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Cited by 313Telomeres, Telomerase, and SenescenceAdipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic Diseases

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

Open access
Islam, Md Torikul, Tuday, Eric, Allen, Shanena, Kim, John, Trott, Daniel W., Holland, William L., Donato, Anthony J., Lesniewski, Lisa A.·2023·Aging Cell
DOI 10.1111/acel.13767PMC PMC9924942
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Abstract

Aging results in an elevated burden of senescent cells, senescence‐associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low‐grade inflammation and a host of age‐related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age‐related increase in senescence‐associated β‐galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age‐related increase in the expression of a subset of pro‐inflammatory SASP genes ( mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10 ), crown‐like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age‐related difference in glucose tolerance, D&Q treatment improved fasting blood glucose ( p = 0.001) and glucose tolerance ( p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin‐stimulated suppression of plasma NEFAs ( p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance ( p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.

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Written from the paper’s full text.

TL;DR

In old male C57BL/6 mice, intermittent dasatinib plus quercetin (D&Q) reduced senescence and inflammatory markers in perigonadal white adipose tissue and improved systemic glucose and lipid metabolism. Improved glucose tolerance was linked to suppressed hepatic gluconeogenesis and was independent of pancreatic beta-cell function or peripheral insulin sensitivity.

Key findings

  • In pgWAT, D&Q reduced age-related SA β-gal+ cells, crown-like structures, p16 and p21 gene expression, and P16 protein (all p ≤ 0.04), and lowered SASP genes mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10 (all p ≤ 0.03). It also reduced T cells and total, M1, and M2 macrophages in pgWAT (all p ≤ 0.04 or p ≤ 0.01).
  • D&Q reduced fasting blood glucose (p = 0.002) and improved glucose tolerance (interaction p ≤ 0.0001; AUC p = 0.0004) in old mice. Pyruvate tolerance improved (interaction p = 0.012; treatment p = 0.004), with lower hepatic gluconeogenic gene expression (pck1, pck2, fbp2, g6pc; all p ≤ 0.04) and lower p-CREB/CREB ratio (p = 0.047).
  • D&Q improved insulin-stimulated suppression of plasma NEFAs (p = 0.009), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved lipid tolerance (interaction p = 0.014; treatment p = 0.006; AUC p = 0.006), without altering plasma cholesterol, LDL/VLDL, or HDL (p ≥ 0.62).
  • Effects were tissue-specific: liver p16 gene expression was reduced (p ≤ 0.003) but P16 protein was not altered by D&Q (p = 0.83); liver mcp1 was reduced (p = 0.04) but tnf-α and il-1β were not (p ≥ 0.31); gastrocnemius senescence/inflammatory markers were unchanged (p ≥ 0.19). Liver collagen deposition was reduced by D&Q (p = 0.007).

Methods

  • Male C57BL/6 mice: young controls and 21-month-old old mice received D&Q (dasatinib 5 mg/kg, quercetin 50 mg/kg) by oral gavage on 3 consecutive days every 2 weeks for 3 months, or vehicle (10% polyethylene glycol 4000). Group sizes were N = 5–8/group for many assays; Table 1 reports N = 8 young control, 15 old control, 17 old D&Q.
  • Outcomes included glucose, insulin, pyruvate, and intralipid tolerance tests; glucose-stimulated insulin; insulin-stimulated NEFA suppression; plasma triglycerides and cholesterols; flow cytometry for pgWAT T cells and macrophages; qPCR and western blots for senescence, SASP, gluconeogenic, and insulin-signaling markers; and SA β-gal, H&E, and picrosirius red histology.
  • Statistics used one-way or two-way ANOVA, repeated-measures ANOVA, and Student’s t tests, with significance set at p < 0.05.

Limitations

  • Stated: young and old control mice did not differ in fasting glucose, glucose tolerance, pyruvate tolerance, or lipid tolerance; the C57BL/6 model may not recapitulate all human metabolic dysfunction; human aging includes diet, lifestyle, and microbiota confounders absent in mice; mouse cholesterol metabolism differs from humans; mechanisms and the relative contribution of senescence in individual tissues/cell types require further investigation.
  • Evident: only male mice were studied, so sex differences are not addressed. Several assays used small group sizes (N = 5–8/group), and D&Q effects were not robust in liver or skeletal muscle, limiting conclusions about those tissues.

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Integrity signals

Registry

Crossref · 10.1111/acel.13767

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 75 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    D&Q treatment reduces the age-related increase in P16 protein expression in perigonadal white adipose tissue (pgWAT) of old mice.

    “P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04)”
    • Also stated in: § Advanced age and D&Q treatment demonstrated differential impacts on senescence and inflammatory markers in pgWAT, liver, and muscle · plain
      “Advanced age also increased P16 protein expression and D&Q treatment reduced P16 (both p ≤ 0.001; Figure 1f,g).”
    Quote in the paperSubstantial claim
  • Findingown data

    D&Q treatment reduced fed and fasted plasma triglycerides in old mice.

    “reduced fed and fasted plasma triglycerides (both p ≤ 0.04)”
    Quote in the paperSubstantial claim
  • Findingown data

    D&Q treatment reduces the age-related increase in senescence-associated β-galactosidase (SA β-gal) in perigonadal white adipose tissue (pgWAT) of old mice.

    “reducing age‐related increase in senescence‐associated β‐galactosidase”
    • Also stated in: § Advanced age and D&Q treatment demonstrated differential impacts on senescence and inflammatory markers in pgWAT, liver, and muscle · plain
      “Aging increased senescence‐associated β‐galactosidase (SA β‐gal) + cells and crown‐like structures (CLS) in pgWAT, and these were lower in pgWAT of D&Q‐treated old mice (all p ≤ 0.001; Figure 1b–d).”
    Quote in the paperSubstantial claim
  • Findingown data

    D&Q treatment suppresses the age-related increase in expression of a subset of pro-inflammatory SASP genes (mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10) in perigonadal white adipose tissue (pgWAT) of old mice.

    “This treatment also suppressed age‐related increase in the expression of a subset of pro‐inflammatory SASP genes (mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10)”
    • Also stated in: § Advanced age and D&Q treatment demonstrated differential impacts on senescence and inflammatory markers in pgWAT, liver, and muscle · plain
      “Gene expression of a subset of inflammatory SASP markers such as mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10 was higher in pgWAT from old compared with young mice and D&Q treatment reduced these markers in pgWAT from old mice (all p ≤ 0.03; Figure 1h).”
    Quote in the paperSubstantial claim
  • Findingown data

    D&Q treatment reduces crown-like structures (CLS) in perigonadal white adipose tissue (pgWAT) of old mice.

    “crown‐like structures”
    • Also stated in: § Advanced age and D&Q treatment demonstrated differential impacts on senescence and inflammatory markers in pgWAT, liver, and muscle · plain
      “Aging increased senescence‐associated β‐galactosidase (SA β‐gal) + cells and crown‐like structures (CLS) in pgWAT, and these were lower in pgWAT of D&Q‐treated old mice (all p ≤ 0.001; Figure 1b–d).”
    Quote in the paperSubstantial claim
  • May combine two claims. 34
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    No difference in plasma insulin at baseline or during glucose tolerance test (GTT) was observed between old control and old D&Q-treated mice.

    “During the GTT, we observed an expected increase in plasma insulin concentration in both old control and old D&Q‐treated mice (both p ≤ 0.01); however, no difference in plasma insulin at baseline or during GTT was observed between the groups (both p ≥ 0.69; Figure 3c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No difference in later time points or overall time response curve during insulin tolerance test (ITT) was found between old control and old D&Q-treated mice.

    “we found a difference in blood glucose at baseline and at 15 min during ITT (both p ≤ 0.02; Figure 3d), but no difference in later time points (all p ≥ 0.37) or overall time response curve between the groups (interaction, p˂0.0001; treatment, p = 0.19; Figure 3d).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    D&Q did not alter kidney mass in old mice.

    “Kidney mass was higher in old compared with young mice (p = 0.02; Table 1) and D&Q did not alter kidney mass in old mice (p = 0.53; Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Age did not alter heart mass.

    “Although age did not alter heart mass (p = 0.97; Table 1), D&Q increased heart mass in old mice (p = 0.05; Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    D&Q increased heart mass in old mice.

    “Although age did not alter heart mass (p = 0.97; Table 1), D&Q increased heart mass in old mice (p = 0.05; Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Kidney mass was higher in old compared with young mice.

    “Kidney mass was higher in old compared with young mice (p = 0.02; Table 1) and D&Q did not alter kidney mass in old mice (p = 0.53; Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Insulin-stimulated suppression of plasma NEFAs was better in D&Q-treated compared with control mice, despite no difference in systemic insulin sensitivity.

    “Despite no difference in systemic insulin sensitivity, insulin‐stimulated suppression of plasma NEFAs was better in D&Q‐treated compared with control mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Advanced age reduced HDL and increased LDL/VLDL in mice.

    “but reduced HDL and increased LDL/VLDL (both p ≤ 0.004; Figure S4g)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    D&Q administration reduced fasting glucose and improved glucose tolerance in old mice.

    “D&Q administration reduced fasting glucose and improved glucose tolerance in old mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Blood glucose response during pyruvate tolerance test, phosphorylation of CREB, and gluconeogenic gene expression was lower in D&Q-treated compared with control mice.

    “However, blood glucose response during a pyruvate tolerance test, phosphorylation of c‐AMP‐response element‐binding protein, and gluconeogenic gene expression was lower in D&Q‐treated compared with control mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plasma insulin during glucose tolerance, blood glucose response during insulin tolerance test, and insulin-stimulated Akt phosphorylation did not differ between D&Q-treated and control mice.

    “Plasma insulin during the glucose tolerance, blood glucose response during an insulin tolerance test, and insulin‐stimulated Akt phosphorylation did not differ between D&Q‐treated and control mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Despite no difference in fasting blood glucose, glucose-, pyruvate-, and lipid tolerance between young and old mice, administration of D&Q improved metabolic function in old mice.

    “Despite no difference in fasting blood glucose, glucose‐, pyruvate‐, and lipid tolerance between young and old mice, we demonstrate that the administration of D&Q improved metabolic function in old mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Our study demonstrates that the improvement in glucose tolerance was accompanied by suppressed hepatic gluconeogenesis and was independent of increased systemic insulin sensitivity or pancreatic beta cell function.

    “our study demonstrates that the improvement in glucose tolerance was accompanied by suppressed hepatic gluconeogenesis and was independent of increased systemic insulin sensitivity or pancreatic beta cell function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells, contributing to chronic low-grade inflammation and age-related diseases.

    “Aging results in an elevated burden of senescent cells, senescence‐associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low‐grade inflammation and a host of age‐related diseases.”
    • Also stated in: § INTRODUCTION · plain
      “Senescent cells and the SASP result in a chronic sterile inflammation with advancing age and contribute to numerous age‐related pathologies”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Borghesan et al., 2020

      Not checked in the free run.

    • cites Gorgoulis et al., 2019

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    Premisecitation

    Senescent cells accumulate in multiple tissues and organs with advancing age and act as a mediator of inflammation.

    “Senescent cells accumulate in multiple tissues and organs with advancing age and act as a mediator of inflammation (Borghesan et al., 2020; Gorgoulis et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Borghesan et al., 2020

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    • cites Gorgoulis et al., 2019

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    Study design and conductown data

    Liver histology slides were assessed by an examiner blinded to the treatment condition.

    “H&E‐stained slides were scanned and assessed by an examiner, typically a veterinary pathologist, blinded to the treatment condition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age.

    “Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    SA β-gal+ cells were quantified by an examiner blinded to the treatment group.

    “SA β‐gal+ cells as a percent of all cells were quantified by an examiner blinded to the treatment group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Senescent cells and the SASP result in chronic sterile inflammation with advancing age and contribute to numerous age-related pathologies.

    “Senescent cells and the SASP result in a chronic sterile inflammation with advancing age and contribute to numerous age‐related pathologies (Borghesan et al., 2020; Gorgoulis et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Borghesan et al., 2020

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    • cites Gorgoulis et al., 2019

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    Study design and conductcitation

    The fluorescence minus one technique was used to establish gating for flow cytometry.

    “The “fluorescence minus one” technique was used to establish gating, as described previously (Trott et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Trott et al., 2018

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  • May combine two claims.

    Premisecitation

    D&Q are two of the most studied senolytic drugs and have demonstrated promise in improving age-related pathophysiological dysfunctions in human and mice.

    “Dasatinib and quercetin (D&Q) are two of the most studied senolytic drugs and have demonstrated promise in improving age‐related pathophysiological dysfunctions in human and mice (Hickson et al., 2019; Wissler Gerdes et al., 2020; Xu et al., 2018).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hickson et al., 2019

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    • cites Wissler Gerdes et al., 2020

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    • cites Xu et al., 2018

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    Premisecitation

    Genetic clearance of p16-positive senescent cells prevents age-related lipodystrophy.

    “genetic clearance of p16‐positive senescent cells prevents age‐related lipodystrophy (Xu, Palmer, et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xu, Palmer, et al., 2015

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    Premisecitation

    Advancing age is accompanied by metabolic dysfunction such as an impairment in glucose and lipid metabolism.

    “Advancing age is accompanied by metabolic dysfunction such as an impairment in glucose and lipid metabolism (Chia et al., 2018; Petersen et al., 2017; Rines et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chia et al., 2018

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    • cites Rines et al., 2016

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    Premisecitation

    Adipose tissue from both obese and old mice demonstrates elevated senescence burden and immune cell infiltration that is linked to impairments in glucose metabolism.

    “Adipose tissue from both obese and old mice demonstrates elevated senescence burden and immune cell infiltration that is linked to impairments in glucose metabolism (Borghesan et al., 2020; Kalathookunnel Antony et al., 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Borghesan et al., 2020

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    • cites Kalathookunnel Antony et al., 2018

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    Interpretationown data

    D&Q reduces fasting blood glucose and improves glucose tolerance in old age.

    “Taken together, our findings indicate that the senolytic drug cocktail D&Q reduces fasting blood glucose and improves glucose tolerance in old age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    D&Q treatment results in lower CREB phosphorylation, leading to attenuated transcription of gluconeogenic genes and hepatic gluconeogenesis.

    “Taken together, these findings suggest that D&Q treatment results in lower CREB phosphorylation, leading to attenuated transcription of gluconeogenic genes and hepatic gluconeogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    D&Q treatment reduces age-related increases in collagen deposition in the liver that may contribute to improvement in metabolic function such as suppressed gluconeogenesis.

    “These data suggest that the D&Q treatment reduces age‐related increases in collagen deposition in the liver that may contribute to the improvement in metabolic function such as suppressed gluconeogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    D&Q reduces age-related increases in senescence and inflammatory burden in adipose tissue and demonstrates no major effects in liver and skeletal muscle.

    “Treatment with D&Q reduces age‐related increases in senescence and inflammatory burden in the adipose tissue and demonstrates no major effects in the liver and skeletal muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Advanced age increases the numbers of T cells and macrophages in perigonadal white adipose tissue (pgWAT) and treatment with D&Q reverses these age-related increases in immune cells in pgWAT.

    “Thus, our findings demonstrate that advanced age increases the numbers of T cells and macrophages in the pgWAT and treatment with D&Q reverses these age‐related increases in immune cells in the pgWAT.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Induction of senescence in cutaneous fibroblasts in older adults resulted in infiltration of monocytes via SASP chemokine CCL2, demonstrating a direct role of senescent cells in recruiting immune cells.

    “Induction of senescence in cutaneous fibroblasts in older adults resulted in infiltration of monocytes via SASP chemokine CCL2, demonstrating a direct role of senescent cells in recruiting immune cells (Chambers et al., 2021).”
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    • cites Chambers et al., 2021

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    Premisecitation

    High-fat diet-induced obesity, which is known to induce adipose tissue senescence, promotes adipose tissue accumulation of T cells and macrophages.

    “Shirakawa et al. (2016) report that high‐fat diet‐induced obesity, which is known to induce adipose tissue senescence, promotes adipose tissue accumulation of T cells and macrophages.”
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    • cites Shirakawa et al., 2016

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    Premisecitation

    When administered as a drug cocktail, D&Q has been demonstrated to be effective at inducing apoptosis and thus eliminating senescent cells and SASP burden in adipose tissue from both humans and mice.

    “When administered as a drug cocktail, D&Q has been demonstrated to be effective at inducing apoptosis and thus eliminating senescent cells and SASP burden in adipose tissue from both humans and mice (Hickson et al., 2019; Palmer et al., 2019; Wissler Gerdes et al., 2020).”
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    • cites Hickson et al., 2019

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    • cites Palmer et al., 2019

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    • cites Wissler Gerdes et al., 2020

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    Premisecitation

    Advancing age results in elevated senescence and SASP burden across multiple organs and tissues.

    “Advancing age results in elevated senescence and SASP burden across multiple organs and tissues (Yousefzadeh et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yousefzadeh et al., 2020

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  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationown data

    Our findings support the investigation of D&Q to treat age-related metabolic dysfunction in humans and have the potential for rapid translation.

    “Our findings support the investigation of D&Q to treat age‐related metabolic dysfunction in humans and have the potential for rapid translation.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Elevated burden of cellular senescence and SASP as well as T-cell mediated chronic sterile inflammation contributes to a host of age-related pathologies.

    “Elevated burden of cellular senescence and SASP as well as T‐cell mediated chronic sterile inflammation contributes to a host of age‐related pathologies (Chung et al., 2019; Wissler Gerdes et al., 2020).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Chung et al., 2019

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    • cites Wissler Gerdes et al., 2020

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    Premisecitation

    Quercetin inhibits anti-apoptotic BCL-xL, HIF-1α, and other senescence-associated anti-apoptotic proteins and eliminates senescent endothelial cells by inducing apoptosis.

    “quercetin inhibits anti‐apoptotic BCL‐xL, HIF‐1α, and other senescence‐associated anti‐apoptotic proteins and eliminates senescent endothelial cells by inducing apoptosis”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kirkland & Tchkonia, 2020

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    • cites Lindauer & Hochhaus, 2018

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    • cites Marunaka et al., 2017

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    Interpretationown data

    Improved glucose tolerance in D&Q-treated old mice was primarily due to suppressed hepatic gluconeogenesis but was independent of improvements in pancreatic beta cell function or peripheral insulin sensitivity.

    “Together, these results indicate that the improved glucose tolerance was primarily due to suppressed hepatic gluconeogenesis but was independent of improvements in pancreatic beta cell function or peripheral insulin sensitivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dasatinib is a tyrosine kinase inhibitor that primarily targets senescent adipocyte progenitor cells.

    “Dasatinib is a tyrosine kinase inhibitor that primarily targets senescent adipocyte progenitor cells”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kirkland & Tchkonia, 2020

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    • cites Lindauer & Hochhaus, 2018

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    Interpretationown data

    Our results are in agreement with previous reports and further demonstrate novel evidence that D&Q attenuates senescence and SASP burden in a tissue-specific manner in old age.

    “Taken together, our results are in agreement with previous reports and further demonstrate novel evidence that D&Q attenuates senescence and SASP burden in a tissue‐specific manner in old age.”
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    Premisecitation

    Cholesterol metabolism in mice is distinct from humans.

    “cholesterol metabolism in mice is distinct from humans.”
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    • cites Emini Veseli et al., 2017

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    Premisecitation

    Studies that demonstrate D&Q improved obesity-associated glucose tolerance did not report any findings on hepatic gluconeogenesis and one study indicated that insulin sensitivity was improved.

    “studies that demonstrate D&Q improved obesity‐associated glucose tolerance did not report any findings on hepatic gluconeogenesis and one study indicated that insulin sensitivity was improved (Palmer et al., 2019; Sierra‐Ramirez et al., 2020).”
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    • cites Palmer et al., 2019

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    Premisecitation

    Senescence and inflammation have emerged as potential targets for therapeutics aimed at treating a multitude of age-related diseases, for example, diabetes, cardiovascular diseases, cancers, neurological disorders, and fibrotic diseases.

    “Therefore, senescence and inflammation have emerged as potential targets for therapeutics aimed at treating a multitude of age‐related diseases, for example, diabetes, cardiovascular diseases, cancers, neurological disorders, and fibrotic diseases (Farr et al., 2017; Kirkland & Tchkonia, 2020; Palmer et al., 2019).”
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    • cites Farr et al., 2017

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    Premisecitation

    One study examined the effects of pharmacological inhibition of activin A and found that this inhibition reduced plasma-free fatty acids, but not triglycerides, in contrast to the effects of D&Q that we observed.

    “One study examined the effects of pharmacological inhibition of activin A and found that this inhibition reduced plasma‐free fatty acids, but not triglycerides, in contrast to the effects of D&Q that we observed (Xu, Palmer, et al., 2015).”
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    Premisecitation

    Genetic deletion of p16 positive cells prevented age-related loss of adipose tissue by enhancing adipogenesis in old mice.

    “genetic deletion of p16 positive cells prevented age‐related loss of adipose tissue by enhancing adipogenesis in old mice (Xu, Palmer, et al., 2015)”
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    • cites Xu, Palmer, et al., 2015

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    Premisecitation

    The C57BL/6 mouse remains one of the most common models to study metabolic function in old age.

    “the C57BL/6 mouse remains one of the most common models to study metabolic function in old age (Green et al., 2022; Martin‐Montalvo et al., 2013; Xu, Palmer, et al., 2015).”
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    • cites Green et al., 2022

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    Our previous work has revealed that aging results in increased infiltration of T cells in pgWAT and pharmacological depletion of T cells can improve metabolic function in old age.

    “Our previous work has revealed that aging results in increased infiltration of T cells in pgWAT and pharmacological depletion of T cells can improve metabolic function in old age (Trott et al., 2021).”
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    • cites Trott et al., 2021

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    Premisecitation

    Without genetic manipulation, mice do not demonstrate a robust change in plasma cholesterol with aging.

    “without genetic manipulation, mice do not demonstrate a robust change in plasma cholesterol with aging (Emini Veseli et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Emini Veseli et al., 2017

      Not checked in the free run.

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

    Premisecitation

    Inhibition of senescent adipocyte-secreted product activin A using ruxolitinib improved glucose tolerance and insulin sensitivity in old mice.

    “inhibition of senescent adipocyte‐secreted product activin A using ruxolitinib improved glucose tolerance and insulin sensitivity in old mice (Xu, Palmer, et al., 2015)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xu, Palmer, et al., 2015

      Not checked in the free run.

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

    Premisecitation

    Shirakawa et al. (2016) provides evidence that obesity results in the accumulation of adipose tissue senescent T cells.

    “Shirakawa et al. (2016), provides evidence that obesity results in the accumulation of adipose tissue senescent T cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shirakawa et al., 2016

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationown data

    Our study uncovers important insight into the effects of lowering senescence, SASP, and inflammation on systemic lipid metabolism.

    “Taken together, our study uncovers important insight into the effects of lowering senescence, SASP, and inflammation on systemic lipid metabolism.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    Our findings support these previous results and provide a more comprehensive picture of the mechanisms that underlie these improvements in metabolic function in old age after treatment with D&Q.

    “Our findings support these previous results and provide a more comprehensive picture of the mechanisms that underlie these improvements in metabolic function in old age after treatment with D&Q.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Reduction in senescence and inflammatory SASP burden attenuates the abundance of immune cells in the pgWAT and improves metabolic function in old age.

    “In summary, our study demonstrates that reduction in senescence and inflammatory SASP burden attenuates the abundance of immune cells in the pgWAT and improves metabolic function in old age.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Inhibition of activin A reduced hepatic triglyceride content and improved the gene expression of adipogenesis, triglyceride synthesis, and lipolysis.

    “it was found that inhibition of activin A reduced hepatic triglyceride content and improved the gene expression of adipogenesis, triglyceride synthesis, and lipolysis (Xu, Palmer, et al., 2015)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xu, Palmer, et al., 2015

      Not checked in the free run.

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

    Premisecitation

    Beneficial effects of reducing senescent cells and inhibiting their secreted products on metabolic function in old age has been suggested by the literature.

    “Beneficial effects of reducing senescent cells and inhibiting their secreted products on metabolic function in old age has been suggested by the literature.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xu, Palmer, et al., 2015

      Not checked in the free run.

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

    Premisecitation

    Human plasma contains more LDL compared with HDL, while mice carry more HDL compared with LDL.

    “while human plasma contains more LDL (considered detrimental) compared with HDL (considered beneficial), mice carry more HDL compared with LDL (Emini Veseli et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Emini Veseli et al., 2017

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    The effect of D&Q on metabolic function in old age remains poorly understood or unexplored.

    “However, the effect of this intervention on metabolic function in old age remains poorly understood.”
    “However, the effects of D&Q on metabolic function in old age remain unexplored.”

  • The paper relies on this without support.

    The interactions between senescent cells and immune cells, and whether clearing senescent cells can attenuate the abundance of immune cells in adipose tissue, remain unknown.

    “However, the interactions between senescent cells and immune cells, and particularly, if clearing senescent cells can attenuate the abundance of immune cells in the adipose tissue remains unknown.”

  • The paper relies on this without support.

    A preclinical model that recapitulates every aspect of metabolic dysfunction observed in older humans is currently unavailable.

    “However, a preclinical model that recapitulates every aspect of metabolic dysfunction that is observed in older human is currently unavailable.”

  • The paper relies on this without support.

    The impact of D&Q on plasma cholesterol in old age has not been reported previously.

    “The impact of D&Q on plasma cholesterol in old age has not been reported previously.”
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 [342]

  • 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 [111]

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.

  • Different p-values for the fasting blood glucose result

    Minor

    The abstract and results report different p-values for D&Q's effect on fasting blood glucose in old mice: 0.001 and 0.002, respectively.

1 of 1

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Related

Authors
Islam, M. T., Tuday, E., Allen, S., Kim, J., Trott, D. W., Holland, W. L., Donato, A. J., & Lesniewski, L. A.
Affiliations
  • University of Utah (US)
  • VA Salt Lake City Healthcare System (US)
  • The University of Texas at Arlington (US)
Corresponding author
Lesniewski, Lisa A.
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2023-01-13
Volume
22
Issue
2
Pages
e13767-e13767
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13767
PMC
PMC9924942
OpenAlex
W4315928863
Semantic Scholar
9694b1aab7ca7b2241690c441b27816970100487
Cited by
313
References
51
Citations by year
2026: 94 · 2025: 128 · 2024: 68 · 2023: 23
FWCI
55.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Biomedical Laboratory Research and Development, VA Office of Research and Development (BX004492)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T35 DK103596, DK112826, DK108833)
  • National Institute on Aging (AG048366, AG050238, AG060395, K08AG070281)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
senolytics, dasatinib, quercetin, senescence-associated secretory phenotype, adipose tissue inflammation, white adipose tissue, aging, metabolic dysfunction, glucose tolerance, hepatic gluconeogenesis, triglycerides, free fatty acids, insulin sensitivity, macrophages, T cells, p16, p21, low-grade inflammation
MeSH terms
Dasatinib, Senotherapeutics, Adipose Tissue, Animals, Glucose, Inflammation, Quercetin, Cellular Senescence, Mice

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

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