Senescent Microglia Secrete DLK1, Which Causes Dysfunction in the Aging Brain
Senescent cells accumulate with age in tissues throughout the body, disrupting tissue structure and function with inflammatory secretions. The growing burden of senescent cells is an important contributing cause of degenerative aging. A cell becomes senescent in response to damage induced by some form of stress, or more often when a somatic cell reaches the Hayflick limit on cellular replication. In youth senescent cells are efficiently cleared by the immune system, but immune system aging allows senescent cells to linger and grow in number. Immune cells themselves are prone to reaching the Hayflick limit and entering replicative senescence because they respond to a variety of issues with greater replication to multiply their efforts.
Research into neurodegenerative conditions and the state of the aging brain has increasingly focused on maladaptive behavior on the part of microglia, innate immune cells resident in the central nervous system that are analogous to macrophages elsewhere in the body. Microglia do not just attack pathogens and malfunctioning cells, but also participate in normal tissue maintenance and aid in maintenance of neural circuits. When microglia become too inflammatory, whether or not this includes entering a senescent state, the brain suffers. Inflammatory microglia appear to be an important component of neurodegenerative conditions and age-related deterioration in cognitive function. As today's open access paper shows, senescent microglia are clearly harmful in specific ways.
Critical shortening of telomeres by the end replication problem induces cell-cycle arrest and causes the cell to enter replicative senescence. Glial cells in the brain (e.g., microglia, astrocytes, and oligodendrocytes) retain proliferative capabilities after development and become more proliferative in response to damage to the central nervous system (CNS) and other stressors. Thus, glial cells are under heavy replicative stress, and telomere shortening is detected in the white matter, whereas telomere length in the gray matter remains relatively unchanged.
Glial senescence has been suggested to transform the brain from normal aging to pathological aging and to drive the buildup and spread of AD pathologies. Microglia are the resident macrophages in the CNS responsible for immune surveillance and innate immune responses to damage and pathogenic species. Microglia are susceptible to increased replicative stress associated with the reactivation of the proliferative program in response to neurodegenerative pathologies, including tauopathy and amyloid beta (Aβ) accumulation.
Here, we report direct evidence that senescent microglia exert detrimental influences on other cell types through an altered secretion profile. We investigated the brains of telomere-shortened mice and observed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single-nucleus RNA sequencing (snRNA-seq) revealed accelerated glial aging and elevated microglial senescence pathways. In a senescence model of human induced pluripotent stem cell (iPSC)-derived microglia, delta-like non-canonical Notch ligand 1 (DLK1) was identified as a novel senescence-associated ligand. Soluble DLK1 (sDLK1) was increased in the cerebrospinal fluid of telomere-shortened and naturally aged mice, and this increase was eliminated by microglial depletion.
In vivo elevation of sDLK1 caused hypomyelination and blocked oligodendrocyte lineage progression, and these effects demonstrate the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.