With the caveat that the behavior of cells in culture is not necessarily all that relevant to their behavior amidst the full complexities of living tissue, this study is an interesting initial exploration of the ways in which the cellular senescence of supporting cells in the brain might contribute to the progression of neurodegeneration. Senescent cells secrete a potent mix of inflammatory and other signaling; while they serve a useful purpose when present for a short time, not all are successfully destroyed. Their numbers grow with age, and the presence of these errant cells and their signaling is very harmful over the long term. Thus the development of senolytic therapies to selectively destroy senescent cells is a very promising line of work in the treatment of aging as a medical condition.
Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemotherapy or radiotherapy. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies.
Among the essential cell types in the brain, astrocytes are the most abundant population. Astrocytes retain proliferative capacity, and their functions are crucial for neuron survival. Astrocytes are critical for mediating ion homeostasis, growth factor responses and neurotransmitter functions in the brain. Previous studies showed that astrocyte dysfunction is associated with multiple neurodegenerative diseases. Importantly, senescent astrocytes were identified in aged and Alzheimer's disease brain tissue, and other studies identified several factors that are responsible for inducing senescence in astrocytes. These studies reported a link between an inflammatory environment and neurodegenerative diseases, but how astrocyte senescence might alter brain function in general remains unclear.
Here, we investigated the phenotype of primary human astrocytes made senescent by irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Genes that regulate glutamate homeostasis as well as potassium ion and water transport are essential for normal astrocyte function. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.