Disrupted synaptogenic capacity of senescent astrocytes contributes to aging-related synaptic impairments

Aging is marked by complex and progressive physiological changes that lead to a decline in brain function. Increased content of senescent cells in the brain, such as glial cells, have been reported to impact cognition in animal models for neurodegenerative diseases. Recently, our group described that senescent astrocytes accumulate in the aging hippocampus and undergo nuclear deformations associated with the loss of lamin-B1, and upregulation of glutamate-glutamine cycle-related proteins. However, the contribution of astrocyte changes in the context of physiological aging and cognitive decline is still poorly understood. Here, we investigated the cognitive performance of aged mice and the functional profile of astrocytes in physiological aging models. To do so, young (2-5 months) and aged (18-24 months) C57BL/6 mice were tested on the Novel Object Recognition test (NOR) and Barnes maze. Additionally, we used hippocampal tissue from young and aged mice, and an in vitro model for astrocyte senescence, in which cultures were maintained for 30-35 days in vitro (DIV) (senescent astrocytes) or 7-10 DIV (control astrocytes). We observed that aged mice lost their ability to discriminate between novel objects in the NOR test and displayed diminished learning and short and long-term memory performance on the Barnes maze, indicating an age-dependent cognitive decline. In agreement, we observed a reduced synaptic density, and levels of synaptophysin, GluR1, and thrombospondin-1 (TSP-1) in the hippocampus of old mice. Furthermore, the conditioned medium from mouse senescent astrocytes (CM-S) had a reduced capacity to support neurite outgrowth and synaptogenesis in neuronal cultures in vitro, associated with diminished TSP-1 expression and levels in senescent astrocytes. In contrast, restoration of TSP-1 in the CM-S reverted the synaptic loss in vitro. Therefore, our findings show significant changes in astrocyte functions with aging, suggesting their contribution to age-related synaptic loss and cognitive decline. The protocols of this study were approved by the Research Ethics Committees of the UFRJ, UMCU-Utrecht, and Plataforma Brasil. Support: CNPq, CAPES, FAPERJ, Ministério da Saúde.