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Blockade of the NLRP3 inflammasome improves metabolic health and lifespan in obese mice

Abstract

Aging is the major risk factor for many metabolic chronic diseases. Several metabolic pathways suffer a progressive impairment during aging including body composition and insulin resistance which are associated to autophagy dysfunction and increased inflammation. Many of these alterations are aggravated by non-healthy lifestyle such as obesity and hypercaloric diet which have been shown to accelerate aging. Here, we show that the deleterious effect of hypercaloric diets is reverted by the NLRP3 inflammasome inhibition. NLRP3 deficiency extends mean lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by metabolic health benefits including reduced liver steatosis and cardiac damage, improved glucose and lipid metabolism, and improved protein expression profiles of SIRT-1, mTOR, autophagic flux, and apoptosis. These findings suggest that the suppression of NLRP3 prevented many age-associated changes in metabolism impaired by the effect of hypercaloric diets.

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Funding

This study was supported by a grant from the Andalusian regional government (Grupo de Investigacion Junta de Andalucia CTS113). FMA has the benefit of a FPU Fellowship (FPU 13/03173) from The Ministry of Education, Science and Sport. JRC is supported by grants from the Ministerio de Economía, Industria y Competitividad (MEIC) (SAF2017-84494-C2-R), Programa Red Guipuzcoana de Ciencia, Tecnología e Información 2018-CIEN-000058-01 and from the Gobierno Vasco, Dpto. Industria, Innovación, Comercio y Turismo under the ELKARTEK Program (Grant No. KK-2019/bmG19). JRC received funding from the BBVA Foundation (Ayudas a Equipos de investigación científica Biomedicina 2018). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency – Grant No. MDM-2017-0720.

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Correspondence to Mario D. Cordero.

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Animal studies were performed in accordance with the European Union guidelines (2010/63/EU) and the corresponding Spanish regulations for the use of laboratory animals in chronic experiments (RD 53/2013 on the care of experimental animals). All experiments were approved by the local institutional animal care committee.

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The authors declare that there is no conflict of interest.

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Cañadas-Lozano, D., Marín-Aguilar, F., Castejón-Vega, B. et al. Blockade of the NLRP3 inflammasome improves metabolic health and lifespan in obese mice. GeroScience 42, 715–725 (2020). https://doi.org/10.1007/s11357-019-00151-6

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  • DOI: https://doi.org/10.1007/s11357-019-00151-6

Keywords

  • NLRP3 inflammasome
  • High-fat diet
  • Aging
  • Autophagy
  • Longevity
  • Obesity