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Here, we searched for known compounds that elicit a similar gene expression signature to caloric restriction and identified rilmenidine, an I1\u2010imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating <jats:italic>Caenorhabditis elegans<\/jats:italic> with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress\u2010resilience, health span, and lifespan benefits of rilmenidine treatment in <jats:italic>C. elegans<\/jats:italic> are mediated by the I1\u2010imidazoline receptor <jats:italic>nish\u20101<\/jats:italic>, implicating this receptor as a potential longevity target. Consistent with the shared caloric\u2010restriction\u2010mimicking gene signature, supplementing rilmenidine to calorically restricted <jats:italic>C. elegans<\/jats:italic>, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine\u2010induced longevity required the transcription factors FOXO\/DAF\u201016 and NRF1,2,3\/SKN\u20101. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine\u2010induced longevity. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine. Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound.<\/jats:p>","DOI":"10.1111\/acel.13774","type":"journal-article","created":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T03:09:30Z","timestamp":1674270570000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Rilmenidine extends lifespan and healthspan in <i>Caenorhabditis elegans<\/i> via a nischarin <scp>I1<\/scp>\u2010imidazoline receptor"],"prefix":"10.1111","volume":"22","author":[{"given":"Dominic F.","family":"Bennett","sequence":"first","affiliation":[{"name":"Integrative Genomics of Ageing Group Institute of Ageing and Chronic Disease, University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Goyala","sequence":"additional","affiliation":[{"name":"Department of Health Sciences 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Women's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Belozersky Institute of Physico\u2010Chemical Biology Moscow State University  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0372-7016","authenticated-orcid":false,"given":"Vadim N.","family":"Gladyshev","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine Brigham and Women's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1166-4171","authenticated-orcid":false,"given":"Collin Y.","family":"Ewald","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology, Laboratory of Extracellular Matrix Regeneration Institute of Translational Medicine, ETH Z\u00fcrich  Schwerzenbach 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