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dc.contributor.authorTimmons, James A.
dc.contributor.authorVolmar, Claude-Henry
dc.contributor.authorCrossland, Hannah
dc.contributor.authorPhillips, Bethan E.
dc.contributor.authorSood, Sanjana
dc.contributor.authorJanczura, Karolina J.
dc.contributor.authorTörmäkangas, Timo
dc.contributor.authorKujala, Urho
dc.contributor.authorKraus, William E.
dc.contributor.authorAtherton, Philip J.
dc.contributor.authorWahlestedt, Claes
dc.date.accessioned2019-07-23T04:55:16Z
dc.date.available2019-07-23T04:55:16Z
dc.date.issued2019
dc.identifier.citationTimmons, J. A., Volmar, C.-H., Crossland, H., Phillips, B. E., Sood, S., Janczura, K. J., Törmäkangas, T., Kujala, U., Kraus, W. E., Atherton, P. J., & Wahlestedt, C. (2019). Longevity-related molecular pathways are subject to midlife “switch” in humans. <i>Aging Cell</i>, <i>18</i>(4), e12970. <a href="https://doi.org/10.1111/acel.12970" target="_blank">https://doi.org/10.1111/acel.12970</a>
dc.identifier.otherCONVID_31221450
dc.identifier.otherTUTKAID_81701
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/65088
dc.description.abstractEmerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF‐1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the “pro‐longevity” direction. Quantitative network modeling demonstrated that age‐regulated ncRNA equaled the contribution of protein‐coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with “neuron apoptotic processes” in protein–protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age‐related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome‐wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.fi
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherAnatomical Society; John Wiley & Sons Ltd.
dc.relation.ispartofseriesAging Cell
dc.rightsCC BY 4.0
dc.subject.otherAlzheimer's
dc.subject.otherECSIT
dc.subject.otheraging
dc.subject.otherlong noncoding RNA
dc.subject.othermTOR
dc.subject.othermitochondrial complex 1
dc.subject.otherreactive oxygen species
dc.subject.otherskeletal muscle
dc.titleLongevity-related molecular pathways are subject to midlife “switch” in humans
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201907223652
dc.contributor.laitosLiikuntatieteellinen tiedekuntafi
dc.contributor.laitosFaculty of Sport and Health Sciencesen
dc.contributor.oppiaineGerontologia ja kansanterveysfi
dc.contributor.oppiaineLiikuntalääketiedefi
dc.contributor.oppiaineGerontology and Public Healthen
dc.contributor.oppiaineSports and Exercise Medicineen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2019-07-22T09:15:13Z
dc.description.reviewstatuspeerReviewed
dc.format.pagerangee12970
dc.relation.issn1474-9718
dc.relation.numberinseries4
dc.relation.volume18
dc.type.versionpublishedVersion
dc.rights.copyright© 2019 The Authors.
dc.rights.accesslevelopenAccessfi
dc.subject.ysoikääntyminen
dc.subject.ysoRNA
dc.subject.ysotranskriptio (biologia)
dc.subject.ysolihakset
dc.subject.ysoaivot
dc.subject.ysoiho
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p5056
jyx.subject.urihttp://www.yso.fi/onto/yso/p7689
jyx.subject.urihttp://www.yso.fi/onto/yso/p2788
jyx.subject.urihttp://www.yso.fi/onto/yso/p2784
jyx.subject.urihttp://www.yso.fi/onto/yso/p7040
jyx.subject.urihttp://www.yso.fi/onto/yso/p1769
dc.rights.urlhttps://creativecommons.org/licenses/by/4.0/
dc.relation.doi10.1111/acel.12970


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