Enhancing Mitochondrial Matrix Antioxidant SOD2 in Astrocytes Mitigates Cellular Senescence and Cognitive Impairment in Aging

Accumulating evidence implicates hallmarks of brain aging, namely oxidative stress, reactive gliosis, and cellular senescence, as key contributors to hippocampal dysfunction and associated age-related cognitive deficits. Astrocytes robustly express antioxidants such as superoxide dismutases to detoxify reactive oxygen species (ROS) generated as a result of the high metabolic activity in the brain. However, aging is associated with transcriptional downregulation of antioxidant genes concomitant with polarization towards reactive, proinflammatory phenotypes in astrocytes. Given prior findings that astrocyte-specific ablation of SOD2 induces phenotypes of cognitive aging, we hypothesized that enhancing astrocyte antioxidant capacity via SOD2 overexpression (aSOD2OE) would ameliorate molecular hallmarks of aging and preserve cognitive function. To test this, we overexpressed SOD2 in astrocytes of aged (22 mo) male C57Bl/6N mice using an AAV(PHP.eB)-GFAP-hSOD2 viral vector and assessed hippocampal-dependent spatial working memory using a high-resolution, automated home-cage behavioral testing platform. We found that aSOD2OE significantly improved spatial working memory performance compared to aged GFP controls. Using molecular and histological approaches, aSOD2OE was associated with reductions in markers of cellular senescence and reactive astrogliosis within the hippocampus. These findings suggest that enhancement of astrocyte mitochondrial antioxidant activity is sufficient to alleviate maladaptive cellular programs associated with cognitive decline. Together, these data identify astrocyte redox biology as a potential therapeutic target in preserving hippocampal function in aging.