Target diseases: ALS, OCD, Depression, Schizophrenia, Panic disorder
Key words:Brain aging Network, Senescent microglia, Rejuvenation, Neuroimmunology, Stem Cells, Precision medicine,
Our Aim
Single-cell omics technologies have uncovered remarkable heterogeneity among microglial populations, shaped by age, brain region, sex, and disease context. While transcriptomic profiling has defined numerous subtypes—including disease-associated microglia (DAM), MGnD, PAM, LDAM, and WAM—functional characterization of these populations remains substantially incomplete. Against this backdrop, senescent microglia have gained recognition as a phenotypically and clinically distinct subpopulation, particularly relevant to brain aging—the predominant risk factor for neurodegenerative disease. A hallmark of microglial senescence is disrupted lipid metabolism, most visibly manifested as intracellular lipid droplet accumulation. This metabolic dysfunction has emerged as a tractable target for functional restoration strategies. Here, we present evidence for the central contribution of senescent microglia to neurodegenerative disease progression. We propose that the selective vulnerability of microglia to aging-associated metabolic stress renders lipid droplet–directed reprogramming a compelling therapeutic axis. Normalizing lipid homeostasis in senescent microglia may restore their phagocytic and neuroprotective capacity, offering a broadly applicable intervention for age-driven neurodegeneration—including amyotrophic lateral sclerosis (ALS). Together, these findings position microglial metabolic rejuvenation as a promising frontier in the treatment of late-onset neurodegenerative conditions.