Journal
CELL METABOLISM
Volume 29, Issue 5, Pages 1061-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2018.12.008
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Funding
- Newcastle University Faculty of Medical Sciences Fellowship (UK)
- Academy of Medical Sciences [SBF003\ 1179]
- NIH [AG13925]
- Glenn/American Federation for Aging Research (AFAR) BIG Award (USA)
- Noaber Foundations (USA)
- NIH NRCDP K12 (USA)
- Regenerative Medicine Minnesota
- Humor for the Tumor (USA)
- Cancer Research UK (CRUK) [C12161/A24009]
- BBSRC [BB/S006710/1, BB/K017314/1, BB/F010966/1, BB/H022384/1, BB/I020748/1] Funding Source: UKRI
- MRC [MR/P020941/1, MR/L016354/1] Funding Source: UKRI
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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.
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