Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice

Abstract

Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16 Ink4a and p21 Cip1) and inflammation (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n=10) compared to age-matched placebo-treated mice (n=10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1β, Il6, Mcp1 and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation and microbial dysbiosis in older subjects.

Potential Implications of Citrulline and Quercetin on Gut Functioning of Monogastric Animals and Humans: A Comprehensive Review

“…In a study investigating the effects of magnolol (an active ingredient utilized in traditional Chinese medicine) in L-arginine-induced gastrointestinal motility disorder, it was reported that magnolol alleviated gut disorder via reducing NO production, and its relaxing properties on GIT [193]. Another study employing the combination of dasatinib and quercetin as senolytic drugs in aged mice revealed that their long-term treatment reduced senescence cells, reduced inflammatory markers, and altered metabolic signatures in the intestines, thus improving gut health [194]. Additionally, studies have combined polyphenols such as resveratrol and quercetin widely for their health benefits, and their role in modulating the gut microbial ecosystem [2,28].…”

Dietary Fish Hydrolysate Improves Memory Performance Through Microglial Signature Remodeling During Aging

“…Another possible mechanism of action of the fish hydrolysate during aging has been explored. We focused on the intestinal tract, which is involved in several physiological processes including nutrient intake as well as immune modulation ( 97 ). Indeed, a close link between gut inflammation, gut permeability and cognition has been demonstrated before ( 14 ).…”

Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: An Emerging Frontier

“…A recent report has demonstrated that the consumption of a senolytic combination of Dasatinib and Quercetin resulted in lower SC burden (p16 Inka4a and p21 expression) and SASP phenotype (Cxcl1, IL1β, IL6, MCP1, and TNF-α expression) in small and large intestine as compared with control mice. Remarkably, specific microbial composition in ileal, cecal, colonic, and fecal regions were also distinctly modulated by D+Q, suggesting that senolytics might improve health via reducing intestinal senescence, inflammation, and gut microbial dysbiosis in older subjects (Saccon et al, 2021). Our recent report also observed that dietary consumption of another putative senolytic, green tea EGCG, decreased SC burden in multiple tissues which correlated with increased suppression of pathogenic bacteria in the gut microbiome of aged mice (Sharma et al, 2021).…”

“…Given that these dietary components first interact with the gut microbiome, it is plausible to envisage that the known anti-cellular senescence or other age-associated health beneficial effects of nutraceuticals may also be related to the modulation of gut microbiome and gut metabolites thereof (Sharma and Padwad, 2020b;Sharma and Padwad, 2020d). For instance, the mechanisms of anti-cellular senescence and senolytic attributes of putative senolytics such as quercetin, EGCG, resveratrol and fistein are incompletely understood, and could be mediated by influencing the composition of the gut microbiome (Saccon et al, 2021). This is especially plausible given the fact that bioactive phytomolecules can promote the proliferation of probiotic bacteria, suppress the growth of pathogenic bacteria, and also act as second generation synbiotics (Sharma et al, 2019;Zhang et al, 2013).…”