Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

• Published in: Cell metabolism Vol. 29; no. 5; pp. 1061 - 1077.e8
• Main Authors: Ogrodnik, Mikolaj, Zhu, Yi, Langhi, Larissa G.P., Tchkonia, Tamar, Krüger, Patrick, Fielder, Edward, Victorelli, Stella, Ruswhandi, Rifqha A., Giorgadze, Nino, Pirtskhalava, Tamar, Podgorni, Oleg, Enikolopov, Grigori, Johnson, Kurt O., Xu, Ming, Inman, Christine, Palmer, Allyson K., Schafer, Marissa, Weigl, Moritz, Ikeno, Yuji, Burns, Terry C., Passos, João F., von Zglinicki, Thomas, Kirkland, James L., Jurk, Diana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-05-2019; Cell Press
• Subjects: aging; Animals; anxiety; Anxiety - drug therapy; Anxiety - etiology; anxiety-like behavior; Astrocytes - metabolism; Behavior, Animal - drug effects; brain; Brain - cytology; Brain - embryology; Cells, Cultured; Cellular Senescence - drug effects; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Dasatinib - pharmacology; Diet, High-Fat - adverse effects; Disease Models, Animal; Female; Fibroblasts - metabolism; high-fat diet; Lipid Droplets; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; obesity; Obesity - complications; Obesity - etiology; Quercetin - pharmacology; senescence; stem cells; Tacrolimus - analogs & derivatives; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; senescence; anxiety; stem cells; high-fat diet; neurogenesis; aging; anxiety-like behavior; brain; lipid droplets; obesity
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.12.008

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.
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•Obesity drives senescence in glial cells in the LV of mouse brains•Obesity-induced senescence drives fat deposits in PV areas of the brain•Senescent cell clearance in obesity restores neurogenesis in the SVZ•Senescent cell clearance alleviates obesity-induced anxiety-like behavior
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.