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M Ogrodnik, Y Zhu, LGP Langhi, T Tchkonia, P Kr├╝ger, E Fielder, S Victorelli, RA Ruswhandi, N Giorgadze, T Pirtskhalava, O Podgorni, G Enikolopov, KO Johnson, M Xu, C Inman, M Schafer, M Weigl, Y Ikeno, TC Burns, JF Passos, T von Zglinicki, JL Kirkland and D Jurk
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.
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