Soluble DLK1 secreted by telomere-shortening-induced senescent microglia impairs oligodendrocyte functions and alters neuronal activity [DLK1_snRNA-seq]

Here, we investigated the impact of telomere shortening, a physiological hallmark of aging, on brain function. Telomere-shortened mice exhibited cognitive decline and exacerbated lipofuscinosis, accompanied by the emergence of senescent microglia with a senescence-associated secretory phenotype and oligodendrocyte lineage cells with impaired maturation.

Using iPSC-derived microglia with shortened telomeres, we identified DLK1 as a novel senescence-associated ligand secreted by senescent microglia. Elevated soluble DLK1 was detected in the cerebrospinal fluid of both telomere-shortened and physiologically aged mice, and this increase was abolished by microglial depletion, confirming its microglial origin. Functionally, AAV-mediated expression of sDLK1 in mouse brains induced hypomyelination and disrupted oligodendrocyte differentiation in vivo.