Depletion of senescent cells improves surgery-induced neuroinflammation in aged mice.

Aging has been identified as a leading risk factor for many diseases, including neurodegenerative disorders. While cellular senescence has been linked to age-related neurodegenerative conditions, its involvement in peripheral stress-associated brain disorders is just beginning to be explored. In this study, we investigated the impact of senescent cells on peripheral stress-induced neuroinflammation using orthopedic surgery as a model. Our results demonstrate an increased accumulation of senescent cells and neuroinflammation in the aged mouse hippocampus following surgery. Intermittent treatment of the mice with the senolytic drugs dasatinib and quercetin (D/Q) showed a significant reduction in surgery-induced senescent cell burden. This reduction in senescent cell accumulation was correlated with reduced surgery-induced neuroinflammation, as evidenced by decreased glial cell activity. Consistent with these observations, we also observed reduced levels of proinflammatory senescence-associated secretory phenotype factors in circulation, following fracture surgery, in mice treated with D/Q. Overall, our findings underscore the pivotal role of cellular senescence in surgery-induced neuroinflammation and highlight the therapeutic potential of eliminating senescent cells as a potential strategy to manage peripheral stress-induced neuroinflammatory conditions.