New research identifies DLK1 as a key molecule released by aging microglia that may contribute to impaired myelin and nerve-cell function in the aging brain.

As the brain ages, changes in its immune cells may play a larger role in cognitive and neurological decline than previously understood. A new study has identified a potential mechanism linking cellular aging to damage in the brain, pointing to a molecule called DLK1 as an important driver of age-related dysfunction.

The findings focus on microglia, the brain’s resident immune cells. Similar to macrophages elsewhere in the body, microglia help protect the brain, remove damaged material and support the maintenance of neural circuits. However, as the brain ages, these cells can become increasingly dysfunctional and inflammatory.

The study provides evidence that when microglia become senescent, a state in which cells stop dividing but remain metabolically active—they can release substances that negatively affect neighboring brain cells.

Aging cells release a harmful signal

Cellular senescence normally serves as a protective response to damage or excessive replication. Young and healthy bodies generally remove senescent cells through the immune system. With age, however, immune surveillance becomes less efficient, allowing these cells to accumulate and alter the tissues around them.

Microglia are particularly relevant because they can experience repeated demands to multiply in response to injury, inflammation and neurodegenerative processes. This repeated replication can lead to shortening of their telomeres, protective structures at the ends of chromosomes, eventually pushing the cells into replicative senescence.

Researchers studying mice with shortened telomeres found several signs of accelerated brain aging, including reduced myelin, abnormal accumulation of cellular waste, changes in microglia and cognitive deficits.

Further analysis using single-nucleus RNA sequencing showed increased activity in cellular-aging pathways, particularly in microglia.

The researchers then turned to human induced pluripotent stem cell-derived microglia to investigate what these aging cells were releasing. They identified delta-like non-canonical Notch ligand 1 (DLK1) as a previously unrecognized molecule associated with microglial senescence.

DLK1 affects myelin and neurons

The soluble form of the molecule, known as sDLK1, was found at higher levels in the cerebrospinal fluid of both telomere-shortened mice and naturally aged mice. Importantly, removing microglia eliminated this increase, supporting the conclusion that aging microglia are a major source of the molecule.

The researchers next examined what happens when sDLK1 levels rise.

In animal experiments, elevated sDLK1 was associated with hypomyelination, a reduction in the protective myelin coating that surrounds many nerve fibers. It also interfered with the normal development of oligodendrocyte-lineage cells, which are responsible for producing myelin in the central nervous system.

Experiments using human cell models produced similar concerns. Excess sDLK1 impaired the maturation of oligodendrocytes and disrupted calcium signaling in excitatory neurons, processes important for normal communication between nerve cells.

Together, the findings suggest that senescent microglia may contribute to brain aging not only through inflammation, but also by releasing specific molecules that directly interfere with the function of other brain cells.

A potential target for future research

The study identifies sDLK1 as a microglia-derived senescence-associated signal that can affect both oligodendrocytes and neurons.

The researchers’ findings add to growing evidence that cellular senescence may be an important contributor to age-related changes in the brain. They also raise the possibility that targeting senescent microglia or the harmful molecules they release could eventually become a strategy for protecting brain function during aging.

However, the findings are still at the research stage. The experiments were conducted primarily in mice and laboratory-grown human cell systems, so further studies will be needed to determine whether the same mechanism operates in humans and whether blocking DLK1 can safely prevent or reverse age-related brain dysfunction.

The research highlights an increasingly important idea in neuroscience: aging may not simply reflect the gradual wear and tear of brain cells, but also the changing behavior of the cells that are supposed to protect and maintain them.