Long-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism

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dc.authorid0000-0002-1222-9211
dc.contributor.authorDoeppner, Thorsten R.
dc.contributor.authorComan, Cristin
dc.contributor.authorBurdusel, Daiana
dc.contributor.authorAncuta, Diana Larisa
dc.contributor.authorBrockmeier, Ulf
dc.contributor.authorPirici, Daniel Nicolae
dc.contributor.authorKuang Yaoyun
dc.contributor.authorHermann, Dirk M.
dc.contributor.authorPopa Wagner, Aurel
dc.date.accessioned2022-09-22T11:09:00Z
dc.date.available2022-09-22T11:09:00Z
dc.date.issued2022
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.description.abstractPrevious studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. Since spermidine increases autophagy, we asked if treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Recently, chloroquine has intensively been discussed as a treatment option for COVID-19 patients. To rule out unfavorable long-term effects on longevity, we examined the effect of chronic treatment with chloroquine given in the drinking water on the lifespan and organ pathology of male middle-aged NMRI mice. We report that, surprisingly, daily treatment with chloroquine extended the median life span by 11.4% and the maximum life span of the middle-aged male NMRI mice by 11.8%. Subsequent experiments show that the chloroquine-induced lifespan elevation is associated with dose-dependent increase in LC3B-II, a marker of autophagosomes, in the liver and heart that was confirmed by transmission electron microscopy. Quite intriguingly, chloroquine treatment was also associated with a decrease in glycogenolysis in the liver suggesting a compensatory mechanism to provide energy to the cell. Accumulation of autophagosomes was paralleled by an inhibition of proteasome-dependent proteolysis in the liver and the heart as well as with decreased serum levels of insulin growth factor binding protein-3 (IGFBP3), a protein associated with longevity. We propose that inhibition of proteasome activity in conjunction with an increased number of autophagosomes and decreased levels of IGFBP3 might play a central role in lifespan extension by chloroquine in male NMRI mice.
dc.description.sponsorshipUEFISCDI (EU Horizon 2020 Research and Innovation Programme), Consiliul National al Cercetarii Stiintifice (CNCS), Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI)en_US
dc.identifier.citationDoeppner, T. R., Coman, C., Burdusel, D., Ancuta, D. L., Brockmeier, U., Pirici, D. N. ... Popa Wagner, A. (2022). Long-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism. Aging, 14(10), 4195-4210. https://doi.org/10.18632/aging.204069
dc.identifier.doi10.18632/aging.204069
dc.identifier.endpage4210
dc.identifier.issn1945-4589
dc.identifier.issue10
dc.identifier.pmid35609021
dc.identifier.scopus2-s2.0-85131410350
dc.identifier.scopusqualityQ2
dc.identifier.startpage4195
dc.identifier.urihttps://doi.org/10.18632/aging.204069
dc.identifier.urihttps://hdl.handle.net/20.500.12511/9737
dc.identifier.volume14
dc.identifier.wos000851337000023en_US
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorDoeppner, Thorsten R.
dc.language.isoen
dc.publisherImpact Journals LLC
dc.relation.ispartofAgingen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution 3.0 Unported*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/*
dc.subjectAutophagy
dc.subjectChloroquine
dc.subjectLongevity
dc.subjectMiddle-Aged Mice
dc.subjectProteasome
dc.subjectToxicity
dc.titleLong-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism
dc.typeArticle

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