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Targeting senescent cells alleviates obesity-induced metabolic dysfunction

Palmer, A. K., Xu, M., Zhu, Y., Pirtskhalava, T., Weivoda, M. M., Hachfeld, C. M., Prata, L. G., van Dijk, T. H., Verkade, E., Casaclang-Verzosa, G., Johnson, K. O., Cubro, H., Doornebal, E. J., Ogrodnik, M., Jurk, D., Jensen, M. D., Chini, E. N., Miller, J. D., Matveyenko, A., Stout, M. B., Schafer, M. J., White, T. A., Hickson, L. J., Demaria, M., Garovic, V., Grande, J., Arriaga, E. A., Kuipers, F., von Zglinicki, T., LeBrasseur, N. K., Campisi, J., Tchkonia, T. & Kirkland, J. L., Jun-2019, In : Aging Cell. 18, 3, 15 p., 12950.

Research output: Contribution to journalArticleAcademicpeer-review

  • Allyson K. Palmer
  • Ming Xu
  • Yi Zhu
  • Tamar Pirtskhalava
  • Megan M. Weivoda
  • Christine M. Hachfeld
  • Larissa G. Prata
  • Theo H. van Dijk
  • Esther Verkade
  • Grace Casaclang-Verzosa
  • Kurt O. Johnson
  • Hajrunisa Cubro
  • Ewald J. Doornebal
  • Mikolaj Ogrodnik
  • Diana Jurk
  • Michael D. Jensen
  • Eduardo N. Chini
  • Jordan D. Miller
  • Aleksey Matveyenko
  • Michael B. Stout
  • Marissa J. Schafer
  • Thomas A. White
  • LaTonya J. Hickson
  • Marco Demaria
  • Vesna Garovic
  • Joseph Grande
  • Edgar A. Arriaga
  • Folkert Kuipers
  • Thomas von Zglinicki
  • Nathan K. LeBrasseur
  • Judith Campisi
  • Tamar Tchkonia
  • James L. Kirkland

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 p16(Ink4a) 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.

Original languageEnglish
Article number12950
Number of pages15
JournalAging Cell
Volume18
Issue number3
Early online date2019
Publication statusPublished - Jun-2019

    Keywords

  • adipogenesis, aging, cellular senescence, dasatinib, quercetin, senolytics, type 2 diabetes, CELLULAR SENESCENCE, INSULIN-RESISTANCE, TISSUE, PHARMACOKINETICS, DIFFERENTIATION, PROLIFERATION, ADIPOGENESIS, MACROPHAGES, NAVITOCLAX, CLEARANCE

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