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dc.contributor.authorViscomi, CF
dc.date.accessioned2018-06-20T09:33:24Z
dc.date.available2018-06-20T09:33:24Z
dc.date.issued2018-04-25
dc.identifier.issn1474-9718
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/277266
dc.description.abstractLoss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity and mitochondrial biogenesis) in Surf1-/- mice. The lack of deleterious phenotypes in Surf1-/- mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (non-significant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1-/- versus Surf1+/+ mice despite substantial decreases in COX activity (22-87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1+/+ and Surf1-/- mice (36 and 19%, respectively). We measured gene expression, metabolites and targeted expression of key metabolic proteins in adipose tissue, liver and brain in Surf1+/+ and Surf1-/- mice. Gene expression was differentially regulated in a tissue specific manner. Many proteins and metabolites are downregulated in Surf1-/- adipose tissue and reversed by DR, while in brain most metabolites that changed were elevated in Surf1-/- mice. Finally, mitochondrial unfolded protein response (UPRmt)-associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1-/- mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.
dc.languageeng
dc.publisherWiley-Blackwell
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectcytochrome c oxidase
dc.subjectdietary restriction
dc.subjectlifespan
dc.subjectmitochondria
dc.subjectSURF1
dc.subjectmitochondrial unfolded protein response
dc.titleLifelong Reduction in Complex IV Induces Tissue Specific Metabolic Effects But Does Not Reduce Lifespan or Healthspan in Mice
dc.typeArticle
prism.numbere12769
prism.publicationDate2018
prism.publicationNameAging Cell
dc.identifier.doi10.17863/CAM.24552
dcterms.dateAccepted2018-03-28
rioxxterms.versionofrecord10.1111/acel.12769
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2018-04-25
dc.contributor.orcidViscomi, Carlo [0000-0001-6050-0566]
dc.identifier.eissn1474-9726
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-04-25
cam.orpheus.successThu Jan 30 12:58:24 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International