{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T19:06:10Z","timestamp":1789239970088,"version":"build-2803163510"},"posted":{"date-parts":[[2025,5,9]]},"group-title":"Physiology","reference-count":92,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["F31AG084146-01"],"award-info":[{"award-number":["F31AG084146-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AG058717"],"award-info":[{"award-number":["R01AG058717"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100023581","name":"National Science Foundation Graduate Research Fellowship Program","doi-asserted-by":"crossref","award":["DGE1841052"],"award-info":[{"award-number":["DGE1841052"]}],"id":[{"id":"10.13039\/100023581","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in\n                  <jats:italic>C. elegans<\/jats:italic>\n                  . However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous signaling pathway downstream of genetic activation of the hypoxic response. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights develop a circuit for how genetic induction of the hypoxic response cell-nonautonomously modulates aging and suggests valuable targets for modulating aging in mammals.\n                <\/jats:p>","DOI":"10.1101\/2025.05.04.652087","type":"posted-content","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T07:30:15Z","timestamp":1746775815000},"source":"Crossref","is-referenced-by-count":1,"title":["The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3414-1509","authenticated-orcid":false,"given":"Elizabeth S.","family":"Kitto","sequence":"first","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1867-4794","authenticated-orcid":false,"given":"Shijiao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4143-2522","authenticated-orcid":false,"given":"Mira","family":"Bhandari","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7673-7295","authenticated-orcid":false,"given":"Cassie","family":"Tian","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6251-087X","authenticated-orcid":false,"given":"Rebecca L.","family":"Cox","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8068-3953","authenticated-orcid":false,"given":"Safa","family":"Beydoun","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cellular and Developmental Biology; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Shave","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hillary A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0849-8363","authenticated-orcid":false,"given":"Sarah A.","family":"Easow","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Henry","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Chung","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L.","family":"Schaller","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8003-2955","authenticated-orcid":false,"given":"Scott F.","family":"Leiser","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States"},{"name":"Department of Internal Medicine; University of Michigan, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091211551160000_2025.05.04.652087v3.1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glu041"},{"key":"2026091211551160000_2025.05.04.652087v3.2","doi-asserted-by":"publisher","DOI":"10.12703\/P5-5"},{"key":"2026091211551160000_2025.05.04.652087v3.3","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/gln063"},{"key":"2026091211551160000_2025.05.04.652087v3.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.02.020"},{"key":"2026091211551160000_2025.05.04.652087v3.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-7536-1"},{"key":"2026091211551160000_2025.05.04.652087v3.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006348"},{"key":"2026091211551160000_2025.05.04.652087v3.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2012.08.011"},{"key":"2026091211551160000_2025.05.04.652087v3.8","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-015-9601-0"},{"key":"2026091211551160000_2025.05.04.652087v3.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2007.03.002"},{"key":"2026091211551160000_2025.05.04.652087v3.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01251-0"},{"key":"2026091211551160000_2025.05.04.652087v3.11","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02357"},{"key":"2026091211551160000_2025.05.04.652087v3.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30869-5"},{"key":"2026091211551160000_2025.05.04.652087v3.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1136610"},{"key":"2026091211551160000_2025.05.04.652087v3.14","doi-asserted-by":"publisher","DOI":"10.1101\/2024.04.19.590228"},{"key":"2026091211551160000_2025.05.04.652087v3.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3515-12.2013"},{"key":"2026091211551160000_2025.05.04.652087v3.16","unstructured":"Veuthey, T. , Giunti, S. , Rosa, D. J. M. , Alkema, M. & Rayes, D. (2024)."},{"key":"2026091211551160000_2025.05.04.652087v3.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.10.024"},{"key":"2026091211551160000_2025.05.04.652087v3.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1524-5"},{"key":"2026091211551160000_2025.05.04.652087v3.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.051"},{"key":"2026091211551160000_2025.05.04.652087v3.20","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5489.147"},{"key":"2026091211551160000_2025.05.04.652087v3.21","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-006-9008-6"},{"key":"2026091211551160000_2025.05.04.652087v3.22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1078223"},{"key":"2026091211551160000_2025.05.04.652087v3.23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060254"},{"key":"2026091211551160000_2025.05.04.652087v3.24","doi-asserted-by":"publisher","DOI":"10.1038\/nature01298"},{"key":"2026091211551160000_2025.05.04.652087v3.25","doi-asserted-by":"publisher","DOI":"10.1038\/nature12143"},{"key":"2026091211551160000_2025.05.04.652087v3.26","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.62659"},{"key":"2026091211551160000_2025.05.04.652087v3.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501894200"},{"key":"2026091211551160000_2025.05.04.652087v3.28","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00507-4"},{"key":"2026091211551160000_2025.05.04.652087v3.29","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.4161\/cc.8.15.9126","article-title":"The hypoxic response and aging","volume":"8","year":"2009","journal-title":"Cell Cycle"},{"key":"2026091211551160000_2025.05.04.652087v3.30","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009050497"},{"key":"2026091211551160000_2025.05.04.652087v3.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac9257"},{"key":"2026091211551160000_2025.05.04.652087v3.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002117"},{"key":"2026091211551160000_2025.05.04.652087v3.33","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.105"},{"key":"2026091211551160000_2025.05.04.652087v3.34","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2014.0500274"},{"key":"2026091211551160000_2025.05.04.652087v3.35","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.80774"},{"key":"2026091211551160000_2025.05.04.652087v3.36","doi-asserted-by":"publisher","DOI":"10.1586\/ern.11.124"},{"key":"2026091211551160000_2025.05.04.652087v3.37","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13643-4"},{"key":"2026091211551160000_2025.05.04.652087v3.38","doi-asserted-by":"publisher","DOI":"10.1038\/nrc885"},{"key":"2026091211551160000_2025.05.04.652087v3.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33849-x"},{"key":"2026091211551160000_2025.05.04.652087v3.40","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.84"},{"key":"2026091211551160000_2025.05.04.652087v3.41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000689"},{"key":"2026091211551160000_2025.05.04.652087v3.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.09.008"},{"key":"2026091211551160000_2025.05.04.652087v3.43","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12301"},{"key":"2026091211551160000_2025.05.04.652087v3.44","doi-asserted-by":"publisher","DOI":"10.1002\/bies.202400029"},{"key":"2026091211551160000_2025.05.04.652087v3.45","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2152"},{"key":"2026091211551160000_2025.05.04.652087v3.46","doi-asserted-by":"publisher","DOI":"10.1038\/35000609"},{"key":"2026091211551160000_2025.05.04.652087v3.47","doi-asserted-by":"crossref","unstructured":"Sinakevitch, I. T. , Daskalova, S. M. & Smith, B. H . The Biogenic Amine Tyramine and its Receptor (AmTyr1) in Olfactory Neuropils in the Honey Bee (Apis mellifera) Brain. Frontiers in Systems Neuroscience 11 (2017).","DOI":"10.3389\/fnsys.2017.00077"},{"key":"2026091211551160000_2025.05.04.652087v3.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.042"},{"key":"2026091211551160000_2025.05.04.652087v3.49","doi-asserted-by":"crossref","unstructured":"Haeussler, S. & Conradt, B. in Methods in Molecular Biology 249\u2013259 (2022).","DOI":"10.1007\/978-1-0716-1732-8_16"},{"key":"2026091211551160000_2025.05.04.652087v3.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.001"},{"key":"2026091211551160000_2025.05.04.652087v3.51","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.105.044495"},{"key":"2026091211551160000_2025.05.04.652087v3.52","doi-asserted-by":"publisher","DOI":"10.1007\/s10158-006-0033-z"},{"key":"2026091211551160000_2025.05.04.652087v3.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.06.023"},{"key":"2026091211551160000_2025.05.04.652087v3.54","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12499"},{"key":"2026091211551160000_2025.05.04.652087v3.55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006697"},{"key":"2026091211551160000_2025.05.04.652087v3.56","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-016-0341-7"},{"key":"2026091211551160000_2025.05.04.652087v3.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.02.024"},{"key":"2026091211551160000_2025.05.04.652087v3.58","doi-asserted-by":"publisher","DOI":"10.1895\/wormbook.1.161.1"},{"key":"2026091211551160000_2025.05.04.652087v3.59","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02787.x"},{"key":"2026091211551160000_2025.05.04.652087v3.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.04.013"},{"key":"2026091211551160000_2025.05.04.652087v3.61","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3495-07.2007"},{"key":"2026091211551160000_2025.05.04.652087v3.62","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03180.x"},{"key":"2026091211551160000_2025.05.04.652087v3.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.02.013"},{"key":"2026091211551160000_2025.05.04.652087v3.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.02.023"},{"key":"2026091211551160000_2025.05.04.652087v3.65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707469105"},{"key":"2026091211551160000_2025.05.04.652087v3.66","unstructured":"Z.F, A. & D.H, H. in WormAtlas."},{"key":"2026091211551160000_2025.05.04.652087v3.67","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.09.007"},{"key":"2026091211551160000_2025.05.04.652087v3.68","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1466-07.2007"},{"key":"2026091211551160000_2025.05.04.652087v3.69","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14237"},{"key":"2026091211551160000_2025.05.04.652087v3.70","doi-asserted-by":"publisher","DOI":"10.1895\/wormbook.1.142.1"},{"key":"2026091211551160000_2025.05.04.652087v3.71","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-06-02122.2003"},{"key":"2026091211551160000_2025.05.04.652087v3.72","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-1878(200006)22:6<545::AID-BIES7>3.0.CO;2-F"},{"key":"2026091211551160000_2025.05.04.652087v3.73","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802164105"},{"key":"2026091211551160000_2025.05.04.652087v3.74","doi-asserted-by":"publisher","DOI":"10.1038\/465554a"},{"key":"2026091211551160000_2025.05.04.652087v3.75","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-020-00194-0"},{"key":"2026091211551160000_2025.05.04.652087v3.76","unstructured":"Bach, M. , Bergs, A. , Mulcahy, B. , Zhen, M. & Gottschalk, A. (2023)."},{"key":"2026091211551160000_2025.05.04.652087v3.77","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12098-5"},{"key":"2026091211551160000_2025.05.04.652087v3.78","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.10.009"},{"key":"2026091211551160000_2025.05.04.652087v3.79","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010665"},{"key":"2026091211551160000_2025.05.04.652087v3.80","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100367"},{"key":"2026091211551160000_2025.05.04.652087v3.81","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297923110020"},{"key":"2026091211551160000_2025.05.04.652087v3.82","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glz276"},{"key":"2026091211551160000_2025.05.04.652087v3.83","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/5460732"},{"key":"2026091211551160000_2025.05.04.652087v3.84","doi-asserted-by":"publisher","DOI":"10.4155\/fso.15.21"},{"key":"2026091211551160000_2025.05.04.652087v3.85","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09651-x"},{"key":"2026091211551160000_2025.05.04.652087v3.86","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.04377.x"},{"key":"2026091211551160000_2025.05.04.652087v3.87","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-024-01207-y"},{"key":"2026091211551160000_2025.05.04.652087v3.88","doi-asserted-by":"publisher","DOI":"10.1895\/wormbook.1.132.1"},{"key":"2026091211551160000_2025.05.04.652087v3.89","doi-asserted-by":"publisher","DOI":"10.3791\/833"},{"key":"2026091211551160000_2025.05.04.652087v3.90","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-018-9915-1"},{"key":"2026091211551160000_2025.05.04.652087v3.91","unstructured":"Kitto, E. , Dean, J. & Leiser, S. (microPublication Biology, 2025)."},{"key":"2026091211551160000_2025.05.04.652087v3.92","doi-asserted-by":"publisher","DOI":"10.3791\/52321"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.04.652087","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T18:55:19Z","timestamp":1789239319000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.04.652087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":92,"URL":"https:\/\/doi.org\/10.1101\/2025.05.04.652087","relation":{"has-version":[{"id-type":"doi","id":"10.7554\/eLife.107651.1","asserted-by":"object"}]},"subject":[],"published":{"date-parts":[[2025,5,9]]},"subtype":"preprint"}}