Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

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 p16 Ink4a -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.

Abstract of "Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis" by Ogrodnik M, Zhu Y, Langhi LGP et al., https://doi.org/10.1016/j.cmet.2018.12.008, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.