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J Gerontol A Biol Sci Med Sci. 2019 Oct 11. pii: glz239. doi: 10.1093/gerona/glz239. [Epub ahead of print]

NLRP3 inflammasome inhibition by MCC950 in aged mice improves health via enhanced autophagy and PPARα activity.

Author information

1
Research Laboratory, Oral Medicine Department, University of Sevilla, Sevilla, Spain.
2
Departamento de Psicología Experimental, Facultad de Psicología, Universidad de Sevilla, Seville Spain.
3
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
4
Department of General Surgery, Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain.
5
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas- Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain.
6
Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía, Sevilla, Spain.
7
Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orléans, France; IDM, University of Cape Town, South Africa.
8
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
9
CIC biomaGUNE, San Sebastian-Donostia, Spain.
10
IKERBASQUE, Basque Foundation for Science, Spain.
11
CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
12
Universidad Complutense Madrid, Spain.
13
Institute of Nutrition and Food Technology "José Mataix Verdú", Department of Physiology, Biomedical Research Center, University of Granada, Granada, Spain.
14
Cátedra de Reproducción y Genética Humana del Instituto para el Estudio de la Biología de la Reproducción Humana (INEBIR)-Universidad Europea del Atlántico (UNEATLANTICO)-Fundación Universitaria Iberoamericana (FUNIBER).

Abstract

The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-associated diseases as reported in NLRP3 deficient mice. Here we asked whether in old mice C57BL6J the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age- assocociated metabolic syndrome providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. MCC950 inhibited the Pi3K/AKT/mTOR pathway, and enhanced autophagy and activated peroxisome proliferator-activated receptor alpha (PPARα) in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by mTOR inhibiton activating autophagy and PPARα. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-associated metabolic syndrome.

KEYWORDS:

MCC950; NLRP3-inflammasome; PPAR-α; aging; autophagy

PMID:
31603987
DOI:
10.1093/gerona/glz239

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