Senescent Astrocytes in the Aging of the Brain

Cellular senescence in the supporting cells of the brain is increasingly implicated in the onset and progression of neurodegenerative conditions. Senescent cells accumulate with age, as the immune system becomes less competent and falters in their timely removal. These errant cells secrete pro-inflammatory factors that are disruptive of tissue structure and function, contributing to the neuroinflammation that is characteristic of age-related cognitive decline and dementia. We can hope that senolytic treatments capable of passing the blood-brain barrier will help to prevent and treat many forms of neurodegenerative disease but reducing the burden of cellular senescence, both in the brain, and elsewhere in the body.

For many decades after their discovery, astrocytes, the abundant glial cells of the brain, were believed to work as a glue, supporting the structure and metabolic functions of neurons. A revolution that started over 30 years ago revealed many additional functions of these cells, including neurogenesis, gliosecretion, glutamate homeostasis, assembly and function of synapses, neuronal metabolism with energy production, and others. These properties have been confirmed, limited however, to proliferating astrocytes.

During their aging or following severe brain stress lesions, proliferating astrocytes are converted into their no-longer-proliferating, senescent forms, similar in their morphology but profoundly modified in their functions. The changed specificity of senescent astrocytes is largely due to their altered gene expression. The ensuing effects include downregulation of many properties typical of proliferating astrocytes, and upregulation of many others, concerned with neuroinflammation, release of pro-inflammatory cytokines, dysfunction of synapses, etc., specific to their senescence program. The ensuing decrease in neuronal support and protection by astrocytes induces the development, in vulnerable brain regions, of neuronal toxicity together with cognitive decline. Similar changes, ultimately reinforced by astrocyte aging, are also induced by traumatic events and molecules involved in dynamic processes.

Senescent astrocytes play critical roles in the development of many severe brain diseases. The first demonstration, obtained for Alzheimer's disease less than 10 years ago, contributed to the elimination of the previously predominant neuro-centric amyloid hypothesis. The initial astrocyte effects, operating a considerable time before the appearance of known Alzheimer's symptoms evolve with the severity of the disease up to their proliferation during the final outcome. Involvement of astrocytes in other neurodegenerative diseases is now intensely investigated.