Aging is characterized by the accumulation of molecular and cellular damage over an organism’s lifespan, leading to physical deterioration and an increased risk of diseases. Brain aging involves physiological, structural, and functional changes that contribute to
cognitive decline and the risk of neurodegenerative diseases. Microglia, as key non-neuronal cells, perform immune surveillance, synaptic pruning, and debris clearance, playing an essential role in maintaining neural health. In this study, we used data from the Brain-aging-atlas on the Nygen platform, a comprehensive resource of single-cell transcriptomic data, to investigate aging-associated changes in the brain. This dataset includes gene expression profiles, spatial distributions, and pathway-level insights across various brain cell types, including neurons, astrocytes, and microglia, sampled from the frontal cortex and striatum of young (۴ weeks) and aged (۹۰ weeks) mice. Differential expression analysis revealed three key differentially expressed genes (DEGs) in aged microglia:
Adamtsl۱ (fold change: ۷۴.۴۷, score: ۰.۹۶۵),
Kcna۱ (fold change: ۵۶.۵۲, score: ۰.۹۶۴), and
Klhdc۴ (fold change: ۵۳.۰۵, score: ۰.۹۶۵), highlighting significant molecular changes with aging. ADAMTSL۱ is a secreted glycoprotein in the ADAMTS family, playing a key role in extracellular matrix (ECM) organization, synaptic maintenance, and cellular adhesion. A GWAS study identified it as a significant genetic variant linked to Alzheimer’s and Parkinson’s diseases. KCNA۱, a voltage-gated potassium channel, is essential for neuronal excitability and synaptic transmission. RNA editing of KCNA۱ by ADAR۲ has been associated with Alzheimer’s disease and neuronal signaling dysregulation during aging. KLHDC۴ was significantly upregulated in aged microglia, indicating involvement in ubiquitin signaling, innate immunity regulation, and lysosomal and autophagy pathways, all linked to neurodegenerative processes. Its CpG methylation site (cg۰۸۷۳۴۲۳۷) strongly correlated with cognitive aging, suggesting an epigenetic regulatory role in neurological signaling and neurodegeneration. These findings provide valuable insights into the molecular mechanisms of brain aging, highlighting the significant roles of ADAMTSL۱, KCNA۱, and KLHDC۴ in microglial function and their associations with neurodegenerative processes. The identification of these genes underscores the importance of extracellular matrix remodeling, neuronal excitability regulation, and epigenetic modulation in aging and age-related diseases such as Alzheimer’s and Parkinson’s disease. Future research should validate these pathways in animal models and human studies, paving the way for targeted interventions to address
cognitive decline and
neurodegeneration in aging populations.
