Age-dependent glioma progression and functional decline in a syngeneic murine model: Host vulnerabilities and opportunities for targeted intervention.

Background: GBM disproportionately affects older adults, who experience worse survival outcomes and reduced tolerance to aggressive therapies. Despite this, most preclinical GBM studies rely on young animal models, limiting insight into how aging influences tumor progression and treatment vulnerability. The aim of this study was to determine how aging alters glioma growth, survival outcomes, and host brain responses. Methods: We used a syngeneic murine glioma model to compare young (6-7 weeks) and aged (85-86 weeks) mice implanted with SB28 glioma cells. We assessed survival, functional status (nesting behavior, weight loss), whole-brain tumor infiltration, and glial reactivity. Quantitative histology and image registration to the Allen Brain Atlas enabled region-specific tumor and glial burden analyses. Results: Aged glioma-bearing mice exhibited significantly reduced survival, increased functional impairment (including impaired nesting and weight loss), and broader tumor infiltration, particularly within white matter tracts. Tumor volume alone did not account for these differences; multivariable logistic regression identified age as the only independent predictor of mortality. Aged brains also displayed heightened extratumoral neuroinflammation, especially in regions involved in motivation and cognitive function. Conclusions: Aging is associated with a brain environment that permits greater glioma infiltration and is further characterized by heightened glial reactivity and reduced functional resilience to tumor burden. These findings underscore the limitations of relying solely on young animal models in GBM research and support incorporating aging as a critical variable. Targeting neuroinflammatory responses in the aged brain may represent a promising adjunct strategy to improve survival and preserve neurological function in older GBM patients.