Metadata language
Włodarczyk, Jakub : Supervisor ; Krzystyniak, Adam : Auxiliary supervisor
Publisher:Nencki Institute of Experimental Biology PAS
Place of publishing: Date issued/created: Description:166 pages : illustrations ; 30 cm ; Bibliography ; Summary in Polish
Degree name: Degree discipline : Degree grantor:Nencki Institute of Experimental Biology PAS ; degree obtained: 2026
Type of object: Subject and Keywords:Dasatinib and Quercetin ; Microbiome ; Gut-brain-barrier ; Blood-brain-barrier ; Rejuvenation
Abstract:
Aging is characterized by the accumulation of senescent cells, which significantly contributes to the development of age-related diseases, including cognitive impairment and compromised integrity of the gut–brain axis. Senolytic intervention aimed at eliminating senescent cells, particularly the combination of Dasatinib and Quercetin (D+Q), represent a promising strategy to mitigate these dysfunctions. The aim of this dissertation was to examine the multidirectional effects of senolytic treatment (D+Q) on cognitive function, gut microbiota composition, bacterial metabolites, and the integrity of the intestinal and brain barriers in aged Wistar rats. Using cognitive behavioural tests, especially the Active Allothetic Place Avoidance task (AAPAT), it was shown that D+Q treatment significantly improves spatial memory and cognitive abilities in aged rats, with beneficial effects persisting even after the end of treatment. Analysis of the gut microbiota of these animals demonstrated that D+Q administration led to significant changes in its composition, including an increased abundance of Lactobacillus acidophilus, a bacterial species previously associated with beneficial effects on cognitive function and metabolic processes. Metabolomic analysis revealed a marked reduction in faecal levels of short-chain fatty acids (SCFAs) and bile acids, consistent with altered microbial production and/or altered host handling of these metabolites, including changes in utilization, degradation, reabsorption, and absorption, while systemic profiles remained largely stable apart from a selective reduction in serum formic acid. Histological and molecular analyses revealed region-specific changes in intestinal mucosal architecture, expression of tight junction proteins, mucin production, and inflammatory markers in response to D+Q treatment. In the small intestine, mucosal thickening and increased mucin production were observed, whereas in the large intestine a reduced mucosal thickness and decreased mucin synthesis were noted. These changes were accompanied by a decrease in pro-inflammatory markers (TNF-α, IFN-γ) alongside an increase in anti- inflammatory cytokines (IL-10), indicating a protective and anti-inflammatory effect of D+Q at the intestinal level. Importantly, D+Q administration contributed to improved blood–brain barrier integrity, confirmed by increased expression of tight junction proteins (zonula occludens-1, Occludin, claudin-1) in brain tissue. Moreover, reduced inflammatory markers and increased IL-10 expression indicate a shift in the brain milieu toward an anti-inflammatory state, which may explain the observed improvement in cognitive function. These results indicate systemic benefits of senolytic of intermittent D+Q intervention through modulation of the gut microbiota, reduction of inflammation, region-specific remodelling of intestinal barrier-associated features, and improvement of blood–brain barrier integrity. Together, these findings suggest that intermittent administration of D+Q may represent a promising strategy to counteract cognitive impairment, while underscoring the key role of the gut–brain axis as a key mechanistic axis and intervention target in age-related dysfunction
Copyright-protected material. May be used within the limits of statutory user freedoms
Copyright holder:Publication made available with the written permission of the author
Digitizing institution:Nencki Institute of Experimental Biology of the Polish Academy of Sciences
Original in:Library of the Nencki Institute of Experimental Biology PAS
Access: