Abstract
SummaryCellular 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.
Highlights
Obesity is associated with a range of neurodegenerative and psychiatric disorders, including depression and anxiety (Gariepy et al, 2010; Hryhorczuk et al, 2013; Stunkard and Wadden, 1992), with the latter being one of the most common behavioral traits in obese patients (Gariepy et al, 2010)
We found that body weight and body fat content were increased in high-fat diet (HFD) mice in comparison to chow-fed controls
HFD-fed mice were less inclined to explore the central area of the OF test chamber than the peripheral zone (Figures 1A–1C and S1D), and likewise the total distance covered was significantly decreased in HFD animals during the test (Figure S1C)
Summary
Obesity is associated with a range of neurodegenerative and psychiatric disorders, including depression and anxiety (Gariepy et al, 2010; Hryhorczuk et al, 2013; Stunkard and Wadden, 1992), with the latter being one of the most common behavioral traits in obese patients (Gariepy et al, 2010). Increased anxietylike behavior has been reported in rodents genetically predisposed to develop obesity, e.g., db/db mice (Dinel et al, 2011), and in high-fat diet (HFD)-induced obesity (Heyward et al, 2012; Mizunoya et al, 2013). Processes such as inflammation (Capuron and Miller, 2011; Lasselin and Capuron, 2014), altered hormone signaling (Ulrich-Lai and Ryan, 2014), and stem cell dysfunction (Anacker and Hen, 2017; Gao et al, 2017) have been speculated to underlie obesity-related anxiety, but the underlying mechanisms have not been identified. Senescent cells display a variety of markers, including telomere-associated DNA damage foci (TAF) (Hewitt et al, 2012), increased activity of lysosomal senescence-associated b-galactosidase (Dimri et al, 1995), chromatin changes (senescence associated heterochromatin foci, SAHF) (Narita et al, 2003), and frequently increased expression of the cyclin-dependent kinase inhibitor proteins, p16Ink4a and p21Cip
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