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Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

aging senescence obesity anxiety anxiety-like behaviour neurogenesis high-fat diet brain lipid droplets stem cells

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#1 Engadin

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Posted 19 May 2019 - 05:08 PM


Highlights
  • 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

 

 

Summary

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 drugsdasatinib 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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Introduction

 

Obesity is associated with a range of neurodegenerative and psychiatric disorders, including depression and anxiety (Gariepy et al., 2010Hryhorczuk et al., 2013Stunkard and Wadden, 1992), with the latter being one of the most common behavioral traits in obese patients (Gariepy et al., 2010). Increased anxiety-like 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., 2012Mizunoya et al., 2013). Processes such as inflammation(Capuron and Miller, 2011Lasselin and Capuron, 2014), altered hormone signaling(Ulrich-Lai and Ryan, 2014), and stem cell dysfunction (Anacker and Hen, 2017Gao et al., 2017) have been speculated to underlie obesity-related anxiety, but the underlying mechanisms have not been identified. Here, we investigate the hypothesis that anxiety-like behavior in obesity can be caused by increased senescent cell burden.

 

Cellular senescence is an irreversible cell-cycle arrest caused by a range of stresses, including telomere dysfunction (d'Adda di Fagagna et al., 2003), oxidative stress(Passos et al., 2010), inflammation (Jurk et al., 2014), intracellular accumulation of damage (Ogrodnik et al., 2018), and metabolic dysfunction (Wiley and Campisi, 2016). Senescent cells display a variety of markers, including telomere-associated DNA damage foci (TAF) (Hewitt et al., 2012), increased activity of lysosomal senescence-associated β-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 p21Cip1.

 

While cell senescence is a potent tumor suppression mechanism (Muñoz-Espín and Serrano, 2014), over the long term, accumulation of senescent cells may impede the regeneration and maintenance of renewable tissues and, therefore, contribute to tissue aging. Additionally, senescent cells secrete a number of inflammatory cytokineschemokines, and matrix proteases (the senescence associated secretory phenotype, SASP) (Coppé et al., 2008). The SASP is thought to have evolved as a means for senescent cells to communicate with the immune system in order to orchestrate senescent cell clearance and stimulate progenitor cells to repair tissues(Tchkonia et al., 2013). However, chronic exposure to the SASP leads to damage to neighboring healthy cells, thereby contributing to tissue dysfunction during agingand in age-related diseases (Acosta et al., 2013Nelson et al., 2012Xu et al., 2018).

 

Accumulation of senescent cells has been observed during obesity (Minamino et al., 2009Ogrodnik et al., 2017Schafer et al., 2016), during aging (Baker et al., 2016Jurk et al., 2012Wang et al., 2009Xu et al., 2015Yousefzadeh et al., 2018), and at the sites of pathogenesis in multiple chronic and age-related diseases (Tchkonia et al., 2013). Clearance of senescent cells can delay, prevent, or alleviate multiple age-related disorders (Kirkland and Tchkonia, 2017Xu et al., 2018). These include age-related cardiac and vascular dysfunction (Childs et al., 2016Roos et al., 2016), frailty (Baar et al., 2017Baker et al., 2016Xu et al., 2018Zhu et al., 2015), hepatic steatosis(Ogrodnik et al., 2017), liver fibrosis (Moncsek et al., 2018), osteoporosis (Farr et al., 2017), osteoarthritis (Jeon et al., 2017), and pulmonary fibrosis (Schafer et al., 2016), among others. In the context of the brain, recent reports have shown that removing senescent cells improves phenotypes in mouse models of Parkinson’s disease (Chinta et al., 2018) and tau-dependent neurodegenerative diseases (Musi et al., 2018Bussian et al., 2018). However, the relationship between senescence and neuropsychiatric disorders such as anxiety has not been investigated thus far.

 

Here, we demonstrate that in obesity, glial cells show increased markers of cellular senescence in the periventricular region of the lateral ventricle (LV), a region in close proximity to the neurogenic niche. Senescent glial cells in obese mice show excessive fat accumulation, a phenotype we termed “accumulation of lipids in senescence” (ALISE). Importantly, we show that clearance of senescent cells alleviates the obesity-related impairment in adult neurogenesis and decreases obesity-induced anxiety-like behavior. Our work suggests that targeting senescent cells may represent a new therapeutic avenue for treating obesity-induced neuropsychiatric dysfunction.

 

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F U L L   T E X T :  ScienceDirect

 







Also tagged with one or more of these keywords: aging, senescence, obesity, anxiety, anxiety-like behaviour, neurogenesis, high-fat diet, brain, lipid droplets, stem cells

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