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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\u00a0years in human muscle and brain. In silico analysis demonstrated that this temporary linear \u201csignature\u201d was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF\u20101\/PI3K\/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (<jats:italic>n<\/jats:italic>\u00a0=\u00a032 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 \u201cpro\u2010longevity\u201d direction. Quantitative network modeling demonstrated that age\u2010regulated ncRNA equaled the contribution of protein\u2010coding 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 <jats:italic>not<\/jats:italic> respond to Rapamycin, and was associated with \u201cneuron apoptotic processes\u201d in protein\u2013protein interaction analysis (FDR\u00a0=\u00a02.4%). ECSIT links inflammation with the continued age\u2010related downwards trajectory of mitochondrial complex I gene expression (FDR\u00a0&lt;\u00a00.01%), 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\u2010wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.<\/jats:p>","DOI":"10.1111\/acel.12970","type":"journal-article","created":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T08:00:14Z","timestamp":1559808014000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Longevity\u2010related molecular pathways are subject to midlife \u201cswitch\u201d in humans"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2255-1220","authenticated-orcid":false,"given":"James A.","family":"Timmons","sequence":"first","affiliation":[{"name":"Division of Genetics and Molecular Medicine King's College London London UK"},{"name":"Scion House Stirling University Innovation Park Stirling UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude\u2010Henry","family":"Volmar","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Crossland","sequence":"additional","affiliation":[{"name":"Division of Genetics and Molecular Medicine King's College London London UK"},{"name":"School of Medicine, Royal Derby Hospital University of Nottingham Derby UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethan E.","family":"Phillips","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal Derby Hospital University of Nottingham Derby UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana","family":"Sood","sequence":"additional","affiliation":[{"name":"Division of Genetics and Molecular Medicine King's College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina J.","family":"Janczura","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation University of Miami Miller School of Medicine Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"T\u00f6rm\u00e4kangas","sequence":"additional","affiliation":[{"name":"Faculty of Sport and Health Sciences University of Jyv\u00e4skyl\u00e4 Jyv\u00e4skyl\u00e4 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urho M.","family":"Kujala","sequence":"additional","affiliation":[{"name":"Faculty of Sport and Health Sciences University of Jyv\u00e4skyl\u00e4 Jyv\u00e4skyl\u00e4 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Kraus","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine 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