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

The DOI matches its Crossref record; 49 of the 51 references it cites were found in a registry or an index; none of the 75 sources its claims cite is checked for support yet.

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.

Overview

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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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Crossref · 10.1111/acel.13767

Cites

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Figures

FIGURE 1 Administration of D&Q suppresses age‐related increases in senescence and inflammatory markers in pgWAT. (a) Schematic representation of the dasatinib and quercetin (D&Q) treatment and the non‐terminal experiments such as glucose‐, insulin‐, pyruvate‐, and intralipid‐tolerance tests (GTT, ITT, PTT, and LTT), insulin secretion during GTT, insulin‐stimulated free fatty acid suppression (Ins‐FFA) measurement, (b) representative H&E images of perigonadal white adipose tissue (pgWAT) after staining with senescence‐associated β‐galactosidase (SA β‐gal), blue arrowheads indicate SA β‐gal+ cells and red arrowheads indicate crown‐like structures (CLS) (c and d) quantification of SA β‐gal+ cells and CLS, (e) p16 and p21 gene expression relative to 18s in pgWAT, (f and g) Western blot images and quantification of P16 protein expression relative to vinculin, (h) mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10 gene expression relative to 18s in pgWAT. Data are shown as mean ± SEM with individual data points in the bar graphs. N = 5–8/group. *Denote p ≤ 0.04 versus Y Ctrl, †denote p ≤ 0.04 versus O Ctrl. Group differences were assessed by one‐way ANOVA with Tukey's post hoc tests.
FIGURE 1 Administration of D&Q suppresses age‐related increases in senescence and inflammatory markers in pgWAT. (a) Schematic representation of the dasatinib and quercetin (D&Q) treatment and the non‐terminal experiments such as glucose‐, insulin‐, pyruvate‐, and intralipid‐tolerance tests (GTT, ITT, PTT, and LTT), insulin secretion during GTT, insulin‐stimulated free fatty acid suppression (Ins‐FFA) measurement, (b) representative H&E images of perigonadal white adipose tissue (pgWAT) after staining with senescence‐associated β‐galactosidase (SA β‐gal), blue arrowheads indicate SA β‐gal+ cells and red arrowheads indicate crown‐like structures (CLS) (c and d) quantification of SA β‐gal+ cells and CLS, (e) p16 and p21 gene expression relative to 18s in pgWAT, (f and g) Western blot images and quantification of P16 protein expression relative to vinculin, (h) mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10 gene expression relative to 18s in pgWAT. Data are shown as mean ± SEM with individual data points in the bar graphs. N = 5–8/group. *Denote p ≤ 0.04 versus Y Ctrl, †denote p ≤ 0.04 versus O Ctrl. Group differences were assessed by one‐way ANOVA with Tukey's post hoc tests.CC BY · PubMed Central
FIGURE 2 Suppressed senescence and inflammatory burden is concomitant to reduced T cells and macrophages in pgWAT. (a and b) representative images and quantification of total T cells (CD45+, CD3+) in perigonadal white adipose tissue (pgWAT), (c) CD3e and FoxP3 gene expression relative to 18s in pgWAT, (d–g) representative images and quantification of total, M1 (CD206−) and M2 (CD206+) macrophages in pgWAT. Data are shown as mean ± SEM with individual data points in the bar graphs. N = 7/group. *Denote p ≤ 0.01 versus Y Ctrl, †denote p ≤ 0.04 versus O Ctrl. Group differences were assessed by one‐way ANOVA with Tukey's post hoc tests.
FIGURE 2 Suppressed senescence and inflammatory burden is concomitant to reduced T cells and macrophages in pgWAT. (a and b) representative images and quantification of total T cells (CD45+, CD3+) in perigonadal white adipose tissue (pgWAT), (c) CD3e and FoxP3 gene expression relative to 18s in pgWAT, (d–g) representative images and quantification of total, M1 (CD206−) and M2 (CD206+) macrophages in pgWAT. Data are shown as mean ± SEM with individual data points in the bar graphs. N = 7/group. *Denote p ≤ 0.01 versus Y Ctrl, †denote p ≤ 0.04 versus O Ctrl. Group differences were assessed by one‐way ANOVA with Tukey's post hoc tests.CC BY · PubMed Central
FIGURE 3 Administration of D&Q ameliorates glucose tolerance and insulin‐stimulated NEFA suppression independent of the Akt signaling. (a and b) Blood glucose response curves and area under the curves (AUC) during glucose tolerance test (GTT: 2 g/kg, ip), (c) plasma insulin at baseline and during GTT, (d) blood glucose response during insulin tolerance test (ITT: 1 U/kg, ip), (e) plasma non‐esterified fatty acids (NEFA) at baseline and during ITT, (f) irs‐1 and cpt‐1α gene expression relative to 18s in pgWAT, (g–j) Western blot images and quantification for total Akt, phosphorylated Akt and vinculin form the liver and pgWAT. Data in the time response curves are shown as mean ± SEM. Other data are shown as mean ± SEM with individual data points in the bar graphs. N = 7–12/group. *Denote p ≤ 0.03 versus O Ctrl, †denote p ≤ 0.02 versus baseline. Group differences in GTT, ITT and plasma insulin at baseline and during GTT as well as plasma NEFA at baseline and during ITT were assessed by two‐way repeated measure ANOVA with Tukey's post hoc tests. Unpaired Student's t tests were used when comparing two groups.
FIGURE 3 Administration of D&Q ameliorates glucose tolerance and insulin‐stimulated NEFA suppression independent of the Akt signaling. (a and b) Blood glucose response curves and area under the curves (AUC) during glucose tolerance test (GTT: 2 g/kg, ip), (c) plasma insulin at baseline and during GTT, (d) blood glucose response during insulin tolerance test (ITT: 1 U/kg, ip), (e) plasma non‐esterified fatty acids (NEFA) at baseline and during ITT, (f) irs‐1 and cpt‐1α gene expression relative to 18s in pgWAT, (g–j) Western blot images and quantification for total Akt, phosphorylated Akt and vinculin form the liver and pgWAT. Data in the time response curves are shown as mean ± SEM. Other data are shown as mean ± SEM with individual data points in the bar graphs. N = 7–12/group. *Denote p ≤ 0.03 versus O Ctrl, †denote p ≤ 0.02 versus baseline. Group differences in GTT, ITT and plasma insulin at baseline and during GTT as well as plasma NEFA at baseline and during ITT were assessed by two‐way repeated measure ANOVA with Tukey's post hoc tests. Unpaired Student's t tests were used when comparing two groups.CC BY · PubMed Central
FIGURE 4 Improvement in glucose tolerance is accompanied by attenuated hepatic gluconeogenesis and collagen content. (a) Blood glucose response during pyruvate tolerance test (PTT: 2 g/kg, ip), (b) gluconeogenic gene (pck1, pck2, fbp2, and g6pc) expression relative to 18s in liver, (c) representative Western blot images of phosphorylated‐ and total‐cAMP‐response element‐binding protein (CREB) as well as vinculin in liver, (d) densitometric quantification of p‐CREB and CREB, (e) fgf21 and pparα gene expression relative to 18s in liver, (f) representative hematoxylin and eosin (H&E) and picrosirius red (PSR) staining of liver, (g) quantification of the pixel positivity for collagen in the liver. Data in the time response curves are shown as mean ± SEM. Other data are shown as mean ± SEM with individual data points in the bar graphs. N = 5–12/group. *Denote p ≤ 0.05. Group difference in PTT was assessed by two‐way repeated measure ANOVA with Tukey's post hoc tests. Unpaired Student's t tests were used when comparing two groups.
FIGURE 4 Improvement in glucose tolerance is accompanied by attenuated hepatic gluconeogenesis and collagen content. (a) Blood glucose response during pyruvate tolerance test (PTT: 2 g/kg, ip), (b) gluconeogenic gene (pck1, pck2, fbp2, and g6pc) expression relative to 18s in liver, (c) representative Western blot images of phosphorylated‐ and total‐cAMP‐response element‐binding protein (CREB) as well as vinculin in liver, (d) densitometric quantification of p‐CREB and CREB, (e) fgf21 and pparα gene expression relative to 18s in liver, (f) representative hematoxylin and eosin (H&E) and picrosirius red (PSR) staining of liver, (g) quantification of the pixel positivity for collagen in the liver. Data in the time response curves are shown as mean ± SEM. Other data are shown as mean ± SEM with individual data points in the bar graphs. N = 5–12/group. *Denote p ≤ 0.05. Group difference in PTT was assessed by two‐way repeated measure ANOVA with Tukey's post hoc tests. Unpaired Student's t tests were used when comparing two groups.CC BY · PubMed Central
FIGURE 5 Administration of D&Q ameliorates plasma triglycerides and lipid tolerance but does not alter plasma cholesterols. (a) Fed plasma triglycerides, (b and c) plasma triglycerides response curves and area under the curves (AUC) during an intralipid‐tolerance test (LTT: 15 μl/g, oral gavage), (d) plasma cholesterol, (e) plasma low‐density and very low‐density lipoprotein, (f) plasma high‐density lipoprotein. Data in the time response curves are shown as mean ± SEM. Other data are shown as mean ± SEM with individual data points in the bar graphs. N = 8–10/group. *Denote p ≤ 0.01. Group difference in LTT was assessed by two repeated measure ANOVA with Tukey's post hoc tests. Other differences were assessed by unpaired Student's t test.
FIGURE 5 Administration of D&Q ameliorates plasma triglycerides and lipid tolerance but does not alter plasma cholesterols. (a) Fed plasma triglycerides, (b and c) plasma triglycerides response curves and area under the curves (AUC) during an intralipid‐tolerance test (LTT: 15 μl/g, oral gavage), (d) plasma cholesterol, (e) plasma low‐density and very low‐density lipoprotein, (f) plasma high‐density lipoprotein. Data in the time response curves are shown as mean ± SEM. Other data are shown as mean ± SEM with individual data points in the bar graphs. N = 8–10/group. *Denote p ≤ 0.01. Group difference in LTT was assessed by two repeated measure ANOVA with Tukey's post hoc tests. Other differences were assessed by unpaired Student's t test.CC BY · PubMed Central

Verification

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  • It may state two separate claims as one. 34
  • Probably not a substantial claim. 26
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  • 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.”
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Metadata

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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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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