Senescent microglia release DLK1 and accelerate cognitive decline

Senescent microglia—immune cells resident in the central nervous system—emerge as an active driver of brain dysfunction when their telomeres shorten. In telomere-shortened mice, researchers observed lipofuscinosis, hypomyelination, and cognitive deficits, with single-nucleus RNA sequencing revealing accelerated glial aging pathways. The culprit: delta-like non-canonical Notch ligand 1 (DLK1), a soluble protein secreted by senescent microglia in elevated concentrations, detected in cerebrospinal fluid of both naturally aged and telomere-shortened mice. In human induced pluripotent stem cell systems, soluble DLK1 blocked oligodendrocyte maturation—the process that produces myelin—and disrupted calcium signaling in excitatory neurons. For longevity-focused readers, this identifies a direct therapeutic target: inhibiting DLK1 or clearing senescent microglia could restore neuronal function without waiting for broader cellular senescence interventions.