Supplementary MaterialsDocument S1. mice (Dinel et?al., 2011), and in high-fat diet plan (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. 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 -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 Prochlorperazine mechanism (Mu?oz-Espn and Serrano, 2014), over the long term, accumulation of senescent cells may impede the regeneration and maintenance of renewable tissues Prochlorperazine and, therefore, contribute to tissue aging. Additionally, senescent cells secrete a number of inflammatory cytokines, chemokines, and matrix proteases (the senescence associated secretory phenotype, SASP) (Copp 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 aging and in age-related diseases (Acosta et?al., 2013, Nelson et?al., 2012, Xu et?al., 2018). Accumulation of senescent cells has been observed during obesity (Minamino et?al., 2009, Ogrodnik et?al., 2017, Schafer et?al., 2016), during aging (Baker et?al., 2016, Jurk et?al., 2012, Wang et?al., 2009, Xu et?al., 2015, Yousefzadeh et?al., 2018), and at the sites of pathogenesis in multiple chronic and age-related diseases (Tchkonia et?al., Prochlorperazine 2013). Clearance of senescent cells can delay, prevent, or alleviate multiple age-related disorders (Kirkland and Tchkonia, 2017, Xu et?al., 2018). These include age-related cardiac and vascular dysfunction (Childs et?al., 2016, Roos et?al., 2016), frailty (Baar et?al., 2017, Baker et?al., 2016, Xu et?al., 2018, Zhu 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 Parkinsons disease (Chinta et?al., 2018) and tau-dependent neurodegenerative diseases (Musi et?al., 2018, Bussian 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 display improved Rabbit Polyclonal to APOL2 markers of mobile senescence in the periventricular area from the lateral ventricle (LV), an area near the neurogenic market. Senescent glial cells in obese mice display excessive fat build up, a phenotype we termed build up of lipids in senescence (ALISE). Significantly, we display that clearance of senescent cells alleviates the obesity-related impairment in adult neurogenesis and reduces obesity-induced anxiety-like behavior. Our function shows that focusing on senescent cells may stand for a fresh restorative avenue for treating obesity-induced neuropsychiatric dysfunction. Results Obese Mice Show Increased Anxiety-like Behavior Not Related to Body Mass In order to investigate the relationship between obesity and anxiety, 8-month-old C57Bl/6 mice were fed an HFD (60% of calories from fat) or standard chow diet for 2?months. As expected, we found that body weight and body fat content were increased in HFD mice in comparison to chow-fed controls (Figures S1A and S1B). To measure anxiety-like behavior, we first employed.