Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

Mikolaj Ogrodnik, Yi Zhu, Larissa G.P. Langhi, Tamar Tchkonia, Patrick Krüger, Edward Fielder, Stella Victorelli, Rifqha A. Ruswhandi, Nino Giorgadze, Tamar Pirtskhalava, Oleg Podgorni, Grigori Enikolopov, Kurt O. Johnson, Ming Xu, Christine Inman, Allyson K. Palmer, Marissa Schafer, Moritz Weigl, Yuji Ikeno, Terry C. BurnsJoão F. Passos, Thomas von Zglinicki, James L. Kirkland, Diana Jurk

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed “accumulation of lipids in senescence.” Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders. Obesity, a growing health problem in western societies, is associated with increased senescent cells and neuropsychiatric disorders, including anxiety and depression. Ogrodnik and colleagues found that clearance of senescent cells in obese mice alleviates anxiety. Our study provides proof-of-concept evidence that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.

Original languageEnglish (US)
Pages (from-to)1061-1077.e8
JournalCell Metabolism
Volume29
Issue number5
DOIs
StatePublished - May 7 2019

Keywords

  • aging
  • anxiety
  • anxiety-like behavior
  • brain
  • high-fat diet
  • lipid droplets
  • neurogenesis
  • obesity
  • senescence
  • stem cells

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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