Senolytic therapy ameliorates high-fat diet-induced hippocampal senescence and cognitive decline in mice.

Obesity is a recognized risk factor for cognitive decline and neurodegenerative diseases, including Alzheimer's disease (AD). Obese individuals typically consume high-fat diet (HFD), particularly those rich in palmitate. However, the potential for HFD to induce neurodegeneration and their underlying mechanisms remain poorly understood. In this study, we demonstrate that HFD exposure induced significant deficits in hippocampal-dependent behaviors in mice and decreased synaptic protein expression. Transcriptomic analysis revealed differentially expressed genes in the hippocampus of HFD-fed mice, with enrichment predominantly in senescence-associated pathways. Furthermore, HFD-fed mice exhibited elevated hippocampal senescence markers, including increased SA-β-gal-positive cells, upregulated p16/p21 expression, elevated SASP factors and reduced Lamin B1. Remarkably, a palmitate-enriched diet recapitulated the hippocampal senescence phenotype and cognitive deficits induced by HFD, indicating that palmitate-the principal saturated fatty acid in HFD-served as a key mediator of cellular senescence. Finally, treatment with the senolytic cocktail dasatinib plus quercetin significantly reduced senescent cell burden, suppressed p16 protein expression, and normalized SASP factor levels. This intervention effectively restored cognitive function and synaptic protein expression. This work uncovers a novel HFD-induced cognitive impairment mechanism and suggests potential therapeutic strategies for mitigating obesity-associated neurodegeneration.