2. Academic Validation
  3. Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

  • Cell Metab. 2019 May 7;29(5):1061-1077.e8. doi: 10.1016/j.cmet.2018.12.008.
Mikolaj Ogrodnik 1,  Yi Zhu 2,  Larissa G P Langhi 2,  Tamar Tchkonia 2,  Patrick Krüger 3,  Edward Fielder 3,  Stella Victorelli 3,  Rifqha A Ruswhandi 3,  Nino Giorgadze 2,  Tamar Pirtskhalava 2,  Oleg Podgorni 4,  Grigori Enikolopov 5,  Kurt O Johnson 2,  Ming Xu 2,  Christine Inman 2,  Allyson K Palmer 2,  Marissa Schafer 2,  Moritz Weigl 2,  Yuji Ikeno 6,  Terry C Burns 7,  João F Passos 8,  Thomas von Zglinicki 9,  James L Kirkland 10,  Diana Jurk 11
Affiliations

Affiliations

  • 1 Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
  • 2 Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
  • 3 Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
  • 4 Department of Anesthesiology, Stony Brook School of Medicine, 101 Nicolls Road, Stony Brook, New York, NY 11794, USA; Center for Developmental Genetics, Stony Brook University, 100 Nicolls Road, Stony Brook, New York, NY 11794, USA.
  • 5 Department of Anesthesiology, Stony Brook School of Medicine, 101 Nicolls Road, Stony Brook, New York, NY 11794, USA; Center for Developmental Genetics, Stony Brook University, 100 Nicolls Road, Stony Brook, New York, NY 11794, USA; Department of Nano-, Bio-, Information Technology and Cognitive Science, Moscow Institute of Physics and Technology, Moscow, Russia; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.
  • 6 The Barshop Institute for Longevity and Aging Studies, San Antonio, Department of Pathology, The University of Texas Health Science Center at San Antonio, Research Service, Audie L. Murphy VA Hospital (STVHCS), San Antonio, TX 78229, USA.
  • 7 Departments of Neurologic Surgery and Neuroscience, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
  • 8 Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.
  • 9 Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK; Near East University, Arts and Sciences Faculty, Molecular Biology and Genetics, Nicosia, North Cyprus POB 99138 Mersin 10, Turkey.
  • 10 Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: [email protected].
  • 11 Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: [email protected].
PMID: 30612898 DOI: 10.1016/j.cmet.2018.12.008
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.

Keywords

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

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