{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:47:27Z","timestamp":1785433647873,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,9]]},"group-title":"Systems Biology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["R35GM118144"],"award-info":[{"award-number":["R35GM118144"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1764421"],"award-info":[{"award-number":["1764421"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MP-TMPS-00005320"],"award-info":[{"award-number":["MP-TMPS-00005320"]}],"id":[{"id":"https:\/\/ror.org\/01cmst727","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  While aging and thermal stress are phenotypically intertwined, their transcriptomic signatures remain paradoxically distinct in\n                  <jats:italic>Drosophila<\/jats:italic>\n                  . Here, we demonstrate that this parallel modularity is not an inherent genomic constraint but is actively maintained by Insulin\/IGF-1 signaling (IIS). Using transcriptomic analysis, we show that high IIS activity partitions the genome into orthogonal regulatory layers where aging and heat stress function as independent additive inputs. Systemic attenuation of IIS triggers a transition to an integrated architecture. In this state, the genome\u2019s perception of heat stress becomes age-dependent, enabling a hyper-adaptive induction of heat shock proteins in old adults\u2014effectively reversing the typical age-related decline in proteostasis. We propose that the IIS pathway functions as a topological switch, shifting the genome from a modular growth-mode to an integrated maintenance-mode. Thus, dampening the response to heat stress with age is an adaptable regulatory state rather than an inevitable consequence of cellular senescence.\n                <\/jats:p>","DOI":"10.64898\/2026.07.08.737295","type":"posted-content","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:20:22Z","timestamp":1783603222000},"source":"Crossref","is-referenced-by-count":0,"title":["Insulin Signaling Functions as a Topological Switch That Couples Aging and Heat Stress Responsiveness"],"prefix":"10.64898","author":[{"given":"Manny J.","family":"Widuch","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences, Northwestern University, Evanston IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra M.","family":"Siepka","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, Northwestern University, Evanston IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0343-0156","authenticated-orcid":false,"given":"Richard W","family":"Carthew","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, Northwestern University, Evanston IL"},{"name":"NSF-Simons National Institute for Theory and Mathematics in Biology, Chicago IL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071304150817000_2026.07.08.737295v1.1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1023\/B:BGEN.0000017681.46326.9e","article-title":"Stress resistance declines with age: analysis of data from a survival experiment with Drosophila melanogaster","volume":"5","year":"2004","journal-title":"Biogerontology"},{"key":"2026071304150817000_2026.07.08.737295v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.039"},{"key":"2026071304150817000_2026.07.08.737295v1.3","doi-asserted-by":"crossref","first-page":"730","DOI":"10.2307\/2390232","article-title":"Costs and Benefits of Activation of the Heat-Shock Response in Drosophila melanogaster","volume":"8","year":"1994","journal-title":"Functional Ecology"},{"key":"2026071304150817000_2026.07.08.737295v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.16.7540"},{"key":"2026071304150817000_2026.07.08.737295v1.5","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.35.4.832"},{"key":"2026071304150817000_2026.07.08.737295v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/52A.1.B48"},{"key":"2026071304150817000_2026.07.08.737295v1.7","doi-asserted-by":"publisher","DOI":"10.1023\/A:1024197806855"},{"key":"2026071304150817000_2026.07.08.737295v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2006.09.004"},{"key":"2026071304150817000_2026.07.08.737295v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2010.09.002"},{"key":"2026071304150817000_2026.07.08.737295v1.10","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1657108"},{"key":"2026071304150817000_2026.07.08.737295v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2003.09.023"},{"key":"2026071304150817000_2026.07.08.737295v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2008.12.005"},{"key":"2026071304150817000_2026.07.08.737295v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/BF02715811"},{"key":"2026071304150817000_2026.07.08.737295v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-006-9018-x"},{"key":"2026071304150817000_2026.07.08.737295v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(92)90088-F"},{"key":"2026071304150817000_2026.07.08.737295v1.16","doi-asserted-by":"crossref","unstructured":"Liu, A.Y.-C. , Lee, Y.-K. , Manalo, D. , and Huang, L.E . (1996). Attenuated heat shock transcriptional response in aging: Molecular mechanism and implication in the biology of aging. In Stress-Inducible Cellular Responses, U. Feige , R.I. Morimoto , I. Yahara and B. Polla , eds. (Basel Switzerland: Birkhauser Verlag), pp. 393\u2013408.","DOI":"10.1007\/978-3-0348-9088-5_26"},{"key":"2026071304150817000_2026.07.08.737295v1.17","doi-asserted-by":"publisher","DOI":"10.1379\/1466-1268(1996)001<0251:DHSRIT>2.3.CO;2"},{"key":"2026071304150817000_2026.07.08.737295v1.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902882106"},{"key":"2026071304150817000_2026.07.08.737295v1.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000450"},{"key":"2026071304150817000_2026.07.08.737295v1.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.11.4099"},{"key":"2026071304150817000_2026.07.08.737295v1.21","doi-asserted-by":"crossref","first-page":"9332","DOI":"10.1016\/S0021-9258(18)31590-4","article-title":"Aging affects expression of 70-kDa heat shock proteins in Drosophila","volume":"266","year":"1991","journal-title":"J Biol Chem"},{"key":"2026071304150817000_2026.07.08.737295v1.22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083701"},{"key":"2026071304150817000_2026.07.08.737295v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/nature01789"},{"key":"2026071304150817000_2026.07.08.737295v1.24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.723049"},{"key":"2026071304150817000_2026.07.08.737295v1.25","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5341.1319"},{"key":"2026071304150817000_2026.07.08.737295v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/40194"},{"key":"2026071304150817000_2026.07.08.737295v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nature02549"},{"key":"2026071304150817000_2026.07.08.737295v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2006.09.014"},{"key":"2026071304150817000_2026.07.08.737295v1.29","doi-asserted-by":"publisher","DOI":"10.1159\/000225957"},{"key":"2026071304150817000_2026.07.08.737295v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2005.06.007"},{"key":"2026071304150817000_2026.07.08.737295v1.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072152"},{"key":"2026071304150817000_2026.07.08.737295v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00808-4"},{"key":"2026071304150817000_2026.07.08.737295v1.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307605101"},{"key":"2026071304150817000_2026.07.08.737295v1.34","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-018-9750-z"},{"key":"2026071304150817000_2026.07.08.737295v1.35","doi-asserted-by":"publisher","DOI":"10.1379\/CSC-128R1.1"},{"key":"2026071304150817000_2026.07.08.737295v1.36","first-page":"768","article-title":"Gene expression changes in response to aging compared to heat stress, oxidative stress and ionizing radiation in Drosophila melanogaster","volume":"4","year":"2012","journal-title":"Aging (Albany NY"},{"key":"2026071304150817000_2026.07.08.737295v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39882-8"},{"key":"2026071304150817000_2026.07.08.737295v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/366461a0"},{"key":"2026071304150817000_2026.07.08.737295v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/382536a0"},{"key":"2026071304150817000_2026.07.08.737295v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.10.002"},{"key":"2026071304150817000_2026.07.08.737295v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2007.02.007"},{"key":"2026071304150817000_2026.07.08.737295v1.42","doi-asserted-by":"publisher","DOI":"10.1126\/science.1070058"},{"key":"2026071304150817000_2026.07.08.737295v1.43","doi-asserted-by":"crossref","unstructured":"Nichols, C.D. , Becnel, J. , and Pandey, U.B . (2012). Methods to assay Drosophila behavior. J Vis Exp.","DOI":"10.3791\/3795-v"},{"key":"2026071304150817000_2026.07.08.737295v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2005.02.005"},{"key":"2026071304150817000_2026.07.08.737295v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2008.04.011"},{"key":"2026071304150817000_2026.07.08.737295v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2017.07.002"},{"key":"2026071304150817000_2026.07.08.737295v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14529"},{"key":"2026071304150817000_2026.07.08.737295v1.48","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s43586-022-00184-w","article-title":"Principal component analysis","volume":"2","year":"2022","journal-title":"Nature Reviews Methods Primers"},{"key":"2026071304150817000_2026.07.08.737295v1.49","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1198\/106186006X113430","article-title":"Sparse principal component analysis","volume":"15","year":"2006","journal-title":"J Comp Graphical Stat"},{"key":"2026071304150817000_2026.07.08.737295v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1205-1499"},{"key":"2026071304150817000_2026.07.08.737295v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/srep33667"},{"key":"2026071304150817000_2026.07.08.737295v1.52","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-5308-3"},{"key":"2026071304150817000_2026.07.08.737295v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2008.02.005"},{"key":"2026071304150817000_2026.07.08.737295v1.54","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098219"},{"key":"2026071304150817000_2026.07.08.737295v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00649-0"},{"key":"2026071304150817000_2026.07.08.737295v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.10.006"},{"key":"2026071304150817000_2026.07.08.737295v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31268-6"},{"key":"2026071304150817000_2026.07.08.737295v1.58","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-7-69"},{"key":"2026071304150817000_2026.07.08.737295v1.59","doi-asserted-by":"publisher","DOI":"10.1101\/gr.6216607"},{"key":"2026071304150817000_2026.07.08.737295v1.60","doi-asserted-by":"crossref","first-page":"14692","DOI":"10.1038\/s41598-025-98888-y","article-title":"Characterization of transcriptomics during aging and genes required for lifespan in Drosophila intestine","volume":"15","year":"2025","journal-title":"Sci Rep"},{"key":"2026071304150817000_2026.07.08.737295v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.05.057"},{"key":"2026071304150817000_2026.07.08.737295v1.62","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad331"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.08.737295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T11:15:22Z","timestamp":1783941322000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.08.737295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":62,"URL":"https:\/\/doi.org\/10.64898\/2026.07.08.737295","relation":{},"subject":[],"published":{"date-parts":[[2026,7,9]]},"subtype":"preprint"}}