The study by Hickman et al. investigates the transcriptomic profile of microglia, the primary immune cells in the brain, using direct RNA sequencing (DRS) without amplification or cDNA synthesis. The researchers isolated microglia from healthy adult and aged mice and validated their findings through dual in-situ hybridization, proteomic analysis, and quantitative PCR. They identified a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes, termed the "sensome." The sensome includes genes involved in recognizing microbial ligands and endogenous ligands. With aging, the expression of sensome transcripts for endogenous ligand recognition decreases, while those involved in microbe recognition and host defense increase. Additionally, aging is associated with an overall upregulation of genes involved in neuroprotection. The study also highlights the distinct transcriptomic signature of microglia compared to macrophages and provides insights into the microglial priming states, showing a shift towards a more neuroprotective phenotype with aging. The findings contribute to a better understanding of microglial biology and its role in various pathological conditions.The study by Hickman et al. investigates the transcriptomic profile of microglia, the primary immune cells in the brain, using direct RNA sequencing (DRS) without amplification or cDNA synthesis. The researchers isolated microglia from healthy adult and aged mice and validated their findings through dual in-situ hybridization, proteomic analysis, and quantitative PCR. They identified a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes, termed the "sensome." The sensome includes genes involved in recognizing microbial ligands and endogenous ligands. With aging, the expression of sensome transcripts for endogenous ligand recognition decreases, while those involved in microbe recognition and host defense increase. Additionally, aging is associated with an overall upregulation of genes involved in neuroprotection. The study also highlights the distinct transcriptomic signature of microglia compared to macrophages and provides insights into the microglial priming states, showing a shift towards a more neuroprotective phenotype with aging. The findings contribute to a better understanding of microglial biology and its role in various pathological conditions.