Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice

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dc.contributor.authorMartínez Cisuelo, V.
dc.contributor.authorGómez, J.
dc.contributor.authorGarcía Junceda, I.
dc.contributor.authorNaudí, Alba
dc.contributor.authorCabré, R.
dc.contributor.authorMota Martorell, N.
dc.contributor.authorLópez Torres, Mónica
dc.contributor.authorGonzález Sánchez, Mónica
dc.contributor.authorPamplona, R.
dc.contributor.authorBarja de Quiroga, Gustavo
dc.date.accessioned2023-06-17T21:54:46Z
dc.date.available2023-06-17T21:54:46Z
dc.date.issued2016-10
dc.description.abstractRapamycin consistently increases longevity in mice although the mechanism of action of this drug is unknown. In the present investigation we studied the effect of rapamycin on mitochondrial oxidative stress at the same dose that is known to increase longevity in mice (14 mg of rapamycin/kg of diet). Middle aged mice (16 months old) showed significant age-related increases in mitochondrial ROS production at complex I, accumulation of mtDNA fragments inside nuclear DNA, mitochondrial protein lipoxidation, and lipofuscin accumulation compared to young animals (4 months old) in the liver. After 7 weeks of dietary treatment all those increases were totally or partially (lipofuscin) abolished by rapamycin, middle aged rapamycin-treated animals showing similar levels in those parameters to young animals. The decrease in mitochondrial ROS production was due to qualitative instead of quantitative changes in complex I. The decrease in mitochondrial protein lipoxidation was not due to decreases in the amount of highly oxidizable unsaturated fatty acids. Rapamycin also decreased the amount of RAPTOR (of mTOR complex) and increased the amounts of the PGC1-α and ATG13 proteins. The results are consistent with the possibility that rapamycin increases longevity in mice at least in part by lowering mitochondrial ROS production and increasing autophagy, decreasing the derived final forms of damage accumulated with age which are responsible for increased longevity. The decrease in lipofuscin accumulation induced by rapamycin adds to previous information suggesting that the increase in longevity induced by this drug can be due to a decrease in the rate of aging.
dc.description.departmentDepto. de Genética, Fisiología y Microbiología
dc.description.facultyFac. de Ciencias Biológicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Economía y Competitividad (MINECO)
dc.description.sponsorshipGobierno Autónomo de Cataluña
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/42451
dc.identifier.doi10.1016/j.exger.2016.08.002
dc.identifier.issn0531-5565
dc.identifier.officialurlhttps://www.journals.elsevier.com/experimental-gerontology/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/17774
dc.journal.titleExperimental Gerontology
dc.language.isoeng
dc.page.final138
dc.page.initial130
dc.publisherElsevier
dc.relation.projectIDRD12/0043/0018; PI1400328; BFU2011-23888
dc.relation.projectID2014SGR168
dc.rights.accessRightsrestricted access
dc.subject.cdu591.1
dc.subject.cdu599.32
dc.subject.keywordRapamycin
dc.subject.keywordLipofuscin
dc.subject.keywordMitochondria
dc.subject.keywordFree radicals
dc.subject.keywordTor
dc.subject.keywordAging
dc.subject.ucmFisiología animal (Biología)
dc.subject.ucmMamíferos
dc.subject.unesco2401.13 Fisiología Animal
dc.subject.unesco2401.18 Mamíferos
dc.titleRapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice
dc.typejournal article
dc.volume.number83
dspace.entity.typePublication
relation.isAuthorOfPublication39d740ea-13ce-4671-8278-4f3161d26f23
relation.isAuthorOfPublication5eb4770a-aa71-4908-ad28-b483e1d18f6c
relation.isAuthorOfPublication.latestForDiscovery39d740ea-13ce-4671-8278-4f3161d26f23
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