Academic Journal
Senolytic therapy ameliorates high-fat diet-induced hippocampal senescence and cognitive decline in mice.
| Title: | Senolytic therapy ameliorates high-fat diet-induced hippocampal senescence and cognitive decline in mice. |
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| Authors: | Xia X; Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; National Demonstration Center for Experimental Basic Medical Science Education (Xuzhou Medical University), Xuzhou 221004, China; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Yi F; Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China., Zhang R; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Wu R; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Zhang X; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Zhang Y; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Liu J; The First Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Qin H; National Demonstration Center for Experimental Basic Medical Science Education (Xuzhou Medical University), Xuzhou 221004, China; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., He B; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Duan Y; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Xu Y; The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China., Huang XF; Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: xhuang@uow.edu.au., Yu Y; Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: yinghuayu@xzhmu.edu.cn., Hu M; Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: huminmin@xzhmu.edu.cn. |
| Source: | Experimental neurology [Exp Neurol] 2026 Jul; Vol. 401, pp. 115745. Date of Electronic Publication: 2026 Mar 25. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Orlando Fl : Academic Press Original Publication: New York. |
| MeSH Terms: | Diet, High-Fat*/adverse effects , Hippocampus*/drug effects , Hippocampus*/pathology , Hippocampus*/metabolism , Senotherapeutics*/pharmacology , Senotherapeutics*/therapeutic use , Cognitive Dysfunction*/drug therapy , Cognitive Dysfunction*/etiology , Cognitive Dysfunction*/metabolism , Cognitive Dysfunction*/pathology , Cellular Senescence*/drug effects , Cellular Senescence*/physiology , Dasatinib*/pharmacology , Dasatinib*/therapeutic use, Quercetin/pharmacology ; Quercetin/therapeutic use ; Animals ; Mice ; Male ; Mice, Inbred C57BL |
| Abstract: | 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. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Cellular senescence; Cognitive impairment; Obesity; Palmitate; Senolytic |
| Substance Nomenclature: | 0 (Senotherapeutics) 9IKM0I5T1E (Quercetin) RBZ1571X5H (Dasatinib) |
| Entry Date(s): | Date Created: 20260327 Date Completed: 20260714 Latest Revision: 20260714 |
| Update Code: | 20260714 |
| DOI: | 10.1016/j.expneurol.2026.115745 |
| PMID: | 41895394 |
| Database: | MEDLINE |
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