The broad category of glial cell includes all of the cells making up the nervous system that are not neurons. This includes the innate immune cells known as microglia, the astrocytes that manage brain metabolism and make up much of the brain's structure, the oligodendrocytes that maintain the myelin sheathing necessary for nerves to conduct electrical impulses, and a few other smaller or more localized populations. These are all very different cell types with very different functions, so one can't really talk about them in sweeping terms. Nonetheless, they all become dysfunctional with advancing age for the same underlying reasons, each population contributing to the complexities of brain aging, and in turn being negatively affected by other aspects of aging.
In today's open access review paper, the authors take a tour of what is known of both the ways in which glial cells contribute to the aging of the brain, and the ways in which the aging of the brain harms glial cell function. Aging is sufficiently complex that it is challenging to fully map all of the ways in which the various known changes and dysfunctions interact with one another. Robustly identifying cause and consequence is difficult when the consequence can in turn interact with the cause, and it isn't just one cause and one consequence, but rather an interacting network of effects and their outcomes, all of which can influence one another.
Interplay Between Aging and Glial Cell Dysfunction: Implications for Central Nervous System Health
At the molecular level, aging induces extensive reprogramming of glial cell gene expression, driven by the cumulative impact of epigenetic drift (defined as stochastic alterations in the epigenome that accumulate over time) encompassing changes in DNA methylation patterns, histone modifications, and chromatin remodeling. In aging glial cells, chromatin accessibility is often reduced at loci associated with neuroprotective and metabolic genes, while pro-inflammatory and stress-response genes might become more accessible, driving a maladaptive transcriptional shift. Mitochondrial dysfunction, a well-established hallmark of aging, plays a central role in this process. In glial cells, compromised electron transport chain efficiency reduces ATP production, impairing the high-energy-demanding functions of those cells. This inefficiency also leads to excessive production of reactive oxygen species (ROS), which induce oxidative damage on lipids, proteins, and nucleic acids.
Astrocytes, which play essential roles in maintaining central nervous system (CNS) homeostasis, supporting neuronal function, and regulating the blood-brain barrier (BBB), undergo a shift toward a reactive phenotype in response to aforementioned insults. Their reactive state is characterized by hypertrophy, increased expression of intermediate filament proteins like GFAP and vimentin, and the secretion of several pro-inflammatory mediators, such as IL-1β, TNF-α, and CCL2. Sustained activation of the NF-κB signaling pathway locks astrocytes into an inflammatory state, further impairing their neuroprotective roles. One functional consequence is the reduction in glutamate clearance due to decreased expression of excitatory amino acid transporters EAAT1 and EAAT2, creating conditions favorable for excitotoxic neuronal damage.
Microglia, the resident immune sentinels of the CNS, undergo a parallel but distinct aging trajectory, a process often known as microglial priming. With aging process, pattern recognition receptor pathways, particularly TLR4 signaling, become dysregulated, making microglia hyperresponsive to secondary insults including infections or trauma. Primed microglia exhibit amplified and sustained inflammatory responses, but paradoxically show reduced phagocytic efficiency, compromising the clearance of myelin debris, apoptotic cells, and aggregated proteins such as amyloid-β. Dysfunction in purinergic signaling, especially through P2X7 and P2Y12 receptors, further disrupts microglial chemotaxis and injury sensing. Autophagic flux declines with age, leading to lysosomal dysfunction, which traps damaged organelles and undigested materials inside the cell. This failure of clearance mechanisms sustains the presence of damage-associated molecular patterns (DAMPs) in the CNS microenvironment, perpetuating a self-reinforcing cycle of inflammation and neuronal stress.
Oligodendrocyte precursor cells (OPCs), the main source of new myelinating oligodendrocytes in the adult CNS, also exhibit significant age-related decline. Aging OPCs show impaired proliferation and differentiation capacity, largely driven by epigenetic repression of the genes implied in myelin synthesis, such as MBP and PLP1. Furthermore, OPCs become less responsive to mitogenic growth factors, including PDGF-A and FGF2, which usually promote OPC expansion and maturation. The loss of regenerative capacity impairs remyelination efficiency and contributes to the progressive degradation of white matter integrity, a crucial substrate for cognitive processing speed and executive function.
These issues are exacerbated by systemic aging factors, including chronic low-grade inflammation (known as inflammaging), characterized by increased levels of circulating pro-inflammatory cytokines, as well as alterations in metabolic hormones such as insulin and IGF-1. These systemic molecules facilitate glial senescence via activation of the cell cycle inhibitors p16 and p21, inducing an irreversible growth arrest that further impairs the CNS reparative and adaptive capacity. Over time, these converging cellular and molecular deficits create a CNS environment more susceptible to neurodegenerative processes. Furthermore, these glial modifications do not occur in isolation but rather within a complex and bidirectional interplay with aging neurons, vascular elements, and the immune system.
View the full article at FightAging
