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Cited by 247Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsGut microbiota and health

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

Open access
Saccon, Tatiana Dandolini, Nagpal, Ravinder, Yadav, Hariom, Cavalcante, Marcelo Borges, Nunes, Allancer Divino de Carvalho, Schneider, Augusto, Gesing, Adam, Hughes, Brian +6 more·2021·The Journals of Gerontology: Series A
DOI 10.1093/gerona/glab002PMC PMC8514064
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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 (p16Ink4a and p21Cip1) 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.

AI snapshot

Written from the paper’s full text.

TL;DR

In aged female BALB/c mice, intermittent 10-week dasatinib plus quercetin (D+Q) treatment reduced intestinal expression of senescence markers p16Ink4a and p21Cip1 and inflammatory/SASP markers in ileum, caecum, and colon, while increasing Lmnb1. D+Q also modulated gut microbiota composition, most prominently in the ileum, with specific taxa correlating with senescence and inflammation markers, although alpha- and beta-diversity did not differ remarkably.

Key findings

D+Q-treated old mice showed significantly lower p16Ink4a and p21Cip1 expression in all intestinal segments versus placebo-treated old mice; p16Ink4a expression was lowest in ileum (p < .001) compared with colon (p < .01). Inflammatory markers Cxcl1, Il1β, Il6, Mcp1, and Tnfα were lower in all intestinal tissues, with Mcp1 and Tnfα significantly lower in caecum and colon and an insignificant decline in ileum; Lmnb1 was highest in D+Q-treated old mice for ileum, caecum, and colon (p < .01). Young D+Q-treated versus nontreated mice showed no statistically significant differences in these genes (p > .05).

  • Microbiota alpha- and beta-diversity did not show remarkable differences between old D+Q-treated and old control mice. In ileum, D+Q-treated old mice had higher Verrucomicrobia and lower Firmicutes (not statistically significant), higher Akkermansia and lower Lactobacillus, and a higher gram-positive/gram-negative ratio; significant ileal taxa included higher Sutterella and Dorea and lower unknown Lachnospiraceae. Caecum showed higher Proteobacteria, Ruminococcus, and unclassified Coriobacteriaceae and lower OD1; colon showed no significant differences; feces showed higher OD1 and Parabacteroides and lower Proteobacteria, Sutterella, Roseburia, and Butyricicoccus pullicaecorum.
  • Across gut sections, Akkermansia muciniphila and Ruminococcus were higher and Staphylococcus lower in D+Q-treated old mice; Proteobacteria, Sutterella, Dehalobacterium, and rc4-4 were higher in ileum, caecum, and colon but not feces, while Clostridium cocleatum was lower. Correlation analyses found Clostridiales:f:g, Staphylococcus, and Lachnospiraceae positively correlated with all senescence/inflammation markers in all intestinal tissues, whereas Coriobacteriaceae;g and Akkermansia correlated negatively; network hubs were Il6 in ileum, Cxcl1 in caecum, and p16Ink4a in colon.
  • The effect on microbiota was most prominent in ileum followed by caecum, feces, and colon. Young mice showed no difference in alpha- or beta-diversity and only few, contrasting taxon-level differences after D+Q.

Methods

Female BALB/c mice (n = 40 total; 3 and 18 months old) were randomized into young control, young D+Q-treated, old control, and old D+Q-treated groups (n = 10 each). D+Q (dasatinib 5 mg/kg plus quercetin 50 mg/kg) or placebo was given by oral gavage for 3 consecutive days every 2 weeks over a 10-week period.

  • Ileum, caecum, colon, and fecal samples were collected. Senescence and inflammation markers (p16Ink4a, p21Cip1, Il1β, Il6, Tnfα, Mcp1, Cxcl1, Lmnb1) were measured by qRT-PCR normalized to Gapdh; microbiota was analyzed by 16S rRNA V4 sequencing.
  • Gene expression was analyzed with two-tailed Wilcoxon rank-sum tests. Microbiome data used QIIME2/DADA2, alpha- and beta-diversity, PERMANOVA, Student’s t-test, LEfSe (LDA > 2.0, p < .01), and Spearman correlations. Of 12,257,715 original sequences, 8,238,099 (mean 82,381 ± 3,981) remained after quality filtering; alpha-rarefaction was performed at 9,000 bp.

Limitations

Stated: small sample size prevented construction of modularity networks with FDR-adjusted p-values, and some phylum-level differences did not reach statistical significance, probably due to lower sample size and higher standard deviation. Stated: the authors describe the health-span and microbiota-link interpretations as speculations requiring considerable further testing, and the study does not establish causality between D+Q, microbiota, and senescence/inflammation.

  • Evident from the text: all mice were female BALB/c, so sex-, strain-, and generalizability issues are not addressed. The microbiome–marker analyses are correlational, and the study does not directly test mechanisms such as intestinal barrier integrity, microbial metabolites, or whether microbiota changes mediate D+Q effects.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/gerona/glab002

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    In caecum, Ruminococci, Coriobacteria, and Oscillospira remained negatively connected to most markers.

    “On bacterial side, Ruminococci, Coriobacteria, and Oscillospira remained negatively connected to most of the markers (Figure 5e).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    In colon, the co-occurrence network was centrally dominated by p16Ink4a, which connected positively with Clostridia, Roseburia, Lachnospiraceae, and Butyricicococcus and negatively with Coriobacteriaceae.

    “On the other hand, the co-occurrence network in colon was centrally dominated by p16Ink4a, which connected positively with Clostridia, Roseburia, Lachnospiraceae, and Butyricicococcus and negatively with Coriobacteriaceae (Figure 5f).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    In ileum, the genus Dorea and its unknown species Dorea;s were consistently negatively connected to Il6, p16Ink4a, and p21Cip1.

    “The genus Dorea and one of its unknown species Dorea;s were consistently and negatively connected to Il6, p16Ink4a and p21Cip1;”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    The ratio of gram-positive versus gram-negative taxa was slightly lower in feces of D+Q-treated old mice compared with control old mice.

    “In contrast, this ratio was slightly lower in the feces of OT versus OC mice (Figure 2l).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    Alpha- and beta-diversity did not show remarkable differences between D+Q-treated old and control old groups in any intestinal samples.

    “The analysis of alpha- and beta-diversity did not show remarkable differences between the OT (D+Q treated) versus the OC (control) groups (Supplementary Figure 1) in any of the intestinal samples.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 36
  • The quote only partly states this claim. 6
  • Classified as probably not a substantial claim. 26

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Results

    In ileum, abundance of genera Sutterella and Dorea was significantly higher while that of an unknown taxon from Lachnospiraceae family was significantly lower in D+Q-treated old mice versus control old mice.

    “In ileum, the abundance of genera Sutterella and Dorea was significantly higher while that of an unknown taxon from Lachnospiraceae family was significantly lower in OT versus OC mice (Figure 3a).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § Results

    Abundance of genus Lactobacillus was lower in the ileum of D+Q-treated old mice versus control old mice.

    “Furthermore, the abundance of genus Lactobacillus (belonging to the phylum Firmicutes) was lower in the ileum of OT versus OC mice (Figure 2m).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In caecum, Cxcl1 correlated positively with Firmicutes and Lachnospiraceae and negatively with Ruminococcus, Bacteroides, and Dehalobacterium.

    “Cxcl1 correlated positively with Firmicutes and Lachnospiraceae and negatively to Ruminococcus, Bacteroides and Dehalobacterium.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Results

    In caecum, abundance of phylum Proteobacteria, genus Ruminococcus, and an unclassified genus of family Coriobacteriaceae was significantly higher while that of an unclassified taxon from phylum OD1 was significantly lower in D+Q-treated old mice versus control old mice.

    “In addition, the abundance of phylum Proteobacteria, genus Ruminococcus and an unclassified genus of family Coriobacteriaceae was significantly higher while that of an unclassified taxon from the phylum OD1 (also known as Parcubacteria) was significantly lower in the caecum of OT versus OC mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Overall, abundance of A muciniphila and Ruminococcus was higher while that of Staphylococcus was lower-with different magnitudes-in all four specimens of D+Q-treated old mice versus control old mice.

    “Overall, the abundance of A muciniphila and Ruminococcus was higher while that of Staphylococcus was lower—with different magnitudes—in all of the four specimens of OT versus OC mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In caecum, abundance of Sutterella and an unknown taxon from genus Dorea was significantly higher while that of an unclassified genus of Lachnospiraceae family was lower in D+Q-treated old mice versus control old mice.

    “Interestingly, as in the case of ileum, the abundance of Sutterella and an unknown taxon from the genus Dorea was significantly higher while that of an unclassified genus of the Lachnospiraceae family was lower in the caecum of OT versus OC mice (Figure 3b).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Results

    In feces, abundance of genus Parabacteroides was significantly higher while that of genus Roseburia and species B pullicaecorum was significantly lower in D+Q-treated old mice versus control old mice.

    “In addition, the abundance of genus Parabacteroides was significantly higher while that of genus Roseburia and species B pullicaecorum was significantly lower in OT versus OC mice (Figure 3d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In caecum, p16 expression was associated negatively with Ruminococci, Coriobacteria, and Oscillospira and positively with Clostridiales.

    “The expression of p16 was associated negatively with Ruminococci, Coriobacteria and Oscillospira and positively with Clostridiales.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In caecum, the correlation network was different and more dense and was centrally dominated by Cxcl1 followed by p16Ink4a and Mcp1.

    “In contrast, the correlation network was different and more dense in caecum and was centrally dominated by Cxcl1 followed by p16Ink4a and Mcp1 (Figure 5e).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In ileum, Il6 expression was the most central marker, followed by p16Ink4a, and both were centrally and negatively linked with several bacterial taxa.

    “In ileum, Il6 expression remained the most central marker followed by p16Ink4a, both of which were centrally and negatively linked with several bacterial taxa (Figure 5d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Major genera distinguished microbiota composition between D+Q-treated old and control old mice, with the difference more prominent in ileum than caecum, colon, or feces.

    “Further analysis at the level of major genera also clearly distinguished the microbiota composition in OT versus OC mice, although the difference was more prominent in ileum when compared with caecum, colon, or feces (Figure 2m–p).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Proportion of Proteobacteria, Sutterella, Dehalobacterium, and rc4-4 was higher while that of Clostridium cocleatum was lower in ileum, caecum, and colon, but not feces, in D+Q-treated old mice versus control old mice.

    “Furthermore, the proportion of Proteobacteria, Sutterella, Dehalobacterium, and rc4-4 was higher while that of Clostridium cocleatum was lower in ileum, caecum, and colon, but not feces.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In the ileum, D+Q-treated old mice had considerably higher abundance of phylum Verrucomicrobia and lower abundance of phylum Firmicutes compared with control old mice.

    “Specifically, we found considerably higher abundance of the phylum Verrucomicrobia and lower abundance of the phylum Firmicutes in the ileum of OT versus OC mice (Figure 2a and e).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Results

    In feces, abundance of phylum OD1 and 2 of its unclassified family and genus taxa was significantly higher, while that of phylum Proteobacteria and genus Sutterella was significantly lower in D+Q-treated old mice versus control old mice.

    “The abundance of phylum OD1 and 2 of its unclassified family and genus taxa was significantly higher, while that phylum Proteobacteria and genus Sutterella was significantly lower in the feces of OT versus OC mice (Figure 3d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Ileal microbiota is unique from all other sections in terms of differences in abundance of bacterial taxa, with most prominent and broadest differences, and is relatively similar to caecal microbiota followed by colonic and fecal microbiota.

    “Hierarchical clustering showed that, in terms of differences in the abundance of different bacterial taxa, ileal microbiota is unique from all of the other sections with the most prominent and broadest differences and is relatively similar to caecal microbiota followed by colonic and fecal microbiota (Figure 3e).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Results

    The same trend of higher Verrucomicrobia and lower Firmicutes abundance was seen in descending parts of the GI tract but did not achieve statistical significance.

    “A similar but less prominent trend in abundance of these 2 phyla was also seen in the descending parts of the gastrointestinal tract (Figure 2b–d and j–l). However, these numerically considerable differences did not achieve statistical significance in terms of p-value, probably due to lower sample size and higher standard deviation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Specific arrays of positive and negative correlation of cellular senescence and inflammatory markers with specific microbiota clades were found, and these arrays differed greatly between different sections of the gut.

    “This revealed specific arrays of positive and negative correlation of cellular senescence and inflammatory markers with specific microbiota clades (Figure 5); however, these arrays differed greatly between different sections of the gut.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Results

    Abundance of genus Akkermansia was higher in D+Q-treated old mice versus control old mice, with the difference more prominent in ileum followed by caecum, colon, and feces.

    “the abundance of genus Akkermansia (the representative member of the phylum Verrucomicrobia) was higher in OT versus OC mice, wherein the difference was more prominent in ileum followed by caecum, colon, and feces.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    D+Q-treated old mice had a higher overall ratio of gram-positive versus gram-negative taxa in the ileum compared with control old mice, but not in caecum and colon.

    “In addition, we found higher overall ratio of gram-positive versus gram-negative taxa in the ileum of OT versus OC mice, but not in the descending parts of the gut, that is, caecum and colon (Figure 2i–k).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    The expression of Mcp1 and Tnfα was significantly lower in caecum and colon, with an insignificant decline in ileum, in D+Q-treated mice.

    “The expression of Cxcl1, Il1β, and Il6 was lower in all the intestinal sections in D+Q-treated mice, while that of Mcp1 and Tnfα was significantly lower in caecum and colon with an insignificant decline in ileum.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    D+Q-treated mice had slightly lower Firmicutes-Bacteroidetes ratio and higher abundance of A muciniphila, which correlated negatively with inflammatory and senescence markers in all intestinal sections.

    “We also found slightly lower Firmicutes-Bacteroidetes ratio and higher abundance of A muciniphila in D+Q-treated mice, which correlated negatively with inflammatory and senescence markers in all of the intestinal sections.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    D+Q-treated mice, besides having lower intestinal senescence and inflammation burden, also showed distinct microbiota signatures when compared with control mice.

    “Our data show that D+Q-treated mice, besides having lower intestinal senescence and inflammation burden, also showed distinct microbiota signatures when compared with control mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    The genus Akkermansia, which was higher in all intestinal segments of D+Q-treated older mice, was lower in the ileum of D+Q-treated young mice.

    “For instance, the genus Akkermansia, which was found to be higher in all the intestinal segments of D+Q-treated older mice, was found to be lower in the ileum of D+Q-treated young mice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    The microbiota play a contributing role in certain types of age-related dysfunction, such as changes in innate immunity, sarcopenia, frailty, and cognitive dysfunction.

    “In particular context to host aging, the microbiota appear to play a contributing role in certain types of age-related dysfunction, such as changes in innate immunity, sarcopenia, frailty, and cognitive dysfunction (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] O’Toole, 2015, Gut microbiota and aging, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    The composition of the gut microbiome plays a role in host longevity.

    “There is increasing evidence that the composition of the gut microbiome plays a role in host longevity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] O’Toole, 2015, Gut microbiota and aging, Science source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    Aging has physiological effects on both the host and the microbiome, suggesting that host-microbiota interactions impact the progression and qualities of age-related changes.

    “Aging has physiological effects on both the host (23) and the microbiome (24), suggesting that host–microbiota interactions impact the progression and qualities of age-related changes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] López-Otín, 2013, The hallmarks of aging, Cell source

      Not checked in the free run.

    • cites [24] Biagi, 2017, The gut microbiota of centenarians: signatures of longevity in the gut microbiota profile, Mech Ageing Dev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders.

    “Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders.”
    • Also stated in: § Abstract · hedged
      “Emerging evidence suggests that the senescent cell burden is increased by chronological aging and that the short-term treatment with senolytic drugs in chronologically aged mice can alleviate several aging-related phenotypes (4,10–12).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Zhu, 2015, The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source

      Not checked in the free run.

    • cites [10] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease, EBioMedicine source

      Not checked in the free run.

    • cites [11] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source

      Not checked in the free run.

    • cites [12] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study, EBioMedicine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Cellular senescence contributes to aging and age-related diseases and is a target of therapeutic interventions.

    “Cellular senescence, a process that essentially entails permanent proliferative arrest of cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related diseases and hence is a target of therapeutic interventions (3).”
    • Also stated in: § Abstract · plain
      “Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Childs, 2015, Cellular senescence in aging and age-related disease: from mechanisms to therapy, Nat Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    D+Q treatment improves metabolic health and survival.

    “Several studies have shown that the D+Q tretment decreases the burden of senescent cells (10) and improves metabolic health and survival (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    The first human trial with D+Q showed beneficial effects against fibrotic pulmonary disease and potential health benefits in diabetic patients.

    “In addition, the first human trial with this combination showed beneficial effects against fibrotic pulmonary disease and potential health benefits in diabetic patients (10,12).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease, EBioMedicine source

      Not checked in the free run.

    • cites [12] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study, EBioMedicine source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Some flavonoids, such as quercetin, resveratrol, and catechin, can regulate the gut microbiota in animal models.

    “The ability of some flavonoids, such as quercetin, resveratrol, and catechin, to regulate the gut microbiota has been documented in animal models (25–27).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Sung, 2017, Improved glucose homeostasis in obese mice treated with resveratrol is associated with alterations in the gut microbiome, Diabetes source

      Not checked in the free run.

    • cites [26] Tamura, 2017, Quercetin metabolism by fecal microbiota from healthy elderly human subjects, PLoS One source

      Not checked in the free run.

    • cites [27] Huang, 2016, Different flavonoids can shape unique gut microbiota profile in vitro, J Food Sci source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § Method

    All procedures used in this study were approved by the Institutional Animal Care and Use Committee of the University of Central Florida.

    “All the procedures used in this study were approved by the Institutional Animal Care and Use Committee of the University of Central Florida.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    Cellular senescence plays a crucial role in aging and age-related diseases.

    “It is widely accepted that cellular senescence plays a crucial role in aging and age-related diseases (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] van Deursen, 2014, The role of senescent cells in ageing, Nature source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Method

    qRT-PCR expression levels were analyzed by the ΔΔCt method using Gapdh as housekeeping control for normalization.

    “quantified by qRT-PCR and analyzed by the ΔΔCt method using Gapdh (Glyceraldehyde 3-phosphate dehydrogenase) gene as housekeeping control for normalizing the expression levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning
    § Method

    Alpha-rarefaction was performed at the lowest sequencing depth (9000 bp) to avoid bias of sequencing depth.

    “Alpha-rarefaction was performed at the lowest sequencing depth, that is, 9000 bp, to avoid the bias of sequencing depth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    This study points to the potential role of senolytics (D+Q) for alleviating intestinal senescent cell abundance and inflammation and modulating the gut microbiota in aged mice.

    “This study points to the potential role of senolytics (D+Q) for alleviating intestinal senescent cell abundance and inflammation and modulating the gut microbiota in aged mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The role of D+Q in intestinal aging and gut microbiota modulation remains unexplored.

  • Classified as probably not a substantial claim.

    Study design and conductnone given
    § Method

    Mice were randomly divided into four groups: young control, young treatment, old control, and old treatment.

    “The mice were randomly divided into the following 4 groups: (i) Young control (YC): placebo group (n = 10); (ii) Young treatment (YT): D+Q-treated group; (iii) Old controls (OC): placebo group (n = 10); and (iv) Old treatment (OT): D+Q-treated group (n = 10).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Method

    Because of the small sample size, modularity networks with a false discovery rate-adjusted p-value could not be constructed.

    “Because of the small sample size, we were unable to construct modularity networks with a FDR (false discovery rate)-adjusted p-value.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    D+Q treatment decreases the burden of senescent cells.

    “Several studies have shown that the D+Q tretment decreases the burden of senescent cells (10) and improves metabolic health and survival (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Hickson, 2019, Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease, EBioMedicine source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Mice that lack a functional Lmnb1 gene die minutes after birth.

    “Mice that lack a functional Lmnb1 gene die minutes after birth (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Vergnes, 2004, Lamin B1 is required for mouse development and nuclear integrity, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    D+Q has been shown to improve cardiac function and carotid vascular reactivity following short- or long-term treatment.

    “Furthermore, D+Q has been shown to improve cardiac function and carotid vascular reactivity (4), osteoporosis symptoms, and physical function (11) following short- or long-term treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Zhu, 2015, The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    Age-related changes in the microbiota toward gram-negative and endotoxigenic bacteria are known to induce cellular senescence and apoptosis in endothelial cells and damage to intestinal epithelial cells and gut-associated lymphoid tissues, thereby disrupting intestinal epithelial barrier integrity.

    “Furthermore, age-related changes in the microbiota toward gram-negative and endotoxigenic bacteria are known to induce cellular senescence and apoptosis in endothelial cells and damage to intestinal epithelial cells and gut-associated lymphoid tissues thereby disrupting the intestinal epithelial barrier integrity (50–54).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [50] Richter, 2012, LPS-binding protein enables intestinal epithelial restitution despite LPS exposure, J Pediatr Gastroenterol Nutr source

      Not checked in the free run.

    • cites [51] Nagele, 2013, Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease, PLoS One source

      Not checked in the free run.

    • cites [52] Ke, 2018, Erratum to Gut flora-dependent metabolite trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress [Free Radic. Biol. Med. 116C (2018) 88-100], Free Radic Biol Med source

      Not checked in the free run.

    • cites [53] Sanada, 2018, Source of chronic inflammation in aging, Front Cardiovasc Med source

      Not checked in the free run.

    • cites [54] Hou, 2019, Blocking the REDD1/TXNIP axis ameliorates LPS-induced vascular endothelial cell injury through repressing oxidative stress and apoptosis, Am J Physiol Cell Physiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Unhealthy perturbations in gut microbiota are related to disrupted host nutrient signaling pathways and metabolism, which may contribute to age-associated pathologies and negatively affect host health.

    “Unhealthy perturbations in gut microbiota are related to disrupted host nutrient signaling pathways and metabolism (45), which may contribute to age-associated pathologies, thereby negatively affecting host health (46).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Yan, 2016, Gut microbiota induce IGF-1 and promote bone formation and growth, Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [46] Kim, 2018, The gut microbiota and healthy aging: a mini-review, Gerontology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    D+Q has been shown to improve osteoporosis symptoms and physical function following short- or long-term treatment.

    “Furthermore, D+Q has been shown to improve cardiac function and carotid vascular reactivity (4), osteoporosis symptoms, and physical function (11) following short- or long-term treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Increased Akkermansia abundance has been linked with reduced intestinal permeability and gut-to-blood leakage of endotoxins, thereby alleviating diet-induced obesity and insulin resistance.

    “Increased Akkermansia abundance has been linked with reduced intestinal permeability and gut-to-blood leakage of endotoxins (eg, lipopolysaccharides), thereby alleviating diet-induced obesity and insulin resistance (49).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Anhê, 2015, A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice, Gut source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Conclusion

    The data hint toward a possible link of gut microbiota with the effects of senolytic drugs as well as with the hallmarks of host cellular senescence and aging.

    “In addition, our data hint toward the possible link of gut microbiota with the effects of senolytic drugs as well as with the hallmarks of host cellular senescence and aging.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    The gut microbiome can modulate many host physiological processes including metabolism, cognitive function, innate immunity, and cellular senescence, thereby potentially contributing to frailty, dysfunction, and disease.

    “The gut microbiome can modulate many of the host physiological processes including metabolism, cognitive function, innate immunity as well as cellular senescence, thereby potentially contributing to frailty, dysfunction, and disease (44,47).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Nagpal, 2018, Gut microbiome and aging: Physiological and mechanistic insights, Nutr Healthy Aging source

      Not checked in the free run.

    • cites [47] Frey, 2018, Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics, Nat Rev Gastroenterol Hepatol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    The SASP factors Cxcl1, Il1β, Il6, Mcp1, and Tnfα measured in the present study have previously been shown to have higher expression in senescent versus non-senescent cells in different tissues.

    “The SASP factors (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) measured in the present study have previously been shown to have higher expression in senescent versus non-seescent cells in different tissues (39), consistent with their importance as SASP factors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Yousefzadeh, 2020, Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice, Aging Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    The microbiota change drastically over the course of the host's lifetime, and aging is correlated with a reduction in microbial diversity and alterations in microbiota composition.

    “The microbiota change drastically over the course of host’s lifetime, and aging is correlated with a reduction in microbial diversity and alterations in microbiota composition (24,44).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Biagi, 2017, The gut microbiota of centenarians: signatures of longevity in the gut microbiota profile, Mech Ageing Dev source

      Not checked in the free run.

    • cites [44] Nagpal, 2018, Gut microbiome and aging: Physiological and mechanistic insights, Nutr Healthy Aging source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    The nuclear surface of the nuclear envelope is lined by structural proteins, which contributes to the size, shape, and stability of the nucleus.

    “The nuclear surface of the nuclear envelope is lined by structural proteins, which contributes to the size, shape, and stability o the nucleus (41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Bridger, 2007, The nuclear lamina. Both a structural framework and a platform for genome organization, FEBS J source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Gut microbiota imbalance (dysbiosis) is associated with the development of age-associated disorders and reduced survival.

    “Emerging evidence suggests that the gut microbiota imbalance (dysbiosis) is associated with the development of age-associated disorders and reduced survival (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Nagpal, 2018, Gut microbiome and aging: Physiological and mechanistic insights, Nutr Healthy Aging source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    The Lamin B family of proteins is required for proper organogenesis and cell survival.

    “This family of proteins is required to a proper organogenesis and cell survival (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Kim, 2011, Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells, Science source

      Not checked in the free run.

52 of 52

  • The paper relies on this without support.

    The effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown.

    “However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown.”
    “However, effects of treatment with senolytics such as the dasatinib and quercetin (D+Q) on the state of intestinal senescence and inflammatory burden in aged mice remain unclear.”
    “However, whether and how the oral ingestion of these senolytic agents affects gut microbiome composition in aged mice remains largely unstudied.”

  • The paper relies on this without support.

    The role of D+Q in intestinal aging and gut microbiota modulation remains unexplored.

    “However, to our knowledge, the role of this senolytic drug combination in intestinal aging and gut microbiota modulation remains unexplored.”

  • The paper relies on this without support.

    This is the first report demonstrating the effect of senolytic treatment on intestinal senescence and inflammatory burden as well as gut microbiota composition along different intestinal sections in aged mice.

    “To our knowledge, this is the first report demonstrating the effect of senolytic treatment on intestinal senescence and inflammatory burden as well as the gut microbiota composition along different intestinal sections in aged mice.”

  • The paper relies on this without support.

    Ruminococcus, Oscillospira, Dorea, Sutterella, and Butyrivibrio are gut commensals and play an important role in host health through aiding in host nutrition and metabolism and secreting beneficial metabolites such as butyrate.

    “Besides Akkermansia, the other taxa that were higher in D+Q-treated mice included Ruminococcus, Oscillospira, Dorea, Sutterella, and Butyrivibrio, all of which are gut commensals and play an important role in host health through aiding in host nutrition and metabolism and secreting beneficial metabolites such as butyrate.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In several mouse experiments, Dasatinib + Quercetin treatment alleviated inflammation and age-related diseases of the intestines and bone.

    “In several mouse experiments, the treatment alleviated inflammation342 and age-related diseases of the intestines343 and bone.344”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [343]

    Citation 343 is attached to the intestinal part of the sentence, not the separately cited inflammation or bone claims. The Results report reduced senescence and inflammatory markers in the ileum, caecum, and colon of aged mice given dasatinib plus quercetin, but the study does not show that treatment alleviated a diagnosed intestinal disease. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Recent publications indicate that treatments with D+Q in animal models reduce markers of inflammation associated with the pro-inflammatory SASP, including IL1β.

    “Recent publications indicate that treatments with D + Q in animal models reduce markers of inflammation associated with the pro-inflammatory SASP, including IL1β (as measured in intestinal and adipose tissue in mouse models) [110,111], which was also reduced in this trial.”

    From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [110]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Abstract claims significant reductions for markers that were not significant in ileum

    Major

    The abstract reports significantly lower expression of all five inflammatory markers in the small and large intestine. The discussion instead says the declines in Mcp1 and Tnfα were insignificant in the ileum, the small-intestinal segment studied.

  • A young-mouse microbiome change is described as contrasting despite matching the older-mouse direction

    Minor

    The paper says all microbiome differences observed in young mice contrasted with those in older mice, but its Staphylococcus example describes a decrease in both age groups.

2 of 2

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Authors
Saccon, T. D., Nagpal, R., Yadav, H., Cavalcante, M. B., Nunes, A. D. D. C., Schneider, A., Gesing, A., Hughes, B., Yousefzadeh, M., Tchkonia, T., Kirkland, J. L., Niedernhofer, L. J., Robbins, P. D., & Masternak, M. M.
Affiliations
  • University of Central Florida (US)
  • Florida State University (US)
  • Wake Forest University Health Sciences (US)
  • Universidade Federal de Pelotas (BR)
  • Medical University of Lodz (PL)
  • University of Minnesota (US)
  • Mayo Clinic (US)
  • Burnet School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, USA
ORCID
Venue
The Journals of Gerontology: Series A
Publisher
Oxford University Press (OUP)
Published
2021-01-06
Volume
76
Issue
11
Pages
1895-1905
ISSN
  • 1079-5006 (ISSN-L)
  • 1758-535X
DOI
10.1093/gerona/glab002
PMC
PMC8514064
OpenAlex
W3118535008
Semantic Scholar
e5c2210de37df38c5f32768331adc74ef6749390
Cited by
247
References
55
Citations by year
2026: 37 · 2025: 50 · 2024: 63 · 2023: 44 · 2022: 38 · 2021: 15
FWCI
25.14
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • The Journals of Gerontology Series A (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  • National Institutes of Health
  • National Institute on Aging (R15 AG059190, R03 AG059846, R56 AG061414, R37 AG013925, P01 AG062413, P01 AG043376, U19 AG056278, RO1 AG063543, R56 AG059676)
  • Glenn Foundation
  • Connor Fund
  • Robert J. and Theresa W. Ryan
  • Noaber Foundation
  • Irene Diamond Fund/American Federation on Aging Research Postdoctoral Transition Award (2016/21/B/NZ4/03192, 507/1-168-02/507-10-105)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
senolytics, dasatinib, quercetin, cellular senescence, intestinal inflammation, gut microbiota, aging, p16INK4a, p21, inflammatory cytokines, dysbiosis, aged mice
MeSH terms
Gastrointestinal Microbiome, Dasatinib, Senotherapeutics, Animals, Inflammation, Intestines, Quercetin, Tumor Necrosis Factor-alpha, Biomarkers, Interleukin-6, Cellular Senescence, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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