This study examined how telomere shortening in mice drives brain aging, using snRNA-seq, iPSC-derived microglia, and in vivo sDLK1 elevation to identify microglial senescence and its downstream effects on oligodendrocytes and neurons.
Senescent microglia with shortened telomeres secrete soluble DLK1 (sDLK1), which was elevated in CSF of telomere-shortened and naturally aged mice; microglial depletion eliminated this increase. In vivo sDLK1 elevation caused hypomyelination, blocked oligodendrocyte lineage progression, impaired oligodendrocyte maturation in human iPSC systems, and altered calcium signaling in excitatory neurons.
Findings rely heavily on telomere-shortened mouse models and iPSC-derived systems, which may not fully recapitulate human physiological aging; causal human in vivo data are absent. The study does not establish whether blocking sDLK1 can reverse established aging-associated deficits.
While not yet clinically actionable, sDLK1 emerges as a candidate CSF biomarker and therapeutic target linking microglial senescence to hypomyelination and cognitive decline in aging — clinicians should watch for translational studies targeting this pathway.
Explore related topics
