Decoding Brain Aging: How Glial Cells Impact Myelin and Regeneration

The central nervous system (CNS) depends on neurons and glial cells, with glial cells playing equally important roles in its efficient function. Glial cells include oligodendrocyte lineage cells, astrocytes, and microglia. These cells support CNS development and neuronal function during adulthood through myelination, synapse formation, neurotransmitter recycling, and maintenance of the blood-brain barrier. Glial cells also play a prominent role during CNS aging, especially regarding neurodegenerative diseases and myelin regeneration.

A recent review article from the *Annals of the New York Academy of Sciences* focuses on how aging affects glial cells and impacts the regeneration of myelin in the CNS. This blog post summarizes some key insights from the article.

Oligodendrocytes and Myelin: Key Players in CNS Function
Oligodendrocytes, which come from oligodendrocyte progenitor cells (OPCs), are essential for myelination in the CNS. Each oligodendrocyte can extend myelin internodes to facilitate faster signal propagation and provide metabolic support to axons.

In multiple sclerosis (MS), the autoimmune system targets oligodendrocytes, resulting in loss of myelin sheaths, slower axon conduction, and a lack of trophic support. Remyelination, a spontaneous healing process, can restore rapid axon propagation and is a potential therapeutic avenue for MS.

Aging affects oligodendrocytes and OPCs:

* White matter volume declines during normal aging, compromising white matter integrity and cognitive function.

* Electron microscope studies show myelin integrity loss, decompaction, and splits in intraperiod and major dense lines in the aging rodent and non-human primate CNS.

* Aging oligodendrocytes show decreased expression of myelin protein-encoding genes and downregulation of cholesterol synthesis genes, along with an upregulation of genes involved in ribosome biogenesis and immune-related genes.

* Aging OPCs exhibit stem cell aging hallmarks, such as mitochondrial dysfunction, inflammasome signaling, dysregulated nutrient sensing, autophagy, and unfolded protein response.

* Aging OPCs have a slower ability to differentiate.

Astrocytes: Multifaceted Glial Cells
Astrocytes, which come from radial glial cells during embryogenesis, are involved in synapse formation, synaptic pruning, and myelination. In adulthood, astrocytes maintain homeostasis, recycle neurotransmitters, maintain the blood-brain barrier, and provide trophic support for axons.

Aging impacts astrocytes through:

* Morphological changes, including increased expression of cytoskeletal proteins, cell body hypertrophy, and a reduction in long, slender processes.

* Increased reactivity and upregulation of genes related to bacterial endotoxins or ischemia.

* Downregulation of genes involved in cholesterol synthesis, mitochondrial function, energy production, and antioxidant defense.

* Upregulation of genes involved in the complement pathway, cytokines, and antigen presentation.

* Region-specific changes, with cerebellar astrocytes upregulating proinflammatory genes and visual cortex astrocytes increasing Bmp6.

Microglia: Immune Defenders of the CNS
Microglia, the CNS's resident macrophage population, originate from erythromyeloid progenitors in the fetal yolk sac. Microglia are essential for establishing neuronal circuitry, remodeling synapses, and supporting OPC development and myelination.

Microglia age through:

* A gradual functional decrease, most notably in chemotactic and phagocytic capacity.

* Reduced motility within demyelinating spinal cord lesions.

* Impaired ability to phagocytose Aβ fibrils and myelin debris.

* Increased lipofuscin and lysosomal inclusions within their cytoplasms.

* Uneven distribution throughout the CNS and increased parenchymal density.

* Cytoplasmic hypertrophy with fewer ramifications.

* Upregulation of proinflammatory cytokines, reactive oxygen species, and inflammatory signaling molecules, resulting in a primed state.

* Accumulation of lipid droplets.

* Adoption of a unique aging signature in the white matter, dependent on Trem2 and associated with continuous myelin turnover.

* A proinflammatory primed state, termed inflammaging.

Glial Cell Aging and CNS Regeneration
Aging significantly affects oligodendrocyte lineage cells, astrocytes, and microglia, impacting neurodegenerative diseases and CNS regeneration. Myelin regeneration, efficient in young adult rodents, slows with age and contributes to MS progression.

Effective remyelination requires coordinated action by OPCs, astrocytes, and microglia:

* OPCs upregulate genes, proliferate, migrate, and engage denuded axons to form new myelin sheaths.

* Microglia and monocyte-derived macrophages facilitate remyelination by clearing inhibitory myelin debris.

* Astrocytes secrete growth factors for OPCs and recruit microglia to facilitate myelin debris removal.

Age-related changes impair remyelination:
* Remyelination is incomplete in aging rats.

* The macrophage/microglia response is delayed, resulting in slower growth factor expression.

* Exposure to cells and factors from a youthful circulation can rejuvenate OPC remyelination.

* Aging affects the phagocytic pathway, from receptor-mediated myelin uptake and degradation to reverse cholesterol efflux.

* The aging extracellular matrix (ECM) becomes stiffer, inhibiting OPCs through the mechanosensing channel, Piezo1.

* Histone deacetylation of differentiation inhibitor promoter regions is delayed in aging OPCs.

Therapeutic Strategies to Enhance CNS Regeneration
Several therapeutic approaches have been explored to counteract glial cell aging and enhance CNS regeneration:

* Drug Screens: Large-scale drug screens have identified medications like clemastine that enhance OPC differentiation.

* Niche Composition: Recognizing the importance of the aging niche, researchers emphasize that medications effective in young OPCs may fail in aging OPCs or when applied to inhibitory ECM substrates.

* Enhancing Phagocytosis: Medications like niacin and RXR agonists such as bexarotene enhance myelin debris removal by aging microglia.

* Combination Therapies: Addressing both intrinsic and extrinsic changes in the aging CNS is crucial. Calorie restriction and metformin have shown promise in rejuvenating aging OPCs and enhancing myelin debris phagocytosis. A clinical trial is currently recruiting relapsing-remitting MS patients to evaluate the combination of metformin and clemastine.

Conclusion
Normal aging causes changes in glial cells, contributing to neurodegenerative diseases and cognitive decline. Changes in oligodendrocytes compromise white matter integrity, while alterations in astrocytes and microglia lead to increased inflammation in the aging CNS. Understanding the molecular changes contributing to the aging glial phenotype is essential for developing therapeutic strategies to slow cognitive decline and enhance regenerative events like remyelination. Recent advances in single-cell multiomic sequencing and computational biology offer hope for unraveling the complexities of CNS aging and identifying novel therapeutic targets.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

Reference:
Rawji, K. S., Neumann, B., & Franklin, R. J. (2023). Glial aging and its impact on central nervous system myelin regeneration. Annals of the new York Academy of Sciences, 1519(1), 34-45.