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18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression in Caenorhabditis elegans and Neuronal Cultures
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Faculty of Biology and Pharmacy, Institute of Nutrition, Friedrich Schiller University of Jena, Jena, Germany.
Örebro University, School of Medical Sciences. Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Translational Cancer Biology Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece; Faculty of Medicine, Department of Basic Sciences, University of Crete, Heraklion, Greece.
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2016 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 25, no 16, 855-869 p.Article in journal (Refereed) Published
Abstract [en]

Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression.

Results: Feeding of wild-type Caenorhabditis elegans with 18α-glycyrrhetinic acid (18α-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1- and proteasome activation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased Aβ deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18α-GA treatment.

Innovation: This is the first report of the use of 18α-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism.

Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet.

Place, publisher, year, edition, pages
New Rochelle, USA: Mary Ann Liebert, 2016. Vol. 25, no 16, 855-869 p.
Keyword [en]
Proteasome activation, lifespan extension, aging, Alzheimer’s disease, aggregation, proteostasis
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-49639DOI: 10.1089/ars.2015.6494ISI: 000388262600001PubMedID: 26886723OAI: oai:DiVA.org:oru-49639DiVA: diva2:921535
Note

Funding Agencies:

U.S. National Institutes of Health National Center for Research Resources

Thales GenAge QALHS AP:10479/3.7.12 MIS380228

MAESTRO by the European Union (European Social Fund)

Operational Program, Education and Lifelong Learning, of the National Strategic Reference Framework (NSRF)

European Union 266486

IKYDA fellowship

Empirikion Foundation Scientific Project

John S. Latsis Public Benefit Foundation

Academy of Finland 259797

COST Actions PROTEOS-TASIS BM1307

GENiE BM1408

COST (European Cooperation in Science and Technology)

Available from: 2016-04-20 Created: 2016-04-05 Last updated: 2017-10-17Bibliographically approved

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