Senolytics ameliorate cognitive decline in D-galactose-induced aging mice by inhibiting astrocytic cholesterol accumulation.

Abstract

Cellular senescence plays a crucial role in brain aging and the decline of cognitive abilities. Although senolytic treatments, particularly the combination of dasatinib and quercetin (D+Q), show potential for improving cognition, the specific mechanisms involved are not well understood. In this study, we present strong evidence that senolytics enhance cognitive function by modulating cholesterol biosynthesis in astrocytes. Using a murine model of accelerated aging (via D-galactose exposure), we show that administering D + Q results in significant improvements in cognitive performance and a decrease in cellular senescence. A comprehensive multi-omics analysis subsequently demonstrated that senolytics are especially effective at downregulating cholesterol biosynthesis in the hippocampus. Notably, this effect was localized to astrocytes, where senolytics significantly reduced intracellular lipid accumulation and subsequent neuroinflammation. Critically, pharmacological activation of cholesterol synthesis and genetic overexpression of Hsd17b7, a key enzyme in the cholesterol synthesis pathway, in astrocytes reversed the anti-senescence benefits of senolytics in vitro, establishing a causal link between cholesterol pathway inhibition and the therapeutic effects. Overall, our work identifies the suppression of astrocytic cholesterol biosynthesis as a fundamental mechanism of senolytic action, repositioning these compounds as modulators of brain lipid metabolism and highlighting a promising therapeutic axis for combating age-related cognitive decline.