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Title: Targeting senescent cells alleviates obesity-induced metabolic dysfunction

Abstract

Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [3];  [3];  [1];  [1];  [1];  [1];  [4];  [4];  [1];  [1];  [1];  [1];  [5] more »;  [1];  [1];  [1];  [6];  [1];  [1];  [7];  [3];  [8];  [1];  [9];  [1];  [1] « less
+ Show Author Affiliations
  1. Mayo Clinic, Rochester, MN (United States)
  2. Mayo Clinic, Rochester, MN (United States); Univ. of Connecticut Health, Farmington, CT (United States)
  3. Univ. of Groningen, Groningen (The Netherlands)
  4. Mayo Clinic, Rochester, MN (United States); Newcastle Univ., Newcastle upon Tyne (United Kingdom)
  5. Mayo Clinic, Rochester, MN (United States); Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)
  6. Buck Inst. for Research on Aging, Novato, CA (United States); Univ. of Groningen, Groningen (The Netherlands)
  7. Univ. of Minnesota, Minneapolis, MN (United States)
  8. Newcastle Univ., Newcastle upon Tyne (United Kingdom)
  9. Buck Inst. for Research on Aging, Novato, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1560598
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Aging Cell
Additional Journal Information:
Journal Volume: 18; Journal Issue: 3; Journal ID: ISSN 1474-9718
Publisher:
Anatomical Society - Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; adipogenesis; aging; cellular senescence; dasatinib; quercetin; senolytics; type 2 diabetes

Citation Formats

Palmer, Allyson K., Xu, Ming, Zhu, Yi, Pirtskhalava, Tamar, Weivoda, Megan M., Hachfeld, Christine M., Prata, Larissa G., Dijk, Theo H., Verkade, Esther, Casaclang‐Verzosa, Grace, Johnson, Kurt O., Cubro, Hajrunisa, Doornebal, Ewald J., Ogrodnik, Mikolaj, Jurk, Diana, Jensen, Michael D., Chini, Eduardo N., Miller, Jordan D., Matveyenko, Aleksey, Stout, Michael B., Schafer, Marissa J., White, Thomas A., Hickson, LaTonya J., Demaria, Marco, Garovic, Vesna, Grande, Joseph, Arriaga, Edgar A., Kuipers, Folkert, Zglinicki, Thomas von, LeBrasseur, Nathan K., Campisi, Judith, Tchkonia, Tamar, and Kirkland, James L. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. United States: N. p., 2019. Web. doi:10.1111/acel.12950.
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Palmer, Allyson K., Xu, Ming, Zhu, Yi, Pirtskhalava, Tamar, Weivoda, Megan M., Hachfeld, Christine M., Prata, Larissa G., Dijk, Theo H., Verkade, Esther, Casaclang‐Verzosa, Grace, Johnson, Kurt O., Cubro, Hajrunisa, Doornebal, Ewald J., Ogrodnik, Mikolaj, Jurk, Diana, Jensen, Michael D., Chini, Eduardo N., Miller, Jordan D., Matveyenko, Aleksey, Stout, Michael B., Schafer, Marissa J., White, Thomas A., Hickson, LaTonya J., Demaria, Marco, Garovic, Vesna, Grande, Joseph, Arriaga, Edgar A., Kuipers, Folkert, Zglinicki, Thomas von, LeBrasseur, Nathan K., Campisi, Judith, Tchkonia, Tamar, & Kirkland, James L. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. United States. https://doi.org/10.1111/acel.12950
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Palmer, Allyson K., Xu, Ming, Zhu, Yi, Pirtskhalava, Tamar, Weivoda, Megan M., Hachfeld, Christine M., Prata, Larissa G., Dijk, Theo H., Verkade, Esther, Casaclang‐Verzosa, Grace, Johnson, Kurt O., Cubro, Hajrunisa, Doornebal, Ewald J., Ogrodnik, Mikolaj, Jurk, Diana, Jensen, Michael D., Chini, Eduardo N., Miller, Jordan D., Matveyenko, Aleksey, Stout, Michael B., Schafer, Marissa J., White, Thomas A., Hickson, LaTonya J., Demaria, Marco, Garovic, Vesna, Grande, Joseph, Arriaga, Edgar A., Kuipers, Folkert, Zglinicki, Thomas von, LeBrasseur, Nathan K., Campisi, Judith, Tchkonia, Tamar, and Kirkland, James L. Mon . "Targeting senescent cells alleviates obesity-induced metabolic dysfunction". United States. https://doi.org/10.1111/acel.12950. https://www.osti.gov/servlets/purl/1560598.
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@article{osti_1560598,
title = {Targeting senescent cells alleviates obesity-induced metabolic dysfunction},
author = {Palmer, Allyson K. and Xu, Ming and Zhu, Yi and Pirtskhalava, Tamar and Weivoda, Megan M. and Hachfeld, Christine M. and Prata, Larissa G. and Dijk, Theo H. and Verkade, Esther and Casaclang‐Verzosa, Grace and Johnson, Kurt O. and Cubro, Hajrunisa and Doornebal, Ewald J. and Ogrodnik, Mikolaj and Jurk, Diana and Jensen, Michael D. and Chini, Eduardo N. and Miller, Jordan D. and Matveyenko, Aleksey and Stout, Michael B. and Schafer, Marissa J. and White, Thomas A. and Hickson, LaTonya J. and Demaria, Marco and Garovic, Vesna and Grande, Joseph and Arriaga, Edgar A. and Kuipers, Folkert and Zglinicki, Thomas von and LeBrasseur, Nathan K. and Campisi, Judith and Tchkonia, Tamar and Kirkland, James L.},
abstractNote = {Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.},
doi = {10.1111/acel.12950},
journal = {Aging Cell},
number = 3,
volume = 18,
place = {United States},
year = {Mon Mar 25 00:00:00 EDT 2019},
month = {Mon Mar 25 00:00:00 EDT 2019}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1111/acel.12950
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Cited by: 256 works
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Figures / Tables:

FIGURE 1 FIGURE 1: Removal of obesity‐induced senescent cells from adipose tissue. (a, b) Renilla luciferase activity in DIO p16‐3MR mice (a, representative image), quantified in b (n = 6–9 per group). (c) Renilla luciferase activity localization in DIO p16‐3MR dissected tissues. (d, e) Senescence‐associated beta‐galactosidase (SA‐β‐gal) activity as whole tissue activitymore » (d; representative image) and % positive cells of total DAPI+ cells in p16‐3MR VAT (e; chow n = 3, DIO n = 7–9 per group). (f) Expression of p16‐3MR transgene (eGFP) components (Renilla luciferase and mRFP) and p16Ink4a (chow n = 3, DIO n = 11 per group) in p16‐3MR VAT. (g, h) Senescence‐associated beta‐galactosidase (SA‐β‐gal) activity as whole tissue activity (g; representative image) and % positive cells of total DAPI+ cells in p16‐3MR VAT (h; n = 3–4 per group). (i) p16Ink4a mRNA levels (c; chow n = 8, DIO n = 19–21 per group) in VAT of D + Q‐treated DIO mice. (j) Percent of VAT stromal vascular fraction (SVF) cells highly expressing FLAG (a component of the p16Ink4a promoter‐driven ATTAC fusion protein), CENP‐B, and p21Cip1 after a single course of D + Q (o, n = 6 per group) in DIO INK‐ATTAC mice. Means ± SEM are shown. Box and whisker plot show minimum, mean, maximum, 25th and 75th percentiles. *$ρ$ < 0.05, **$ρ$< 0.005, ***$p$ < 0.0005; one‐way ANOVA with Bonferroni correction or two‐tailed Student's t test when comparing two groups« less
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journal, December 2008

New agents that target senescent cells: the flavone, fisetin, and the BCL-X<sub>L</sub> inhibitors, A1331852 and A1155463
journal, March 2017

Activin A Plays a Critical Role in Proliferation and Differentiation of Human Adipose Progenitors
journal, June 2010

  • Zaragosi, L. -E.; Wdziekonski, B.; Villageois, P.
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Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity
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Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue
journal, March 2016

  • Schafer, Marissa J.; White, Thomas A.; Evans, Glenda
  • Diabetes, Vol. 65, Issue 6
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IL-17 Regulates Adipogenesis, Glucose Homeostasis, and Obesity
journal, October 2010

  • Zúñiga, Luis A.; Shen, Wen-Jun; Joyce-Shaikh, Barbara
  • The Journal of Immunology, Vol. 185, Issue 11
  • DOI: 10.4049/jimmunol.1001269

Targeting senescent cells enhances adipogenesis and metabolic function in old age
journal, December 2015

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    Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging
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    • Alique, Matilde; Sánchez-López, Elsa; Bodega, Guillermo
    • Cells, Vol. 9, Issue 1
    • DOI: 10.3390/cells9010195

    Meta‐inflammaging at the crossroad of geroscience
    journal, September 2019

    Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy
    journal, December 2019

    • Bian, Xiaohui; Griffin, Tomás P.; Zhu, Xiangyang
    • BMJ Open Diabetes Research & Care, Vol. 7, Issue 1
    • DOI: 10.1136/bmjdrc-2019-000720

    Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia
    journal, September 2019

    • Suvakov, Sonja; Cubro, Hajrunisa; White, Wendy M.
    • Biology of Sex Differences, Vol. 10, Issue 1
    • DOI: 10.1186/s13293-019-0263-5

    Transient DNMT3L Expression Reinforces Chromatin Surveillance to Halt Senescence Progression in Mouse Embryonic Fibroblast
    journal, March 2020

    • Yu, Yoyo Chih-Yun; Hui, Tony ZK; Kao, Tzu-Hao
    • Frontiers in Cell and Developmental Biology, Vol. 8
    • DOI: 10.3389/fcell.2020.00103

    The Multi-faceted Ecto-enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases
    journal, May 2019

    • Hogan, Kelly A.; Chini, Claudia C. S.; Chini, Eduardo N.
    • Frontiers in Immunology, Vol. 10
    • DOI: 10.3389/fimmu.2019.01187

    Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging
    journal, January 2020

    • Alique, Matilde; Sánchez-López, Elsa; Bodega, Guillermo
    • Cells, Vol. 9, Issue 1
    • DOI: 10.3390/cells9010195
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