Aging shifts microglial priming states toward a neuroprotective phenotype, with significant changes in the sensome, including downregulation of endogenous ligand sensing genes and upregulation of microbial sensing genes. The study provides a comprehensive understanding of microglial gene expression and function, highlighting the importance of the sensome in maintaining brain homeostasis and responding to injury or infection. The findings suggest that microglia play a crucial role in neurodegenerative diseases and that targeting microglial functions could be a therapeutic approach. The study also identifies new microglial markers and highlights the importance of the sensome in brain health and disease.